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 Invention This invention relates to compounds that inhibit discoidine domain receptors (DDR inhibitors), methods for producing such compounds, pharmaceutical compositions containing them, and therapeutic uses thereof.

[0002] The compounds of the present invention may be useful, for example, in treating many disorders associated with the DDR mechanism. [Background technology]

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

[0004] DDR is a unique receptor among the RTK superfamily in that it is activated by collagen, while 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, DDR is an unusual RTK because it forms a ligand-independent stable dimer bound non-covalently (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-fixed isoforms, while the DDR2 subfamily is represented by a single protein. All five DDR1 isoforms share common extracellular and transmembrane domains, but their cytoplasmic regions differ (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 shown to be associated with pulmonary fibrosis and a range of fibrotic diseases, particularly idiopathic pulmonary fibrosis (IPF). The first evidence of the 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 remarkably protected against bleomycin (BLM)-induced injury. Furthermore, myofibroblast expansion and apoptosis were significantly lower in these animals compared to wild-type counterparts. The absence of inflammation in knockout mice was confirmed by lavage cell count and cytokine ELISA. These results suggest that DDR1 expression is an essential prerequisite for pneumonia and fibrosis.

[0007] DDR2 deficiency or downregulation controls 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 a crucial role in inducing fibrosis and angiogenesis in the lung, and in particular, that DDR2, in coordination with transforming growth factor (TGF)-β, induces myofibroblast differentiation. Furthermore, they showed that treatment of injured mice with specific siRNA against DDR2 demonstrated 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 are 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 are described in the literature as DDR1 or DDR2 antagonists.

[0009] WO2016064970 (Guangzhou) discloses tetrahydroisoquinoline-7-carboxamide as a selective DDR1 inhibitor and a useful therapeutic agent for the prevention and treatment of inflammation, hepatic fibrosis, renal fibrosis, pulmonary fibrosis, skin scarring, atherosclerosis, and cancer.

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

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

[0012] Despite the aforementioned prior literature, there remains room to develop selective inhibitors of both DDR1 and DDR2 receptors that are administered via inhalation and are characterized by a good inhalation profile that accommodates good activity in the lungs, good lung retention, and low metabolic stability to minimize systemic exposure and associated safety issues. These inhibitors are useful for treating diseases or conditions associated with DDR receptor dysregulation in the respiratory domain, particularly idiopathic pulmonary fibrosis (IPF). [Overview of the project] [Problems that the invention aims to solve]

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

[0014] Summary of the Invention In a first embodiment, the present invention relates to formula (I) [ka] [During the ceremony, L is selected from the group consisting of -C(O)- and -CH2-; Hy is It is a monocyclic heteroaryl, and this Depending on the case, -(C1-C4) alkyl, halogen atom, 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 which may be substituted with one or more -(C1-C4)alkyl groups. The heteroaryl may have 1 or more -(C) 1 -C 4 ) Substituted with alkyl -NH-heteroary Luna Furthermore, it is substituted with one or more groups selected from heterocycloalkyls, which may be substituted with one or more groups selected from oxo and -(C1-C6)alkyl groups; R1 is: - Het is a heteroaryl which is 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] A group consisting of the following is selected, 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 either H or 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 a heteroaryl substituted with one or more -(C1-C4)alkyl groups, where the heterocycloalkyl is optionally substituted with one or more -(C1-C4)alkyl groups; n is 0, 1, or 2; R4 is either H or a -(C1-C4) alkyl group; R5 is either H or a -(C1-C4) alkyl group. This relates to the compounds and their pharmaceutically acceptable salts.

[0015] In a second embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof mixed with one or more pharmaceutically acceptable carriers or additives.

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

[0017] In a further embodiment, the present invention relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of diseases, disorders or conditions involving dysregulation of DDR.

[0018] In a further embodiment, the present invention relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0019] In a further embodiment, the present invention relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of idiopathic pulmonary fibrosis (IPF). [Modes for carrying out the invention]

[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 pharmaceutically acceptable salts thereof.

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

[0022] The term "pharmaceutically acceptable salt" as used herein refers to a derivative of the compound of formula (I) in which the parent compound is preferably modified by converting the parent compound, if present, to a corresponding addition salt of any base or acid conventionally intended to be pharmaceutically acceptable, whether a free acid or basic group.

[0023] Suitable examples of the salt may therefore include inorganic or organic acid addition salts of basic residues such as amino groups, and inorganic or organic basic addition salts of acidic residues such as carboxylic acid groups.

[0024] Inorganic base cations that can be appropriately used in salt preparation include ions of alkali or alkaline earth metals such as potassium, sodium, calcium, or magnesium.

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

[0026] The term "stereoisomer" refers to isomers of the same composition but with different arrangements of atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

[0027] The term "enantiomer" refers to a pair of molecular species that are mirror images of each other and cannot be superimposed.

[0028] The term "diastereomer" refers to stereoisomers that are not mirror images of each other.

[0029] The term "racemate" or "racemic mixture" refers to a composition consisting of equimolar amounts of two enantiomeric species that lacks 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 )alkyl" (where x and y are integers) refers to a straight-chain or branched-chain alkyl group having from x to y carbon atoms. Thus, when x is 1 and y is 4, for example, the term 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 resulting from the removal of two hydrogen atoms from different carbon atoms of an alkane and having from x to y carbon atoms, for example, methylenyl.

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

[0034] Examples of the "O(C x -C y )haloalkyl" group may thus include halogenated, poly-halogenated, and fully halogenated O-alkyl groups in which all hydrogen atoms are replaced by halogen atoms, for example, trifluoromethoxy and difluoromethoxy.

[0035] The term "(C x -C y )alkylene-NR x’ Ry’ (where x and y are integers) is a carbon atom that is NR x’ R y’ (where x' and y' are integers) is bonded to a nitrogen atom via the defined "(C x -C y ) refers to "alkylene".

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

[0037] The term “(C x -C y A "(C)haloalkyl" (where x and y are integers) is defined as a halogen atom 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 ) refers to the alkyl group. The "(C x -C y Examples of the "haloalkyl" group therefore may include halogenated, polyhalated, and fully halogenated alkyl groups in which all hydrogen atoms are replaced by halogen atoms, such as trifluoromethyl, 1,1,1-trifluoro-2-methylpropan-2-yl, and 1,1-difluoroethyl.

[0038] The term "aryl" refers to an aromatic monocyclic carbocyclic system containing six ring atoms. A suitable example of an aryl monocyclic system is phenyl.

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

[0040] The term “-C(O)NH-(C x -C y ) Alkilen-NR x’ R y’ (where x' and y' are integers) is defined above as "(C) NH-" where the alkylene is bonded to -C(O)NH- by its nitrogen atom. x -C y ) Alkilen-NR x’ R y’ This means "..."

[0041] The term “NHC(O)-(C x -C y ) Alkilen-NR x’ R y’ " is defined as "(C x -C y ) Alkilen-NR x’ R y’ This means "..."

[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 via oxygen, and the above-defined "(C x -C y )Alkylene is bonded to the amide group via its carbonyl portion, as defined above, "O(C x -C y )alkyl" and the above-defined "(C x -C y ) refers to "alkylene".

[0043] The term "NH-heteroaryl" refers to the "heteroaryl" defined above, in which the heteroaryl is bonded 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 heterocycloalkyls may include, for example, piperazinyl, oxopiperazinyl, dioxide thiomorpholino, oxetanyl, and pyrrolidinyl.

[0045] The term "heterocycloalkyl-(C) x -C y Alkylene is a linear or branched chain (C) having x to y carbon atoms. x -C y This refers to a heterocycloalkyl group bonded to an alkylene group.

[0046] The structural formula used here [ka] Bonds pointing towards wavy or curved lines, such as those shown above, indicate bonds that are attachment points to the core or main chain structure of the moiety or substituent.

[0047] When referring to a substituent, a dash ("-") without a space between two letters, words, or symbols indicates a point of connection between such substituents.

[0048] Here, the carbonyl group is preferably represented as -C(O)- as an alternative to other common notations such as -CO-, -(CO)-, or -C(=O)-.

[0049] When a basic amino group is present in the compound of formula (I), physiologically acceptable anions selected from chlorides, bromides, iodides, trifluoroacetates, formates, sulfates, phosphates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates, oxalates, succinates, benzoates, p-toluenesulfonates, pamoates, and naphthalenedisulfonates may be present. Similarly, in the presence of an acidic group, corresponding physiological cationic salts, for example, containing alkali or alkaline earth metal ions, may also be present.

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

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

[0052] As described above, the present invention provides inhibitory activity against receptors DDR1 and DDR2, with the general formula (I) detailed below. This relates to a series of compounds represented by [the specified formula]. Antagonization of receptors DDR1 and DDR2 may be particularly effective in treating diseases in which DDR receptors play a role, such as fibrosis and fibrosis-related diseases, disorders, and conditions.

[0053] In particular, as detailed in the experimental section below, the compounds of formula (I) of the present invention can act as inhibitors of both DDR1 and DDR2 receptors in a substantially effective manner. Specifically, Table 5 below shows the affinity for either the DDR1 or DDR2 receptor and the inhibitory activity for either the DDR1 or DDR2 receptor for the compounds of the present invention, respectively, in binding (indicated by Ki) and cell-based assays (IC). 50This indicates that the concentration is less than approximately 80 nM (as shown by ). This confirms that the compound of formula (I) can inhibit two isoforms of the DDR receptor, which are primarily 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] In contrast to the comparative compound of Example C1, which is characterized by the absence of a linker between the tetrahydrothienopyridine ring and the Hy group, as shown in the experimental portion and comparative examples, particularly Table 6, the presence of a -CH2- or -C(O)- linker at that position in the compound of the present invention unexpectedly and significantly determines the associated increase in inhibitory activity of DDR1 and DDR2 receptors.

[0055] Furthermore, as shown in the same experimental section, the data reveals 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 α position relative to the sulfur atom rather than at the β position in Example 3 of the present invention, the presence of the linker and the β-position substitution in the compound of the present invention unexpectedly and remarkably leads to a corresponding increase in inhibitory activity of DDR1 and DDR2 receptors.

[0056] The compounds of the present invention are advantageous because they possess extremely high efficacy and can be administered to humans at lower doses compared to compounds in the prior art, thereby reducing the adverse events that typically occur with the administration of high doses of drugs.

[0057] In addition to exhibiting remarkably potent inhibitory activity against both DDR1 and DDR2 receptors, the compounds of the present invention are characterized by their selective inhibitory properties of DDR1 and DDR2 receptors compared to other human protein kinases, a favorable inhalation profile that allows for effective action in the pulmonary region, and low metabolic stability that minimizes the drawbacks associated with systemic exposure, such as safety and tolerability issues.

[0058] Therefore, the compounds of the present invention are particularly well recognized by those skilled in the art who seek suitable and effective compounds useful for the treatment of fibrosis, especially idiopathic pulmonary fibrosis, which are administered via inhalation and are characterized by a good inhalation profile that corresponds to good activity in the lungs, good lung retention, and low metabolic stability that minimizes systemic exposure and associated safety issues.

[0059] Therefore, in one embodiment, the present invention relates to general formula (I) [ka] [During the ceremony, L is selected from the group consisting of -C(O)- and -CH2-; Hy can be -(C1-C4) alkyl, halogen atom, cyano, or -(CH2) depending on the case. 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 A monocyclic heteroaryl selected from alkyl, -NH-(C1-C6)alkylene-OH, -heteroaryl optionally substituted with one or more -(C1-C4)alkyl groups, and -NH-heteroaryl, wherein the heteroaryl is optionally substituted with one or more -(C1-C4)alkyl groups and optionally with one or more heterocycloalkyl groups selected from oxo and -(C1-C6)alkyl groups; R1 is: - Het is a heteroaryl which is 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] Selected from the group consisting of, Here, R2 is selected from the group consisting of -O(C1-C4) haloalkyl, halogen atoms, -O(C3-C7) cycloalkyl, and -(C1-C4) haloalkyl; R3 is either H or 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 a heteroaryl substituted with one or more -(C1-C4)alkyl groups, where the heterocycloalkyl is optionally substituted with one or more -(C1-C4)alkyl groups; n is 0, 1, or 2; R4 is either H or a -(C1-C4) alkyl group; R5 is either H or a -(C1-C4) alkyl group. This relates to the compounds and their pharmaceutically acceptable salts.

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

[0061] In another preferred embodiment, the present invention is such that R1 is X' [ka] The general formula is (Ia) [ka] [In the formula, L, Hy, R2, and R3 are as defined above.] This relates to compounds of general formula (I), represented by [formula].

[0062] In a more preferred embodiment, the present invention relates to formula (Iaa) where L is -CH2- [ka] [In the formula, Hy, R2, and R3 are as defined above.] This relates to the compound of formula (Ia), which is represented by [formula].

[0063] In other preferred embodiments, the present invention includes Hy, pyridine-3-yl, pyrimidine-5-yl, ((1-methyl-1H-pyrazole-4-yl)amino)pyrimidine-5-yl, 4-(2-methoxyacetamide)pyridine-3-yl, 5-cyanopyridine-3-yl, 5-chloropyridine-3-yl, 5-methoxypyridine-3-yl, 5-methylpyridine-3-yl, 5-(trifluoromethyl)pyridine-3-yl, 3-aminopyrazine-2-yl, 2-aminopyrimidine-5-yl, 5-(4-methyl-3-oxopiperazine-1-yl)pyridine-3-yl, 5-(1,1-dioxidethiomorpholino)pyridine-3-yl, -((5-(2-(dimethylamino)acetamide)pyridine-3-yl, 2-(oxetane-3- This invention relates to compounds of general formula (Iaa) selected from the group consisting of ylamino)pyrimidine-5-yl, 2-acetamidopyrimidine-5-yl, (2-(methylamino)pyrimidine-5-yl, ((2-methoxyethyl)amino)pyrimidine-5-yl, 6-acetamidopyridine-3-yl, 2-aminopyridine-3-yl, ((2-hydroxyethyl)amino)pyrimidine-5-yl, 4-aminopyrimidine-5-yl, 2-amino-4-methylpyrimidine-5-yl, (2-fluoropropan-2-yl)pyrimidine-5-yl, 4-methoxypyrimidine-5-yl, 4-cyclopropoxypyrimidine-5-yl, (1-methyl-1H-pyrazole-4-yl)pyridine-3-yl, and (5-fluoropyridine-3-yl)methyl.

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

[0065] In other particularly preferred embodiments, the present invention relates to compounds of general formula (Iaa) in which R3 is H or selected from the group consisting of (4-methylpiperazine-1-yl)methyl, 4-methyl-1H-imidazole-1-yl, fluorine, (3-(dimethylamino)pyrrolidine-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) listed in Table 1 below and its pharmaceutically acceptable salts. These compounds are particularly active against 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 is characterized in that L is -CH2- and R1 is X'' [ka] The expression is (Iaa'). [ka] [In the formula, Hy, R2, and R3 are as defined above.] This relates to the compound of formula (I), which is represented by [formula].

[0069] In another preferred embodiment, the present invention relates to a compound of general formula (Iaa') in which R2 is trifluoromethyl.

[0070] In a more preferred embodiment, the present invention relates to a compound of general formula (Iaa') in which R3 is fluorine.

[0071] In a particularly preferred embodiment, the present invention relates to a compound of general formula (Iaa') in which Hy is pyrimidine-5-yl.

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

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

[0074] In a particularly preferred embodiment, the present invention relates to a compound of general formula (Iaa'') in which R2 is selected from the group consisting of trifluoromethyl and trifluoromethoxy.

[0075] In other particularly preferred embodiments, the present invention relates to compounds of general formula (Iaa'') in which R3 is selected from the group consisting of fluorine, chlorine, and (dimethylamino)methyl.

[0076] In a more preferred embodiment, the present invention relates to a compound of general formula (Iaa'') in which Hy is pyrimidine-5-yl and 2-aminopyrimidine-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 pharmaceutically acceptable salts thereof. These compounds are particularly active against receptors DDR1 and DDR2, as shown in Table 5.

[0078] [Table 11]

[0079] In another preferred embodiment, the present invention is a formula (Iab) in which L is -C(O)- [ka] [In the formula, Hy, R2, and R3 are as defined above.] This relates to the compound represented by formula (Ia).

[0080] In a particularly preferred embodiment, the present invention relates to a compound of general formula (Iab) in which R2 is trifluoromethyl.

[0081] In other particularly preferred embodiments, the present invention relates to compounds of general formula (Iab) in which R3 is fluorine.

[0082] In a more preferred embodiment, the present invention relates to a compound of general formula (Iab) in which Hy is 1-methyl-1H-imidazole-5-yl. According to a preferred embodiment, the present invention relates to a compound of formula (Iab) shown in Table 7 below and its pharmaceutically acceptable salts. [Table 12]

[0083] In a more preferred embodiment, the present invention relates to formula (Ib), where R1 is Het. [ka] [During the ceremony, L is selected from the group consisting of -C(O)- and -CH2-; Hy can be -(C1-C4) alkyl, halogen atom, cyano, or -(CH2) depending on the case. n A 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 (where the heteroaryl is optionally substituted with one or more -(C1-C4)alkyl groups); Het is a heteroaryl atom optionally substituted with one or more groups selected from -(C1-C4)alkyl, -(C1-C4)haloalkyl, and aryl atoms, wherein the aryl atom optionally substituted with one or more groups selected from -(C1-C4)alkyl and halogen atoms; R4 is H; R5 is either H or a -(C1-C4) alkyl group. This relates to the compound of formula (I) represented by and its pharmaceutically acceptable salts.

[0084] In another preferred embodiment, the present invention relates to a formula (Iba) where L is -CH2- [ka] [In the formula, Hy and Het are as defined above.] This relates to the compound represented by formula (Ib).

[0085] In a more preferred embodiment, the present invention relates to a compound of general formula (Iba) in which Hy is selected from the group consisting of pyrimidine-5-yl, 3-aminopyrazine-2-yl, 5-methoxypyridine-3-yl, 5-fluoropyridine-3-yl, pyridine-3-yl, 3-aminopyrazine-2-yl, and (2-((1-methyl-1H-pyrazole-4-yl)amino)pyrimidine-5-yl)methyl.

[0086] In other particularly preferred embodiments, the present invention relates to compounds of general formula (Iba) in which Het is selected from the group consisting of 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazole-3-yl, (trifluoromethyl)pyridine-3-yl, 2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridine-4-yl, 5-(trifluoromethoxy)pyridine-3-yl and 3-(tert-butyl)-1-methyl-1H-pyrazole-5-yl.

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

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

[0089] In a more preferred embodiment, the present invention relates to formula (Ibb) where L is -C(O)- [ka] [In the formula, Hy and Het are as defined above.] This relates to the compound represented by formula (Ib).

[0090] The compounds of the present invention, including all of the compounds listed above, can be prepared from readily available starting materials by following the general methods and procedures described herein or by using slightly modified procedures readily available to those skilled in the art. While specific embodiments of the present invention may be shown or described herein, those skilled in the art will recognize that all embodiments or aspects of the present invention can be obtained using the methods described herein or by other known methods, reagents, and starting materials. Even when typical or preferred process conditions (i.e., reaction temperature, time, molar concentration of reagents, solvent, pressure, etc.) are given, other process conditions may also be used unless specifically denied. Optimal reaction conditions may vary depending on the specific reagent or solvent used, but such conditions can be readily determined by those skilled in the art through routine optimization procedures.

[0091] In some cases, when masking or protection of sensitive or reactive moieties is necessary, commonly known protecting groups (PGs) can be used in accordance with general principles of chemistry (Protective group in organic syntheses, 3rd ed. TW Greene, PGM Wuts).

[0092] The compounds of formula (I) of the present invention have surprisingly been found to efficiently inhibit both receptors DDR1 and DDR2. Advantageously, inhibition of receptors DDR1 and DDR2 may result in effective treatment of diseases or conditions involving DDR receptors.

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

[0094] Furthermore, as shown in the experimental section, affinity for both DDR1 and DDR2 receptors and inhibitory activity for both DDR1 and DDR2 receptors were measured by binding (indicated by Ki) and cell-based assay (IC), respectively. 50 It was found to be less than approximately 80 nM (as shown). Preferably, the compounds of the present invention have Ki and / or IC of less than 50 nM for DDR1 and DDR2 receptors. 50 The compound of the present invention has a Ki and / or IC of less than 25 nM for DDR1 and DDR2 receptors. More preferably, the compound of the present invention has a Ki and / or IC of less than 25 nM for DDR1 and DDR2 receptors. 50 It has.

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

[0096] In a preferred embodiment, the present invention relates to a compound of formula (I) and its pharmaceutically acceptable salts for use in treating diseases, disorders, or conditions associated with dysregulation of DDR.

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

[0098] In a preferred embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the prevention and / or treatment of diseases, disorders or conditions associated with the DDR receptor mechanism. In a certain embodiment, the present invention relates to a compound of formula (I) useful for the prevention and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0099] The terms “fibrosis” or “fibrotic disorder” as used herein refer to conditions associated with the abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased fibroblast recruitment, and include, but are not limited to, fibrosis of individual organs or tissues such as the heart, kidneys, liver, joints, lungs, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal system, and gastrointestinal tract.

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

[0101] More preferably, the compound of formula (I) is 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 a disorder associated with the DDR receptor mechanism, comprising administering a therapeutically effective amount of the compound of formula (I) to a patient in need of such treatment.

[0103] In a further embodiment, the present invention relates to the use of compounds of formula (I) above for the treatment of disorders of the DDR receptor mechanism and related disorders.

[0104] In another embodiment, the present invention relates to the use of the compound of formula (I) in the manufacture of a pharmaceutical product for treating disorders associated with the DDR receptor mechanism.

[0105] In a further embodiment, 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 a therapeutically effective amount of the compound of formula (I) to a patient in need of such treatment.

[0106] In a further embodiment, the present invention relates to the use of compounds of formula (I) above for the treatment of diseases, disorders or conditions involving dysregulation of DDR receptors 1 and 2.

[0107] As used herein in relation to the compound of formula (I) or its pharmaceutically acceptable salt or other pharmaceutically active agent, the “safe and effective amount” means an amount of the compound that is sufficient to treat the patient’s condition but low enough to avoid serious side effects, and such an amount can be routinely determined by those skilled in the art.

[0108] The compound of formula (I) may be administered in single or multiple doses in a dosing regimen at various intervals over a period of time. The typical daily dose may vary depending on the chosen route of administration.

[0109] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) according to any embodiment, mixed with at least one pharmaceutically acceptable carrier or additive.

[0110] In one embodiment, the present invention relates to a pharmaceutical composition obtained by mixing a compound of formula (I) with one or more pharmaceutically acceptable carriers or additives, for example, those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA.

[0111] The compounds of the present invention and their pharmaceutical compositions can be administered, depending on the patient's needs, for example, orally, nasally, non-enterally (subcutaneous, intravenously, intramuscularly, intrasternally, and intravenously), and by inhalation.

[0112] Preferably, the compound of the present invention is administered orally or by inhalation.

[0113] In one preferred embodiment, the pharmaceutical composition comprising the compound of formula (I) is in the form of a solid oral dosage form such as a tablet, gel cap, capsule, caplet, granule, lozenge, or powder.

[0114] In one embodiment, the pharmaceutical composition containing the compound of formula (I) is a tablet.

[0115] The compounds of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (e.g., sucrose, mannitol, lactose, starch), and known additives, including suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, colorants, flavoring agents, and lubricants.

[0116] In further embodiments, the pharmaceutical composition comprising the compound of formula (I) is in the form of a liquid oral administration, such as aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such liquid administration forms may also include a suitable known inert diluent such as water, as well as suitable known additives such as preservatives, humectants, sweeteners, flavorings, and agents for emulsifying and / or suspending the compound of the present invention.

[0117] In further embodiments, the pharmaceutical composition comprising the compound of formula (I) is an inhalable agent such as an inhalable powder, a quantified aerosol containing a propellant, or an inhalable formulation without a propellant.

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

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

[0120] An inhalation aerosol containing a propellant gas such as a hydrofluoroalkane can be incorporated into the compound of the present invention in solution or dispersion form. The propellant-driven formulation may also contain other components such as a cosolvent, stabilizer, and optionally other additives.

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

[0122] The compounds of the present invention can be administered as a sole active ingredient or in combination with other pharmaceutically active ingredients.

[0123] The dosage of the compound of the present invention depends on a variety of factors, including, in particular, the specific disease being treated, the severity of the symptoms, and the route of administration.

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

[0125] All of the above preferred groups or embodiments of compounds of formula (I) can be applied similarly to each other, in combination with modifications where appropriate.

[0126] The compounds of the present invention, including all of the compounds listed above, can be prepared from readily available starting materials by following the following general methods and procedures or by using slightly modified procedures readily available to those skilled in the art. While specific embodiments of the present invention may be shown or described herein, those skilled in the art will recognize that all embodiments or aspects of the present invention can be carried out using the methods described herein or other known methods, reagents, and starting materials. Where typical or preferred process conditions (i.e., reaction temperature, time, molar concentration of reagents, solvent, pressure, etc.) are given, other process conditions may also be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reagent or solvent used, but such conditions can be readily determined by those skilled in the art through routine optimization procedures.

[0127] Therefore, the steps described below and in the following scheme should not be considered to limit the range of synthetic methods available for the production of the compounds of the present invention.

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

[0129] In the first embodiment of the present invention, where R1, L, and Hy are as defined above, the compound of formula (I) can be prepared as shown in Scheme 1.

[0130] The compound of formula (I) can be prepared according to scheme 1 below, which provides at least one non-restrictive synthetic route for the production of all example compounds.

[0131] [ka] According to Scheme 1, intermediate III can be prepared by a one-step synthesis starting from intermediate II, using butyllithium as a promoter under direct ester amidation (amino group transfer) conditions, in a suitable organic solvent such as THF or dioxane, at a temperature in the range of -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 a solution of HCl in dioxane or TFA in a suitable solvent such as DCM, at a suitable temperature in the range of 0°C to room temperature. The compound of formula (I) can be obtained by using a suitable alkyl bromide intermediate XII and a suitable base such as DIPEA or TEA, in a suitable solvent such as DMF or DMA, at room temperature, under suitable alkylation conditions.

[0132] Alternatively, intermediate III can be produced by hydrolyzing intermediate II with a suitable aqueous inorganic base such as NaOH in a suitable solvent such as MeOH at room temperature, and then carrying out amide coupling with a suitable amine VIII or IX in a suitable organic solvent such as DCM or DMF and generally at approximately room temperature, in the presence of a reagent that activates a carboxylic acid partner such as TBTU or HATU or T3P and an organic base such as DIPEA or TEA.

[0133] Alternatively, intermediate III can be produced from intermediate II by obtaining a transiently activated acylimidazolinium intermediate in the presence of TCFH and 1-methylimidazole, or via amidation, and then reacting this with a suitable amine VIII or IX in a solvent such as DMF at RT. Alternatively, intermediate III can be produced from intermediate II by obtaining the corresponding acyl chloride in the presence of a suitable chlorinating agent such as POCl3, 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 a temperature ranging from 5°C to room temperature, and then directly treating this with a suitable amine VIII or IX.

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

[0135] Using a different approach, intermediate VI, intermediate IV Therefore, it can be prepared by applying the above appropriate reductive amination conditions using a suitable aldehyde XI, and then converting it to the compound of formula (I) via amidation with a suitable acyl chloride XIV in a suitable solvent such as THF at room temperature using a suitable base such as TEA or DIPEA. The compound of formula (I) can also be obtained from intermediate IV using a suitable aldehyde XIII according to the above reductive amination conditions. Alternatively, the compound of formula (I) can be prepared from intermediate IV by amidation with a suitable carboxylic acid by applying the above conditions.

[0136] In other embodiments, 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 appropriate deprotection conditions, for example, using aqueous HCl or a solution of HCl, dioxane, or TFA, in a suitable solvent such as DCM or diethyl ether, at a suitable temperature in the range of 0°C to room temperature. Intermediate XV can be obtained by 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 in the range of room temperature to 50°C. Next, the compound of formula (I) can be prepared by hydrolyzing intermediate XVI in a suitable solvent such as MeOH at room temperature using a suitable aqueous inorganic base such as NaOH, followed by amide coupling with a suitable amine VIII or IX in a suitable organic solvent such as DCM or DMF and generally at approximately room temperature, under suitable amide coupling conditions, in the presence of a reagent that activates the carboxylic acid partner such as TBTU or HATU or T3P, and in the presence of an organic base such as DIPEA or TEA. Alternatively, the compound of formula (I) can be prepared by hydrolyzing intermediate XVII in the presence of a suitable chlorinating agent such as POCl3, thionyl chloride, or oxalyl chloride, in a solvent such as pyridine or cyclopentyl methyl ether if necessary, in the presence of a catalytic amount of DMF if necessary, at a temperature in the range of 5°C to 50°C, obtaining the corresponding acyl chloride XVIII, and then subjecting it to amide coupling with a suitable amide VIII in a suitable solvent such as DCM at approximately room temperature using a suitable base such as TEA.

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

[0139] Preparation of intermediates and example compounds The compound names were created using the Structure To Name Place IUPAC Name Name method in PerkinElmer ChemDraw Professional 19.1.1.21. All reagents whose synthesis is not described in the experimental section are either commercially available, known compounds, or can be manufactured by a person skilled in the art from known compounds by known methods.

[0140] In the following methods, some of the starting materials are identified by "Intermediate" or "Example" number, along with the step number designation. These are provided solely for the assistance of experienced chemists.

[0141] "Similar" or "equivalent" methods mean that such methods may involve minor modifications, for example, to reaction temperature, reagent / solvent ratios, reaction time, workup conditions, or chromatographic purification conditions.

[0142] Abbreviations - Meaning RM = reaction mixture; TEA = triethylamine; HATU = (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridine-3-yloxy)methaneiminium hexafluorophosphate; DMAP = 4-dimethylaminopyridine; TCFH = chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate; DMF = N,N-dimethylformamide; Et2O = diethyl ether; Depositphotos = ethyl acetate; THF = tetrahydrofuran; DCM = dichloromethane; ACN = acetonitrile; MeOH = methyl alcohol; IMS = industrial denatured alcohol; RT = room temperature; LCMS = liquid chromatography / mass spectrometry; HPLC = high-performance liquid chromatography Graphy; TLC = Thin-layer chromatography; SCX = Solid cation exchange; DMSO-d6 = Deuterated dimethyl sulfoxide; CDCl3 = Deuterated chloroform; NaBH3CN = Sodium cyanobolohydride; ACN-d3 = Deuterated acetonitrile; NMR = Nuclear magnetic resonance; DIPEA = N,N-diisopropylethylamine; HCOOH = Formic acid; ULC = Ultra-performance 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-dicyclohexylphosphin-2',6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate; STAB = sodium triacetoxyborohydride; AcOH = acetic acid; T3P = propanephosphonic anhydride; Preparative 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: 1¹H NMR spectra were recorded using a Varian MR-400 spectrometer or a Bruker Avance III HD 400 MHz or Bruker Fourier 300 MHz, operated with a quadrature digital detection unit featuring a 5 mm 1H / nX broadband probe head with a self-shielding Z gradient coil 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 expressed in Hertz (Hz), and multiplicity is reported using the following abbreviations: s=singlet, d=doublet, t=triplet, q=quadruplet, dd=doublet of doublet, dt=triplet of doublet, m=multitlet, br=broad, nd=undetermined.

[0144] In some cases, the NH signal from an amide or amine bond (exchangeable proton) is invisible.

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

[0146] LC / UV / MS analysis method The LC / MS retention time is estimated to be affected by an experimental error of ±0.5 minutes.

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

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

[0149] Method 3: Kinetex® XB-C18 column, 4.6 × 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: ACN (0.1% HCOOH) in water (0.1% HCOOH), 95% to 20% within 4.75 minutes; 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 × 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: ACN (0.1% HCOOH) in water (0.1% HCOOH), 90% to 5% within 3.90 minutes; 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 × 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: ACN (0.1% HCOOH) in water (0.1% HCOOH), 70% to 5% within 3.90 minutes; flow rate: 1.0 ml / min; wavelength: 190 to 340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus.

[0152] Method 6: Kinetex® XB-C18 column, 4.6 × 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: ACN (0.1% HCOOH) in water (0.1% HCOOH), 70% to 5% within 3.90 minutes; flow rate: 1.0 ml / min; wavelength: 190 to 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 × 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: ACN (0.1% HCOOH) in water (0.1% HCOOH), 80% to 5% within 3.90 minutes; flow rate: 1.0 ml / min; wavelength: 190 to 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 × 2.1 mm, 1.72 μm (Plus Guard cartridge), maintained at 40°C. Mobile phase: ACN + 10 nM ammonium bicarbonate in water, 5% to 95% within 5.6 minutes. 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 × 2.1 mm, 1.8 μm (Plus Guard cartridge), maintained at 40°C. Mobile phase: ACN (0.1% HCOOH) in water (0.1% HCOOH). 5% to 95% within 5.6 minutes. 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 × 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 minutes; flow rate: 0.4 ml / min; wavelength: 100 to 800 nm DAD. Acquity UPLC with PDA detector and ZQ mass spectrometer.

[0157] Method 11: Agilent Zorbax column 4.6 × 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 minutes. Flow rate: 3.0 ml / min. Wavelength: 210 to 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 × 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 minutes; flow rate: 0.8 ml / min; wavelength: 210 to 400 nm. DAD. Acquity H-Class UPLC with PDA detector and QDa.

[0159] Method 13: Waters Sunfire C18 column, 4.6 × 50 mm, 3.5 μm, maintained at 40°C. Mobile phase: ACN + 10 mM ammonium bicarbonate in water, 5-95% within 2.5 minutes. Flow rate: 2.0 ml / min. Wavelength: 210-400 nm. DAD. Waters 2795 separation module + Waters DAD + Micromass ZQ, single quadrupole LC-MS.

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

[0161] Preparative HPLC was performed using reverse-phase (C18) preparative HPLC under both basic conditions (ACN + 0.1% NH3, H2O + 0.1% NH3) and acidic conditions (ACN + 0.1% HCOOH, H2O + 0.1% HCOOH). In the latter case, unless otherwise specified, the residue was ground with NaHCO3 (15% aqueous solution), and the precipitate was then filtered through a Schott funnel, rinsed with water, transferred to a vial, and dried overnight under high vacuum using RT or using SCX(NH) to obtain the free base 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 synthesis procedure General Procedure A N,N-diisopropylethylamine (3.00-8.00 equivalents) was added to a mixture of the required carboxylic acid (1.00 equivalent) and HATU (1.20-2.00 equivalents) in DMF (0.1 M concentration). The reaction mixture was stirred at RT for 15 minutes, and then the required amine (1.00 equivalent) was added. The reaction mixture was stirred at RT by LC-MS until the consumption of the starting materials was indicated, and then concentrated.

[0163] General Procedure B The required carboxylic acid (1.00 equivalent) was suspended in thionyl chloride (30 equivalents), and the reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was suspended in toluene and reconcentrated to obtain the intermediate asyl chloride. The asyl chloride was added to a 0.1 M solution of the required aniline (1.00 equivalent) and TEA (3.00 equivalents). The reaction mixture was stirred to RT until consumption of the starting materials was indicated by LC-MS, and then concentrated under reduced pressure.

[0164] General procedure C A solution of the required amine (1.00 equivalent) and the required aldehyde (1.00 equivalent) in MeOH (0.03 M concentration) was added with titanium(IV) isopropoxide (3.00 equivalents) and refluxed for 2 h. The reaction mixture was cooled to RT, added with NaBH3CN (2.50 equivalents), and stirred 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 equivalent) in DCM (0.1 M concentration) were added the required amine (1.10 equivalents), titanium(IV) isopropoxide (2.00 equivalents) and AcOH (3.00 equivalents). The reaction mixture was stirred at room temperature for 1 h. STAB (2.00 equivalents) was added and the reaction mixture was stirred at room temperature until LCMS indicated consumption of the starting materials. The residue was loaded onto an Isolute SCX-II cartridge, washed with MeOH, and then eluted with 2 M NH3 / MeOH. The eluate was concentrated under reduced pressure.

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

[0167] General procedure F AcOH (10 equivalents) was added to a mixture of the required aldehyde (1.00 equivalent) and the required amine (1.00 equivalent) in MeOH (0.075 M concentration), 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 (0.025 M concentration), and sodium STAB (3.50 equivalents) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with DCM, and KHSO 4(水性)The mixture was treated with a 10% solution of [the substance]. After stirring for 15 minutes, the mixture was basicized with saturated aqueous solution Na2CO3, and the layers were separated. The aqueous layer was extracted with DCM, and the combined organic extract was filtered through hydrophobic frit and concentrated under reduced pressure.

[0168] General Procedure G TCFH (1.20-1.50 equivalents) was added to a solution of the required acid (1.00 equivalent), the required amine (1.00-1.30 equivalents), and 1-methylimidazole (3.50 equivalents) in ACN (0.2 M concentration). The reaction mixture was stirred at room temperature until LCMS showed consumption of the starting materials, and saturated NaHCO3 was added. 3(水性) The two phases were then separated and the aqueous phase was extracted with 2× SiO2. The combined organic phase was then concentrated under reduced pressure by passing it through hydrophobic frit.

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

[0170] Preparation of intermediate 1:2-((1-methyl-1H-pyrazole-4-yl)amino)pyrimidine-5-carboaldehyde [ka] Step 1; 2-((1-methyl-1H-pyrazole-4-yl)amino)pyrimidine-5-carboaldehyde 2-Chloropyrimidine-5-carboaldehyde (50 mg, 0.351 mmol) was dissolved in THF (3.5 mL), and then 1-methyl-1H-pyrazole-4-amine (41 mg, 0.421 mmol) was added. The reaction mixture was stirred overnight in RT. The reaction was stopped by adding DCM and brine to the mixture. The phases were separated, and the aqueous layer was washed with DCM (×2). All combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC elution with hexane / Âi 1:1 to obtain 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] Preparation of intermediate 20: 2-(oxetane-3-ylamino)pyrimidine-5-carbaldehyde [ka] Step 1: 2-(oxetane-3-ylamino)pyrimidine-5-carbaldehyde To a solution of 2-chloropyrimidine-5-carboaldehyde (50 mg, 0.351 mmol, 1.00 equivalent) in DMSO (1.5 mL), TEA (0.049 mL, 0.351 mmol, 1.00 equivalent) and 3-aminooxetane (0.027 mL, 0.386 mmol, 1.10 equivalent) were added, and the solution was stirred at 60°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with DCM, and washed with water and brine. The organic layer was dried in (MgSO4) and concentrated to obtain the title compound (62 mg, 100%). LC-MS (ESI): m / z (M+1) = 180.2; t R = 1.00 minutes Method 11

[0172] Preparation of intermediate 21: 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-carboaldehyde (3000 mg, 21.0 mmol, 1.00 equivalent) and p-toluenesulfonic acid monohydrate (400 mg, 2.10 mmol, 0.10 equivalent) in EtOH (60 mL), triethyl orthoformate (11 mL, 63.1 mmol, 3.00 equivalent) was added, and the mixture was heated to 80°C and stirred for 3 hours. The mixture was cooled to 0°C, and 10 mL of saturated aqueous solution NaHCO3 was added to evaporate the EtOH. The resulting suspension was extracted with ethyl acetate, the organic layers were combined, dried, and concentrated in (MgSO4). The residue was purified on silica gel in a cyclohexane solution of 0-20% ethyl acetate (120 g) to obtain 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)pyrimidine-2-amine (intermediate 23) [ka] To a solution of intermediate 22 (200 mg, 0.923 mmol, 1.00 equivalent) and 2-methoxyethylamine (80 μL, 0.923 mmol, 1.00 equivalent) in DMF (3.0 mL), K2CO3 (319 mg, 2.31 mmol, 2.50 equivalents) was added, and the mixture was stirred at 80°C for 2 hours. The reaction mixture was diluted with RINKAN, washed with water, 1:1 water / brine solution, and brine, dried over MgSO4, and concentrated. The residue was purified with silica FCC (12 g, cyclohexane solution of 0-80% RINKAN) to obtain the title compound (103 mg, 44%). 1 1H 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 = 7.0 Hz, 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 eq) in THF (1.0 mL) was added 1M HCl solution (21 mL, 20.6 mmol, 52.0 eq), 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 1H 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

Chemical Structure

Chemical Structure

[0176] Step 2: 2-(2-hydroxyethylamino)pyrimidine-5-carbaldehyde (intermediate 24) To a solution of intermediate 25 (61 mg, 0.253 mmol, 1.00 equivalent) in THF (1.00 mL), a solution of H2O in 1 M HCl (13 mL, 13.1 mmol, 52.0 equivalents) was added, and the mixture was stirred at RT for 5 hours, followed by overnight stirring at 50°C. The mixture was cooled in an ice bath and basicized to approximately pH 13 with 2 M aqueous NaOH. The aqueous layer was extracted with RINKAN. The majority of the target substance remained in the aqueous layer. This was concentrated, and the solid was ground with MeOH. The dissolved substance was combined with the organic extract and concentrated to obtain the title compound (42 mg). Based on the estimated quantitative yield, it 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] Preparation of intermediate 26: 2-amino-4-methylpyrimidine-5-carboaldehyde [ka] Step 1: (2-amino-4-methylpyrimidine-5-yl)methanol (intermediate 27) [ka] To a suspension of 2-amino-4-methylpyrimidine-5-carboxylic acid (250 mg, 1.63 mmol, 1.00 equivalent) in THF (12 mL), isobutyl chloroformate (0.25 mL, 1.96 mmol, 1.20 equivalent), followed by 4-methylmorpholine (0.22 mL, 1.96 mmol, 1.20 equivalent), was added at 0°C. After stirring for 2 hours, the precipitate was removed by filtration. The filtrate was added to a solution of NaBH4 (93 mg, 2.45 mmol, 1.50 equivalent) in water (0.60 mL) at 0°C. The reaction mixture was heated to rt and stirred for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was used directly in the next step.

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

[0179] Preparation of Intermediate 28: (R)-1-(3-amino-5-(trifluoromethyl)benzyl)-N,N-dimethylpyrrolidine-3-amine [ka] Step 1: (R)-N,N-dimethyl-1-(3-nitro-5-(trifluoromethyl)benzyl)pyrrolidine-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), titanium(IV) isopropoxide (2.0 mL, 6.85 mmol) and AcOH (588 μL, 10.3 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. STAB (1.45 g, 6.85 mmol) was then added, and the reaction mixture was stirred at room temperature for a further 2.5 hours. The reaction mixture was stopped by adding water, and the layers were separated. The aqueous phase was adjusted to pH 9 by adding NaOH, and DCM was added. The combined phases were filtered through a Celite pad and then separated. The aqueous phase was re-extracted with DCM, and the combined organic phases were filtered through hydrophobic frit and concentrated under reduced pressure. Purification using silica FCC (24g cartridge, 0-5% 2M NH3 / MeOH DCM solution) yielded the title compound (786 mg, 72%). 1 1H 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). No 1H signal was observed, presumably due to overlap with the DMSO signal.

[0180] Step 2: (R)-1-(3-amino-5-(trifluoromethyl)benzyl)-N,N-dimethylpyrrolidine-3-amine (intermediate 28) Palladium (10% by weight on carbon, 79 mg, 0.739 mmol) was mixed with a 24.5 mL IMS solution of intermediate 29 (786 mg, 2.48 mmol). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through Celite, and the filter bed was washed with DCM. The filtrate was concentrated under reduced pressure to obtain 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 and steps 1-2, using the corresponding commercially available amine and / or aryl aldehyde in step 1. [Table 16]

[0182] Preparation of intermediate 32:4-(cyclopropoxy)pyrimidine-5-carbaldehyde [ka] Step 1: Ethyl 4-(cyclopropoxy)pyrimidine-5-carboxylate (intermediate 33) [ka] A cyclopropanol solution (0.9 M in THF, 2.7 mL, 2.41 mmol, 1.50 equivalents) was added to a THF (2.0 mL) solution of NaH (60% dispersed in mineral oil, 129 mg, 3.22 mmol, 2.00 equivalents). The reaction mixture was stirred on ice water for 10 minutes, and then a THF (0.7 mL) solution of ethyl 4-chloropyrimidine-5-carboxylate (300 mg, 1.61 mmol, 1.00 equivalent) was added. The reaction mixture was stirred for 10 minutes, warmed to room temperature, and stirred for 1.5 hours. The reaction mixture was cooled with ice / water and saturated with NH4Cl (水性)The following compound was added. The aqueous phase was extracted with 3× siRNA, and the combined organic phase was passed through hydrophobic frit and concentrated under reduced pressure to obtain 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)pyrimidine-5-yl]methanol (intermediate 34) [ka] Argon was passed through a solution of intermediate 33 (251 mg, 1.21 mmol, 1.00 equivalent) in anhydrous THF (10.9 mL) for 10 minutes, cooled in a dry ice / acetone bath, and then 2 M LiAlH4 (2 M in THF, 0.54 mL, 1.08 mmol, 0.900 equivalents) was added dropwise. The reaction mixture was stirred for 10 minutes until the TLC showed consumption of SM, and then diluted with anhydrous Et2O (10 mL). The flask was transferred to an ice bath and filled with water (41 μL) and 15% NaOH. (水性) (41 μL) and water (123 μL) were added, and the reaction mixture was stirred for 15 minutes while warming to room temperature. MgSO4 was added, and the reaction mixture was stirred for 15 minutes and filtered. The filtrate was concentrated under reduced pressure. The obtained solid was purified using a 15 μm silica gel FCC (25 g cartridge, 0-7% 2M NH3 / MeOH DCM solution) to obtain 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 equivalent) in anhydrous DCM (4 mL), Dess-Martin periodinane (431 mg, 1.02 mmol, 1.30 equivalents) was added while stirring on an ice / water bath. The reaction mixture was warmed to room temperature, stirred for 2 hours, and diluted with DCM. The organic phase was washed with 10 wt% Na2S2O 5(水性) , followed by saturated NaHCO 3(水性) . The NaHCO 3(水性) solution was extracted with DCM, and the combined organic phases were passed through a hydrophobic frit and concentrated in part under reduced pressure to give the title compound (194 mg, >100%). 1 1H 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] Intermediate 35: Preparation of 2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-amine

Chemical Structure

Chemical Structure

[0186] Step 2: 4-amino-6-(trifluoromethyl)picolinealdehyde (intermediate 37) [ka] To a THF (4.82 mL) solution of intermediate 36 (308 mg, 1.24 mmol) cooled in an ice / water bath and stirred, LiAlH4 (2 M in THF, 0.62 mL, 1.24 mmol) was added dropwise while maintaining the internal temperature at 6°C. The reaction mixture was stirred for 1 hour 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 warmed to room temperature and stirred for 15 minutes. Anhydrous MgSO4 was added, and the reaction mixture was stirred for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain 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)pyridine-4-amine (intermediate 35) The compound was prepared according to general procedure D from intermediate 37 (126 mg, 0.663 mmol) and dimethylamine (2M solution in THF) (0.33 mL, 0.663 mmol). It was purified using silica FCC (12 g cartridge, 0-8% 2M NH3 / MeOH DCM solution) to obtain 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] Preparation of intermediate 38: 5-(trifluoromethoxy)pyridine-3-amine (hydrochloride) Step 1: tert-butyl N-[5-(trifluoromethoxy)-3-pyridyl]carbamate (intermediate 39) [Chemistry] A mixture of tert-butyl carbamate (102 mg, 0.868 mmol, 1.20 eq), Xantphos (63 mg, 0.108 mmol, 0.150 eq), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (37 mg, 0.0362 mmol, 0.0500 eq) and Cs2CO3 (283 mg, 0.868 mmol, 1.20 eq) in 1,4-dioxane (5 mL) was degassed with nitrogen and treated with 3-bromo-5-(trifluoromethoxy)pyridine (175 mg, 0.723 mmol, 1.00 eq). The reaction was stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature, filtered through a pad of celite, then washed with dioxane, and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica FCC (0 - 100%, cyclohexane solution of EtOAc) and then dried overnight under reduced pressure 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) (Intermediate 38) To a solution of Intermediate 39 (115 mg, 0.413 mmol, 1.00 eq) in 1,4-dioxane (3 mL) was added 4N HCl in 1,4-dioxane (3.0 mL, 0.413 mmol, 1.00 eq). 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 min Method 13

[0190] Intermediate 40: Preparation of N-(5-formylpyrimidine-2-yl)acetamide [ka] Step 1: N-(5-formylpyrimidine-2-yl)acetamide (intermediate 40) 2-aminopyrimidine-5-carboxyaldehyde (100 mg, 0.812 mmol, 1.00 equivalent) was dissolved in anhydride acetic acid (2.0 mL, 22.8 mmol, 28.1 equivalents), and the reaction mixture was heated at 140°C for 90 minutes. The reaction mixture was cooled to room temperature, a solid precipitated, the reaction mixture was washed with 2:1 cyclohexane / Et2O, filtered, the solid was washed with cyclohexane, and dried under reduced pressure. The title compound (84 mg, 0.509 mmol, 62.6% yield) was obtained. 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-methylpiperazine-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyridine-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1; tert-butyl3-((3-((4-methylpiperazine-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (intermediate 2) [ka] 3-((4-methylpiperazine-1-yl)methyl)-5-(trifluoromethyl)aniline (1050 mg, 3.84 mmol) was dissolved in dry THF (vol.: 50 ml, ratio: 2.500) under nitrogen, and the mixture was stirred at -78°C for 15 minutes. Then, 2.5 M n-BuLi (1.342 ml, 3.36 mmol) in hexane was added dropwise over 5 minutes, and the reaction mixture was stirred at -78°C for 1 hour. 6-(tert-butyl)3-ethyl 4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (950 mg, 3.05 mmol) in THF (vol.: 20 ml, ratio: 1.000) was added dropwise over 10 minutes, the temperature was raised to RT, and the reaction mixture was stirred for 1 hour. 10 mL of water was added to stop the reaction, 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 × 20 mL) and brine (1 × 20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by reverse-phase FCC to obtain 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-methylpiperazine-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 minutes. 50 mL of ethanol was added to the reactants, and the solvent was evaporated under reduced pressure until the title compound (1.31 g, 2.391 mmol, 91% yield) was obtained.

[0193] Step 3; 6-(4-cyanobenzyl)-N-(3-((4-methylpiperazine-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) and 3-(bromomethyl)pyridine hydrobromide (13.85 mg, 0.055 mmol) were dissolved in DMF (volume: 3 ml), and then DIPEA (0.057 ml, 0.329 mmol) was added all at once. The solution was stirred with RT. The crude product was preparatively HPLC (column XSelect). (登録商標) CSHTM preparative C18 5μm OBDTM 19×100mm; purified by 5-95% ACN / H2O (0.1% HCOOH), 20 ml / min, RT). Related fractions were combined and isolated. (登録商標) The compound was loaded onto an SCX-2 cartridge, washed with MeOH, and the product was eluted with 7N methanolic ammonia. The residue was concentrated under reduced pressure to obtain 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-imidazole-1-yl)-5-(trifluoromethyl)phenyl)-6-(pyrimidine-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1; tert-butyl3-((3-(4-methyl-1H-imidazole-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-imidazole-1-yl)-5-(trifluoromethyl)aniline (1.277 g, 5.29 mmol) in DCM (26.5 ml), DIPEA (5.55 ml, 31.8 mmol), followed by T3P (6.30 ml, 10.59 mmol), was added and the reaction mixture was stirred over RT over the weekend. The reaction mixture was diluted with DCM, water was added, and the mixture was stirred for 10 minutes. The aqueous phase was washed with DCM (3 × 50 mL), then the combined organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by FCC (DCM solution of DCM ~ 10% MeOH) to obtain 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-imidazole-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), 4N HCl in dioxane (0.893 ml, 3.57 mmol) was added, and the reaction mixture was stirred overnight in RT. Et2O was added to the reaction mixture until no precipitate was observed, and the precipitate was then filtered to obtain 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-imidazole-1-yl)-5-(trifluoromethyl)phenyl)-6-(pyrimidine-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 an argon atmosphere and treated with STAB (104 mg, 0.492 mmol). The reaction mixture was stirred for 16 hours. The reaction mixture was diluted with MeOH and concentrated under reduced pressure. The dried reaction mixture was redissolved in DCM and 1 M NaOH, followed by washing with water and brine. The combined organic layer was concentrated and purified by preparative HPLC to obtain 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-(pyrimidine-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-ethyl4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (4.88 g, 15.67 mmol) in diethyl ether (vol: 78 ml), 4N HCl in dioxane (19.59 ml, 78 mmol) was added, and the reaction mixture was stirred overnight under RT. The solid was separated and dried under reduced pressure to obtain the title compound (3.58 g, 14.45 mmol, 92% yield).

[0199] Step 2; Ethyl 6-(pyrimidine-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-carboaldehyde (1.309 g, 12.11 mmol) were placed in a flask under argon. Anhydrous DCM (121 ml), followed by AcOH (0.693 ml, 12.11 mmol), was added. The reaction mixture was stirred at RT for 30 minutes. Next, STAB (5.13 g, 24.22 mmol) was 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 (saturated) and water. The aqueous phase was extracted twice with DCM, the organic layers were combined, dried over MgSO4, and evaporated under reduced pressure. The crude product was purified by FCC using DCM / MeOH (DCM solution of DCM ~ 10% MeOH) to obtain 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-(pyrimidine-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), 1N NaOH (6.49 ml, 6.49 mmol) was added, and the reaction mixture was stirred over the weekend in RT. The solvent was evaporated under reduced pressure to obtain 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-(pyrimidine-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 minutes, then 3-fluoro-5-(trifluoromethyl)aniline (0.044 ml, 0.336 mmol) was added. The reaction mixture was stirred at 60°C for a weekend. Then DCM and brine were added to the reaction mixture and stirred for 20 minutes. Next, the phases were separated, the organic layer was washed with water, separated, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM:MeO, 1:0~0:1). It was re-purified by preparative TLC (DCM:MeOH, 95:5) to obtain 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 by applying the corresponding commercially available arylamine in step 4, as described in steps 1-4 of Example 4. Such procedures may include minor modifications. In some examples, when the modification involves a coupling agent (e.g., HATU instead of T3P) or chromatographic purification conditions (e.g., preparative HPLC or flash chromatography), such modifications are indicated in the table. In Example 8, the starting material in step 3 was converted to the corresponding carboxylic acid by unblocking of the sodium salt, as described in step 1 of Example 9. [Table 18]

[0203] Example 9: Preparation of N-(3-(1,1-difluoroethyl)phenyl)-6-(pyrimidine-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: 6-(pyrimidine-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (intermediate 9) [ka] Intermediate 7 (880 mg, 2.90 mmol, 1.00 equivalent) in a 20 mL MeOH solution, 5 M NaOH (水性) (1.50 mL) was added. The reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was cooled to room temperature and 1 M HCl was added. (水性) The mixture was neutralized by the addition of [substance name] and concentrated under reduced pressure. The residue was washed with water and filtered to obtain 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-(pyrimidine-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 9) The compound was 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. The title compound (17.5 mg, 22.2%) was obtained by purification by reverse-phase preparative HPLC (Sunfire C18 3×50 mm, 3 μm 5~95% ACN / H2O (0.1% HCOOH), 1.7 ml / min, RT). 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 compound was 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-aminopyrazine-2-yl)methyl)-N-(3-(tert-butyl)-1-methyl-1H-pyrazole-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 1 M NaOH (120.5 ml, 120.5 mmol) was added, and the RM was stirred under RT until the conversion was complete. The RM was dried under reduced pressure to obtain 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-butyl3-((3-(tert-butyl)-1-methyl-1H-pyrazole-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 measured into a reaction tube backfilled with argon (×3). DCM (24.56 ml) and DMF (8.19 ml), followed by DIPEA (9.16 ml, 52.4 mmol), were added to the reaction mixture. The reaction mixture was stirred for 30 minutes, and 3-(tert-butyl)-1-methyl-1H-pyrazole-5-amine (0.502 g, 3.28 mmol) was added. The reaction mixture was heated to 45°C and stirred until consumption of the starting materials was indicated by LC-MS. Further addition of HATU and DIPEA was required to complete the transformation. The reaction mixture was then extracted with DCM / H2O (×3), and the combined organic layers were washed with a 1:1 saturated NaCl:H2O solution, followed by brine. The combined organic layers were then concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography (0-50% siRNA / hexane; the product was eluted with 50% siRNA) to obtain 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-pyrazole-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 (3.37 ml, 13.50 mmol) was added dropwise to the dioxane, and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was concentrated, and the residue was ground with diethyl ether to obtain 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-aminopyrazine-2-yl)methyl)-N-(3-(tert-butyl)-1-methyl-1H-pyrazole-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-carboaldehyde (41.6 mg, 0.338 mmol) were added to a small reaction tube and backfilled with argon (×3). MeOH (1409 μl), followed by AcOH (48.4 μl, 0.845 mmol), was added to the reaction mixture, the tube was sealed, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was then cooled to RT, NaBH3CN (80 mg, 1.268 mmol) was added, and the reaction mixture was stirred at 50°C. Further addition of aldehyde (2 equivalents) and NaBH3CN (1 equivalent) was necessary for complete conversion. The reaction mixture was stopped with saturated NaHCO3, transferred to a separatory funnel, and the desired product was extracted by DCM (×3). The combined organic layer was washed once with brine, concentrated under reduced pressure, and the crude mixture was purified by preparative HPLC to obtain 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 the previously synthesized or commercially available aryl aldehyde in Step 4. Such procedures may include minor modifications. In some examples, where any modifications relate to the procedure of use, the reducing agent (e.g., STAB instead of NaBH3CN), or the chromatographic purification conditions, such modifications are noted in the table. [Table 21]

[0211] Example 17: Preparation of 6-((4-(2-methoxyacetamido)pyridine-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 in RT for 15 minutes, and 3-(trifluoromethyl)aniline (1.964 ml, 15.72 mmol) was added. The RM was stirred overnight at 40°C. The RM was diluted in DCM, and water was added. The mixture was stirred for 15 minutes, the phases were separated, and the organic phase was washed with water, 5% wt citrate solution, twice with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by FCC (DCM ~ 10% MeOH DCM) to obtain 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 the minimum amount of DCM (6.01 ml), then Et2O (60.1 ml), followed by 4N HCl in dioxane (16.53 ml, 66.1 mmol), and the RM was stirred overnight under RT. Et2O was added to the RM until no precipitate was observed, then the solid was filtered, and the remaining solvent was evaporated under reduced pressure to obtain 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-aminopyridine-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 (×3). MeOH (1378 μl), followed by AcOH (47.3 μl, 0.827 mmol), was added, and the solution was stirred at 50°C for 1 hour. NaBH3CN (78 mg, 1.240 mmol) was added to the reaction mixture, and the mixture was stirred at 50°C until consumption of the starting materials was indicated by LC-MS. Further addition of aldehyde (1.2 equivalents) and NaBH3CN (1 equivalent) was required to complete the conversion. The reaction mixture was transferred to a separatory funnel and diluted with DCM. NaHCO3 (saturated) was added, and the organic layer was separated (×3). The combined organic layers were washed once with brine, concentrated under reduced pressure, and the crude material was purified using FCC (0-2% 6.5M NH3 in MeOH solution and 10% MeOH in DCM solution) to obtain 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-methoxyacetamide)pyridine-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 (×3). THF (867 μl) was added to dissolve the starting material, followed by TEA (48.3 μl, 0.347 mmol). The reaction mixture was stirred for 10 minutes, and then 2-methoxyacetyl chloride (20.70 mg, 0.191 mmol) was added at 0°C. The reaction mixture was stirred for 1 hour, and after confirming completion by UPLC, the reaction mixture was transferred to a separatory funnel and stopped with water. The desired product was extracted with DCM (×3), the combined organic layers were washed once (×1) with brine, and concentrated. The crude material was purified by preparative HPLC and then ground with water to obtain 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 the previously synthesized or commercially available aryl aldehyde in Step 3. Such procedures may include minor modifications. In some examples, when the modifications relate to the procedure of use or chromatographic purification conditions, such modifications are indicated in the table. [Table 22] [Table 23] [Table 24]

[0216] Example 29: Preparation of 6-((5-(4-methyl-3-oxopiperazin-1-yl)pyridine-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1; 6-((5-bromopyridine-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 equivalent), MgSO4 (148 mg, 1.23 mmol, 2.00 equivalent), and 5-bromo-3-pyridinecarboxaldehyde (114 mg, 0.613 mmol, 1.00 equivalent) in DCM (10 mL), STAB (325 mg, 1.53 mmol, 2.50 equivalent) was added, and the mixture was stirred at room temperature for 21 hours. The mixture was slowly added to a saturated aqueous solution of NaHCO3 and extracted with DCM (×3). The combined organic extract was dried (Na2SO4) and evaporated. The crude compound was purified by removing the residue with silica FCC (12 g cartridge, 0-70% siRNA cyclohexane solution) to obtain 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)pyridine-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 equivalent), 1-methylpiperazine-2-one (13 mg, 0.111 mmol, 1.10 equivalent), and Cs2CO3 (66 mg, 0.201 mmol, 2.00 equivalent) in anhydrous 1,4-dioxane (1.50 mL) was degassed, and RuPhos Pd G3 (8.4 mg, 0.0101 mmol, 0.10 equivalent) was added. The reaction mixture was stirred under argon at 80 °C for 21 hours. The reaction mixture was cooled, filtered through a Celite pad, and concentrated. The title compound (15.8 mg, 29%) was obtained by purification using reverse-phase HPLC (Sunfire C18 19 × 150 mm, 10 μm 20-80% ACN / H2O (10 mM NH4CO3), 20 ml / min, RT). 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 a commercially available amine in step 2. Such procedures may include minor modifications. [Table 25]

[0219] Example 31: Preparation of N-6-((5-(2-(dimethylamino)acetamide)pyridine-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)acetamide)pyridine-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 equivalent), intermediate 41 (20 mg, 0.0403 mmol, 1.00 equivalent), 2-(dimethylamino)acetamide (4.1 mg, 0.0403 mmol, 1.00 equivalent), Pd(dba)2 (2.3 mg, 4.03 μmol, 0.100 equivalent), XantPhos (2.3 mg, 4.03 μmol, 0.100 equivalent), and Cs2CO3 (13 mg, 0.0403 mmol, 1.00 equivalent) in degassed (argon)toluene (2.00 mL) was heated at 110°C for 64 hours. The reaction mixture was diluted with DCM (15 mL), dried, and evaporated (Na2SO4). The crude product 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 obtain 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-methoxypyridine-3-yl)methyl)-N-(5-(trifluoromethyl)pyridine-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Preparation of tert-butyl 3-((5-(trifluoromethyl)pyridine-3-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (intermediate 42) [ka] The compound was prepared from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (250 mg, 0.882 mmol, 1.00 equivalent) and 5-(trifluoromethyl)pyridine-3-amine (157 mg, 0.971 mmol, 1.10 equivalent) according to general procedure G. The residue was purified with silica FCC (80 g cartridge, 0-25% ethyl acetate in cyclohexane solution + 0.1% NET3) to obtain 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)pyridine-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide intermediate 43) [ka] To a 6.78 mL solution of anhydrous DCM containing intermediate 42 (290 mg, 0.678 mmol, 1.00 equivalent) while being cooled in an ice / water bath under an argon atmosphere and stirring, TFA (0.52 mL, 6.78 mmol, 10.0 equivalent) was added dropwise over 5 minutes. The reaction mixture was stirred for 3 hours. Further TFA (0.17 mL, 2.26 mmol, 3.33 equivalents) was added, and the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 1:1 DCM:MeOH, loaded onto a 5 g Isolute SCX-II cartridge pre-conditioned with MeOH, washed with MeOH, and then eluted with 2 M NH3 / MeOH. The 2 M NH3 / MeOH eluent was concentrated under reduced pressure to obtain 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-methoxypyridine-3-yl)methyl)-N-(5-(trifluoromethyl)pyridine-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 32) The compound was prepared from intermediate 43 (45 mg, 0.138 mmol) and 5-methoxy-3-pyridinecarboxaldehyde (18 mg, 0.131 mmol) according to general procedure D. The title compound (19 mg, 30%) was obtained by purification using reverse-phase preparative HPLC (Xbridge Phenyl 19 × 150 mm, 10 μm 40-100% MeOH / water (10 mM NH4HCO3), 20 mL / min, RT). 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 the previously synthesized or commercially available aryl aldehyde in Step 3. Such procedures may include minor modifications. In some examples, when the modification involves the use of a reducing agent (e.g., NaBH3CN instead of STAB) or chromatographic purification conditions, such modifications are noted in the table. [Table 26]

[0224] Example 37: Preparation of N-[3-fluoro-5-(trifluoromethyl)phenyl]-6-[[2-(oxetane-3-ylamino)pyrimidine-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 equivalent) and HATU (2560 mg, 6.73 mmol, 1.20 equivalents) in DMF (22.50 mL), DIPEA (2.9 mL, 16.8 mmol, 3.00 equivalent) was added, and the RM was stirred at room temperature for 15 minutes. Then, 3-fluoro-5-(trifluoromethyl)aniline (1055 mg, 5.89 mmol, 1.05 equivalent) was added. The reaction mixture was stirred at room temperature for a further 16 hours. The reaction mixture was purified with silica FCC (alkyl / cyclohexane 0%~100%) to obtain 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 equivalent), which was dissolved in DCM (35 mL), and TFA (5.0 mL, 65.9 mmol, 21.7 equivalents) was added. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The reaction mixture was partitioned into saturated aqueous Na2CO3 (50 mL) and alkyl (40 mL). The aqueous layer was extracted with alkyl (30 mL), dried over MgSO4, filtered through hydrophobic frit, and concentrated under reduced pressure. The crude product was purified with silica FCC (Â / cyclohexane 0%-100%, followed by 3:1 Â:EtOH / Â 0%-100%) to obtain the title compound (500 mg, 2.69 mmol, yield 48%). 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-(oxetane-3-ylamino)pyrimidine-5-yl]methyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 37) The compound was prepared from intermediate 20 (62 mg, 0.34 mmol, 1.00 equivalent) and intermediate 44 (119 mg, 0.34 mmol, 1.00 equivalent) according to general procedure C. The residue reaction product 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 obtained solid was dissolved in SiO2, washed with saturated aqueous NaHCO3, dried, and concentrated in (MgSO4). The residue was freeze-dried to obtain 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 Steps 1-2 of Example 37, using the previously synthesized or commercially available aryl aldehyde in Step 2. Such procedures may include minor modifications. In some examples, when the modification relates to the reducing agent (e.g., NaBH3CN instead of STAB) or chromatographic purification conditions, such modifications are 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) To a solution of intermediate 44HCl salt (150 mg, 0.394 mmol, 1.00 equivalent), DIPEA (0.14 mL, 0.788 mmol, 2.00 equivalent), and 6-(methylamino)pyridine-3-carbaldehyde (54 mg, 0.394 mmol, 1.00 equivalent) in MeOH (7.5 mL), titanium(IV) isopropoxide (0.35 mL, 1.18 mmol, 3.00 equivalent) was added. The reaction mixture was heated overnight at reflux temperature. The reaction mixture was cooled to room temperature, and NaBH3CN (62 mg, 0.985 mmol, 2.50 equivalent) was added. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with DCM, the reaction was stopped with NH4Cl, and the solid was filtered. The organic layer was separated, and the aqueous layer was washed twice with DCM. The combined organic phase was filtered through hydrophobic frit, and the solvent was concentrated under reduced pressure to obtain 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 obtain 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) The compound was prepared from 1-methyl-1H-imidazole-5-carboxylic acid (22 mg, 0.174 mmol, 1.20 equivalents) and intermediate 44 (50 mg, 0.145 mmol, 1.00 equivalent) according to general procedure A. 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 obtain the crude product (34 mg). This was re-purified by preparative HPLC (Sunfire C18 19×150 mm, 10 μm 5-60% ACN / H2O (0.1% FA), 20 ml / min, RT) to obtain 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-aminopyrimidine-5-yl)methyl)-N-(3-((3-(dimethylamino)pyrrolidine-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)pyrrolidine-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (intermediate 45) [ka] The compound was prepared from 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (350 mg, 1.24 mmol, 1.0 equivalent) and intermediate 28 (355 mg, 1.24 mmol, 1.0 equivalent) according to general procedure G. The residue was purified with silica FCC (40 g cartridge, 0-10% 2M NH3 / MeOH DCM solution) to obtain 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)pyrrolidine-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), TFA (1.6 mL, 20.8 mmol) was added dropwise over 5 minutes while stirring under an argon atmosphere on an ice bath. The reaction mixture was stirred for 1.5 hours, concentrated under reduced pressure, and the residue was dissolved in MeOH. This was loaded onto a 20 g Isolute SCX-II cartridge pre-treated with methanol, washed with MeOH, and then eluted with 2 M NH3 / MeOH. The 2 M NH3 / MeOH eluent was concentrated under reduced pressure to obtain 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)pyrrolidine-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 50) The compound was prepared from intermediate 46 (58 mg, 0.128 mmol) and 2-aminopyrimidine-5-carboaldehyde (15 mg, 0.122 mmol) according to general procedure D. It was purified by reverse-phase preparative HPLC (Sunfire C18 19 × 150 mm, 10 μm 20-80%, acetonitrile / water (10 mM NH4HCO3), 20 mL / min, RT), and then re-purified by (Luna Phenyl-Hexyl 21.2 × 150 mm, 10 μm 5-60% MeOH / water (0.1% FA), 20 mL / min, RT) to obtain the formate of the title compound. The substance was dissolved in MeOH, loaded onto a 2 g Isolute SCX-II cartridge pre-treated with MeOH, washed with MeOH, and then eluted with 2 M NH3 / MeOH. The 2M NH3 / MeOH eluent was concentrated and dried under reduced pressure to obtain 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, using the previously synthesized or commercially available aryl aldehydes in Step 3. Such procedures may include minor modifications. In some examples, when the modification relates to the reducing agent (e.g., NaBH3CN instead of STAB) or chromatographic purification conditions, such modifications are indicated 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 the arylamine previously synthesized in Step 1 or a commercially available arylamine. [Table 32] [Table 33]

[0234] Example 58: Preparation of 6-((2-aminopyrimidine-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] Following general procedure G, the compound was prepared by adding 3-(1,1-difluoroethyl)aniline (291 mg, 1.85 mmol, 1.05 equivalent) to 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (500 mg, 1.76 mmol, 1.0 equivalent). The combined organic phase was dried over MgSO4, filtered, concentrated, and dried overnight under reduced pressure to obtain 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 equivalent) in 1,4-dioxane (10 mL), 4N HCl (10 mL) was added to the 1,4-dioxane. The reaction mixture was stirred overnight at room temperature. The reaction was stopped with Et2O, filtered, and the resulting solid was washed with Et2O and dried under reduced pressure. The title compound (684 mg, 1.72 mmol, 146%) was obtained. This substance 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-aminopyrimidine-5-yl)methyl)-N-(3-(1,1-difluoroethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 58) The compound was prepared from intermediate 48 (90%, 60 mg, 0.150 mmol, 1.00 equivalent) and 2-aminopyrimidine-5-carboxyaldehyde (19 mg, 0.150 mmol, 1.00 equivalent) according to general procedure C. The residue was washed with DCM / MeOH, the combined washing solution was evaporated, and the residue was dried under reduced pressure. The residue was purified by preparative HPLC on a 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 the arylamine previously synthesized in Step 1 or a commercially available arylamine. [Table 34]

[0238] Example 61: Preparation of 6-((2-aminopyrimidine-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] Following general procedure G, 4-chloro-3-(trifluoromethyl)aniline (181 mg, 0.926 mmol, 1.05 equivalents) was mixed with 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (250 mg, 0.882 mmol, 1.0 equivalent) to prepare the compound. The reaction mixture was stirred at room temperature for 90 minutes, the reaction was stopped with water, stirred for 30 minutes, 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 substance 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 equivalent) in 1,4-dioxane (3 mL), 4N HCl (3.0 mL) was added to the 1,4-dioxane. The reaction mixture was stirred at room temperature for 18 hours. The reaction was stopped with Et2O, filtered, the solid was washed with Et2O, and dried under reduced pressure to obtain the title compound (289 mg, 0.666 mmol, 85%) as its 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-aminopyrimidine-5-yl)methyl)-N-(4-chloro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 61) The compound was prepared from intermediate 49 (60 mg, 0.151 mmol, 1.00 equivalent) and 2-aminopyrimidine-5-carboxyaldehyde (27 mg, 0.223 mmol, 1.47 equivalents) according to general procedure H. The crude product was purified by preparative HPLC (Luna Phenyl-Hexyl 21.2 × 150 mm, 10 μm 20-80% MeOH / H2O (0.1% FA), 20 ml / min, RT) to obtain 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-aminopyrimidine-5-yl)methyl)-N-(5-(1,1,1-trifluoro-2-methylpropane-2-yl)isoxazole-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)isoxazole-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 equivalent) and DMF (0.0034 mL, 0.0441 mmol, 0.05 equivalent) in cyclopentyl methyl ether (2 mL), 0.088 mL, 1.06 mmol, 1.20 equivalents was added dropwise at 20 °C. The reaction mixture was stirred at room temperature for 2 hours. 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 a solution of 5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)isoxazole-3-amine (171 mg, 0.882 mmol, 1.00 equivalent) and pyridine (0.14 mL, 1.76 mmol, 2.00 equivalent) in ACN (1 mL) was added to the mixture. The reaction mixture was warmed to room temperature and stirred for 45 minutes. The reaction mixture was concentrated under reduced pressure. The residue was partitioned into DCM and water. The combined organic layer was filtered through hydrophobic frit, and the solvent was concentrated under reduced pressure. The residue was purified with silica FCC (eluted with 0-100% ethyl cyclohexane solution) to obtain the title compound (255 mg, 0.555 mmol, 63%). This substance 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)isoxazole-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 equivalent) in 1,4-dioxane (3 mL), 4N HCl (3.0 mL, 0.555 mmol, 1.00 equivalent) in 1,4-dioxane was added at 0°C. The reaction mixture was warmed to room temperature and stirred at room temperature over the weekend. The reaction mixture was diluted with Et2O (20 mL), filtered, the solid was washed with Et2O, and dried under reduced pressure to obtain 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-aminopyrimidine-5-yl)methyl)-N-(5-(1,1,1-trifluoro-2-methylpropane-2-yl)isoxazole-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 62) To a solution of 2-aminopyrimidine-5-carboxyaldehyde (16 mg, 0.126 mmol, 1.00 equivalent), intermediate 52 (50 mg, 0.126 mmol, 1.00 equivalent), and DMF (0.044 mL, 0.253 mmol, 2.00 equivalent) in MeOH (3.00 mL), titanium(IV) isopropoxide (0.11 mL, 0.379 mmol, 3.00 equivalent) was added. The reaction mixture was heated under reflux temperature for 2 hours. The reaction mixture was cooled to room temperature, and NaBH3CN (20 mg, 0.316 mmol, 2.50 equivalent) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction was stopped with water (30 mL), and filtered through Celite. The residue was washed with DCM / MeOH, the combined washing solution was evaporated, and the residue was dried under reduced pressure over P2O5. The residue was purified by preparative HPLC. Sunfire C18, 19×150mm, 10μm, 5-60% ACN / H2O (0.1% FA), 20 ml / min, RT. The title compound (17 mg, 0.0343 mmol, 27%) was obtained. 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 a commercially available heteroarylamine in Step 1. [Table 35]

[0245] Example 65: Preparation of N-(3-(tert-butyl)isoxazole-5-yl)-6-((5-methoxypyridine-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Preparation of ethyl(6-((5-methoxypyridine-3-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (intermediate 53) [ka] The compound was prepared from 5-methoxy-3-pyridinecarboxaldehyde (91 mg, 0.666 mmol) and intermediate 6 (150 mg, 0.605 mmol) according to general procedure F. Purification was carried out using silica FCC (25 g) eluted with DCM (0-100%) in a 15:1% solution of 2 M methanolic ammonia to obtain 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-methoxypyridine-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 equivalents) was added to a solution of intermediate 53 (217 mg, 0.653 mmol, 1.00 equivalent) in MeOH (10 mL) and water (0.5 mL), and the mixture was stirred at 50°C for 18 hours. The mixture was cooled in an ice bath, and 1 M HCl (1.8 mL, 1.78 mmol, 2.73 equivalents) was added dropwise. The solution was concentrated under reduced pressure to obtain a solid precipitate, which was filtered and washed with acetone (2 mL) to obtain 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)isoxazole-5-yl)-6-((5-methoxypyridine-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 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in toluene and reconcentrated to obtain intermediate asyl chloride. To a solution of 3-tert-butylisoxazole-5-amine (21 mg, 0.148 mmol) and DMAP (2.4 mg, 0.020 mmol) in pyridine (0.1 M concentration), asyl chloride was added, followed by DIPEA (51.5 μL, 0.296 mmol). The reaction mixture was stirred at 40°C until consumption of the starting material was indicated by LC-MS, and then concentrated under reduced pressure. Purification was performed 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 obtain 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, a compound differing in the following respects was synthesized separately: - 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 that substitutes the thienyl ring at the α-position for the sulfur atom (Example C2).

[0249] Example C1 Manufacturing of N-(3-((4-methylpiperazine-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyrimidine-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1; Ethyl 6-(pyrimidine-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (intermediate 16) [ka] 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) were placed in a 20 mL vial equipped with a magnetic stirring bar and fitted with a seal cap. The container was evacuated, backfilled with argon, and then toluene (4 ml) was added via syringe. The solution was heated to 120°C and stirred. After cooling to RT, the solution was filtered through a Celite pad and then concentrated to dryness. The crude product was purified by FCC (column silica-NH gradient n-heptane / acetone 100:0~60:40) to obtain 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-methylpiperazine-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyrimidine-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example C1) 3-((4-methylpiperazine-1-yl)methyl)-5-(trifluoromethyl)aniline (76 mg, 0.276 mmol) was dissolved in dry THF (vol.: 6 ml, ratio: 1.500) under nitrogen, and the mixture was stirred at -78°C for 15 minutes. Then n-BuLi (0.105 ml, 0.263 mmol) was added dropwise over 5 minutes, and the solution was stirred at -78°C for 1 hour. Ethyl intermediate 16 (40 mg, 0.138 mmol) in THF (vol.: 4 ml, ratio: 1.000) solution was added dropwise over 10 minutes, and then the temperature was raised to RT, and the reactants were stirred for a further 1 hour. 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 100:0~0:100, eluent A:H2O:ACN:HCOOH 95:5:0.1, eluent B:H2O:ACN:HCOOH 5:95:0.1). The associated fractions were combined, packed into 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 obtain 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-methylpiperazine-1-yl)methyl)-5-trifluoromethyl)phenyl)-5-(pyrimidine-5-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide [ka] Step 1; 6-(tert-butyl)2-methyl4,7-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 (vol: 10 ml), and then CH3I (0.066 ml, 1.059 mmol) was added all at once. The solution was stirred at room temperature for 3 hours. 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 obtain 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 together with intermediate 17 (181.6 mg, 0.611 mmol). The reaction proceeded with gas formation and was completed at rt for 5 minutes. 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-(pyrimidine-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (intermediate 19) [ka] 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) were placed in a 20 mL microwave vial equipped with a magnetic stirring bar and fitted with a seal cap. The container was evacuated, backfilled with argon, and then toluene (vol: 5 ml) was added via syringe. The solution was heated to 110°C and stirred. After cooling to rt, the solution was filtered through a Celite pad and then concentrated to dryness. The crude product was purified by FCC (gradient A:B 100:0~60:40, eluent A:n-heptane eluent B:acetone) to obtain the title compound (118.5 mg, 0.430 mmol, 80% yield). 1 ¹H 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-methylpiperazine-1-yl)methyl)-5-trifluoromethyl)phenyl)-5-(pyrimidine-5-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (Example C2) 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline (52.4 mg, 0.217 mmol) was dissolved in dry THF (vol: 4) under nitrogen, and the mixture was stirred at -78°C for 15 minutes. Then, 2.5 M n-BuLi (0.083 ml, 0.206 mmol) in hexane was added dropwise over 5 minutes, and the solution was stirred at -78°C for 1 hour. A solution of methyl intermediate 19 (29.9 mg, 0.109 mmol) in THF (vol: 2 ml) was added dropwise over 10 minutes, the temperature was raised to rt, and the reaction mixture was stirred for 1 hour. 10 mL of water was added to stop the reaction, and the crude product was extracted with AcOEt (2 × 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 100:0~0:100; eluent A:H2O:ACN:HCOOH 95:5:0.1; eluent B:H2O:ACN:HCOOH 5:95:0.1). Appropriate fractions were combined and evaporated to obtain 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 compound of the present invention In vitro assay Binding assay DDR1 and DDR2 binding assays are performed at LanthaScreen TMThe assay was performed using a Europium Kinase Binding assay. The compounds were incubated for 1 hour at room temperature in a white 384-well OptiPlate (PerkinElmer) containing 20 nM or 10 nM Kinase Tracer 178 and 2 nM Europium-labeled anti-GST antibody (Life Technologies), respectively, in assay buffer (50 mM HEPES pH 7.5, 10 mM MgCI2, 1 mM EGTA, and 0.01% BRIJ35), with 5 nM DDR1 (Carna Biosciences) or 5 nM DDR2 (Life Technologies). The 665nm / 615nm fluorescence emission ratio after excitation at 340nm was obtained using a Tecan Spark 20M plate reader. 50 The values ​​were determined using GraphPad Prism 7.0 software with a 4-parameter model: log(inhibitor) vs. response. 50 The value is expressed using the Chen-Prusov formula (Ki=IC 50 The result was converted to Ki using / (1+[tracer] / Kd).

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

[0257] DDR2 cell-based assay The inhibition of DDR2 phosphorylation by compounds was evaluated in recombinant HEK293T-DDR2 cells by phospho-ELISA assay. Briefly, HEK293T-DDR2 cells were seeded at a density of 250,000 cells / well in poly-D-lysine coated 24-well plates and incubated in DMEM + 10% FBS for 1.5 hours at 37°C and 5% CO2. Subsequently, the medium was changed to serum-free DMEM and the cells were incubated for 3 hours. Then, test compounds were added at various concentrations for 30 minutes, followed by stimulation with 50 μg / ml bovine type II collagen for a further 3 hours. For the DDR2 phospho-ELISA assay (DuoSet IC Human Phospho-DDR2; R&D Systems), protein extracts were obtained by adding 60 μl / well of lysis buffer prepared according to the manufacturer's instructions. Sample protein concentrations were determined by BCA assay, and phospho-DDR2 levels were determined according to R&D Systems' instructions. Raw data were normalized to the maximum inhibitory control (0% for normalization) and the positive control (100% for normalization; cells treated with 20 μg / ml collagen II), and IC was calculated. 50 The parameters were calculated using GraphPad Prism 8.0 software with variable-slope sigmoid dose-response curve fitting.

[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 their inhibitory activity against DDR1 and DDR2: [Table 36] [Table 37] +:Ki 50~80nM ++: Ki 25~50nM +++: Ki less than 25nM +:IC 50 50-80 nM ++:IC50 25~50nM +++:IC 50 Less than 25 nM -: Not applicable

[0259] As can be recognized, the compounds in Table 5, i.e., the compounds of the present invention, exhibit 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, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, and systemic sclerosis.

[0260] Comparative Example The compounds of Examples C1 and C2 were tested using the same binding assay as described above. [Table 38] The compounds of the present invention shown in Table 5 exhibit binding affinity to DDR1 and DDR2 receptors, represented as Ki, and IC2. 50 The inhibitory activity against both DDR1 and DDR2 receptors, expressed as , is less than 80 nM, and for most compounds, it is less than 50 nM or even less than 25 nM. Conversely, Comparative Example C1 has a binding affinity higher than 230 nM for the DDR1 receptor and higher than 170 nM for DDR2; and Comparative Example C2 has a binding affinity of 29,000 nM for the DDR1 receptor and 50,000 nM for DDR2.

[0261] These data show that, 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, the compound of Example 2 of the present invention, in which a -CH2-linker is present at that position, unexpectedly and significantly determines the associated increase in inhibitory activity of DDR1 and DDR2 receptors.

[0262] As further evidence, unlike 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 α-position relative to the sulfur atom, rather than at the β-position as in Example 2 of the present invention, the presence of the linker and the β-position substitution in the compound of the present invention unexpectedly and significantly determines the associated increase in inhibitory activity against DDR1 and DDR2 receptors. The present invention further includes the following embodiments. 1. Equation (I) [ka] [During the ceremony, L is selected from the group consisting of -C(O)- and -CH2-; Hy is It is a monocyclic heteroaryl, and this Depending on the case, -(C1-C4) alkyl, halogen atom, 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 which may be substituted with one or more -(C1-C4)alkyl groups. The heteroaryl may have 1 or more -(C) 1 -C 4 ) Substituted with alkyl -NH-heteroary Luna Furthermore, it is substituted with one or more groups selected from heterocycloalkyls, which may be substituted with one or more groups selected from oxo and -(C1-C6)alkyl groups; R1 is: - Het is a heteroaryl which is 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] A group consisting of the following is selected, 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 either H or 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 a heteroaryl substituted with one or more -(C1-C4)alkyl groups, where the heterocycloalkyl is optionally substituted with one or more -(C1-C4)alkyl groups; n is 0, 1, or 2; R4 is either H or a -(C1-C4) alkyl group; R5 is either H or a -(C1-C4) alkyl group. Compounds of and their pharmaceutically acceptable salts. 2. R1 is X' [ka] Equation (Ia) [ka] A compound of formula (I) in item 1, represented by the above. 3. Equation (Iaa) where L is -CH2- [ka] The compound represented by formula (I) in item 2. 4. A compound of formula (Ia) in item 2 or a compound of formula (Iaa) in item 3, selected from at least one of the following: N-(3-((4-methylpiperazine-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyridine-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-((4-methylpiperazine-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyrimidine-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)phenyl)-6-(pyrimidine-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(pyrimidine-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyrimidine-5-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethoxy)phenyl)-6-(pyrimidine-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(1,1-difluoroethyl)phenyl)-6-(pyrimidine-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(difluoromethoxy)-5-fluorophenyl)-6-(pyrimidine-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(difluoromethoxy)phenyl)-6-(pyrimidine-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-cyano-5-(trifluoromethyl)phenyl)-6-(pyrimidine-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((4-(2-methoxyacetamide)pyridine-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-((1-methyl-1H-pyrazole-4-yl)amino)pyrimidine-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-cyanopyridine-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-chloropyridine-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-methoxypyridine-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-methylpyridine-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)pyridine-3-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-fluoropyridine-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyridine-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((3-aminopyrazine-2-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidine-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-(4-methyl-3-oxopiperazine-1-yl)pyridine-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-(1,1-dioxidethiomorpholino)pyridine-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-(2-(dimethylamino)acetamide)pyridine-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)pyrimidine-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidine-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-acetamidopyrimidine-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)pyrimidine-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)pyrimidine-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((6-acetamidopyridine-3-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyridine-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)pyrimidine-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((4-aminopyrimidine-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((3-aminopyrazine-2-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-amino-4-methylpyrimidine-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)pyridine-3-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)-6-((2-aminopyrimidine-5-yl)methyl)-N-(3-((3-(dimethylamino)pyrrolidine-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)-N-(3-((3-(dimethylamino)pyrrolidine-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-((4-(2-fluoropropan-2-yl)pyrimidine-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)-N-(3-((3-(dimethylamino)pyrrolidine-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-((4-methoxypyrimidine-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)-6-((4-cyclopropoxypyrimidine-5-yl)methyl)-N-(3-((3-(dimethylamino)pyrrolidine-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)-N-(3-((3-(dimethylamino)pyrroridine-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-((5-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidine-5-yl)methyl)-N-(3-((dimethylamino)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidine-5-yl)methyl)-N-(3-(1,1-difluoroethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidine-5-yl)methyl)-N-(3-cyano-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide. 5. L is -CH2- and R1 is X'' [ka] The expression is (Iaa'). [ka] A compound of formula (I) in item 1, represented by the above. 6. L is -CH2- and R1 is X''' [ka] The expression is (Iaa''). [ka] A compound of formula (I) in item 1, represented by the above. 7. Equation (Iab) where L is -C(O)- [ka] The compound of formula (Ia) in term 2, represented by the above. 8. Equation (Ib) where R1 is Het. [ka] A compound of formula (I) in item 1, represented by the above. 9. Equation (Iba) where L is -CH2- [ka] The compound of formula (Ib) in item 8, represented by [formula]. 10. A pharmaceutical composition comprising a compound of any of formula (I) from items 1 to 9, mixed with one or more pharmaceutically acceptable carriers or additives. 11. The pharmaceutical composition of item 10 for administration by inhalation. 12. A compound of any of formula (I) from items 1 to 9 or a pharmaceutical composition of item 10 or 11, for use as a pharmaceutical. 13. A compound or pharmaceutical composition of formula (I) for use in accordance with item 12 in the prevention and / or treatment of diseases, disorders or conditions associated with dysregulation of discoidine domain receptors. 14. Compounds or pharmaceutical compositions of formula (I) for use in accordance with item 12 or 13 in the prevention and / or treatment of diseases, disorders or conditions involving fibrosis and / or fibrosis. 15. Compounds or pharmaceutical compositions of formula (I) for use in accordance with item 14 in the prevention and / or treatment of fibrosis, including pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis. 16. A compound or pharmaceutical composition of formula (I) for use in accordance with item 15 in the prevention and / or treatment of idiopathic pulmonary fibrosis (IPF).

Claims

1. Equation (I) 【Chemistry 1】 [During the ceremony, L is -C(O)- and -CH ２ Selected from the group consisting of: Hy is a monocyclic heteroaryl, which is unsubstituted or -(C １ -C ４ )alkyl, a halogen atom, cyano,-(CH ２ ) ｎ NR 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, unsubstituted or substituted with one or more -(C １ -C ４ )alkyl-substituted heteroaryl, heteroaryl being unsubstituted or substituted with one or more -(C1-C4)alkyl-substituted -NH-heteroaryl and unsubstituted or oxo and -(C １ -C ６ )alkyl-selected one or more groups substituted heteroheterocycloalkyl selected from one or more groups; R １ teeth: - Non-substitution or -(C １ -C ４ ) alkyl, -(C １ -C ４ ) Haloalkyl and aryl (where the aryl is unsubstituted or -(C) １ -C ４ Het is a heteroaryl substituted with one or more groups selected from alkyl and halogen atoms; and - X 【Chemistry 2】 A group consisting of the following is selected, where, R ２ -O(C) １ -C ４ ) Haloalkyl, halogen atom, -O(C ３ -C ７ )Cycloalkyl and -(C １ -C ４ ) Selected from the group consisting of haloalkyl groups; 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 unsubstituted or one or more -(C １ -C ４ Selected from the group consisting of heteroaryls substituted with alkyl, where the heterocycloalkyl is unsubstituted or has one or more -(C １ -C ４ ) Substituted with alkyl; n is 0, 1, or 2; R ４ is H or -(C １ -C ４ ) is alkyl; R ５ is H or -(C １ -C ４ )It is alkyl. Compounds of or pharmaceutically acceptable salts thereof.

2. R １ is X' 【Transformation 3】 Equation (Ia) 【Chemistry 4】 A compound of formula (I) of claim 1 or a pharmaceutically acceptable salt thereof, represented by .

3. L is -CH ２ - is the equation (Iaa) 【Transformation 5】 A compound of formula (I) of claim 2 or a pharmaceutically acceptable salt thereof, represented by .

4. A compound of formula (Ia) of claim 2 or a compound of formula (Iaa) of claim 3, selected from the following, or a pharmaceutically acceptable salt thereof: N-(3-((4-methylpiperazine-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyridine-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-((4-methylpiperazine-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyrimidine-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)phenyl)-6-(pyrimidine-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(pyrimidine-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyrimidine-5-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethoxy)phenyl)-6-(pyrimidine-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(1,1-difluoroethyl)phenyl)-6-(pyrimidine-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(difluoromethoxy)-5-fluorophenyl)-6-(pyrimidine-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(difluoromethoxy)phenyl)-6-(pyrimidine-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-cyano-5-(trifluoromethyl)phenyl)-6-(pyrimidine-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((4-(2-methoxyacetamide)pyridine-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-((1-methyl-1H-pyrazole-4-yl)amino)pyrimidine-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-cyanopyridine-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-chloropyridine-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-methoxypyridine-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-methylpyridine-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)pyridine-3-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-fluoropyridine-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyridine-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((3-aminopyrazine-2-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidine-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-(4-methyl-3-oxopiperazine-1-yl)pyridine-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-(1,1-dioxidethiomorpholino)pyridine-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-(2-(dimethylamino)acetamide)pyridine-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)pyrimidine-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidine-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-acetamidopyrimidine-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)pyrimidine-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)pyrimidine-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((6-acetamidopyridine-3-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyridine-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)pyrimidine-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((4-aminopyrimidine-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((3-aminopyrazine-2-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-amino-4-methylpyrimidine-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)pyridine-3-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)-6-((2-aminopyrimidine-5-yl)methyl)-N-(3-((3-(dimethylamino)pyrrolidine-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)-N-(3-((3-(dimethylamino)pyrrolidine-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-((4-(2-fluoropropan-2-yl)pyrimidine-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)-N-(3-((3-(dimethylamino)pyrrolidine-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-((4-methoxypyrimidine-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)-6-((4-cyclopropoxypyrimidine-5-yl)methyl)-N-(3-((3-(dimethylamino)pyrrolidine-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-pyrazole-4-yl)pyridine-3-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidine-5-yl)methyl)-N-(3-((dimethylamino)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidine-5-yl)methyl)-N-(3-(1,1-difluoroethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidine-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'' 【Transformation 6】 The expression is (Iaa'). 【Transformation 7】 A compound of formula (I) of claim 1 or a pharmaceutically acceptable salt thereof, represented by .

6. L is -CH ２ - and R １ is X''' 【Transformation 8】 The expression is (Iaa''). 【Chemistry 9】 A compound of formula (I) of claim 1 or a pharmaceutically acceptable salt thereof, represented by .

7. Equation (Iab) where L is -C(O)- 【Chemistry 10】 A compound of formula (Ia) of claim 2, represented by the above, or a pharmaceutically acceptable salt thereof.

8. R １ Equation (Ib) is Het 【Chemistry 11】 A compound of formula (I) of claim 1 or a pharmaceutically acceptable salt thereof, represented by .

9. L is -CH ２ - is the equation (Iba) 【Chemistry 12】 A compound of formula (Ib) of claim 8 or a pharmaceutically acceptable salt thereof, represented by .

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

11. A pharmaceutical composition according to claim 10 for administration by inhalation.

12. A pharmaceutical product comprising a compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient.

13. A pharmaceutical composition according to claim 10 or 11 or a pharmaceutical according to claim 12 for the prevention and / or treatment of diseases, disorders or conditions associated with dysregulation of discoidine domain receptors.

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

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

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

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