Heteroaryl derivatives as DDR inhibitors

Abstract

The present invention relates to compounds of formula (I) (DDR inhibitors) that inhibit discoid domain receptors, processes for preparing such compounds, intermediate compounds used in such preparation, pharmaceutical compositions comprising them and therapeutic uses thereof. The compounds of the invention can be used, for example, in the treatment of various diseases associated with the DDR mechanism. # imgabs0 #

Description

Field of the Invention

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

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

[0004] The discoidin domain receptor (DDR) is a type I transmembrane receptor tyrosine kinase (RTK). The DDR family contains two distinct members: DDR1 and DDR2.

[0005] DDR is a unique receptor among other members of the RTK superfamily because DDR is activated by collagen, while other members of the RTK superfamily are usually activated by soluble peptide-like growth factors (see Vogel, W. (1997) Mol. Cell 1, 13-23; Shrivastava A. Mol Cell. 1997; 1: 25-34). In addition, DDR is an unusual RTK because they form non-covalently linked ligand-independent stable dimers (see Noordeen, NA (2006) J. Biol. Chem. 281, 22744-22751; Mihai CJ Mol Biol. 2009; 385: 432-445).

[0006] The DDR1 subfamily consists of five membrane-anchored isoforms, and the DDR2 subfamily is represented by a single protein. The five DDR1 isoforms have extracellular and transmembrane domains in common, but differ in the cytoplasmic region (see Valiathan, RR (2012) Cancer Metastasis Rev. 31, 295-321; Alves, F. (2001) FASEB J. 15, 1321-1323).

[0007] The DDR receptor family has been found to be involved in a range of fibrotic diseases, such as pulmonary fibrosis, and in particular idiopathic pulmonary fibrosis (IDF). The first evidence for the protective effect of DDR1 deficiency in pulmonary fibrosis was generated by Dr. Vogel's research group in 2006 (see Avivi-Green C, Am J Respir Crit Care Med 2006; 174: 420-427). The authors demonstrated that DDR1-deficient mice were largely protected from bleomycin (BLM)-induced damage. In addition, myofibroblast proliferation and apoptosis in these animals were much lower than in their wild-type counterparts. The absence of inflammation in knockout mice was confirmed by lavage cell counts and cytokine ELISA. These results indicate that DDR1 expression is a prerequisite for the occurrence of lung inflammation and fibrosis.

[0008] DDR2 deficiency or downregulation reduces bleomycin-induced lung fibrosis (see Zhao H, Bian H, Bu X, Zhang S, Zhang P, Yu J, et al., Mol Ther 2016; 24: 1734-1744). Zhao et al. demonstrated that DDR2 plays a key role in inducing fibrosis and angiogenesis in the lung, in particular, DDR2 synergizes with transforming growth factor (TGF)-β to induce myofibroblast differentiation. In addition, they showed that treating injured mice with specific siRNA against DDR2 exhibited therapeutic efficacy against lung fibrosis. In a second publication, Jia et al. demonstrated that mice lacking DDR2 were protected from bleomycin-induced lung fibrosis (see Jia S, Am J Respir Cell Mol Biol 2018; 59: 295-305). In addition, DDR2-free fibroblasts were significantly more prone to apoptosis than wild-type fibroblasts, supporting a paradigm in which fibroblast resistance to apoptosis is critical for the progression of fibrosis.

[0009] Some compounds have been described in the literature as DDR1 or DDR2 antagonists.

[0010] Notably, antagonizing DDR receptors may be useful in treating fibrosis and diseases, disorders and conditions resulting from fibrosis. Even more, antagonizing both receptors DDR1 and DDR2 may be particularly effective in treating the aforementioned diseases, disorders and conditions.

[0011] Several efforts have been made in the last few years to develop novel DDR1 and DDR2 receptor antagonists that can be used to treat several diseases, and some of these compounds have also shown efficacy in humans. However, there is still the potential to develop selective inhibitors of both receptors DDR1 and DDR2 that can be used to treat diseases, disorders or conditions associated with DDR receptor dysregulation in the respiratory field, in particular idiopathic pulmonary fibrosis (IPF), administered by the inhalation route, and characterized by good inhalation properties, which correspond to good activity in the lungs, good lung retention and low metabolic stability, so as to minimize systemic exposure and related safety issues.

[0012] In this direction, surprisingly, a series of novel compounds of formula (I) as described below have been found, which solve the problem of providing inhibitors of receptors DDR1 and DDR2 for administration by inhalation, which are selective inhibitors of DDR1 and DDR2 receptors relative to other human protein kinases. Such compounds show high efficacy, good inhalation properties, low metabolic stability, low systemic exposure, improved safety and tolerability. SUMMARY OF THE INVENTION

[0014] In a first aspect, the present invention relates to a compound of formula (I)

[0015]

[0016] in

[0017] A is a ring selected from the following:

[0018]

[0019] and phenyl, wherein represents a direct bond to NH;

[0020] W1 and W2 are substituents of ring A selected from 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, preferably selected from H, F, CH 3 , OCH 3 , OCF 3 , C.F. 3 , C(CH3 ) 3 , CH 2 CH 3 , C(CH 3 ) 2 CF 3 , OCF 2 H,CHF 2 , CH 2 CF 3 , CH 2 N(CH 3 ) 2 and cyclopropyl;

[0021] Z is selected from (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, preferably selected from CH 3 , C.F. 2 H, OCH 3 , CH 2 OH and cyclopropyl;

[0022] L is selected from

[0023]

[0024] in represents a direct bond to the phenyl ring and represents a direct bond to B;

[0025] B is a mono- or bi-cyclic heteroaryl ring, preferably selected from pyridinyl, pyrimidinyl, pyrazinyl, pyrazolo[1,5-a]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, 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;

[0026] Y1 and Y2 are substituents of Ring B, independently selected from hydrogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C1 -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, wherein Y1 is preferably selected from CONH 2 , C.F. 2 H, OCH 3 , cyano, Br, NHCOCH 3 , NH 2 , 4-methylpiperazine-1-carbonyl, 4-methylpiperazin-1-yl and 1-methyl-1H-pyrazol-4-yl, and Y2 is preferably hydrogen;

[0027] R1 and R2 are independently selected from 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 and are selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl and (C 1 -C 4 ) haloalkoxy; and wherein R1 and R2 are preferably independently selected from CH 2 CH 2 N(CH 3 ) 2 , CH 2 CH 2 OCH 3 , CH 3 , CH 2 CH 2 OH, oxetan-3-yl and 3-hydroxycyclobutyl;

[0028] R3 is selected from hydrogen and (C 1 -C 4 ) alkyl, preferably hydrogen and methyl;

[0029] or stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

[0030] In a second aspect, the present invention relates 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.

[0031] In a third aspect, the present invention relates 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.

[0032] In another aspect, the present invention relates 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 preventing and / or treating a disease, disorder or condition associated with DDR dysregulation.

[0033] In another aspect, the present invention relates 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 preventing and / or treating fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0034] In still another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in preventing and / or treating idiopathic pulmonary fibrosis (IPF).

[0035] In another aspect, the present invention relates to a process for preparing compounds of formula (I) and intermediate compounds useful in their preparation. DETAILED DESCRIPTION OF THE INVENTION

[0037] definition

[0038] Unless otherwise indicated, the compounds of formula (I) of the present invention are intended to include stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

[0039] Unless otherwise stated, compounds of formula (I) of the present invention are intended to include compounds of formula (I) and (Ic).

[0040] As used in this application, the term "pharmaceutically acceptable salt" refers to a derivative of a compound of formula (I) wherein the parent compound is appropriately modified by converting any free acid or basic group (if present) into a corresponding addition salt with any base or acid conventionally expected to be pharmaceutically acceptable. Thus, suitable examples of the salt may include inorganic or organic acid addition salts of basic residues such as amino groups, and inorganic or organic base addition salts of acid residues such as carboxyl groups.

[0041] Suitable cations of inorganic bases for preparing salts include ions of alkali metals or alkaline earth metals, such as potassium, sodium, calcium or magnesium.

[0042] Salts obtained by reacting the main compound acting as a base with an inorganic or organic acid include, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid and citric acid.

[0043] The term "stereoisomer" refers to isomers of identical composition that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

[0044] The term "enantiomer" refers to one of a pair of molecular structures that are mirror images of each other and are non-superimposable.

[0045] The term "racemate" or "racemic mixture" refers to a composition consisting of equimolar amounts of two enantiomeric structures, wherein the composition is devoid of optical activity.

[0046] As used in this application, the term "halogen" or "halogen atom" or "halo" includes fluorine, chlorine, bromine and iodine atoms.

[0047] The term “(C x -C y ) alkyl”, wherein x and y are integers, refers to a straight or branched chain alkyl group having from x to y carbon atoms. Thus, for example, when x is 1 and y is 4, the term “(C 1 -C 4 )alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Such groups are also represented herein by their atomic arrangement, i.e., CH 3 , CH 2 CH 3 wait.

[0048] The term “(C x -C y )haloalkyl", wherein x and y are integers, refers to a straight or branched chain alkyl group having x to y carbon atoms, which contains at least one halogen substituent. Examples include CF 3 , C(CH 3 ) 2 CF 3 and OCF 2 H.

[0049] The term “(C x -C y )alkoxy", wherein x and y are integers, refers to a straight or branched alkyl group having x to y carbon atoms, which contains at least one oxygen atom, especially but not limited to an oxygen atom directly attached to ring A or ring B or a phenyl ring, i.e. when W, Y or Z are respectively (C 1 -C 4 ) alkoxy. Examples include OCH 3 and OCH 2 CH 3 .

[0050] The term “(C x -C y )haloalkoxy”, wherein x and y are integers, refers to a “(C x -C y ) alkoxy. Examples include OCF 3 and OCF2 H.

[0051] The term “(C x -C y )hydroxyalkyl", wherein x and y are integers, refers to a (C x -C y ) alkyl. Examples include CH 2 OH, CH(OH)CH 3 and CH 2 CH 2 OH.

[0052] The term “(C x -C y )"cycloalkyl" refers to a saturated hydrocarbon ring containing from x to y number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0053] The term "mono- or bi-cyclic heteroaryl ring" refers to a mono- or bi-cyclic aromatic group containing from 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 a monocyclic aromatic ring, such as a phenyl ring, which are fused by a common bond or connected by a single bond. The mono- or bi-cyclic heteroaryl rings include pyrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyridazinyl, imidazolyl, benzofuranyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, benzothienyl, benzo[c]thienyl, quinazolinyl, pteridinyl, 1H-pyrazolo[5,1-c][1,2,4]triazolyl, pyrrolizinyl, 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, thiazo[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, imidazo[ 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, furano[3,2-d]pyrimidin-4-yl and pyrazolo[1,5-a]pyrimidinyl.

[0054] The term "heterocycloalkyl" refers to a saturated or partially unsaturated mono-, bi- or spiro-cyclic ring system having 3 to 12 ring atoms, containing one or more heteroatoms independently selected from N, S and O. Examples of heterocycloalkyl include piperazinyl, pyrrolidinyl, azetidinyl, morpholinyl and piperidinyl.

[0055] The term "spiro-cyclic ring system" refers to a saturated or partially unsaturated bi-cyclic ring system having 5 to 12 ring atoms, which contains one or more heteroatoms selected from N, S and O, wherein the two rings have only one common atom.

[0056] Any compound term such as "(C 1 -C 4 )alkyl-heterocycloalkyl-carbonyl", shall be based on its derived parts, for example, (C 1 -C 4 )alkyl, heterocycloalkyl and carbonyl are to be understood in accordance with the conventional explanations of )alkyl, heterocycloalkyl and carbonyl, and wherein the carbonyl carbon atom is the point of attachment to the remainder of the compound of formula (I).

[0057] When referring to substituents, a dash ("-") that is not between two letters, words or symbols is meant to indicate the point of attachment of such substituent.

[0058] Carbonyl is preferably represented herein as CO, as an alternative to other common representations such as -C(O)-, -CO-, -(CO)- or -C(=O)-.

[0059] Whenever a basic amino group or a quaternary ammonium group is present in a compound of formula (I), a physiologically acceptable anion may be present, selected from chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate and naphthalene disulfonate. Likewise, in the presence of an acidic group, a corresponding physiological cation may also be present, for example comprising an alkali metal or alkaline earth metal ion.

[0060] The term "Ki" refers to the dissociation constant of the enzyme-inhibitor complex, expressed in molar units. It is an indicator of the binding affinity between the inhibitor and the DDR1 or DDR2 receptor.

[0061] As mentioned above, the present invention relates to a series of compounds represented by formula (I) as described in detail below, which have inhibitory activity on receptors DDR1 and DDR2. Antagonism of 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 related to fibrosis.

[0062] In fact, as described in detail in the experimental part below, the compounds of formula (I) of the present invention are able to act as inhibitors of DDR1 and DDR2 receptors in a substantial and effective manner. In particular, Table 2 below shows that for representative compounds of the present invention, in binding assays (expressed as Ki), the inhibitory activity against DDR1 or DDR2 receptors is less than 100 nM. This confirms that the compounds of formula (I) are able to inhibit two isoforms of DDR receptors that are primarily involved in fibrosis and diseases caused by fibrosis. Therefore, when it comes to DDR1 and DDR2, the compounds of formula (I) can be used to treat fibrosis, particularly pulmonary fibrosis.

[0063] As shown in the experimental part, the comparative examples part and in particular in Table 3, in contrast to the comparative compound C1 characterized by a -CO- linker between L and the heteroaryl ring B, the presence of a direct link between L and the heteroaryl ring B in the compounds of the invention unexpectedly and significantly determines a relevant increase in the inhibitory activity towards DDR1 and DDR2 receptors.

[0064] Advantageously, the compounds of the present invention have very high potency and can be administered to humans at lower doses relative to prior art compounds, thereby reducing adverse events that typically occur when higher doses of the drug are administered.

[0065] In addition to their remarkable effectiveness in the inhibitory activity on the receptors DDR1 and DDR2, the compounds of the invention are characterized by being selective inhibitors of the DDR1 and DDR2 receptors relative to other human protein kinases, good inhalation properties, which allow an effective action on the lung compartment, and at the same time low metabolic stability, which allows minimizing the disadvantages related to systemic exposure, such as safety and tolerability problems.

[0066] Therefore, when searching for suitable and effective compounds useful for the treatment of fibrosis, in particular idiopathic pulmonary fibrosis, the compounds of the present invention may be of particular interest, said compounds being administered by the inhalation route and being characterized by good inhalation properties, which correspond to good lung activity, good lung retention and low metabolic stability, thereby minimizing systemic exposure and related safety issues.

[0067] Therefore, the present invention relates to compounds of formula (I)

[0068]

[0069] in

[0070] A is a ring selected from the following:

[0071]

[0072] and phenyl, wherein represents a direct bond to NH;

[0073] W1 and W2 are substituents of ring A selected from 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;

[0074] Z is selected from (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;

[0075] L is selected from

[0076]

[0077] in represents a direct bond to the phenyl ring and represents a direct bond to B;

[0078] B is a mono- or bi-cyclic heteroaryl ring;

[0079] Y1 and Y2 are substituents of Ring B, independently selected from 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 -C4 )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;

[0080] R1 and R2 are independently selected from 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 and are selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C4 ) haloalkyl and (C 1 -C 4 ) haloalkoxy;

[0081] R3 is selected from hydrogen and (C 1 -C 4 ) alkyl, preferably hydrogen and methyl;

[0082] or stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

[0083] All listed meanings of the individual variable moieties A, B, L, Z, W1, W2, Y1, Y2, R1, R2 and R3 of the compounds of formula (I) of the present invention are to be considered as alternatives and can be combined with each other in the embodiments included within the scope of the present invention.

[0084] (C 1 -C 4 ) haloalkyl and (C 1 -C 4 ) Preferred halogens in the haloalkoxy substituents are fluorine and chlorine, with fluorine being more preferred. Fluorine is also a preferred choice for halogens in the W and Y substituents.

[0085] W1 and W2 are substituents of ring A, which may be attached to any available position of A. W1 and W2 are preferably selected from H, F, CH 3 , OCH 3 , OCF 3 , C.F. 3 , C(CH 3 ) 3 , CH 2 CH 3 , C(CH 3 ) 2 CF 3 , OCF 2 H,CHF 2 , CH 2 CF 3 , CH 2 N(CH 3 ) 2 and cyclopropyl.

[0086] Z is preferably selected from CH 3 , C.F. 2 H, OCH 3 , CH 2 OH and cyclopropyl.

[0087] In one embodiment, L is selected from

[0088]

[0089] In a preferred embodiment, L is selected from

[0090]

[0091] B is a mono- or bi-cyclic heteroaryl ring, preferably selected from pyridinyl, pyrimidinyl, pyrazinyl, pyrazolo[1,5-a]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, 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.

[0092] Y1 is a substituent of ring B, which may be attached to any available position of B. Y1 is preferably selected from 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, more preferably Y1 is selected from hydrogen, CONH 2 , C.F. 2 H, OCH 3 , cyano, NHCOCH 3 , NH 2 , 4-methylpiperazine-1-carbonyl, 4-methylpiperazin-1-yl and 1-methyl-1H-pyrazol-4-yl.

[0093] Y2 is a substituent of ring B which may be attached to any available position of B. In a preferred embodiment, Y2 is hydrogen.

[0094] R1 and R2 are independently preferably selected from CH 2 CH 2 N(CH 3 ) 2 , CH 2 CH 2 OCH 3 , CH 3 , CH 2 CH2 OH, oxetan-3-yl and 3-hydroxycyclobutyl.

[0095] R3 is preferably hydrogen or methyl.

[0096] The optional substituents of R1 and / or R2 are one or more, preferably 1 to 3, and are selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl and (C 1 -C 4 ) haloalkoxy, preferably selected from CH 3 , OCH 3 , OCF 3 , C.F. 3 , C.F. 2 H, C(CH 3 ) 3 , C(CH 3 ) 2 CF 3 and OCF 2 H.

[0097] Therefore, in a preferred embodiment, the present invention relates to compounds of formula (I), wherein

[0098] A is a ring selected from the following:

[0099]

[0100] and phenyl;

[0101] W1 and W2 are selected from H, F, CH 3 , OCH 3 , OCF 3 , C.F. 3 , C(CH 3 ) 3 , CH 2 CH 3 , C(CH 3 ) 2 CF 3 , OCF 2 H,CHF 2 , CH 2 CF 3 , CH 2 N(CH 3 ) 2 and cyclopropyl;

[0102] Z is selected from CH 3 , C.F. 2H, OCH 3 , CH 2 OH and cyclopropyl;

[0103] L is selected from

[0104]

[0105] or L is selected from

[0106]

[0107] 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]pyridinyl, 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;

[0108] Y1 is selected from hydrogen, CONH 2 , C.F. 2 H, OCH 3 , cyano, NHCOCH 3 , NH 2 , 4-methylpiperazine-1-carbonyl and 4-methylpiperazin-1-yl, and Y2 is hydrogen;

[0109] R1 and R2 are independently selected from CH 2 CH 2 N(CH 3 ) 2 , CH 2 CH 2 OCH 3 , CH 3 , CH 2 CH 2 OH, oxetan-3-yl and 3-hydroxycyclobutyl;

[0110] R3 is hydrogen or methyl;

[0111] or stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

[0112] The present invention relates to compounds of formula (I), wherein L is selected from G, M, Q, T, U and V as defined above, which are also referred to as compounds of formula (Ic):

[0113]

[0114] Wherein L1 is selected from O, NR3, CHR3, S and SO 2, or is absent, L1 is preferably selected from O, NR3 and CHR3, and R3 is preferably hydrogen or methyl.

[0115] Further particularly preferred embodiments of the present invention are compounds of formula (Ic) and pharmaceutically acceptable salts thereof listed in Table 1 below. These compounds are particularly active against receptors DDR1 and DDR2, as shown in Table 2 below.

[0116] Table 1: List of representative compounds of formula (Ic)

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128] The compounds of the present invention, including all compounds listed above, can be prepared from readily available raw materials using the following general methods and processes or by using a slightly modified method that is readily available to a person of ordinary skill in the art. Although specific embodiments of the present invention may be shown or described in this application, it will be appreciated by those skilled in the art that all embodiments or aspects of the present invention can be obtained using the methods described in this application or by using other known methods, reagents and raw materials. When typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions may also be used, except as otherwise specified. Although the optimal reaction conditions may vary depending on the specific reactants or solvents used, those skilled in the art can easily determine these conditions by conventional optimization methods. Therefore, the following methods should not be considered to limit the scope of the synthetic methods that can be used to prepare the compounds of the present invention.

[0129] In some cases, when it is necessary to mask or protect sensitive or reactive moieties, a commonly known protecting group (PG) may be used according to general principles of chemistry (Protective groups in organic syntheses, 3rd ed. TW Greene, PGM Wuts).

[0130] Compounds of formula (I) can be prepared as described in Schemes 1 to 7 below, where at least one non-limiting synthetic route is provided for the preparation of exemplary compounds (ie, Examples).

[0131] Solution 1

[0132]

[0133] The compound of formula (Ic), wherein L1 is selected from O, S and SO 2 , and it is a compound of formula (I), wherein L is selected from:

[0134]

[0135] It can be prepared as shown in Scheme 1 by starting from the corresponding compounds of formula (XXIX) and formula (XX).

[0136] As shown in Scheme 1, the compound of formula (XXIX) (wherein Z is as defined above, and R is (C 1 -C 4 )alkyl, preferably ethyl, and wherein L1 is O or S) can be subjected to Mitsunobu reaction with tert-butyl 3-hydroxyazetidine-1-carboxylate (XX) in the presence of a coupling reagent such as Tsunoda reagent, in a suitable solvent such as toluene, at elevated temperature (about 70°C) overnight. The compound of formula (XXX) can be reacted by oxidation-reduction (ox-red) reaction in the presence of potassium persulfate (oxone) and in a suitable solvent such as ethanol. The compound of formula (XXXIII) can be prepared by reacting the compound of formula (XXX) or (XXXI) with a heteroaryl amine in the presence of a strong base such as BuLi, LiHMDS or LDA, in a suitable solvent such as THF, by transamidation reaction, and then removing the protecting group using TFA or HCl in 4-dioxane under acidic conditions. The compound of formula (XXXIII) can be prepared by Buchwald coupling reaction using a suitable palladium catalyst such as Pd 2 (dppf)Cl 2 , Buchwald third generation catalyst or any other palladium source / phosphine-based ligand, at high temperature (about 100°C) for several hours in the presence of a base such as Cs 2 CO 3, NaOtBu or LiHMDS in a suitable solvent such as 4-dioxane or DMA, and converted to a compound of formula (Ic).

[0137] Alternatively, the compound of formula (XXXIII) may be prepared by nucleophilic aromatic substitution (S N Ar), is converted to a compound of formula (Ic) using an appropriate commercially available fluoro-heteroaryl or chloro-heteroaryl compound in the presence of a suitable base such as DIPEA and an appropriate solvent such as acetonitrile.

[0138] If there are protecting groups on Y1 and / or Y2, compounds of formula (Ic) can be obtained, for example, using TFA in a suitable solvent such as DCM (an optional step, represented as "2) TFA" in Scheme 1).

[0139] Solution 2

[0140]

[0141] A compound of formula (Ic) wherein L1 is NR3 is a compound of formula (I) wherein L is

[0142]

[0143] It can be prepared starting from a compound of formula (II) or (XXI) as shown in Scheme 2. A compound of formula (II) or a compound of formula (XXI) (wherein Z is as defined above, and R is (C 1 -C 4 )alkyl, preferably ethyl) can be reacted with a compound of formula (XXXIV), such as tert-butyl 3-aminoazetidine-1-carboxylate or tert-butyl 3-(methylamino)azetidine-1-carboxylate, using an appropriate palladium catalyst such as Buchwald third generation catalyst or any other palladium source / phosphine-based ligand at elevated temperature (about 100° C.) for several hours in the presence of a base such as Cs 2 CO 3 , NaOtBu or LiHMDS in a suitable solvent such as 4-dioxane or DMA, to obtain the compound of formula (XXXV) or the compound of formula (XXXVI), respectively.

[0144] 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 (XXXVI) by removing the Boc protecting group using TFA or HCl in 1,4-dioxane under acidic conditions. Compounds of formula (XXXVII) can then be reacted by Buchwald coupling using a suitable palladium catalyst such as Pd 2 (dppf)Cl 2 , Buchwald third generation catalyst or any other palladium source / phosphine-based ligand, at high temperature (about 100°C) for several hours in the presence of a base such as Cs 2 CO 3 , NaOtBu or LiHMDS in a suitable solvent such as 4-dioxane or DMA, and converted to a compound of formula (Ic).

[0145] Solution 3

[0146]

[0147] In addition, as shown in Scheme 3, the compound of formula (II) (wherein Z is as defined above, and R is (C 1 -C 4 ) alkyl, preferably ethyl) can be reacted with tert-butyl 3-hydroxyazetidine-1-carboxylate (XX) or a compound of formula (XXXIV) using an appropriate palladium catalyst such as Buchwald third generation catalyst or any other palladium source / phosphine-based ligand at elevated temperature (about 100° C.) for several hours in the presence of a base such as Cs 2 CO 3 , NaOtBu or LiHMDS in the presence of a suitable solvent such as 4-dioxane or DMA, by performing a Buchwald coupling reaction to obtain a compound of formula (XXXVIII). The compound of formula (XXXIX) can be prepared by removing the Boc protecting group using TFA or HCl in 4-dioxane under acidic conditions. The reaction can then be carried out by using a suitable palladium catalyst such as Buchwald third generation catalyst or any other palladium source / phosphine-based ligand at high temperature (about 100° C.) for several hours in a base such as Cs 2 CO 3, NaOtBu or LiHMDS in the presence of a suitable solvent such as 4-dioxane or DMA, by performing a Buchwald coupling reaction to obtain a compound of formula (XL). A compound of formula (Ic) (wherein L1 is O or NR3) can be prepared by reacting a compound of formula (XL) with a heteroarylamine in the presence of a strong base such as BuLi, LiHMDS or LDA in a suitable solvent such as THF through a transamidation reaction. Alternatively, a common coupling reagent such as HATU can be used to perform amidation in the presence of an organic base such as DIPEA in a suitable solvent such as DMF to obtain a compound of formula (Ic).

[0148] Solution 4

[0149]

[0150] A compound of formula (Ic) wherein L1 is CHR3 or absent, and a compound of formula (I) wherein L is

[0151]

[0152] It can be prepared from the corresponding compounds of formula (XLI) and (II) as shown in Scheme 4. As shown in Scheme 4, the compound of formula (II) (wherein Z is as defined above, and R is (C 1 -C 4 ) alkyl, preferably ethyl) can be reacted with a compound of formula (XLI) (wherein R3 is as defined above, and n is 0 or 1) in the presence of nickel dibromide and in the presence of a salt such as silver nitrate in a suitable solvent such as NMP by an electrochemical reaction to obtain a compound of formula (XLII). The compound of formula (XLIV) can be prepared by reacting a compound of formula (XLII) with a heteroaryl amine by a transamidation reaction in the presence of a strong base such as BuLi, LiHMDS or LDA in a suitable solvent such as THF, and then removing the protecting group using TFA or HCl in 4-dioxane under acidic conditions. A suitable palladium catalyst, such as Pd 2 (dppf)Cl 2 , Buchwald third generation catalyst or any other palladium source / phosphine ligand, at high temperature (about 100 °C) for several hours in the presence of a base such as Cs 2 CO 3 , NaOtBu or LiHMDS in a suitable solvent such as 4-dioxane or DMA, by Buchwald coupling reaction to obtain the compound of formula (Ic) (wherein L1 is CHR3).

[0153] Formula (Ic) compounds (wherein L1 is CHR3 and R3 is not hydrogen) contain a stereocenter, which is a carbon atom with R3. These compounds are obtained in the form of a racemic mixture. The separation of the racemic mixture can be achieved by chiral resolution methods such as chiral purification. Both enantiomers of the formula (Ic) compound are included within the scope of the present invention.

[0154] Solution 5

[0155]

[0156] In a different approach, as shown in Scheme 5, the reaction can be carried out by starting with a compound of formula (XXXIII) and reacting it with an appropriate palladium catalyst such as Pd 2 (dppf)Cl 2 , Buchwald third generation catalyst or any other palladium source / phosphine-based ligand, at high temperature (about 100°C) for several hours in the presence of a base such as Cs 2 CO 3 , NaOtBu or LiHMDS in the presence of, in a suitable solvent such as 4-dioxane or DMA, a Buchwald coupling reaction is carried out to obtain a compound of formula (XLV). The nitro group can be reduced to an amine group in a hydrogen atmosphere and in the presence of a suitable catalyst such as Pd / C in a suitable solvent such as EtOH or EtOAc to obtain a compound of formula (XLVI). The compound of formula (Ic) can be prepared by acylating the compound of formula (XLVI) with a suitable commercially available acyl chloride, i.e., R1COCl or anhydride, in the presence of a suitable base such as pyridine or TEA.

[0157] Solution 6

[0158]

[0159] In a different method, the compound of formula (Ic) can be prepared as shown in Scheme 6: from a compound of formula (XXXIII) in the presence of a suitable palladium source / phosphine-based ligand at elevated temperature in a suitable solvent such as DMA and an inorganic base such as Cs 2 CO 3 In the presence of a peroxide such as hydrogen peroxide, an inorganic base such as K 2 CO 3 After conversion of the cyano group (CN) to the primary amide in the presence of a suitable solvent such as DMSO, the compound of formula (Ic) can be obtained.

[0160] Solution 7

[0161]

[0162] Alternatively, the alkyl group may be substituted by nucleophilic aromatic substitution (S) using a suitable commercially available chloro-heteroaryl compound in the presence of a suitable base such as DIPEA and a suitable solvent such as acetonitrile. N Ar), the compound of formula (XXXIII) can be converted to the compound of formula (XLVIII).

[0163] As shown in Scheme 7, the esterification reaction can be carried out by reacting a compound of formula (XLVIII) with an aryl or heteroaryl boric acid ester / acid according to the common Suzuki protocol in a suitable organic solvent such as THF and water in the presence of an inorganic base such as K 3 PO 4 Compounds of formula (Ic) can be prepared by reacting with an appropriate palladium catalytic system such as Pd-170 in the presence of , under heating (eg, about 50°C) for several hours.

[0164] Accordingly, the present invention provides intermediate compounds of formula (XXI), (XXX), (XXXI), (XXXII), (XXXIII), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL), (XLI), (XLII), (XLIII), (XLIV), (XLV) and (XLVI) as defined above, and their use in the preparation of compounds of formula (Ic).

[0165] In particular, the present invention provides an intermediate compound of formula (XXXIII)

[0166]

[0167] in

[0168] A is a ring selected from the following:

[0169]

[0170] and phenyl, wherein represents a direct bond to NH;

[0171] W1 and W2 are substituents of ring A selected from 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;

[0172] R1 and R2 are independently selected from 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 and are selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl and (C 1 -C 4 ) haloalkoxy;

[0173] Z is selected from (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;

[0174] L1 is selected from O, NR3, CHR3, S and SO 2 , or does not exist;

[0175] R3 is selected from hydrogen and (C 1 -C 4 )alkyl;

[0176] or stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

[0177] Embodiments of compounds of formula (XXXIII) include:

[0178] A compound of formula (XXXVII), wherein L1 is NR3;

[0179] A compound of formula (XLIV) wherein L1 is CH3 or absent.

[0180] In a further embodiment of the compound of formula (XXXIII), L1 is selected from O, S and SO 2 , preferably O.

[0181] In a preferred embodiment, the variables of the formula (XXXIII) have the preferred meanings of the preferred compounds of the formula (I) according to the invention.

[0182] The present invention also provides the use of a compound of formula (XXXIII) as defined above in the preparation of a compound of formula (Ic).

[0183] The present invention also provides an intermediate compound of formula (XXXIX)

[0184]

[0185] in

[0186] L1 is selected from O, NR3, CHR3, S and SO 2 , or does not exist;

[0187] R is (C 1 -C 4 ) alkyl, preferably ethyl, and

[0188] Z is selected from (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;

[0189] or stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

[0190] The present invention also provides the use of a compound of formula (XXXIX) as defined above in the preparation of a compound of formula (Ic).

[0191] The present invention also provides an intermediate compound of formula (XL)

[0192]

[0193] in

[0194] L1 is selected from O, NR3, CHR3, S and SO 2 , or does not exist;

[0195] R is (C 1 -C 4 ) alkyl, preferably ethyl;

[0196] Z is selected from (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;

[0197] B is a mono- or bi-cyclic heteroaryl ring;

[0198] Y1 and Y2 are substituents of ring B, independently selected from: 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;

[0199] R1 and R2 are independently selected from 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 and are selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl and (C 1 -C 4 ) haloalkoxy;

[0200] R3 is selected from hydrogen and (C 1 -C 4 ) alkyl, preferably hydrogen and methyl;

[0201] or stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

[0202] The present invention also provides the use of a compound of formula (XL) as defined above in the preparation of a compound of formula (Ic).

[0203] The present invention therefore 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).

[0204] In a preferred embodiment, the variables of the formulae (XXXIII), (XXXIX) and (XL) each have the preferred meanings according to the invention for the preferred compounds of the formula (I).

[0205] It has surprisingly been found that the compounds of formula (I) of the present invention effectively inhibit both receptors DDR1 and DDR2. Advantageously, inhibition of receptors DDR1 and DDR2 may lead to effective treatment of diseases, disorders or conditions in which DDR receptors are involved.

[0206] In this regard, it has been found that the compounds of formula (I) of the present invention have very high antagonist drug potency against DDR1 and DDR2. Table 2 in this experimental section reports the potency for representative compounds of formula (I) of the present invention, expressed as the inhibition constant Ki. Specifically, potency where Ki is less than 100 nM is reported. Preferred compounds of the present invention have Ki between 25 and 5 nM against DDR1 and DDR2. More preferred compounds of the present invention have Ki less than 5 nM against DDR1 and DDR2.

[0207] In one aspect the invention relates to a compound of formula (I) according to any of the embodiments disclosed above for use as a medicament.

[0208] In a preferred embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof for use in the treatment of diseases, disorders or conditions associated with DDR dysregulation.

[0209] In another aspect, the present invention relates to the use of the compound of formula (I) as described above and its pharmaceutically acceptable salt in the preparation of a medicament for treating diseases associated with DDR dysregulation.

[0210] In another preferred embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof for use in preventing and / or treating diseases, disorders or conditions associated with the DDR receptor mechanism. In a more preferred embodiment, the present invention relates to compounds of formula (I) for use in preventing and / or treating fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0211] As used in this application, the term "fibrosis" or "fibrotic disorder" refers to a disorder associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased recruitment of fibroblasts, and includes, but is not limited to, fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lungs, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract.

[0212] Preferably, the compounds of formula (I) as described above can be used for the treatment and / or prevention of fibrosis, such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, kidney fibrosis, eye fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

[0213] More preferably, the compounds of formula (I) as described above can be used to treat idiopathic pulmonary fibrosis (IPF).

[0214] In one aspect, the present invention also relates to a method for preventing and / or treating diseases associated with the DDR receptor mechanism, comprising the step of administering a therapeutically effective amount of a compound of formula (I) as described above to a patient in need thereof.

[0215] In another aspect, the present invention relates to the use of a compound of formula (I) as described above for the treatment of disorders associated with the DDR receptor mechanism.

[0216] In another aspect, the present invention relates to the use of a compound of formula (I) as described above in the preparation of a medicament for treating a disorder associated with the DDR receptor mechanism.

[0217] In another aspect, the present invention relates to a method for preventing and / or treating a disease or condition associated with DDR receptor 1 and receptor 2 dysregulation, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) as described above.

[0218] In another aspect, the present invention relates to the use of a compound of formula (I) as described above for treating a disease, disorder or condition associated with DDR receptor 1 and receptor 2 dysregulation.

[0219] As used in this application, "a safe and effective amount" with respect to a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects, and it can still be determined by conventional methods by those skilled in the art.

[0220] The compounds of formula (I) may be administered once or according to a dosing regimen in which multiple doses are administered at varying intervals over a given period of time. The typical daily dose may vary depending on the route of administration chosen.

[0221] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) according to any embodiment thereof in admixture with at least one or more pharmaceutically acceptable carriers and / or excipients.

[0222] In one embodiment, the invention relates to pharmaceutical compositions of compounds of formula (I) in admixture with at least one or more pharmaceutically acceptable carriers and / or excipients, such as those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA.

[0223] Administration of the compounds of the invention and pharmaceutical compositions thereof can be accomplished according to the patient's needs, for example, orally, intranasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternal and by infusion) and by inhalation.

[0224] Preferably, the compounds of the invention are administered orally or by inhalation.

[0225] In a preferred embodiment, the pharmaceutical composition comprising the compound of formula (I) is a solid oral dosage form, such as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders.

[0226] In one embodiment, the pharmaceutical composition comprising a compound of formula (I) is a tablet.

[0227] The compounds of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (e.g., sucrose, mannitol, lactose, starch) and known excipients, including suspending agents, solubilizing agents, buffers, binders, disintegrating agents, preservatives, colorants, flavoring agents, lubricants, etc.

[0228] In another embodiment, the pharmaceutical composition comprising the compound of formula (I) is a liquid oral dosage form, such as an aqueous solution and a non-aqueous solution, an emulsion, a suspension, a syrup and an elixir. Such liquid dosage forms may also include suitable known inert diluents (e.g., water) and suitable known excipients (e.g., preservatives, wetting agents, sweeteners, flavoring agents) and agents for emulsifying and / or suspending the compounds of the invention.

[0229] In another embodiment, the pharmaceutical composition comprising a compound of formula (I) is an inhalable formulation, such as an inhalable powder, a propellant-containing metered aerosol or a propellant-free inhalable formulation.

[0230] For administration as a dry powder, single-dose or multi-dose inhalers known in the prior art can be used. In this case, the powder can be filled in gelatin, plastic or other capsules, cartridges or blister packs or in reservoirs.

[0231] A diluent or carrier which is chemically inert to the compounds of the invention, for example lactose or any other additive suitable for improving the respirable fraction, may be added to the powdered compounds of the invention.

[0232] Inhalation aerosols containing propellant gases such as hydrofluoroalkanes may contain the compounds of the invention in solution or dispersed form. Propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers and optionally other excipients.

[0233] Propellant-free inhalable preparations containing the compounds of the invention may be in the form of solutions or suspensions in water, alcohol or hydroalcoholic media, and they may be delivered by means of jet or ultrasonic nebulizers or by soft mist nebulizers known in the art.

[0234] The compounds of the present invention may be administered as the sole active agent or in combination with other pharmaceutically active ingredients.

[0235] The dosage of the compounds of the invention will depend on a variety of factors, including the specific disease to be treated, the severity of the symptoms, the route of administration, and the like.

[0236] The present invention also relates to a device comprising a pharmaceutical composition comprising a compound of formula (I) according to the invention, in the form of a single-dose or multi-dose dry powder inhaler or a metered dose inhaler.

[0237] All preferred groups or embodiments described above for the compounds of the formula (I) can be combined with one another and, mutatis mutandis, can also be applied to one another.

[0238]

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

[0239] Preparation of Intermediates and Examples

[0240] The chemical names of the compounds were generated using the Structure-To-Name tool of 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, or are known compounds, or can be formed from known compounds by known methods by those skilled in the art.

[0241] In the following methods, some starting materials are identified by "Intermediate" or "Example" numbers and the step numbers are indicated. This is provided solely to assist chemists skilled in the art.

[0242] When reference is made to the use of "similar" or "analogous" methods, such methods may involve minor variations, such as reaction temperatures, amounts of reagents / solvents, reaction times, workup conditions or chromatographic purification conditions, as will be understood by those skilled in the art. Unless otherwise stated, all compounds were obtained as free bases.

[0243] abbreviation

[0244] AcOH = acetic acid; acetone-d 6 = deuterated acetone; ACN = acetonitrile; ACN-d 3 = deuterated acetonitrile; CDCl 3 = deuterated chloroform; CV = column volume; DCM = dichloromethane; DIPEA = N,N-diisopropylethylamine; DMF = dimethylformamide; DMSO = dimethyl sulfoxide; DMSO-d 6 = deuterated dimethyl sulfoxide; ee = enantiomeric excess; Et 2 O = diethyl ether; EtOAc = ethyl acetate; eq. = equivalent; FCC = flash column chromatography; h = hour; HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxo 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 = methanol; min = minute; TBAF = tetrabutylammonium fluoride; 2-MeTHF = 2-methyltetrahydrofuran; NaBH 3 CN = sodium cyanoborohydride; NMR = nuclear magnetic resonance; MeOH-d 4 = deuterated methanol; Pd(dba) 2 =Bis(dibenzylideneacetone)palladium(0); Pd(dppf)Cl 2 = [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 generation 3; tBuOK = potassium tert-butoxide; TBDMS = tert-butyldimethylsilyl; TBTU = 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate; TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin layer chromatography; tR = 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.

[0245] General Experimental Details

[0246] NMR Characterization:

[0247] Recorded on a Varian MR-400 spectrometer operating at 400 MHz (proton frequency) equipped with: self-shielded Z-gradient coil for reverse detection, 5 mm 1H / nX broadband probe, deuterium digital locked channel unit, quadrature digital detection unit with emitter offset frequency shift 1 HNMR spectra. Chemical shifts are reported as δ values ​​in ppm relative to tetramethylsilane (TMS) as an internal standard. Coupling constants (J values) are given in Hertz (Hz), and multiplicities are reported using the following abbreviations (s=singlet, d=doublet, t=triplet, q=quartet, dd=doublet of doublets, dt=doublet of triplets, m=multiplet, br=broad, nd=not determined).

[0248] In some cases, the NH signals of amide or amine bonds (exchangeable protons) are not visible. In a few cases, some signals may be hidden under the water signal or the signal of DMSO or other residual solvents.

[0249] LC / UV / MS analysis method

[0250] The LC / MS retention times were estimated to be subject to an experimental error of ±0.5 min.

[0251] 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), from 1% to 99.9% in 1.5 min. Flow rate: 1 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters PDA + Waters QDA.

[0252] Method 2: Waters Sunfire C18 column, 4.6×50 mm, 3.5 μm, maintained at 40°C. Mobile phase ACN aqueous solution + 10 mM ammonium bicarbonate, from 5 to 95% in 2.5 min. Flow rate: 2.0 mL / min. Wavelength: 210-400 nm DAD. Waters 2795 separation module + Waters DAD + Micromass ZQ, single quadrupole LC-MS.

[0253] 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), from 1% to 99.9% in 3.5 min. Flow rate: 1 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters PDA + Waters QDA.

[0254] Method 4: Waters Acquity QSM, Kinetex C8 column, 100 mm × 2.1 mm 1.7 μm, maintained at 55 ° C; mobile phase: eluent A (HCOONH 4 0.025M pH 3), eluent B (ACN + 0.1% FA). Gradient mode: from 0 to 3 min, eluent B increased from 1% to 30%, from 3 to 6.50 min, from 30% to 50%, from 6.50 to 7.50 min, from 50% to 80%, from 7.50 to 8 min, kept at 80%, from 8 to 8.10 min, decreased from 80% to 1%, and from 8.10 min, it was kept at 1% until the end of 10 min. Flow rate: 0.5 mL / min. Wavelength: 210-400 nm PAD. UPLC + Waters PDA + Xevo TQSMS instrument.

[0255] Method 5: Acquity UPLC HSS C18 column, 100×2.1 mm, 1.8 μm (with guard column), maintained at 40°C. Mobile phase ACN (0.1% formic acid) in water (0.1% formic acid), from 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.

[0256] Method 6: Agilent Zorbax column, 4.6×50 mm, 3.5 μm, maintained at 40°C. Mobile phase: ACN (0.1% formic acid) in water (0.1% formic acid), from 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.

[0257] Method 7: Acquity BEH C18 (2.1 mm×50 mm, 1.7 um), maintained at 60°C; flow rate 1.0 mL / min; detector wavelength 220-300 nm; injection volume 1.0 uL; mobile phase eluent B CAN, eluent A water (0.1% v / v TFA), from 2% to 98% in 2 min. Flow rate: 1 mL / min. Wavelength: 220-300 nm.

[0258] Method 8: Acquity UPLC BEH Shield RP18 column, 100×2.1 mm, 1.72 μm (with guard column), maintained at 40°C. Mobile phase: ACN aqueous solution + 10 nM ammonium bicarbonate, from 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.

[0259] Method 9: XB-C18 column, 4.6×50 mm, 2.6 μm, maintained at 25° C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), from 80% to 5% in 3.90 min; flow rate: 1.0 mL / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 equipped with DAD detector / Thermo Scientific ISQ EC mass spectrometer.

[0260] Method 10: XB-C18 column, 4.6×50 mm, 2.6 μm, maintained at 25° C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), from 90% to 5% in 3.90 min; flow rate: 1.0 mL / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 equipped with DAD detector / Thermo Scientific ISQEC mass spectrometer.

[0261] Method 11: XB-C18 column, 4.6×50 mm, 2.6 μm, maintained at 25° C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), from 60% to 5% in 3.90 min; flow rate: 1.0 mL / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 equipped with DAD detector / Thermo Scientific ISQEC mass spectrometer.

[0262] 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), from 1% to 99.9% in 1.5 min. Flow rate: 1 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters PDA + Waters QDA.

[0263] 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), from 1% to 99.9% in 3.5 min. Flow rate: 1 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters PDA + Waters QDA.

[0264] Method 14: Waters TM Acquity QSM, Acquity UPLC CSH C18 column, 50 mm × 2.1 mm 1.7 μm, maintained at 50 ° C; mobile phase: eluent A (HCOONH 4 0.025M pH 3), eluent B (ACN + 0.1% FA). Gradient mode: from 0 to 5.50min, eluent B increased from 20% to 80%, from 5.50 to 7.50min, kept at 80%, from 7.50 to 8min, decreased from 80% to 20%, and from 8min, it was kept at 20% until the end of 10min. Flow rate: 0.35mL / min. Wavelength: 210-400nm DAD. UPLC+Waters TM PDA+Xevo TQS MS instrument.

[0265] Method 15: XB-C18 column, 4.6×50 mm, 2.6 μm, maintained at 25° C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), from 50% to 5% in 3.90 min; flow rate: 1.0 mL / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 equipped with DAD detector / Thermo Scientific ISQEC mass spectrometer.

[0266] Method 16: Acquity UPLC BEH-Waters, 1.7 μm C18 (2.1×100 mm), Maintained at 25° C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid), from 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.

[0267] Chiral Supercritical Fluid Chromatography (SFC) Separation Protocol

[0268] Separation of diastereoisomers of the compounds was achieved by supercritical fluid chromatography (SFC) using a Gilson preparative LC system. Both enantiomers were analyzed from the reconstituted final sample.

[0269] Otherwise, a Waters Thar Prep100 preparative SFC system (P200 CO 2 Pump, 2545 Modified Pump, 2998 UV / VIS Detector, 2767 Liquid Handler with Stacked Injection Module) to achieve diastereoisomer separation of compounds by supercritical fluid chromatography (SFC). The Waters 2767 Liquid Handler can be used as both an autosampler and a fraction collector. Under unmodified or basic conditions, appropriate isocratic methods are selected based on methanol, ethanol, or isopropanol solvent systems. Standard SFC methods use modifiers, CO 2 , 100mL / min, 120 bar back pressure, 40°C column temperature, diethylamine (0.1% V / V) as the modifier under alkaline conditions. Formic acid (0.1% V / V) or trifluoroacetic acid (0.1% V / V) as the modifier used under acidic conditions. SFC purification was controlled by Waters Fractionlynx software, monitored at 210-400nm, and triggered at the threshold collection value (usually 260nm). The collected fractions were analyzed by SFC (Waters / Thar SFC system, equipped with Waters SQD). The fractions containing the desired product were concentrated by vacuum centrifugation.

[0270] Supercritical fluid chromatography-mass spectrometry analysis conditions

[0271] Method 17: SFC-MS with Waters TM Waters by SQD TM / Thar SFC system, using a LUXCellulose-1 (20×250 mm, 5 μm) column, isocratic operation (30% MeOH (NH 4 OH 0.1%):CO 2 ), flow rate 100 mL / min, 120 bar, column temperature 40 °C, DAD wavelength 265 nm.

[0272] All solvents were purchased from commercial sources and used without additional purification. Flash chromatography (FCC) was performed on a Biotage Isolera followed by SCX(NH) to obtain the free base of the product unless otherwise stated.

[0273] For reversed phase FCC, the following gradient / eluent was used: gradient A:B from 100:0 to 0:10, 12 CV, eluent A:H 2 O / ACN / HCOOH 95:5:0.1, eluent B: H 2 O / ACN / HCOOH 5:95:0.1.

[0274] General synthetic method

[0275] Intermediate 4: N-(5-bromopyridin-3-yl)acetamide

[0276]

[0277] 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 washed with NaHCO 3 The saturated solution (20 mL) was diluted and extracted with DCM (20 mL×2), and then with EtOAc (20 mL). The organic layer was washed with MgSO 4 and dried under reduced pressure.The crude product was purified by FCC on a silica gel column eluting with a gradient of 0-80% EtOAc in n-heptane to afford the title compound (1.1 g, 5.17 mmol, 88% yield).

[0278] LC-MS (ESI, m / z): Method 1, t R=0.56min,m / z(M+1)=214.8 / 216.8

[0279] Intermediate 6: 5-(tert-butyl)-1-methyl-1H-pyrazol-3-amine

[0280]

[0281] To 3-chloro-4,4-dimethylpent-2-enenitrile (5.00 g, 34.8 mmol, 1.00 eq) and K 2 CO 3 To a solution of methylhydrazine (4812 mg, 34.8 mmol, 1.00 eq) in EtOH (25 mL) was added methylhydrazine (2.0 mL, 38.3 mmol, 1.10 eq) and the reaction mixture was heated at 80 °C for 4 h. The reaction mixture was cooled to room temperature and The residue was purified by silica gel column 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: its regioisomers. The mixture was washed with cyclohexane and filtered. The resulting residue was purified by achiral SFC (YMC Cellulose-SC 20×250 mm, 5 μm 10 / 90 IPA (0.1% DEA) / CO 2 , 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%).

[0282] LC-MS (ESI, m / z): (Method 6), t R =2.09min, m / z(M+1)=154.2

[0283] 1 H NMR (400 MHz, CDCl 3 )δ5.40 (s, 1H), 3.76 (s, 3H), 3.32-3.31 (m, 2H), 1.32 (s, 9H).

[0284] Intermediate 7: 5-(Trifluoromethoxy)pyridin-3-amine hydrochloride

[0285]

[0286] Step 1 - tert-Butyl N-[5-(trifluoromethoxy)-3-pyridyl]carbamate (Intermediate 8)

[0287]

[0288] Tert-butyl carbamate (102 mg, 0.868 mmol, 1.20 eq), Xantphos (63 mg, 0.108 mmol, 0.150 eq), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (37 mg, 0.0362 mmol, 0.0500 eq) and Cs 2 CO 3 A mixture of 5-(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 The residue was purified by column chromatography on silica gel, eluting with 0-100% EtOAc in cyclohexane, then dried in vacuo overnight to give the title compound (115 mg, 0.413 mmol, 57%).

[0289] LC-MS (ESI, m / z): (Method 2), t R =1.24min, m / z(M+1)=279.1

[0290] 1 H NMR (400MHz, CDCl3) δ8.33 (d, J=2.3Hz, 1H), 8.23-8.21 (m, 1H), 8.07 (s, 1H), 7.04 (s, 1H), 1.54 (s, 9H).

[0291] Step 2-5-(Trifluoromethoxy)pyridin-3-amine hydrochloride (Intermediate 7)

[0292] 4N HCl (3.0 mL, 0.413 mmol, 1.00 eq) in dioxane 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 ether (20 mL) and filtered to give a white solid, which was washed with ether and dried in vacuo to give the title compound (60 mg, 0.280 mmol, 68%).

[0293] LC-MS (method 2): t R =0.88min; m / z(M+1)=179.0.

[0294] 1 H NMR (400 MHz, DMSO-d 6) δ 8.07 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 1.5 Hz, 1H), 7.30 (d, J = 1.0 Hz, 1H).

[0295] Intermediate 40-3-Bromo-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine

[0296]

[0297] 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 to 100 °C overnight. The reaction mixture was diluted in EtOAc and eluted with NaHCO 3 The organic phase was washed with MgSO 4 Dry, filter and concentrate in vacuo. The residue is purified by FCC (0-100% EtOAc in cyclohexane followed by 10% 0.7N NH 3 , in DCM) to afford the title compound (610 mg, 2.06 mmol, 96%).

[0298] LC-MS (ESI): Method 2, t R =1.32min; m / z(M+1)=296.0; 298.1

[0299] The following intermediates were prepared using the procedure described for the synthesis of intermediate 40.

[0300]

[0301]

[0302] Intermediate 43: N-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)acetamide

[0303]

[0304] A solution of 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine (500 mg, 2.151 mmol) in THF (10 mL) was charged into one chamber of the COware gas reactor, followed by the addition of TEA (0.300 mL, 2.15 mmol). 3The mixture was stirred for 2 hours at room temperature for 1 hr at 40 ℃ for 2 h. The mixture was stirred for 2 hours at 40 ℃ for 3 hours ... 3 , NH 4 The organic layer was washed with NaCl and brine. 2 SO 4 Drying and evaporation in vacuo afforded the title compound (336 mg, 1.32 mmol, 61% yield) which was used as such in the next step.

[0305] LC-MS (ESI): Method 13t R =0.97min; m / z(M+1)=254.9.0-226.8

[0306] Example 142-4-methyl-3-((1-(pyrazolo[1,5-a]pyrimidin-3-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide

[0307]

[0308] Step 1: tert-Butyl 3-(5-(ethoxycarbonyl)-2-methylphenoxy)azetidine-1-carboxylate (Intermediate 103)

[0309]

[0310] 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), and then a solution of 2-(tributyl-λ5-phosphine methylene) acetonitrile (6.54 mL, 24.97 mmol) in toluene (1.2 mL) was added. The reaction mixture was stirred at 70 ° C overnight. The mixture was washed with saturated NaHCO 3 The organic layers were combined and washed with Na 2 SO 4 Dry and concentrate.The crude material was purified by FCC (100% heptane to 100% AcOEt) to give the title compound (5.5 g, 16.31 mmol, 89%).

[0311] LC-MS (ESI, m / z): Method 13, t R =2.53min, m / z(M-tBu)=280.2

[0312] Step 2: tert-Butyl 3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenoxy)azetidine-1-carboxylate (Intermediate 104)

[0313]

[0314] 5-(Trifluoromethyl)pyridin-3-amine (0.873 g, 5.4 mmol) was dissolved in 1M LiHMDS / THF (16 mL, 16.1 mmol), and the solution was stirred at room temperature overnight. Next, 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 h; it was then diluted with water and extracted with AcOEt. All organic layers were combined and washed with Na 2 SO 4 Dry, filter and concentrate. Purify by FCC (eluting with 100% CycHex to 50% AcOEt in CycHex) to give the title compound (1.94 g, 4.30 mmol, 80%).

[0315] LC-MS (ESI, m / z): Method 13, t R =2.43min, m / z(M+1)=452.1

[0316] Similarly, the following intermediates were prepared by reaction with the appropriate corresponding amines.

[0317]

[0318]

[0319] Step 3: 3-(azetidin-3-yloxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Intermediate 111)

[0320]

[0321] 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 washed with saturated NaHCO 3 Quench with CHCl 3 :i-PrOH extraction. All organic layers were combined and washed with Na 2 SO 4 Dry, filter and concentrate. Purify by FCC (2M NH4OH in DCM / MeOH) 3, from 100 / 0 to 80 / 20) to give the desired product (1.35 g, 3.8 mmol, 89%).

[0322] LC-MS (ESI, m / z): Method 13, t R = 0.91 min, m / z (M+1) = 352.2 Similarly, the following intermediates were prepared by reacting the appropriate analogs.

[0323]

[0324]

[0325]

[0326] The following examples were prepared in the same manner:

[0327]

[0328] 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)

[0329] 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) were charged into a 0.5-2 mL microwave vial. The mixture was stirred at 80 °C for 1 h. The solution was diluted with DCM and washed with water. The organic phase was evaporated in vacuo. Purification by RFFCC gave the title compound (72 mg, 0.154 mmol, 54%).

[0330] LC-MS (ESI, m / z): Method 14, t R =5.95min, m / z(M+1)=469.2

[0331] 1 H NMR (acetone-d 6,400MHz)δ10.05(br s, 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)

[0332] Similarly, the following examples or intermediates were prepared by reacting the appropriate analogs.

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349] Intermediate 129-tert-Butyl 3-(5-(ethoxycarbonyl)-2-methylbenzyl)azetidine-1-carboxylate

[0350]

[0351] 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), nickel dibromide 1-methoxy-2-(2-methoxyethoxy)ethane (98 mg, 0.28 mmol) and 2,2'-bipyridine (43.3 mg, 0.28 mmol) were added directly as solid / oil to an oven dried 10 mL ElectraSyn 2.0 vial. Anhydrous NMP (8 mL) was then added and the contents of the vial were stirred until all solids were dissolved. Silver nitrate (118 mg, 0.69 mmol) was then added directly to the reaction mixture as a solid. The vial was closed with an ElectraSyn 2.0 vial cap with a (+) magnesium sacrificial anode (WE) and a 100 ppi (-) graphite cathode (3 mm×7 mm×51 mm) (CE). The vial was then placed on an IKA ElectraSyn 2.0 stirring plate and the electrolysis was set to 12 mA, 1,37 mmol, 3.0 F / mol. The electrodes were rinsed with ACN and then water was added, with solid precipitation. The solution was filtered onto a diatomaceous earth pad and the resulting clear solution was extracted with MTBE. The organic layer was collected and eluted with Na 2 SO 4 The solvent was removed in vacuo and the crude product was purified by reverse phase FCC (eluent A / eluent B: from 100:0 to 0:100) to afford the title compound (137 mg, 0.41 mmol, 30%).

[0352] LC-MS (ESI, m / z): Method 13, t R =2.49min, m / z(M+1-BOC)=234.06

[0353] The following intermediates were prepared according to the above described procedures by starting from the relevant intermediates.

[0354]

[0355] Intermediate 131-tert-Butyl 3-((5-(ethoxycarbonyl)-2-methylphenyl)thio)azetidine-1-carboxylate

[0356]

[0357] 3-mercapto-4-methylbenzoic acid ethyl ester (715mg, 3.64mmol) and 3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (820mg, 4.74mmol) were dissolved in toluene (12mL), and then 2-(tributyl-λ5-phosphine methylene) acetonitrile (1.43mL, 5.46mmol) was added at one time, and the solution was purged with Ar for 2min. 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 3 and brine, the organic layer was washed with MgSO 4 Dry. The crude product was purified by FCC (eluent A: n-heptane, eluent B: ethyl acetate, gradient A:B from 100:0 to 60:40). The relevant fractions were collected and dried to dryness to give the title compound (971.1 mg, 2.76 mmol, 76% yield).

[0358] LC-MS (ESI, m / z): Method 13, t R =2.64min, m / z (M+1-tert-butyl) = 295.97

[0359] 1 H NMR (acetone-d 6 , 400MHz) δ7.76 (dd, 1H, J=1.4, 7.8Hz), 7.66 (s, 1H), 7.37 (d, 1H, J=7.9Hz), 4.46 (br s, 2H), 4.34 (q, 2H, J=7.0Hz), 4.2-4.3 (m, 1H), 3.80 (br s, 2H), 2.39 (s, 3H), 1.42 (s, 9H), 1.36 (t, 3H, J=7.1Hz)

[0360] The same procedure was used to prepare the following intermediates.

[0361]

[0362] 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

[0363]

[0364] Intermediate 111 (80 mg, 0.227 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (61 mg, 0.34 mmol) were charged into a microwave vial 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 NaHCO 3 The residue was washed, dried over sodium sulfate, filtered and concentrated. The residue was purified by direct phase FCC silica gel flash chromatography (28 g Sfar-D amino column, gradient A: B from 100:0 to 0:10, 12CV, eluent A: n-heptane, eluent B: acetone). The relevant fractions were collected and the solvent was evaporated to give the desired product (73 mg, 0.15 mmol, 65%).

[0365] LC-MS (ESI, m / z): Method 4, t R =6.57min,m / z(M+1)=494.19

[0366] 1 H NMR (400 MHz, DMSO-d 6 )δppm 10.72 (1H, m), 9.19 (1H, br s), 8.69 (1H, br s), 8.65 (1H, s), 8.05 (1H, s), 7.77 (1H, s), 7.61 (1H, d, J = 7.67Hz), 7.39 (1H, br d, 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)

[0367] The following intermediates were prepared using the procedures described for the synthesis of Example 173 starting from the appropriate intermediates using ACN or DMA as solvent.

[0368]

[0369]

[0370] Intermediate 139-3-((1-(5-aminopyridin-3-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide

[0371]

[0372] In a 50 mL steel reaction vessel, intermediate 133 (75 mg, 0.16 mmol) was added in one portion, followed by JMPd / C10R424 (50% wet, 16.86 mg, 7.92 μmol). The vessel was sealed and subjected to 3 cycles of vacuum-H2O. 2 To start the reaction. The reaction was carried out at 40 ° C under 3 bar hydrogen (0.639mg, 0.317mmol), and stirred until completion. The mixture was filtered through a diatomaceous earth pad and then the solvent was removed under reduced pressure. The residue was purified by FCC (6g Sfar-D amino column, gradient n-heptane: acetone from 100: 0 to 0: 100), to obtain the title compound (41mg, 0.092mmol, 58% yield).

[0373] LC-MS (ESI): Method 4, t R =4.30min, m / z(M+1)=444.2

[0374] Example 139-5-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenoxy)azetidin-1-yl)nicotinamide

[0375]

[0376] Intermediate 128 (0.150 g, 0.33 mmol) was dissolved in DMSO (1 mL) and K 2 CO 3 (0.082 g, 0.595 mmol). The suspension was stirred at room temperature for 5 min, and then 30% H 2 O 2 To the 4-nitro-2-yl pyridine ...

[0377] LC-MS (ESI): Method 10, t R =2.80min,m / z(M+1)=472.87

[0378] 1 H NMR (400 MHz, DMSO-d 6) δ10.69 (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, 1 H), 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).

[0379] 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

[0380]

[0381] Fill the microwave vial with K 3 PO 4 (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 backfilled with Ar, and then the solution was stirred at 50 ° C for 1 h. The solvent was evaporated in vacuo. After purification by FCC (NH silica gel 6 g, gradient elution with 40% acetone in n-heptane), the title compound (16 mg, 0.03 mmol, 46%) was obtained.

[0382] LC-MS (ESI): Method 4, t R =5.08min, m / z(M+1)=509.2

[0383] 1 H NMR (DMSO-d 6, 400MHz) δ10.66 (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 .44 (dd, 2H, J=6.2, 8.4Hz), 3.89 (dd, 2H, J=3.9, 8.8Hz), 3.82 (s, 3H), 2.25 (s, 3H)

[0384] The same method was used to prepare the following examples.

[0385]

[0386] Example 145-3-((1-(5-acetylaminopyridin-3-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide

[0387]

[0388] In a 50 mL steel reaction vessel, intermediate 139 (32 mg, 0.072 mmol) was dissolved in pyridine (0.5 mL) and acetyl chloride (0.015 mL, 0.216 mmol) was added once. The reaction was stirred at room temperature until completion. The solvent was removed under reduced pressure and the crude product was purified by FCC (Sfar-D amino column, gradient A: B from 100: 0 to 0: 100, 12 CV, eluent A: n-heptane, eluent B: acetone) to give the title compound (29 mg, 0.059 mmol, 82% yield).

[0389] LC-MS (ESI): Method 4, t R =4.61min,m / z(M+1)=486.22

[0390] 1 H NMR (acetone-d 6, 400MHz) δ9.98 (br s, 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 (br s, 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).

[0391] The following examples and intermediates were prepared using the procedure described for the synthesis of intermediate 104 by reacting the corresponding precursors with the appropriate amine.

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399] Example 161-4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)oxy)-N-(3-(trifluoromethoxy)phenyl)benzamide

[0400]

[0401] Intermediate 127 (100 mg, 0.30 mmol) was placed in a flask, and then DMF (0.86 mL) was added, followed by 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, and Na 2 SO 4Dry and concentrate on a rotary evaporator.The crude material was purified by FCC (hexanes / (3:1 AcOEt:iPrOH) from 100 / 0 to 60 / 40) to afford the title compound (12 mg, 0.025 mmol, 8%).

[0402] LC-MS (ESI): Method 15, t R =2.12min, m / z(M+1)=483.93

[0403] 1 H NMR (400 MHz, DMSO-d 6 )δ10.41 (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).

[0404] The following examples were prepared using the same procedure starting from the corresponding amines.

[0405]

[0406]

[0407]

[0408] 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

[0409] 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% NH 4 OH) / CO 2 , 15 mL / min, 120 bar, 40°C, DAD 230 nm), and two isomers were obtained.

[0410] The first and second eluting isomers 1 H NMR spectrum of the racemic mixture 1H NMR spectra overlap.

[0411]

[0412]

[0413] The following compound of formula (Ic) was prepared by applying the above experimental conditions:

[0414] 4-methyl-3-((1-(pyrazin-2-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide;

[0415] 4-methyl-3-((1-(pyrazin-2-yl)azetidin-3-yl)amino)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide;

[0416] 4-methyl-3-((1-(pyrazolo[1,5-a]pyrimidin-6-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide;

[0417] 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;

[0418] 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;

[0419] 3-((1-(1H-pyrrolo[2,3-c]pyridin-4-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide;

[0420] 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;

[0421] 3-((1-(Furo[3,2-d]pyrimidin-4-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide;

[0422] 5-(3-((2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)amino)azetidin-1-yl)nicotinamide;

[0423] 3-((1-(5-acetylaminopyridin-3-yl)azetidin-3-yl)amino)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide;

[0424] 3-((1-(5-aminopyridin-3-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide;

[0425] 3-((1-(5-aminopyridin-3-yl)azetidin-3-yl)amino)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide;

[0426] N-(5-ethylisoxazol-3-yl)-4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)amino)benzamide;

[0427] 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;

[0428] N-(4-(difluoromethoxy)pyridin-2-yl)-4-methyl-3-((1-(pyrazolo[1,5-a]pyrazin-3-yl)azetidin-3-yl)amino)benzamide;

[0429] 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;

[0430] 4-methyl-3-((1-(1-methyl-1H-indazol-7-yl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; and

[0431] 4-methyl-3-((1-(pyrazolo[1,5-a]pyrazine-3-carbonyl)azetidin-3-yl)oxy)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide.

[0432] A comparative novel synthetic compound C1 characterized by having a -CO- linker between L and the heteroaryl ring B was prepared as follows:

[0433] Compound C1: 4-methyl-3-((1-(pyrazolo[1,5-a]pyrazine-3-carbonyl)azetidin-3-yl)amino)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide

[0434]

[0435] Pyrazolo[1,5-a]pyrazine-3-carboxylic acid (0.05 g, 0.30 mmol) was placed in a flask, and then DMF (0.82 mL) and DIPEA (0.110 mL, 0.63 mmol) were added together. 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. It was diluted with water and extracted with DCM. The organic layer was washed with water, brine, and Na 2 SO 4 Dried and evaporated. The crude material was purified by FCC (eluting with DCM / MeOH from 100 / 0 to 90 / 10) to give the title compound (51 mg, 0.103 mmol, 36%).

[0436] LC-MS (ESI, m / z): Method 9, t R =2.65min, m / z(M+1)=496.16

[0437] 1 H NMR (400 MHz, DMSO-d 6 ) δ10.59 (s, 1H), 9.59 (d, J = 1.4Hz, 1H), 9.18 (s, 1H), 8.92 (dd, J = 4.7, 1.5 Hz, 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).

[0438] Pharmacological activities of the compounds of the present invention

[0439] In vitro assay

[0440] Binding assay

[0441] Using Life Technologies LanthaScreen TMEuropium kinase binding assays DDR1 and DDR2 binding assays were performed. Compounds were incubated with 5 nM DDR1 (Carna Biosciences) or 5 nM DDR2 (Life Technologies) at room temperature for 1 h in a white 384-well Optiplate (PerkinElmer), which contained 20 nM or 10 nM kinase tracer 178 and 2 nM europium-labeled anti-GST antibody (Life Technologies) in assay buffer (50 mM HEPES pH 7.5, 10 mM MgCI2, 1 mM EGTA, and 0.01% BRIJ35), respectively. The ratio of 665 nm / 615 nm fluorescence emission after excitation at 340 nm was obtained using a Tecan Spark 20M plate reader. IC was determined in GraphPad Prism 7.0 software using a 4-parameter model: log(inhibitor) vs. response. 50 The Cheng-Prusoff equation (Ki = IC 50 / (1+[tracer] / Kd), IC 50 The value is converted to Ki.

[0442] The results for individual compounds are provided in Table 2 below, where the compounds are classified according to their potency (nM) in the combination for inhibitory activity against DDR1 and DDR2.

[0443] Table 2

[0444]

[0445]

[0446]

[0447] +: Ki is 25 to 100 nM

[0448] ++: Ki is 5nM to 25nM

[0449] +++: Ki below 5 nM

[0450] -: Ki higher than 100nM

[0451] As can be appreciated, the compounds of Table 2, i.e. the compounds according to the present invention, show good activity as DDR1 and DDR2 antagonists. Therefore, the compounds of the present invention can be effectively used to treat diseases, disorders or conditions associated with DDR receptors, such as fibrosis, such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, kidney fibrosis, eye fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

[0452] Comparative Example

[0453] Compound C1 was tested in the same binding assay as described above.

[0454] Table 3

[0455] Example No. DDR1 Ki(nM) DDR2 Ki(nM) C1 114 311

[0456] As shown in Table 2, the binding affinities of the compounds of the present invention to DDR1 and DDR2 receptors are all lower than 100 nM, and for most compounds, lower than 25 nM or even lower than 5 nM. In contrast, the binding affinity of comparative compound C1 to DDR1 receptor is 114 nM, while the binding affinity to DDR2 receptor is higher than 300 nM.

[0457] Thus, the presence of a direct link between L and the heteroaryl ring B unexpectedly and notably determines a significant increase in the inhibitory activity towards DDR1 and DDR2 receptors.

Claims

1. Compound of formula (I) in A is a ring selected from the following: and phenyl, wherein represents a direct bond to NH; W1 and W2 are substituents of ring A selected from 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 (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl and (C3-C6)cycloalkyl; L is selected from in represents a direct bond to the phenyl ring and represents a direct bond to B; B is a mono- or bi-cyclic heteroaryl ring; Y1 and Y2 are substituents of Ring B independently selected from 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, 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 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; R3 is selected from hydrogen and (C1-C4)alkyl; or stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, which is a compound of formula (Ic) wherein L1 is selected from O, NR3, CHR3, S and SO2, or is absent; or stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

3. The compound according to claim 1 or claim 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]pyridinyl, 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 compound according to any one of the preceding claims, wherein A is a ring selected from the following: and phenyl.

5. A compound according to any one of the preceding claims, wherein W1 and W2 are 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 CH3, CF2H, OCH3, CH2OH and cyclopropyl; L is selected from 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]pyridinyl, 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 hydrogen, (C1-C4)haloalkyl, (C1-C4)alkoxy, cyano, CONR1R2, NHCOR1, NR1R2, (C1-C4)alkyl-heterocycloalkyl-carbonyl and monocyclic (C1-C4)alkyl-heteroaryl; and Y2 is hydrogen; R1 and R2 are independently selected from CH2CH2N(CH3)2, CH2CH2OCH3, CH3, CH2CH2OH, oxetan-3-yl and 3-hydroxycyclobutyl; R3 is hydrogen or methyl; or stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

6. A compound of formula (I) according to claim 1 or a compound of formula (Ic) according to claim 2, which is 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-acetylaminopyrazolo[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-acetylaminopyridin-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, second 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) according to 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, 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. The compound of formula (I) or pharmaceutical composition for use according to claim 9, for preventing and / or treating diseases, disorders or conditions associated with DDR dysregulation.

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

12. A compound of formula (I) or a pharmaceutical composition for use according to claim 11, for preventing and / or treating fibrosis, including pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, kidney fibrosis, eye fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

13. The compound of formula (I) or the pharmaceutical composition for use according to claim 12, for preventing and / or treating idiopathic pulmonary fibrosis (IPF).

14. An intermediate compound selected from the compound of formula (XXXIII) Intermediate compound of formula (XXXIX) and intermediate compound of formula (XL) in R is (C1-C4) alkyl, preferably ethyl, and A, B, L1, Z, W1, W2, Y1 and Y2 are as defined in any one of claims 1 to 6, or stereoisomers, tautomers, solvates and pharmaceutically acceptable salts 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 for the preparation of a compound of formula (Ic) as defined in claim 2.

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