Thiophene derivatives as inhibitors of ddr

Abstract

The present invention relates to compounds of Formula (I) that inhibit discoidin domain receptors (DDR inhibitors), methods of making such compounds, pharmaceutical compositions containing them, and therapeutic uses thereof. The compounds of the invention can be used, for example, to treat a variety of diseases associated with DDR mechanisms.

Description

Invention Field

[0001] This invention relates to compounds that inhibit discoidin domain receptors (DDR inhibitors), methods for preparing the compounds, pharmaceutical compositions comprising the compounds, and the therapeutic use of the compounds.

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

[0004] Disk-domain receptors (DDRs) are type I transmembrane receptor tyrosine kinases (RTKs). The DDR family contains two distinct members: DDR1 and DDR2.

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

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

[0007] The DDR receptor family has been found to be involved in a range of fibrotic diseases, such as pulmonary fibrosis, and particularly idiopathic pulmonary fibrosis (IPF). The first evidence of the protective role of DDR1 deficiency in pulmonary fibrosis was presented by Dr. Vogel's research group in 2006 (see Avivi-Green C, Am J Respir Crit Care Med 2006; 174: 420-427). The authors demonstrated that DDR1-deficient mice were largely protected from bleomycin (BLM)-induced damage. Furthermore, these animals exhibited significantly lower myofibroblast expansion and apoptosis compared to their wild-type counterparts. Inflammation was confirmed absent in the knockout mice by perfusion cell counting and cytokine ELISA. These results suggest that DDR1 expression is a prerequisite for the development of pulmonary inflammation and fibrosis.

[0008] DDR2 deficiency or downregulation reduces 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. demonstrated that DDR2 plays a crucial role in inducing fibrosis and angiogenesis in the lungs, particularly by synergistically inducing myofibroblast differentiation with transforming growth factor (TGF)-β. Furthermore, they showed that treatment of injured mice with DDR2-specific siRNA exhibited therapeutic efficacy against pulmonary fibrosis. In a second publication, Jia et al. demonstrated that DDR2-deficient mice were protected from bleomycin-induced pulmonary fibrosis (see Jia S, Am J Respir Cell Mol Biol 2018; 59: 295-305). Moreover, DDR2-deficient fibroblasts were significantly more prone to apoptosis than wild-type fibroblasts, supporting an example where fibroblast resistance to apoptosis is crucial for fibrosis progression.

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

[0010] WO2016064970 (Guangzhou) discloses tetrahydroisoquinoline-7-carboxamide as a selective DDR1 inhibitor, which can be used as a therapeutic agent for the prevention and treatment of inflammation, liver fibrosis, kidney fibrosis, pulmonary fibrosis, skin scarring, atherosclerosis and cancer.

[0011] It is worth noting that antagonizing DDR receptors can be used to treat fibrosis and diseases, disorders and symptoms caused by fibrosis, and even antagonizing both DDR1 and DDR2 receptors may be particularly effective in treating the aforementioned diseases, disorders and symptoms.

[0012] Several efforts have been made in recent years to develop novel DDR1 and DDR2 receptor antagonists that can be used to treat several diseases, and some of these compounds have shown efficacy in humans.

[0013] Despite the prior art cited above, there remains the potential to develop selective inhibitors of both DDR1 and DDR2 receptors for the treatment of respiratory diseases or conditions associated with DDR receptor dysregulation, particularly idiopathic pulmonary fibrosis (IPF), administered via inhalation, characterized by good inspiratory properties corresponding to good activity in the lungs, good lung retention, and low metabolic stability, in order to minimize systemic exposure and associated safety concerns.

[0014] In this direction, we unexpectedly discovered a new series of compounds of formula (I), as described below, which solve the problem of providing inhibitors of the receptors DDR1 and DDR2 for inhalation administration, exhibiting activity relative to other human protein kinases as selective inhibitors of DDR1 and DDR2 receptors. These compounds show high potency, good inhalation properties, low metabolic stability, low systemic exposure, and improved safety and tolerability. Invention Overview

[0016] In a first aspect, the present invention relates to compounds of formula (I).

[0017]

[0018] in

[0019] L is selected from -C(O)- and -CH2-;

[0020] Hy is a monocyclic heteroaryl group, optionally substituted with one or more groups selected from: -(C1-C4)alkyl, halogen atom, cyano, -(CH2). nNR4R5, -NH-heterocyclic alkyl, -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-(C 1-C4)alkyl, -NH-(C1-C6)alkylene-O-(C1-C4)alkyl, -NH-(C1-C6)alkylene-OH, -heteroaryl optionally substituted with one or more -(C1-C4)alkyl groups, wherein the heteroaryl is optionally substituted with one or more -(C1-C4)alkyl groups, -NH-heteroaryl, and heterocyclic alkyl optionally substituted with one or more groups selected from oxo and -(C1-C6)alkyl groups;

[0021] R1 is selected from:

[0022] -Het, which is a heteroaryl group, wherein the heteroaryl group is optionally substituted with one or more groups selected from -(C1-C4)alkyl, -(C1-C4)haloalkyl, and aryl groups, wherein the aryl group is optionally substituted with one or more groups selected from -(C1-C4)alkyl and halogen atoms; and

[0023] -X

[0024]

[0025] in

[0026] R2 is selected from -O(C1-C4) haloalkyl, halogen atom, -O(C3-C7) cycloalkyl and -(C1-C4) haloalkyl;

[0027] R3 is H or selected from halogen atoms, cyano, -O(C1-C4)alkyl, -O(C1-C4)haloalkyl, heterocyclic alkyl-(C1-C4)alkylene-, -(C1-C4)alkylene-heterocyclic alkyl-NR4R5 and heteroaryl groups optionally substituted with one or more -(C1-C4)alkyl groups, wherein the heterocyclic alkyl group is optionally substituted with one or more -(C1-C4)alkyl groups;

[0028] n is 0, 1, or 2;

[0029] R4 is H or -(C1-C4) alkyl;

[0030] R5 is H or -(C1-C4) alkyl;

[0031] And its pharmaceutically acceptable salts.

[0032] In a second aspect, the present invention relates to pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof, which are mixed with one or more pharmaceutically acceptable carriers or excipients.

[0033] In a third aspect, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising compounds of formula (I) and pharmaceutically acceptable salts thereof, which are used as pharmaceuticals.

[0034] In another aspect, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising compounds of formula (I) and pharmaceutically acceptable salts thereof, for the prevention and / or treatment of diseases, disorders or conditions associated with DDR disorder.

[0035] In another aspect, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising compounds of formula (I) and pharmaceutically acceptable salts thereof, for the prevention and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0036] In another aspect, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising compounds of formula (I) and pharmaceutically acceptable salts thereof, for the prevention and / or treatment of idiopathic pulmonary fibrosis (IPF). Invention Details

[0038] definition

[0039] Unless otherwise stated, compounds of formula (I) of the present invention also include their stereoisomers or pharmaceutically acceptable salts.

[0040] Unless otherwise stated, the compounds of formula (I) of the present invention also include compounds of (Ia), (Iaa), (Iaa'), (Iaa”), (Iab), (Ib), (Iba) and (Ibb).

[0041] As used in this application, the term "pharmaceutically acceptable salt" refers to a derivative of a compound of formula (I), wherein the parent compound is suitably modified by converting any free acid or basic group (if present) into the corresponding addition salt using any base or acid conventionally expected to be pharmaceutically acceptable.

[0042] Therefore, suitable examples of the salt may include inorganic or organic acid addition salts of basic residues such as amino groups, and inorganic or organic base addition salts of acid residues such as carboxyl groups.

[0043] The cations of inorganic bases suitable for preparing salts include ions of alkali metals or alkaline earth metals such as potassium, sodium, calcium, or magnesium.

[0044] Salts obtained by reacting the main alkali-acting compound 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.

[0045] The term "stereoisomer" refers to isomers with the same composition but different spatial arrangements of atoms. Enantiomers and diastereomers are examples of stereoisomers.

[0046] The term "enantiomer" refers to one of a pair of molecular structures that are mirror images of each other and cannot be overlapped.

[0047] The term "diamera" refers to a stereoisomer that is not a mirror image.

[0048] The term "racemate" or "racemic mixture" refers to a composition consisting of two enantiomers in equimolar amounts, wherein the composition is optically inactive.

[0049] As used in this application, the terms "halogen" or "halogen atom" or "halogenated" include fluorine, chlorine, bromine and iodine atoms.

[0050] The term "(C)" x -C y "alkyl" refers to a straight-chain or branched alkyl group having x to y carbon atoms, where x and y are integers. Therefore, for example, when x is 1 and y is 4, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0051] The term "(C)" x -C y "alkylene", where x and y are integers, refers to a divalent saturated aliphatic chain derived from alkanes by removing two hydrogen atoms from different carbon atoms, having x to y carbon atoms, such as methylene.

[0052] The term "O(C)" x -C y "(C)haloalkyl", where x and y are integers, refers to "(C)haloalkyl" as defined above. x -C y "Halogenated alkyl", in which a carbon atom is bonded to an oxygen atom.

[0053] Therefore, the "O(C)" x -C y Examples of “halogenated alkyl” can include halogenated, polyhalogenated, and fully halogenated O-alkyl in which all hydrogen atoms are replaced by halogen atoms, such as trifluoromethoxy and difluoromethoxy.

[0054] The term "(C)" x -C y )alkylene-NR x’ Ry’ In the string, x and y are integers, referring to the definition above: "(C x -C y )alkylene", where the carbon atom is bonded to NR via a nitrogen atom x’ R y’ Connect the integers x' and y'.

[0055] The term "O(C)" x -C y "(C)alkyl", where x and y are integers, refers to "(C)alkyl" as defined above. x -C y "alkyl" refers to a carbon atom bonded to an oxygen atom, such as ethoxy and methoxy.

[0056] The term "(C)" x -C y "(C)haloalkyl", where x and y are integers, refers to "(C)haloalkyl" as defined above. x -C y "(C)alkyl", in which one or more hydrogen atoms are replaced by one or more halogen atoms (which may be the same or different). Therefore, the "(C)alkyl" is... x -C y Examples of “halogenated alkyl” can include halogenated, polyhalogenated, and fully halogenated alkyl groups in which all hydrogen atoms are replaced by halogen atoms, such as trifluoromethyl, 1,1,1-trifluoro-2-methylpropyl-2-yl, and 1,1-difluoroethyl.

[0057] The term "aryl" refers to a monocyclic carbon ring system having six ring atoms, wherein the ring is aromatic. Examples of suitable aryl monocyclic ring systems include, for example, phenyl.

[0058] 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 fused together by a common bond, or one such monocyclic ring and a monocyclic aryl ring, such as pyridinyl, pyrimidinyl, 1-methyl-1H-pyrazolyl, pyrazinyl, 1-methyl-1H-imidazolyl, and isoxazolyl.

[0059] The term "-C(O)NH-(C x -C y )alkylene-NR x’ R y’ ", where x' and y' are integers, referring to "(C" as defined above. x -C y )alkylene-NR x’ R y’ “”, where the alkylene group is linked to the -C(O)NH- group through its nitrogen atom.

[0060] The term "NHC(O)-(C" is missing from the original text.) x -C y )alkylene-NR x’ R y’ "Refers to the "(C" defined above x -C y )alkylene-NR x’ R y’ “”, where the alkylene group is linked to the -NHC(O)- group through its carbonyl group.

[0061] The term "NHC(O)-(C" is missing from the original text.) x -C y )alkylene-O-(C x -C y "alkyl" refers to "O(C)" as defined above. x -C y )alkyl and the "(C)" defined above x -C y )alkylene", where "O(C) x -C y )alkyl" and "(C x -C y The alkylene group is linked by an oxygen atom, and the alkylene group defined above is... x -C y The alkylene group is further linked to an amide group via its carbonyl moiety.

[0062] The term "NH-heteroaryl" refers to the "heteroaryl" as defined above, in which the heteroaryl group is bonded to a nitrogen atom.

[0063] The term "heterocyclic alkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic cyclic system comprising 3 to 12 ring atoms selected from N, S, or O. Examples of heterocyclic alkyl groups may include, for example, piperazinyl, oxopiperazinyl, dioxothiomorpholino, oxoheterobutyl, and pyrrolidinyl.

[0064] The term "heterocyclic alkyl-(C)" x -C y "alkylene" refers to a straight or branched chain (C) attached to a carbon atom having x to y carbon atoms. x -C y Heterocyclic alkyl groups on alkylene groups.

[0065] The key pointing to the wavy line or the wavy line used in the structural formula of this application, for example Describes the bond that serves as a connection point between a part or substituent and the core or skeletal structure.

[0066] When referring to substituents, the dash ("-") not between two letters, words, or symbols indicates the connection point of such substituents.

[0067] In this application, the carbonyl group is preferably represented as -C(O)-, as an alternative to other common representations such as -CO-, -(CO)- or -C(=O)-.

[0068] Whenever a basic amino or quaternary ammonium group is present in a compound of formula (I), a physiologically acceptable anion may be present, selected from chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, dihydroxynaphthylate, and naphthalenedisulfonate. Similarly, in the presence of an acidic group, a corresponding physiologically acceptable cation salt may also be present, including alkali metal or alkaline earth metal ions.

[0069] The term "half-maximum inhibitory concentration" (IC50) 50 () indicates the concentration of a specific compound or molecule required to achieve 50% inhibition of a biological process in vitro.

[0070] The term "Ki" represents the dissociation constant of the enzyme-inhibitor complex, expressed in molar units. It is an indicator of the binding affinity between the inhibitor and the DDR1 or DDR2 receptor.

[0071] As described above, the present invention relates to a series of compounds represented by formula (I), as detailed below, which have inhibitory activity against receptors DDR1 and DDR2. Antagonizing receptors DDR1 and DDR2 can be particularly effective in treating diseases in which DDR receptors play a role, such as fibrosis and fibrosis-related diseases, disorders, and conditions.

[0072] In fact, as detailed in the experimental section below, the compounds of formula (I) of the present invention can act as inhibitors of DDR1 and DDR2 receptors in a substantial and effective manner. Specifically, Table 5 below shows that, for the compounds of the present invention, the affinity for DDR1 and DDR2 receptors and the inhibitory activity against either DDR1 or DDR2 receptors are both below about 80 nM in both binding (expressed as Ki) and cell-based assays (expressed as IC50). This confirms that the compounds of formula (I) can inhibit two isoforms of the DDR receptors that are primarily involved in fibrosis and the diseases caused by fibrosis. Therefore, when DDR1 and DDR2 are involved, the compounds of formula (I) can be used to treat fibrosis, particularly pulmonary fibrosis.

[0073] As shown in the Experimental section, the Comparative Examples, particularly in Table 6, demonstrate that, in contrast to the comparative compound of Example C1 (characterized by the lack of a linker between the tetrahydrothiophenepyridine ring and the Hy group), the presence of a -CH2- or -C(O)- linker at this position in the compounds of the present invention unexpectedly and significantly determines the associated increase in inhibitory activity against DDR1 and DDR2 receptors.

[0074] Furthermore, as shown in the same experimental section, the data indicate that, in contrast to the compound of Example C2 (characterized by the absence of a linker between the tetrahydrothiophenepyridine ring and the Hy group and the -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 aforementioned linker and the simultaneous occurrence of substitution at the β position in the compounds of the present invention unexpectedly and notably determined the associated increase in inhibitory activity against DDR1 and DDR2 receptors.

[0075] Advantageously, the compounds of the present invention have very high potency and can be administered to humans at lower doses compared to prior art compounds, thereby reducing adverse events that typically occur when administering higher doses of the drug.

[0076] In addition to their significantly effective inhibitory activity against receptors DDR1 and DDR2, the compounds of the present invention are characterized as selective inhibitors of DDR1 and DDR2 receptors relative to other human protein kinases, as well as having good inhalation properties that allow for effective action on the lung compartments, and at the same time have low metabolic stability that allows for minimizing the disadvantages associated with systemic exposure, such as safety and tolerability issues.

[0077] Therefore, the compounds of the present invention are of particular interest to those skilled in the art when they seek suitable and effective compounds for the treatment of fibrosis, particularly idiopathic pulmonary fibrosis, said compounds being administered by inhalation and characterized by good inhalation properties, which correspond to good pulmonary activity, good pulmonary retention and low metabolic stability, thereby minimizing systemic exposure and associated safety issues.

[0078] Therefore, in one aspect, the present invention relates to compounds of formula (I).

[0079]

[0080] in

[0081] L is selected from -C(O)- and -CH2-;

[0082] Hy is a monocyclic heteroaryl group, optionally substituted with one or more groups selected from: -(C1-C4)alkyl, halogen atom, cyano, -(CH2). nNR4R5, -NH-heterocyclic alkyl, -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-(C 1-C4)alkyl, -NH-(C1-C6)alkylene-O-(C1-C4)alkyl, -NH-(C1-C6)alkylene-OH, -heteroaryl optionally substituted with one or more -(C1-C4)alkyl groups, wherein the heteroaryl is optionally substituted with one or more -(C1-C4)alkyl groups, -NH-heteroaryl, and heterocyclic alkyl optionally substituted with one or more groups selected from oxo and -(C1-C6)alkyl groups;

[0083] R1 is selected from:

[0084] -Het, which is a heteroaryl group, wherein the heteroaryl group is optionally substituted with one or more groups selected from -(C1-C4)alkyl, -(C1-C4)haloalkyl, and aryl groups, wherein the aryl group is optionally substituted with one or more groups selected from -(C1-C4)alkyl and halogen atoms; and

[0085] -X

[0086]

[0087] in

[0088] R2 is selected from -O(C1-C4) haloalkyl, halogen atom, -O(C3-C7) cycloalkyl and -(C1-C4) haloalkyl;

[0089] R3 is H or selected from halogen atoms, cyano, -O(C1-C4)alkyl, -O(C1-C4)haloalkyl, heterocyclic alkyl-(C1-C4)alkylene-, -(C1-C4)alkylene-heterocyclic alkyl-NR4R5 and heteroaryl groups optionally substituted with one or more -(C1-C4)alkyl groups, wherein the heterocyclic alkyl group is optionally substituted with one or more -(C1-C4)alkyl groups;

[0090] n is 0, 1, or 2;

[0091] R4 is H or -(C1-C4) alkyl;

[0092] R5 is H or -(C1-C4) alkyl;

[0093] And its pharmaceutically acceptable salts.

[0094] In a preferred embodiment, the present invention relates to compounds of formula (I), wherein L is -CH2.

[0095] In another preferred embodiment, the present invention relates to compounds of formula (I) wherein R1 is X'.

[0096]

[0097] The compound is represented by formula (Ia).

[0098]

[0099] L, Hy, R2, and R3 are defined as above.

[0100] In a further preferred embodiment, the present invention relates to compounds of formula (Ia) wherein L is -CH2-, said compounds being represented by formula (Iaa).

[0101]

[0102] Hy, R2, and R3 are defined as above.

[0103] In another preferred embodiment, the invention relates to compounds of formula (Iaa), wherein Hy is selected from pyridin-3-yl, pyrimidin-5-yl, ((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl, 4-(2-methoxyacetamido)pyridin-3-yl, 5-cyanopyridin-3-yl, 5-chloropyridin-3-yl, 5-methoxypyridin-3-yl, 5-methylpyridin-3-yl, 5-(trifluoromethyl)pyridin-3-yl, 3-aminopyrazin-2-yl, 2-aminopyrimidin-5-yl, 5-(4-methyl-3-oxopiperazin-1-yl)pyridin-3-yl, 5-(1,1-dioxothiomorpholino)pyridin-3-yl, -((5-(2-(dimethyl) (2-(oxetane-3-ylamino)pyridin-5-yl, 2-acetaminopyrimin-5-yl, (2-(methylamino)pyrimin-5-yl, ((2-methoxyethyl)amino)pyrimin-5-yl, 6-acetaminopyridin-3-yl, 2-aminopyridin-3-yl, ((2-hydroxyethyl)amino)pyrimin-5-yl, 4-aminopyrimin-5-yl, 2-amino-4-methylpyrimin-5-yl, (2-fluoroprop-2-yl)pyrimin-5-yl, 4-methoxypyrimin-5-yl, 4-cyclopropoxypyrimin-5-yl, (1-methyl-1H-pyrazol-4-yl)pyridin-3-yl and (5-fluoropyridin-3-yl)methyl.

[0104] In a further preferred embodiment, the present invention relates to a compound of formula (Iaa), wherein R2 is selected from trifluoromethyl, trifluoromethoxy, 1,1-difluoroethyl and difluoromethoxy.

[0105] In another particularly preferred embodiment, the invention relates to a compound of formula (Iaa), wherein R3 is H or selected from (4-methylpiperazin-1-yl)methyl, 4-methyl-1H-imidazol-1-yl, fluorine, (3-(dimethylamino)pyrrolidone-1-yl)methyl, (dimethylamino)methyl and cyano.

[0106] 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 salt. These compounds are particularly active against receptors DDR1 and DDR2, as shown in Table 5.

[0107] Table 1: List of compounds of formula (Iaa)

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120] In another preferred embodiment, the present invention relates to compounds of formula (I), wherein L is -CH2- and R1 is X".

[0121]

[0122] The compound is represented by the formula (Iaa').

[0123]

[0124] Hy, R2, and R3 are defined as above.

[0125] In another preferred embodiment, the present invention relates to a compound of formula (Iaa'), wherein R2 is trifluoromethyl.

[0126] In a further preferred embodiment, the present invention relates to a compound of formula (Iaa'), wherein R3 is fluorine.

[0127] In a further particularly preferred embodiment, the present invention relates to compounds of formula (Iaa'), wherein Hy is pyrimidin-5-yl.

[0128] According to a preferred embodiment, the present invention relates to compounds of formula (Iaa') listed in Table 2 below and their pharmaceutically acceptable salts. These compounds are particularly active against receptors DDR1 and DDR2, as shown in Table 5.

[0129] Table 2: List of compounds of formula (Iaa')

[0130]

[0131] In another preferred embodiment, the present invention relates to compounds of formula (I), wherein L is -CH2- and R1 is X”'.

[0132]

[0133] The compound is represented by the formula (Iaa”).

[0134]

[0135] Hy, R2, and R3.

[0136] In a particularly preferred embodiment, the present invention relates to compounds of formula (Iaa”), wherein R2 is selected from trifluoromethyl and trifluoromethoxy.

[0137] In another particularly preferred embodiment, the present invention relates to compounds of formula (Iaa"), wherein R3 is selected from fluorine, chlorine and (dimethylamino)methyl.

[0138] In a further preferred embodiment, the present invention relates to compounds of formula (Iaa”), wherein Hy is pyrimidin-5-yl and 2-aminopyrimidin-5-yl.

[0139] According to a preferred embodiment, the present invention relates to at least one compound of formula (Iaa”) listed in Table 3 below, and its pharmaceutically acceptable salt. These compounds are particularly active against receptors DDR1 and DDR2, as shown in Table 5.

[0140] Table 3: List of compounds with formula (Iaa”)

[0141]

[0142]

[0143] In another preferred embodiment, the present invention relates to compounds of formula (Ia), wherein L is -C(O)-, said compounds being represented by formula (Iab).

[0144]

[0145] Hy, R2, and R3 are defined as above.

[0146] In a particularly preferred embodiment, the present invention relates to a compound of formula (Iab), wherein R2 is trifluoromethyl.

[0147] In another particularly preferred embodiment, the present invention relates to compounds of formula (Iab), wherein R3 is fluorine.

[0148] In a further preferred embodiment, the present invention relates to compounds of formula (Iab), wherein Hy is 1-methyl-1H-imidazol-5-yl.

[0149] According to a preferred embodiment, the present invention relates to compounds of formula (Iab) in Table 7 below and pharmaceutically acceptable salts thereof.

[0150] Table 7: List of compounds of formula (Iab)

[0151]

[0152] In a further preferred embodiment, the present invention relates to a compound of formula (I), wherein R1 is Het, and the compound is represented by formula (Ib).

[0153]

[0154] in

[0155] L is selected from -C(O)- and -CH2-;

[0156] Hy is a monocyclic heteroaryl group, optionally substituted with one or more groups selected from -(C1-C4)alkyl, halogen atom, cyano, -(CH2). n NR4R5, -O-(C1-C6)alkyl, -(C1-C6)haloalkyl, -NHC(O)-(C1-C6)alkylene-O-(C1-C4)alkyl and -NH-heteroaryl, wherein the heteroaryl is optionally substituted by one or more -(C1-C4)alkyl groups;

[0157] Het is a heteroaryl group, optionally substituted with one or more groups selected from -(C1-C4)alkyl, -(C1-C4)haloalkyl, and aryl, wherein the aryl group is optionally substituted with one or more groups selected from -(C1-C4)alkyl and halogen atoms; wherein

[0158] R4 is H;

[0159] R5 is H or -(C1-C4) alkyl;

[0160] And its pharmaceutically acceptable salts.

[0161] In another preferred embodiment, the present invention relates to compounds of formula (Ib), wherein L is -CH2-, said compounds being represented by formula (Iba).

[0162]

[0163] Hy and Het are defined as above.

[0164] In a further preferred embodiment, the present invention relates to a compound of formula (Iba), wherein Hy is selected from pyrimidin-5-yl, 3-aminopyrazin-2-yl, 5-methoxypyridin-3-yl, 5-fluoropyridin-3-yl, pyridin-3-yl, 3-aminopyrazin-2-yl and (2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl.

[0165] In another particularly preferred embodiment, the invention relates to compounds of formula (Iba), wherein Het is selected from 5-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazol-3-yl, (trifluoromethyl)pyridin-3-yl, 2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-yl, 5-(trifluoromethoxy)pyridin-3-yl, and 3-(tert-butyl)-1-methyl-1H-pyrazole-5-yl.

[0166] 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 salt. These compounds are particularly active against receptors DDR1 and DDR2, as shown in Table 5.

[0167] Table 4: List of compounds of formula (Iba)

[0168]

[0169]

[0170]

[0171]

[0172] In a further preferred embodiment, the present invention relates to compounds of formula (Ib), wherein L is -C(O)-, said compounds being represented by formula (Ibb).

[0173]

[0174] Hy and Het are defined as above.

[0175] The compounds of this invention, including all those listed above, can be prepared from readily available starting materials using the general methods and approaches described below, or by slightly modified methods readily available to those skilled in the art. Although specific embodiments of the invention may be shown or described herein, those skilled in the art will recognize that all embodiments or aspects of the invention can be obtained using the methods described herein or by using other known methods, reagents, and starting materials. Other process conditions may also be used when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, unless otherwise stated. While optimal reaction conditions can vary depending on the specific reactants or solvents used, these conditions can be readily determined by those skilled in the art using conventional optimization methods.

[0176] In some cases, according to general principles of chemistry (Protective group in organic synthesses, 3rd ed. TW Greene, PGM Uts), when it is necessary to mask or protect sensitive or reactive parts, a commonly known protecting group (PG) can be used.

[0177] Surprisingly, the compounds of formula (I) of the present invention effectively inhibit both receptors DDR1 and DDR2. Advantageously, inhibition of receptors DDR1 and DDR2 can lead to effective treatment of diseases or conditions involving DDR receptors.

[0178] In this regard, it has been found that, as shown in this experimental section, the compounds of formula (I) of the present invention have antagonistic drug efficacy of less than 80 nM, expressed as an inhibition constant Ki for DDR1 and DDR2. Preferably, the compounds of the present invention have a Ki of less than 50 nM for DDR1 and DDR2. Even more preferably, the compounds of the present invention have a Ki of less than 25 nM for DDR1 and DDR2.

[0179] Furthermore, as shown in this experimental section, the compounds of formula (I) of the present invention have been found to have an affinity for DDR1 or DDR2 receptors and inhibitory activity for DDR1 or DDR2 receptors of less than about 80 nM in both binding (denoted as Ki) and cell-based assays (denoted as IC50). Preferably, the compounds of the present invention have a Ki and / or IC50 for DDR1 and DDR2 receptors of less than 50 nM. Even more preferably, the compounds of the present invention have a Ki and / or IC50 for DDR1 and DDR2 receptors of less than 25 nM.

[0180] In one aspect, the present invention relates to compounds of formula (I) according to any of the embodiments disclosed above, which are used as pharmaceuticals.

[0181] In a preferred embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof for treating diseases, disorders or conditions associated with DDR disorder.

[0182] In another aspect, the present invention relates to the use of compounds of formula (I) as described above in the preparation of medicaments for treating diseases associated with DDR disorder.

[0183] In a preferred embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of diseases, disorders, or conditions associated with DDR receptor mechanisms. In one embodiment, the present invention relates to a compound of formula (I) which can be used for the prevention and / or treatment of fibrosis and / or diseases, disorders, or conditions involving fibrosis.

[0184] As used in this application, the term "fibrosis" or "fibrotic condition" refers to a condition associated with the abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased recruitment of fibroblasts, and includes, but is not limited to, fibrosis of individual organs or tissues such as the heart, kidneys, liver, joints, lungs, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal system, and digestive tract.

[0185] Preferably, the compounds of formula (I) as described above can be used to treat and / or prevent fibrosis, such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, kidney fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, and systemic sclerosis.

[0186] More preferably, the compound of formula (I) as described above can be used to treat idiopathic pulmonary fibrosis (IPF).

[0187] In one aspect, the invention also relates to a method for preventing and / or treating diseases associated with DDR receptor mechanisms, the method comprising administering a therapeutically effective amount of a compound of formula (I) as described above to a patient in need of such treatment.

[0188] In another aspect, the present invention relates to the use of compounds of formula (I) as described above for the treatment of conditions related to the DDR receptor mechanism.

[0189] In another aspect, the present invention relates to the use of compounds of formula (I) as described above in the preparation of medicaments for treating conditions related to the DDR receptor mechanism.

[0190] In another aspect, the present invention relates to a method for preventing and / or treating diseases or conditions associated with dysregulation of DDR receptor 1 and receptor 2, the method comprising administering a therapeutically effective amount of a compound of formula (I) as described above to a patient in need of such treatment.

[0191] In another aspect, the present invention relates to the use of compounds of formula (I) as described above for the treatment of diseases, disorders or conditions associated with dysregulation of DDR receptor 1 and receptor 2.

[0192] As used in this application, a “safe and effective amount” of a compound of formula (I) or a pharmaceutically acceptable salt or other pharmaceutical-active agent thereof means an amount of compound sufficient to treat a patient’s condition but low enough to avoid serious side effects, and which can still be determined by a person skilled in the art using conventional methods.

[0193] The compound of formula (I) can be administered once or according to a dosing regimen in which multiple doses are administered at different time intervals over a given period of time. Typical daily doses can vary depending on the chosen route of administration.

[0194] The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) according to any embodiment thereof, which is mixed with at least one or more pharmaceutically acceptable carriers or excipients.

[0195] In one embodiment, the present invention relates to a pharmaceutical composition of a compound of formula (I) mixed with one or more pharmaceutically acceptable carriers or excipients, such as those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA.

[0196] The administration of the compounds of the present invention and the pharmaceutical compositions thereof can be performed as needed by the patient, for example by oral, intranasal, parenteral (subcutaneous, intravenous, intramuscular, intrasternal and by infusion) and inhalation.

[0197] Preferably, the compounds of the present invention are administered orally or by inhalation.

[0198] In a preferred embodiment, the pharmaceutical composition comprising the compound of formula (I) is a solid oral dosage form, such as tablets, soft capsules, capsules, capsule-shaped tablets, granules, lozenges, and bulk powders.

[0199] In one embodiment, the pharmaceutical composition comprising the compound of formula (I) is a tablet.

[0200] The compounds of the present invention can be applied alone or in combination with various pharmaceutically acceptable carriers, diluents (e.g., sucrose, mannitol, lactose, starch) and known excipients, including suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, colorants, flavoring agents, lubricants, etc.

[0201] In another embodiment, the pharmaceutical composition comprising the compound of formula (I) is a liquid oral dosage form, such as an aqueous and non-aqueous solution, emulsion, suspension, syrup, and elixir. Such liquid dosage forms may also comprise a suitable known inert diluent (e.g., water) and suitable known excipients (e.g., preservatives, wetting agents, sweeteners, flavoring agents) as well as agents for emulsifying and / or suspending the compounds of the present invention.

[0202] In another embodiment, the pharmaceutical composition comprising the compound of formula (I) is an inhalable formulation, such as an inhalable powder, a metered aerosol containing a propellant, or an inhalable formulation without a propellant.

[0203] For administration as dry powder, single-dose or multi-dose inhalers known in the art can be used. In this case, the powder can be filled in gelatin, plastic or other capsules, cartridges or blister packs or storage containers.

[0204] A chemically inert diluent or carrier, such as lactose or any other additive suitable for improving the inhalable fraction, may be added to the powdered compound of the present invention.

[0205] Inhalation aerosols containing propellant gases such as hydrofluorocarbons may contain the compounds of the present invention in solution or dispersion form. Propellant-driven formulations may also contain other components, such as co-solvents, stabilizers, and optional other excipients.

[0206] Propellant-free inhalable formulations containing the compounds of the present invention may be in the form of solutions or suspensions in water, alcohol, or aqueous alcohol media, and may be delivered by jet or ultrasonic atomizers known in the art or by soft atomizers.

[0207] The compounds of this invention can be used as the sole active agent or in combination with other pharmaceutical active ingredients.

[0208] The dosage of the compounds of this invention depends on a variety of factors, including the specific disease to be treated, the severity of symptoms, and the route of administration.

[0209] The present invention also relates to a device comprising a pharmaceutical composition comprising a compound according to formula (I) of the present invention, the device being in the form of a single-dose or multi-dose dry powder inhaler or a metered-dose inhaler.

[0210] All preferred groups or embodiments described above for compounds of formula (I) can be combined with each other, and necessary adjustments can also be made to each other.

[0211] The compounds of this invention, including all those listed above, can be prepared from readily available starting materials using the general methods and approaches described below, or by slightly modified methods readily available to those skilled in the art. Although specific embodiments of the invention may be shown or described herein, those skilled in the art will recognize that all embodiments or aspects of the invention can be obtained using the methods described herein or by using other known methods, reagents, and starting materials. Other process conditions may also be used when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, unless otherwise stated. While optimal reaction conditions can vary depending on the specific reactants or solvents used, these conditions can be readily determined by those skilled in the art using conventional optimization methods.

[0212] Therefore, the methods described below and reported in the following schemes should not be considered as limiting the scope of synthetic methods that can be used to prepare the compounds of the present invention.

[0213] Compounds of formula (I) (including all or at least one of the above compounds) can generally be prepared using commonly known methods according to the methods outlined in detail in the schemes shown below.

[0214] In a first embodiment of the invention, the compound of formula (I) as defined above, wherein R1, L and Hy can be prepared as described in Scheme 1.

[0215] The compounds of formula (I) can be prepared according to Scheme 1 described below, which provides at least one non-limiting synthetic route for the preparation of all embodiments.

[0216]

[0217] According to Scheme 1, intermediate III can be prepared from intermediate II by a one-step synthesis for several hours under direct amidation (amid transfer) conditions of the ester, using, for example, butyllithium as a promoter in a suitable organic solvent such as THF or dioxane, at a temperature ranging from -78°C to room temperature. Under suitable deprotection conditions, using, for example, an aqueous solution of HCl or a solution of HCl in dioxane or TFA, in a suitable solvent such as DCM, at a suitable temperature ranging from 0°C to room temperature, intermediate IV can be obtained from intermediate III. At room temperature, in a suitable solvent such as DMF or DMA, using, for example, a suitable base such as DIPEA or TEA, using a suitable alkyl bromide intermediate XII, and applying suitable alkylation conditions, the compound of formula (I) can be obtained.

[0218] Alternatively, at room temperature, hydrolysis can be performed using a suitable aqueous inorganic base such as NaOH in a suitable solvent such as MeOH, followed by amide coupling with a suitable amine VIII or IX under suitable amide coupling conditions, in the presence of a reagent that activates the carboxylic acid pair such as TBTU, HATU, or T3P, in the presence of an organic base such as DIPEA or TEA, in a suitable organic solvent such as DCM or DMF, at a temperature typically around room temperature, to prepare intermediate III from intermediate II.

[0219] Alternatively, intermediate II can be prepared by amidation in the presence of TCFH and 1-methylimidazolium to obtain a transiently activated acylimidazolinetonium intermediate, which is then reacted with a suitable amine VIII or IX in a solvent such as DMF at room temperature. In different methods, intermediate II is given 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 cyclopentylmethyl ether, in a catalytic amount of DMF, at a temperature from 5°C to room temperature. This acyl chloride can then be directly treated with a suitable amine VIII or IX to prepare intermediate III.

[0220] In contrast, intermediate IV can be converted to intermediate V 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 ligand such as titanium tetrahydroisopropoxide, at a temperature from room temperature to 50°C, using a suitable aldehyde X, a suitable reducing agent such as Na(OAc)3BH or NaCNBH3, and applying reducing amination conditions. In a suitable solvent such as DMF or dioxane, using a suitable palladium catalyst such as RuPhos Pd G3 and a suitable base such as cesium carbonate, and by Buchwald-Hartwig cross-coupling with a suitable amine, intermediate V can be converted to a compound of formula (I). Alternatively, by using a suitable palladium catalyst such as Pd(dba)2, with a suitable ligand such as XantPhos, in a suitable solvent such as toluene, in the presence of a catalytic amount of aluminum trifluoromethanesulfonate, at a temperature of 110°C, Pd-catalyzed N-arylation of the amide can convert intermediate V into a compound of formula (I).

[0221] In different methods, using the suitable reducing amination conditions described above and employing a suitable aldehyde XI, intermediate VI can be prepared from intermediate IV, which is then converted to a compound of formula (I) by amidation with a suitable acyl chloride XIV at room temperature in a suitable solvent such as THF and using a suitable base such as TEA or DIPEA. Alternatively, using the suitable aldehyde XIII, a compound of formula (I) can also be obtained from intermediate IV by using the reducing amination conditions described above. In contrast, using the conditions described above, a compound of formula (I) can be prepared from intermediate IV by amidation with a suitable carboxylic acid.

[0222] In another implementation, the compound of formula (I) can be prepared according to scheme 2.

[0223] Option 2

[0224]

[0225] According to Scheme 2, under suitable deprotection conditions, using, for example, an aqueous solution of HCl or a solution of HCl in dioxane or TFA, in a suitable solvent such as DCM or diethyl ether, at a suitable temperature from 0°C to room temperature, intermediate XV can be obtained from intermediate II. 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 ligand such as titanium tetrahydroisopropoxide, at a temperature range from room temperature to 50°C, using a suitable reducing agent such as Na(OAc)3BH or NaCNBH3, intermediate XV can be reductively amination with a suitable aldehyde XIII to obtain intermediate XVI. Subsequently, hydrolysis is performed at room temperature in a suitable solvent such as MeOH using a suitable aqueous inorganic base such as NaOH. Following this, under suitable amide coupling conditions, in the presence of a reagent activating the carboxylic acid pair such as TBTU, HATU, or T3P, and in the presence of an organic base such as DIPEA or TEA, in a suitable organic solvent such as DCM or DMF, at a temperature typically around room temperature, amide coupling with a suitable amine VIII or IX can be performed from intermediate XVI to prepare the compound of formula (I). Alternatively, in the presence of a suitable chlorinating agent such as POCl3, thionyl chloride, or oxalyl chloride, if desired, in a solvent such as pyridine or cyclopentyl methyl ether, and if desired, in the presence of a catalytic amount of DMF, at a temperature between 5°C and 50°C, the corresponding acyl chloride XVIII can be obtained from intermediate XVII. This acyl chloride XVIII can then be amide-coupled with a suitable amide VIII at approximately room temperature in a suitable solvent such as DCM using a suitable base such as TEA to prepare the compound of formula (I).

[0226] The various aspects of the invention described in this application are illustrated by the following embodiments, which are not intended to limit the invention in any way.

[0227] Preparation of intermediates and examples

[0228] The chemical names of the compounds were generated using the Structure To Name Place IUPAC Name in PerkinElmer ChemDraw Professional 19.1.1.21. All reagents not described in the experimental section are either commercially available, known compounds, or compounds that can be formed by those skilled in the art from known compounds using known methods.

[0229] In the subsequent methods, some starting materials are identified by “intermediate” or “example” designations, and the step numbers are indicated. This is only to assist chemists in the art.

[0230] "Similar" or "resemblance" methods refer to methods that may include minor variations, such as reaction temperature, reagent / solvent volume, reaction time, post-treatment conditions, or chromatographic purification conditions.

[0231] Abbreviation - Meaning

[0232] RM = reaction mixture; TEA = triethylamine; HATU = (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylimine hexafluorophosphate; DMAP = 4-dimethylaminopyridine; TCFH = chloro-N,N,N',N'-tetramethylformamidin hexafluorophosphate; DMF = N,N-dimethylformamide; Et2O = diethyl ether; EtOAc = ethyl acetate; THF = tetrahydrofuran; DCM = dichloromethane; ACN = acetonitrile; MeOH = methanol; IMS = industrial methylated alcohol; RT = room temperature; LCMS = liquid chromatography / mass spectrometry; HPLC = high performance liquid chromatography Spectroscopy; TLC = Thin-layer chromatography; SCX = Solid cation exchange; DMSO-d6 = Deuterated dimethyl sulfoxide; CDCl3 = Deuterated chloroform; NaBH3CN = Sodium cyanoborohydride; ACN-d3 = Deuterated acetonitrile; NMR = Nuclear magnetic resonance; DIPEA = N,N-diisopropylethylamine; HCOOH = Formic acid; UPLC = Ultra-high 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(dibenzylacetone)palladium(0); RuPhos Pd G3 = (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II); STAB = sodium triacetoxyborohydride; AcOH = acetic acid; T3P = propylphosphonic anhydride; prep HPLC = preparative high-performance liquid chromatography; pTLC = preparative thin-layer chromatography; FCC = fast column chromatography; SM = starting material; eq. = equivalent.

[0233] General Experimental Details

[0234] NMR characterization:

[0235] Recordings were performed on a Varian MR-400 spectrometer operating at 400 MHz (proton frequency), equipped with a self-shielded Z-gradient coil 5 mm 1H / nX broadband probe for reverse detection, a deuterium digitally locked channel unit, and an orthogonal digital detection unit with emitter offset frequency shift, or on a Bruker Avance III HD 400 MHz or a Bruker Fourier 300 MHz spectrometer. 11H NMR spectra. Chemical shifts are reported as δ values ​​in ppm relative to tetramethylsilane (TMS) as an internal standard. Coupling constants (J values) are given in Hertz (Hz), and multiplicity is reported using the following abbreviations (s = singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, dt = double triplet, m = multiplet, br = broad peak, nd = not determined).

[0236] In some cases, the signal NH from amide or amine bonds (exchangeable protons) is not visible.

[0237] In rare cases, some signals may be hidden beneath the signals of water or DMSO or other residual solvents.

[0238] LC / UV / MS analysis methods

[0239] The estimated LC / MS retention time is affected by an experimental error of ±0.5 min.

[0240] Method 1: Acquity CSH C18 column, 50 mm x 2.1 mm 1.7 μm, maintained at 40 °C; mobile phase: eluent B (ACN / water 95:5 + 0.05% HCOOH) in eluent A (water / ACN 95:5 + 0.05% HCOOH), from 1% to 99.9% in 3.5 min. Flow rate: 1 mL / min. Wavelength: 210-400 nm. DAD. UPLC + Waters PDA + Waters QDA.

[0241] Method 2: XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25 °C. Mobile phase: water (0.1% HCOOH) in ACN (0.1% HCOOH), from 80% to 5% in 3.90 min; flow rate: 1.0 mL / min; wavelength: 190–340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQPlus with DAD detector.

[0242] Method 3: XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25 °C. Mobile phase: water (0.1% HCOOH) in ACN (0.1% HCOOH), from 95% to 20% in 4.75 min; flow rate: 1.0 mL / min; wavelength: 190–340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQPlus with DAD detector.

[0243] Method 4: XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25 °C. Mobile phase: water (0.1% HCOOH) in ACN (0.1% HCOOH), from 90% to 5% in 3.90 min; flow rate: 1.0 mL / min; wavelength: 190–340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQPlus with DAD detector.

[0244] Method 5: XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25 °C. Mobile phase: water (0.1% HCOOH) in ACN (0.1% HCOOH), from 70% to 5% in 3.90 min; flow rate: 1.0 mL / min; wavelength: 190–340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQPlus with DAD detector.

[0245] Method 6: XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25 °C. Mobile phase: water (0.1% HCOOH) in ACN (0.1% HCOOH), from 70% to 5% in 3.90 min; flow rate: 1.0 mL / min; wavelength: 190–340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific ISQ EC mass spectrometer with DAD detector.

[0246] Method 7: XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25 °C. Mobile phase: water (0.1% HCOOH) in ACN (0.1% HCOOH), from 80% to 5% in 3.90 min; flow rate: 1.0 mL / min; wavelength: 190–340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific ISQ EC mass spectrometer with DAD detector.

[0247] Method 8: Acquity UPLC BEH Shield RP18 column, 100x2.1mm, 1.72μm (with guard column), maintained at 40℃. Mobile phase: ACN in water + 10nM ammonium bicarbonate, from 5% to 95% in 5.6 min. Flow rate: 0.4 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters DAD + Waters SQD2, single quadrupole UPLC-MS.

[0248] Method 9: Acquity UPLC HSS C18 column, 100 x 2.1 mm, 1.8 μm (with guard column), maintained at 40 °C. Mobile phase: ACN (0.1% HCOOH) in water (0.1% HCOOH), from 5% to 95% over 5.6 min. Flow rate: 0.4 mL / min. Wavelength: 210-400 nm. UPLC + Waters DAD + Waters SQD2, single quadrupole UPLC-MS.

[0249] Method 10: Acquity UPLC BEH C18 column, 100 x 2.1 mm, 1.7 μm, maintained at 40 °C. Mobile phase: ACN (0.03% NH3) in water (0.03% NH3), from 5% to 95% in 5.6 min; flow rate: 0.4 mL / min; wavelength: 100-800 nm. Acquity UPLC with PDA detector and ZQ mass spectrometer.

[0250] Method 11: Agilent Zorbax column, 4.6 x 50 mm, 3.5 μm, maintained at 40 °C. Mobile phase: ACN (0.1% HCOOH) in water (0.1% HCOOH), from 5% to 95% over 2 min. Flow rate: 3.0 mL / min. Wavelength: 210-400 nm. Waters 2795 / 2695 separation module + Waters DAD + Micromass ZQ, single quadrupole LC-MS.

[0251] Method 12: Acquity BEH UPLC column, 2.1 x 50 mm, 1.7 μm, maintained at 40 °C. Mobile phase: ACN (0.03% NH3) in water (0.03% NH3), from 8% to 97% in 1.5 min; flow rate: 0.8 mL / min; wavelength: 210–400 nm. Acquity H-Class UPLC with PDA detector and QDa.

[0252] Method 13: Waters Sunfire C18 column, 4.6 x 50 mm, 3.5 μm, maintained at 40 °C. Mobile phase: ACN in water + 10 mM ammonium bicarbonate, from 5% to 95% in 2.5 min. Flow rate: 2.0 mL / min. Wavelength: 210-400 nm. Waters 2795 separation module + Waters DAD + Micromass ZQ, single quadrupole LC-MS.

[0253] Without description of the preparation of starting materials, these are commercially available, known in the literature, or readily available to those skilled in the art using standard methods. All solvents were purchased from commercial sources and used without additional purification.

[0254] Preparative HPLC was performed using reversed-phase (C18) preparative HPLC under alkaline conditions (ACN + 0.1% NH3, H2O + 0.1% NH3) and acidic conditions (ACN + 0.1% HCOOH, H2O + 0.1% HCOOH). In the latter case, the residue was ground with NaHCO3 (15% aqueous solution), and the precipitate was filtered through a Schott funnel, washed with water, transferred to a vial, and dried under high vacuum overnight at room temperature, or the free base of the product was obtained using SCX(NH3), unless otherwise specified. Thin-layer chromatography was performed on Merck silica gel 60F254 TLC plates. Preparative thin-layer chromatography (pTLC) was performed using Uniplate 1000 μm or 500 μm silica gel plates. Rapid chromatography was also performed.

[0255] General Synthesis Method

[0256] General Method A

[0257] Add N,N-diisopropylethylamine (3.00 to 8.00 eq) to a mixture of the desired carboxylic acid (1.00 eq) and HATU (1.20 to 2.00 eq) in DMF (0.1 M concentration). Stir the reaction mixture at room temperature for 15 min, then add the desired amine (1.00 eq). Stir the reaction mixture at room temperature until LCMS indicates that the starting material has been consumed, then concentrate.

[0258] General Method B

[0259] The desired carboxylic acid (1.00 eq) was suspended in thionyl chloride (30 eq), and the reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was suspended in toluene and further concentrated to give the intermediate acyl chloride. The acyl chloride was added to a solution of the desired aniline (1.00 eq) and TEA (3.00 eq) in DCM (0.1 M concentration). The reaction mixture was stirred at room temperature until LCMS indicated that the starting material had been consumed, and then concentrated under vacuum.

[0260] General Method C

[0261] Titanium isopropoxide (IV) (3.00 eq) was added to a solution of the desired amine (1.00 eq) and the desired aldehyde (1.00 eq) in MeOH (0.03 M concentration), and the mixture was refluxed for 2 h. The reaction was cooled to room temperature, and NaBH3CN (2.50 eq) was added, and the mixture was stirred overnight at room temperature. The reaction was quenched with water, filtered through diatomaceous earth, and concentrated under vacuum.

[0262] General Method D

[0263] Add the desired amine (1.10 eq), titanium isopropoxide (IV) (2.00 eq), and AcOH (3.00 eq) to a DCM (0.1 M) solution of the desired aldehyde (1.00 eq). Stir the reaction mixture at room temperature for 1 h. Add STAB (2.00 eq) and stir the reaction mixture at room temperature until LCMS indicates that the starting material has been consumed. Load the residue onto an Isolute SCX-II column, wash with MeOH, and then release with 2 M NH3 / MeOH. Concentrate the eluent under vacuum.

[0264] General Method E

[0265] STAB (2.00 eq) was added to a mixture of aldehyde (1.25 eq), amine (1.00 eq), AcOH (0.01 eq), and MgSO4 (4.00 eq) in DCM (15.00 mL), and the mixture was stirred at room temperature until LCMS indicated that the starting material had been consumed. The mixture was partitioned between saturated NaHCO3 (aq) and DCM, and then extracted again with DCM. The combined organic extracts were dried (Na2SO4) and concentrated under vacuum.

[0266] General Method F

[0267] AcOH (10 eq) was added to a mixture of the desired aldehyde (1.00 eq) and the desired amine (1.00 eq) 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 vacuum. The residue was suspended in DCM (0.025 M concentration), and sodium STAB (3.50 eq) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with DCM and treated with a 10% KHSO4 (aq) solution. After stirring for 15 min, the mixture was alkalized with a saturated Na2CO3 aqueous solution, and the layers were separated. The aqueous layer was extracted with DCM, and the combined organic extracts were filtered through a hydrophobic glass filter and concentrated under vacuum.

[0268] General method G

[0269] Add TCFH (1.20 to 1.50 eq) to a solution of the desired acid (1.00 eq), the desired amine (1.00 to 1.30 eq), and 1-methylimidazole (3.50 eq) in ACN (0.2 M concentration). Stir the reaction mixture at room temperature until LCMS indicates that the starting material has been consumed and partitioned between saturated NaHCO3 (aq) and EtOAc. Separate the phases, extract the aqueous phase with 2x EtOAc, and combine the organic phases through a hydrophobic glass frit and concentrate under vacuum.

[0270] General Method H

[0271] AcOH (2.00 eq) and MgSO4 (2.00 eq) were added to a mixture of the desired aldehyde (1.00 eq) and the desired amine (1.50 eq) in DMF (0.075 M concentration). The reaction mixture was stirred at room temperature for 1 h, and then STAB (2.00 eq) was added. The reaction mixture was heated at 60 °C overnight. The reaction was partitioned between DCM and an aqueous solution of NaHCO3. The combined organic phases were filtered through a hydrophobic glass frit, and the solvent was concentrated under vacuum.

[0272] Preparation of intermediate 1: 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxaldehyde

[0273]

[0274] Step 1: 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxaldehyde

[0275] 2-Chloropremine-5-carboxaldehyde (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 at room temperature. The mixture was quenched with DCM and brine. The phases were separated, and the aqueous layer was washed with DCM (x2). All combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude product was purified by FCC and eluted with hexane / EtOAc 1:1 to give the title product (35 mg, 39%).

[0276] 1 H NMR (300MHz, DMSO-d6) δ10.45 (s, 1H), 9.80 (s, 1H), 8.92-8.79 (m, 2H), 7.99 (d, J = 0.8Hz, 1H), 7.56 (d, J = 0.8Hz, 1H), 3.83 (s, 3H).

[0277] Preparation of intermediate 20: 2-(oxetane-3-ylamino)pyrimidine-5-carboxaldehyde

[0278]

[0279] Step 1: 2-(oxetane-3-ylamino)pyrimidine-5-carboxaldehyde

[0280] TEA (0.049 mL, 0.351 mmol, 1.00 eq) and 3-aminooxetane (0.027 mL, 0.386 mmol, 1.10 eq) were added to a solution of 2-chloropyrimidine-5-carboxaldehyde (50 mg, 0.351 mmol, 1.00 eq) in DMSO (1.5 mL), and the solution was stirred at 60 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with DCM, and washed with water and brine. The organic layer was dried (MgSO4) and concentrated to give the title compound (62 mg, 100%).

[0281] LC-MS(ESI): m / z(M+1)=180.2; t R =1.00min; Method 11

[0282] Preparation of intermediate 21: 2-((2-methoxyethyl)amino)pyrimidine-5-carboxaldehyde

[0283]

[0284] Step 1: 2-Chloro-5-(diethoxymethyl)pyrimidine (intermediate 22)

[0285]

[0286] Triethyl orthoformate (11 mL, 63.1 mmol, 3.00 eq) was added to a suspension of 2-chloropyrimidine-5-carboxaldehyde (3000 mg, 21.0 mmol, 1.00 eq) and p-toluenesulfonic acid monohydrate (400 mg, 2.10 mmol, 0.10 eq) in ethanol (60 mL), and the mixture was heated to 80 °C and stirred for 3 h. The mixture was cooled to 0 °C, and 10 mL of saturated NaHCO3 aqueous solution was added, and EtOH was evaporated. The resulting suspension was extracted with EtOAc, the organic matter was combined, dried (MgSO4), and concentrated. The residue was purified by silica gel FCC (120 g, 0-20% EtOAc in cyclohexane solution) to give the title compound (3760 mg, 17.4 mmol, 82%).

[0287] 1 H NMR (400MHz, DMSO-d6)d 8.77 (s, 2H), 5.70 (s, 1H), 3.65-3.56 (m, 4H), 1.19 (t, J = 7.1Hz, 6H).

[0288] Step 2: 5-(diethoxymethyl)-N-(2-methoxyethyl)pyrimidine-2-amine (intermediate 23)

[0289]

[0290] K₂CO₃ (319 mg, 2.31 mmol, 2.50 eq) was added to a DMF (3.0 mL) solution of intermediate 22 (200 mg, 0.923 mmol, 1.00 eq) and 2-methoxyethylamine (80 μL, 0.923 mmol, 1.00 eq), and the mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with EtOAc, washed with water, 1:1 water / salt water, and brine, dried over MgSO₄, and concentrated. The residue was purified with silica FCC (12 g, 0-80% EtOAc in cyclohexane solution) to give the title compound (103 mg, 44%).

[0291] 1 H NMR (400MHz, DMSO-d6)d 8.25 (s, 2H), 7.23 (dd, J = 5.5, 5.5Hz, 1H), 5.42 (s, 1H), 3.57-3.44 (m, 8H), 3.26 (s, 3H), 1.16 (t, J = 7.0Hz, 6H).

[0292] Step 3: 2-((2-methoxyethyl)amino)pyrimidine-5-carboxaldehyde (intermediate 21)

[0293] To a solution of intermediate 23 (101 mg, 0.396 mmol, 1.00 eq) in THF (1.0 mL), 1 M HCl solution (21 mL, 20.6 mmol, 52.0 eq) was added, and the mixture was stirred at room temperature for 5 h, then stirred overnight at 50 °C. The mixture was cooled in an ice bath and alkalized to ~pH 13 with 2 M NaOH aqueous solution. The aqueous layer was extracted with EtOAc, dried (MgSO4), and the combined organic matter was concentrated to give the title compound (60 mg, 84%).

[0294] 1 H NMR (400MHz, DMSO-d6)d 9.74(s,1H),8.77(d,J=2.9Hz,1H),8.71(d,J=2.9Hz,1H),8.36(t,J=5.3Hz,1H),3.57-3.47(m,4H),3.27(s,3H).

[0295] Preparation of intermediate 24: 2-(2-hydroxyethylamino)pyrimidine-5-carboxaldehyde

[0296]

[0297] Step 1: 2-[[5-(diethoxymethyl)pyrimidin-2-yl]amino]ethanol (intermediate 25)

[0298]

[0299] K₂CO₃ (319 mg, 2.31 mmol, 2.50 eq) was added to a solution of 2-chloro-5-(diethoxymethyl)pyrimidine (200 mg, 0.923 mmol, 1.00 eq) and ethanolamine (0.056 mL, 0.923 mmol, 1.00 eq) in DMF (3.00 mL), and the mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted in EtOAc, washed with water, 1:1 water / saline solution, and brine, dried over MgSO₄, filtered, and concentrated. The residue was purified by silica FCC (12 g, 0–100% EtOAc in c-Hex solution, 15 CV) to give the title compound (63 mg, 28%).

[0300] 1 H NMR (400MHz, DMSO-d6) δ8.24 (s, 2H), 7.14 (t, J = 5.6Hz, 1H), 5.42 (s, 1H), 4.67 (t,J=5.6Hz,1H),3.59-3.45(m,6H),3.38-3.34(m,2H),1.16(t,J=7.0Hz,6H)

[0301] Step 2: 2-(2-hydroxyethylamino)pyrimidine-5-carboxaldehyde (intermediate 24)

[0302] To a solution of intermediate 25 (61 mg, 0.253 mmol, 1.00 eq) in THF (1.00 mL), a solution of 1 M HCl in H₂O (13 mL, 13.1 mmol, 52.0 eq) was added. The mixture was stirred at room temperature for 5 h, then stirred overnight at 50 °C. The mixture was cooled in an ice bath and alkalized to ~pH 13 with 2 M NaOH aqueous solution. The aqueous layer was extracted with EtOAc. Most of the substance remained in the aqueous layer. It was concentrated, and the solid was ground in MeOH. The dissolved substance was combined with the organic extract and concentrated to give the title compound (42 mg), which was proceeded to the next step without further purification, assuming a quantifiable yield.

[0303] LC-MS(ESI): m / z(M+1)=168.2; t R =0.88min; Method 11

[0304] Preparation of intermediate 26: 2-amino-4-methylpyrimidine-5-carboxaldehyde

[0305]

[0306] Step 1: (2-Amino-4-methylpyrimidin-5-yl)methanol (Intermediate 27)

[0307]

[0308] At 0 °C, isobutyl chloroformate (0.25 mL, 1.96 mmol, 1.20 eq) was added to a suspension of 2-amino-4-methylpyrimidin-5-carboxylic acid (250 mg, 1.63 mmol, 1.00 eq) in THF (12 mL), followed by 4-methylmorpholine (0.22 mL, 1.96 mmol, 1.20 eq). After stirring for 2 h, the precipitate was removed by filtration. At 0 °C, a solution of NaBH4 (93 mg, 2.45 mmol, 1.50 eq) in water (0.60 mL) was added to the filtrate. The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was diluted in EtOAc, washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was used directly for the next step.

[0309] Step 2: 2-Amino-4-methylpyrimidine-5-carboxaldehyde (Intermediate 26)

[0310] Add manganese oxide (IV) (462 mg, 5.32 mmol, 5.00 eq) to a THF (6.00 mL) solution of intermediate 27 (100%, 148 mg, 1.06 mmol, 1.00 eq) and stir the mixture overnight at room temperature. Dilute the mixture in EtOAc, filter through a diatomaceous earth pad, and concentrate. The crude product proceeds directly to the next step.

[0311] Preparation of intermediate 28: (R)-1-(3-amino-5-(trifluoromethyl)benzyl)-N,N-dimethylpyrrolidine-3-amine

[0312]

[0313] Step 1: (R)-N,N-dimethyl-1-(3-nitro-5-(trifluoromethyl)benzyl)pyrrolidine-3-amine (Intermediate 29)

[0314]

[0315] At room temperature, titanium isopropoxide (IV) (2.0 mL, 6.85 mmol) and AcOH (588 μL, 10.3 mmol) were added 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). The reaction mixture was stirred at room temperature for 1 h. Then STAB (1.45 g, 6.85 mmol) was added, and the reaction mixture was stirred at room temperature for another 2.5 h. The reaction mixture was quenched by adding water, and the phases were separated. The pH of the aqueous phase was adjusted to 9 by adding NaOH, and DCM was added. The combined phases were filtered through a diatomaceous earth mat and then separated. The aqueous phase was re-extracted with DCM, and the combined organic phases were filtered through a hydrophobic glass frit and concentrated under vacuum. The title compound (786 mg, 72%) was obtained by purification via silica FCC (24 g column, 0-5% DCM solution of 2 M NH3 / MeOH).

[0316] 1 H NMR (300MHz, DMSO-d6) δ 8.43(s, 1H), 8.38(s, 1H), 8.13(s, 1H), {3.86(d, J=14.2Hz, 1H), 3.73(d, J=14.2Hz, 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 was observed; it is assumed to overlap with the DMSO signal.

[0317] Step 2: (R)-1-(3-amino-5-(trifluoromethyl)benzyl)-N,N-dimethylpyrrolidine-3-amine (Intermediate 28)

[0318] A solution of intermediate 29 (786 mg, 2.48 mmol) in IMS (24.5 mL) was added to palladium (10% wt. on carbon, 79 mg, 0.739 mmol). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2 h. The reaction mixture was filtered through diatomaceous earth, and the filter bed was washed with DCM. The filtrate was concentrated under vacuum to give the title compound (710 mg, 99%).

[0319] 1 H NMR (400MHz, CDCl3) δ6.94(s,1H),6.84(s,1H),6.77(s,1H),3.81(s,2H),3.58(d,J=13.2Hz,1H),3.50(d,J=13.3Hz,1H ),2.83-2.69(m,3H),2.53-2.45(m,1H),2.31(dd,J=6.8,8.3Hz,1H),2.20(s,6H),2.05-1.95(m,1H),1.77-1.68(m,1H)

[0320] The intermediates reported in the table below were prepared by reductive amination as described in steps 1-2 of intermediate 28, using the corresponding commercial amine and / or the corresponding aryl aldehyde in step 1.

[0321]

[0322] Preparation of intermediate 32: 4-(cyclopropoxy)pyrimidine-5-carboxaldehyde

[0323]

[0324] Step 1: Ethyl 4-(cyclopropoxy)pyrimidine-5-carboxylate (Intermediate 33)

[0325]

[0326] A solution of cyclopropanol (0.9 M in THF, 2.7 mL, 2.41 mmol, 1.50 eq) was added to a solution of NaH (60% dispersed in mineral oil, 129 mg, 3.22 mmol, 2.00 eq) in THF (2.0 mL). The reaction mixture was stirred on ice / water for 10 min, and then a solution of ethyl 4-chloropyrimidine-5-carboxylate (300 mg, 1.61 mmol, 1.00 eq) in THF (0.7 mL) was added. The reaction mixture was stirred for 10 min, heated to room temperature, and stirred for 1.5 h. The reaction mixture was cooled on ice / water, and saturated NH4Cl (aq) was added. The aqueous phase was extracted with 3xEtOAc, and the combined organic phases were passed through a hydrophobic glass frit and concentrated under vacuum to give the title compound (326 mg, 97%).

[0327] 1 H NMR (400MHz, CDCl3) δ8.97(s,1H),8.91(s,1H),4.52-4.47(m,1H),4.36(q,J=7.1Hz,2H),1.37(t,J=7.1Hz,3H),0.88(d,J=4.6Hz,4H)

[0328] Step 2: [4-(cyclopropoxy)pyrimidin-5-yl]methanol (intermediate 34)

[0329]

[0330] The solution of intermediate 33 (251 mg, 1.21 mmol, 1.00 eq) in anhydrous THF (10.9 mL) was bubbled with argon for 10 min and cooled on a dry ice / acetone bath. Then, 2 M LiAlH4 (2 M in THF, 0.54 mL, 1.08 mmol, 0.900 eq) was added dropwise. The reaction mixture was stirred for 10 min until TLC indicated complete consumption of SM, and diluted with anhydrous Et2O (10 mL). The flask was transferred to an ice / water bath, and water (41 μL), 15% NaOH (aq) (41 μL), and water (123 μL) were added. The reaction mixture was stirred while simultaneously heating to room temperature for 15 min. MgSO4 was added, the reaction mixture was stirred for 15 min, and filtered. The filtrate was concentrated under vacuum. The resulting solid was purified by 15 μm silica gel FCC (25 g column, 0-7% DCM solution of 2 M NH3 / MeOH) to give the title compound (107 mg, 53%).

[0331] LC-MS(ESI): m / z(M+1)=167; t R =0.72min; Method 12

[0332] Step 3: 4-(cyclopropoxy)pyrimidine-5-carboxaldehyde (intermediate 32)

[0333] Under stirring on an ice / water bath, Dess-Martin periodinane (431 mg, 1.02 mmol, 1.30 eq) was added to an anhydrous DCM (4 mL) solution of intermediate 34 (130 mg, 0.782 mmol, 1.00 eq). The reaction mixture was warmed to room temperature and stirred for 2 h, then diluted with DCM. The organic phase was washed with 10% wt. Na₂S₂O₅ (aq) followed by saturated NaHCO₃ (aq). The NaHCO₃ (aq) solution was extracted with DCM, and the combined organic phases were partially concentrated under vacuum through a hydrophobic glass frit to give the title compound (194 mg, >100%).

[0334] 1 H NMR (400MHz, CDCl) δ10.27(s,1H),8.98(s,1H),8.93(s,1H),4.59-4.54(m,1H),0.94-0.85(m,4H).

[0335] Preparation of intermediate 35: 2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridine-4-amine

[0336]

[0337] Step 1: 4-Amino-N-methoxy-N-methyl-6-(trifluoromethyl)pyridinecarboxamide (intermediate 36)

[0338]

[0339] The title compound was prepared according to general method A from 4-amino-6-(trifluoromethyl)pyridinecarboxylic acid (445 mg, 2.16 mmol) and N,O-dimethylhydroxyamine hydrochloride (232 mg, 2.37 mmol). Purification was performed by silica FCC (80 g column, 0-50% EtOAc in cyclohexane solution (+0.1% NEt3)) to give the title compound (369 mg, 68%).

[0340] 1 H NMR (400MHz, DMSO-d6) δ6.96 (d, J = 2.1Hz, 1H), 6.84-6.78 (m, 3H), 3.67 (s, 3H), 3.24 (s, 3H)

[0341] Step 2: 4-Amino-6-(trifluoromethyl)pyridinecarboxaldehyde (intermediate 37)

[0342]

[0343] LiAlH4 (2M in THF, 0.62 mL, 1.24 mmol) was added dropwise to a stirred solution of intermediate 36 (308 mg, 1.24 mmol) cooled in an ice / water bath in 4.82 mL of THF, while maintaining the internal temperature below 6 °C. The reaction mixture was stirred for 1 h and diluted with anhydrous Et2O (5 mL). Water (47 μL), 15% NaOH (aq) (47 μL), and water (141 μL) were added, and the reaction mixture was heated to room temperature and stirred for 15 min. Anhydrous MgSO4 was added, and the reaction mixture was stirred for 15 min. The mixture was filtered, and the filtrate was concentrated under vacuum to give the title compound (252 mg, >100%), which was used unpurified for the next step.

[0344] LC-MS(ESI): m / z(M+1)=191; t R =0.95min; Method 12

[0345] Step 3: 2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridine-4-amine (intermediate 35)

[0346] The compound was prepared according to general method D from intermediate 37 (126 mg, 0.663 mmol) and dimethylamine (2 M solution in THF) (0.33 mL, 0.663 mmol). The title compound (65 mg, 44%) was obtained by purification via silica FCC (12 g column, 0–8% 2 M NH3 / MeOH in DCM).

[0347] 1 H NMR (400MHz, DMSO-d6) δ6.78-6.77(m,2H),6.49(s,2H),3.34(s,2H),2.18(s,6H).

[0348] Preparation of intermediate 38: 5-(trifluoromethoxy)pyridine-3-amine (hydrochloride)

[0349] Step 1: N-[5-(trifluoromethoxy)-3-pyridyl]tert-butyl carbamate (intermediate 39)

[0350]

[0351] A mixture of tert-butyl carbamate (102 mg, 0.868 mmol, 1.20 eq), Xantphos (63 mg, 0.108 mmol, 0.150 eq), tris(dibenzylacetone)dipalladium(O)-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 mixture was stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth mat, washed with dioxane, and the combined organic phases were concentrated under vacuum. The residue was purified by silica FCC (0-100%, EtOAc in cyclohexane) and then dried under vacuum overnight to give the title compound (115 mg, 0.413 mmol, 57%).

[0352] 1 H NMR (400MHz, CDCl3) δ8.33 (d, J = 2.3Hz, 1H), 8.23-8.21 (m, 1H), 8.07 (s, 1H), 7.04 (s, 1H), 1.54 (s, 9H).

[0353] Step 2: 5-(trifluoromethoxy)pyridine-3-amine (hydrochloride) (intermediate 38)

[0354] A solution of 4N HCl in 1,4-dioxane (3.0 mL, 0.413 mmol, 1.00 eq) was added to a solution of intermediate 39 (115 mg, 0.413 mmol, 1.00 eq) in 1,4-dioxane (3 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with Et₂O (20 mL) and filtered. The solid was washed with Et₂O and dried under vacuum to give the title compound (60 mg, 0.280 mmol, 68%).

[0355] LC-MS(ESI): m / z(M+1)=179; t R =0.88min; Method 13

[0356] Preparation of intermediate 40: N-(5-formylpyrimidin-2-yl)acetamide

[0357]

[0358] Step 1: N-(5-formylpyrimidin-2-yl)acetamide (intermediate 40)

[0359] 2-Aminopyrimidine-5-carboxaldehyde (100 mg, 0.812 mmol, 1.00 eq) was dissolved in acetic anhydride (2.0 mL, 22.8 mmol, 28.1 eq), and the reaction mixture was heated at 140 °C for 90 min. The reaction mixture was cooled to room temperature, and a solid precipitated out. The reactants were washed with 2:1 cyclohexane / Et₂O and filtered. The solid was washed with cyclohexane and dried under vacuum to give the title compound (84 mg, 0.509 mmol, 62.6% yield).

[0360] 1 H NMR (400MHz, CDCl3)d 10.03(s,1H),9.04(s,2H),8.76(s,1H),2.58(s,3H).

[0361] Example 1: Preparation of N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyridin-3-ylmethyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0362] Example 1

[0363] Step 1: 3-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (intermediate 2)

[0364]

[0365] Under nitrogen atmosphere, 3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)aniline (1050 mg, 3.84 mmol) was dissolved in dry THF (50 mL, 2.500 ratio), and the mixture was stirred at -78 °C for 15 min. Then, 2.5 M n-BuLi (1.342 mL, 3.36 mmol) in hexane was added dropwise over 5 min, and the reaction was stirred at -78 °C for 1 h. A solution of 6-(tert-butyl)-3-ethyl 4,7-dihydrothiopheno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid (950 mg, 3.05 mmol) in THF (20 mL, 1.000 ratio) was added dropwise over 10 min, and the reaction was heated and stirred at room temperature for 1 h. 10 mL of water was added to quench the reaction, and the solvent was evaporated under reduced pressure. The solid was dissolved in DCM (50 mL), and the organic layer was washed with H2O (2 x 20 mL) and brine (1 x 20 mL). The organic layer was dried with Na2SO4, filtered, and concentrated to dryness. The crude product was purified by reverse-phase FCC to give the title compound (1.41 g, 2.62 mmol, 86% yield).

[0366] 1 ¹H NMR (400MHz, 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=5.81Hz,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).

[0367] Step 2: N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide trihydrochloride (intermediate 3)

[0368]

[0369] Intermediate 2 (1.41 g, 2.62 mmol) was dissolved in concentrated HCl (3.0 mL, 99 mmol), and the solution was stirred at room temperature for 10 min. 50 mL of ethanol was added to the reaction mixture, and the solvent was evaporated under reduced pressure until the title compound (1.31 g, 2.391 mmol, 91% yield) was obtained.

[0370] Step 3: 6-(4-cyanobenzyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 1)

[0371] Intermediate 3 (30 mg, 0.055 mmol), 3-(bromomethyl)pyridine hydrobromide (13.85 mg, 0.055 mmol) was dissolved in DMF (3 mL), and then DIPEA (0.057 mL, 0.329 mmol) was added in a single batch. The solution was stirred at room temperature. The crude product was analyzed by preparative HPLC (column chromatography). Purification was performed using CSH™ Prep C18 5μm OBD™ 19x100mm; 5-95% ACN / H2O (0.1% HCOOH), 20 mL / min, RT. Relevant fractions were combined and loaded into… The product was washed with methanol on an SCX-2 column and eluted with 7N methanol-ammonia. The residue was concentrated under vacuum to give the title compound (17.6 mg, 0.033 mmol, 60.7% yield).

[0372] 1H NMR(400MHz,ACN-d3)δppm 8.70(br s,1H),8.56(s,1H),8.49(d,J=4.60Hz,1H),7.99(s,1H),7.84(d,J=7.23Hz,2H),7.76(br d,J=7.67Hz,1H),7.30-7.36(m,2H),3.73(s,2H),3.67(s,2H),3.54(s,2H),2.94(br t,J=5.59Hz,2H),2.78(t,J=5.70Hz,2H),2.27-2.53(br s,8H),2.20(s,3H).

[0373] LC-MS(ESI): m / z(M+1)=530.4; t R =0.53, Method 1

[0374] The following compounds were prepared by nucleophilic substitution as described in steps 1-3 of Example 1, with the corresponding commercially available benzyl bromide used in step 3.

[0375]

[0376] Example 3: Preparation of N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0377] Example 3

[0378] Step 1: 3-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (intermediate 4)

[0379]

[0380] To a solution of 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (1.5 g, 5.29 mmol) and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (1.277 g, 5.29 mmol) in DCM (26.5 mL), DIPEA (5.55 mL, 31.8 mmol) was added, followed by T3P (6.30 mL, 10.59 mmol), and the reaction mixture was stirred at room temperature for the entire weekend. The reaction mixture was diluted with DCM, water was added, and the mixture was stirred for 10 min. The aqueous phase was washed with DCM (3 x 50 mL), followed by washing the combined organic phases with brine, drying with Na2SO4, filtering, and concentrating under reduced pressure. The crude product was purified by FCC (DCM to 10% MeOH in DCM solution) to give the title compound (362 mg, 0.715 mmol, 13.50% yield).

[0381] 1 H NMR (300MHz, DMSO-d6) δ10.52(s,1H),8.19(q,J=1.9,1.4Hz,3H),8.07(d,J=1.9Hz,1H),7.74-7.67(m,1H),7.46 (t,J=1.3Hz,1H),4.60(s,2H),3.58(t,J=5.8Hz,2H),2.87(t,J=5.8Hz,2H),2.18(d,J=1.0Hz,3H),1.43(s,9H).

[0382] Step 2: N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (intermediate 5)

[0383]

[0384] To intermediate 4 (0.362 g, 0.715 mmol) in DCM (3.57 mL), a dioxane solution of 4 N HCl (0.893 mL, 3.57 mmol) was added, and the reaction mixture was stirred overnight at room temperature. Et₂O was added to the reaction mixture until no more precipitation was observed, and then the precipitate was filtered off to give the title compound (0.33 g, 0.745 mmol, 104% yield).

[0385] 1H NMR(300MHz,DMSO-d6)δ11.05(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=1.1Hz,3H).

[0386] Step 3: N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 3)

[0387] Intermediate 5 (100 mg, 0.246 mmol) and pyrimidine-5-carboxaldehyde (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 h. The reaction mixture was diluted with methanol and concentrated under vacuum. The dried reaction mixture was redissolved in DCM, washed with 1 M NaOH, and then washed with water and brine. The combined organic layers were concentrated and purified by preparative HPLC to give the title compound (22 mg, 0.044 mmol, 17.94% yield).

[0388] 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),9.13(s,1H),8.80(s,2H),8.20(dd,J=4.6,2.6Hz,3H),8.08(d,J=1.9Hz,1H),7. 70(s,1H),7.47(s,1H),3.77(s,2H),3.69(s,2H),2.90(d,J=6.0Hz,2H),2.76(t,J=5.8Hz,2H),2.18(d,J=1.0Hz,3H).

[0389] LC-MS(ESI): m / z(M+1)=499.0; t R =2.75, Method 3

[0390] Example 4: Preparation of N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0391] Example 4

[0392] Step 1: 4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride (Intermediate 6)

[0393]

[0394] A solution of 4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tert-butyl)3-ethyl ester (4.88 g, 15.67 mmol) in diethyl ether (volume: 78 mL) was added to a solution of 4N HCl in dioxane (19.59 mL, 78 mmol), and the reaction mixture was stirred overnight at room temperature. The solid was separated and dried under reduced pressure to give the title compound (3.58 g, 14.45 mmol, 92% yield).

[0395] Step 2: Ethyl 6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (intermediate 7)

[0396]

[0397] Under argon atmosphere, intermediate 6 (3.0 g, 12.11 mmol) and pyrimidine-5-carboxaldehyde (1.309 g, 12.11 mmol) were placed in a flask. Anhydrous DCM (121 mL) was added, followed by AcOH (0.693 mL, 12.11 mmol). The reaction mixture was stirred at room temperature for 30 min. STAB (5.13 g, 24.22 mmol) was then added, and the reaction mixture was stirred at room temperature for the entire 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 with DCM / MeOH (DCM in DCM to 10% MeOH) to give the title compound (1.97 g, 6.49 mmol, 54% yield).

[0398] 1 H NMR (300MHz, CDCl3) δ9.16 (s, 1H), 8.76 (s, 2H), 7.95 (s, 1H), 4.29 (q, J = 7.1Hz, 2H), 3.7 4(s,2H),3.70(s,2H),3.07-2.97(m,2H),2.84(t,J=5.9Hz,2H),1.34(t,J=7.1Hz,3H).

[0399] Step 3: Sodium 6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (intermediate 8)

[0400]

[0401] 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 at room temperature over the entire weekend. The solvent was evaporated under vacuum to give the title compound.

[0402] 1 H NMR (300MHz, DMSO-d6) δ9.10(s,1H),8.77(s,2H),7.45(s,1H),3.70(s,2H),3.58(s,2H),2.90(t,J=5.8Hz,2H),2.66(t,J=5.8Hz,2H).

[0403] Step 4: N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 4)

[0404] Intermediate 8 (0.1 g, 0.336 mmol) was dissolved in DMF (0.841 mL) and DCM (2.52 mL), followed by the addition of DIPEA (0.352 mL, 2.018 mmol) and HATU (0.256 g, 0.673 mmol). The mixture was stirred for 15 min, followed by the addition of 3-fluoro-5-(trifluoromethyl)aniline (0.044 mL, 0.336 mmol). The reaction mixture was stirred at 60 °C over the entire weekend. DCM and brine were then added to the reaction mixture, and the mixture was stirred for 20 min. The phases were then separated, the organic layer was washed with water, separated, and concentrated under vacuum. The crude product was purified by rapid column chromatography (DCM:MeO from 1:0 to 0:1). It was further purified by preparative TLC (DCM:MeOH, 95:5) to give the title compound (20 mg, 0.046 mmol, 14% yield).

[0405] 1 H NMR(300MHz,DMSO-d6)δ10.52(s,1H),9.12(s,1H),8.79(s,2H),8.13(s,1H),7.99-7.90(m,2H) ,7.36(d,J=8.3Hz,1H),3.75(s,2H),3.67(s,2H),2.88(t,J=5.6Hz,2H),2.75(t,J=5.7Hz,2H).

[0406] LC-MS(ESI): m / z(M+1)=437.0; tR = 1.92 min; Method 2

[0407] The following compounds were prepared as described in steps 1-4 of Example 4, using the corresponding commercially available arylamine in step 4. This method may involve minor variations. In some cases, these variations are reported in the table when modifications involve coupling agents (e.g., HATU instead of T3P) or chromatographic purification conditions (e.g., preparative HPLC or rapid chromatography). In Example 8, the starting material of step 3 was converted to the corresponding carboxylic acid by unblocking the sodium salt obtained as described in step 1 of Example 9.

[0408]

[0409]

[0410] Example 9: Preparation of N-(3-(1,1-difluoroethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0411] Example 9

[0412] Step 1: 6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (intermediate 9)

[0413]

[0414] Add 5M NaOH (aq) (1.50 mL) to a MeOH (20 mL) solution of intermediate 7 (880 mg, 2.90 mmol, 1.00 eq). Stir the reaction mixture at 60 °C for 2 h. Cool the reaction mixture to room temperature, neutralize with 1M HCl (aq), and concentrate under vacuum. Wash the residue with water and filter to give the title compound (478 mg, 57%).

[0415] 1 H NMR (400MHz, DMSO) δ9.16(s,1H),8.83(s,2H),8.12(s,1H),3.79(s,2H),3.70(s,2H),2.91(t,J=5.7Hz,2H),2.78(t,J=5.7Hz,2H)

[0416] Step 2: N-(3-(1,1-difluoroethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 9)

[0417] The compound was prepared according to general method B from 3-(1,1-difluoroethyl)aniline (31 mg, 0.197 mmol) and intermediate 9 (54 mg, 0.197 mmol). The title compound (17.5 mg, 22.2%) was obtained by reversed-phase preparative HPLC (Sunfire C18 3x50 mm, 3 μm, 5-95% ACN / H2O (0.1% HCOOH), 1.7 mL / min, RT).

[0418] 1 H NMR(400MHz,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=8.4Hz,1 H),7.46(t,J=7.9,7.9Hz,1H),7.26(d,J=7.8Hz,1H),3.77(s,2H),3.69(s,2H),2.89(t J=5.5Hz, 2H), 2.76 (t, J=5.8Hz, 2H), 1.97 (t, J=18.8Hz, 3H).

[0419] LC-MS(ESI): m / z(M+1)=415; t R = 4.28 min; Method 9

[0420] The following compounds were prepared by amide coupling as described in steps 1-2 of Example 9, using the corresponding commercially available arylamine in step 2.

[0421]

[0422]

[0423] Example 15: Preparation of 6-((3-aminopyrazin-2-yl)methyl)-N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

[0424] Example 15

[0425] Step 1: Sodium 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (intermediate 10)

[0426]

[0427] 15 g (48.2 mmol) of 6-(tert-butyl)3-ethyl 4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid was dissolved in MeOH (482 mL), and then 1 M NaOH (120.5 mL, 120.5 mmol) was added. The mixture was stirred at room temperature until complete conversion. The mixture was dried under reduced pressure to give the title compound.

[0428] 1 H NMR (300MHz, DMSO-d6) δ7.46 (s, 1H), 4.49 (s, 2H), 3.51 (t, J = 5.8Hz, 2H), 2.89 (t, J = 5.8Hz, 2H), 1.41 (s, 9H).

[0429] Step 2: 3-((3-(tert-butyl)-1-methyl-1H-pyrazole-5-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (intermediate 11)

[0430]

[0431] Intermediate 10 (1 g, 3.28 mmol) and HATU (4.982 g, 13.10 mmol) were weighed into a reaction tube purged with argon (x3). DCM (24.56 mL) and DMF (8.19 mL) were added to the reaction mixture, followed by DIPEA (9.16 mL, 52.4 mmol). The reaction mixture was stirred for 30 min, 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 LC-MS indicated complete consumption of the starting material. Further addition of HATU and DIPEA was required to obtain complete conversion. The reaction mixture was then extracted with DCM / H2O (x3), and the combined organic layers were washed with a 1:1 NaCl (saturated):H2O solution, followed by washing with brine. The combined organic layers were then concentrated under vacuum to obtain a crude substance, which was purified by rapid column chromatography (0-50% EtOAc / hexane). The product was eluted with 50% EtOAc to give the title compound (1.13 g, 2.70 mmol, 82% yield).

[0432] 1 H NMR (300MHz, DMSO-d6) δ10.01(s,1H),8.14(s,1H),6.08(s,1H),4.59(s,2H),3.59(m,5H),2.82(d,J=5.7Hz,2H),1.43(s,9H),1.23(s,9H).

[0433] Step 3: N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (intermediate 12)

[0434]

[0435] 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) dissolved in dioxane was added dropwise. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated, and the residue was prepared with diethyl ether to give the title compound.

[0436] 1 H NMR(300MHz,DMSO-d6)δ10.21(s,1H),9.46(s,2H),8.34(s,1H),6.09(s,1H),4.3 8(s,2H),3.63(s,3H),3.37(t,J=6.8Hz,2H),3.07(t,J=6.0Hz,2H),1.23(s,9H).

[0437] Step 4: 6-((3-aminopyrazin-2-yl)methyl)-N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 15)

[0438] Intermediate 12 (100 mg, 0.282 mmol) and 3-aminopyrazine-2-carboxaldehyde (41.6 mg, 0.338 mmol) were added to a small reaction tube and purged with argon (x3). MeOH (1409 μl) was added to the reaction mixture, followed by AcOH (48.4 μl, 0.845 mmol). The tube was sealed and stirred at 50 °C for 1 h. The reaction was then cooled to room temperature, and NaBH3CN (80 mg, 1.268 mmol) was added, with the reaction stirred at 50 °C. Further addition of aldehyde (2 eq) and NaBH3CN (1 eq) was required to achieve complete conversion. The reaction mixture was quenched with saturated NaHCO3, transferred to a separatory funnel, and the desired product was extracted with DCM (x3). The combined organic layers were washed once with brine and concentrated under vacuum. The crude mixture was purified by preparative HPLC to give the title compound (28 mg, 0.066 mmol, 23.35% yield).

[0439] 1H NMR (300MHz, DMSO-d6) δ10.00(s,1H),8.10(s,1H),7.89(d,J=2.8Hz,1H),7.70(d,J=2.8Hz,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=5.9Hz,2H),2.74(d,J=5.4Hz,2H),1.22(s,9H).

[0440] LC-MS(ESI): m / z(M+1)=425.8; t R =3.07min; Method 4

[0441] The following compounds were prepared by reductive amination as described in steps 1-4 of Example 15, using a previously synthesized or commercially available aryl aldehyde in step 4. This method may involve minor variations. In some cases, such modifications are reported in a table if they involve the method used or the reducing agent (e.g., replacing NaBH3CN with STAB) or the chromatographic purification conditions.

[0442]

[0443] Example 17: Preparation of 6-((4-(2-methoxyacetamido)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide

[0444] Example 17

[0445] Step 1: 3-((3-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (intermediate 13)

[0446]

[0447] Intermediate 10 (4 g, 13.10 mmol) was dissolved in DMF (32.8 mL) and DCM (98 mL), followed by the addition of DIPEA (4.58 mL, 26.2 mmol) and HATU (9.96 g, 26.2 mmol). RM was stirred at room temperature for 15 min, and 3-(trifluoromethyl)aniline (1.964 mL, 15.72 mmol) was added. RM was stirred overnight at 40 °C. RM was diluted with DCM and water was added. The mixture was stirred for 15 min and phase separation was performed. The organic phase was washed with water, 5% wt citric acid solution, and twice with water and brine. The mixture was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by FCC (DCM to 10% MeOH in DCM solution) to give the title compound (4.36 g, 10.22 mmol, 78% yield).

[0448] 1 H NMR (300MHz, DMSO-d6) δ10.38(s,1H),8.19(d,J=2.0Hz,1H),8.16(s,1H),8.00-7.92(m,1H),7.58(t,J =8.0Hz,1H),7.47-7.38(m,1H),4.59(s,2H),3.58(t,J=5.8Hz,2H),2.85(t,J=5.8Hz,2H),1.43(s,9H).

[0449] Step 2: N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (intermediate 14)

[0450]

[0451] Intermediate 13 (2.82 g, 6.61 mmol) was dissolved in a minimal amount of DCM (6.01 mL), followed by the addition of Et₂O (60.1 mL), and then a solution of dioxane in 4N HCl (16.53 mL, 66.1 mmol). The mixture was stirred overnight at room temperature. Et₂O was added to the mixture until no further precipitation was observed. The solid was then filtered off and the residual solvent was evaporated under vacuum to give the title compound (2.3353 g, 6.44 mmol, 97% yield).

[0452] 1H NMR (300MHz, DMSO-d6) δ10.51(s,1H),8.27(s,1H),8.16(d,J=2.1Hz,1H),7.95-7.86(m,1H),7.58( t,J=8.0Hz,1H),7.48-7.40(m,1H),4.36(s,2H),3.36(td,J=6.5,5.1Hz,2H),3.09(t,J=6.1Hz,2H).

[0453] Step 3: 6-((4-aminopyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide (Intermediate 15)

[0454]

[0455] Weigh intermediate 14 (100 mg, 0.276 mmol) and 4-aminonicotinaldehyde (37.0 mg, 0.303 mmol) into a reaction tube refilled with argon (x3). Add MeOH (1378 μl), followed by AcOH (47.3 μl, 0.827 mmol), and stir the solution at 50 °C for 1 h. Add NaBH3CN (78 mg, 1.240 mmol) to the reaction mixture and stir at 50 °C until LCMS indicates that the starting material has been consumed. Further addition of aldehyde (1.2 eq) and NaBH3CN (1 eq) is required to achieve complete conversion. Transfer the reaction mixture to a separatory funnel and dilute with DCM. Add NaHCO3 (saturated) and separate the organic layer (x3). The combined organic layers were washed once with brine, concentrated under vacuum, and the crude material was purified by FCC (0-2% MeOH solution of 6.5M NH3 and DCM solution of 10% MeOH) to give the title compound (75 mg, 0.173 mmol, 62.9% yield).

[0456] 1 H NMR (300MHz, DMSO-d6) δ10.35(s,1H),8.19(d,J=2.1Hz,1H),8.11(s,1H),7.97(d,J=8.3Hz,3H),7.58(t,J=8.0Hz,1H),7.4 3(d,J=7.8Hz,1H),6.54(d,J=5.5Hz,1H),6.08(s,2H),3.61(d,J=3.3Hz,4H),2.87(d,J=5.9Hz,2H),2.71(t,J=5.7Hz,2H).

[0457] Step 4: 6-((4-(2-methoxyacetamido)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide (Example 17)

[0458] The flask containing intermediate 15 (75 mg, 0.173 mmol) was purged with argon (x3). THF (867 μL) was added, followed by TEA (48.3 μL, 0.347 mmol) to dissolve the starting material. The reaction mixture was stirred for 10 min, and then 2-methoxyacetyl chloride (20.70 mg, 0.191 mmol) was added at 0 °C. The reaction mixture was stirred for 1 h, and after confirmation by UPLC, the mixture was transferred to a separatory funnel and quenched with water. The desired product was extracted with DCM (x3), and the combined organic layers were washed once with brine (x1) and concentrated. The crude material was purified by preparative HPLC and then treated with water to give the compound (22.38 mg, 0.044 mmol, 25.6% yield).

[0459] 1 H NMR (300MHz, DMSO-d6) δ11.33(s,1H),10.38(s,1H),8.49-8.38(m,2H),8.24-8.12(m,3H),7.98(d,J=8.2Hz,1H),7.58(t,J =8.0Hz,1H),7.43(d,J=7.8Hz,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=5.6Hz,2H).

[0460] LC-MS(ESI): m / z(M+1)=505.1; t R = 2.27 min. Method 2

[0461] The following compounds were prepared by reductive amination as described in steps 1-4 of Example 17, using previously synthesized or commercially available aryl aldehydes in step 3. This method may involve minor variations. In some cases, if modifications involve the method used or the chromatographic purification conditions, these variations will be reported in the table.

[0462]

[0463]

[0464]

[0465]

[0466]

[0467] Example 29: Preparation of 6-((5-(4-methyl-3-oxoperazin-1-yl)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide

[0468] Example 29

[0469] Step 1: 6-((5-bromopyridin-3-yl)methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 41)

[0470]

[0471] STAB (325 mg, 1.53 mmol, 2.50 eq) was added to a mixture of intermediate 14 (200 mg, 0.613 mmol, 1.00 eq), MgSO4 (148 mg, 1.23 mmol, 2.00 eq), and 5-bromo-3-pyridinecarboxaldehyde (114 mg, 0.613 mmol, 1.00 eq) in DCM (10 mL), and the mixture was stirred at room temperature for 21 h. The mixture was slowly added to a saturated aqueous solution of NaHCO3 and extracted with DCM (x3). The combined organic extracts were dried (Na2SO4) and evaporated. The crude compound was purified, and the residue was purified by silica FCC (12 g column, 0-70% EtOAc in cyclohexane solution) to give the title compound (128 mg, 0.257 mmol, 42%).

[0472] 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.63(d,J=2.3Hz,1H),8.55(d,J=1.7Hz,1H),8.19(s,1H),8.11(s,1H),8.04-7.95(m, 2H),7.57(t,J=8.0Hz,1H),7.44-7.41(m,1H),3.75(s,2H),3.67-3.65(m,2H),2.88(t,J=5.6Hz,2H),2.74(t,J=5.7Hz,2H).

[0473] Step 2: 6-((5-(4-methyl-3-oxoperpiperazin-1-yl)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide (Example 29)

[0474] The mixture of intermediate 41 (50 mg, 0.101 mmol, 1.00 eq), 1-methylpiperazin-2-one (13 mg, 0.111 mmol, 1.10 eq), and Cs₂CO₃ (66 mg, 0.201 mmol, 2.00 eq) in anhydrous 1,4-dioxane (1.50 mL) was degassed, and RuPhos Pd G₃ (8.4 mg, 0.0101 mmol, 0.10 eq) was added. The reaction mixture was stirred at 80 °C for 21 h under argon atmosphere. The reaction mixture was cooled, filtered through a diatomaceous earth mat, and concentrated. Purification by reversed-phase HPLC (Sunfire C1819 x 150 mm, 10 μm, 20–80% ACN / H₂O (10 mM NH₄CO₃), 20 mL / min, RT) gave the title compound (15.8 mg, 29%).

[0475] 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.23(d,J=2.9Hz,1H),8.21(s,1H),8.12(s,1H),8 .02(d,J=1.5Hz,1H),7.98(d,J=8.7Hz,1H),7.59(t,J=8.0Hz,1H),7.45-7.43(m,1H),7. 31(t,J=2.1Hz,1H),3.85(s,2H),3.69(s,2H),3.66(s,2H),3.57(dd,J=4.3,6.4Hz,2H), 3.46(dd,J=4.4,6.6Hz,2H),2.92-2.91(m,3H),2.90-2.88(m,2H),2.74(t,J=5.8Hz,2H).

[0476] LC-MS(ESI): m / z(M+1)=530; t R = 3.06 min. Method 9

[0477] The following compounds were prepared by Hartwig-Buchwald CN coupling as described in steps 1-2 of Example 29, using a commercially available amine in step 2. This method may involve minor variations.

[0478]

[0479] Example 31: Preparation of N-6-((5-(2-(dimethylamino)acetamido)pyridin-3-yl)methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide

[0480] Example 31

[0481] Step 1: Preparation of N-6-((5-(2-(dimethylamino)acetamido)pyridin-3-yl)methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide (Example 31)

[0482] A mixture of aluminum trifluoromethanesulfonate (1.9 mg, 4.03 μmol, 0.100 eq), intermediate 41 (20 mg, 0.0403 mmol, 1.00 eq), 2-(dimethylamino)acetamide (4.1 mg, 0.0403 mmol, 1.00 eq), Pd(dba)2 (2.3 mg, 4.03 μmol, 0.100 eq), XantPhos (2.3 mg, 4.03 μmol, 0.100 eq), and Cs2CO3 (13 mg, 0.0403 mmol, 1.00 eq) in toluene (2.00 mL) was degassed (argon) and heated at 110 °C for 64 h. The reaction mixture was diluted with DCM (15 mL), dried (Na2SO4), and evaporated. The crude product was purified by reversed-phase preparative HPLC (Luna Phenyl-Hexyl 21.2x150mm, 10µm, 20-80% MeOH / H2O (0.1% FA), 20mL / min, RT) to obtain the title compound (7mg, 34%).

[0483] 1 H NMR (400MHz, DMSO-d6) δ10.37 (s, 1H), 9.99 (s, 1H), 8.76 (d, J = 2.4Hz, 1H), 8.2 4(t,J=1.6Hz,1H),8.21(t,J=2.0Hz,1H),8.16(t,J=2.0Hz,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=5.4Hz,2H),2.75(t,J=6.4Hz,2H),2.29(s,6H). LC-MS(ESI): m / z(M+1)=518.3; t R = 2.71 min. Method 9.

[0484] Example 32: Preparation of 6-((5-methoxypyridin-3-yl)methyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide

[0485] Example 32

[0486] Step 1: Preparation of tert-butyl 3-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (intermediate 42)

[0487]

[0488] G was prepared according to general method from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (250 mg, 0.882 mmol, 1.00 eq) and 5-(trifluoromethyl)pyridine-3-amine (157 mg, 0.971 mmol, 1.10 eq). The residue was purified by silica FCC (80 g column, 0-25% EtOAc in cyclohexane + 0.1% NEt3) to give the title compound (265 mg, 70%).

[0489] 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),9.12(d,J=2.3Hz,1H),8.68(d,J=1.0Hz,1H),8.58(t, J=1.9Hz,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).

[0490] Step 2: Preparation of N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide (intermediate 43)

[0491]

[0492] Under an argon atmosphere, TFA (0.52 mL, 6.78 mmol, 10.0 eq) was added dropwise over 5 min to an anhydrous DCM (6.78 mL) solution of intermediate 42 (290 mg, 0.678 mmol, 1.00 eq) cooled in an ice / water bath and stirred. The reaction mixture was stirred for 3 h. Further TFA (0.17 mL, 2.26 mmol, 3.33 eq) was added, and the reaction mixture was heated to room temperature and stirred for 1 h. The reaction mixture was concentrated under vacuum, and the residue was dissolved in a 1:1 DCM:MeOH solution and added to a 5 g Isolute SCX-II column pretreated with MeOH. The solution was washed with MeOH and then released with 2 M NH3 / MeOH. The 2 M NH3 / MeOH eluent was concentrated under vacuum to give the title compound (193 mg, 87%).

[0493] 1 H NMR (400MHz, DMSO-d6) δ10.58(s,1H),9.12(d,J=2.3Hz,1H),8.67(d,J=1.0Hz,1H),8.59-8.57(m ,1H),8.12(s,1H),3.88(s,2H),3.17(d,J=5.0Hz,1H),2.90(t,J=5.7Hz,2H),2.78-2.73(m,2H).

[0494] Step 3: Preparation of 6-((5-methoxypyridin-3-yl)methyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide (Example 32)

[0495] The compound was prepared according to general method D from intermediate 43 (45 mg, 0.138 mmol) and 5-methoxy-3-pyridinecarboxaldehyde (18 mg, 0.131 mmol). The title compound (19 mg, 30%) was obtained by reversed-phase preparative HPLC (Xbridge Phenyl 19 x 150 mm, 10 μm, 40–100% MeOH / water (10 mM NH4HCO3), 20 mL / min, RT).

[0496] 1H NMR (400MHz, DMSO-d6) δ10.61(s,1H),9.13(d,J=2.3Hz,1H),8.69(d,J=1.0Hz,1H),8.60-8.59(m,1H),8.23(d,J=2.9Hz,1H), 8.19-8.16(m,2H),7.36(dd,J=1.8,2.8Hz,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).

[0497] LC-MS(ESI): m / z(M+1)=449.4; t R = 2.95 min. Method 9.

[0498] The following compounds were prepared by reductive amination as described in steps 1-3 of Example 32, using previously synthesized or commercially available aryl aldehydes in step 3. This method may involve minor variations. In some cases, such variations are documented in the table when modifications involve reducing agents (e.g., NaBH3CN instead of STAB) or chromatographic purification conditions.

[0499]

[0500]

[0501] Example 37: Preparation of N-[3-fluoro-5-(trifluoromethyl)phenyl]-6-[[2-(oxetane-3-ylamino)pyrimidin-5-yl]methyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide

[0502] Example 37

[0503] Step 1: Preparation of N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide (intermediate 44)

[0504]

[0505] 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 eq) and HATU (2560 mg, 6.73 mmol, 1.20 eq) in DMF (22.50 mL), DIPEA (2.9 mL, 16.8 mmol, 3.00 eq) was added and the mixture was stirred at room temperature for 15 min. Then, 3-fluoro-5-(trifluoromethyl)aniline (1055 mg, 5.89 mmol, 1.05 eq) was added. The reaction mixture was stirred at room temperature for another 16 h. The reaction mixture was purified with silica FCC (ethyl acetate / cyclohexane from 0% to 100%) to give tert-butyl 3-((3-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (1.35 g, 3.04 mmol, 1.00 eq), which was dissolved in DCM (35 mL) and TFA (5.0 mL, 65.9 mmol, 21.7 eq) was added. The reaction mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The reaction mixture was partitioned between a saturated aqueous solution of Na₂CO₃ (50 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (30 mL), dried over MgSO₄, filtered through a hydrophobic glass frit, and concentrated under reduced pressure. The crude product was purified by silica FCC (0% to 100% EtOAc / cyclohexane, followed by 0% to 100% 3:1 EtOAc:EtOH / EtOAc) to give the title compound (500 mg, 2.69 mmol, yield 48%).

[0506] 1 H NMR(400MHz, CDCl3)δ7.80(td,J=2.1,10.4Hz,1H),7.73(s,1H),7.63(s,1H),7.52(s,1H),7.10 (d, J = 8.3Hz, 1H), 4.07 (s, 2H), 3.15 (t, J = 5.8Hz, 2H), 2.93 (t, J = 5.7Hz, 2H), 1.27-1.22 (m, 1H).

[0507] Step 2: Preparation of N-[3-fluoro-5-(trifluoromethyl)phenyl]-6-[[2-(oxecyclobutane-3-ylamino)pyrimidin-5-yl]methyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 37)

[0508] The intermediates 20 (62 mg, 0.34 mmol, 1.00 eq) and 44 (119 mg, 0.34 mmol, 1.00 eq) were prepared according to general method C. The residues were purified by reversed-phase preparative HPLC (Luna Phenyl-Hexyl 21.2 x 150 mm, 10 μm, 20-80% MeOH / H₂O (0.1% FA), 20 mL / min, RT). The resulting solid was dissolved in EtOAc, washed with saturated NaHCO₃ aqueous solution, dried (MgSO₄), and concentrated. The residues were lyophilized to give the title compound (12 mg, 7%).

[0509] 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.27(s,2H),8.13(s,1H),7.99-7.90(m,3H),7.38(d,J=8.5Hz,1H),4.96-4.88( m,1H),4.77(t,J=6.7Hz,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).

[0510] LC-MS(ESI): m / z(M+1)=508.2; t R = 2.95 min. Method 8.

[0511] The following compounds were prepared by reductive amination as described in steps 1-2 of Example 37, using previously synthesized or commercially available aryl aldehydes in step 2. This method may involve minor variations. In some cases, such variations are documented in the table when modifications involve reducing agents (e.g., NaBH3CN instead of STAB) or chromatographic purification conditions.

[0512]

[0513]

[0514]

[0515]

[0516]

[0517] 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

[0518] Example 48

[0519] 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)

[0520] Titanium isopropoxide (IV) (0.35 mL, 1.18 mmol, 3.00 eq) was added to a solution of intermediate 44HCl salt (150 mg, 0.394 mmol, 1.00 eq), DIPEA (0.14 mL, 0.788 mmol, 2.00 eq), and 6-(methylamino)pyridine-3-carboxaldehyde (54 mg, 0.394 mmol, 1.00 eq) in methanol (7.5 mL). The reaction mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature and NaBH3CN (62 mg, 0.985 mmol, 2.50 eq) was added. The reaction mixture was stirred at room temperature for 4 h. The reactants were diluted with DCM, quenched with NH4Cl, and the solids were filtered off. The organic layer was separated, and the aqueous layer was washed twice with DCM. The combined organic phases were filtered through a hydrophobic glass frit and the solvent was concentrated under vacuum to give 190 mg of crude product. The compound was purified by preparative HPLC (Sunfire C18 19x150mm, 10µm, 20-80% ACN / H2O (10mM NH4CO3), 20mL / min, RT) to give the title compound (29mg, 0.0579mmol, 15%).

[0521] 1 H NMR (400MHz, DMSO-d6) δ10.52(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 = 5.7Hz, 2H), 2.77 (d, J = 4.8Hz, 3H), 2.71 (t, J = 5.8Hz, 2H).

[0522] LC-MS(ESI): m / z(M+1)=465.2; t R = 2.98 min. Method 9

[0523] Example 49: Preparation of N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(1-methyl-1H-imidazol-5-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0524] Example 49

[0525] Step 1: Preparation of N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(1-methyl-1H-imidazol-5-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide (Example 49)

[0526] The product was prepared according to general method A from 1-methyl-1H-imidazol-5-carboxylic acid (22 mg, 0.174 mmol, 1.20 eq) and intermediate 44 (50 mg, 0.145 mmol, 1.00 eq). The residue was purified by preparative HPLC (Xbridge Phenyl 19x150 mm, 10 μm, 40-100% MeOH / H2O (10 mM NH4CO3), 20 mL / min, RT) to give crude product (34 mg). This was further purified by preparative HPLC (Sunfire C18 19x150 mm, 10 μm, 5-60% ACN / H2O (0.1% FA), 20 mL / min, RT) to give the title compound (16 mg, 25%).

[0527] 1 H NMR(400MHz,DMSO-d6)δ10.58(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=1.0Hz,1H),4.91(s,2H),3.89(t,J=5.7Hz,2H),3.72(s,3H),3.05-2.98(m,2H).

[0528] LC-MS(ESI): m / z(M+1)=453.3; t R = 3.71 min. Method 9

[0529] Example 50: Preparation of (R)-6-((2-aminopyrimidin-5-yl)methyl)-N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

[0530] Example 50

[0531] Step 1: Preparation of (R)-3-((3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (intermediate 45)

[0532]

[0533] G was prepared according to general method from 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (350 mg, 1.24 mmol, 1.0 eq) and intermediate 28 (355 mg, 1.24 mmol, 1.0 eq). The residue was purified by silica FCC (40 g column, 0-10% 2MNH3 / MeOH in DCM) to give the title compound (580 mg, 84%).

[0534] 1 H NMR (300MHz, CDCl3) δ8.29-8.22(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=6.4,11.5Hz,1H),2.46-2.23(m,2H),2.07-1.99(m,1H),1.48(s,9H)

[0535] Step 2: Preparation of (R)-N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 46)

[0536]

[0537] Under an argon atmosphere, TFA (1.6 mL, 20.8 mmol) was added dropwise over 5 min to a solution of tert-butyl intermediate 45 (576 mg, 1.04 mmol) stirred on an ice / water bath in anhydrous DCM (10.4 mL). The reaction mixture was stirred for 1.5 h and concentrated under vacuum. The residue was dissolved in MeOH and added to a 20 g Isolute SCX-II column pretreated with methanol. The column was washed with methanol and then eluented with 2 M NH3 / MeOH. The 2 M NH3 / MeOH eluent was concentrated under vacuum to give the title compound (356 mg, 75%).

[0538] 1H NMR (300MHz, CDCl3) δ8.00-7.92(m,2H),7.69(d,J=5.3Hz,2H),7.34(s,1H),4.06(s,2H),3.71(d,J=13.5Hz,1H),3.59(d,J=13.3Hz,1H) ,3.17-3.11(m,2H),2.99-2.92(m,2H),2.87-2.54(m,5H),2.45(dd,J=6.3,8.5Hz,1H),2.24(s,6H),2.09-1.95(m,1H),1.84-1.72(m,1H)

[0539] Step 3: Preparation of (R)-N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 50)

[0540] The formate of the title compound was prepared according to general method D from intermediate 46 (58 mg, 0.128 mmol) and 2-aminopyrimidine-5-carboxaldehyde (15 mg, 0.122 mmol). It was purified by reversed-phase preparative HPLC (Sunfire C18 19 x 150 mm, 10 μm, 20–80% acetonitrile / water (10 mM NH4HCO3), 20 mL / min, RT), followed by further purification (Luna Phenyl-Hexyl 21.2 x 150 mm, 10 μm, 5–60% MeOH / water (0.1% FA), 20 mL / min, RT). This formate was dissolved in MeOH, loaded onto a MeOH-pretreated 2 g Isolute SCX-II column, washed with MeOH, and then released with 2 M NH3 / MeOH. The 2 M NH3 / MeOH eluent was concentrated and dried under vacuum to give the title compound (23 mg, 33%).

[0541] 1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.18(s,2H),8.11-8.08(m,2H),7.92(s,1 H),7.32(s,1H),6.56(s,2H),3.69(d,J=13.7Hz,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=5.7,7.7Hz,1H),2.07(s,6H),1.91-1.81(m,1H),1.66-1.57(m,1H).

[0542] LC-MS(ESI): m / z(M+1)=560.1; t R = 3.91 min. Method 10

[0543] The following compounds were prepared by reductive amination as described in steps 1-3 of Example 50, using a previously synthesized or commercially available aryl aldehyde in step 3. This method may involve minor variations. In some cases, such variations are documented in the table when modifications involve reducing agents (e.g., NaBH3CN instead of STAB) or chromatographic purification conditions.

[0544]

[0545]

[0546] The following compounds were prepared by reductive amination as described in steps 1-3 of Example 50, using previously synthesized or commercially available arylamines in step 1.

[0547]

[0548]

[0549] Example 58: Preparation of 6-((2-aminopyrimidin-5-yl)methyl)-N-(3-(1,1-difluoroethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0550] Example 58

[0551] 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)

[0552]

[0553] G was prepared according to general method from 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (500 mg, 1.76 mmol, 1.0 eq) with the addition of 3-(1,1-difluoroethyl)aniline (291 mg, 1.85 mmol, 1.05 eq). The combined organic phases were dried over MgSO4, filtered, concentrated, and dried under vacuum overnight to give the title compound (1140 mg, 1.78 mmol, 101%).

[0554] 1 H NMR (400MHz, CDCl3) δ7.91 (s, 1H), 7.77-7.67 (m, 2H), 7.65 (s, 1H), 7.41 (t, J = 8.0Hz, 1H), 7.28 (s ,1H),4.62(s,2H),3.67(t,J=5.3Hz,2H),3.00-2.96(m,2H),1.93(t,J=18.2Hz,3H),1.49(s,9H).

[0555] Step 2: Preparation of N-(3-(1,1-difluoroethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide (intermediate 48)

[0556]

[0557] A solution of 4N HCl in 1,4-dioxane (10 mL) was added to a solution of intermediate 47 (750 mg, 1.17 mmol, 1.00 eq) in 1,4-dioxane (10 mL). The reaction mixture was stirred overnight at room temperature. The reaction was quenched with Et₂O and filtered. The resulting solid was washed with Et₂O and dried under vacuum. The title compound (684 mg, 1.72 mmol, 146%) was given. This substance was proceeded to the next step without further purification.

[0558] 1 H NMR (400MHz, DMSO-d6) δ10.47(s,1H),8.44(s,1H),8.06(s,1H),7.92(d,J=7.8Hz,1H),7.73(m,1H),7.51(t, J=8.0Hz,1H),7.33(d,J=7.3Hz,1H),4.42(s,2H),3.40(m,2H),3.16(t,J=5.7Hz,2H),2.01(t,J=18.8Hz,3H).

[0559] Step 3: Preparation of 6-((2-aminopyrimidin-5-yl)methyl)-N-(3-(1,1-difluoroethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 58)

[0560] The compound was prepared according to general method C from intermediate 48 (90%, 60 mg, 0.150 mmol, 1.00 eq) and 2-aminopyrimidine-5-carboxaldehyde (19 mg, 0.150 mmol, 1.00 eq). The residue was washed with DCM / MeOH, the combined washes were evaporated, and the residue was dried under vacuum. The residue was purified by preparative HPLC. Sunfire C18 19x150 mm, 10 μm, 5-60% ACN / H2O (0.1% FA), 20 mL / min, RT. The title compound was given (20.47 mg, 0.0469 mmol, 31.3% yield).

[0561] 1 H NMR (400MHz, DMSO) δ10.20(s,1H),8.20(s,2H),8.08(s,1H),7.99(t,J=2.1Hz,1H),7.84(d,J=8.2Hz,1H),7.46(t J=8.0Hz,1H),7.27(d,J=8.0Hz,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=18.8Hz,3H).

[0562] LC-MS(ESI): m / z(M+1)=430.6; t R =4.02min. Method 8

[0563] The following compounds were prepared by reductive amination as described in steps 1-3 of Example 58, using previously synthesized or commercially available arylamines in step 1.

[0564]

[0565] Example 61: Preparation of 6-((2-aminopyrimidin-5-yl)methyl)-N-(4-chloro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0566] Example 61

[0567] 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)

[0568]

[0569] The title compound was prepared according to general method G from 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (250 mg, 0.882 mmol, 1.0 eq) with the addition of 4-chloro-3-(trifluoromethyl)aniline (181 mg, 0.926 mmol, 1.05 eq). The reaction mixture was stirred at room temperature for 90 min, quenched with water, stirred for 30 min, and filtered. The solid was washed with water and dried under vacuum. The title compound was given (360 mg, 0.781 mmol, 89%). This substance was proceeded to the next step without further purification.

[0570] 1 H NMR (400MHz, CDCl3) δ7.93 (s, 2H), 7.86-7.82 (m, 1H), 7.64 (s, 1H), 7.48 (d, J = 8.8Hz, 1H ), 4.61 (s, 2H), 3.68 (t, J = 5.3Hz, 2H), 2.99 (t, J = 5.7Hz, 2H), 1.57 (s, 4H), 1.50 (s, 9H).

[0571] Step 2: Preparation of N-(4-chloro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 50)

[0572]

[0573] A solution of intermediate 49 (360 mg, 0.781 mmol, 1.00 eq) in 1,4-dioxane (3 mL) was added to a solution of 1,4-dioxane (3.0 mL) in 4N HCl. The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with Et₂O and filtered. The solid was washed with Et₂O and dried under vacuum to give the title compound in hydrochloride form (289 mg, 0.666 mmol, 85%).

[0574] 1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),9.66-9.57(m,2H),8.49(s,1H),8.42(d,J=2.5Hz,1 H),8.14(dd,J=2.3,8.8Hz,1H),7.75(d,J=8.8Hz,1H),4.43(s,2H),3.16(t,J=5.8Hz,2H)-

[0575] Step 3: Preparation of 6-((2-aminopyrimidin-5-yl)methyl)-N-(4-chloro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 61)

[0576] H was prepared by conventional method from intermediate 49 (60 mg, 0.151 mmol, 1.00 eq) and 2-aminopyrimidine-5-carboxaldehyde (27 mg, 0.223 mmol, 1.47 eq). The crude product was purified by preparative HPLC (Luna Phenyl-Hexyl 21.2 x 150 mm, 10 μm, 20-80% MeOH / H2O (0.1% FA), 20 mL / min, RT) to give the title compound (17 mg, 0.0352 mmol, 23%).

[0577] 1 H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.32(d,J=2.3Hz,1H),8.19(s,2H),8.12(s,1H),8.04(dd,J=2.4,8.8Hz, 1H), 7.70 (d, J = 8.7Hz, 1H), 6.58 (s, 2H), 3.61 (s, 2H), 3.51 (s, 2H), 2.87 (d, J = 5.0Hz, 2H), 2.71 (t, J = 5.8Hz, 2H).

[0578] LC-MS(ESI): m / z(M+1)=468.4; t R = 4.57 min. Method 8

[0579] Example 62: Preparation of 6-((2-aminopyrimidin-5-yl)methyl)-N-(5-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

[0580] Example 62

[0581] Step 1: Preparation of tert-butyl 3-((5-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazol-3-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (intermediate 51)

[0582]

[0583] At 20 °C, oxalyl chloride (0.088 mL, 1.06 mmol, 1.20 eq) was added dropwise 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 eq) and DMF (0.0034 mL, 0.0441 mmol, 0.05 eq) in cyclopentylmethyl ether (2 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum, the residue was azeotropically reacted with cyclopentylmethyl ether, and the residue was suspended in ACN (1 mL). The mixture was 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 eq) and pyridine (0.14 mL, 1.76 mmol, 2.00 eq) in ACN (1 mL) was added. The reaction mixture was heated to room temperature and stirred for 45 min. The reaction mixture was concentrated under vacuum. The residue was partitioned between DCM and water. The combined organic phases were filtered through a hydrophobic glass frit, and the solvent was concentrated under vacuum. The residue was purified by silica FCC (eluting with a cyclohexane solution of 0–100% EtOAc) to give the title compound (255 mg, 0.555 mmol, 63%). This substance proceeded to the next step without further purification.

[0584] 1 H NMR (400MHz, CDCl3)d 9.65 (s, 1H), 7.91 (s, 1H), 7.13 (s, 1H), 4.64 (s, 2H), 3.68 (t, J = 5.4Hz, 2H), 3.01 (t, J = 5.8Hz, 2H), 1.60 (s, 6H), 1.49 (s, 9H).

[0585] Step 2: Preparation of N-(5-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 52)

[0586]

[0587] At 0 °C, a solution of 4N HCl in 1,4-dioxane (3.0 mL, 0.555 mmol, 1.00 eq) was added to a solution of intermediate 51 (255 mg, 0.555 mmol, 1.00 eq) in 1,4-dioxane (3 mL). The reaction mixture was heated to room temperature and stirred at room temperature over the entire weekend. The reaction mixture was diluted with Et2O (20 mL) and filtered. The solid was washed with Et2O and dried under vacuum to give the title compound (190 mg, 0.480 mmol, 86%) as an HCl salt.

[0588] 1 H NMR (400MHz, 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 = 5.6Hz, 2H), 1.63 (s, 6H).

[0589] Step 3: Preparation of 6-((2-aminopyrimidin-5-yl)methyl)-N-(5-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 62)

[0590] Titanium isopropoxide (IV) (0.11 mL, 0.379 mmol, 3.00 eq) was added to a methanol (3.00 mL) solution of 2-aminopyrimidine-5-carboxaldehyde (16 mg, 0.126 mmol, 1.00 eq), intermediate 52 (50 mg, 0.126 mmol, 1.00 eq), and DMF (0.044 mL, 0.253 mmol, 2.00 eq). The reaction mixture was heated under reflux for 2 h. The reaction mixture was cooled to room temperature, and NaBH3CN (20 mg, 0.316 mmol, 2.50 eq) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with water (30 mL) and filtered through diatomaceous earth. The residue was washed with DCM / MeOH, the combined washes were evaporated, and the residue was dried under vacuum with P2O5. The residue was purified by preparative HPLC. Sunfire C18 19x150mm, 10µm, 5-60% ACN / H2O (0.1% FA), 20mL / min, RT. The title compound was obtained (17 mg, 0.0343 mmol, 27%).

[0591] 1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),8.29(s,1H),8.19(s,2H),7.08(s,1H),6.5 8(s,2H),3.60(s,2H),3.50(s,2H),2.87(m,2H),2.71-2.67(m,2H),1.59(s,6H).

[0592] LC-MS(ESI): m / z(M+1)=467.7; t R = 3.17 min. Method 11

[0593] The following compounds were prepared by reductive amination as described in steps 1-3 of Example 62, using commercially available heteroarylamines in step 1.

[0594]

[0595] Example 65: Preparation of N-(3-(tert-butyl)isoxazo-5-yl)-6-((5-methoxypyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

[0596] Example 65

[0597] Step 1: Preparation of ethyl (6-((5-methoxypyridin-3-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (intermediate 53)

[0598]

[0599] F was prepared according to general method from 5-methoxy-3-pyridinecarboxaldehyde (91 mg, 0.666 mmol) and intermediate 6 (150 mg, 0.605 mmol). Purification was performed by silica FCC (25 g), followed by elution with a 2 M methanol-ammonia DCM (15:1) solution in DCM (0 to 100%) to give the title compound (190 mg, 94%).

[0600] 1 H NMR (400MHz, CDCl3) δ8.25-8.23(m,1H),8.18(d,J=1.2Hz,1H),7.95-7.94(m,1H),7.28(t,J=2.3Hz,1H),4.29(q ,J=7.1Hz,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=7.1Hz,3H)

[0601] Step 2: Preparation of (6-((5-methoxypyridin-3-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (intermediate 54)

[0602]

[0603] NaOH (81 mg, 2.03 mmol, 3.10 eq) was added to a solution of intermediate 53 (217 mg, 0.653 mmol, 1.00 eq) in MeOH (10 mL) and water (0.5 mL), and the mixture was stirred at 50 °C for 18 h. The mixture was cooled in an ice bath, and 1 M HCl (1.8 mL, 1.78 mmol, 2.73 eq) was added dropwise. The solution was concentrated under vacuum, producing a solid precipitate, which was filtered off and washed with acetone (2 mL) to give the title compound (166 mg, 83%).

[0604] LC-MS(ESI): m / z(M+1)=305.2; t R =0.68min. Method 12

[0605] Step 3: Preparation of N-(3-(tert-butyl)isoxazol-5-yl)-6-((5-methoxypyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 65)

[0606] Intermediate 54 (30 mg, 0.0986 mmol) was suspended in thionyl chloride (0.21 mL, 2.93 mmol), and the reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was suspended in toluene and concentrated again to give intermediate acyl chloride. Acyl chloride was added 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), followed by the addition of DIPEA (51.5 μL, 0.296 mmol). The reaction mixture was stirred at 40 °C until LCMS indicated that the starting material was consumed, and then concentrated under vacuum. The title compound (28 mg, 0.065 mmol, 66%) was purified by reversed-phase preparative HPLC (Luna Phenyl-Hexyl 21.2 x 150 mm, 10 μm, 20-80% MeOH / H2O (0.1% FA), 20 mL / min, RT).

[0607] 1H NMR (400MHz, DMSO-d6) δ11.73-11.69(m,1H),8.28(s,1H),8.23(d,J=3.2Hz,1H),8.16(d,J=0.9Hz,1H),7.35(dd,J=1.8,2. 8Hz,1H),6.37(s,1H),3.84(s,3H),3.73(s,2H),3.65(s,2H),2.90(t,J=5.6Hz,2H),2.76-2.71(m,2H),1.29-1.28(m,9H).

[0608] LC-MS(ESI): m / z(M+1)=427.2; t R = 3.14 min. Method 9

[0609] Compared with the newly synthesized compound, it is characterized by optionally:

[0610] - There is no linking group between the tetrahydrothiophenepyridine ring and the Hy group (Example C1), and

[0611] - There is no linking group between the tetrahydrothiophenepyridine ring and the Hy group, and the -C(O)NH- group is substituted at the α-position of the sulfur atom on the thiophene ring (Example C2).

[0612] Example C1: Preparation of N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0613] Example C1

[0614] Step 1: ethyl 6-(pyrimidin-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (intermediate 16)

[0615]

[0616] 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 added to a 20 mL vial equipped with a magnetic stir bar and a sealed cap. The vial was evacuated and refilled with argon, and then toluene (4 mL) was added via syringe. The solution was heated to 120 °C and stirred continuously. After cooling to room temperature, the solution was filtered through a diatomaceous earth filter and then concentrated to dryness. The crude product was purified by FCC (silica gel column-NH gradient n-heptane / acetone from 100:0 to 60:40) to give the title compound (100 mg, 0.346 mmol, 52.5% yield).

[0617] 1 H NMR(400MHz, CDCl3)d ppm 8.72(s,1H)8.47(s,2H)8.03(s,1H)4.54(s,2H)4.32(q,J=7.16Hz,2H)3.70(t,J=5.81Hz,2H)3.16(br t,J=5.59Hz,2H)1.38(t,J=7.13Hz,3H)

[0618] Step 2: N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example C1)

[0619] Under nitrogen atmosphere, 3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)aniline (76 mg, 0.276 mmol) was dissolved in dry THF (6 mL, 1.500 ratio). The mixture was stirred at -78 °C for 15 min, followed by dropwise addition of n-BuLi (0.105 mL, 0.263 mmol) over 5 min, and the solution was stirred at -78 °C for 1 h. A solution of ethyl intermediate 16 (40 mg, 0.138 mmol) in THF (4 mL, 1.000 ratio) was added dropwise over 10 min, and the temperature was raised to room temperature while stirring for another 1 h. 10 mL of water was added to the solution to evaporate the solvent. The product was obtained by reversed-phase rapid chromatography (C18 column, supergradient A:B from 100:0 to 0:100, eluent A:H2O:ACN:HCOOH 95:5:0.1, eluent B:H2O:ACN:HCOOH 5:95:0.1). The relevant fractions were combined and loaded onto an Isolute SCX-2 column, washed with MeOH, and eluted with 7N methanol-ammonia. The residue was concentrated under vacuum to give the title compound (23.5 mg, 0.045 mmol, 32.9% yield).

[0620] 1 H NMR(400MHz,ACN-d3)δppm 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=5.81Hz,2H),3.54(s,2H),2.95-3.13(m,2H),2.30-2.44(br s,8H),2.20(s,3H).

[0621] LC-MS(ESI): m / z(M+1)=517.2; t R = 1.03 min (Method 1)

[0622] Example C2: N-(3-((4-methylpiperazin-1-yl)methyl)-5-trifluoromethyl)phenyl)-5-(pyrimidin-5-yl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-2-carboxamide

[0623] Example C2

[0624] Step 1: 4,7-Dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxylic acid 6-(tert-butyl)2-methyl ester (Intermediate 17)

[0625]

[0626] 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 (10 mL), and then CH₃I (0.066 mL, 1.059 mmol) was added in a single batch. The solution was stirred at room temperature for 3 h. The reaction mixture was diluted with Et₂O (20 mL) and then washed with saturated NH₄Cl (10 mL) and brine (10 mL). The organic phase was separated, dried over Na₂SO₄, filtered, and concentrated to dryness to give the title compound (182 mg, 0.611 mmol, 87% yield).

[0627] Step 2: 4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-2-carboxylate methyl hydrochloride (Intermediate 18)

[0628]

[0629] 1 mL of concentrated hydrochloric acid was added together with intermediate 17 (181.6 mg, 0.611 mmol) into a round-bottom flask. The reaction proceeded with gas formation and was completed within 5 min at room temperature. 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.

[0630] Step 3: Methyl 6-(pyrimidin-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (intermediate 19)

[0631]

[0632] 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 added to a 20 mL microwave-safe vial equipped with a magnetic stir bar and a sealed cap. The vial was evacuated and refilled with argon, and then toluene (5 mL) was added via syringe. The solution was heated to 110 °C and stirred continuously. After cooling to room temperature, the solution was filtered through a diatomaceous earth filter and then concentrated to dryness. The crude product was purified by FCC (gradient A:B from 100:0 to 60:40, eluent A: n-heptane, eluent B: acetone) to give the title compound (118.5 mg, 0.430 mmol, 80% yield).

[0633] 1¹H 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).

[0634] Step 4: N-(3-((4-methylpiperazin-1-yl)methyl)-5-trifluoromethyl)phenyl)-5-(pyrimidin-5-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (Example C2)

[0635] Under nitrogen atmosphere, 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (52.4 mg, 0.217 mmol) was dissolved in dry THF (volume: 4), and the mixture was stirred at -78 °C for 15 min. Then, 2.5 M n-BuLi (0.083 mL, 0.206 mmol) in hexane was added dropwise over 5 min, and the solution was stirred at -78 °C for 1 h. A solution of methyl intermediate 19 (29.9 mg, 0.109 mmol) in THF (volume: 2 mL) was added dropwise over 10 min, and the temperature was increased at room temperature while stirring the reaction for 1 h. 10 mL of water was added to quench the reaction, and the crude product was extracted in 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 from 100:0 to 0:100, eluent A:H2O:ACN:HCOOH 95:5:0.1, eluent H2O:ACN:HCOOH 5:95:0.1). Appropriate fractions were combined and evaporated to give the title compound (8.7 mg, 0.018 mmol, 16.53% yield).

[0636] 1 H NMR(400MHz,ACETONITRILE-d3)δppm 8.97(br s,1H),8.59(s,1H),8.49(s,2H),8.11(s,1H),8.00(s,1H),7.89(s,1H),7.59( s,1H),7.54(s,1H),7.23(s,1H),4.60(s,2H),3.73(t,J=5.81Hz,2H),2.88(br t,J=5.70Hz,2H),2.23(s,3H). LC-MS(ESI): m / z(M+1)=485.1; t R = 1.15 min (Method 1)

[0637] Pharmacological activity of the compounds of this invention

[0638] In vitro assay

[0639] Combined measurement

[0640] Using Life Technologies LanthaScreen TM Europium kinase binding assays were performed using DDR1 and DDR2 binding assays. The compounds were incubated for 1 h at room temperature in white 384-well Optiplates (PerkinElmer) containing either 5 nM DDR1 (Carna Biosciences) or 5 nM DDR2 (Life Technologies) in assay buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, and 0.01% BRIJ35) with either 20 nM or 10 nM kinase tracer 178 or 2 nM europium-labeled anti-GST antibody (Life Technologies).

[0641] The ratio of fluorescence emission at 665nm / 615nm after excitation at 340nm was obtained using a Tecan Spark 20M reader. The IC50 was determined using a 4-parameter model: log(inhibitor) versus response in GraphPad Prism 7.0 software. 50 Value. Using the Cheng-Prusoff equation (Ki = IC) 50 / (1+[tracer] / Kd), IC 50 Convert the value to Ki.

[0642] DDR1 cell-based assay

[0643] According to the manufacturer's instructions, via The U2OSDDR1 assay (Eurofins DiscoverX) evaluated the inhibitory effect of the compound on DDR1 receptor activation. In short, U2OS-DDR1 cells were seeded at a density of 5000 cells / well in white 384-well plates and incubated at 37°C and 5% CO2 for 2 h. Cells were then treated with different concentrations of the compound and incubated for 30 min, followed by stimulation with 20 μg / mL bovine type II collagen and overnight incubation at 37°C and 5% CO2. PathHunter assay reagents were prepared according to the protocol provided by DiscoverX, and 20 μL / well of the mixture was added to each well. After incubation in the dark at room temperature for 1 h, luminescence signals were obtained using a plate reader. Raw data were calibrated relative to a media control (0% for calibration) and a positive control (100% for calibration; cells treated with 20 μg / mL collagen II), and IC50 was calculated in GraphPad Prism 8.0 software using an sigmoid dose-response curve with a variable slope. 50 parameter.

[0644] DDR2 cell-based assay

[0645] The inhibitory effect of the compounds on DDR2 phosphorylation was evaluated in HEK293T-DDR2 recombinant cells using a phosphorylation-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 for 1.5 h in DMEM + 10% FBS at 37 °C and 5% CO2. Subsequently, the medium was replaced with serum-free DMEM, and the cells were incubated for 3 h. Different concentrations of the test compounds were then added 30 min before restimulation with 50 μg / mL bovine type II collagen for 3 h. For the DDR2 phosphorylation-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. Protein concentrations in the samples were determined by the BCA assay, and DDR2 phosphorylation levels were determined according to R&D Systems instructions. The raw data were calibrated against the maximum inhibition control (calibrated 0%) and the positive control (calibrated 100%; cells treated with 20 μg / mL collagen II), and the IC50 was calculated in GraphPadPrism 8.0 software using an sigmoid dose-response curve fitted with a variable slope. 50 parameter.

[0646] Table 5 below provides results for individual compounds, which are categorized according to their inhibitory activity (nM) against DDR1 and DDR2 in both binding and cell-based assays:

[0647] Table 5

[0648]

[0649]

[0650]

[0651]

[0652] +:Ki is between 50 and 80 nM

[0653] ++: Ki is between 25 and 50 nM

[0654] +++: Ki is below 25nM

[0655] +: IC50 is between 50 and 80 nm.

[0656] ++: IC50 is between 25 and 50 nm.

[0657] +++: IC50 is below 25nM

[0658] -: Not obtained

[0659] As can be understood, the compounds in Table 5, namely the compounds of the present invention, exhibit good activity as DDR1 and DDR2 antagonists. Therefore, the compounds of the present invention can be effectively used to treat diseases, disorders, or conditions associated with DDR receptors, such as fibrosis, including pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, kidney fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, and systemic sclerosis.

[0660] Comparative Examples

[0661] The compounds in Examples C1 and C2 were tested in the same binding assays described above.

[0662] Table 6

[0663] Example No. DDR1 Ki(nM) DDR2 Ki(nM) C1 238 172 C2 29000 50000

[0664] As shown in Table 5, the binding affinity (expressed as Ki) and inhibitory potency (expressed as IC50) of the compounds of the present invention to DDR1 and DDR2 receptors are both below 80 nM, and for most compounds, below 50 nM or even below 25 nM. In contrast, Comparative Example C1 has a binding affinity to the DDR1 receptor above 230 nM and a binding affinity to DDR2 above 170 nM; and Comparative Example C2 has a binding affinity to the DDR1 receptor of 29000 nM and a binding affinity to DDR2 of 50000 nM.

[0665] These data indicate that, in contrast to the comparative compound of Example C1 (characterized by the lack of a linker between the tetrahydrothiophenepyridine ring and the Hy group), the presence of a -CH2- linker at this position in the compound of Example 2 of the present invention unexpectedly and significantly determines the associated increase in inhibitory activity against DDR1 and DDR2 receptors.

[0666] As further evidence, unlike the compound of Example C2 (characterized by the lack of a linker between the tetrahydrothiophenepyridine ring and the Hy group and the -C(O)NH- group being substituted at the α position relative to the sulfur atom instead of the β position as in Example 2 of the present invention), the presence of the aforementioned linker and the simultaneous occurrence of substitution at the β position in the compounds of the present invention unexpectedly and notably determines the corresponding increase in inhibitory activity against DDR1 and DDR2 receptors.

Claims

1. Compounds of formula (I) (I) in L is selected from -C(O)- and -CH2-; Hy is a monocyclic heteroaryl group, optionally substituted with one or more groups selected from: -(C1-C4)alkyl, halogen atom, cyano, -(CH2). n NR4R5, -NH-heterocyclic alkyl, -O-(C1-C6)alkyl, -(C1-C6)haloalkyl, -C(O)NH-(C1-C6)alkylene-NR4R5, -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, optionally distilled by a One or more -(C1-C4)alkyl-substituted -heteroaryl, -NH-heteroaryl, and heterocyclic alkyl groups optionally substituted with one or more groups selected from oxo and -(C1-C6)alkyl groups, wherein the heteroaryl is selected from pyridinyl, pyrimidinyl, 1-methyl-1H-pyrazolyl, pyrazinyl, 1-methyl-1H-imidazolyl and isoxazolyl, and the heterocyclic alkyl group is selected from piperazinyl, oxopiperazinyl, dioxothiomorpholino, oxoheterobutyl and pyrrolidinyl, wherein the heteroaryl in the -NH-heteroaryl is optionally substituted with one or more -(C1-C4)alkyl groups; R1 is selected from: - Het, which is a heteroaryl group, said heteroaryl group optionally substituted with one or more groups selected from -(C1-C4)alkyl and -(C1-C4)haloalkyl groups, said heteroaryl group being selected from pyridinyl, pyrimidinyl, 1-methyl-1H-pyrazolyl, pyrazinyl, 1-methyl-1H-imidazolyl, and isoxazolyl; and - X (X) in R2 is selected from -O(C1-C4) haloalkyl, halogen atoms and -(C1-C4) haloalkyl; R3 is H or selected from halogen atoms, cyano, -O(C1-C4)alkyl, -O(C1-C4)haloalkyl, heterocyclic alkyl-(C1-C4)alkylene-, -(C1-C4)alkylene-heterocyclic alkyl-NR4R5 and heteroaryl groups optionally substituted with one or more -(C1-C4)alkyl groups, wherein the heterocyclic alkyl group is optionally substituted with one or more -(C1-C4)alkyl groups, wherein the heteroaryl group is selected from pyridinyl, pyrimidinyl, 1-methyl-1H-pyrazolyl, pyrazinyl, 1-methyl-1H-imidazolyl and isoxazolyl, and wherein the heterocyclic alkyl group is selected from piperazinyl, oxopiperazinyl, dioxothiomorpholino, oxoheterobutylyl and pyrrolidinyl; n is 0, 1, or 2; R4 is H or -(C1-C4) alkyl; R5 is H or -(C1-C4) alkyl; And its pharmaceutically acceptable salts.

2. The compound of formula (I) according to claim 1, wherein R1 is X', (X’) The compound is represented by formula (Ia). (It)。 3. The compound of formula (I) according to claim 2, wherein L is -CH2-, said compound is represented by formula (Iaa). (Iaa) 。 4. The compound of formula (I) according to claim 1, wherein L is -CH2- and R1 is X''. (X’’) The compound is represented by the formula (Iaa'). (Iaa’) 。 5. The compound of formula (I) according to claim 1, wherein L is -CH2- and R1 is X'''. (X’’’) The compound is represented by the formula (Iaa''). (Iaa’’) 。 6. The compound of formula (Ia) according to claim 2, wherein L is -C(O)-, said compound is represented by formula (Iab). (Iab).

7. The compound of formula (I) according to claim 1, wherein R1 is Het, and the compound is represented by formula (Ib). (Ib)。 8. The compound of formula (Ib) according to claim 7, wherein L is -CH2-, said compound is represented by formula (Iba). (Other)。 9. A compound selected from at least one of the following: N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyridin-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(pyrimidin-5-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethoxy)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-(1,1-difluoroethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-(difluoromethoxy)-5-fluorophenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-(difluoromethoxy)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-cyano-5-(trifluoromethyl)phenyl)-6-(pyrimidin-5-ylmethyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-((4-(2-methoxyacetamido)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; 6-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-cyanopyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-((5-chloropyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-methoxypyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((5-methylpyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-(trifluoromethyl)phenyl)-6-((5-(trifluoromethyl)pyridin-3-yl)methyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide; 6-((5-fluoropyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(pyridin-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide; 6-((3-aminopyrazin-2-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-((5-(4-methyl-3-oxopiperazin-1-yl)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; 6-((5-(1,1-dioxothiomorpholino)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; 6-((5-(2-(dimethylamino)acetamido)pyridin-3-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-((2-(oxecyclobutane-3-ylamino)pyrimidin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-((2-acetaminopyrimidin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-((2-(methylamino)pyrimidin-5-yl)methyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-((2-((2-methoxyethyl)amino)pyrimidin-5-yl)methyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-((6-acetamidopyridin-3-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyridin-3-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-((2-((2-hydroxyethyl)amino)pyrimidin-5-yl)methyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-((4-aminopyrimidin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((3-aminopyrazin-2-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-((2-amino-4-methylpyrimidin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-((6-(methylamino)pyridin-3-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; (R)-6-((2-aminopyrimidin-5-yl)methyl)-N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)-N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-((4-(2-fluoroprop-2-yl)pyrimidin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)-N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-((4-methoxypyrimidin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)-6-((4-cyclopropoxypyrimidin-5-yl)methyl)-N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)-N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidin-5-yl)methyl)-N-(3-((dimethylamino)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidin-5-yl)methyl)-N-(3-(1,1-difluoroethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((2-aminopyrimidin-5-yl)methyl)-N-(3-cyano-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide.

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

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

12. Use of a compound according to any one of claims 1-9 or a pharmaceutical composition according to claim 10 or 11 in the preparation of a medicament for the prevention and / or treatment of diseases, disorders or conditions associated with discoid domain receptor dysregulation.

13. The use according to claim 12, wherein the drug is used for the prevention and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis.

14. The use according to claim 13, wherein the drug is used for the prevention and / or treatment of fibrosis, the fibrosis being selected from pulmonary fibrosis, liver fibrosis, kidney fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis, and systemic sclerosis.

15. The use according to claim 13, wherein the drug is used for the prevention and / or treatment of idiopathic pulmonary fibrosis.

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