Tetrahydrothienopyridine derivatives as DDR inhibitors

Abstract

The present invention relates to compounds of general formula (I) that inhibit discoidin domain receptors (DDR inhibitors), processes for the preparation of such compounds, pharmaceutical compositions containing them and their therapeutic use. The compounds of the invention may, for example, be useful in the treatment of a number of disorders associated with the DDR mechanism. JPEG2024510849000140.jpg5188

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to compounds that inhibit discoidin domain receptors (DDR inhibitors), methods for the preparation of such compounds, pharmaceutical compositions containing them and their therapeutic uses.

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

[0003] 2. Background of the Invention Discoidin domain receptors (DDRs) are type I transmembrane receptor tyrosine kinases (RTKs). The DDR family includes two distinct members, DDR1 and DDR2.

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

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

[0006] The DDR receptor family has been implicated in a series of fibrotic diseases, including pulmonary fibrosis and especially idiopathic pulmonary fibrosis (IPF). The first evidence of a protective role of DDR1 deletion in pulmonary fibrosis was provided in 2006 by Dr. Vogel's research group (see Avivi-Green C, Am J Respir Crit Care Med 2006; 174: 420-427). The authors showed that DDR1 null mice were highly protected against bleomycin (BLM)-induced injury. Furthermore, myofibroblast expansion and apoptosis were much lower in these animals compared to their wild-type counterparts. The absence of inflammation in the knockout mice was confirmed by lavage cell counts and cytokine ELISA. These results indicate that DDR1 expression is an essential prerequisite for pulmonary inflammation and fibrosis.

[0007] DDR2 deficiency or downregulation regulates bleomycin-induced pulmonary fibrosis (see Zhao H, Bian H, Bu X, Zhang S, Zhang P, Yu J, et al Mol Ther 2016; 24: 1734-1744). Zhao et al. showed that DDR2 plays an important role in inducing fibrosis and angiogenesis in the lung, and in particular, DDR2 cooperates with transforming growth factor (TGF)-β to induce myofibroblast differentiation. Furthermore, they showed that treatment of injured mice with specific siRNA against DDR2 showed therapeutic efficacy against pulmonary fibrosis. In a subsequent publication, Jia et al. showed that mice lacking DDR2 were protected from bleomycin-induced pulmonary fibrosis (see Jia S, Am J Respir Cell Mol Biol 2018; 59: 295-305). Furthermore, DDR2-null fibroblasts were significantly more susceptible to apoptosis than wild-type fibroblasts, supporting the paradigm that fibroblast resistance to apoptosis is important for fibrosis progression.

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

[0009] WO2016064970 (Guangzhou) discloses tetrahydroisoquinoline-7-carboxamides as selective DDR1 inhibitors as useful therapeutic agents for the prevention and treatment of inflammation, liver fibrosis, renal fibrosis, pulmonary fibrosis, skin scarring, atherosclerosis and cancer.

[0010] Of note, antagonism of DDR receptors may be useful in the treatment of fibrosis and diseases, disorders and conditions that result from fibrosis, and further, antagonism of both DDR1 and DDR2 receptors may be particularly effective in treating the above diseases, disorders and conditions.

[0011] In the past few years, several attempts have been made to develop novel DDR1 and DDR2 receptor antagonists useful for the treatment of several diseases, and some of these compounds have also shown efficacy in humans.

[0012] Notwithstanding the above prior art, there remains a scope for the development of selective inhibitors of both DDR1 and DDR2 receptors useful for the treatment of diseases or conditions associated with dysregulation of DDR receptors in the respiratory tract, in particular idiopathic pulmonary fibrosis (IPF), administered by inhalation route and characterized by a good inhalation profile corresponding to good activity in the lungs, good lung retention and low metabolic stability to minimize systemic exposure and associated safety issues. Summary of the Invention [Problem to be solved by the invention]

[0013] In this direction, we have surprisingly solved the problem of providing inhibitors of the receptors DDR1 and DDR2 for administration by inhalation and have discovered a novel series of compounds of general formula (I) as described below, which are active as selective inhibitors of the DDR1 and DDR2 receptors relative to other human protein kinases, and which exhibit high potency, a good inhalation profile, low metabolic stability, low systemic exposure, improved safety and tolerability. [Means for solving the problem]

[0014] Summary of the Invention In a first aspect, the present invention provides a compound of formula (I) [ka] [During the ceremony, L is selected from the group consisting of -C(O)- and -CH2-; Hy may optionally be -(C1-C4) alkyl, halogen, cyano, -(CH2) nNR4R5, -NH-heterocycloalkyl, -O-(C1-C6)alkyl, -(C1-C6)haloalkyl, -C(O)NH-(C1-C6)alkylene-NR4R5, -O-(C1-C6)alkylene-cycloalkyl, -NHC(O)-(C1-C6)alkyl, -NHC(O)-(C1-C6)alkylene-NR4R5, -NHC(O)-(C1-C6)alkylene-O-(C1-C4)alkyl, -NH-(C1-C6)alkylene-O-(C1-C4 )alkyl, -NH-(C1-C6)alkylene-OH, -heteroaryl optionally substituted with one or more -(C1-C4)alkyl, -NH-heteroaryl, where the heteroaryl is optionally substituted with one or more groups selected from -(C1-C4)alkyl and heterocycloalkyl optionally substituted with one or more groups selected from oxo and -(C1-C6)alkyl; R1: - Het, which is heteroaryl optionally substituted with one or more groups selected from -(C1-C4)alkyl, -(C1-C4)haloalkyl and aryl, where the aryl is optionally substituted with one or more groups selected from -(C1-C4)alkyl and halogen atoms; and -X [ka] wherein: R2 is selected from the group consisting of -O(C1-C4)haloalkyl, halogen atoms, -O(C3-C7)cycloalkyl and -(C1-C4)haloalkyl; R3 is H or is selected from the group consisting of a halogen atom, cyano, -O(C1-C4)alkyl, -O(C1-C4)haloalkyl, heterocycloalkyl-(C1-C4)alkylene-, -(C1-C4)alkylene-heterocycloalkyl-NR4R5 and heteroaryl optionally substituted with one or more -(C1-C4)alkyl, wherein said heterocycloalkyl is optionally substituted with one or more -(C1-C4)alkyl; n is 0, 1 or 2; R4 is H or -(C1-C4)alkyl; R5 is H or -(C1-C4)alkyl. and pharma- ceutically acceptable salts thereof.

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

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

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

[0018] In a further aspect, the present invention relates to compounds of formula (I) and pharma- ceutically acceptable salts or pharmaceutical compositions comprising compounds of formula (I) and pharma- ceutically acceptable salts thereof for use in the prophylaxis and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0019] In a further aspect, the present invention relates to compounds of formula (I) and pharma- ceutically acceptable salts or pharmaceutical compositions comprising compounds of formula (I) and pharma- ceutically acceptable salts thereof for use in the prophylaxis and / or treatment of idiopathic pulmonary fibrosis (IPF). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Detailed Description of the Invention definition Unless otherwise specified, the compounds of formula (I) of the present invention are also intended to include their stereoisomers or pharma- ceutically acceptable salts.

[0021] Unless otherwise specified, the compounds of formula (I) of the present invention are also intended to include compounds of formula (Ia), (Iaa), (Iaa'), (Iaa''), (Iab), (Ib), (Iba) and (Ibb).

[0022] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the compounds of formula (I) where the parent compound is suitably modified by converting either the free acid or basic group, if any, of the compound into the corresponding addition salt with any base or acid that is conventionally intended to be pharmaceutically acceptable.

[0023] Suitable examples of such salts may thus include inorganic or organic acid addition salts of basic residues such as amino groups as well as inorganic or organic base addition salts of acidic residues such as carboxylic acid groups.

[0024] Cations of inorganic bases suitable for use in the preparation of salts include those of alkali or alkaline earth metals, such as potassium, sodium, calcium or magnesium.

[0025] Those obtained by reacting the main compound functioning as a base with an inorganic or organic acid to form a salt include, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid and citric acid.

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

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

[0028] The term "diastereomers" refers to stereoisomers that are not mirror images.

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

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

[0031] The term “(C x -C y "(x)alkyl" (where x and y are integers) refers to a straight or branched chain alkyl group having x to y carbon atoms. Thus, when x is 1 and y is 4, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl.

[0032] The term “(C x -C y ) Alkylene" (where x and y are integers) refers to a divalent saturated aliphatic chain derived from an alkane by the removal of two hydrogen atoms from different carbon atoms, having from x to y carbon atoms, e.g., methylenyl.

[0033] The term “O(C x -C y (C)haloalkyl" (wherein x and y are integers) refers to a "(C)haloalkyl" as defined above, in which a carbon atom is bonded to an oxygen atom. x -C y )haloalkyl group.

[0034] The “O(C x -C y Examples of "haloalkyl" groups thus can include halogenated, poly-halogenated and fully halogenated O-alkyl groups in which all hydrogen atoms have been replaced with halogen atoms, such as trifluoromethoxy and difluoromethoxy.

[0035] The term “(C x -C y ) Alkylene-NR x’ Ry’ " (where x and y are integers) means that the carbon atom is NR x’ R y’ (wherein x' and y' are integers) is bonded to the above-defined "(C x -C y ) alkylene.

[0036] The term “O(C x -C y (C )alkyl" (where x and y are integers) refers to a "(C )alkyl" as defined above, in which a carbon atom is bonded to an oxygen atom. x -C y ) alkyl groups, such as ethoxy and methoxy.

[0037] The term “(C x -C y (C)haloalkyl" (wherein x and y are integers) refers to a "(C)haloalkyl" as defined above in which one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different. x -C y The "(C ) alkyl" group refers to the x -C y Examples of "haloalkyl" groups thus include halogenated, poly-halogenated and fully halogenated alkyl groups in which all hydrogen atoms have been replaced with halogen atoms, such as trifluoromethyl, 1,1,1-trifluoro-2-methylpropan-2-yl and 1,1-difluoroethyl.

[0038] The term "aryl" refers to a monocyclic carbocyclic ring system having 6 ring atoms that is aromatic. Examples of suitable aryl monocyclic ring systems include, for example, phenyl.

[0039] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic group containing one or more heteroatoms selected from S, N and O, including groups having two such monocyclic rings or one such monocyclic ring and one cyclic aryl ring fused through a common bond, such as pyridinyl, pyrimidinyl, 1-methyl-1H-pyrazolyl, pyrazinyl, 1-methyl-1H-imidazolyl, isoxazolyl.

[0040] The term “-C(O)NH-(C x -C y ) Alkylene-NR x’ R y’ " (where x' and y' are integers) is the above-defined "(C(O)NH-" in which alkylene is attached to -C(O)NH- through its nitrogen atom. x -C y ) Alkylene-NR x’ R y’ "

[0041] The term “NHC(O)-(C x -C y ) Alkylene-NR x’ R y’ " refers to "(C)" as defined above, in which alkylene is bonded to -NHC(O)- through its carbonyl group. x -C y ) Alkylene-NR x’ R y’ "

[0042] The term “NHC(O)-(C x -C y )Alkylene-O-(C x -C y ) alkyl" is "O(C x -C y ) alkyl" and "(C x -C y ) alkylene" is bonded through oxygen and is defined as "(C x -C y )alkylene" is additionally attached to the amide group through its carbonyl moiety, as defined above. x -C y )alkyl" and "(C x -C y ) alkylene.

[0043] The term "NH-heteroaryl" refers to a "heteroaryl" as defined above, wherein the heteroaryl is attached to a nitrogen atom.

[0044] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic ring system of 3 to 12 ring atoms containing one or more heteroatoms selected from N, S, or O. Examples of heterocycloalkyl can include, for example, piperazinyl, oxopiperazinyl, dioxidothiomorpholino, oxetanyl, and pyrrolidinyl.

[0045] The term "heterocycloalkyl-(C x -C y "Alkylene" refers to a straight or branched chain (C x -C y ) Heterocycloalkyl attached to an alkylene group.

[0046] The structural formula used here is [ka] A bond pointing to a wavy or serpentine line, such as, indicates a bond that is the point of attachment of the moiety or substituent to the core or backbone structure.

[0047] When referring to a substituent, a dash ("-") that is not between two letters, words or symbols is meant to represent a point of attachment for such substituent.

[0048] Carbonyl groups herein are preferably represented as -C(O)- as alternative to other common representations such as -CO-, -(CO)- or -C(=O)-.

[0049] When a basic amino group is present in the compound of formula (I), a physiologically acceptable anion may be present, selected from chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate and naphthalenedisulfonate.Similarly, when an acidic group is present, the corresponding physiological cationic salts, including, for example, alkali or alkaline earth metal ions, may also be present.

[0050] The term "half maximal inhibitory concentration" (IC 50 ) indicates the concentration of a particular compound or molecule required to inhibit a biological process by 50% in vitro.

[0051] The term "Ki" refers to the dissociation constant of the enzyme-inhibitor complex, expressed in molar units, and is an indicator of the binding affinity between the inhibitor and the DDR1 or DDR2 receptor.

[0052] As mentioned above, the present invention provides compounds having inhibitory activity against the receptors DDR1 and DDR2, which are represented by the general formula (I) detailed below: The present invention relates to a series of compounds represented by the formula: Antagonism of the receptors DDR1 and DDR2 may be particularly effective in treating diseases in which DDR receptors play a role, such as fibrosis and diseases, disorders and conditions associated with fibrosis.

[0053] In particular, as detailed in the experimental section below, the compounds of formula (I) of the present invention can act as both DDR1 and DDR2 receptor inhibitors in a substantial and effective manner. In particular, Table 5 below shows that for the compounds of the present invention, both the affinity to either DDR1 or DDR2 receptors and the inhibitory activity to either DDR1 or DDR2 receptors are measured by binding (expressed as Ki) and cell-based assays (IC 50The results show that the β-glucose concentration (βglucose concentration) of the compound of formula (I) is less than about 80 nM. This confirms that the compound of formula (I) can inhibit the two isoforms of DDR receptors that are mainly involved in fibrosis and diseases caused by fibrosis. Therefore, the compound of formula (I) can be used to treat fibrosis, particularly pulmonary fibrosis, in which DDR1 and DDR2 are involved.

[0054] As shown in the experimental section, comparative examples and especially in Table 6, it is shown that the presence of a -CH2- or -C(O)- linker at this position in the compounds of the present invention, contrary to the comparative compound of Example C1, which is characterized by the absence of a linker between the tetrahydrothienopyridine ring and the Hy group, unexpectedly and significantly determines an associated increase in inhibitory activity of the DDR1 and DDR2 receptors.

[0055] Furthermore, as shown in the same experimental section, the data reveal that contrary to the compound of Example C2, which is characterized by the absence of a linker between the tetrahydrothienopyridine ring and the Hy group and the -C(O)NH- group substituted at the alpha position relative to the sulfur atom instead of the beta position in Example 3 of the present invention, the presence of said linker in the compound of the present invention together with the substitution at the beta position unexpectedly and remarkably reveals an associated increase in the inhibitory activity of the DDR1 and DDR2 receptors.

[0056] The compounds of the present invention advantageously have extremely high potency and can be administered to humans at lower doses than prior art compounds, thereby reducing the adverse events typically associated with the administration of high doses of drugs.

[0057] In addition to their remarkably potent inhibitory activity against both the DDR1 and DDR2 receptors, the compounds of the present invention are characterized by being selective inhibitors of the DDR1 and DDR2 receptors over other human protein kinases, by having a good inhalation profile that allows them to act effectively in the pulmonary region, and at the same time, by having low metabolic stability that minimizes the drawbacks associated with systemic exposure, such as safety and tolerability issues.

[0058] The compounds of the present invention will therefore be particularly appreciated by those skilled in the art searching for suitable and effective compounds useful in the treatment of fibrosis, in particular idiopathic pulmonary fibrosis, administered by the inhalation route and characterized by a good inhalation profile corresponding to good pulmonary activity, good pulmonary retention and low metabolic stability minimizing systemic exposure and associated safety issues.

[0059] Thus, in one embodiment, the present invention provides a compound of general formula (I): [ka] [During the ceremony, L is selected from the group consisting of -C(O)- and -CH2-; Hy may optionally be -(C1-C4) alkyl, halogen, cyano, -(CH2) n NR4R5, -NH-heterocycloalkyl, -O-(C1-C6)alkyl, -(C1-C6)haloalkyl, -C(O)NH-(C1-C6)alkylene-NR4R5, -O-(C1-C6)alkylene-cycloalkyl, -NHC(O)-(C1-C6)alkyl, -NHC(O)-(C1-C6)alkylene-NR4R5, -NHC(O)-(C1-C6)alkylene-O-(C1-C4)alkyl, -NH-(C1-C6)alkylene-O-(C1-C4 )alkyl, -NH-(C1-C6)alkylene-OH, -heteroaryl optionally substituted with one or more -(C1-C4)alkyl, -NH-heteroaryl, where the heteroaryl is optionally substituted with one or more groups selected from -(C1-C4)alkyl and heterocycloalkyl optionally substituted with one or more groups selected from oxo and -(C1-C6)alkyl; R1: - Het, which is heteroaryl optionally substituted with one or more groups selected from -(C1-C4)alkyl, -(C1-C4)haloalkyl and aryl, where the aryl is optionally substituted with one or more groups selected from -(C1-C4)alkyl and halogen atoms; and -X [ka] is selected from the group consisting of Where: R2 is selected from the group consisting of -O(C1-C4)haloalkyl, halogen atoms, -O(C3-C7)cycloalkyl and -(C1-C4)haloalkyl; R3 is H or is selected from the group consisting of a halogen atom, cyano, -O(C1-C4)alkyl, -O(C1-C4)haloalkyl, heterocycloalkyl-(C1-C4)alkylene-, -(C1-C4)alkylene-heterocycloalkyl-NR4R5 and heteroaryl optionally substituted with one or more -(C1-C4)alkyl, wherein said heterocycloalkyl is optionally substituted with one or more -(C1-C4)alkyl; n is 0, 1 or 2; R4 is H or -(C1-C4)alkyl; R5 is H or -(C1-C4)alkyl. and pharma- ceutically acceptable salts thereof.

[0060] In a preferred embodiment, the present invention relates to compounds of general formula (I), wherein L is -CH2.

[0061] In another preferred embodiment, the present invention relates to a method for treating a cancer comprising administering to a patient a disease comprising administering to the ... [ka] The general formula (Ia) [ka] (wherein L, Hy, R2 and R3 are as defined above.) The present invention relates to compounds of general formula (I) represented by:

[0062] In a further preferred embodiment, the present invention relates to a compound of formula (Iaa), [ka] (wherein Hy, R2 and R3 are as defined above.) The present invention relates to a compound of formula (Ia), represented by:

[0063] In another preferred embodiment, the present invention relates to a compound according to the present invention, wherein Hy is pyridin-3-yl, pyrimidin-5-yl, ((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl, 4-(2-methoxyacetamido)pyridin-3-yl, 5-cyanopyridin-3-yl, 5-chloropyridin-3-yl, 5-methoxypyridin-3-yl, 5-methylpyridin-3-yl, 5-(trifluoromethyl)pyridin-3-yl, 3-aminopyrazin-2-yl, 2-aminopyrimidin-5-yl, 5-(4-methyl-3-oxopiperazin-1-yl)pyridin-3-yl, 5-(1,1-dioxidethiomorpholino)pyridin-3-yl, -((5-(2-(dimethylamino)acetamido)pyridin-3-yl, 2-(oxetane-3-yl), The present invention relates to compounds of the general formula (Iaa) selected from the group consisting of (1-methyl-1H-pyrazol-4-yl)pyrimidin-3-yl, (5-fluoropyridin-3-yl)methyl, ... and (5-fluoropyridin-3-yl)methyl.

[0064] In a further preferred embodiment, the invention relates to compounds of general formula (Iaa), wherein R2 is selected from the group consisting of trifluoromethyl, trifluoromethoxy, 1,1-difluoroethyl and difluoromethoxy.

[0065] In another particularly preferred embodiment, the present invention relates to compounds of general formula (Iaa), wherein R3 is H or is selected from the group consisting of (4-methylpiperazin-1-yl)methyl, 4-methyl-1H-imidazol-1-yl, fluorine, (3-(dimethylamino)pyrrolidin-1-yl)methyl, (dimethylamino)methyl and cyano.

[0066] According to a preferred embodiment, the present invention relates to at least one compound of formula (Iaa) and its pharma- ceutically acceptable salts as listed in Table 1 below. These compounds are particularly active on the receptors DDR1 and DDR2, as shown in Table 5.

[0067] [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9]

[0068] In another preferred embodiment, the present invention relates to a compound in which L is -CH2- and R1 is X'' [ka] Formula (Iaa') [ka] (wherein Hy, R2 and R3 are as defined above.) The present invention relates to a compound of formula (I) represented by:

[0069] In another preferred embodiment, the invention relates to compounds of general formula (Iaa'), wherein R2 is trifluoromethyl.

[0070] In a further preferred embodiment, the invention relates to compounds of general formula (Iaa'), wherein R3 is fluorine.

[0071] In a further particularly preferred embodiment, the invention relates to compounds of general formula (Iaa'), wherein Hy is pyrimidin-5-yl.

[0072] According to a preferred embodiment, the present invention relates to compounds of formula (Iaa') and their pharma- ceutically acceptable salts as listed in Table 2 below. These compounds are particularly active on the receptors DDR1 and DDR2, as shown in Table 5. [Table 10]

[0073] In another preferred embodiment, the present invention relates to a compound in which L is -CH2- and R1 is X''' [ka] Formula (Iaa″) [ka] (Wherein, Hy, R2 and R3.) The present invention relates to a compound of formula (I) represented by:

[0074] In a particularly preferred embodiment, the invention relates to compounds of general formula (Iaa″), wherein R2 is selected from the group consisting of trifluoromethyl and trifluoromethoxy.

[0075] In another particularly preferred embodiment, the invention relates to compounds of general formula (Iaa″), wherein R3 is selected from the group consisting of fluorine, chlorine and (dimethylamino)methyl.

[0076] In a further preferred embodiment, the invention relates to compounds of general formula (Iaa''), wherein Hy is pyrimidin-5-yl and 2-aminopyrimidin-5-yl.

[0077] According to a preferred embodiment, the present invention relates to at least one compound of formula (Iaa″) listed in Table 3 below and its pharma- ceutically acceptable salts. These compounds are particularly active on the receptors DDR1 and DDR2, as shown in Table 5.

[0078] [Table 11]

[0079] In another preferred embodiment, the present invention relates to a compound of formula (Iab) [ka] (wherein Hy, R2 and R3 are as defined above.) The present invention relates to a compound of formula (Ia) represented by:

[0080] In a particularly preferred embodiment, the invention relates to compounds of general formula (Iab), wherein R2 is trifluoromethyl.

[0081] In another particularly preferred embodiment, the present invention relates to compounds of general formula (Iab), wherein R3 is fluorine.

[0082] In a further preferred embodiment, the present invention relates to compounds of general formula (Iab), wherein Hy is 1-methyl-1H-imidazol-5-yl. According to a preferred embodiment, the present invention relates to compounds of formula (Iab) in Table 7 below, and their pharma- ceutically acceptable salts. [Table 12]

[0083] In a further preferred embodiment, the present invention relates to a compound of formula (Ib), wherein R1 is Het. [ka] [During the ceremony, L is selected from the group consisting of -C(O)- and -CH2-; Hy may optionally be -(C1-C4) alkyl, halogen, cyano, -(CH2) n monocyclic heteroaryl substituted with one or more groups selected from the group consisting of NR4R5, -O-(C1-C6)alkyl, -(C1-C6)haloalkyl, -NHC(O)-(C1-C6)alkylene-O-(C1-C4)alkyl, and -NH-heteroaryl, wherein said heteroaryl is optionally substituted with one or more -(C1-C4)alkyl; Het is heteroaryl optionally substituted with one or more groups selected from -(C1-C4)alkyl, -(C1-C4)haloalkyl and aryl, where the aryl is optionally substituted with one or more groups selected from -(C1-C4)alkyl and halogen atoms; R4 is H; R5 is H or -(C1-C4)alkyl. and pharma- ceutically acceptable salts thereof.

[0084] In another preferred embodiment, the present invention relates to a compound of formula (Iba), [ka] (wherein Hy and Het are as defined above). The present invention relates to a compound of formula (Ib) represented by:

[0085] In a further preferred embodiment, the present invention relates to compounds of general formula (Iba), wherein Hy is selected from the group consisting of pyrimidin-5-yl, 3-aminopyrazin-2-yl, 5-methoxypyridin-3-yl, 5-fluoropyridin-3-yl, pyridin-3-yl, 3-aminopyrazin-2-yl and (2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl.

[0086] In another particularly preferred embodiment, the present invention relates to compounds of general formula (Iba), wherein Het is selected from the group consisting of 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl, (trifluoromethyl)pyridin-3-yl, 2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-yl, 5-(trifluoromethoxy)pyridin-3-yl and 3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl.

[0087] According to a preferred embodiment, the present invention relates to at least one compound of formula (Iba) and its pharma- ceutically acceptable salts as listed in Table 4 below. These compounds are particularly active on the receptors DDR1 and DDR2, as shown in Table 5.

[0088] [Table 13] [Table 14] [Table 15]

[0089] In a further preferred embodiment, the present invention relates to a compound of formula (Ibb), [ka] (wherein Hy and Het are as defined above). The present invention relates to a compound of formula (Ib) represented by:

[0090] The compounds of the present invention, including all of those listed above, can be prepared from readily available starting materials according to the following general methods and procedures or using slightly modified procedures readily available to those of skill in the art. Although specific embodiments of the invention may be shown or described herein, those of skill in the art will recognize that all embodiments or aspects of the invention can be obtained using the methods described herein or using other known methods, reagents and starting materials. Even when typical or preferred process conditions (i.e., reaction temperatures, times, molar concentrations of reactants, solvents, pressures, etc.) are given, other process conditions can be used unless specifically stated otherwise. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be readily determined by one of skill in the art by routine optimization procedures.

[0091] In some cases, when it is necessary to mask or protect sensitive or reactive moieties, commonly known protecting groups (PG) can be used according to general principles of chemistry (Protective groups in organic syntheses, 3rd ed. TW Greene, PGM Wuts).

[0092] It has surprisingly been found that the compounds of formula (I) of the present invention effectively inhibit both the receptors DDR1 and DDR2. Advantageously, the inhibition of the receptors DDR1 and DDR2 can result in the effective treatment of diseases or conditions in which the DDR receptors are involved.

[0093] In this regard, as shown in the experimental section, the compound of formula (I) of the present invention has antagonist activity expressed as inhibition constant Ki for DDR1 and DDR2 of less than 80nM.Preferably, the compound of the present invention has Ki for DDR1 and DDR2 of less than 50nM.Even more preferably, the compound of the present invention has Ki for DDR1 and DDR2 of less than 25nM.

[0094] Furthermore, as shown in the experimental section, the affinity for both DDR1 and DDR2 receptors and the inhibitory activity for both DDR1 and DDR2 receptors were measured by binding (indicated by Ki) and cell-based assays (IC 50 Preferably, the compounds of the present invention have a Ki and / or IC for the DDR1 and DDR2 receptors of less than 50 nM. 50 Even more preferably, the compounds of the present invention have a Ki and / or IC for the DDR1 and DDR2 receptors of less than 25 nM. 50 has.

[0095] In one aspect, the invention relates to a compound of formula (I) according to any of the above embodiments for use as a medicament.

[0096] In a preferred embodiment, the present invention relates to compounds of formula (I) and pharma- ceutically acceptable salts thereof for use in the treatment of a disease, disorder or condition associated with dysregulation of the DDR.

[0097] In another embodiment, the present invention relates to the use of a compound of formula (I) as defined above in the manufacture of a medicament for the treatment of a disorder associated with dysregulation of the DDR.

[0098] In a preferred embodiment, the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the prophylaxis and / or treatment of a disease, disorder or condition associated with the DDR receptor mechanism.In one embodiment, the present invention relates to a compound of formula (I) useful for the prophylaxis and / or treatment of a disease, disorder or condition involving fibrosis.

[0099] As used herein, the term "fibrosis" or "fibrotic disorder" refers to a condition associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased recruitment of fibroblasts, including, but not limited to, fibrosis of individual organs or tissues, such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and gastrointestinal tract.

[0100] Preferably, the compounds of formula (I) above are useful for the treatment and / or prevention of fibrosis such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

[0101] More preferably, the compounds of formula (I) above are for the treatment of idiopathic pulmonary fibrosis (IPF).

[0102] In one embodiment, the present invention also relates to a method for preventing and / or treating disorders associated with the DDR receptor mechanism, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) as defined above.

[0103] In a further aspect, the present invention relates to the use of the compounds of formula (I) as defined above for the treatment of disorders associated with the DDR receptor mechanism.

[0104] In another aspect, the present invention relates to the use of a compound of formula (I) as defined above in the manufacture of a medicament for the treatment of a disorder associated with the DDR receptor mechanism.

[0105] In a further aspect, the present invention relates to a method for preventing and / or treating disorders or conditions associated with dysregulation of DDR receptors 1 and 2, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) as defined above.

[0106] In a further aspect, the present invention relates to the use of the compounds of formula (I) as defined above for the treatment of diseases, disorders or conditions in which dysregulation of DDR receptors 1 and 2 is involved.

[0107] A "safe and effective amount" as used herein in connection with a compound of formula (I) or a pharma- ceutically acceptable salt thereof or other pharma- ceutical active agent means an amount of the compound that is sufficient to treat the patient's condition but low enough to avoid severe side effects, such an amount can be routinely determined by one of skill in the art.

[0108] The compounds of formula (I) may be administered in one or multiple doses at various intervals over a period of time. The typical daily dosage may vary depending on the route of administration selected.

[0109] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) according to any of the embodiments in admixture with at least one or more pharma- ceutically acceptable carriers or excipients.

[0110] In certain embodiments, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) in admixture with one or more pharma- ceutically acceptable carriers or excipients, such as those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA.

[0111] Administration of the compounds of the present invention and pharmaceutical compositions thereof can be accomplished, for example, orally, nasally, parenterally (subcutaneous, intravenous, intramuscular, intrasternal and infusion) and by inhalation, depending on the needs of the patient.

[0112] Preferably, the compounds of the present invention are administered orally or by inhalation.

[0113] In certain preferred embodiments, the pharmaceutical compositions comprising the compounds of formula (I) are solid oral dosage forms such as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders.

[0114] In certain embodiments, the pharmaceutical composition comprising a compound of Formula (I) is a tablet.

[0115] The compounds of the present invention can be administered alone or in combination with various pharma- ceutically acceptable carriers, diluents (e.g., sucrose, mannitol, lactose, starch) and known additives, including suspending agents, solubilizing agents, buffers, binders, disintegrating agents, preservatives, coloring agents, flavoring agents, lubricants, and the like.

[0116] In further embodiments, the pharmaceutical compositions comprising the compounds of formula (I) are liquid oral dosage forms, such as aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs. Such liquid dosage forms may also contain suitable known inert diluents, such as water, and suitable known additives, such as preservatives, wetting agents, sweeteners, flavoring agents, and agents for emulsifying and / or suspending the compounds of the present invention.

[0117] In a further embodiment, the pharmaceutical composition comprising a compound of formula (I) is an inhalable formulation, such as an inhalable powder, a propellant-containing metered dose aerosol or a propellant-free inhalable formulation.

[0118] For administration as a dry powder, single or multi-dose inhalers known from the prior art may be utilized, in which case the powder may be filled into gelatin, plastic or other capsules, cartridges or blister packs or reservoirs.

[0119] A diluent or carrier which is chemically inert to the compound of the invention, such as lactose or any other additive suitable for improving the inhalable fraction, may be added to the powdered compound of the invention.

[0120] Inhalation aerosols containing a propellant gas, such as hydrofluoroalkanes, may contain the compounds of the invention in solution or dispersion form. Propellant-driven formulations may also contain other ingredients such as cosolvents, stabilizers and other additives if desired.

[0121] Propellant-free inhalable formulations containing the compounds of the invention may be in the form of a solution or suspension in an aqueous, alcoholic or hydroalcoholic medium and may be delivered by jet or ultrasonic nebulizers or soft mist nebulizers known from the prior art.

[0122] The compounds of the invention may be administered as the sole active agent or in combination with other pharma- ceutical active ingredients.

[0123] The dosage of the compounds of the present invention will depend on a variety of factors, including the particular disease being treated, the severity of the condition, the route of administration, and the like, among others.

[0124] The present invention also relates to a device containing a pharmaceutical composition comprising a compound of formula (I) of the present invention in the form of a single or multi-dose dry powder inhaler or a metered dose inhaler.

[0125] All of the preferred groups or embodiments described above for compounds of formula (I) may be equally applied in combination with one another mutatis mutandis.

[0126] The compounds of the present invention, including all of those listed above, can be prepared from readily available starting materials according to the following general methods and procedures or using slightly modified procedures readily available to one of ordinary skill in the art. Although specific embodiments of the invention may be shown or described herein, one of ordinary skill in the art will recognize that all embodiments or aspects of the invention can be practiced using the methods described herein or using other known methods, reagents, and starting materials. When typical or preferred process conditions (i.e., reaction temperatures, times, molar concentrations of reactants, solvents, pressures, etc.) are given, other process conditions can also be used, unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be readily determined by one of ordinary skill in the art by routine optimization procedures.

[0127] Therefore, the processes described below and in the following schemes should not be construed as limiting the scope of synthetic methods available for preparing the compounds of the present invention.

[0128] Compounds of formula (I), including at least one or all of the compounds listed above, can generally be prepared by the procedures detailed in the schemes below, using generally known methods.

[0129] In a first embodiment of the present invention, compounds of formula (I), wherein R 1 , L and Hy are as defined above, can be prepared as depicted in Scheme 1.

[0130] Compounds of formula (I) can be prepared according to Scheme 1 below, which provides at least one non-limiting synthetic route for the preparation of all example compounds.

[0131] [ka] According to scheme 1, intermediate III can be prepared according to a one-step synthesis starting from intermediate II under direct ester amidation (transamination) conditions, using for example butyllithium as a promoter, in a suitable organic solvent such as THF or dioxane, at a temperature ranging from -78°C to room temperature for several hours. Intermediate IV can be obtained from intermediate III under suitable deprotection conditions, for example using aqueous HCl or HCl in dioxane or TFA in a suitable solvent such as DCM, at a suitable temperature ranging from 0°C to room temperature. Compounds of formula (I) can be obtained by subjecting the appropriate alkyl bromide intermediate XII to suitable alkylation conditions, using for example a suitable base such as DIPEA or TEA, in a suitable solvent such as DMF or DMA, at room temperature.

[0132] Alternatively, intermediate III can be prepared from intermediate II by hydrolysis using a suitable aqueous inorganic base such as NaOH in a suitable solvent such as MeOH at room temperature, followed by amide coupling with the appropriate amine VIII or IX under suitable amide coupling conditions in the presence of an agent for activating the carboxylic acid partner such as TBTU or HATU or T3P and an organic base such as DIPEA or TEA in a suitable organic solvent such as DCM or DMF and generally at a temperature around room temperature.

[0133] Alternatively, intermediate III can be prepared from intermediate II in the presence of TCFH and 1-methylimidazole or via amidation to give a temporarily activated acylimidazolinium intermediate, which reacts with the appropriate amine VIII or IX in a solvent such as DMF at RT. In a different approach, intermediate III can be prepared from intermediate II by treating it directly with the appropriate amine VIII or IX in the presence of a suitable chlorinating agent such as POCl3 or thionyl chloride or oxalyl chloride in a solvent such as pyridine or cyclopentyl methyl ether in the presence of a catalytic amount of DMF at temperatures ranging from 5° C. to room temperature to give the corresponding acyl chloride.

[0134] Alternatively, intermediate IV can be converted to intermediate V by reductive amination conditions using an appropriate aldehyde X and a suitable reducing agent such as Na(OAc)3BH or NaCNBH3 in a suitable solvent such as DCM or EtOH in the presence of an acid such as acetic acid and, if necessary, a dehydrating agent such as magnesium sulfate or, if necessary, a suitable coordinating agent such as titanium tetrahydroisopropoxide at a temperature ranging from room temperature to 50° C. Intermediate V can be converted to compounds of formula (I) by Buchwald-Hartwig cross-coupling with a suitable amine in a suitable solvent such as DMF or dioxane using a suitable palladium catalyst such as RuPhos Pd G3 and a suitable base such as cesium carbonate. Alternatively, intermediate V can be converted to compounds of formula (I) by Pd-catalyzed amide N-arylation with an appropriate amide using a suitable palladium catalyst such as Pd(dba)2, using a suitable ligand such as XantPhos, in a suitable solvent such as toluene, in the presence of a catalytic amount of aluminium triflate at a temperature of 110°C.

[0135] In a different approach, intermediate VI can be prepared from intermediate V by applying the appropriate reductive amination conditions described above with a suitable aldehyde XI, followed by conversion to a compound of formula (I) via amidation with a suitable acyl chloride XIV using a suitable base such as TEA or DIPEA in a suitable solvent such as THF at room temperature. Compounds of formula (I) can also be obtained from intermediate IV using a suitable aldehyde XIII following the reductive amination conditions described above. Alternatively, compounds of formula (I) can be prepared from intermediate IV by amidation with a suitable carboxylic acid by applying the conditions described above.

[0136] In another embodiment, compounds of formula (I) can be prepared according to Scheme 2.

[0137] [ka] According to Scheme 2, intermediate XV can be obtained from intermediate II under suitable deprotection conditions, for example using aqueous HCl or HCl in dioxane or TFA in a suitable solvent such as DCM or diethyl ether at a suitable temperature ranging from 0° C. to room temperature. Intermediate XV can be subjected to reductive amination with a suitable aldehyde XIII with a suitable reducing agent such as Na(OAc)3BH or NaCNBH3 in a suitable solvent such as DCM or EtOH in the presence of an acid such as acetic acid and, if necessary, a dehydrating agent such as magnesium sulfate or, if necessary, a suitable coordinating agent such as titanium tetrahydroisopropoxide at a temperature ranging from room temperature to 50° C. to obtain intermediate XVI. Compounds of formula (I) can then be prepared from intermediate XVI by hydrolysis using a suitable aqueous inorganic base such as NaOH in a suitable solvent such as MeOH at room temperature, followed by amide coupling with a suitable amine VIII or IX under suitable amide coupling conditions, in the presence of an activating agent for the carboxylic acid partner such as TBTU or HATU or T3P and an organic base such as DIPEA or TEA, in a suitable organic solvent such as DCM or DMF and generally at a temperature around room temperature. Alternatively, compounds of formula (I) can be prepared from intermediate XVII by amide coupling with a suitable amide VIII using a suitable base such as TEA in a suitable solvent such as DCM at about room temperature in the presence of a suitable chlorinating agent such as POCl3 or thionyl chloride or oxalyl chloride, if necessary in a solvent such as pyridine or cyclopentyl methyl ether, if necessary in the presence of a catalytic amount of DMF, at a temperature in the range of 5°C to 50°C to give the corresponding acyl chloride XVIII.

[0138] Various aspects of the invention described herein are illustrated by the following examples, which are not intended to limit the invention in any way. EXAMPLES

[0139] Preparation of intermediates and example compounds Compound names were generated using Structure To Name Place IUPAC Name Name in PerkinElmer ChemDraw Professional 19.1.1.21. All reagents whose synthesis is not described in the experimental section are either commercially available or known compounds or can be prepared from known compounds by known methods by one skilled in the art.

[0140] In the methods below, some of the starting materials are identified with "Intermediate" or "Example" numbers along with a designation of the step number, which are provided solely as an aid to the skilled chemist.

[0141] "Similar" or "substantial" methods mean that such methods may involve minor modifications, for example, reaction temperatures, amounts of reagents / solvents, reaction times, work-up conditions, or chromatographic purification conditions.

[0142] Acronyms - Meanings RM = reaction mixture; TEA = triethylamine; HATU = (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate; DMAP = 4-dimethylaminopyridine; TCFH = chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate; DMF = N,N-dimethylformamide; Et2O = diethyl ether; EtOAc = ethyl acetate; THF = tetrahydrofuran; DCM = dichloromethane; ACN = acetonitrile; MeOH = methyl alcohol; IMS = methylated alcohol; RT = room temperature; LCMS = liquid chromatography / mass spectrometry; HPLC = high performance liquid chromatography. Chromatography;TLC=thin layer chromatography;SCX=solid cation exchange;DMSO-d6=deuterated dimethylsulfoxide;CDCl3=deuterated chloroform;NaBH3CN=sodium cyanoborohydride;ACN-d3=deuterated acetonitrile;NMR=nuclear magnetic resonance;DIPEA=N,N-diisopropylethylamine;HCOOH=formic acid;UPLC=ultraperformance liquid chromatography;n-BuLi=n-butyllithium;RuPhos=2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl;XantPhos=4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;Pd(dba)2=bis(dibenzylideneacetone)palladium(0);RuPhos Pd G3 = (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium (II) methanesulfonate; STAB = sodium triacetoxyborohydride; AcOH = acetic acid; T3P = propanephosphonic anhydride; Prep HPLC = preparative high performance liquid chromatography; pTLC = preparative thin layer chromatography; FCC = flash column chromatography; SM = starting material; eq. = equivalent.

[0143] General Experiment Details NMR Details: 1H NMR spectra were recorded on a Varian MR-400 spectrometer or a Bruker Avance III HD 400 MHz or a Bruker Fourier 300 MHz operating with a quadrature digital detection unit equipped with a self-shielded Z-gradient coil 5 mm 1H / nX broadband probe head for reverse detection, a deuterium digital lock channel unit, and a transmitter offset frequency shift. Chemical shifts are reported as δ values ​​(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=undetermined).

[0144] In some instances, the signal NH from the amide or amine bond (exchangeable proton) is not visible.

[0145] In some cases, some signals may be masked under the water signal or under the DMSO or other residual solvent signal.

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

[0147] Method 1 Acquity CSH C18 column 50mm x 2.1mm 1.7μm, maintained at 40℃; Mobile phase: 1%-99.9% eluent B (ACN / water 95:5 + 0.05% HCOOH) in eluent A (water / ACN 95:5 + 0.05% HCOOH) within 3.5 min. Flow rate: 1mL / min. Wavelength: 210-400nm DAD. UPLC+Waters PDA+Waters QDA.

[0148] Method 2 Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm maintained at 25°C. Mobile phase: water (0.1% HCOOH) in ACN (0.1% HCOOH), 80% to 5% within 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus.

[0149] Method 3 Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm maintained at 25°C. Mobile phase: water (0.1% HCOOH) in ACN (0.1% HCOOH), 95% to 20% within 4.75 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus.

[0150] Method 4 Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm maintained at 25°C. Mobile phase: water (0.1% HCOOH) in ACN (0.1% HCOOH), 90% to 5% within 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus.

[0151] Method 5 Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm maintained at 25°C. Mobile phase: water (0.1% HCOOH) in ACN (0.1% HCOOH), 70% to 5% within 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus.

[0152] Method 6 Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm maintained at 25 °C. Mobile phase: water (0.1% HCOOH) in ACN (0.1% HCOOH), 70% to 5% within 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC mass spectrometer.

[0153] Method 7 Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm maintained at 25 °C. Mobile phase: water (0.1% HCOOH) in ACN (0.1% HCOOH), 80% to 5% within 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC mass spectrometer.

[0154] Method 8 Acquity UPLC BEH Shield RP18 column, 100 x 2.1 mm, 1.72 μm (PlusGuard cartridge), maintained at 40 °C. Mobile phase: ACN in water + 10 nM ammonium bicarbonate 5% to 95% within 5.6 min. Flow rate: 0.4 ml / min. Wavelength: 210-400 nm DAD. UPLC + Waters DAD + Waters SQD2, single quadrupole UPLC-MS

[0155] Method 9 Acquity UPLC HSS C18 column, 100 x 2.1 mm, 1.8 μm (PlusGuard cartridge), maintained at 40 °C. Mobile phase: ACN (0.1% HCOOH) in water (0.1% HCOOH). 5% to 95% within 5.6 min. Flow rate: 0.4 ml / min. Wavelength: 210-400 nm DAD. UPLC+Waters DAD+Waters SQD2, single quadrupole UPLC-MS

[0156] Method 10: Acquity UPLC BEH C18 column, 100 x 2.1 mm, 1.7 μM, maintained at 40 °C. Mobile phase: ACN (0.03% NH3) in water (0.03% NH3), 5% to 95% within 5.6 min; Flow rate: 0.4 ml / min; Wavelength: 100-800 nm DAD. Acquity UPLC with PDA detector and ZQ mass spectrometer.

[0157] Method 11: Agilent Zorbax column 4.6 x 50 mm, 3.5 μm, maintained at 40°C. Mobile phase: ACN (0.1% HCOOH) in water (0.1% HCOOH), 5% to 95% within 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.

[0158] Method 12: Acquity BEH UPLC column, 2.1 x 50 mm, 1.7 μm, maintained at 40 °C. Mobile phase: ACN (0.03% NH3) in water (0.03% NH3), 8% to 97% within 1.5 min; Flow rate: 0.8 ml / min; Wavelength: 210-400 nm DAD. Acquity H-Class UPLC with PDA detector and QDa.

[0159] Method 13: Waters Sunfire C18 column, 4.6 x 50 mm, 3.5 μm, maintained at 40 °C. Mobile phase ACN in water + 10 mM ammonium bicarbonate, 5-95% within 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.

[0160] When the preparation of starting materials is not described, they are either commercially available, known from the literature or readily obtainable by one skilled in the art using standard procedures. All solvents were purchased from commercial suppliers and used without further purification.

[0161] Preparative HPLC was performed using reversed-phase (C18) preparative HPLC under both basic (ACN+0.1% NH3, H2O+0.1% NH3) and acidic (ACN+0.1% HCOOH, H2O+0.1% HCOOH) conditions, in the latter case the residue was triturated with NaHCO3 (15% aq.) unless otherwise stated, and the precipitate was then filtered through a Schott funnel, rinsed with water, transferred to a vial, and dried under high vacuum overnight at RT or utilizing SCX(NH) to give the free base of the product. Thin layer chromatography was performed on Merck silica gel 60 F254 TLC plates. Preparative thin layer chromatography (pTLC) was performed on Uniplate 1000 micron or 500 micron silica gel plates. Flash chromatography was performed.

[0162] General synthetic procedure General Procedure A To a mixture of the requisite carboxylic acid (1.00 equiv.) and HATU (1.20-2.00 equiv.) in DMF (0.1M concentration) was added N,N-diisopropylethylamine (3.00-8.00 equiv.). The reaction mixture was stirred at RT for 15 min, then the requisite amine (1.00 equiv.) was added. The reaction mixture was stirred at RT until LCMS showed consumption of starting material, then concentrated.

[0163] General Procedure B The requisite carboxylic acid (1.00 equiv.) was suspended in thionyl chloride (30 equiv.) and the reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was suspended in toluene and reconcentrated to give the intermediate acyl chloride. To a solution of the requisite aniline (1.00 equiv.) and TEA (3.00 equiv.) in DCM (0.1 M concentration) was added the acyl chloride. The reaction mixture was stirred at RT until LCMS showed consumption of starting material and then concentrated under reduced pressure.

[0164] General procedure C To a solution of the required amine (1.00 equiv.) and the required aldehyde (1.00 equiv.) in MeOH (0.03M concentration) was added titanium(IV) isopropoxide (3.00 equiv.) and refluxed for 2 h. The reaction was cooled to RT, NaBH3CN (2.50 equiv.) was added and stirring was continued at RT overnight. The reaction was quenched with water, filtered through Celite and concentrated under reduced pressure.

[0165] General Procedure D To a solution of the required aldehyde (1.00 equiv.) in DCM (0.1M concentration) was added the required amine (1.10 equiv.), titanium(IV) isopropoxide (2.00 equiv.) and AcOH (3.00 equiv.). The reaction mixture was stirred at room temperature for 1 h. STAB (2.00 equiv.) was added and the reaction mixture was stirred at room temperature until LCMS showed consumption of starting material. The residue was loaded onto an Isolute SCX-II cartridge, washed with MeOH and then eluted with 2M NH3 / MeOH. The eluent was concentrated under reduced pressure.

[0166] General Procedure E STAB (2.00 equiv.) was added to a mixture of aldehyde (1.25 equiv.), amine (1.00 equiv.), AcOH (0.01 equiv.) and MgSO4 (4.00 equiv.) in DCM (15.00 mL) and the mixture was stirred at room temperature until LCMS showed consumption of starting material. The mixture was diluted with saturated NaHCO 3(水性) The mixture was partitioned between ethyl acetate and DCM and then re-extracted with DCM. The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure.

[0167] General Procedure F To a mixture of the required aldehyde (1.00 equiv.) and the required amine (1.00 equiv.) in MeOH (0.075M) was added AcOH (10 equiv.) and the reaction mixture was stirred at 65° C. for 90 min. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in DCM (0.025M) and sodium STAB (3.50 equiv.) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with DCM and diluted with KHSO 4(水性)After stirring for 15 min, the mixture was basified with saturated aqueous Na2CO3 and the layers were separated. The aqueous layer was extracted with DCM and the combined organic extracts were passed through a hydrophobic frit and concentrated under reduced pressure.

[0168] General Procedure G To a solution of the required acid (1.00 equiv.), the required amine (1.00-1.30 equiv.), and 1-methylimidazole (3.50 equiv.) in ACN (0.2 M concentration) was added TCFH (1.20-1.50 equiv.). The reaction mixture was stirred at room temperature until LCMS showed consumption of starting material and was diluted with saturated NaHCO. 3(水性) and EtOAc. The phases were separated, the aqueous phase extracted 2×EtOAc and the combined organic phases passed through a hydrophobic frit and concentrated under reduced pressure.

[0169] General Procedure H To a mixture of the required aldehyde (1.00 equiv.) and the required amine (1.50 equiv.) in DMF (0.075M concentration) was added AcOH (2.00 equiv.) and MgSO4 (2.00 equiv.). The reaction mixture was stirred at room temperature for 1 h followed by the addition of STAB (2.00 equiv.). The reaction mixture was heated at 60° C. overnight. The reaction was partitioned between DCM and aqueous NaHCO3. The combined organic phase was filtered through a hydrophobic frit and the solvent was concentrated under reduced pressure.

[0170] Intermediate 1: Preparation of 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carbaldehyde [ka] Step 1: 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carbaldehyde 2-Chloropyrimidine-5-carbaldehyde (50 mg, 0.351 mmol) was dissolved in THF (3.5 mL) and then 1-methyl-1H-pyrazol-4-amine (41 mg, 0.421 mmol) was added. The reaction mixture was stirred overnight at RT. The mixture was quenched by adding DCM and brine. The phases were separated and the aqueous layer was washed with DCM (x2). All combined organic phases were dried over Na2SO4, filtered and concentrated. The crude material was purified by FCC eluting with hexane / EtOAc 1:1 to give the title product (35 mg, 39%). 1 H NMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.80 (s, 1H), 8.92 - 8.79 (m, 2H), 7.99 (d, J = 0.8 Hz, 1H), 7.56 (d, J = 0.8 Hz, 1H), 3.83 (s, 3H)

[0171] Intermediate 20: Preparation of 2-(oxetan-3-ylamino)pyrimidine-5-carbaldehyde [ka] Step 1: 2-(oxetan-3-ylamino)pyrimidine-5-carbaldehyde To a solution of 2-chloropyrimidine-5-carbaldehyde (50 mg, 0.351 mmol, 1.00 equiv) in DMSO (1.5 mL) was added TEA (0.049 mL, 0.351 mmol, 1.00 equiv) and 3-aminooxetane (0.027 mL, 0.386 mmol, 1.10 equiv) and the solution was stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with DCM and washed with water and brine. The organic layer was dried (MgSO4) and concentrated to give the title compound (62 mg, 100%). LC-MS (ESI): m / z (M+1) = 180.2; t R = 1.00 minutes Method 11

[0172] Intermediate 21: Preparation of 2-((2-methoxyethyl)amino)pyrimidine-5-carbaldehyde [ka] Step 1: 2-Chloro-5-(diethoxymethyl)pyrimidine (Intermediate 22) [ka] To a suspension of 2-chloropyrimidine-5-carbaldehyde (3000 mg, 21.0 mmol, 1.00 equiv) and p-toluenesulfonic acid monohydrate (400 mg, 2.10 mmol, 0.10 equiv) in EtOH (60 mL) was added triethyl orthoformate (11 mL, 63.1 mmol, 3.00 equiv) and the mixture was heated to 80 °C and stirred for 3 h. The mixture was cooled to 0 °C, 10 mL of saturated aqueous NaHCO3 was added, and EtOH was evaporated. The resulting suspension was extracted with EtOAc, and the organic layers were combined, dried (MgSO4), and concentrated. The residue was purified by FCC on silica gel (120 g, 0-20% EtOAc in cyclohexane) to give the title compound (3760 mg, 17.4 mmol, 82%). 1 H NMR (400 MHz, DMSO-d6) d 8.77 (s, 2H), 5.70 (s, 1H), 3.65 - 3.56 (m, 4H), 1.19 (t, J = 7.1 Hz, 6H)

[0173] Step 2: 5-(diethoxymethyl)-N-(2-methoxyethyl)pyrimidin-2-amine (Intermediate 23) [ka] To a solution of intermediate 22 (200 mg, 0.923 mmol, 1.00 equiv) and 2-methoxyethylamine (80 μL, 0.923 mmol, 1.00 equiv) in DMF (3.0 mL), K2CO3 (319 mg, 2.31 mmol, 2.50 equiv) was added and the mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with EtOAc, washed with water, 1:1 water / brine and brine, dried over MgSO4 and concentrated. The residue was purified on silica FCC (12 g, 0-80% EtOAc in cyclohexane) to give the title compound (103 mg, 44%). 1 H NMR (400 MHz, DMSO-d6) d 8.25 (s, 2H), 7.23 (dd, J = 5.5, 5.5 Hz, 1H), 5.42 (s, 1H), 3.57 - 3.44 (m, 8H), 3.26 (s, 3H), 1.16 (t, J = 7.0Hz, 6H)

[0174] Step 3: 2-((2-methoxyethyl)amino)pyrimidine-5-carbaldehyde (Intermediate 21) To a solution of intermediate 23 (101 mg, 0.396 mmol, 1.00 equiv) in THF (1.0 mL) was added 1M HCl solution (21 mL, 20.6 mmol, 52.0 equiv) and the mixture was stirred at RT for 5 h and then at 50° C. overnight. The mixture was cooled in an ice bath and basified to about pH 13 with 2M aqueous NaOH. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (MgSO4) and concentrated to give the title compound (60 mg, 84%). 1 H NMR (400 MHz, DMSO-d6) d 9.74 (s, 1H), 8.77 (d, J = 2.9 Hz, 1H), 8.71 (d, J = 2.9 Hz, 1H), 8.36 (t, J = 5.3 Hz, 1H), 3.57 - 3.47 (m, 4H), 3.27 (s, 3H)

[0175] Intermediate 24: Preparation of 2-(2-hydroxyethylamino)pyrimidine-5-carbaldehyde [ka] Step 1: 2-[[5-(diethoxymethyl)pyrimidin-2-yl]amino]ethanol (Intermediate 25) [ka] To a solution of 2-chloro-5-(diethoxymethyl)pyrimidine (200 mg, 0.923 mmol, 1.00 equiv) and ethanolamine (0.056 mL, 0.923 mmol, 1.00 equiv) in DMF (3.00 mL) was added K2CO3 (319 mg, 2.31 mmol, 2.50 equiv) and the mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with EtOAc, washed with water, 1:1 water / brine, brine, dried over MgSO4, filtered and concentrated. The residue was purified on silica FCC (12 g, 0-100% EtOAc in c-Hex, 15 CV) to give the title compound (63 mg, 28%). 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 2H), 7.14 (t, J = 5.6 Hz, 1H), 5.42 (s, 1H), 4.67 (t, J = 5.6 Hz, 1H), 3.59 - 3.45 (m, 6H), 3.38 - 3.34 (m, 2H), 1.16 (t, J = 7.0 Hz, 6H)

[0176] Step 2: 2-(2-hydroxyethylamino)pyrimidine-5-carbaldehyde (Intermediate 24) To a solution of intermediate 25 (61 mg, 0.253 mmol, 1.00 equiv) in THF (1.00 mL) was added 1M HCl in HO (13 mL, 13.1 mmol, 52.0 equiv) and the mixture was stirred at RT for 5 h and then at 50° C. overnight. The mixture was cooled in an ice bath and basified to about pH 13 with 2M aqueous NaOH. The aqueous layer was extracted with EtOAc. Most of the desired material remained in the aqueous layer. It was concentrated and the solid was triturated with MeOH. The dissolved material was combined with the organic extract and concentrated to give the title compound (42 mg). The yield was assumed quantitative and was used in the next step without further purification. LC-MS (ESI): m / z (M+1) = 168.2; t R = 0.88 minutes Method 11

[0177] Intermediate 26: Preparation of 2-amino-4-methylpyrimidine-5-carbaldehyde [ka] Step 1: (2-Amino-4-methylpyrimidin-5-yl)methanol (Intermediate 27) [ka] To a suspension of 2-amino-4-methyl-pyrimidine-5-carboxylic acid (250 mg, 1.63 mmol, 1.00 equiv) in THF (12 mL) was added isobutyl chloroformate (0.25 mL, 1.96 mmol, 1.20 equiv) followed by 4-methylmorpholine (0.22 mL, 1.96 mmol, 1.20 equiv) at 0° C. After stirring for 2 h, the precipitate was removed by filtration. The filtrate was added to a solution of NaBH4 (93 mg, 2.45 mmol, 1.50 equiv) in water (0.60 mL) at 0° C. The reaction was allowed to warm to rt and stirred for 3 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was used directly in the next step.

[0178] Step 2: 2-Amino-4-methylpyrimidine-5-carbaldehyde (Intermediate 26) To a solution of intermediate 27 (100%, 148 mg, 1.06 mmol, 1.00 equiv) in THF (6.00 mL) was added manganese(IV) oxide (462 mg, 5.32 mmol, 5.00 equiv) and the mixture was stirred at rt overnight. The mixture was diluted with EtOAc, filtered through a pad of Celite, and concentrated. The crude product was used directly in the next step.

[0179] Intermediate 28: Preparation of (R)-1-(3-amino-5-(trifluoromethyl)benzyl)-N,N-dimethylpyrrolidin-3-amine [ka] Step 1: (R)-N,N-Dimethyl-1-(3-nitro-5-(trifluoromethyl)benzyl)pyrrolidin-3-amine (Intermediate 29) [ka] To a solution of 3-nitro-5-(trifluoromethyl)benzaldehyde (750 mg, 3.42 mmol) and (R)-(+)-3-(dimethylamino)pyrrolidine (478 μL, 3.77 mmol) in DCM (23.00 mL) at room temperature was added titanium(IV) isopropoxide (2.0 mL, 6.85 mmol) and AcOH (588 μL, 10.3 mmol). The reaction mixture was stirred at room temperature for 1 h. STAB (1.45 g, 6.85 mmol) was then added and the reaction mixture was stirred at room temperature for a further 2.5 h. The reaction mixture was quenched by the addition of water and the layers were separated. The aqueous phase was adjusted to pH 9 by the addition of NaOH and DCM was added. The combined phases were filtered through a pad of Celite and then separated. The aqueous phase was re-extracted with DCM and the combined organic phases were filtered through a hydrophobic frit and concentrated under reduced pressure. Purification by silica FCC (24 g cartridge, 0-5% 2M NH3 / MeOH in DCM) afforded the title compound (786 mg, 72%). 1 H NMR (300 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.38 (s, 1H), 8.13 (s, 1H), {3.86 (d, J = 14.2 Hz, 1H), 3.73 (d, J = 14.2 Hz, 1H), AB system}, 2.79 - 2.53 (m, 3H), 2.39 - 2.30 (m, 1H), 2.08 (s, 6H), 1.94 - 1.81 (m, 1H), 1.69 - 1.57 (m, 1H). 1H not observed, presumed to overlap with DMSO signal.

[0180] Step 2: (R)-1-(3-amino-5-(trifluoromethyl)benzyl)-N,N-dimethylpyrrolidin-3-amine (Intermediate 28) To palladium (10 wt% on carbon, 79 mg, 0.739 mmol) was added a solution of intermediate 29 (786 mg, 2.48 mmol) in IMS (24.5 mL). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2 h. The reaction mixture was filtered through Celite and the filter bed was washed with DCM. The filtrate was concentrated under reduced pressure to give the title compound (710 mg, 99%). 1H NMR (400 MHz, CDCl3) δ 6.94 (s, 1H), 6.84 (s, 1H), 6.77 (s, 1H), 3.81 (s, 2H), 3.58 (d, J = 13.2 Hz, 1H), 3.50 (d, J = 13.3 Hz, 1H), 2.83 - 2.69 (m, 3H), 2.53 - 2.45 (m, 1H), 2.31 (dd, J = 6.8, 8.3 Hz, 1H), 2.20 (s, 6H), 2.05 - 1.95 (m, 1H), 1.77 - 1.68 (m, 1H)

[0181] The intermediates listed in the table below were prepared by reductive amination as described for Intermediate 28, steps 1-2, using the corresponding commercially available amine and / or the corresponding arylaldehyde in step 1. [Table 16]

[0182] Intermediate 32: Preparation of 4-(cyclopropoxy)pyrimidine-5-carbaldehyde [ka] Step 1: Ethyl 4-(cyclopropoxy)pyrimidine-5-carboxylate (Intermediate 33) [ka] The cyclopropanol solution (0.9 M in THF, 2.7 mL, 2.41 mmol, 1.50 equiv) was added to a solution of NaH (60% dispersion in mineral oil, 129 mg, 3.22 mmol, 2.00 equiv) in THF (2.0 mL) and the reaction mixture was stirred on ice-water for 10 min, after which a solution of ethyl 4-chloropyrimidine-5-carboxylate (300 mg, 1.61 mmol, 1.00 equiv) in THF (0.7 mL) was added. The reaction mixture was stirred for 10 min, warmed to room temperature, and stirred for 1.5 h. The reaction mixture was cooled with ice / water and saturated NH4Cl (水性)The aqueous phase was extracted 3×EtOAc and the combined organic phases passed through a hydrophobic frit and concentrated under reduced pressure to give the title compound (326 mg, 97%). 1 H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.91 (s, 1H), 4.52 - 4.47 (m, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 0.88 (d, J = 4.6Hz, 4H)

[0183] Step 2: [4-(cyclopropoxy)pyrimidin-5-yl]methanol (Intermediate 34) [ka] A solution of intermediate 33 (251 mg, 1.21 mmol, 1.00 equiv) in anhydrous THF (10.9 mL) was purged with argon for 10 min, cooled in a dry ice / acetone bath, and then 2M LiAlH4 (2M in THF, 0.54 mL, 1.08 mmol, 0.900 equiv) was added dropwise. The reaction mixture was stirred for 10 min until TLC showed consumption of SM, then diluted with anhydrous Et2O (10 mL). The flask was transferred to an ice-water bath and diluted with water (41 μL), 15% NaOH, and 10% ethyl acetate. (水性) (41 μL) and water (123 μL) were added and the reaction mixture was stirred for 15 min while warming to room temperature. MgSO4 was added and the reaction mixture was stirred for 15 min and filtered. The filtrate was concentrated under reduced pressure. The resulting solid was purified by FCC on 15 μm silica gel (25 g cartridge, 0-7% 2M NH3 / MeOH in DCM) to give the title compound (107 mg, 53%). LC-MS (ESI): m / z (M+1) = 167; t R = 0.72 minutes Method 12

[0184] Step 3: 4-(Cyclopropoxy)pyrimidine-5-carbaldehyde (Intermediate 32) To a solution of intermediate 34 (130 mg, 0.782 mmol, 1.00 equiv) in anhydrous DCM (4 mL) was added Dess-Martin periodinane (431 mg, 1.02 mmol, 1.30 equiv) while stirring on an ice / water bath. The reaction mixture was warmed to room temperature, stirred for 2 h, and diluted with DCM. The organic phase was washed with 10 wt% NaSO. 5(水性) , followed by saturated NaHCO 3(水性) Washed with NaHCO 3(水性) The solution was extracted with DCM and the combined organic phases passed through a hydrophobic frit and partially concentrated in vacuo to give the title compound (194 mg, >100%). 1 H NMR (400 MHz, CDCl) δ 10.27 (s, 1H), 8.98 (s, 1H), 8.93 (s, 1H), 4.59 - 4.54 (m, 1H), 0.94 - 0.85 (m, 4H)

[0185] Preparation of Intermediate 35: 2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-amine [ka] Step 1: 4-Amino-N-methoxy-N-methyl-6-(trifluoromethyl)picolinamide (Intermediate 36) [ka] Prepared from 4-amino-6-(trifluoromethyl)picolinic acid (445 mg, 2.16 mmol) and N,O-dimethylhydroxylamine hydrochloride (232 mg, 2.37 mmol) according to general procedure A. Purification by silica FCC (80 g cartridge, 0-50% EtOAc in cyclohexane (+0.1% NEt3)) afforded the title compound (369 mg, 68%). 1 H NMR (400 MHz, DMSO-d6) δ 6.96 (d, J = 2.1 Hz, 1H), 6.84 - 6.78 (m, 3H), 3.67 (s, 3H), 3.24 (s, 3H)

[0186] Step 2: 4-Amino-6-(trifluoromethyl)picolinaldehyde (Intermediate 37) [ka] To a stirred solution of intermediate 36 (308 mg, 1.24 mmol) in THF (4.82 mL) cooled in an ice / water bath was added LiAlH4 (2 M in THF, 0.62 mL, 1.24 mmol) dropwise while maintaining the internal temperature at 6 °C. The reaction mixture was stirred for 1 h and diluted with anhydrous Et2O (5 mL). Water (47 μL), 15% NaOH (水性) (47 μL) and water (141 μL) were added and the reaction mixture was allowed to warm to room temperature and stirred for 15 min. Anhydrous MgSO4 was added and the reaction mixture was stirred for 15 min, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (252 mg, >100%), which was used in the next step without purification. LC-MS (ESI): m / z (M+1) = 191; t R = 0.95 minutes Method 12

[0187] Step 3: 2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-amine (Intermediate 35) Prepared from intermediate 37 (126 mg, 0.663 mmol) and dimethylamine (2M solution in THF) (0.33 mL, 0.663 mmol) following general procedure D. Purification by silica FCC (12 g cartridge, 0-8% 2M NH3 / MeOH in DCM) afforded the title compound (65 mg, 44%). 1 H NMR (400 MHz, DMSO-d6) δ 6.78 - 6.77 (m, 2H), 6.49 (s, 2H), 3.34 (s, 2H), 2.18 (s, 6H)

[0188] Intermediate 38: Preparation of 5-(trifluoromethoxy)pyridin-3-amine (hydrochloride) Step 1: tert-Butyl N-[5-(trifluoromethoxy)-3-pyridyl]carbamate (Intermediate 39) [ka] A mixture of tert-butyl carbamate (102 mg, 0.868 mmol, 1.20 equiv), Xantphos (63 mg, 0.108 mmol, 0.150 equiv), trisdibenzylideneacetone)dipalladium(0)-chloroform adduct (37 mg, 0.0362 mmol, 0.0500 equiv) and Cs2CO3 (283 mg, 0.868 mmol, 1.20 equiv) 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 equiv). The reaction was stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature and filtered through a pad of Celite, which was then washed with dioxane, and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica FCC (0-100%, EtOAc in cyclohexane) and then dried under vacuum overnight to give the title compound (115 mg, 0.413 mmol, 57%). 1 H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 2.3 Hz, 1H), 8.23 ​​- 8.21 (m, 1H), 8.07 (s, 1H), 7.04 (s, 1H), 1.54 (s, 9H)

[0189] Step 2: 5-(Trifluoromethoxy)pyridin-3-amine (hydrochloride salt) (Intermediate 38) To a solution of intermediate 39 (115 mg, 0.413 mmol, 1.00 equiv) in 1,4-dioxane (3 mL) was added 4N HCl in 1,4-dioxane (3.0 mL, 0.413 mmol, 1.00 equiv). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with Et2O (20 mL) and filtered. The solid was washed with Et2O and dried under reduced pressure to give the title compound (60 mg, 0.280 mmol, 68%). LC-MS (ESI): m / z (M+1) = 179; t R = 0.88 minutes Method 13

[0190] Intermediate 40: Preparation of N-(5-formylpyrimidin-2-yl)acetamide [ka] Step 1: N-(5-formylpyrimidin-2-yl)acetamide (Intermediate 40) 2-Aminopyrimidine-5-carboxaldehyde (100 mg, 0.812 mmol, 1.00 equiv) was dissolved in acetic anhydride (2.0 mL, 22.8 mmol, 28.1 equiv) and the reaction mixture was heated at 140° C. for 90 min. The reaction mixture was cooled to room temperature, a solid precipitated, the reaction washed with 2:1 cyclohexane / Et2O, filtered, the solid washed with cyclohexane and dried under reduced pressure to give the title compound (84 mg, 0.509 mmol, 62.6% yield). 1 H NMR (400 MHz, CDCl3) d 10.03 (s, 1H), 9.04 (s, 2H), 8.76 (s, 1H), 2.58 (s, 3H)

[0191] Example 1: Preparation of N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyridin-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-Butyl 3-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 2) [ka] 3-((4-Methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)aniline (1050 mg, 3.84 mmol) was dissolved in dry THF (volume: 50 ml, ratio: 2.500) under nitrogen, the mixture was stirred at -78°C for 15 min, then 2.5M n-BuLi in hexane (1.342 ml, 3.36 mmol) was added dropwise over 5 min and the reaction was stirred for 1 h at -78°C. A solution of 6-(tert-butyl)3-ethyl 4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (950 mg, 3.05 mmol) in THF (volume: 20 ml, ratio: 1.000) was added dropwise over 10 min, the temperature was raised to RT and the reaction was stirred for 1 h. The reaction was quenched by the addition of 10 mL of water and the solvent was removed under reduced pressure. The solid was dissolved in DCM (50 mL) and the organic layer was washed with H2O (2 x 20 mL) and brine (1 x 20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to dryness. The crude was purified by reverse phase FCC to give the title compound (1.41 g, 2.62 mmol, 86% yield). 1 H NMR (400 MHz, acetone-d6) d ppm 9.58 (s, 1H) 8.19 (s, 1H) 8.09 (s, 1H) 7.94 (s, 1H) 7.38 (s, 1H) 4.65 (s, 2H) 3.67 (t, J = 5.81 Hz, 2H) 3.57 (s, 2H) 2.91 - 3.05 (m, 2H) 2.32 - 2.56 (m, 8H) 2.21 (s, 3H) 1.47 (s, 9H)

[0192] Step 2: N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide trihydrochloride (Intermediate 3) [ka] Intermediate 2 (1.41 g, 2.62 mmol) was dissolved in concentrated HCl (3.0 ml, 99 mmol) and the solution was stirred at RT for 10 min. 50 mL of ethanol was added to the reaction and the solvent was evaporated under reduced pressure to give the title compound (1.31 g, 2.391 mmol, 91% yield).

[0193] Step 3: 6-(4-cyanobenzyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 1) Intermediate 3 (30 mg, 0.055 mmol), 3-(bromomethyl)pyridine hydrobromide (13.85 mg, 0.055 mmol) were dissolved in DMF (volume: 3 ml), then DIPEA (0.057 ml, 0.329 mmol) was added in one portion. The solution was stirred at RT. The crude was purified by preparative HPLC (column XSelect (登録商標) The fractions were purified on a CSH™ Prep C18 5 μm OBD™ 19 × 100 mm column (5–95% ACN / H2O (0.1% HCOOH), 20 ml / min, RT). Relevant fractions were combined and isolated. (登録商標) Loaded onto an SCX-2 cartridge, washed with MeOH, and the product eluted with 7N methanolic ammonia. The residue was concentrated under reduced pressure to give the title compound (17.6 mg, 0.033 mmol, 60.7% yield). 1 H NMR (400 MHz, ACN-d3) δ ppm 8.70 (br s, 1H), 8.56 (s, 1H), 8.49 (d, J = 4.60 Hz, 1H), 7.99 (s, 1H), 7.84 (d, J = 7.23 Hz, 2H), 7.76 (br d, J = 7.67 Hz, 1H), 7.30 - 7.36 (m, 2H), 3.73 (s, 2H), 3.67 (s, 2H), 3.54 (s, 2H), 2.94 (br t, J = 5.59 Hz, 2H), 2.78 (t, J = 5.70 Hz, 2H), 2.27 - 2.53 (br s, 8H), 2.20 (s, 3H) LC-MS (ESI): m / z (M+1) = 530.4; t R = 0.53 Method 1

[0194] The following compounds were prepared by nucleophilic substitution as described in Example 1, steps 1-3, using the corresponding commercially available benzyl bromide in step 3. [Table 17]

[0195] Example 3: Preparation of N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-Butyl 3-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 4) [ka] To a solution of 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (1.5 g, 5.29 mmol) and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (1.277 g, 5.29 mmol) in DCM (26.5 ml) was added DIPEA (5.55 ml, 31.8 mmol) followed by T3P (6.30 ml, 10.59 mmol) and the reaction mixture was stirred at RT over the weekend. The reaction mixture was diluted with DCM, water was added and the mixture was stirred for 10 min. The aqueous phase was washed with DCM (3×50 mL) and then the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by FCC (DCM to 10% MeOH in DCM) to give the title compound (362 mg, 0.715 mmol, 13.50% yield). 1 H NMR (300 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.19 (q, J = 1.9, 1.4 Hz, 3H), 8.07 (d, J = 1.9 Hz, 1H), 7.74 - 7.67 (m, 1H), 7.46 (t, J = 1.3 Hz, 1H), 4.60 (s, 2H), 3.58 (t, J = 5.8 Hz, 2H), 2.87 (t, J = 5.8 Hz, 2H), 2.18 (d, J = 1.0 Hz, 3H), 1.43 (s, 9H)

[0196] Step 2: N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (Intermediate 5) [ka] To a solution of intermediate 4 (0.362 g, 0.715 mmol) in DCM (3.57 ml) was added 4N HCl in dioxane (0.893 ml, 3.57 mmol) and the reaction mixture was stirred at RT overnight. Et2O was added to the reaction mixture until no more precipitate was observed, and the precipitate was then filtered to give the title compound (0.33 g, 0.745 mmol, 104% yield). 1 H NMR (300 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.61 (s, 1H), 9.55 (s, 1H), 8.60 (s, 1H), 8.57 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 7.91 (s, 1H), 4.39 (s, 2H), 3.37 (m, 2H), 3.13 (m, 2H), 2.36 (d, J = 1.1 Hz, 3H)

[0197] Step 3: N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 3) Intermediate 5 (100 mg, 0.246 mmol) and pyrimidine-5-carbaldehyde (27.9 mg, 0.258 mmol) were suspended in AcOH (1230 μl) under argon atmosphere and treated with STAB (104 mg, 0.492 mmol). The reaction was stirred for 16 h. The reaction mixture was diluted with MeOH and concentrated under reduced pressure. The dried reaction mixture was redissolved in DCM and 1M NaOH, followed by washing with water and brine. The combined organic layers were concentrated and purified by preparative HPLC to give the title compound (22 mg, 0.044 mmol, 17.94% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 9.13 (s, 1H), 8.80 (s, 2H), 8.20 (dd, J = 4.6, 2.6 Hz, 3H), 8.08 (d, J = 1.9 Hz, 1H), 7.70 (s, 1H), 7.47 (s, 1H), 3.77 (s, 2H), 3.69 (s, 2H), 2.90 (d, J = 6.0 Hz, 2H), 2.76 (t, J = 5.8 Hz, 2H), 2.18 (d, J = 1.0 Hz, 3H) LC-MS (ESI): m / z (M+1) = 499.0; t R = 2.75 Method 3

[0198] Example 4: Preparation of N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Ethyl 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate hydrochloride (Intermediate 6) [ka] To a solution of 6-(tert-butyl) 3-ethyl 4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (4.88 g, 15.67 mmol) in diethyl ether (volume: 78 ml) was added 4N HCl in dioxane (19.59 ml, 78 mmol) and the reaction mixture was stirred at RT overnight. The solid was isolated and dried under reduced pressure to give the title compound (3.58 g, 14.45 mmol, 92% yield).

[0199] Step 2: Ethyl 6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 7) [ka] Intermediate 6 (3.0 g, 12.11 mmol) and pyrimidine-5-carbaldehyde (1.309 g, 12.11 mmol) were placed in a flask under argon. Anhydrous DCM (121 ml) was added followed by AcOH (0.693 ml, 12.11 mmol). The reaction mixture was stirred for 30 min at RT. STAB (5.13 g, 24.22 mmol) was then added and the reaction mixture was stirred at RT over the weekend. The reaction mixture was then diluted with DCM and washed with a 1:1 mixture of K2CO3 (sat.) and water. The aqueous phase was extracted twice with DCM and the organic layers were combined, dried over MgSO4 and evaporated under reduced pressure. The crude was purified by FCC using DCM / MeOH (DCM to 10% MeOH in DCM) to give the title compound (1.97 g, 6.49 mmol, 54% yield). 1 H NMR (300 MHz, CDCl3) δ 9.16 (s, 1H), 8.76 (s, 2H), 7.95 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.74 (s, 2H), 3.70 (s, 2H), 3.07 - 2.97 (m, 2H), 2.84 (t, J = 5.9 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H)

[0200] Step 3: Sodium 6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 8) [ka] To a solution of intermediate 7 (1.97 g, 6.49 mmol) in MeOH (64.9 ml) was added 1N NaOH (6.49 ml, 6.49 mmol) and the reaction mixture was stirred at RT over the weekend. The solvent was evaporated under reduced pressure to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.77 (s, 2H), 7.45 (s, 1H), 3.70 (s, 2H), 3.58 (s, 2H), 2.90 (t, J = 5.8 Hz, 2H), 2.66 (t, J = 5.8Hz, 2H)

[0201] Step 4: N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 4) Intermediate 8 (0.1 g, 0.336 mmol) was dissolved in DMF (0.841 ml) and DCM (2.52 ml) then DIPEA (0.352 ml, 2.018 mmol) and HATU (0.256 g, 0.673 mmol) were added. The RM was stirred for 15 min then 3-fluoro-5-(trifluoromethyl)aniline (0.044 ml, 0.336 mmol) was added. The reaction was stirred at 60 °C over the weekend. DCM and brine were then added to the reaction mixture and stirred for 20 min. The phases were then separated and the organic layer was washed with water, separated and concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM:MeO, 1:0 to 0:1). Repurification by preparative TLC (DCM:MeOH, 95:5) gave the title compound (20 mg, 0.046 mmol, 14% yield). 1 H NMR (300 MHz, DMSO-d6) δ 10.52 (s, 1H), 9.12 (s, 1H), 8.79 (s, 2H), 8.13 (s, 1H), 7.99 - 7.90 (m, 2H), 7.36 (d, J = 8.3 Hz, 1H), 3.75 (s, 2H), 3.67 (s, 2H), 2.88 (t, J = 5.6 Hz, 2H), 2.75 (t, J = 5.7 Hz, 2H) LC-MS (ESI): m / z (M+1) = 437.0; t R = 1.92 minutes Method 2

[0202] The following compounds were prepared as described in Example 4, steps 1-4, applying the corresponding commercially available arylamine in step 4. Such procedures may include minor variations. In some cases, when the modifications concern coupling agents (e.g. HATU instead of T3P) or chromatographic purification conditions (e.g. preparative HPLC or flash chromatography), such variations are noted in the table. In Example 8, the starting material in step 3 was converted to the corresponding carboxylic acid by deblocking the sodium salt as described in Example 9, step 1. [Table 18]

[0203] Example 9: Preparation of N-(3-(1,1-difluoroethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: 6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (Intermediate 9) [ka] To a solution of intermediate 7 (880 mg, 2.90 mmol, 1.00 equiv) in MeOH (20 mL), 5M NaOH (水性) (1.50 mL) was added. The reaction mixture was stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with 1M HCl (水性) The mixture was neutralized by the addition of water and concentrated under reduced pressure. The residue was washed with water and filtered to give the title compound (478 mg, 57%). 1 H NMR (400 MHz, DMSO) δ 9.16 (s, 1H), 8.83 (s, 2H), 8.12 (s, 1H), 3.79 (s, 2H), 3.70 (s, 2H), 2.91 (t, J = 5.7 Hz, 2H), 2.78 (t, J = 5.7 Hz, 2H)

[0204] Step 2: N-(3-(1,1-difluoroethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 9) Prepared from 3-(1,1-difluoroethyl)aniline (31 mg, 0.197 mmol) and intermediate 9 (54 mg 0.197 mmol) according to general procedure B. Purification by reverse phase preparative HPLC (Sunfire C18 3×50 mm, 3 μm 5-95% ACN / HO (0.1% HCOOH), 1.7 ml / min, RT) afforded the title compound (17.5 mg, 22.2%). 1 H NMR (400 MHz, DMSO) d 10.21 (s, 1H), 9.14 (s, 1H), 8.80 (s, 2H), 8.10 (s, 1H), 7.98 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 7.9, 7.9 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 3.77 (s, 2H), 3.69 (s, 2H), 2.89 (t J = 5.5 Hz, 2H), 2.76 (t, J = 5.8 Hz, 2H), 1.97 (t, J = 18.8Hz, 3H) LC-MS (ESI): m / z (M+1) = 415; t R = 4.28 minutes Method 9

[0205] The following compounds were prepared by amide coupling as described in Example 9, steps 1-2, using the corresponding commercially available arylamine in step 2. [Table 19] [Table 20]

[0206] Example 15: Preparation of 6-((3-aminopyrazin-2-yl)methyl)-N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Sodium 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 10) [ka] 6-(tert-butyl) 3-ethyl 4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (15 g, 48.2 mmol) was dissolved in MeOH (482 ml), then 1M NaOH (120.5 ml, 120.5 mmol) was added and the RM was stirred at RT until conversion was complete. The RM was dried under reduced pressure to give the title compound. 1 H NMR (300 MHz, DMSO-d6) δ 7.46 (s, 1H), 4.49 (s, 2H), 3.51 (t, J = 5.8 Hz, 2H), 2.89 (t, J = 5.8 Hz, 2H), 1.41 (s, 9H)

[0207] Step 2: tert-Butyl 3-((3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 11) [ka] Intermediate 10 (1 g, 3.28 mmol) and HATU (4.982 g, 13.10 mmol) were weighed into a reaction tube backfilled with argon (x3). DCM (24.56 ml) and DMF (8.19 ml) were added to the reaction mixture followed by DIPEA (9.16 ml, 52.4 mmol). The reaction mixture was stirred for 30 min, 3-(tert-butyl)-1-methyl-1H-pyrazol-5-amine (0.502 g, 3.28 mmol) was added and the reaction was heated to 45° C. and stirred until LC-MS showed consumption of starting material. Further addition of HATU and DIPEA was required to complete the conversion. The reaction mixture was then extracted with DCM / H2O (x3) and the combined organic layers were washed with 1:1 NaCl (sat):H2O solution followed by brine. The combined organic layers were then concentrated under reduced pressure to give the crude material which was purified by flash column chromatography (0-50% EtOAc / Hexanes; product eluted with 50% EtOAc) to give the title compound (1.13 g, 2.70 mmol, 82% yield). 1 H NMR (300 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.14 (s, 1H), 6.08 (s, 1H), 4.59 (s, 2H), 3.59 (m, 5H), 2.82 (d, J = 5.7 Hz, 2H), 1.43 (s, 9H), 1.23 (s, 9H)

[0208] Step 3: N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (Intermediate 12) [ka] Intermediate 11 (1.13 g, 2.70 mmol) was dissolved in DCM (27.0 ml) and cooled to 0° C. HCl in dioxane (3.37 ml, 13.50 mmol) was added dropwise and the reaction was stirred at RT for 16 h. The reaction mixture was concentrated and the residue was triturated with diethyl ether to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.46 (s, 2H), 8.34 (s, 1H), 6.09 (s, 1H), 4.38 (s, 2H), 3.63 (s, 3H), 3.37 (t, J = 6.8 Hz, 2H), 3.07 (t, J = 6.0 Hz, 2H), 1.23 (s, 9H)

[0209] Step 4: 6-((3-aminopyrazin-2-yl)methyl)-N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 15) Intermediate 12 (100 mg, 0.282 mmol) and 3-aminopyrazine-2-carbaldehyde (41.6 mg, 0.338 mmol) were added to a small reaction tube and backfilled with argon (×3). MeOH (1409 μl) was added to the reaction mixture followed by AcOH (48.4 μl, 0.845 mmol), the tube was sealed and stirred at 50° C. for 1 h. The reaction was then cooled to RT and NaBH3CN (80 mg, 1.268 mmol) was added and the reaction was stirred at 50° C. Further addition of aldehyde (2 eq.) and NaBH3CN (1 eq.) was required for complete conversion. The reaction mixture was quenched with saturated NaHCO3, transferred to a separatory funnel and the desired product was extracted with DCM (x3), the combined organic layers were washed once with brine and concentrated under reduced pressure and the crude mixture was purified by preparative HPLC to give the title compound (28 mg, 0.066 mmol, 23.35% yield). 1 H NMR (300 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.10 (s, 1H), 7.89 (d, J = 2.8 Hz, 1H), 7.70 (d, J = 2.8 Hz, 1H), 6.45 (s, 2H), 6.07 (s, 1H), 3.77 (s, 2H), 3.66 (s, 2H), 3.61 (s, 3H), 2.85 (d, J = 5.9 Hz, 2H), 2.74 (d, J = 5.4 Hz, 2H), 1.22 (s, 9H) LC-MS (ESI): m / z (M+1) = 425.8; t R = 3.07 minutes Method 4

[0210] The following compounds were prepared by reductive amination as described in Example 15, steps 1-4, using previously synthesized or commercially available aryl aldehydes in step 4. Such procedures may include minor variations. In some instances, when any modifications pertained to the procedure or reducing agent used (e.g., STAB instead of NaBH3CN) or chromatographic purification conditions, such changes were noted in the table. [Table 21]

[0211] Example 17: Preparation of 6-((4-(2-methoxyacetamido)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-Butyl 3-((3-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 13) [ka] Intermediate 10 (4 g, 13.10 mmol) was dissolved in DMF (32.8 ml) and DCM (98 ml) then DIPEA (4.58 ml, 26.2 mmol) and HATU (9.96 g, 26.2 mmol) were added. The RM was stirred at RT for 15 min and 3-(trifluoromethyl)aniline (1.964 ml, 15.72 mmol) was added. The RM was stirred at 40° C. overnight. The RM was diluted with DCM and water was added. The mixture was stirred for 15 min, the phases were separated and the organic phase was washed with water, citric acid 5% wt solution, twice with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by FCC (DCM to 10% MeOH in DCM) to give the title compound (4.36 g, 10.22 mmol, 78% yield). 1 H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.16 (s, 1H), 8.00 - 7.92 (m, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.47 - 7.38 (m, 1H), 4.59 (s, 2H), 3.58 (t, J = 5.8 Hz, 2H), 2.85 (t, J = 5.8 Hz, 2H), 1.43 (s, 9H)

[0212] Step 2: N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (Intermediate 14) [ka] Intermediate 13 (2.82 g, 6.61 mmol) was dissolved in a minimum amount of DCM (6.01 ml) then EtO (60.1 ml) was added followed by 4N HCl in dioxane (16.53 ml, 66.1 mmol) and the RM was stirred at RT overnight. EtO was added to the RM until no more precipitation was observed, then the solid was filtered and the residual solvent was evaporated under reduced pressure to give the title compound (2.3353 g, 6.44 mmol, 97% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.27 (s, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.95 - 7.86 (m, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.48 - 7.40 (m, 1H), 4.36 (s, 2H), 3.36 (td, J = 6.5, 5.1 Hz, 2H), 3.09 (t, J = 6.1 Hz, 2H)

[0213] Step 3: 6-((4-aminopyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 15) [ka] Intermediate 14 (100 mg, 0.276 mmol) and 4-aminonicotinaldehyde (37.0 mg, 0.303 mmol) were weighed into a reaction tube backfilled with argon (x3). MeOH (1378 μl) was added followed by AcOH (47.3 μl, 0.827 mmol) and the solution was stirred for 1 h at 50 °C. NaBH3CN (78 mg, 1.240 mmol) was added to the reaction mixture and stirred at 50 °C until LCMS showed consumption of starting material. Further addition of aldehyde (1.2 equiv) and NaBH3CN (1 equiv) was required to complete the conversion. The reaction mixture was transferred to a separatory funnel and diluted with DCM. NaHCO3 (sat) was added and the organic layer was separated (x3). The combined organic layers were washed once with brine, concentrated under reduced pressure and the crude material was purified by FCC (0-2% 6.5M NH3 in MeOH and 10% MeOH in DCM) to give the title compound (75 mg, 0.173 mmol, 62.9% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.19 (d, J = 2.1 Hz, 1H), 8.11 (s, 1H), 7.97 (d, J = 8.3 Hz, 3H), 7.58 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 6.54 (d, J = 5.5 Hz, 1H), 6.08 (s, 2H), 3.61 (d, J = 3.3 Hz, 4H), 2.87 (d, J = 5.9 Hz, 2H), 2.71 (t, J = 5.7 Hz, 2H)

[0214] Step 4: 6-((4-(2-methoxyacetamido)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 17) A flask containing intermediate 15 (75 mg, 0.173 mmol) was backfilled with argon (x3). THF (867 μl) was added to dissolve the starting material, followed by TEA (48.3 μl, 0.347 mmol) and the reaction mixture was stirred for 10 min, after which 2-methoxyacetyl chloride (20.70 mg, 0.191 mmol) was added at 0° C. The reaction mixture was stirred for 1 h and after completion by UPLC, the reaction mixture was transferred to a separatory funnel and quenched with water. The desired product was extracted with DCM (x3) and the combined organic layers were washed once with brine (x1) and concentrated. The crude material was purified by preparative HPLC and then triturated with water to give the title compound (22.38 mg, 0.044 mmol, 25.6% yield). 1H NMR (300 MHz, DMSO-d6) δ 11.33 (s, 1H), 10.38 (s, 1H), 8.49 - 8.38 (m, 2H), 8.24 - 8.12 (m, 3H), 7.98 (d, J = 8.2 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 3.96 (s, 2H), 3.86 (s, 2H), 3.71 (s, 2H), 3.11 (s, 3H), 2.94 (s, 2H), 2.78 (d, J = 5.6 Hz, 2H). LC-MS (ESI): m / z (M+1) = 505.1;t R = 2.27 minutes. Method 2

[0215] The following compounds were prepared by reductive amination as described in Example 17, steps 1-4, using previously synthesized or commercially available aryl aldehydes in step 3. Such procedures may involve minor variations. In some instances, when variations pertain to the procedures used or chromatographic purification conditions, such variations are noted in the tables. [Table 22] [Table 23] [Table 24]

[0216] Example 29: Preparation of 6-((5-(4-methyl-3-oxopiperazin-1-yl)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: 6-((5-bromopyridin-3-yl)methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 41) [ka] To a mixture of intermediate 14 (200 mg, 0.613 mmol, 1.00 equiv), MgSO4 (148 mg, 1.23 mmol, 2.00 equiv) and 5-bromo-3-pyridinecarboxaldehyde (114 mg, 0.613 mmol, 1.00 equiv) in DCM (10 mL), STAB (325 mg, 1.53 mmol, 2.50 equiv) was added and the mixture was stirred at room temperature for 21 h. The mixture was slowly added to a saturated aqueous solution of NaHCO3 and extracted with DCM (x3). The combined organic extracts were dried (Na2SO4) and evaporated. The crude compound was purified by silica FCC (12 g cartridge, 0-70% EtOAc in cyclohexane) to give the title compound (128 mg, 0.257 mmol, 42%). 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8.55 (d, J = 1.7 Hz, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 8.04 - 7.95 (m, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.44 - 7.41 (m, 1H), 3.75 (s, 2H), 3.67 - 3.65 (m, 2H), 2.88 (t, J = 5.6 Hz, 2H), 2.74 (t, J = 5.7 Hz, 2H)

[0217] Step 2: 6-((5-(4-methyl-3-oxopiperazin-1-yl)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 29) A mixture of intermediate 41 (50 mg, 0.101 mmol, 1.00 equiv), 1-methylpiperazin-2-one (13 mg, 0.111 mmol, 1.10 equiv) and Cs2CO3 (66 mg, 0.201 mmol, 2.00 equiv) in anhydrous 1,4-dioxane (1.50 mL) was degassed and RuPhos Pd G3 (8.4 mg, 0.0101 mmol, 0.10 equiv) was added. The reaction mixture was stirred at 80 °C under argon for 21 h. The reaction mixture was cooled, filtered through a celite pad and concentrated. Purification by reverse phase HPLC (Sunfire C18 19 × 150 mm, 10 μm 20-80% ACN / H2O (10 mM NH4CO3), 20 ml / min, RT) afforded the title compound (15.8 mg, 29%). 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.23 ​​(d, J = 2.9 Hz, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 8.02 (d, J = 1.5 Hz, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.45 - 7.43 (m, 1H), 7.31 (t, J = 2.1 Hz, 1H), 3.85 (s, 2H), 3.69 (s, 2H), 3.66 (s, 2H), 3.57 (dd, J = 4.3, 6.4 Hz, 2H), 3.46 LC-MS (ESI): m / z (M+1) = 530; t R = 3.06 minutes. Method 9

[0218] The following compounds were prepared by Hartwig-Buchwald CN coupling as described in Example 29, steps 1-2, using commercially available amines in step 2. Such procedures may involve minor variations. [Table 25]

[0219] Example 31: Preparation of N-6-((5-(2-(dimethylamino)acetamido)pyridin-3-yl)methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Preparation of N-6-((5-(2-(dimethylamino)acetamido)pyridin-3-yl)methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 31) A mixture of aluminum trifluoromethanesulfonate (1.9 mg, 4.03 μmol, 0.100 equiv), intermediate 41 (20 mg, 0.0403 mmol, 1.00 equiv), 2-(dimethylamino)acetamide (4.1 mg, 0.0403 mmol, 1.00 equiv), Pd(dba) (2.3 mg, 4.03 μmol, 0.100 equiv), XantPhos (2.3 mg, 4.03 μmol, 0.100 equiv) and CsCO (13 mg, 0.0403 mmol, 1.00 equiv) in degassed (argon) toluene (2.00 mL) was heated at 110° C. for 64 h. The reaction mixture was diluted with DCM (15 mL), dried (NaSO) and evaporated. The crude material was purified by reverse phase preparative HPLC (Luna Phenyl-Hexyl 21.2×150 mm, 10 μm 20-80% MeOH / H2O (0.1% FA), 20 ml / min, RT) to give the title compound (7 mg, 34%). 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 9.99 (s, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.24 (t, J = 1.6 Hz, 1H), 8.21 (t, J = 2.0 Hz, 1H), 8.16 (t, J = 2.0 Hz, 1H), 8.12 (s, 1H), 8.00 - 7.96 (m, 1H), 7.62 - 7.56 (m, 1H), 7.45 - 7.42 (m, 1H), 3.72 (s, 2H), 3.66 (s, 2H), 3.11 (s, 2H), 2.90 (t, J = 5.4 Hz, 2H), 2.75 (t, J = 6.4 Hz, 2H), 2.29 (s, 6H). LC-MS (ESI): m / z (M+1) = 518.3; tR = 2.71 min. Method 9

[0220] Example 32: Preparation of 6-((5-methoxypyridin-3-yl)methyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Preparation of tert-butyl 3-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 42) [ka] Prepared from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (250 mg, 0.882 mmol, 1.00 equiv) and 5-(trifluoromethyl)pyridin-3-amine (157 mg, 0.971 mmol, 1.10 equiv) according to general procedure G. The residue was purified by silica FCC (80 g cartridge, 0-25% EtOAc in cyclohexane + 0.1% NEt3) to give the title compound (265 mg, 70%). 1 H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.12 (d, J = 2.3 Hz, 1H), 8.68 (d, J = 1.0 Hz, 1H), 8.58 (t, J = 1.9 Hz, 1H), 8.22 (s, 1H), 4.60 (s, 2H), 3.61 - 3.56 (m, 2H), 2.89 - 2.84 (m, 2H), 1.43 (s, 9H)

[0221] Step 2: Preparation of N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide intermediate 43) [ka] To a stirred solution of intermediate 42 (290 mg, 0.678 mmol, 1.00 equiv) in anhydrous DCM (6.78 mL) cooled in an ice / water bath under argon was added TFA (0.52 mL, 6.78 mmol, 10.0 equiv) dropwise over 5 min. The reaction mixture was stirred for 3 h. Further TFA (0.17 mL, 2.26 mmol, 3.33 equiv) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 1:1 DCM:MeOH and loaded onto a 5 g Isolute SCX-II cartridge pre-conditioned with MeOH, washed with MeOH and then eluted with 2M NH3 / MeOH. The 2M NH3 / MeOH eluent was concentrated under reduced pressure to give the title compound (193 mg, 87%). 1 H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.12 (d, J = 2.3 Hz, 1H), 8.67 (d, J = 1.0 Hz, 1H), 8.59 - 8.57 (m, 1H), 8.12 (s, 1H), 3.88 (s, 2H), 3.17 (d, J = 5.0 Hz, 1H), 2.90 (t, J = 5.7 Hz, 2H), 2.78 - 2.73 (m, 2H)

[0222] Step 3: Preparation of 6-((5-methoxypyridin-3-yl)methyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 32) Prepared from intermediate 43 (45 mg, 0.138 mmol) and 5-methoxy-3-pyridinecarboxaldehyde (18 mg, 0.131 mmol) following general procedure D. Purification by reverse phase preparative HPLC (Xbridge Phenyl 19×150 mm, 10 μm 40-100% MeOH / water (10 mM NH4HCO3), 20 mL / min, RT) afforded the title compound (19 mg, 30%). 1 H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.13 (d, J = 2.3 Hz, 1H), 8.69 (d, J = 1.0 Hz, 1H), 8.60 - 8.59 (m, 1H), 8.23 ​​(d, J = 2.9 Hz, 1H), 8.19 - 8.16 (m, 2H), 7.36 (dd, J = 1.8, 2.8 Hz, 1H), 3.85 (s, 3H), 3.74 (s, 2H), 3.67 (s, 2H), 2.93 - 2.88 (m, 2H), 2.78 - 2.72 (m, 2H). LC-MS (ESI): m / z (M+1) = 449.4;t R = 2.95 minutes. Method 9

[0223] The following compounds were prepared by reductive amination as described in Example 32, steps 1-3, using previously synthesized or commercially available aryl aldehydes in step 3. Such procedures may include minor variations. In some cases, when modifications involved the use of reducing agents (e.g., NaBH3CN instead of STAB) or chromatographic purification conditions, such variations were noted in the table. [Table 26]

[0224] Example 37: Preparation of N-[3-fluoro-5-(trifluoromethyl)phenyl]-6-[[2-(oxetan-3-ylamino)pyrimidin-5-yl]methyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Preparation of N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 44) [ka] To a solution of 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (1590 mg, 5.61 mmol, 1.00 equiv) and HATU (2560 mg, 6.73 mmol, 1.20 equiv) in DMF (22.50 mL), DIPEA (2.9 mL, 16.8 mmol, 3.00 equiv) was added and the RM was stirred at room temperature for 15 min, after which 3-fluoro-5-(trifluoromethyl)aniline (1055 mg, 5.89 mmol, 1.05 equiv) was added. The reaction mixture was stirred at room temperature for an additional 16 h. The reaction mixture was purified on silica FCC (EtOAc / cyclohexane 0%-100) to give tert-butyl 3-((3-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate, (1.35 g, 3.04 mmol, 1.00 equiv), which was dissolved in DCM (35 mL) and TFA (5.0 mL, 65.9 mmol, 21.7 equiv) was added. The reaction mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The reaction mixture was partitioned between saturated aqueous Na2CO3 (50 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (30 mL), dried over MgSO4, filtered through a hydrophobic frit and concentrated under reduced pressure. The crude material was purified by silica FCC (EtOAc / cyclohexane 0% to 100%, followed by 3:1 EtOAc:EtOH / EtOAc 0% to 100%) to give the title compound (500 mg, 2.69 mmol, 48% yield). 1 H NMR (400 MHz, CDCl3) δ 7.80 (td, J = 2.1, 10.4 Hz, 1H), 7.73 (s, 1H), 7.63 (s, 1H), 7.52 (s, 1H), 7.10 (d, J = 8.3 Hz, 1H), 4.07 (s, 2H), 3.15 (t, J = 5.8 Hz, 2H), 2.93 (t, J = 5.7 Hz, 2H), 1.27 - 1.22 (m, 1H)

[0225] Step 2: Preparation of N-[3-fluoro-5-(trifluoromethyl)phenyl]-6-[[2-(oxetan-3-ylamino)pyrimidin-5-yl]methyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 37) Prepared from intermediate 20 (62 mg, 0.34 mmol, 1.00 equiv) and intermediate 44 (119 mg, 0.34 mmol, 1.00 equiv) according to general procedure C. The residual reaction was purified by reverse phase preparative HPLC (Luna Phenyl-Hexyl 21.2×150 mm, 10 μm 20-80% MeOH / H2O (0.1% FA), 20 ml / min, RT). The resulting solid was dissolved in EtOAc, washed with saturated aqueous NaHCO3, dried (MgSO4), and concentrated. The residue was lyophilized to give the title compound (12 mg, 7%). 1 H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.27 (s, 2H), 8.13 (s, 1H), 7.99 - 7.90 (m, 3H), 7.38 (d, J = 8.5 Hz, 1H), 4.96 - 4.88 (m, 1H), 4.77 (t, J = 6.7 Hz, 2H), 4.52 (t, J = 6.3, Hz, 2H), 3.61 (s, 2H), 3.53 (s, 2H), 2.90 - 2.82 (m, 2H), 2.73 - 2.68 (m, 2H) LC-MS (ESI): m / z (M+1) = 508.2; t R = 2.95 minutes. Method 8

[0226] The following compounds were prepared by reductive amination as described in Example 37, steps 1-2, using previously synthesized or commercially available aryl aldehydes in step 2. Such procedures may involve minor variations. In some instances, when variations involved the reducing agent (e.g., NaBH3CN instead of STAB) or chromatographic purification conditions, such variations were noted in the table. [Table 27] [Table 28] [Table 29]

[0227] Example 48: Preparation of N-[3-fluoro-5-(trifluoromethyl)phenyl]-6-[[6-(methylamino)-3-pyridyl]methyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Preparation of N-[3-fluoro-5-(trifluoromethyl)phenyl]-6-[[6-(methylamino)-3-pyridyl]methyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 48) Intermediate 44 To a solution of HCl salt (150 mg, 0.394 mmol, 1.00 equiv), DIPEA (0.14 mL, 0.788 mmol, 2.00 equiv) and 6-(methylamino)pyridine-3-carbaldehyde (54 mg, 0.394 mmol, 1.00 equiv) in MeOH (7.5 mL) was added titanium(IV) isopropoxide (0.35 mL, 1.18 mmol, 3.00 equiv). The reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and NaBH3CN (62 mg, 0.985 mmol, 2.50 equiv) was added. The reaction mixture was stirred at room temperature for 4 h. The reaction was diluted with DCM, quenched with NH4Cl and the solids were filtered. The organic layer was separated and the aqueous layer was washed twice with DCM. The combined organic phase was filtered through a hydrophobic frit and the solvent concentrated under reduced pressure to give 190 mg of crude material. The compound was purified by preparative HPLC (Sunfire C18 19×150 mm, 10 μm 20-80% ACN / H2O (10 mM NH4CO3), 20 ml / min, RT) to give the title compound (29 mg, 0.0579 mmol, 15%). 1 H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.12 (s, 1H), 7.99 - 7.90 (m, 3H), 7.40 - 7.35 (m, 2H), 6.45 - 6.41 (m, 2H), 3.57 (s, 2H), 3.51 (s, 2H), 2.86 (t, J = 5.7 Hz, 2H), 2.77 (d, J = 4.8 Hz, 3H), 2.71 (t, J = 5.8 Hz, 2H). LC-MS (ESI): m / z (M+1) = 465.2; t R = 2.98 minutes. Method 9

[0228] Example 49: Preparation of N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(1-methyl-1H-imidazole-5-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Preparation of N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(1-methyl-1H-imidazole-5-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 49) Prepared according to general procedure A from 1-methyl-1H-imidazole-5-carboxylic acid (22 mg, 0.174 mmol, 1.20 equiv) and intermediate 44 (50 mg, 0.145 mmol, 1.00 equiv). The residue was purified by preparative HPLC (Xbridge Phenyl 19×150 mm, 10 μm 40-100% MeOH / H2O (10 mM NH4CO3), 20 ml / min, RT) to give the crude product (34 mg), which was repurified by preparative HPLC (Sunfire C18 19×150 mm, 10 μm 5-60% ACN / H2O (0.1% FA), 20 ml / min, RT) to give the title compound (16 mg, 25%). 1 H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.23 ​​(s, 1H), 8.00 - 7.94 (m, 2H), 7.81 (s, 1H), 7.42 - 7.38 (m, 1H), 7.35 (d, J = 1.0 Hz, 1H), 4.91 (s, 2H), 3.89 (t, J = 5.7 Hz, 2H), 3.72 (s, 3H), 3.05 - 2.98 (m, 2H). LC-MS (ESI): m / z (M+1) = 453.3; t R = 3.71 minutes. Method 9

[0229] Example 50: Preparation of (R)-6-((2-aminopyrimidin-5-yl)methyl)-N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Preparation of tert-butyl (R)-3-((3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 45) [ka] Prepared from 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (350 mg, 1.24 mmol, 1.0 equiv) and intermediate 28 (355 mg, 1.24 mmol, 1.0 equiv) following general procedure G. The residue was purified by silica FCC (40 g cartridge, 0-10% 2M NH3 / MeOH in DCM) to give the title compound (580 mg, 84%). 1 H NMR (300 MHz, CDCl3) δ 8.29 - 8.22 (m, 2H), 7.86 (s, 1H), 7.67 (s, 1H), 7.19 (s, 1H), 4.61 (s, 2H), 3.70 - 3.55 (m, 5H), 3.05 - 2.96 (m, 4H), 2.82 (s, 6H), 2.57 (dd, J = 6.4, 11.5 Hz, 1H), 2.46 - 2.23 (m, 2H), 2.07 - 1.99 (m, 1H), 1.48 (s, 9H)

[0230] Step 2: Preparation of (R)-N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 46) [ka] To a solution of tert-butyl intermediate 45 (576 mg, 1.04 mmol) in anhydrous DCM (10.4 mL) was added TFA (1.6 mL, 20.8 mmol) dropwise over 5 min while stirring on an ice-water bath under argon atmosphere. The reaction mixture was stirred for 1.5 h, concentrated under reduced pressure, and the residue was dissolved in MeOH and loaded onto a 20 g Isolute SCX-II cartridge preconditioned with methanol, washed with MeOH, and then eluted with 2M NH3 / MeOH. The 2M NH3 / MeOH eluent was concentrated under reduced pressure to give the title compound (356 mg, 75%). 1 H NMR (300 MHz, CDCl3) δ 8.00 - 7.92 (m, 2H), 7.69 (d, J = 5.3 Hz, 2H), 7.34 (s, 1H), 4.06 (s, 2H), 3.71 (d, J = 13.5 Hz, 1H), 3.59 (d, J = 13.3 Hz, 1H), 3.17 - 3.11 (m, 2H), 2.99 - 2.92 (m, 2H), 2.87 - 2.54 (m, 5H), 2.45 (dd, J = 6.3, 8.5 Hz, 1H), 2.24 (s, 6H), 2.09 - 1.95 (m, 1H), 1.84 - 1.72 (m, 1H)

[0231] Step 3: Preparation of (R)-N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 50) Prepared from intermediate 46 (58 mg, 0.128 mmol) and 2-aminopyrimidine-5-carbaldehyde (15 mg, 0.122 mmol) according to general procedure D. Purification by reverse phase preparative HPLC (Sunfire C18 19×150 mm, 10 μm 20-80%, acetonitrile / water (10 mM NH4HCO3), 20 mL / min, RT) followed by repurification (Luna Phenyl-Hexyl 21.2×150 mm, 10 μm 5-60% MeOH / water (0.1% FA), 20 mL / min, RT) gave the formate salt of the title compound. The material was dissolved in MeOH and loaded onto a 2 g Isolute SCX-II cartridge preconditioned with MeOH, washed with MeOH, then eluted with 2M NH3 / MeOH. The 2M NH3 / MeOH eluent was concentrated and dried under reduced pressure to give the title compound (23 mg, 33%). 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.18 (s, 2H), 8.11 - 8.08 (m, 2H), 7.92 (s, 1H), 7.32 (s, 1H), 6.56 (s, 2H), 3.69 (d, J = 13.7 Hz, 1H), 3.60 - 3.53 (m, 3H), 3.49 (s, 2H), 2.88 - 2.84 (m, 2H), 2.72 - 2.64 (m, 4H), 2.62 - 2.56 (m, 1H), 2.46 - 2.43 (m, 1H), 2.29 (dd, J = 5.7, 7.7 Hz, 1H), 2.07 (s, 6H), 1.91 - 1.81 (m, 1H), 1.66 - 1.57 (m, 1H) LC-MS (ESI): m / z (M+1) = 560.1; t R = 3.91 minutes. Method 10

[0232] The following compounds were prepared by reductive amination as described in Example 50, steps 1-3, applying previously synthesized or commercially available aryl aldehydes in step 3. Such procedures may involve minor modifications. In some cases, when modifications concern the reducing agent (e.g. NaBH3CN instead of STAB) or chromatographic purification conditions, such modifications are noted in the table. [Table 30] [Table 31]

[0233] The following compounds were prepared by reductive amination as described in Example 50, steps 1-3, using previously synthesized or commercially available arylamines in step 1. [Table 32] [Table 33]

[0234] Example 58: Preparation of 6-((2-aminopyrimidin-5-yl)methyl)-N-(3-(1,1-difluoroethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Preparation of tert-butyl 3-((3-(1,1-difluoroethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 47) [ka] Prepared according to general procedure G from 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (500 mg, 1.76 mmol, 1.0 equiv.) with the addition of 3-(1,1-difluoroethyl)aniline (291 mg, 1.85 mmol, 1.05 equiv.). The combined organic phases were dried over MgSO4, filtered, concentrated, and dried under reduced pressure overnight to give the title compound (1140 mg, 1.78 mmol, 101%). 1 H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.77 - 7.67 (m, 2H), 7.65 (s, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.28 (s, 1H), 4.62 (s, 2H), 3.67 (t, J = 5.3 Hz, 2H), 3.00 - 2.96 (m, 2H), 1.93 (t, J = 18.2 Hz, 3H), 1.49 (s, 9H)

[0235] Step 2: Preparation of N-(3-(1,1-difluoroethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 48) [ka] To a solution of intermediate 47 (750 mg, 1.17 mmol, 1.00 equiv) in 1,4-dioxane (10 mL) was added 4N HCl in 1,4-dioxane (10 mL). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with Et2O, filtered, and the resulting solid was washed with Et2O and dried under reduced pressure to give the title compound (684 mg, 1.72 mmol, 146%). This material was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.44 (s, 1H), 8.06 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.73 (m, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 7.3 Hz, 1H), 4.42 (s, 2H), 3.40 (m, 2H), 3.16 (t, J = 5.7 Hz, 2H), 2.01 (t, J = 18.8 Hz, 3H)

[0236] Step 3: Preparation of 6-((2-aminopyrimidin-5-yl)methyl)-N-(3-(1,1-difluoroethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 58) Prepared from intermediate 48 (90%, 60 mg, 0.150 mmol, 1.00 equiv) and 2-aminopyrimidine-5-carboxaldehyde (19 mg, 0.150 mmol, 1.00 equiv) according to general procedure C. The residue was washed with DCM / MeOH, the combined washings were evaporated and the residue was dried under reduced pressure. The residue was subjected to purification by preparative HPLC. Sunfire C18 19×150 mm, 10 μm 5-60% ACN / H2O (0.1% FA), 20 ml / min, RT. The title compound (20.47 mg, 0.0469 mmol, 31.3% yield) was obtained. 1 H NMR (400 MHz, DMSO) δ 10.20 (s, 1H), 8.20 (s, 2H), 8.08 (s, 1H), 7.99 (t, J = 2.1 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.46 (t J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.58 (s, 2H), 3.61 (s, 2H), 3.51 (s, 2H), 2.88 (t, J = 5.4Hz, 2H), 2.74 - 2.68 (m, 2H), 1.97 (t, J = 18.8 Hz, 3H). LC-MS (ESI): m / z (M+1) = 430.6; tR = 4.02 minutes. Method 8

[0237] The following compounds were prepared by reductive amination as described in Example 58, steps 1-3, using previously synthesized or commercially available arylamines in step 1. [Table 34]

[0238] Example 61: Preparation of 6-((2-aminopyrimidin-5-yl)methyl)-N-(4-chloro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Preparation of tert-butyl 3-((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 49) [ka] Prepared according to general procedure G by adding 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (250 mg, 0.882 mmol, 1.0 equiv) to 4-chloro-3-(trifluoromethyl)aniline (181 mg, 0.926 mmol, 1.05 equiv). The reaction mixture was stirred at room temperature for 90 min, quenched with water, stirred for 30 min, and filtered. The solid was washed with water and dried under reduced pressure. The title compound (360 mg, 0.781 mmol, 89%) was obtained. This material was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 2H), 7.86 - 7.82 (m, 1H), 7.64 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 4.61 (s, 2H), 3.68 (t, J = 5.3 Hz, 2H), 2.99 (t, J = 5.7 Hz, 2H), 1.57 (s, 4H), 1.50 (s, 9H)

[0239] Step 2: Preparation of N-(4-chloro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 50) [ka] To a solution of intermediate 49 (360 mg, 0.781 mmol, 1.00 equiv) in 1,4-dioxane (3 mL) was added 4N HCl in 1,4-dioxane (3.0 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with Et2O, filtered, and the solid was washed with Et2O and dried under vacuum to give the title compound (289 mg, 0.666 mmol, 85%) as the hydrochloride salt. 1 H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 9.66 - 9.57 (m, 2H), 8.49 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 8.14 (dd, J = 2.3, 8.8 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 4.43 (s, 2H), 3.16 (t, J = 5.8 Hz, 2H) -

[0240] Step 3: Preparation of 6-((2-aminopyrimidin-5-yl)methyl)-N-(4-chloro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 61) Prepared from intermediate 49 (60 mg, 0.151 mmol, 1.00 equiv) and 2-aminopyrimidine-5-carboxaldehyde (27 mg, 0.223 mmol, 1.47 equiv) following general procedure H. The crude was purified by preparative HPLC (Luna Phenyl-Hexyl 21.2×150 mm, 10 μm 20-80% MeOH / HO (0.1% FA), 20 ml / min, RT) to give the title compound (17 mg, 0.0352 mmol, 23%). 1 H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.32 (d, J = 2.3 Hz, 1H), 8.19 (s, 2H), 8.12 (s, 1H), 8.04 (dd, J = 2.4, 8.8 Hz, 1H), 7.70 (d, J LC-MS (ESI): m / z (M+1) = 468.4;t R = 4.57 minutes. Method 8

[0241] Example 62: Preparation of 6-((2-aminopyrimidin-5-yl)methyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Preparation of tert-butyl 3-((5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 51) [ka] To a solution of 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (250 mg, 0.882 mmol, 1.00 equiv) and DMF (0.0034 mL, 0.0441 mmol, 0.05 equiv) in cyclopentyl methyl ether (2 mL) was added oxalyl chloride (0.088 mL, 1.06 mmol, 1.20 equiv) dropwise at 20° C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, the residue was azeotropically concentrated with cyclopentyl methyl ether, the residue was suspended in ACN (1 mL), cooled to 0° C. in an ice bath, and to the mixture was added 5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)isoxazol-3-amine (171 mg, 0.882 mmol, 1.00 equiv) and pyridine (0.14 mL, 1.76 mmol, 2.00 equiv) in ACN (1 mL). The reaction mixture was allowed to warm to room temperature and stirred for 45 min. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between DCM and water. The combined organic layers were filtered through a hydrophobic frit and the solvent was concentrated under reduced pressure. The residue was purified on silica FCC (eluting with 0-100% EtOAc in cyclohexane) to give the title compound (255 mg, 0.555 mmol, 63%). This material was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) d 9.65 (s, 1H), 7.91 (s, 1H), 7.13 (s, 1H), 4.64 (s, 2H), 3.68 (t, J = 5.4 Hz, 2H), 3.01 (t, J = 5.8 Hz, 2H), 1.60 (s, 6H), 1.49 (s, 9H)

[0242] Step 2: Preparation of N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 52) [ka] To a solution of intermediate 51 (255 mg, 0.555 mmol, 1.00 equiv) in 1,4-dioxane (3 mL) at 0° C. was added 4N HCl in 1,4-dioxane (3.0 mL, 0.555 mmol, 1.00 equiv). The reaction mixture was allowed to warm to room temperature and stirred at room temperature over the weekend. The reaction was diluted with Et2O (20 mL), filtered, and the solid was washed with Et2O and dried under reduced pressure to give the title compound (190 mg, 0.480 mmol, 86%) as the HCl salt. 1 H NMR (400 MHz, DMSO-d6) d 11.49 (s, 1H), 9.64 - 9.55 (m, 2H), 8.52 (s, 1H), 7.11 (s, 1H), 4.42 (s, 2H), 3.15 (t, J = 5.6 Hz, 2H), 1.63 (s, 6H)

[0243] Step 3: Preparation of 6-((2-aminopyrimidin-5-yl)methyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 62) To a solution of 2-aminopyrimidine-5-carboxaldehyde (16 mg, 0.126 mmol, 1.00 equiv), intermediate 52 (50 mg, 0.126 mmol, 1.00 equiv) and DMF (0.044 mL, 0.253 mmol, 2.00 equiv) in MeOH (3.00 mL) was added titanium(IV) isopropoxide (0.11 mL, 0.379 mmol, 3.00 equiv). The reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to room temperature and NaBH3CN (20 mg, 0.316 mmol, 2.50 equiv) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with water (30 mL) and filtered through Celite. The residue was washed with DCM / MeOH, the combined washings were evaporated and the residue was dried under reduced pressure over P2O5. The residue was subjected to purification by preparative HPLC. Sunfire C18 19×150 mm, 10 μm 5-60% ACN / H2O (0.1% FA), 20 ml / min, RT. Obtained the title compound (17 mg, 0.0343 mmol, 27%). 1H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.29 (s, 1H), 8.19 (s, 2H), 7.08 (s, 1H), 6.58 (s, 2H), 3.60 (s, 2H), 3.50 (s, 2H), 2.87 (m, 2H), 2.71 - 2.67 (m, 2H), 1.59 (s, 6H). LC-MS (ESI): m / z (M+1) = 467.7; t R = 3.17 minutes. Method 11

[0244] The following compounds were prepared by reductive amination as described in Example 62, steps 1-3, using commercially available heteroaryl amines in step 1. [Table 35]

[0245] Example 65: Preparation of N-(3-(tert-butyl)isoxazol-5-yl)-6-((5-methoxypyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Preparation of ethyl (6-((5-methoxypyridin-3-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 53) [ka] Prepared from 5-methoxy-3-pyridinecarboxaldehyde (91 mg, 0.666 mmol) and intermediate 6 (150 mg, 0.605 mmol) following general procedure F. Purification was carried out on silica FCC (25 g) eluted with 2M methanolic ammonia in DCM (15:1) in DCM (0-100%) to give the title compound (190 mg, 94%). 1H NMR (400 MHz, CDCl3) δ 8.25 - 8.23 ​​(m, 1H), 8.18 (d, J = 1.2 Hz, 1H), 7.95 - 7.94 (m, 1H), 7.28 (t, J = 2.3 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.86 - 3.86 (m, 3H), 3.72 - 3.66 (m, 4H), 3.03 - 2.98 (m, 2H), 2.83 - 2.79 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H)

[0246] Step 2: Preparation of (6-((5-methoxypyridin-3-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (Intermediate 54) [ka] NaOH (81 mg, 2.03 mmol, 3.10 equiv) was added to a solution of intermediate 53 (217 mg, 0.653 mmol, 1.00 equiv) in MeOH (10 mL) and water (0.5 mL) and the mixture was stirred at 50° C. for 18 h. The mixture was cooled in an ice bath and 1M HCl (1.8 mL, 1.78 mmol, 2.73 equiv) was added dropwise. The solution was concentrated under reduced pressure to give a solid precipitate which was filtered and washed with acetone (2 mL) to give the title compound (166 mg, 83%). LC-MS (ESI): m / z (M+1) = 305.2; t R = 0.68 minutes. Method 12

[0247] Step 3: Preparation of N-(3-(tert-butyl)isoxazol-5-yl)-6-((5-methoxypyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 65) Intermediate 54 (30 mg, 0.0986 mmol) was suspended in thionyl chloride (0.21 mL, 2.93 mmol) and the reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in toluene and reconcentrated to give the intermediate acyl chloride. To a solution of 3-tert-butylisoxazol-5-amine (21 mg, 0.148 mmol) and DMAP (2.4 mg, 0.020 mmol) in pyridine (0.1 M concentration) was added the acyl chloride followed by DIPEA (51.5 μL, 0.296 mmol). The reaction mixture was stirred at 40° C. until LCMS showed consumption of starting material and then concentrated under reduced pressure. Purification was carried out by reverse phase preparative HPLC (Luna Phenyl-Hexyl 21.2×150 mm, 10 μm 20-80% MeOH / H2O (0.1% FA), 20 ml / min, RT) to give the title compound (28 mg, 0.065 mmol, 66%). 1 H NMR (400 MHz, DMSO-d6) δ 11.73 - 11.69 (m, 1H), 8.28 (s, 1H), 8.23 ​​(d, J = 3.2 Hz, 1H), 8.16 (d, J = 0.9 Hz, 1H), 7.35 (dd, J = 1.8, 2.8 Hz, 1H), 6.37 (s, 1H), 3.84 (s, 3H), 3.73 (s, 2H), 3.65 (s, 2H), 2.90 (t, J = 5.6 Hz, 2H), 2.76 - 2.71 (m, 2H), 1.29 - 1.28 (m, 9H). LC-MS (ESI): m / z (M+1) = 427.2;t R = 3.14 minutes. Method 9

[0248] For comparison, compounds were synthesized separately that differed in the following respects: - lacking a linker between the tetrahydrothienopyridine ring and the Hy group (Example C1); and - lacking both the linker between the tetrahydrothienopyridine ring and the Hy group and the -C(O)NH- group substituting the thienyl ring alpha to the sulfur atom (example C2).

[0249] Example C1 ;Preparation of N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Ethyl 6-(pyrimidin-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 16) [ka] A 20 mL vial equipped with a magnetic stir bar and fitted with a seal cap was charged with intermediate 6 (163.1 mg, 0.658 mmol), 5-bromopyrimidine (0.105 ml, 0.658 mmol), Cs2CO3 (0.215 ml, 0.658 mmol), Pd(dba)2 (0.379 ml, 0.658 mmol) and RuPhos (0.307 ml, 0.658 mmol). The vessel was evacuated and backfilled with argon, then toluene (4 ml) was added via syringe. The solution was heated at 120° C. and stirred. After cooling to RT, the solution was filtered through a pad of Celite and then concentrated to dryness. The crude was purified by FCC (column silica-NH gradient n-heptane / acetone 100:0 to 60:40) to give the title compound (100 mg, 0.346 mmol, 52.5% yield). 1 H NMR (400 MHz, CDCl3) d ppm 8.72 (s, 1H) 8.47 (s, 2H) 8.03 (s, 1H) 4.54 (s,2H) 4.32 (q, J = 7.16 Hz, 2H) 3.70 (t, J = 5.81 Hz, 2H) 3.16 (br t, J = 5.59 Hz, 2H) 1.38 (t, J = 7.13 Hz, 3H)

[0250] Step 2: N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example C1) 3-((4-Methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)aniline (76 mg, 0.276 mmol) was dissolved in dry THF (volume: 6 ml, ratio: 1.500) under nitrogen and the mixture was stirred at -78°C for 15 min, then n-BuLi (0.105 ml, 0.263 mmol) was added dropwise over 5 min and the solution was stirred for 1 h at -78°C. A solution of ethyl intermediate 16 (40 mg, 0.138 mmol) in THF (volume: 4 ml, ratio: 1.000) was added dropwise over 10 min, then the temperature was raised to RT and the reaction was stirred for an additional 1 h. 10 mL of water was added to the solution and the solvent was evaporated. The product was obtained by reverse phase flash chromatography (Column C18 Ultra gradient A:B 100:0 to 0:100 eluent A:H2O:ACN:HCOOH 95:5:0.1 eluent B:H2O:ACN:HCOOH 5:95:0.1). Relevant fractions were combined, loaded onto an Isolute SCX-2 cartridge, washed with MeOH and the product was eluted with 7N methanolic ammonia. The residue was concentrated under reduced pressure to give the title compound (23.5 mg, 0.045 mmol, 32.9% yield). 1 H NMR (400 MHz, ACN-d3) δ ppm 8.74 (br s, 1H), 8.58 (s, 1H), 8.49 (s, 2H), 7.99 (s, 1H), 7.93 (s, 1H), 7.84 (s, 1H), 7.36 (s, 1H), 4.57 (s, 2H), 3.70 (t, J = 5.81 Hz, 2H), 3.54 (s, 2H), 2.95 - 3.13 (m, 2H), 2.30 - 2.44 (br s, 8H), 2.20 (s, 3H). LC-MS (ESI): m / z (M+1) = 517.2; t R = 1.03 minutes (method 1)

[0251] Example C2:N-(3-((4-methylpiperazin-1-yl)methyl)-5-trifluoromethyl)phenyl)-5-(pyrimidin-5-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide [ka] Step 1: 6-(tert-butyl) 2-methyl 4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxylate (Intermediate 17) [ka] 6-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylic acid (200 mg, 0.706 mmol) and Cs2CO3 (345 mg, 1.059 mmol) were dissolved in anhydrous DMF (volume: 10 ml) and then CHI (0.066 ml, 1.059 mmol) was added in one portion. The solution was stirred at room temperature for 3 h. The reaction mixture was diluted with Et2O (20 mL) and then washed with saturated NH4Cl (10 mL) and brine (10 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated to dryness to give the title compound (182 mg, 0.611 mmol, 87% yield).

[0252] Step 2: Methyl 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate hydrochloride (Intermediate 18) [ka] 1 mL of concentrated HCl was placed in a round bottom flask with intermediate 17 (181.6 mg, 0.611 mmol). The reaction proceeded with gas formation and was complete in 5 min at rt. 30 mL of ethanol was added to the mixture and the solvent was evaporated under reduced pressure until the title compound was obtained in quantitative yield.

[0253] Step 3: Methyl 6-(pyrimidin-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (Intermediate 19) [ka] A 20 mL microwave vial equipped with a magnetic stir bar and fitted with a seal cap was charged with intermediate 18 (125 mg, 0.535 mmol), 5-bromopyrimidine (111 mg, 0.695 mmol), Cs2CO3 (523 mg, 1.605 mmol), Pd(dba)2 (30.8 mg, 0.053 mmol) and RuPhos (49.8 mg, 0.107 mmol). The vessel was evacuated and backfilled with argon, then toluene (volume: 5 ml) was added via syringe. The solution was heated at 110 °C and stirred. After cooling to rt, the solution was filtered through a pad of Celite and then concentrated to dryness. The crude was purified by FCC (gradient A:B 100:0 to 60:40, eluent A:n-heptane eluent B: acetone) to give the title compound (118.5 mg, 0.430 mmol, 80% yield). 1 H NMR (acetone, 400 MHz) δ 8.5-8.6 (m, 3H), 7.55 (s, 1H), 4.69 (s, 2H), 3.83 (s, 3H), 3.80 (t, 2H, J = 5.8 Hz), 2.89 (t, 2H, J = 5.8 Hz)

[0254] Step 4: N-(3-((4-methylpiperazin-1-yl)methyl)-5-trifluoromethyl)phenyl)-5-(pyrimidin-5-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (Example C2) 3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (52.4 mg, 0.217 mmol) was dissolved in dry THF (vol: 4) under nitrogen, the mixture was stirred at -78°C for 15 min, then 2.5M n-BuLi in hexane (0.083 ml, 0.206 mmol) was added dropwise over 5 min and the solution was stirred for 1 h at -78°C. A solution of methyl intermediate 19 (29.9 mg, 0.109 mmol) in THF (vol: 2 ml) was added dropwise over 10 min, the temperature was raised to rt and the reaction was stirred for 1 h. The reaction was quenched by the addition of 10 mL of water and the crude was extracted with AcOEt (2 x 20 mL), the organic layers were combined and the solvent was evaporated under reduced pressure. The crude product was purified by reversed phase FCC (gradient A:B 100:0 to 0:100. Eluent A: HO:ACN:HCOOH 95:5:0.1 Eluent B: HO:ACN:HCOOH 5:95:0.1). The appropriate fractions were combined and evaporated to give the title compound (8.7 mg, 0.018 mmol, 16.53% yield). 1 H NMR (400 MHz, acetonitrile-d3) δ ppm 8.97 (br s, 1 H), 8.59 (s, 1 H), 8.49 (s, 2 H), 8.11 (s, 1 H), 8.00 (s, 1 H), 7.89 (s, 1 H), 7.59 (s, 1 H), 7.54 (s, 1 H), 7.23 (s, 1 H), 4.60 (s, 2 H), 3.73 (t, J = 5.81 Hz, 2 H), 2.88 (br t, J = 5.70 Hz, 2 H), 2.23 (s, 3 H). LC-MS (ESI): m / z (M+1) = 485.1;t R = 1.15 minutes (method 1)

[0255] Pharmacological activity of the compounds of the invention In vitro assays Binding assays DDR1 and DDR2 binding assays were performed using LanthaScreen TMThe Europium Kinase Binding assay was used to carry out the assay. Compounds were incubated with 5nM DDR1 (Carna Biosciences) or 5nM DDR2 (Life Technologies) in white 384-well OptiPlates (PerkinElmer) containing 20nM or 10nM Kinase Tracer 178 and 2nM Europium-labeled anti-GST antibody (Life Technologies) in assay buffer (50mM HEPES pH7.5, 10mM MgCI2, 1mM EGTA and 0.01% BRIJ35) for 1 hour at room temperature. The 665 nm / 615 nm fluorescence emission ratio after excitation at 340 nm was obtained using a Tecan Spark 20M plate reader. 50 Values ​​were determined with GraphPad Prism 7.0 software using a four-parameter model: log(inhibitor) vs. response. IC 50 The value is calculated using the Cheng-Prusoff equation (Ki=IC 50 Conversion to Ki was performed using / (1+[tracer] / Kd).

[0256] DDR1 cell-based assay DDR1 receptor activation by compounds was evaluated by PathHunter® U2OS DDR1 assay (Eurofins DiscoverX) according to the manufacturer's instructions. Briefly, U2OS-DDR1 cells were seeded in white 384-well plates at a density of 5000 cells / well and incubated for 2 hours at 37°C and 5% CO2. Cells were then treated with various concentrations of compounds, incubated for 30 minutes, and then stimulated with 20 μg / ml bovine type II collagen and incubated overnight at 37°C and 5% CO2. PathHunter Detection Reagents were prepared according to the protocol provided by DiscoverX, and 20 μl / well of this mixture was added to each well. Plates were incubated for 1 hour at room temperature in the dark, after which the luminescence signal w was acquired on a plate reader. Raw data was normalized to vehicle control (0% for normalization) and positive control (100% for normalization; cells treated with 20 μg / ml collagen II) and IC 50 Parameters were calculated with GraphPad Prism 8.0 software using sigmoidal dose-response curve fitting with variable slope.

[0257] DDR2 cell-based assay Inhibition of DDR2 phosphorylation by compounds was evaluated in HEK293T-DDR2 recombinant cells by phospho-ELISA assay. Briefly, HEK293T-DDR2 cells were seeded in poly-D-lysine coated 24-well plates at a density of 250.000 cells / well and incubated in DMEM+10% FBS for 1.5 hours at 37°C and 5% CO2. Afterwards, the medium was changed to serum-free DMEM and the cells were incubated for 3 hours. Test compounds were then added at various concentrations for 30 minutes, followed by stimulation with 50 μg / ml bovine type II collagen for another 3 hours. For DDR2 phospho-ELISA assay (DuoSet IC Human Phospho-DDR2; R&D Systems), protein extracts were obtained by addition of 60 μl / well of lysis buffer prepared according to the manufacturer's instructions. Protein concentrations of samples were determined by BCA assay and phospho-DDR2 levels were determined according to the R&D Systems instructions. Raw data were normalized to the maximum inhibition control (0% for normalization) and positive control (100% for normalization; cells treated with 20 μg / ml collagen II) and IC 50 Parameters were calculated with GraphPad Prism 8.0 software using sigmoidal dose-response curve fitting with variable slope.

[0258] The results for individual compounds are provided in Table 5 below, where the compounds are classified in terms of binding potency (nM) and cell-based assays with respect to inhibitory activity against DDR1 and DDR2: [Table 36] [Table 37] +:Ki 50~80nM ++: Ki 25~50nM +++: Ki less than 25nM +:IC 50 50-80nM ++:IC50 25-50nM +++:IC 50 <25nM -: Not applicable

[0259] As can be seen, the compounds in Table 5, i.e., the compounds of the present invention, show good activity as antagonists of DDR1 and DDR2. Therefore, the compounds of the present invention can be effectively used for diseases, disorders or conditions associated with DDR receptors, such as fibrosis, for example, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

[0260] Comparative Example The compounds of Examples C1 and C2 were tested in the same binding assay as described above. [Table 38] The compounds of the invention shown in Table 5 have binding affinities, expressed as Ki, and IC 50 For both DDR1 and DDR2 receptor inhibitory potencies expressed as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 116, 117, 120, 130, 140, 150, 161, 172, 183, 194, 105, 106, 117, 124, 138, 14

[0261] These data show that, contrary to the comparative compound of Example C1, which is characterized by the lack of a linker between the tetrahydrothienopyridine ring and the Hy group, the compound of Example 2 of the present invention, which has a -CH2- linker in that position, unexpectedly and significantly determines an associated increase in inhibitory activity of the DDR1 and DDR2 receptors.

[0262] As further evidence, contrary to the compound of Example C2, which lacks a linker between the tetrahydrothienopyridine ring and the Hy group and is characterized by having a -C(O)NH- group substitution at the alpha position relative to the sulfur atom, rather than at the beta position as in Example 2 of the present invention, the presence of said linker in the compounds of the present invention together with the substitution at the beta position unexpectedly and significantly determines an associated increase in inhibitory activity against the DDR1 and DDR2 receptors.

Claims

1. Formula (I) 【Chemistry 1】 [During the ceremony, L is -C(O)- and -CH ２ - selected from the group consisting of; Hy may be -(C １ -C ４ ) alkyl, halogen atom, cyano, -(CH ２ ) ｎ N.R. ４ R ５ , —NH-heterocycloalkyl, —O—(C １ -C ６ ) alkyl, -(C １ -C ６ ) haloalkyl, -C(O)NH-(C １ -C ６ ) alkylene-NR ４ R ５ , -O-(C １ -C ６ ) alkylene-cycloalkyl, -NHC(O)-(C １ -C ６ ) alkyl, -NHC(O)-(C １ -C ６ ) alkylene-NR ４ R ５ , -NHC(O)-(C １ -C ６ ) alkylene-O-(C １ -C ４ ) alkyl, -NH-(C １ -C ６ ) alkylene-O-(C １ -C ４ ) alkyl, -NH-(C １ -C ６ ) alkylene-OH, optionally one or more -(C １ -C ４ a monocyclic heteroaryl selected from -heteroaryl, -NH-heteroaryl, optionally substituted with one or more -(C)alkyl; １ -C ４ ) alkyl and optionally oxo and -(C １ -C ６ ) heterocycloalkyl substituted with one or more groups selected from alkyl; R １ teeth: - Depending on the circumstances - (C １ -C ４ ) alkyl, -(C １ -C ４ ) haloalkyl and aryl, where the aryl is optionally -(C １ -C ４ ) alkyl, and halogen; and -X 【Chemistry 2】 wherein: R ２ Ha-O(C １ -C ４ ) haloalkyl, halogen atom, -O(C ３ -C ７ )cycloalkyl and -(C １ -C ４ ) haloalkyl; R ３ is H or a halogen atom, cyano, -O(C １ -C ４ ) alkyl, —O(C １ -C ４ ) haloalkyl, heterocycloalkyl-(C １ -C ４ ) alkylene-, -(C １ -C ４ ) alkylene-heterocycloalkyl-NR ４ R ５ and optionally one or more -(C １ -C ４ )alkyl, wherein the heterocycloalkyl is optionally selected from the group consisting of heteroaryl substituted with one or more —(C １ -C ４ ) alkyl substituted; n is 0, 1 or 2; R ４ is H or -(C １ -C ４ ) alkyl; R ５ is H or -(C １ -C ４ ) alkyl. or a pharma- ceutically acceptable salt thereof.

2. R １ Is X' 【Chemistry 3】 Formula (Ia) 【Chemistry 4】 2. The compound of formula (I) of claim 1, represented by: or a pharma- ceutically acceptable salt thereof.

3. L is -CH ２ -, 【Chemistry 5】 3. The compound of formula (I) of claim 2, represented by: or a pharma- ceutically acceptable salt thereof.

4. A compound of formula (Ia) of claim 2 or a compound of formula (Iaa) of claim 3 selected from the following: N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyridin-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyrimidin-5-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethoxy)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(1,1-difluoroethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(difluoromethoxy)-5-fluorophenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(difluoromethoxy)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-cyano-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((4-(2-methoxyacetamido)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-cyanopyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-chloropyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-methoxypyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-methylpyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(trifluoromethyl)phenyl)-6-((5-(trifluoromethyl)pyridin-3-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-fluoropyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyridin-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((3-aminopyrazin-2-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-(4-methyl-3-oxopiperazin-1-yl)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-(1,1-dioxidothiomorpholino)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-(2-(dimethylamino)acetamido)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-((2-(oxetan-3-ylamino)pyrimidin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-acetamidopyrimidin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-((2-(methylamino)pyrimidin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-((2-((2-methoxyethyl)amino)pyrimidin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((6-acetamidopyridin-3-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyridin-3-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-((2-((2-hydroxyethyl)amino)pyrimidin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((4-aminopyrimidin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((3-aminopyrazin-2-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-amino-4-methylpyrimidin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-((6-(methylamino)pyridin-3-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)-6-((2-aminopyrimidin-5-yl)methyl)-N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)—N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-((4-(2-fluoropropan-2-yl)pyrimidin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)—N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-((4-methoxypyrimidin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)-6-((4-cyclopropoxypyrimidin-5-yl)methyl)-N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)—N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidin-5-yl)methyl)-N-(3-((dimethylamino)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidin-5-yl)methyl)-N-(3-(1,1-difluoroethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidin-5-yl)methyl)-N-(3-cyano-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide.

5. L is -CH ２ - and R １ Is X'' 【Chemistry 6】 Formula (Iaa') 【Chemistry 7】 2. The compound of formula (I) of claim 1, represented by: or a pharma- ceutically acceptable salt thereof.

6. L is -CH ２ - and R １ X''' 【Chemistry 8】 Formula (Iaa″) 【Chemistry 9】 2. The compound of formula (I) of claim 1, represented by: or a pharma- ceutically acceptable salt thereof.

7. L is -C(O)-, 【Chemistry 10】 3. The compound of claim 2, wherein the compound is a phenyl group or a phenyl group.

8. R １ is Het, 【Chemistry 11】 2. The compound of formula (I) of claim 1, represented by: or a pharma- ceutically acceptable salt thereof.

9. L is -CH ２ -, 【Chemistry 12】 9. The compound of formula (Ib) of claim 8, represented by: or a pharma- ceutically acceptable salt thereof.

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

11. 11. The pharmaceutical composition of claim 10 for administration by inhalation.

12. A medicine comprising a compound of formula (I) according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt thereof as an active ingredient.

13. A compound according to claim 10 or 11 or a medicament according to claim 12 for the prevention and / or treatment of a disease, disorder or condition associated with dysregulation of a discoidin domain receptor.

14. The pharmaceutical composition or medicament of claim 13, wherein the disease, disorder or condition associated with dysregulation of a discoidin domain receptor is fibrosis and / or a disease, disorder or condition involving fibrosis.

15. The pharmaceutical composition or medicine of claim 14, wherein the fibrosis is selected from pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

16. A pharmaceutical composition or medicine of claim 15, wherein the fibrosis is idiopathic pulmonary fibrosis (IPF).

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