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 DD2 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 demonstrate 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] Rx, Ry, and Rz are independently H or -(C1-C4) alkyl;

[0020] L is selected from -C(O)- and -CH2-;

[0021] Hy is a bicyclic heteroaryl group, which is optionally substituted with at least one substituent selected from -(C1-C4)alkyl, halogen atom, cyano, -O-(C1-C4)alkyl, -O-(C1-C4)alkylene-OH, -O-(C1-C4)alkylene-O-(C1-C4)alkyl, -O-(C1-C4)alkylene-heterocyclic alkyl, -(C1-C4)alkylene-NR4R5, -(C1-C6)haloalkyl and heterocyclic alkyl, which is optionally substituted with one or more -(C1-C4)alkyl groups, or Hy is a bicyclic semi-saturated heteroaryl group;

[0022] R1 is selected from:

[0023] -Het is a heteroaryl group, optionally substituted with one or more substituents selected from -(C1-C4)alkyl, -(C1-C4)haloalkyl, cycloalkyl optionally substituted with one or more -(C1-C6)haloalkyl, -O-(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -(C1-C4)alkylene-OH, -(C1-C4)alkylene-NR4R5, heterocycloalkyl, -(C1-C4)alkylene-aryl, and aryl, wherein the aryl group is optionally substituted with one or more groups selected from -(C1-C4)alkyl and halogen atoms.

[0024] -X

[0025]

[0026] in

[0027] R2 is H or selected from -O(C1-C4) haloalkyl, halogen atom, -O-cycloalkyl and -(C1-C4) haloalkyl;

[0028] R3 is H or selected from halogen atoms, cyano groups, heterocyclic alkyl groups optionally substituted with one or more -(C1-C4)alkyl groups, -(C1-C4)alkylene-heterocyclic alkyl groups, and -(C1-C4)alkylene-heterocyclic alkyl-(CH2) groups. n -NR4R5, -(C1-C4)alkylene-NR4R5, -(C1-C4)alkylene-NR4R6, -O(C1-C4)alkyl, -O(C1-C4)haloalkyl, -O-(C1-C4)alkylene-OH, heteroaryl groups optionally substituted with -(C1-C4)alkyl, -O-(C1-C4)alkylene-NR4R5, -O-(C1-C4)alkylene-O-(C1-C4)alkyl, -O-(C1-C4)alkylene-heterocyclic alkyl and -O-heterocyclic alkyl, wherein each of the heterocyclic alkyl groups is optionally substituted with one or more groups selected from -(C1-C4)alkyl, oxo, halogen atom, -C(O)-(C1-C4)alkyl and heterocyclic alkyl;

[0029] n is 0, 1, or 2;

[0030] R4 is H or -(C1-C4) alkyl;

[0031] R5 is H or -(C1-C4) alkyl;

[0032] R6 is selected from -heterocyclic alkyl, -(C1-C4)alkylene-O-(C1-C4)alkyl and -(C1-C4)alkylene-OH;

[0033] And its pharmaceutically acceptable salts.

[0034] 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.

[0035] 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.

[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 diseases, disorders or conditions associated with DDR disorder.

[0037] 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.

[0038] 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

[0040] definition

[0041] Unless otherwise stated, compounds of formula (I) contemplated in this invention also include their stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates.

[0042] Unless otherwise stated, the compounds of formula (I) of the present invention also include compounds of (Ia), (Iaa), (Iab), (Iaa'), (Iab'), (Ib), (Iba), and (Ibb).

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] The term "solvent" refers to the physical combination of the compound of the present invention with one or more solvent molecules (whether organic or inorganic). This physical combination includes hydrogen bonding. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvate may contain stoichiometric or non-stoichiometric solvent molecules.

[0048] The term "stereoisomer" refers to isomers with the same composition but different spatial arrangements of atoms. Enantiomers and diastereomers are examples of stereoisomers.

[0049] The term "enantiomer" refers to one of a pair of molecular structures that are mirror images of each other and cannot be overlapped.

[0050] The symbols “R” and “S” denote the configuration of the substituents surrounding the chiral carbon atom. The isomer description symbols “R” and “S” are used as described in this application to denote the atomic configuration relative to the core molecule and are contemplated for use as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemist Ry, 68: 2193-2222 (1996)).

[0051] The term "diamera" refers to a stereoisomer that is not a mirror image.

[0052] The term "racemate" or "racemic mixture" refers to a composition consisting of two enantiomers in equimolar amounts, wherein the composition is optically inactive.

[0053] The term "tautomer" refers to each of two or more isomers of a compound that exist together in a balanced manner and are readily interchangeable by the migration of atoms or groups within the molecule.

[0054] As used in this application, the terms "halogen" or "halogen atom" or "halogenated" include fluorine, chlorine, bromine and iodine atoms.

[0055] 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.

[0056] The term "(C)" x -C y "alkylene", where x and y are integers, refers to a C group having a total of two unsatisfied valences. x -C y Alkyl groups, such as divalent methylene groups.

[0057] The term "(C)" x -C y "alkylene-OH" refers to an alkylene group attached to an OH group.

[0058] The term "(C)" x -C y "alkylene-aryl" refers to an alkylene group attached to an aryl group.

[0059] 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", in which a carbon atom is bonded to an oxygen atom.

[0060] 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.

[0061] 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.

[0062] Therefore, the "O(C)" x -C y Examples of "halogenated alkyl" can include halogenated, polyhalogenated, and perhalogenated O-alkyl in which all hydrogen atoms are replaced by halogen atoms, such as trifluoromethoxy.

[0063] 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.

[0064] 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.

[0065] The term "semi-saturated heteroaryl" refers to a bicyclic group containing one or more heteroatoms selected from S, N, and O, and includes monocyclic heteroaryl groups fused with a monocyclic heterocyclic alkyl ring. Examples of suitable semi-saturated heteroaryl groups include, for example, 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl, and 5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-3-yl.

[0066] The term "heterocyclic alkyl" refers to a saturated monocyclic or bicyclic system comprising 3 to 12 ring atoms, selected from one or more heteroatoms chosen from N, S, or O. Examples of heterocyclic alkyls include piperazinyl, pyrrolyl, morpholinyl, and piperidinyl. The heterocyclic alkyl may be further optionally substituted at available positions in the ring, i.e., on a carbon atom, or on a heteroatom that can be substituted. Substitution may occur on a carbon atom, including spirocyclic disubstituted, forming a bicyclic system in which two heterocyclic alkyl rings or one heterocyclic alkyl and one cycloalkyl ring are linked by a single carbon atom. Substitution may also form additional fused 4- to 6-membered heterocyclic alkyl rings on two adjacent carbon atoms. Examples of spirocyclic rings include, but are not limited to, 6-methyl-2,6-diazaspiro[3.3]heptyl, 6-oxa-1-azaspiro[3.3]heptyl, and 2-methyl-2,8-diazaspiro[4.5]decyl. Furthermore, the heterocyclic alkyl may be a diazabicyclic, azabicyclic, or cyclic carbonate. Examples of diazabicyclo include, but are not limited to, for example, 5-methyl-2,5-diazabicyclo[2.2.1]heptyl and 6-methyl-3,6-diazabicyclo[3.2.2]nonyl; examples of azabicyclo include, but are not limited to, for example, 2-oxa-5-azabicyclo[2.1.1]hept-5-yl; examples of suitable cyclic carbonates include, for example, 1,3-dioxacyclopentan-2-one and 4-methyl-1,3-dioxacyclopentadien-2-one.

[0067] The term "heterocyclic alkyl (C10)" x -C y "(C)alkyl" refers to the alkyl group defined above. x -C y Heterocyclic alkyl groups linked by "alkyl".

[0068] The term "O-heterocyclic alkyl" refers to a heterocyclic alkyl group bonded to an oxygen atom.

[0069] The term "(C)" x -C y"alkylene-heterocyclic alkyl" refers to an alkylene ring linked to a heterocyclic alkyl ring, both as defined above.

[0070] The term "O-(C)" x -C y "(C)alkylene-OH" refers to the "(C)alkylene-OH" defined above. x -C y The alkylene group is an alkylene group, wherein the alkylene group is attached to an oxygen atom.

[0071] The term "O-(C)" x -C y )alkylene-O-(C x -C y "(C)alkyl" refers to "(C)alkyl" as defined above. x -C y )alkyl", wherein the alkyl group is formed by the oxygen atom and the "-O-(C" as defined above". x -C y )alkyl" linker.

[0072] The term "O-(C)" x -C y "alkylene-heterocyclic alkyl" refers to the alkylene group bonded to an oxygen atom as defined above (C x -C y )alkylene-heterocyclic alkyl.

[0073] The term "-C(O)-(C x -C y "(C)alkyl" refers to "(C)alkyl" as defined above. x -C y "alkyl", wherein the alkyl group is attached to a -C(O)- group.

[0074] The term "(C)" x -C y )alkylene-heterocyclic alkyl-(CH2) n -NR x R y "" refers to a direct connection to "(C" as defined above. x -C y "Hypercyclic alkyl group as defined above" is further defined by -(CH2). n -with nitrogen NR x R y Connect, where x and y are integers, and n is an integer. The term "(C x -C y )alkylene-NR x R y "Ref" refers to nitrogen NR x R yThe connection defined above, "(C x -C y ")alkylene", where x and y are integers.

[0075] The term "O-(C)" x -C y )alkylene-NR x R y "Refers to NR" x R y The connection is defined above as "O-(C)". x -C y ")alkylene", where x and y are integers.

[0076] The term "O-(C)" x -C y )alkylene-O-(C x -C y "alkyl" refers to an alkyl group formed by the interaction of an oxygen atom with "O-(C" as described above). x -C y )alkylene" connected as described above "(C x -C y )alkyl".

[0077] 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.

[0078] When referring to substituents, the dash ("-") not between two letters, words, or symbols indicates the connection point of such substituents.

[0079] 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)-.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] In fact, as detailed in the experimental section below, the compounds of formula (I) of the present invention can act as antagonists of DDR1 and DDR2 receptors in a substantial and effective manner. Specifically, Table 6 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 antagonize two isotypes 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.

[0085] As shown in Table 7 of the same experimental section, the data indicate that, contrary to compound C1 (characterized by the -C(O)NH- group being substituted at the α-position relative to sulfur rather than at the β-position as in Example 1 of the present invention), the presence of the above substitution at the β-position in the compounds of the present invention unexpectedly and significantly determines the associated increase in inhibitory activity against DDR1 and DDR2 receptors.

[0086] As further evidence, in contrast to compound C2 (characterized by a -C(O)NH- group that simultaneously substitutes the thiophene ring at the α-position relative to sulfur and a Hy group that substitutes the tetrahydropyridyl ring connected to nitrogen at the 5-position via a spacer group), in Example 1 of the present invention, the presence of a -C(O)NH- group that substitutes the thiophene ring at the β-position relative to sulfur and a Hy group that substitutes the tetrahydropyridyl ring connected to nitrogen at the 6-position via a spacer group unexpectedly and notably determined the associated increase in inhibitory activity against DDR1 and DDR2 receptors.

[0087] 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.

[0088] In addition to their significant inhibitory activity against receptors DDR1 and DDR2, the compounds of the present invention are characterized by good inhalation properties, which allow for effective action on the lung compartments, while simultaneously exhibiting low metabolic stability, which allows for minimization of disadvantages associated with systemic exposure, such as safety and tolerability issues.

[0089] 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.

[0090] Therefore, in one aspect, the present invention relates to compounds of formula (I).

[0091]

[0092] in

[0093] Rx, Ry, and Rz are independently H or -(C1-C4) alkyl;

[0094] L is selected from -C(O)- and -CH2-;

[0095] Hy is a bicyclic heteroaryl group, which is optionally substituted with at least one substituent selected from -(C1-C4)alkyl, halogen atom, cyano, -O-(C1-C4)alkyl, -O-(C1-C4)alkylene-OH, -O-(C1-C4)alkylene-O-(C1-C4)alkyl, -O-(C1-C4)alkylene-heterocyclic alkyl, -(C1-C4)alkylene-NR4R5, -(C1-C6)haloalkyl and heterocyclic alkyl, which is optionally substituted with one or more -(C1-C4)alkyl groups, or Hy is a bicyclic semi-saturated heteroaryl group;

[0096] R1 is selected from:

[0097] -Het is a heteroaryl group, optionally substituted with one or more substituents selected from -(C1-C4)alkyl, -(C1-C4)haloalkyl, cycloalkyl optionally substituted with one or more -(C1-C6)haloalkyl, -O-(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -(C1-C4)alkylene-OH, -(C1-C4)alkylene-NR4R5, heterocycloalkyl, -(C1-C4)alkylene-aryl, and aryl, wherein the aryl group is optionally substituted with one or more groups selected from -(C1-C4)alkyl and halogen atoms.

[0098] -X

[0099]

[0100] in

[0101] R2 is H or selected from -O(C1-C4) haloalkyl, halogen atom, -O-cycloalkyl and -(C1-C4) haloalkyl;

[0102] R3 is H or selected from halogen atoms, cyano groups, heterocyclic alkyl groups optionally substituted with one or more -(C1-C4)alkyl groups, -(C1-C4)alkylene-heterocyclic alkyl groups, and -(C1-C4)alkylene-heterocyclic alkyl-(CH2) groups. n -NR4R5, -(C1-C4)alkylene-NR4R5, -(C1-C4)alkylene-NR4R6, -O(C1-C4)alkyl, -O(C1-C4)haloalkyl, -O-(C1-C4)alkylene-OH, heteroaryl groups optionally substituted with -(C1-C4)alkyl, -O-(C1-C4)alkylene-NR4R5, -O-(C1-C4)alkylene-O-(C1-C4)alkyl, -O-(C1-C4)alkylene-heterocyclic alkyl and -O-heterocyclic alkyl, wherein each of the heterocyclic alkyl groups is optionally substituted with one or more groups selected from -(C1-C4)alkyl, oxo, halogen atom, -C(O)-(C1-C4)alkyl and heterocyclic alkyl;

[0103] n is 0, 1, or 2;

[0104] R4 is H or -(C1-C4) alkyl;

[0105] R5 is H or -(C1-C4) alkyl;

[0106] R6 is selected from -heterocyclic alkyl, -(C1-C4)alkylene-O-(C1-C4)alkyl and -(C1-C4)alkylene-OH;

[0107] And its pharmaceutically acceptable salts.

[0108] In a particularly preferred embodiment, the present invention relates to compounds of formula (I) wherein R1 is X'.

[0109]

[0110] The compound is represented by formula (Ia).

[0111]

[0112] Rx, Ry, Rz, L, Hy, R2, and R3 are defined as above.

[0113] In a particularly preferred embodiment, the present invention relates to compounds of formula (Ia) wherein L is -CH2-, said compounds being represented by formula (Iaa).

[0114]

[0115] Rx, Ry, Rz, Hy, R2, and R3 are defined as above.

[0116] In a preferred embodiment, the present invention relates to compounds of formula (Iaa), wherein Hy is selected from imidazo[1,2-a]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, imidazo[1,2-a]pyrazin-3-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, pyrazolo[1,5-a]pyrimidin-6-yl, 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl, and imidazo[1,2-b]pyridazin-3-yl.

[0117] In another preferred embodiment, the present invention relates to a compound of formula (Iaa), wherein R2 is trifluoromethyl and trifluoromethoxy.

[0118] In another particularly preferred embodiment, the invention relates to a compound of formula (Iaa), wherein R3 is H or selected from 4-methyl-1H-imidazol-1-yl, 3-(dimethylamino)pyrrolidine-1-yl, 2-(pyrrolidine-1-yl)ethoxy and fluorine.

[0119] In another preferred embodiment, the invention relates to a compound of formula (Iaa), wherein Hy is selected from 1H-pyrazolo[3,4-b]pyridin-5-yl and 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl, R2 is selected from trifluoromethoxy and trifluoromethyl, R3 is H or selected from fluorine, (R)-N-(3-((3-(dimethylamino)pyrrolidine-1-yl)methyl and 2-(pyrrolidine-1-yl)ethoxy).

[0120] 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 6.

[0121] Table 1: List of compounds of formula (Iaa)

[0122]

[0123]

[0124]

[0125]

[0126]

[0127] 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).

[0128]

[0129] Rx, Ry, Rz, Hy, R2, and R3 are defined as above.

[0130] In a preferred embodiment, the present invention relates to compounds of formula (Iab), wherein Hy is selected from imidazo[1,2-a]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, imidazo[1,2-a]pyrazin-3-yl, 1H-pyrazo[3,4-b]pyridin-yl, pyrazo[1,5-a]pyrimidin-3-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl, 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl, imidazo[1,2-b]pyridazin-3,6-((dimethylamino)methyl)imidazo[1,2-a]pyridin-3-yl, 4-methylpiperazin-1-yl)imidazo[ [1,2-a]pyridin-3-yl, 5-methylimidazo[1,2-a]pyridin-3-yl, 6-methyl-2,6-diazaspiro[3.3]hept-2-yl)imidazo[1,2-a]pyridin-3-yl, 6-(2-hydroxyethoxy)imidazo[1,2-a]pyridin-3-yl, 2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl, 6-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl, 2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl and pyrazolo[1,5-a]pyrazin-3-yl.

[0131] In another preferred embodiment, the present invention relates to compounds of formula (Iab), wherein R2 is selected from trifluoromethyl and trifluoromethoxy.

[0132] In another particularly preferred embodiment, the invention relates to compounds of formula (Iab), wherein R3 is hydrogen or selected from 4-methyl-1H-imidazol-1-yl, fluorine, pyrrolidone-1-ylmethyl, (dimethylamino)methyl, 3-(morpholinomethyl), 2-morpholinoethoxy, 4-(dimethylamino)piperidin-1-yl)methyl, 3-(dimethylamino)pyrrolidone-1-yl)methyl, 6-oxa-1-azaspiro[3.3]hept-1-yl)methyl, 2-(dimethylamino)ethoxy, 2-(pyrrolidone-1-yl)ethoxy, (2-hydroxyethyl)(methyl)amino)methyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, (2-methoxyethyl)(methyl) (4-Acetylpiperazin-1-yl)methyl, (4-methyl-3-oxopiperazin-1-yl)methyl, (piperidin-1-yl)methyl, (3-fluoropyrrolidine-1-yl)methyl, aziridine-1-ylmethyl, methyl(oxopiperazin-3-yl)amino)methyl, (4-(oxopiperazin-3-yl)piperazin-1-yl)methyl, (3-((dimethylamino)methyl)pyrrolidine-1-yl)methyl, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(dimethylamino)pyrrolidine-1-carbonyl, cyano, 4-methylpiperazin-1-yl, N-morpholino, hydroxymethyl, (4-methylpiperazin-1-yl)methyl and (1-methylpyrrolidine-3-yl)oxy.

[0133] In another particularly preferred embodiment, the invention relates to compounds of formula (Iab), wherein Hy is selected from 6-((dimethylamino)methyl)imidazo[1,2-a]pyridin-3-yl, 6-(2-hydroxyethoxy)imidazo[1,2-a]pyridin-3-yl, 6-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)imidazo[1,2-a]pyridin-3-yl, 6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl, 6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-3-yl and 6-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl, R2 is trifluoromethyl, and R3 is H.

[0134] According to a preferred embodiment, the present invention relates to at least one compound of formula (Iab) listed in Table 2 below and its pharmaceutically acceptable salt.

[0135] Table 2: List of compounds of formula (Iab)

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148] In a further preferred embodiment, the present invention relates to compounds of formula (I) wherein R1 is X”.

[0149]

[0150] The compound is represented by formula (Ia').

[0151]

[0152] Hy, R2, and R3 are defined as above.

[0153] 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').

[0154]

[0155] Hy, R2, and R3 are defined as above.

[0156] In a particularly preferred embodiment, the present invention relates to a compound of formula (Iaa'), wherein R2 is trifluoromethyl.

[0157] In another particularly preferred embodiment, the present invention relates to a compound of formula (Iaa'), wherein R3 is a methoxy group.

[0158] In a further preferred embodiment, the present invention relates to compounds of formula (Iaa'), wherein Hy is 1H-pyrrolo[2,3-b]pyridin-5-yl.

[0159] According to a preferred embodiment, the present invention relates to compounds of formula (Iaa') listed in Table 3a below and their pharmaceutically acceptable salts. These compounds are particularly active against receptors DDR1 and DDR2, as shown in Table 6.

[0160] Table 3a: List of compounds of formula (Iaa')

[0161]

[0162] In a further preferred embodiment, the present invention relates to compounds of formula (Ia') wherein L is -CO-, said compounds being represented by formula (Iab').

[0163]

[0164] Hy, R2, and R3 are defined as above.

[0165] In a particularly preferred embodiment, the present invention relates to a compound of formula (Iab'), wherein R2 is trifluoromethyl.

[0166] In another particularly preferred embodiment, the invention relates to compounds of formula (Iab'), wherein R3 is selected from methoxy, (tetrahydrofuran-3-yl)oxy, (4-methylpiperazin-1-yl)methyl, oxetane-3-yloxy, pyrrolidine-1-ylmethyl, morpholinomethyl, oxetane-3-ylmethoxy, 2-methoxyethoxy, (dimethylamino)methyl, 2-hydroxyethoxy, (1-methylpiperidin-4-yl)oxy, hydroxymethyl, chlorine, and (1-methylpyrrolidine-3-yl)oxy.

[0167] In another preferred embodiment, the present invention relates to a compound of formula (Iab'), wherein Hy is pyrazolo[1,5-a]pyrazin-3-yl, R3 is selected from hydroxymethyl, (dimethylamino)methyl and chlorine, and R2 is trifluoromethyl.

[0168] According to a further preferred embodiment, the present invention relates to compounds of formula (Iab') listed in Table 3b below and their pharmaceutically acceptable salts. These compounds are particularly active against receptors DDR1 and DDR2, as shown in Table 6.

[0169] Table 3b: List of compounds of formula (Iab')

[0170]

[0171]

[0172]

[0173]

[0174] In a particularly preferred embodiment, the present invention relates to compounds of formula (I) wherein R1 is Het, said compounds being represented by formula (Ib).

[0175]

[0176] in

[0177] L is selected from -C(O)- and -CH2-;

[0178] Hy is a bicyclic heteroaryl group, which is optionally substituted by at least one substituent selected from -(C1-C4)alkyl, halogen atom and -(C1-C6)haloalkyl;

[0179] Het is a heteroaryl group, which is optionally substituted with one or more substituents selected from -(C1-C4)alkyl, -(C1-C4)haloalkyl, cycloalkyl, -O-(C1-C4)haloalkyl, -(C1-C4)alkylene-OH, -(C1-C4)alkylene-aryl, and aryl groups optionally substituted with one or more groups selected from -(C1-C4)alkyl and halogen atoms;

[0180] And its pharmaceutically acceptable salts.

[0181] In a particularly preferred embodiment, the present invention relates to compounds of formula (Ib) wherein L is -CH2-, said compounds being represented by formula (Iba).

[0182]

[0183] Rx, Ry, Rz, Hy, and Het are defined as above.

[0184] In a preferred embodiment, the present invention relates to compounds of formula (Iba), wherein Hy is selected from 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, pyrazolo[1,5-a]pyrimidin-6-yl, imidazo[1,2-a]pyrazin-3-yl, (4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl, pyrazolo[1,5-a]pyrazin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl and 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl.

[0185] In another preferred embodiment, the present invention relates to compounds of formula (Iba), wherein Het is selected from 3-(tert-butyl)-1-methyl-1H-pyrazole-5-yl, 3-cyclopropyl-1-methyl-1H-pyrazole-5-yl, 3-(tert-butyl)isoxazole-5-yl, 5-cyclopropylisoxazole-3-yl, 5-(trifluoromethyl)pyridin-3-yl, 5-(tert-butyl)isoxazole-3-yl, 1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl and 3-(tert-butyl)-1-(p-tolyl)-1H-pyrazole-5-yl.

[0186] In another preferred embodiment, the present invention relates to a compound of formula (Iba), wherein Hy is selected from 3-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl, 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-5-ylmethyl, pyrazolo[1,5-a]pyrimidin-6-yl, imidazo[1,2-a]pyrazin-3-yl, pyrazolo[1,5-a]pyrazin-3-yl, and 7H-pyrrolo[2,3-d]pyrimidin-4-yl, and Het is 5-(trifluoromethyl)pyridin-3-yl.

[0187] 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.

[0188] Table 4: List of compounds of formula (Iba)

[0189]

[0190]

[0191]

[0192]

[0193] In a particularly preferred embodiment, the present invention relates to compounds of formula (Ib) wherein L is -C(O)-, said compounds being represented by formula (Ibb).

[0194]

[0195] Rx, Ry, Rz, Hy, and Het are defined as above.

[0196] In a preferred embodiment, the present invention relates to compounds of formula (Ibb), wherein Hy is selected from imidazo[1,2-a]pyridin-3-yl, 6-methylimidazo[1,2-a]pyridin-3-yl, 6-methylimidazo[1,2-a]pyridin-3-yl, 6-fluoroimidazo[1,2-a]pyridin-3-yl, 6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl, 6-chloroimidazo[1,2-a]pyridin-3-yl, pyrazolo[1,5-a]pyrazin-3-yl, pyrazolo[1,5-a]pyrimidin-3-yl, 5,6-dihydro-8H-imidazo[2,1-c][1 [4]Oxazin-3-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-3-yl, pyrazolo[1,5-a]pyridin-3-yl, (4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-3-yl, 5-methoxypyrazolo[1,5-a]pyridin-3-yl, pyrazolo[5,1-b]thiazo-7-yl, 7-methoxyimidazo[1,2-a]pyridin-3-yl, 1-methyl-1H-imidazo[1,2-b]pyrazol-7-yl and imidazo[1,2-a]pyrazin-3-yl.

[0197] In another preferred embodiment, the invention relates to compounds of formula (Ibb), wherein Het is selected from 3-(tert-butyl)-1-(p-tolyl)-1H-pyrazole-5-yl, 3-(tert-butyl)-1-methyl-1H-pyrazole-5-yl, 3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazole-5-yl, 3-(tert-butyl)-1-phenyl-1H-pyrazole-5-yl, 5-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazol-3-yl, 2-(trifluoromethyl)pyridin-4-yl, 6-(trifluoromethyl)pyrimid ... )pyrimidin-4-yl, 4-(trifluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-3-yl, 5-(tert-butyl)isoxazol-3-yl, 3-(tert-butyl)isoxazol-5-yl, 4-(tert-butyl)oxazol-2-yl, 3-cyclobutyl-1-methyl-1H-pyrazole-5-yl, 6-fluoroimidazo[1,2-a]pyridin-3-yl, 6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl, 6-chloroimidazo[1,2-a]pyridin-3-yl, 3-isopropyl-1-methyl-1H-pyrazole-5-yl, 4-(trifluoromethyl)pyrimidin-2-yl, 2 -(tert-butyl)pyridin-4-yl, 3-(tert-butyl)-1-isopropyl-1H-pyrazole-5-yl, 1-methyl-3-propyl-1H-pyrazole-5-yl, 3-(tert-butyl)-1-(2-hydroxyethyl)-1H-pyrazole-5-yl, 3-(tert-butyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-yl, 1-benzyl-3-(tert-butyl)-1H-pyrazole-5-yl, 3-(tert-butyl)-1-ethyl-1H-pyrazole-5-yl, 3-isobutyl-1-methyl-1H-pyrazole-5-yl, 1-methyl-3-(1-(trifluoromethyl)cyclopropyl) 5-(1,1-difluoroethyl)pyridin-3-yl, 5-(tert-butyl)-1-methyl-1H-pyridin-3-yl, 5-(difluoromethoxy)pyridin-3-yl, 3-(tert-amyl)isoxazol-5-yl, 6-methoxy-5-(trifluoromethyl)pyridin-3-yl, 5-(tert-butyl)pyridin-3-yl, 2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-yl, (trifluoromethyl)pyridazine-3-yl, 3-isobutylisoxazol-5-yl, (trifluoromethoxy)pyridin-3-yl and 5-(trifluoromethoxy)pyridin-3-yl.

[0198] In another preferred embodiment, the invention relates to compounds of formula (Ibb), wherein Hy is selected from pyrazolo[1,5-a]pyrazin-3-yl and 6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-3-yl, and Het is selected from 5-(trifluoromethyl)pyridin-3-yl, 3-(tert-butyl)isoxazo-5-yl, 5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl, 6-methoxy-5-( (Trifluoromethyl)pyridin-3-yl, 5-(1,1-difluoroethyl)pyridin-3-yl, 5-(tert-butyl)pyridin-3-yl, 5-(difluoromethoxy)pyridin-3-yl, 5-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazol-3-yl, 5-(trifluoromethoxy)pyridin-3-yl, 5-(tert-butyl)isoxazol-3-yl, 3-(tert-pentyl)isoxazol-5-yl and 3-isobutylisoxazol-5-yl.

[0199] According to a preferred embodiment, the present invention relates to compounds of formula (Ibb) listed in Table 5 below and their pharmaceutically acceptable salts. These compounds are particularly active against receptors DDR1 and DDR2, as shown in Table 6.

[0200] Table 5: List of compounds of formula (Ibb)

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212] In another preferred embodiment, the present invention relates to a compound of formula (I), wherein Rx, Ry and Rz are H.

[0213] In another preferred embodiment, the present invention relates to a compound of formula (I), wherein Rx is H, Ry is methyl, and Rz is H.

[0214] In another preferred embodiment, the present invention relates to a compound of formula (I), wherein Rx is methyl, Ry is H, and Rz is H.

[0215] In another preferred embodiment, the present invention relates to a compound of formula (I), wherein Rx is H, Ry is methyl, and Rz is methyl.

[0216] It will be clearly understood that any compound of the present invention may be included in more than one general formula. For example, but not limited thereto, compounds in which R1 is X' may be included in formulas (Ia) and (Iab).

[0217] The compounds of this invention, including all those listed above, can be prepared from readily available starting materials using the general methods and procedures 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] Furthermore, as shown in this experimental section, the compounds of formula (I) of the present invention have been found to have affinity for DDR1 or DD2 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 Ki and / or IC50 values ​​for DDR1 and DDR2 receptors of less than 50 nM. Even more preferably, the compounds of the present invention have Ki and / or IC50 values ​​for DDR1 and DDR2 receptors of less than 25 nM.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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. More preferably, the compounds of formula (I) of the present invention can be used to treat IPF.

[0228] More preferably, the compound of formula (I) as described above can be used to treat idiopathic pulmonary fibrosis (IPF).

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] Preferably, the compounds of the present invention are administered orally or by inhalation.

[0240] 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.

[0241] In one embodiment, the pharmaceutical composition comprising the compound of formula (I) is a tablet.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] 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.

[0246] 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.

[0247] 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.

[0248] 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.

[0249] The compounds of this invention can be used as the sole active agent or in combination with other pharmaceutical active ingredients.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] The compounds of this invention, including all those listed above, can be prepared from readily available starting materials using the general methods and procedures 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.

[0254] 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.

[0255] 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.

[0256] In a first embodiment of the invention, the compound of formula (I) as defined above, wherein R1, Rx, Ry, Rz, L and Hy, can be prepared as described in Scheme 1.

[0257] 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.

[0258] Option 1

[0259]

[0260] According to Scheme 1, intermediate III can be prepared in a one-step synthesis starting from intermediate II, under suitable ester-forming conditions, in the presence of an alkylating agent such as methyl iodine, using an inorganic base such as cesium carbonate, in a suitable organic solvent such as DMF, at a temperature typically around room temperature, over a period of several hours to overnight. Intermediate III can be converted to intermediate IV by deprotecting the BOC-protected amine under acidic conditions, such as in a concentrated aqueous solution of hydrogen chloride or a dioxane solution of hydrogen chloride, in a suitable solvent such as ethanol or diethyl ether, at room temperature.

[0261] Intermediate V can be prepared in a one-step synthesis starting from intermediate IV and a suitable carboxylic acid under suitable amide coupling conditions, in the presence of an activating carboxylic acid partner 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, and typically at around room temperature. Direct amidation (amid transfer) of the ester can be carried out between intermediate V and intermediate XII or XIII to obtain the compound of formula (I), using, for example, butyllithium as a promoter, in a suitable organic solvent such as THF or dioxane, at a temperature ranging from -78°C to room temperature for several hours. In different methods, intermediate V can be converted to intermediate VI by hydrolysis under alkaline conditions, using, for example, an aqueous solution of sodium hydroxide, in a suitable solvent such as methanol, at room temperature for several hours. Subsequently, intermediate VI reacts with intermediate XII or XIII under suitable amide coupling conditions in the presence of a reagent that activates the carboxylic acid pair, such as TBTU, HATU, or T3P, and then reacts with an amine in the presence of an organic base, such as DIPEA or TEA, in a suitable organic solvent, such as DCM or DMF, and at a temperature typically around room temperature for several hours to overnight.

[0262] Alternatively, compounds of formula (I) can be prepared by an amidation reaction, starting from intermediate VI in the presence of TCFH and 1-methylimidazolium, to give a transiently activated acylimidazolinetonium intermediate, which reacts with a suitable amine XII or XIII in a solvent such as DMF at room temperature. In different methods, starting from intermediate VI at 5°C in the presence of a suitable chlorinating agent such as POCl3 or thionyl chloride in a solvent such as pyridine, the corresponding acyl chloride is given, which is then directly treated in Py at room temperature with a suitable amine XII or XIII to yield compounds of formula (I).

[0263] The compound of formula (I) can also be prepared by starting with intermediate VI to form an acyl chloride in the presence of thionyl chloride at 50 °C, and then reacting it with XXIII in a suitable solvent such as DCM at -78 °C in the presence of a suitable base such as LiHMDS.

[0264] Intermediate VI can be converted into intermediate X by amide coupling with intermediate XIV under the above conditions, and then converted into the compound of formula (I) by silyl deprotection under suitable deprotection conditions such as HCl or TFA in a suitable solvent such as methanol or THF at room temperature.

[0265] In various methods, intermediate VII can be prepared by amide coupling of intermediate VI and intermediate XII under the conditions described above, followed by deprotection of the BOC-protected amine under the same conditions, and final methylation using Eschweiler-Clarke reaction conditions to obtain the compound of formula (I). In various methods, intermediate VII can be converted to intermediate IX by deprotection of the acetal group using a suitable acid such as TFA in a suitable solvent such as DCM at room temperature. Intermediate IX can be converted to the compound of formula (I) by applying reducing amination conditions using a suitable reducing agent such as Na(OAc)3BH or NaCNBH3 in a suitable solvent such as DCM or EtOH, in the presence of an acid such as acetic acid and a ligand such as tetrahydroisopropoxytitanium, at room temperature using a suitable alkylamine.

[0266] In another embodiment, the compound of formula (I) can be prepared according to schemes 2a and 2b.

[0267]

[0268]

[0269] According to scheme 2a, a mixture of intermediates IIIa and IVa can be prepared by refluxing intermediate IIa with ethyl 2-cyanoacetate under Gewald multicomponent cyclization conditions in a suitable solvent such as EtOH using a suitable sulfur source, such as sulfur. The mixture of intermediates IIIa and IVa is then subjected to deamination conditions in a suitable solvent such as THF or acetonitrile at 0°C to reflux temperature using a suitable diazotizing agent such as isoamyl nitrite or isopropyl nitrite. The BOC group is then deprotected at room temperature in an acidic condition, such as a solution of concentrated hydrogen chloride or dioxane in hydrogen chloride, in a suitable solvent such as ethanol or diethyl ether, to yield a mixture of intermediates VIIa and VIIIa. A mixture of intermediates IXa and Xa can be prepared by amide coupling of a mixture of intermediates VIIa and VIIIa with a suitable carboxylic acid in the presence of an activating agent such as TBTU, HATU, or T3P, using an organic base such as DIPEA or TEA in a suitable organic solvent such as DCM or DMF, and typically at approximately room temperature. A mixture of intermediates Xa and IXa can be hydrolyzed at room temperature using a suitable inorganic base such as NaOH or LiOH aqueous solution in a suitable solvent such as MeOH or EtOH. Then, a mixture of intermediates XIIa and XIa is subjected to the above amide coupling conditions with a suitable amine XIIIa or XIVa. Column chromatography using a suitable stationary phase such as silica gel and a suitable mobile phase such as water / acetonitrile, DCM / MeOH, or Hex / AcOEt can separate the compound of formula (I) from the mixture of intermediates XVIa and XVa. In different methods, a mixture of intermediates Va and VIa can be converted into a mixture of intermediates XVIIa and XX by hydrolysis using a suitable inorganic base such as NaOH in a suitable solvent such as EtOH at room temperature. Amid coupling of the mixture of intermediates XVIIa and XVIIIa under the above conditions, followed by deprotection of the BOC group under the above conditions, can convert it into a mixture of intermediates XIXa and XXIIa. The mixture of intermediates XXVIa and XXVa can be obtained by reductive amination at room temperature using a suitable aldehyde XXIIIa with a suitable reducing agent such as Na(OAc)3BH or NaCNBH3 in a suitable solvent such as DCM or EtOH, in the presence of an acid such as acetic acid and a coordinating agent such as titanium tetrahydroisopropoxide.

[0270] In another implementation, the compound of formula (I) can be prepared according to scheme 3.

[0271] Option 3

[0272]

[0273] According to Scheme 3, intermediate XXVIIIa can be obtained by reacting compound IIa with ethyl 2-cyanoethyl acetate under Gewald multicomponent cyclization conditions using a suitable sulfur source such as sulfur, in a suitable solvent such as EtOH, under reflux, followed by suitable column chromatography separation using a suitable stationary phase such as silica gel and a suitable mobile phase such as water / acetonitrile, DCM / MeOH, or Hex / AcOEt. Intermediate XXVIIIa can be deaminated, followed by BOC deprotection, amidation with a suitable acid, hydrolysis of the ethyl ester, and finally amidation with a suitable amine XIIIa or XIVa under the conditions described in Scheme 2b, to convert it into a compound of formula (I).

[0274] In a further preferred embodiment, the compound of formula (I) can be prepared according to scheme 4.

[0275]

[0276] According to scheme 4, intermediate IIIb can be prepared in a one-step synthesis starting from intermediate IIb, under suitable ester-forming conditions, in the presence of an alkylating agent such as methyl iodine, using an inorganic base such as cesium carbonate, in a suitable organic solvent such as DMF, and at a temperature typically around room temperature, over a period of several hours to overnight. Intermediate IIIb can be converted to intermediate IVb by deprotecting a BOC-protected amine under acidic conditions, such as in a concentrated solution of hydrogen chloride or dioxane in a suitable solvent such as ethanol or diethyl ether, at room temperature, and subsequently converted to intermediate Vb by applying reducing amination conditions at room temperature in the presence of a suitable aldehyde, using a suitable reducing agent such as Na(OAc)3BH or NaCNBH3, in a suitable solvent such as DCM or EtOH, in the presence of an acid such as acetic acid. The intermediate Vb is hydrolyzed using a suitable base such as NaOH or LiOH in a suitable solvent such as MeOH or EtOH, followed by amide coupling with a suitable intermediate XIIb or XIIIb under suitable amide coupling conditions, in the presence of an activating agent for the carboxylic acid pair such as TBTU, HATU, or T3P, using 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 obtain the compound of formula (I). Alternatively, starting from intermediate VIb, the corresponding acyl chloride is obtained in the presence of a suitable chlorinating agent such as oxaloyl chloride or thionyl chloride in a solvent such as pyridine at 5°C, which can then be directly treated in Py at room temperature with a suitable amine XIIb or XIIIb to obtain the compound of formula (I).

[0277] In various methods, amide coupling is performed under the conditions described above, or intermediate IIb is reacted in the presence of TCFH and 1-methylimidazolium to yield a transiently activated acylimidazolinetonium intermediate. This intermediate can then be reacted with a suitable amine XIIb or XIIIb in a suitable solvent such as DMF at room temperature to prepare intermediate VIIb. After deprotection of the BOC group, amide coupling with a suitable carboxylic acid is subsequently performed under the conditions described above to prepare a compound of formula (I) from intermediate VIIb.

[0278] In contrast, intermediate VIIIb can be converted into intermediate IXb by reductive amination of an aldehyde protected by a suitable SEM under the aforementioned suitable conditions. It will be apparent to those skilled in the art that if the aldehyde contains a moiety that may interfere with the reaction, this moiety needs to be protected. Using a suitable acid such as acetic acid, in a suitable solvent such as DMF, and applying SEM deprotection conditions to intermediate IXb at room temperature, the compound of formula (I) can be obtained.

[0279] In different methods, intermediate VIIIb can be converted into intermediate Xb by amide coupling with intermediate XIb under the conditions described above. Xb can then be converted into the compound of formula (I) by alkylation with a suitable alkyl halogroup, such as chloroethylmorpholine, using a suitable inorganic base, such as potassium carbonate, in a suitable solvent, such as DMF. Alternatively, using a suitable inorganic base, such as potassium carbonate or sodium carbonate, a suitable catalyst, such as Pd(dppf)Cl2, in a suitable organic solvent, such as DMF or DMA, at 100°C, using a suitable boron reagent, such as 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,2,3,6-tetrahydropyridine, under Suzuki coupling conditions, the compound of formula (I) can be obtained from intermediate Xb.

[0280] In contrast, using the aforementioned amide coupling conditions and a suitable acid, the compound of formula (I) can be obtained from intermediate VIIa. Alternatively, by using a suitable aldehyde and a suitable reducing agent such as Na(OAc)3BH or NaCNBH3, in a suitable solvent such as DCM or EtOH, in the presence of an acid such as acetic acid and a coordinating agent such as titanium tetrahydroisopropoxide, at room temperature, the compound of formula (I) can be prepared from intermediate VIIIb through reductive amination.

[0281] 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.

[0282] Preparation of intermediates and examples

[0283] 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.

[0284] In the subsequent methods, some starting materials are identified by "intermediate" or "example" designations, and step numbers are indicated. This is only to assist those skilled in the art.

[0285] "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.

[0286] Abbreviation - Meaning

[0287] ACN = Acetonitrile; Et2O = Diethyl ether; DCM = Dichloromethane; DMF = N,N-Dimethylformamide; CPME = Cyclopentylmethyl ether; AcOEt = Ethyl acetate; EtOH = Ethanol; MeOH = Methanol; THF = Tetrahydrofuran; HCOOH = Formic acid; FA = Formic acid; AcOH = Acetic acid; TFA = Trifluoroacetic acid; DIPEA = N,N-Diisopropylethylamine; TEA = Triethylamine; Py = Pyridine; Boc2O = Di-tert-butyl dicarbonate; HAT U = (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylimine hexafluorophosphate; TBTU = 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate; T3P = propylphosphonic anhydride; HOBt = 1-hydroxybenzotriazole hydrate; TCFH = chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate; n-BuLi = n-butyllithium; XPhos Pd G3 = (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II); Xphos Pd G2 = (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II); Xphos = 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; RT = room temperature; FCC = rapid column chromatography; MeOH-d4 = deuterated methanol; DMSO-d6 = deuterated dimethyl sulfoxide; CDCl3 = deuterated chloroform; ACN-d3 = deuterated acetonitrile; NMR = nuclear magnetic resonance; LC-MS = liquid chromatography / mass spectrometry; ESI = electrospray ionization; Prep HPLC = Preparative High Performance Liquid Chromatography; SCX = Solid Cation Exchange; SM = Starting Material; DP = Desired Product; wt = Weight; ee = Enantiomer Excess; SEM-Cl = 2-(Trimethylsilyl)ethoxymethyl chloride; PyBOP = Benzotriazol-1-yl-oxy-tri-pyrrolidinyl-phosphonium hexafluorophosphate; Pd2(dba)3 = Tris(dibenzylideneacetone)dipalladium(O); NaBH3CN = Sodium cyanoborohydride; Pd-PEPPSI (TM)-IPent = [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II); Pd(dppf)Cl2·DCM = [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane complex; BINAP = 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; XantPhos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthones.

[0288] General Experimental Details

[0289] NMR characterization:

[0290] 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. 1 1H 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).

[0291] In some cases, the signal NH from amide or amine bonds (exchangeable protons) is not visible.

[0292] In rare cases, some signals may be hidden beneath the signals of water or DMSO or other residual solvents.

[0293] LC / UV / MS analysis methods

[0294] The estimated LC / MS retention time is affected by an experimental error of ±0.5 min.

[0295] 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.

[0296] Method 2: XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25 °C. Mobile phase: water (0.1% formic acid) in ACN (0.1% formic acid), 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 MSQ Plus with DAD detector.

[0297] Method 3: XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25 °C. Mobile phase: water (0.1% formic acid) in ACN (0.1% formic acid), from 80% to 5% in 3.90 min; flow rate: 1.0 mL / min; wavelength: 190–340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQ Plus with DAD detector.

[0298] Method 4: XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25 °C. Mobile phase: water (0.1% formic acid) in ACN (0.1% formic acid), from 70% to 5% in 3.90 min; flow rate: 1.0 mL / min; wavelength: 190–350 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific ISQ EC mass spectrometer with DAD detector.

[0299] Method 5: Acquity UPLC BEH C18 column, 100 x 2.1 mm, 1.7 μm, maintained at 40 °C. Mobile phase: ACN (0.03% ammonia) in water (0.03% ammonia), 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.

[0300] Method 6: 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.

[0301] Method 7: 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% formic acid) in water (0.1% formic acid), from 5% to 95% in 5.6 min. Flow rate: 0.4 mL / min. Wavelength: 210-400 nm. UPLC + Waters DAD + Waters SQD2, single quadrupole UPLC-MS.

[0302] Method 8: XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25 °C. Mobile phase: water (0.1% formic acid) in ACN (0.1% formic acid), from 90% to 5% in 3.90 min; flow rate: 1.0 mL / min; wavelength: 190–340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQ Plus with DAD detector.

[0303] Method 9: XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25 °C. Mobile phase: water (0.1% formic acid) in ACN (0.1% formic acid), from 90% to 5% in 3.90 min; flow rate: 1.0 mL / min; wavelength: 190–340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQ Plus with DAD detector.

[0304] Method 10: Gemini-NX C18 column, 4.6 x 150 mm, 3 μm, maintained at 35 °C. Mobile phase: water (0.1% formic acid) in ACN (0.1% formic acid), from 80% to 5% in 8.50 min; flow rate: 1.0 mL / min; wavelength: 190–340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQ Plus with DAD detector.

[0305] Method 11: Gemini-NX C18 column, 4.6 x 150 mm, 3 μm, maintained at 35 °C. Mobile phase: water (0.1% formic acid) in ACN (0.1% formic acid), from 65% to 5% in 8.50 min; flow rate: 1.0 mL / min; wavelength: 190–340 nm DAD. Dionex UHPLC Ultimate 3000 / Thermo Scientific MSQ Plus with DAD detector.

[0306] Method 12: Lux C1 column, 4.6 x 150 mm, 5 μm, maintained at room temperature. Mobile phase: 90:10 ACN:IPA, under isocratic conditions; flow rate: 1.0 mL / min; wavelength: 254 nm. Waters / Thar SFC system with Waters SQD.

[0307] Method 13: Amy-C column, 4.6 x 250 mm, 5 μm, maintained at 40 °C. Mobile phase: 25:75 MeOH:CO2 (0.2% v / v NH3), under isocratic conditions; flow rate: 4.0 mL / min, 125 Bar back pressure; wavelength: 210-400 nm. Waters / Thar SFC system with Waters SQD.

[0308] Method 14: Agilent Zorbax column, 4.6 x 50 mm, 3.5 μm, maintained at 40 °C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid), from 40% to 100% 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.

[0309] Method 15: Acquity BEH UPLC column, 2.1 x 50 mm, 1.7 μm, maintained at 40 °C. Mobile phase: MeCN (0.03% ammonia) in water (0.03% ammonia), 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.

[0310] Method 16: Waters Sunfire C18 column, 4.6 x 50 mm, 3.5 μm, maintained at 40 °C. Mobile phase: MeCN in water + 10 mM ammonium bicarbonate, from 5% to 95% in 2.5 min. Flow rate: 2.0 mL / min. Wavelength: 210-400 nm. DAD. Waters 2795 separation module + Waters DAD + Micromass ZQ, single quadrupole LC-MS.

[0311] Method 17: Agilent Zorbax column, 4.6 x 50 mm, 3.5 μm, maintained at 40 °C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid), 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.

[0312] LC / SFC chiral preparation method

[0313] Method prep1: Separation was performed on a Gilson preparative LC system (Gilson Pump 333; Gilson 151; Gilson Valvemate 6-position) using a Lux C1 (21.2 mm x 250 mm, 5 μm) column and isocratic operation at 21 mL / min (90 / 10 ACN: i-PrOH, 0.2% v / v NH3), with the column kept at room temperature; wavelength: 210 nm.

[0314] Method prep2: SFC-MS separation was performed on an AmyC (20 mm x 250 mm, 5 μm) column and at an isocratic rate of 50 mL / min (70 / 30 MeOH:CO2, 0.2% v / v NH3, 125 Bar back pressure) on a Gilson preparative LC system (Gilson Pump-333; Gilson 151; Gilson Valvemate 6-position). The column was maintained at 40 °C. Wavelength: 210 nm.

[0315] Method prep3: SFC-MS separation was performed on a Gilson preparative LC system (Gilson Pump-333; Gilson 151; Gilson Valvemate 6-position) using a Lux A1 (21.2 mm x 250 mm, 5 μm) column and isocratic runs at 50 mL / min (40 / 60 MeOH:CO2, 0.2% v / v NH3, 100 Bar back pressure), with the column maintained at 40 °C. Wavelength: 210 nm.

[0316] 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 procedures. All solvents were purchased from commercial sources and used without additional purification.

[0317] The compound was purified by reversed-phase HPLC using a Waters Fractionlynx preparative HPLC system (2525 pump, 2996 / 2998 UV / VIS detector, 2767 liquid processor) or a Gilson preparative HPLC system (322 pump, 155 UV / VIS detector, GX-281 liquid processor) or an equivalent system, 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 residual fractions containing the desired product were combined (identified by TLC and / or LCMS analysis), and the solvent was removed under reduced pressure or lyophilized; alternatively, extraction with SCX(NH) was performed.

[0318] The specific details of the conditions used, including the column, solvent, gradient, and modifier (acidic or basic), are provided for example purposes and are only for assistance. When specific conditions are not provided, those skilled in the art can readily optimize them.

[0319] 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 performed on Interchim PuriFlash 450 and 520Plus plates, or using the Biotage SPA purification system, or using equivalent MPLC with pre-packed silica gel columns.

[0320] General Synthesis Method

[0321] General Method A

[0322] Under an inert atmosphere, sodium hydride (60% from mineral oil, 1.10 eq) was added to a stirred solution of the desired alcohol (1.20 eq) in ACN (0.5 M concentration). The reaction mixture was stirred for 1 h, and then the desired aryl-fluoride (1.00 eq) was added in one batch. The reaction mixture was stirred at room temperature until LCMS indicated that the starting material had been consumed. The reaction mixture was partitioned between water and DCM, and the aqueous phase was re-extracted with DCM (x2). The combined organic phases were filtered through a hydrophobic glass frit and concentrated under vacuum.

[0323] General Method B

[0324] The desired aryl-nitro (1.00 eq) and iron powder (5.00 eq) were combined in acetic acid (0.3 M) and methanol (0.3 M). The reaction mixture was stirred at 50 °C until LCMS indicated that the starting material was consumed. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was partitioned between DCM and saturated Na₂CO₃ (aq). The combined organic phases were filtered through a hydrophobic glass frit and concentrated under vacuum.

[0325] General Method C

[0326] Add the desired amine (1.10 eq), titanium isopropoxide (IV) (2.00 eq), and acetic acid (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 sodium triacetoxyborohydride (2.00 eq) and stir the reaction mixture at room temperature until LCMS indicates that the starting material has been consumed. Partition the reaction mixture between DCM and saturated NaHCO3 (aq), and filter the mixture through a diatomaceous earth bed. Extract the aqueous phase with 2x DCM, wash the combined organic phases with a saturated aqueous NaCl solution (aq), pass through a hydrophobic glass frit, and concentrate under vacuum.

[0327] General Method D

[0328] Add the desired nitro-aryl (1.00 eq) solution in EtOH (0.1 M concentration) to palladium (10% on carbon) (10 wt%). Evacuate the flask and purge with argon (x3), then evacuate and purge with hydrogen (x3). Stir the reaction mixture at room temperature until LCMS indicates that the starting material has been consumed. Dilute the reaction mixture with DCM and filter through diatomaceous earth. Wash the filter cake with DCM and concentrate the combined filtrates under vacuum.

[0329] General Method E

[0330] Add the desired alkyl halide (1.20 eq) to a solution of the desired phenol (1.00 eq) in DMF (0.2 M concentration), followed by cesium carbonate (2.00 eq). Stir the mixture at 80 °C until LCMS shows complete consumption of the starting material. Dilute the reaction mixture with water and extract with DCM (x2). Combine and concentrate the organic phases.

[0331] General Method F

[0332] Under a nitrogen atmosphere, 1-methyl-1,4-cyclohexadiene (30.0 eq) and palladium on carbon (10%) (1.00 eq) were added sequentially to a solution of the desired nitro-aryl group (1.00 eq) in ethanol (0.1 M). The mixture was stirred at 80 °C until the LCMS indicated that the starting material had been consumed. The reaction mixture was cooled to room temperature and filtered through a diatomaceous earth filter, which was washed with EtOH and AcOEt. The filtrate was concentrated under reduced pressure.

[0333] General method G

[0334] Add DIPEA (3.00 to 8.00 eq) to a mixture of the desired sodium carboxylate or acid (1.00 eq) and HATU (1.20 to 2.00 eq) in DMF / DCM (0.1 M concentration). Stir the reaction mixture at room temperature for 15 min, then add the desired amine (1.00 to 2.00 eq). Stir the reaction mixture at room temperature until the LCMS indicates that the starting material has been consumed, then concentrate.

[0335] General Method H

[0336] 1.00 eq of 6-(imidazo[1,2-a]pyridine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid was suspended in 10.0 eq of thionyl chloride, and the reaction mixture was stirred at 50 °C for 20 min. Another 10.0 eq of thionyl chloride was added, and the reaction mixture was stirred at 50 °C for 30 min. The reaction mixture was concentrated under vacuum to give 6-(imidazo[1,2-a]pyridine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic chloride as a white solid. Add 1.30 eq of 6-(imidazo[1,2-a]pyridin-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridin-3-formyl chloride to a DCM (0.1 M) solution of the desired aniline (1.00 eq) and TEA (3.00 eq). Stir the reaction mixture at room temperature until LCMS shows complete consumption of the starting material, and then concentrate under vacuum.

[0337] General Method I

[0338] The desired carboxylic acid (1.00 eq) was suspended in thionyl chloride (0.21 mL, 2.93 mmol, 30.0 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 reconcentrated to give the intermediate acyl chloride. The acyl chloride was added to a solution of the desired aniline (1.00 eq) and DMAP (0.20 eq) in pyridine (0.1 M concentration), followed by the addition of DIPEA (3.00 eq). The reaction mixture was stirred at 40 °C until LCMS indicated that the starting material had been consumed, and then concentrated under vacuum.

[0339] General Method J

[0340] Add the desired amine (1.10 eq), titanium isopropoxide (IV) (2.00 eq), and acetic acid (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 sodium triacetoxyborohydride (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 methanol, and then release with 2 M NH3 / MeOH. Concentrate the eluent under vacuum.

[0341] General Method K

[0342] Titanium isopropoxide (IV) (3.00 eq) was added to a methanol (0.03 M) solution of the desired amine (1.00 eq) and the desired aldehyde (1.00 eq) and refluxed for 2 h. The reaction was cooled to room temperature, and NaBH3CN (2.50 eq) was added. The mixture was stirred overnight at room temperature. The reaction was quenched with water, filtered through diatomaceous earth, and concentrated under vacuum.

[0343] General Method L

[0344] Acetic acid (9.86 eq) was added to a mixture of the desired aldehyde (1.00 eq) and N-[3-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-6-onthium-3-carboxamide hydrochloride (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 triacetoxyborohydride (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 10% KHSO4 (aq) solution. After stirring for 15 min, the mixture was alkalized with saturated Na2CO3 (aq), and the layers were separated. The aqueous layer was extracted with DCM, the combined organic extracts were filtered through a hydrophobic glass frit, and concentrated under vacuum.

[0345] General Method M

[0346] Add DIPEA (3.00 eq) and HATU (1.20 eq) to a DMF (0.1 M) solution of the desired carboxylic acid (1.10 eq). Stir the reaction mixture at room temperature for 30 min. Then, add N-[3-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide hydrochloride (1.00 eq) and stir the reaction mixture overnight at 40 °C. Cool the reaction mixture to room temperature and concentrate.

[0347] General Method N

[0348] 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.

[0349] Preparation of 4-((tetrahydrofuran-3-yl)oxy)-3-(trifluoromethyl)aniline - intermediate 1

[0350]

[0351] Step 1: 3-(4-nitro-2-(trifluoromethyl)phenoxy (intermediate 2)

[0352]

[0353] The title compound (1.52 g, 99%) was prepared by general method A from 3-hydroxytetrahydrofuran (0.53 g, 6.00 mmol) and 2-fluoro-5-nitrotrifluorotoluene (0.69 mL, 5.00 mmol).

[0354] 1 H NMR (400MHz, CDCl3) δ8.52(d,J=3.0Hz,1H),8.42(dd,J=3.0,9.0Hz,1H),7.03(d,J=9. 0Hz,1H),5.16-5.12(m,1H),4.15-4.11(m,1H),4.03-3.97(m,3H),2.35-2.19(m,2H).

[0355] Step 2: 4-((tetrahydrofuran-3-yl)oxy)-3-(trifluoromethyl)aniline (intermediate 1)

[0356] Intermediate 2 (1.52 g, 5.48 mmol) was prepared according to General Method B. The residue was loaded onto an Isolute SCX-II column, washed with DCM / MeOH, and then released with 2 MNH3 / MeOH. The eluent was concentrated to give the title compound (1.10 g, 75%).

[0357] 1H NMR (400MHz, CDCl3) δ6.91 (d, J = 2.0Hz, 1H), 6.79-6.79 (m, 2H), 4.92-4.87 (m, 1H), 4.04-3.90 (m, 4H), 3.56 (s, 2H), 2.18-2.10 (m, 2H).

[0358] The intermediates reported in the table below were prepared by aromatic nucleophilic substitution as described in steps 1-2 of intermediate 1, using the corresponding commercially available alcohol in step 1.

[0359]

[0360]

[0361] Preparation of 2-(4-amino-2-(trifluoromethyl)phenoxy)ethyl-1-ol intermediate 8

[0362]

[0363] Step 1: 2-(4-nitro-2-(trifluoromethyl)phenoxy)ethanol-1-ol (intermediate 9)

[0364]

[0365] Under an inert atmosphere, 2-fluoro-5-nitrotrifluorotoluene (0.69 mL, 5.00 mmol, 1.00 eq), potassium tert-butoxide (1.23 g, 11.0 mmol, 2.20 eq), and ethylene glycol (11 mL, 0.200 mol, 40.0 eq) were combined in THF (10.00 mL). The reaction mixture was heated at 70 °C for 1 h, then cooled to room temperature and poured into ice / HCl (aq). The mixture was allowed to stand for 1 h and filtered. The resulting solid was washed with water and dried under vacuum to give the title compound (1.16 g, 92%).

[0366] 1 H NMR (400MHz, CDCl3) δ8.52(d,J=2.5Hz,1H),8.43(dd,J=2.8,9.1Hz,1H),7.13(d ,J=9.1Hz,1H),4.30(t,J=4.3Hz,2H),4.08-4.02(m,2H),2.02(t,J=6.5Hz,1H).

[0367] Step 2: 2-(4-amino-2-(trifluoromethyl)phenoxy)ethanol-1-ol (intermediate 8)

[0368] The title compound (0.98 g, 89%) was prepared from intermediate 9 (1.16 g, 4.62 mmol) according to general method B.

[0369] 1 H NMR (400MHz, CDCl3) δ6.89 (m, 1H), 6.85 (m, 1H), 6.81-6.76 (m, 1H), 4.07 (t, J = 4.5Hz, 2H), 3.92 (t, J = 4.5Hz, 2H), 3.55 (s, 2H).

[0370] Preparation of 3-((dimethylamino)methyl)-5-(trifluoromethyl)aniline (intermediate 10)

[0371]

[0372] Step 1: N,N-Dimethyl-1-(3-nitro-5-(trifluoromethyl)phenyl)methylamine (Intermediate 11)

[0373]

[0374] The compound was prepared according to general method C from 3-nitro-5-(trifluoromethyl)benzaldehyde (200 mg, 0.913 mmol) and dimethylamine (2 M solution in THF, 0.50 mL, 1.00 mmol). Purification was performed by silica gel column chromatography (12 g column, 0–2.5% 2 M NH3 in MeOH, in DCM) to give the title compound (84 mg, 37%).

[0375] 1 H NMR (400MHz, CDCl3) δ8.41-8.37(m,2H),7.95(s,1H),3.58(s,2H),2.29(s,6H).

[0376] Step 2: 3-((dimethylamino)methyl)-5-(trifluoromethyl)aniline (intermediate 10)

[0377] The title compound (67 mg, 91%) was prepared from intermediate 11 (84 mg, 0.338 mmol) according to general method D.

[0378] 1 H NMR (400MHz, CDCl3) δ6.93(s,1H),6.82(s,1H),6.80(s,1H),3.82(s,2H),3.36(s,2H),2.24-2.24(m,6H).

[0379] The intermediates reported in the table below were prepared by aromatic nucleophilic substitution as described in steps 1-2 of intermediate 10, using the corresponding commercially available amine in step 1.

[0380]

[0381]

[0382] Preparation of 3-(2-morpholinoethoxy)-5-(trifluoromethyl)aniline (intermediate 15)

[0383]

[0384] Step 1: 4-(2-(3-nitro-5-(trifluoromethyl)phenoxy)ethyl)morpholine (intermediate 16)

[0385]

[0386] The compound was prepared from 4-(2-chloroethyl)morpholine hydrochloride (431 mg, 2.32 mmol) according to general method E. The residue was purified by silica gel column chromatography (40 g column, 0-100% AcOEt in cyclohexane) to give the title compound (0.6 g, 97%).

[0387] 1 H NMR (400MHz, DMSO-d6) δ8.05(d,J=2.5Hz,2H),7.81(s,1H),4.34(dd,J=5.6,5.6Hz,2H),3.58(dd ,J=4.6,4.6Hz,4H),2.74(dd,J=5.6,5.6Hz,2H),2.52(s,4H),2.51(ddd,J=5.5,5.5,4.3Hz,4H).

[0388] Step 2: 3-(2-morpholinoethoxy)-5-(trifluoromethyl)aniline (intermediate 15)

[0389] The title compound (84 mg, 93%) was prepared from intermediate 16 (100 mg, 0.312 mmol) according to general method F and used without further purification.

[0390] 1 H NMR (400MHz, CDCl3) δ6.52(d,J=9.5Hz,2H),6.36(t,J=2.0Hz,1H),4.09(t,J=5.6 Hz, 2H), 3.83 (s, 2H), 3.75-3.72 (m, 4H), 2.79 (t, J = 5.7Hz, 2H), 2.59-2.55 (m, 4H).

[0391] The intermediates reported in the table below were prepared by nucleophilic substitution as described in steps 1-2 of intermediate 15, using the corresponding commercially available alkyl chloride in step 1.

[0392]

[0393] Preparation of 4-(pyrrolidone-1-ylmethyl)-3-(trifluoromethyl)aniline (intermediate 20)

[0394]

[0395] Step 1: 3-(trifluoromethyl)-4-vinylaniline (intermediate 21)

[0396]

[0397] A mixture of 4-bromo-3-(trifluoromethyl)aniline (2.50 g, 10.4 mmol, 1.00 eq), XPhos (497 mg, 1.04 mmol, 0.100 eq), XPhos Pd G2 (410 mg, 0.521 mmol, 0.05 eq), and K3PO4 (5.53 g, 26.0 mmol, 2.50 eq) was suspended in 1,4-dioxane (45.00 mL) and water (5.00 mL) and sonicated with argon for 10 min. Vinylboronic acid pinacol ester (2.1 mL, 12.5 mmol, 1.20 eq) was added, and the reaction mixture was stirred at 80 °C under an argon atmosphere for 7 h. The reaction mixture was cooled to room temperature, partitioned between AcOEt and water, and the aqueous layer was re-extracted with AcOEt. The combined organic phases were washed with brine, dried (Na2SO4), and concentrated under vacuum. The residue was purified by silica gel column chromatography (80 g column, 0-30% AcOEt in cyclohexane) to give the title compound (1.12 g, 57%).

[0398] 1 H NMR(400MHz, CDCl3) δ7.48(d,J=8.5Hz,1H),7.04-6.93(m,1H),6.91(d,J=2.5Hz,1H),6.7 8(dd,J=2.5,8.5Hz,1H) 5.58(d,J=17.5Hz,1H),5.22(dd,J=1.0,11.0Hz,1H),3.87(s,2H).

[0399] Step 2: (3-(trifluoromethyl)-4-vinylphenyl) tert-butyl carbamate (intermediate 22)

[0400]

[0401] Boc₂O (1.7 mL, 7.48 mmol, 1.25 eq) was added to a solution of intermediate 21 (1.12 g, 5.98 mmol, 1.00 eq) in toluene (12.00 mL) at room temperature. The reaction mixture was stirred at 100 °C for 6 h and then concentrated under vacuum. The residue was purified by silica gel column chromatography (80 g column, 0-20% AcOEt in cyclohexane) to give the title compound.

[0402] 1 H NMR (400MHz, CDCl3) δ7.66(d,J=2.0Hz,1H),7.59(d,J=8.5Hz,1H),7.51(d,J=8.5Hz,1H) ,7.08-6.97(m,1H),6.59(s,1H),5.67(d,J=17.5Hz,1H),5.35-5.29(m,1H),1.53(s,9H).

[0403] Step 3: (4-Formyl-3-(trifluoromethyl)phenyl)tert-butyl carbamate (intermediate 23)

[0404]

[0405] O3 / O2 was bubbled through a solution of intermediate 22 (1.72 g, 5.99 mmol, 1.00 eq) in DCM (60.00 mL) for 45 min at -78 °C to give a green reaction mixture. DMSO (440 μL, 5.99 mmol, 1.00 eq) was added, and the reaction mixture was heated to room temperature while being purged with argon. The reaction mixture was concentrated under vacuum, and the residue was purified by silica gel FCC (80 g column, 0-20% AcOEt in cyclohexane) to give the crude title compound (1.19 g, 39%).

[0406] 1 H NMR (400MHz, CDCl3) δ10.27 (d, J = 1.94 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 1.94 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 6.87 (s, 1H).

[0407] Step 4: (4-(pyrrolidone-1-ylmethyl)-3-(trifluoromethyl)phenyl)tert-butyl carbamate (intermediate 24)

[0408]

[0409] The title compound (317 mg, 89%) was obtained from intermediate 23 (298 mg, 1.03 mmol) and pyrrolidine (0.095 mL, 1.13 mmol) according to general method C.

[0410] 1 H NMR(400MHz, CDCl3) δ7.69(d,J=8.5Hz,1H),7.65(d,J=2.0Hz,1H),7.49(m,1H),6 .54-6.52(m,1H),3.74(s,2H),2.58-2.51(m,4H),1.82-1.77(m,4H),1.52(s,9H)

[0411] Step 5: 4-(pyrrolidone-1-ylmethyl)-3-(trifluoromethyl)aniline (intermediate 20)

[0412] A solution of 4M HCl in dioxane (1.5 mL, 6.00 mmol, 6.56 eq) was added to a solution of intermediate 24 (315 mg, 0.915 mmol, 1.00 eq) in MeOH (6.10 mL). The reaction mixture was stirred at room temperature for 66 h. The reaction mixture was then evaporated under vacuum to give a quantitative yield of the hydrochloride salt of the title compound.

[0413] 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),7.66(d,J=9.0Hz,1H),6.98(d,J=2.5Hz,1H),6.87(d d,J=2.0,8.5Hz,1H),4.28(d,2H),3.43-3.36(m,2H),3.11-3.02(m,2H),2.03-1.88(m,4H)

[0414] The intermediates reported in the table below were prepared by reductive amination as described in steps 1-5 of intermediate 20, using the corresponding commercially available amine in step 4.

[0415]

[0416] The intermediates reported in the table below were prepared by Suzuky coupling as described in steps 1-5 of intermediate 24, using the corresponding commercially available aryl bromides in step 1. Catalyst modifications are reported in the table below.

[0417]

[0418] Preparation of 4-((dimethylamino)methyl)-3-(trifluoromethyl)aniline (intermediate 27)

[0419]

[0420] Step 1: N,N-Dimethyl-1-(4-nitro-2-(trifluoromethyl)phenyl)methylamine (Intermediate 28)

[0421]

[0422] The title compound (132 mg, 93%) was prepared according to general method C from 4-nitro-2-(trifluoromethyl)benzaldehyde (125 mg, 0.570 mmol) and dimethylamine (2 M solution in THF, 0.31 mL, 0.628 mmol).

[0423] 1 H NMR (400MHz, CDCl3) δ8.50(d,J=2.2Hz,1H),8.38(dd,J=2.3,8.6Hz,1H),8.10(d,J=8.6Hz,1H),3.68(s,2H),2.30(s,6H)

[0424] Step 2: 4-((dimethylamino)methyl)-3-(trifluoromethyl)aniline (intermediate 27)

[0425] The title compound (104 mg, 90%) was prepared from intermediate 28 (132 mg, 0.532 mmol) according to general method D.

[0426] 1 H NMR (400MHz, CDCl3) δ7.45 (d, J = 8.5 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.81 (dd, J = 2.4, 8.3 Hz, 1H), 3.78 (s, 2H), 3.45 (s, 2H), 2.24 (s, 6H).

[0427] Preparation of tert-butyl 3-(3-amino-5-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (intermediate 29)

[0428]

[0429] 3-(3-nitro-5-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 30)

[0430]

[0431] A mixture of tributylphosphine (0.90 mL, 3.62 mmol, 1.50 eq) and diisopropyl azodicarbonate (0.71 mL, 3.62 mmol, 1.50 eq) in 10 mL of THF was stirred for 20 min at 0 °C. Then, a mixture of 3-nitro-5-(trifluoromethyl)phenol (500 mg, 2.41 mmol, 1.00 eq) and N-Boc-3-pyrrolidone (678 mg, 3.62 mmol, 1.50 eq) in 10 mL of THF was added dropwise. The reaction mixture was stirred at room temperature for 3 days and then concentrated under vacuum. The crude substance was purified by silica gel column chromatography (25 g column, 0-100% AcOEt in cyclohexane) to give the title compound (367 mg, 67% yield).

[0432] 1 H NMR (400MHz, CDCl3) δ8.10 (s, 1H), 7.89-7.86 (m, 1H), 7.44 (d, J = 4.8Hz, 1H), 5.05-4.94 (m, 2H), 3.74-3.49 (m, 5H), 2.22-2.21 (m, 2H), 1.48 (s, 9H).

[0433] 3-(3-amino-5-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 29)

[0434] Intermediate 30 (300 mg, 0.805 mmol) was prepared according to general method F. The preparation was performed by reversed-phase preparative HPLC. Purified by C18 19x150mm, 10um 40-100% ACN / H2O (0.1% FA), 20mL / min, RT, to give the title compound (170mg, 61%).

[0435] 1 H NMR (400MHz, CDCl3) δ6.52(s,1H),6.48(s,1H),6.33-6.30(m,1H),4.89-4.83(m,1H),3.65-3.43(m,4H),2.22-2.11(m,2H),1.46(s,9H).

[0436] Preparation of 3-(tert-butyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-5-amine (Intermediate 31)

[0437]

[0438] Step 1: 2-(5-amino-3-(tert-butyl)-1H-pyrazol-1-yl)ethanol-1-ol (intermediate 32)

[0439]

[0440] A solution of 4,4-dimethyl-3-oxopentanilonitrile (5.00 g, 39.9 mmol), 2-hydroxyethylhydrazine (3.0 mL, 43.9 mmol), and concentrated HCl (37%) (0.10 mL, 1.21 mmol) was stirred at 90 °C under a nitrogen atmosphere for 23 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The remaining oily solid was prepared in cyclohexane (30 mL), the solvent was decanted, and the residue was dried under vacuum to give the title compound (7.082 g, 97%).

[0441] 1 H NMR (400MHz, CDCl3) δ5.43 (s, 1H), 4.02-3.95 (m, 4H), 3.64 (brs, 2H), 1.25 (s, 9H).

[0442] Step 2: 3-(tert-butyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-5-amine (Intermediate 31)

[0443] Imidazole (7.89 g, 0.116 mol) was added to a solution of intermediate 32 (7.08 g, 38.6 mmol) in DMF (63.00 mL) under nitrogen atmosphere and stirred at room temperature. Tert-butylchloro-dimethylsilane (8.74 g, 58.0 mmol) was added in three fractions, and the reaction mixture was stirred at room temperature for 2 h. The mixture was cooled on an ice / water bath, and saturated NH4Cl (aq) (60 mL) was slowly added. DCM (70 mL) was added, and the aqueous phase was diluted with water (100 mL). The aqueous phase was extracted with 3x DCM, and the combined organic phases were washed with 3x 5% LiCl (aq), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum and purified by silica gel column chromatography (AcOEt / cyclohexane from 0% to 50%) to give the title compound (8.905 g, 77%).

[0444] 1 H NMR (400MHz, CDCl3) δ5.36 (s, 1H), 4.07 (t, J = 4.7Hz, 2H), 3.90 (t, J = 4.7Hz, 2H), 3.85 (s, 2H), 1.25 (s, 9H), 0.83 (s, 9H), -0.04 (s, 6H).

[0445] Preparation of 3-(dimethoxymethyl)-5-(trifluoromethyl)aniline (intermediate 33)

[0446]

[0447] Step 1: 1-(dimethoxymethyl)-3-nitro-5-(trifluoromethyl)benzene (intermediate 34)

[0448]

[0449] To a solution of 3-nitro-5-(trifluoromethyl)benzaldehyde (2.00 g, 9.13 mmol, 1.00 eq) in MeOH (25.00 mL), p-toluenesulfonic acid monohydrate (864 mg, 4.54 mmol, 0.498 eq) and trimethyl orthoformate (2.9 mL, 26.5 mmol, 2.90 eq) were added. The reaction mixture was stirred at 65 °C for 66 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was partitioned between AcOEt and a saturated aqueous solution of Na₂CO₃ (aq), and the aqueous phase was extracted with 2xAcOEt. The combined organic extracts were dried (Na₂SO₄) and the solvent was evaporated under vacuum to give the title compound in quantitative yield (2.42 g).

[0450] 1 H NMR (400MHz, CDCl3) δ8.53(1H,s),8.47(1H,s),8.08(1H,s),5.53(1H,s),3.37(6H,s)

[0451] Step 2: 3-(dimethoxymethyl)-5-(trifluoromethyl)aniline (intermediate 33)

[0452] Iron powder (3.35 g, 60.0 mmol, 5.00 eq) was added to a solution of intermediate 34 (3.18 g, 12.0 mmol, 1.00 eq) in MeOH (15.00 mL) and acetic acid (15.00 mL). The reaction mixture was stirred vigorously at room temperature for 4 h. The reaction mixture was removed from the iron powder and concentrated under vacuum. The filtrate was dissolved in Et₂O (30 mL), washed with saturated NaHCO₃ (aq), and the aqueous phase was extracted with 2x Et₂O. The combined organic phases were washed with brine, dried (Na₂SO₄), and evaporated under vacuum to give the title compound (1.80 g, 64%).

[0453] 1 H NMR (400MHz, CDCl3) δ7.10(1H,s),6.92(1H,s),6.84(1H,s),5.32(1H,s),4.832H,br s),3.32(6H,s).

[0454] Preparation of 5-(trifluoromethoxy)pyridine-3-amine hydrochloride (intermediate 86)

[0455]

[0456] Step 1: N-[5-(trifluoromethoxy)-3-pyridyl]tert-butyl carbamate (intermediate 87)

[0457]

[0458] A mixture of tert-butyl carbamate (102 mg, 0.868 mmol), XantPhos (63 mg, 0.108 mmol), tris(dibenzylacetone)dipalladium(O)-chloroform adduct (37 mg, 0.0362 mmol), and cesium carbonate (283 mg, 0.868 mmol) in 1,4-dioxane (5 mL) was degassed with nitrogen and treated with 3-bromo-5-(trifluoromethoxy)pyridine (175 mg, 0.723 mmol). The reaction 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 gel column chromatography (0–100%, EtOAc in cyclohexane) and then dried under vacuum overnight to give the title compound (115 mg, 0.413 mmol, 57%).

[0459] 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).

[0460] Step 2: 5-(trifluoromethoxy)pyridine-3-amine hydrochloride (intermediate 86)

[0461] A solution of 4N hydrogen chloride in dioxane (3.0 mL, 0.413 mmol) was added to a solution of intermediate 87 (115 mg, 0.413 mmol) in 1,4-dioxane (3 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with diethyl ether (20 mL) and filtered to give a white solid, which was washed with diethyl ether and dried under vacuum to give the title compound (60 mg, 0.280 mmol, 68%).

[0462] 1 H NMR (400MHz, DMSO-d6) δ 8.07 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 1.5 Hz, 1H), 7.30 (d, J = 1.0 Hz, 1H).

[0463] Preparation of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-3-carboxylic acid (intermediate 88)

[0464]

[0465] Imidazolo[1,2-a]pyrimidine-3-carboxylic acid (100 mg, 0.613 mmol) was dissolved / suspended in EtOH (6.00 mL), and 12 M hydrogen chloride (0.60 M, 7.20 mmol) was added. The mixture was then degassed, and platinum oxide (IV) (22 mg, 0.0969 mmol) was added, followed by hydrogenation. After 2 h under a hydrogen atmosphere, water (1.00 mL) was added, and the reaction mixture was stirred overnight. The reaction mixture was filtered through diatomaceous earth to remove the catalyst and concentrated under reduced pressure to give the desired product (100 mg, 97.58%).

[0466] 1 H NMR (400MHz, DMSO-d6)d 13.09 (s, 1H), 8.78 (s, 1H), 7.71 (s, 1H), 4.18 (t, J = 6.0Hz, 2H), 3.39-3.31 (m, 2H), 2.05-1.99 (m, 2H).

[0467] Preparation of (R)-(3-amino-5-(trifluoromethyl)phenyl)(3-(dimethylamino)pyrrolidone-1-yl)methyl ketone (intermediate 111)

[0468]

[0469] PyBOP (781 mg, 1.50 mmol) was added to a solution of 3-amino-5-(trifluoromethyl)benzoic acid (205 mg, 1.00 mmol), (R)-(+)-3-(dimethylamino)pyrrolidine (0.38 mL, 3.00 mmol), and TEA (0.42 mL, 3.00 mmol) in DCM (5.00 mL) and DMF (5.00 mL). The reaction mixture was stirred for 2 h, partially concentrated under vacuum, and the residue was partitioned between saturated NaCl (aq) and EtOAc. The aqueous phase was extracted with EtOAc, and the organic extract was washed with saturated NaCl (aq), dried (Na2SO4), and concentrated under vacuum. Purification by FCC (0-10% 2M NH3 / MeOH in DCM) gave the desired product (290 mg, 87%).

[0470] 1H NMR(400MHz,DMSO-d6)δ6.90(s,2H),6.84(s,1H),5.76(s,2H),3.73-3.48(m,2H),3.44-3.39(m,1H),3. 27-3.22(m,1H),2.83-2.67(m,1H),2.28-2.21(m,3H),2.14(s,3H),2.09-2.00(m,1H),1.80-1.71(m,1H)

[0471] Preparation of [4-amino-2-(trifluoromethyl)phenyl]methanol (intermediate 112)

[0472]

[0473] Iron powder (2526 mg, 45.2 mmol) was added to a solution of [4-nitro-2-(trifluoromethyl)phenyl]methanol (1000 mg, 4.52 mmol) and NH4Cl (121 mg, 2.26 mmol) in ethanol (50 mL) and water (50 mL) at 75 °C, and the reaction mixture was stirred for 30 min. The reaction mixture was filtered through a diatomaceous earth mat. The combined filtrate was concentrated under vacuum, dissolved in 2:1 DCM / cyclohexane, filtered, and the combined filtrate was evaporated to give the title compound (800 mg, 4.19 mmol, 93%).

[0474] 1 H NMR (400MHz, CDCl3) δ7.40 (d, J = 8.1Hz, 1H), 6.93 (d, J = 2.3Hz, 1H), 6.82 (dd, J = 2.4, 8.2Hz, 1H), 4.72 (s, 2H), 3.90-3.84 (s, 2H), 1.70 (s, 1H).

[0475] Preparation of 6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (intermediate 113)

[0476]

[0477] Step 1: Methyl 6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carboxylate (intermediate 114)

[0478]

[0479] Pd2(dba)3 (275 mg, 0.300 mmol), BINAP (560 mg, 0.900 mmol), and sodium tert-butoxide (403 mg, 4.20 mmol) were added to a solution of ethyl 6-bromoimidazolo[1,2-a]pyridine-3-carboxylate (807 mg, 3.00 mmol) in toluene (10 mL). The reaction mixture was bubbled with nitrogen, and then 1-methylpiperazine (0.37 mL, 3.30 mmol) was added. The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was cooled to room temperature and filtered through a diatomaceous earth pad, followed by washing with MeOH. The combined organic phases were concentrated under vacuum, and the residue was purified by FCC (0-100% EtOAc in cyclohexane, then 0-100% MeOH in EtOAc). This material was carried to the next step without further purification.

[0480] Step 2: 6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (intermediate 113)

[0481] At 0 °C, LiOH (314 mg, 13.1 mmol) in 1 mL of water was added to intermediate 114 (1200 mg, 4.37 mmol) in 1 mL of THF. The reaction mixture was heated to room temperature and stirred for 18 h. The reaction mixture was concentrated under vacuum. The residue was washed with water, and the aqueous phase was adjusted to pH 7 with 1 M HCl (aq) and washed with DCM. The aqueous fraction was concentrated under vacuum to give a mixture of product and inorganic salts. This material was carried to the next step without further purification.

[0482] Preparation of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (intermediate 115)

[0483]

[0484] Step 1: Ethyl 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylate (intermediate 116)

[0485]

[0486] Ethyl 2-chloro-3-oxopropionate (547 mg, 3.63 mmol) was added to a solution of 2-aminopyridin-4-ol (400 mg, 3.63 mmol) in EtOH (12 mL), and the mixture was heated to 80 °C and stirred overnight. The mixture was concentrated and the residue was prepared in EtOAc. The solid was collected and purified by silica FCC (25 g, 0-10% MeOH in DCM, 10 CV), and then concentrated to give the title compound (367 mg, 1.78 mmol, 49%).

[0487] 1 H NMR (400MHz, DMSO-d6) δ12.32(s,1H),9.19(d,J=8.0Hz,1H),8.67(s,1H),7.25-7.18(m,2H),4.44-4.38(m,2H),1.39-1.35(m,3H).

[0488] Step 2: Ethyl 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylate (intermediate 117)

[0489]

[0490] To a solution of intermediate 116 (365 mg, 1.77 mmol, 1.00 eq) in DMF (6.00 mL), K₂CO₃ (367 mg, 2.66 mmol, 1.50 eq) and 2-bromoethyl methyl ether (0.18 mL, 1.95 mmol, 1.10 eq) were added, and the mixture was heated to 85 °C and stirred overnight. The reaction mixture was diluted in EtOAc, washed with water, water / saline 1:1, brine, dried over MgSO₄, filtered, and concentrated to give the title compound (202 mg, 0.764 mmol, 43%).

[0491] 1 H NMR(400MHz,DMSO-d6)δ9.05(d,J=7.7Hz,1H),8.17(s,1H),7.24(d,J=2.3Hz,1H),6.9 7(dd,J=2.6,7.7Hz,1H),4.38-4.25(m,4H),3.74-3.71(m,2H),1.35(t,J=7.1Hz,3H).

[0492] Step 3: 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (intermediate 115)

[0493]

[0494] To a solution of intermediate 117 (200 mg, 0.757 mmol, 1.00 eq) in THF (4 mL), a solution of LiOH monohydrate (79 mg, 1.89 mmol, 2.50 eq) in water (1 mL) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was then heated to 50 °C for 1 h. The reaction mixture was acidified to pH 2 with 2 M HCl aqueous solution, extracted with EtOAc, the organic layer was washed with brine, dried, and concentrated. 18 mg of solid was recovered. The aqueous layer was concentrated, then prepared with MeOH and concentrated to give the title compound (178 mg, quantitative yield).

[0495] 1 H NMR (400MHz, DMSO-d6) δ9.23-9.21 (m, 1H), 8.52 (s, 1H), 7.34 (d, J = 2.4Hz, 1H), 7.2 0(dd,J=2.5,7.7Hz,1H),4.37-4.33(m,2H),3.76-3.72(m,2H),3.35-3.34(m,3H).

[0496] The intermediates reported in the table below were prepared via nucleophilic substitution as described in steps 1-3 of intermediate 115, using the corresponding commercially available alkyl chloride in step 2. Such methods may involve minor variations.

[0497]

[0498] The intermediates reported in the table below were prepared as described in steps 1-3 of intermediate 115, using the corresponding commercially available aminopyridinol in step 1 and the corresponding electrophilic reagent in step 2. Slight variations may be possible with this method.

[0499]

[0500] Preparation of 6-((dimethylamino)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid (intermediate 120)

[0501]

[0502] Step 1: Ethyl 6-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylate (intermediate 121)

[0503]

[0504] Sulfuric acid (0.21 mL, 4.03 mmol) was added dropwise to a suspension of 2-amino-5-pyridinemethanol (0.50 g, 4.03 mmol) and potassium (Z)-2-chloro-3-ethoxy-3-oxo-prop-1-en-1-ol (1.52 g, 8.06 mmol) in ethanol (5.0 mL) at 20 °C. The reaction mixture was stirred at 20 °C for 15 min, and pyridine (0.39 mL, 4.83 mmol) was added. The resulting mixture was stirred overnight at 80 °C. The solvent was concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated NaHCO3(aq). The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (0-100% EtOAc in cyclohexane, then 3 / 1 EtOAc / EtOH) to give the title product (645 mg, 73%).

[0505] 1 H NMR (400MHz, CDCl3) δ9.26 (s, 1H), 8.27-8.26 (m, 1H), 7.68 (d, J=9.3Hz, 1H), 7.45 (dd, J= 1.6, 9.2Hz, 1H), 4.77 (s, 2H), 4.41 (q, J = 7.2Hz, 2H), 2.63 (s, 1H), 1.43 (t, J = 7.2Hz, 3H).

[0506] Step 2: Ethyl 6-formylimidazo[1,2-a]pyridine-3-carboxylate (intermediate 122)

[0507]

[0508] Manganese oxide (IV) (1816 mg, 20.9 mmol) was added to a mixture of intermediate 121 (460 mg, 2.09 mmol) in DCM (25 mL), and the reaction was stirred at room temperature for 3 days. The reaction mixture was filtered through diatomaceous earth and washed with DCM. The filtrate was concentrated under reduced pressure to give the title compound (414 mg, 91%).

[0509] 1 H NMR (400MHz, CDCl3) δ10.05(s,1H),9.85(s,1H),8.38(s,1H),7.92(d,J=9.7Hz,1H),7.81(d,J=9.3Hz,1H),4.47(q,J=7.2Hz,2H),1.46(t,J=7.1Hz,3H)

[0510] Step 3: Ethyl 6-((dimethylamino)methyl)imidazo[1,2-a]pyridine-3-carboxylate (intermediate 123)

[0511]

[0512] 2M dimethylamine (2.2 mL, 4.33 mmol) was added to a solution of intermediate 122 (210 mg, 0.962 mmol) in THF (2.5 mL). The reaction mixture was stirred at room temperature for 16 h. A solution of NaBH3CN (67 mg, 1.06 mmol) in MeOH (0.25 mL) and AcOH (0.31 mL, 5.38 mmol) was added, and the solution was stirred at 60 °C for 2 h. The reaction mixture was diluted with water (10 mL), and the pH was adjusted to 8–9 by adding saturated NaHCO3 (aq). The aqueous layer was extracted with EtOAc, the organic extract was washed with brine (15 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0–100% 3:1 EtOAc:EtOH in EtOAc) to give the title compound (114 mg, 61%).

[0513] 1 H NMR(400MHz, CDCl3)δ9.23(s,1H),8.29-8.28(m,1H),7.72-7.69(m,1H),7.52-7. 48(m,1H),4.42(q,J=7.2Hz,2H),3.56(s,2H),2.33(s,6H),1.43(t,J=7.2Hz,3H)

[0514] Step 4: 6-((dimethylamino)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid (intermediate 120)

[0515] Intermediate 123 (144 mg, 0.582 mmol) was added to a solution of 2 M NaOH (1.2 mL, 2.36 mmol) in MeOH (4.50 mL), and the resulting mixture was stirred at RT for three days. The reaction mixture was concentrated. The pH was acidified to pH 2 with 2 M HCl aqueous solution, and concentrated under reduced pressure to give the title compound (quantitative yield) in the next step without purification.

[0516] 1 H NMR (400MHz, DMSO-d6) δ11.20(s,1H),9.58(s,1H),8.56(s,1H),8.08(dd,J=1.5,9 .3Hz,1H),8.03(dd,J=0.7,9.3Hz,1H),4.57-4.53(m,2H),2.79(s,3H),2.78(s,3H)

[0517] Preparation of pyrazolo[1,5-a]pyrazine-3-carboxaldehyde (intermediate 124)

[0518]

[0519] Step 1: Pyrazolo[1,5-a]pyrazin-3-ylmethanol (Intermediate 125)

[0520]

[0521] Isobutyl chloroformate (0.12 mL, 0.956 mmol) and 4-methylmorpholine (0.11 mL, 0.956 mmol) were added to a solution of pyrazolo[1,5-a]pyrazin-3-carboxylic acid (130 mg, 0.797 mmol) in THF (20 mL) cooled to 0 °C. The reaction mixture was stirred for 2 h, then filtered to remove solid residue, and added to a solution of NaBH4 (45 mg, 1.20 mmol) in EtOH (5.0 mL) at 0 °C, and stirred overnight. The reaction mixture was acidified with 2N HCl, the organic matter was extracted with EtOAc, and then concentrated under reduced pressure to give the desired product (50 mg, 42%), which was used directly for the next step without purification.

[0522] Step 2: Pyrazolo[1,5-a]pyrazine-3-carboxaldehyde (intermediate 124)

[0523] Intermediate 125 (60 mg, 0.402 mmol) was dissolved in THF (5.0 mL), and manganese oxide (IV) (350 mg, 4.02 mmol) was added. The mixture was then refluxed and stirred for 2 h. The reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give the title compound (30 mg, 51%).

[0524] 1 H NMR (400MHz, CDCl3) δ10.15 (s, 1H), 9.72 (d, J = 1.2Hz, 1H), 8.51 (dd, J = 1.5, 4.7Hz, 1H), 8.49 (s, 1H), 8.22 (d, J = 4.4Hz, 1H).

[0525] Preparation of 3-(4-methylpiperazin-1-yl)-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-5-carboxaldehyde (intermediate 126)

[0526]

[0527] Step 1: Methyl 3-bromo-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-5-carboxylate (Intermediate 127)

[0528]

[0529] Methyl 3-bromo-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (512 mg, 2.00 mmol) was dissolved in DMF (6.0 mL), cooled to 0 °C, and then NaH (60%, 96 mg, 2.40 mmol) was added, followed by SEM-Cl (0.71 mL, 4.00 mmol, 2.00 eq), and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water and then extracted with EtOAc. The organic phase was washed with water, dried (MgSO4), and concentrated. The solid was purified by FCC (25 g column, 0-100% EtOAc in cyclohexane solution) to give the title compound (513 mg, 66%).

[0530] 1 H NMR (400MHz, CDCl3) δ9.21(d,J=2.0Hz,1H),8.63(d,J=2.0Hz,1H),5.82(s,2H),3.98(s,3H),3.68-3.57(m,2H),0.95-0.89(m,2H),0.00(s,9H)

[0531] Step 2: Methyl 3-(4-methylpiperazin-1-yl)-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-5-carboxylate (Intermediate 128)

[0532]

[0533] A mixture of intermediate 127 (200 mg, 0.518 mmol), Cs₂CO₃ (253 mg, 0.777 mmol), 1-methylpiperazine (0.29 mL, 2.59 mmol), and Xantphos (45 mg, 0.0777 mmol) in 1,4-dioxane (4 mL) was degassed under N₂, and then Pd₂(DBA)₃ (24 mg, 0.0259 mmol) was added. The tube was capped, and the mixture was stirred overnight at 100 °C. The mixture was concentrated to dryness. The residue was purified by FCC (0–50% [75:15:10EtOAc:EtOH:7MNH₃ / MeOH] in cyclohexane solution) to give the title compound (133 mg, 63%).

[0534] 1H NMR(400MHz, CDCl3) δ9.08(d,J=2.0Hz,1H),8.72(d,J=2.0Hz,1H),5.71(s,2H),3.98(s, 3H),3.69-3.53(m,6H),2.67-2.59(m,4H),2.39(s,3H),0.98-0.89(m,2H),-0.05(s,9H)

[0535] Step 3: [3-(4-methylpiperazin-1-yl)-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-5-yl]methanol (intermediate 129)

[0536]

[0537] The mixture of intermediate 128 (40 mg, 0.0986 mmol) in DCM (2.0 mL) was cooled to 0 °C, and 1 M diisobutylaluminum hydride (0.20 mL, 0.197 mmol) was added. The mixture was stirred overnight at room temperature. The reaction mixture was quenched with water, then with 0.5 mL of NaOH2N. The mixture was stirred for 10 min, and then MgSO4 was added. The mixture was filtered and concentrated to dryness to give (45 mg, 100%), which was used unpurified for the next step.

[0538] Step 4: 3-(4-methylpiperazin-1-yl)-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-5-carboxaldehyde (intermediate 126)

[0539] Following the method of intermediate 125, intermediate 129 (45 mg, 0.119 mmol) was reacted in 2-methyl-THF (1.0 mL) at 50 °C for 2 h to give the title compound (35 mg, 78%), which was used directly in the next step of the reaction without purification.

[0540] Preparation of 2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridine-4-amine (intermediate 130)

[0541]

[0542] Step 1: 4-Amino-N-methoxy-N-methyl-6-(trifluoromethyl)pyridine amide (intermediate 131)

[0543]

[0544] 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-dimethylhydroxylamine hydrochloride (232 mg, 2.37 mmol). Purification was performed by silica FCC (80 g column, 0-50% EtOAc in cyclohexane (+0.1% NEt3)) to give the title compound (369 mg, 68%).

[0545] 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)

[0546] Step 2: 4-Amino-6-(trifluoromethyl)pyridinecarboxaldehyde (intermediate 132)

[0547]

[0548] LiAlH4 (2M in THF, 0.62 mL, 1.24 mol) was added dropwise to a stirred solution of intermediate 131 (308 mg, 1.24 mmol) cooled in an ice / water bath in THF (4.82 mL), 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, the reaction mixture was stirred for 15 min, filtered, and the filtrate was concentrated under vacuum to give the title compound (252 mg, >100%), which was used unpurified for the next step.

[0549] LC-MS (ESI) Method 12: t R =0.95min; m / z(M+1) = 191

[0550] Step 3: 2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridine-4-amine (intermediate 130)

[0551] The compound was prepared according to general method D from intermediate 132 (126 mg, 0.663 mmol) and dimethylamine (2 M THF solution) (0.33 mL, 0.663 mol). Purification was performed by silica FCC (12 g column, 0-8% 2 M NH3 / MeOH in DCM) to give the title compound (65 mg, 44%).

[0552] 1H NMR (400MHz, DMSO-d6) δ6.78-6.77(m,2H),6.49(s,2H),3.34(s,2H),2.18(s,6H).

[0553] Example 1: Preparation of 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

[0554]

[0555] Step 1: 4,7-Dihydrothiopheno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tert-butyl)3-methyl ester (intermediate 35)

[0556]

[0557] 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (1.249 g, 4.41 mmol) and cesium carbonate (2.154 g, 6.61 mmol) were dissolved in anhydrous DMF (15 mL), and then CH3I (0.413 mL, 6.61 mmol) was added in a single batch. The solution was stirred overnight at room temperature. 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. The crude product was purified by direct phase FCC (silica, n-heptane:AcOEt gradient from 100:0 to 80:20) to give the title compound (1.21 g, 4.07 mmol, 92% yield).

[0558] 1 H NMR (400MHz, CDCl3) δppm 7.98 (s, 1H) 4.62 (br s, 2H) 3.84 (s, 1H) 3.67 (t, J = 5.70Hz, 1H) 2.99 (br t, J = 5.48Hz, 1H) 1.49 (s, 1H)

[0559] Step 2: 4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid methyl ester hydrochloride (Intermediate 36)

[0560]

[0561] Intermediate 35 (1.21 g, 4.07 mmol) was dissolved in concentrated HCl (7 mL, 230 mmol), and the reaction mixture was stirred at RT for 10 min. Ethanol was then added to the reaction mixture, and the solvent was evaporated under reduced pressure until the title compound (0.921 g, 3.94 mmol, 97% yield) was obtained. This compound will be used in the next step without further purification.

[0562] Step 3: Methyl 6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (intermediate 37)

[0563]

[0564] Imidazolo[1,2-a]pyridine-3-carboxylic acid (208 mg, 1.284 mmol), intermediate 36 (200 mg, 0.856 mmol), and TBTU (412 mg, 1.284 mmol) were dissolved in 6 mL of DCM / DMF 1:1, and then DIPEA (0.598 mL, 3.42 mmol) was added in a single batch. The solution was stirred at room temperature for 1 h. The crude product was diluted with DCM (10 mL) and then washed with saturated NH4Cl solution (2 × 15 mL) and saturated NaHCO3 solution (2 × 15 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to dryness. The title compound (155.2 mg, 0.455 mmol, 53.1% yield) was obtained by reverse-phase FCC (C18 column, gradient 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).

[0565] 1 H NMR (400MHz, CDCl3) δppm 9.05-9.10(m,1H)8.04(s,1H)7.99-8.03(m,1H)7.81(d,J=8.99Hz,1H)7.42-7.50( m,1H)7.04(t,J=6.91Hz,1H)5.03(s,2H)4.09(t,J=5.81Hz,2H)3.87(s,3H)3.22(br t,J=5.59Hz,2H).

[0566] Step 4: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 1)

[0567] Under nitrogen atmosphere, 3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)aniline (84 mg, 0.308 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 2.5 M n-BuLi in hexane (0.098 mL, 0.246 mmol) over 5 min, and the solution was stirred at -78 °C for 1 h. Intermediate 37 (42 mg, 0.123 mmol) in THF (6 mL) was added dropwise over 10 min, the temperature was raised to room temperature, and the reaction was stirred for another 1 h. 10 mL of water was added to the solution to evaporate the solvent. The crude product was purified by reverse-phase FCC (C18 column, gradient A:B from 100:0 to 0:100, where eluent A = H2O:ACN:HCOOH 95:5:0.1, eluent B = H2O:ACN:HCOOH 5:95:0.1) to give the title compound (32 mg, 0.055 mmol, 45% yield).

[0568] 1 H NMR (400MHz, DMSO-d6) δppm 10.34(s,1H),8.93(d,J=6.80Hz,1H),8.18(s,1H),8.10(s,2H),7.90(s,1H),7.70(d,J=8.99Hz,1H),7.44(br t,J=7.80Hz,1H),7.30(s,1H),7.07(t,J=6.72Hz,1H),4.99(br s,2H),3.95(br t,J=5.59Hz,2H),3.28(s,2H),3.01-3.10(m,2H),2.27-2.43(m,8H),2.15(br s,3H).

[0569] LC-MS (ESI) Method 1: t R =0.92min; m / z(M+1)=583.2.

[0570] Example 2: Preparation of N-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0571]

[0572] Step 1: 4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride (Intermediate 38)

[0573] 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 Et2O (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).

[0574] 1 H NMR (300MHz, DMSO-d6) δ9.58 (s, 2H), 8.31 (s, 1H), 4.35 (s, 2H), 4.25 (q, J = 7.1Hz, 2H), 3.39-3.34 (m, 2H), 3.07 (t, J = 6.1Hz, 2H), 1.29 (t, J = 7.1Hz, 3H).

[0575] Step 2: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl ester (intermediate 39)

[0576]

[0577] To a solution of intermediate 38 (1.40 g, 5.65 mmol) and imidazo[1,2-a]pyridine-3-carboxylic acid (0.916 g, 5.65 mmol) in DCM (28.3 mL), DIPEA (5.92 mL, 33.9 mmol) was added, followed by T3P (6.73 mL, 11.30 mmol), and the reaction mixture was stirred at room temperature over the entire weekend. The crude product was diluted with DCM, water was added, and the mixture was stirred for 10 min. The phases were then separated, the aqueous layer was extracted with DCM (3 x 50 mL), the combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by direct phase FCC (silica, gradient DCM:MeOH from 100:0 to 90:10) to give the title compound (1.75 g, 4.92 mmol, 87% yield).

[0578] 1H NMR (300MHz, CDCl3) δ9.03(dt,J=7.0,1.2Hz,1H),8.03(d,J=0.8Hz,1H),7.98(s,1H),7.72(dt,J=9.0,1.2Hz,1H),7.38(ddd,J=9.0,6.8,1.3Hz,1H) ,6.97(td,J=6.9,1.3Hz,1H),5.01(d,J=1.8Hz,2H),4.32(q,J=7.1Hz,2H) ,4.08(t,J=5.8Hz,2H), 3.20(tt,J=5.9,1.7Hz,2H), 1.37(t,J=7.1Hz,3H).

[0579] Step 3: Sodium 6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (intermediate 40)

[0580]

[0581] To a solution of intermediate 39 (1.75 g, 4.92 mmol) in methanol (49.2 mL), 1 M sodium hydroxide (4.92 mL, 4.92 mmol) was added, and the reaction mixture was stirred at room temperature over the entire weekend. The solvent was evaporated under reduced pressure to give the title compound in quantitative yield.

[0582] 1 H NMR(300MHz,DMSO-d6)δ8.98-8.89(m,1H),8.09(s,1H),7.75-7.68(m,1H),7.55(s,1H),7.49-7 .40(m,1H),7.08(td,J=6.9,1.3Hz,1H),4.93(s,2H),3.92(t,J=5.8Hz,2H),3.12(t,5.8Hz,2H).

[0583] Step 4: N-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 2)

[0584] The crude compound was prepared according to general procedure G from sodium intermediate 40 (100 mg, 0.286 mmol) and 3-(tert-butyl)-1-(p-tolyl)-1H-pyrazole-5-amine (65.6 mg, 0.286 mmol). The crude product was cooled, diluted with DCM, and water was added. The mixture was stirred for 15 min, and the phases were separated. The organic phase was washed with 5% citric acid, water, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give the title compound (23.1 mg, 0.043 mmol, 15% yield).

[0585] 1 H NMR(300MHz,DMSO-d6)δ10.04(s,1H),8.94(dt,J=7.0,1.2Hz,1H),8.10(s,1H) ,8.04(s,1H),7.73(dt,J=9.0,1.2Hz,1H),7.46(ddd,J=9.0,6.8,1.3Hz,1H),7 .43-7.36(m,2H),7.25(d,J=8.2Hz,2H),7.09(td,J=6.9,1.3Hz,1H),6.34(s,1 H), 4.98 (s, 2H), 3.93 (t, J = 5.6Hz, 2H), 2.92 (s, 2H), 2.31 (s, 3H), 1.30 (s, 9H).

[0586] LC-MS (ESI) Method 2: t R =2.18min; m / z(M+1)=539.0.

[0587] The compounds reported in the table below were prepared by amide coupling as described in steps 1-4 of Example 2, using the corresponding commercially available or previously synthesized amine in step 4. Changes in coupling agents (e.g., HATU instead of T3P), salt-free methods, or chromatographic purification conditions (e.g., preparative HPLC or rapid chromatography) are reported in the table. For Examples 44 and 45, non-racemic chemical reactions were carried out on reagents with known absolute configurations by inferring the specified absolute configuration.

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611] Example 46: Preparation of N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0612]

[0613] Step 1: N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0614] Intermediate 40 (100 mg, 0.286 mmol) and 3-fluoro-5-(trifluoromethyl)aniline (0.056 mL, 0.429 mmol) were dissolved in anhydrous pyridine (2.863 mL). The solution was cooled to 5 °C and POCl3 (0.059 mL, 0.630 mmol) was added. The reaction was stirred until the conversion of SM was observed. RM was diluted with AcOEt and washed with NaHCO3 (aq), water, and brine. The organic phase was then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified by FCC (DCM to 10% MeOH in DCM solution) to give the title compound (6 mg, 0.012 mmol, yield 4%).

[0615] 1 H NMR (300MHz, DMSO-d6) δ10.58(s,1H),8.96(d,J=6.9Hz,1H),8.23(s,1H),8.13(s,1H),8.01-7.91(m,2H),7.73(d,J=9.0Hz ,1H),7.46(t,J=8.0Hz,1H),7.38(d,J=8.4Hz,1H),7.10(t,J=6.8Hz,1H),5.03(s,2H),3.98(t,J=5.7Hz,2H),3.07(s,2H).

[0616] LC-MS (ESI) Method 2: t R =2.21min; m / z(M+1) = 489.0

[0617] Example 47: Preparation of N-(4-(tert-butyl)oxazol-2-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0618]

[0619] Step 1: N-(4-(tert-butyl)oxazol-2-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0620] To a suspension of intermediate 40 acid (40 mg, 0.122 mmol) and 4-tert-butyloxazol-2-amine (24 mg, 0.171 mmol) in DMF (0.60 mL), 1-methylimidazole (0.034 mL, 0.428 mmol) was added, followed by TCFH (51 mg, 0.183 mmol). The reaction mixture was stirred at room temperature for 72 h, partitioned between saturated NaHCO3 (aq) and DCM, and the aqueous phase was extracted with 3x DCM. The combined organic phases were washed with saturated NaCl (aq), passed through a hydrophobic glass frit, and concentrated under vacuum. Purification by reversed-phase preparative HPLC (Xbridge Phenyl 19x150 mm, 10 μm, 40–100% MeOH / water (10 mM NH4HCO3), 20 mL / min, RT) gave the title compound (1.55 mg, 2%).

[0621] 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),8.97(td,J=1.1,7.1Hz,1H),8.28(s,1H),8.14(s,1H),7.74(td,J=1.1,9.0Hz,1H),7 .59(s,1H),7.50-7.45(m,1H),7.11(dt,J=1.2,6.9Hz,1H),5.03(s,2H),4.01-3.96(m,2H),3.09-3.04(m,2H),1.23(s,9H).

[0622] LC-MS (ESI) Method 7: t R =3.46 min; m / z(M+1) = 450.2

[0623] The compounds reported in the table below were prepared by amide coupling as described in step 1 of Example 47, using the corresponding commercially available or previously synthesized amine in step 1. If not DMF, the solvent is specified.

[0624]

[0625]

[0626]

[0627] Example 48: Preparation of compound N-(3-((4-(dimethylamino)piperidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0628]

[0629] Step 1: N-(3-(dimethoxymethyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 41)

[0630]

[0631] The compound was prepared according to general procedure H from 3-(dimethoxymethyl)-5-(trifluoromethyl)aniline (216 mg, 0.916 mmol, intermediate 33) and intermediate 40 in acid form (300 mg, 0.916 mmol). The residue was ground under Et2O, and the suspension was filtered to give the title compound (496 mg, 0.910 mmol, 99% yield).

[0632] 1 H NMR (400MHz, DMSO-d6) δ10.46(s,1H),8.98(d,J=7.0Hz,1H),8.25-8.19(m,3H),8.07(s,1H),7.76(d,J=9.1Hz,1H),7.55-7 .49(m,1H),7.39(s,1H),7.15(t,J=6.9Hz,1H),5.50(s,1H),5.03(s,2H),4.01-3.97(m,2H),3.29(s,6H),3.12-3.07(m,2H)

[0633] Step 2: N-(3-formyl-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 42)

[0634]

[0635] At room temperature, TFA (0.50 mL, 6.53 mmol, 7.14 eq) was added to a DCM (5.00 mL) solution of intermediate 41 (498 mg, 0.915 mmol, 1.00 eq), and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated under vacuum to give a light brown flowing oil, which was milled under Et2O and decanted with diethyl ether to give the title compound (450 mg, 0.910 mmol, 99% yield).

[0636] 1H NMR (400MHz, DMSO-d6) δ10.67(s,1H),10.09(s,1H),9.04(d,J=7.0Hz,1H),8.57(s,1H),8.46(s,2H),8.29(s,1H),8.01( s,1H),7.93(d,J=9.0Hz,1H),7.84-7.78(m,1H),7.39(t,J=7.0Hz,1H),5.03(s,2H),4.01-3.96(m,2H),3.14-3.09(m,2H)

[0637] Step 3: N-(3-((4-(dimethylamino)piperidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0638] C was prepared by general method from intermediate 42 (50 mg, 0.100 mmol) and N,N-dimethylpiperidin-4-amine (14 mg, 0.110 mmol). The title compound (16 mg, 26%) was purified by reversed-phase preparative HPLC (Xbridge Phenyl 19x150 mm, 10 μm, 40–100% methanol / water (10 mM NH4HCO3), 20 mL / min, RT).

[0639] 1 H NMR(400MHz, DMSO-d6)δ10.40(s,1H),8.98(td,J=1.0,7.0Hz,1H),8.24(s,1H),8.17-8.15( m,2H),7.93(s,1H),7.75(td,J=1.0,9.0Hz,1H),7.51-7.45(m,1H),7.34(s,1H),7.11(dt,J= 1.0,7.0Hz,1H),5.03(s,2H),4.00(t,J=5.5Hz,2H),3.53(s,2H),3.12-3.07(m,2H),2.87-2 .81(m,2H),2.17(s,6H),2.08-1.94(m,3H),1.76-1.69(m,2H),1.40(dq,J=3.5,11.8Hz,2H).

[0640] LC-MS (ESI) Method 7: t R =2.34min; m / z(M+1) = 611.4

[0641] The compounds reported in the table below were prepared by amide coupling as described in steps 1-3 of Example 48, using the corresponding, commercially available, or previously synthesized amine in step 3. Step 3 can be performed in various ways as reported in the table, according to the general method described above. Modifications include chromatographic purification conditions (e.g., preparative HPLC or rapid chromatography), and such changes are reported as illustrative.

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649] Example 62: Preparation of 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(2-(4-methylpiperazin-1-yl)ethoxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 62)

[0650]

[0651] Step 1: 4-(2-(3-(6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-formamide)-5-(trifluoromethyl)phenoxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 43)

[0652]

[0653] Intermediate 40 was converted to its free acid form by dissolving it in an organic solvent, followed by acid washing, drying with sodium sulfate, and evaporation under vacuum, yielding intermediate 40 in its free acid form (150 mg, 0.458 mmol). This free acid form was then reacted with intermediate 19 (178 mg, 0.458 mmol) according to general method H. Purification was performed by silica gel FCC (eluent A = 3:1 AcOEt / ethanol; eluent B = cyclohexane; gradient = from 0% eluent A to 100% eluent A) to give the title compound (210 mg, 61%).

[0654] 1H NMR (400MHz, CDCl3) δ9.04 (d, J = 6.8Hz, 1H), 8.12 (s, 1H), 7.98-7.97 (m, 1H), 7.70 ( d,J=9.1Hz,1H),7.67(s,1H),7.40-7.35(m,1H),7.32(s,1H),7.00-6.96(m,1H),6. 93(s,1H),5.03-5.01(m,2H),4.16(t,J=5.6Hz,2H),4.10(q,J=4.5Hz,2H),3.45(t, J=5.1Hz,4H),3.29-3.21(m,2H),2.85-2.81(m,2H),2.53-2.51(m,4H),1.46(s,9H)

[0655] Step 2: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(2-(piperazin-1-yl)ethoxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 44)

[0656]

[0657] A solution of intermediate 43 (70 mg, 0.10 mmol, 1.00 eq) in methanol (1.00 mL) was treated with a solution of 4 M HCl in dioxane (0.4 mL, 1.2 mmol, 10.0 eq) at 20 °C, and the resulting reaction mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was analyzed by preparative HPLC (Sunfire). Purified at 19x150mm, 10µm, 5-60% ACN / H2O (0.1% TFA), 20mL / min, RT. The residue was lyophilized to give the title compound (24.3mg, 13.6%).

[0658] 1 H NMR (400MHz, MeOD-d3) δ9.16 (d, J = 9.2Hz, 1H), 8.45 (s, 1H), 8.11 (s, 1H), 7. 96(d,J=3.5Hz,3H),7.76(s,1H),7.61(s,1H),7.50-7.46(m,1H),7.02(s,1 H),5.14-5.12(m,2H),4.28(t,J=5.2Hz,2H),4.13(t,J=5.8Hz,2H),3.32-3 .30(m,4H),3.25-3.16(m,2H),3.04(t,J=5.1Hz,2H),2.97(t,J=5.1Hz,4H)

[0659] Step 3: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(2-(4-methylpiperazin-1-yl)ethoxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 62)

[0660] The suspension of intermediate 44 (120 mg, 0.200 mmol, 1.00 eq) in a mixture of THF (2.00 mL) and methanol (2.00 mL) was treated sequentially with formaldehyde solution (37%, 0.037 mL, 0.501 mmol, 2.50 eq) and NaBH3CN (21 mg, 0.341 mmol, 1.70 eq), and the resulting mixture was stirred at 20 °C for 1 h. The reaction mixture was partitioned between DCM and saturated NaHCO3 (aq), and the organic phase was washed with saturated NaCl (aq), dried (MgSO4), and concentrated. The residue was analyzed by preparative HPLC (Xbridge). Purified at 19x150mm, 10µm, 40-100% MeOH / H2O (10mM NH4CO3), 20mL / min, RT. The residue was lyophilized to give the title compound (37.4mg, 30.6%).

[0661] 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.98(d,J=7.0Hz,1H),8.20(s,1H),8.15( s,1H),7.78-7.74(m,2H),7.67(s,1H),7.50-7.46(m,1H),7.14-7.09(m,1H),7. 01(s,1H),5.06-5.02(m,2H),4.18-4.13(m,2H),4.00(t,J=5.6Hz,2H),3.09-3. 07(m,2H),2.74-2.70(m,2H),2.53-2.50(m,4H),2.35-2.33(m,4H),2.16(s,3H).

[0662] LC-MS (ESI) Method 7: t R =2.88min; m / z(M+1) = 613

[0663] Example 63: Preparation of 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-[3-(1-methylpyrrolidone-3-yl)oxy-5-(trifluoromethyl)phenyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide

[0664]

[0665] Step 1: 3-(3-(6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-formamide)-5-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 45)

[0666]

[0667] Intermediate 40 was converted to its free acid by deblocking the salt (80 mg, 0.244 mmol) as described in step 1 of Example 62, and reacted with tert-butyl 3-[3-amino-5-(trifluoromethyl)phenoxy]pyrrolidine-1-carboxylate (85 mg, 0.244 mmol, intermediate 29) according to general method H. The residue was purified by silica gel FCC (AcOEt / cyclohexane from 0% to 100%, then with AcOEt / EtOH 75% / 25%) to give the title compound.

[0668] 1 H NMR (400MHz, CDCl3) δ9.02(d,J=6.8Hz,1H),8.44-8.37(m,1H),7.99-7.95(m,1H),7.72-7.65(m,2H),7.37(t,J=9.8Hz,2H),6.97(t,J=6. 7Hz,2H),6.86(s,1H),4.96(s,1H),4.14-4.05(m,4H),3.63(s,2H),3.59-3.44(m,2H),3.23-3.21(m,2H),2.24-2.12(m,2H),1.47(s,9H)

[0669] Step 2: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(pyrrolidine-3-yloxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 46)

[0670]

[0671] A solution of intermediate 45 (90 mg, 0.137 mmol, 1.00 eq) in methanol (1.00 mL) was treated with a solution of 4 M HCl in dioxane (0.69 mL, 2.75 mmol, 20.0 eq). The reaction mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure to give the HCl salt of the title compound in a quantitative yield (81 mg, quantitative).

[0672] Step 3: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-[3-(1-methylpyrrolidone-3-yl)oxy-5-(trifluoromethyl)phenyl]-5,7-dihydro-4H-thienozo[2,3-c]pyridine-3-carboxamide (Example 63)

[0673] The suspension of intermediate 46 (81 mg, 0.137 mmol, 1.00 eq) in THF (1 mL) and MeOH (1 mL) was treated sequentially with formaldehyde solution (37%, 0.025 mL, 0.342 mmol, 2.50 eq) and sodium cyanoborohydride (15 mg, 0.233 mmol, 1.70 eq), and the resulting mixture was stirred overnight at room temperature. Another portion of MeOH (1 mL) was added until all solids dissolved, and stirring was continued for 1 h at room temperature. The reaction mixture was partitioned between DCM and saturated NaHCO3 (aq). The organic layer was washed with saturated NaCl (aq), dried (Na2SO4), and concentrated under vacuum. The crude material was analyzed by preparative HPLC (Luna). Purification was performed using a 21.2 x 150 mm, 10 μm filter with 20-80% MeOH / H2O (0.1% FA), 20 mL / min, at RT, to obtain the title compound (11 mg, 14%).

[0674] 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.98(d,J=7.0Hz,1H),8.19(s,1H),8.15(s,1H),7 .78(s,1H),7.75(d,J=9.0Hz,1H),7.61(s,1H),7.51-7.45(m,1H),7.14-7.09(m,1H),6.9 0(s, 1H), 5.03(s, 2H), 4.96-4.91(m, 1H), 4.00(t, J = 5.7Hz, 2H), 3.08(s, 2H), 2.80(dd, J = 6.0, 10.4Hz, 1H), 2.73-2.62(m, 2H), 2.42-2.30(m, 2H), 2.28(s, 3H), 1.85-1.77(m, 1H). LC-MS (ESI) Method 7: t R =2.92min; m / z(M+1) = 570

[0675] Example 64: Preparation of N-(3-(tert-butyl)-1-(2-hydroxyethyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0676]

[0677] Step 1: N-(3-(tert-butyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 47)

[0678]

[0679] Intermediate 31 (254 mg, 0.855 mmol) was prepared according to General Method I. Purification on silica gel by FCC (AcOEt / cyclohexane from 0% to 100%) yielded the title compound (139 mg, 37%).

[0680] 1 H NMR (400MHz, CDCl3) δ9.04(d,J=7.1Hz,1H),8.90(s,1H),7.97(s,1H),7.72-7.67(m,2H),7.40-7.35(m,1H),6.97(t,J=6.9Hz,1H),6.46(s,1 H),5.04(s,2H),4.25(t,J=4.5Hz,2H),4.12-4.09(m,2H),3.99(t,J=4.6Hz,2H),3.28-3.24(m,2H),1.31(s,9H),0.76(s,9H),-0.09(s,6H).

[0681] Step 2: N-(3-(tert-butyl)-1-(2-hydroxyethyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 64)

[0682] A solution of 4M HCl in 1,4-dioxane (0.60 mL, 2.41 mmol) was added to a solution of intermediate 47 (146 mg, 0.241 mmol) in MeOH (1.60 mL) and THF (0.80 mL). The reaction mixture was stirred for 2 h at room temperature under a nitrogen atmosphere. The reaction mixture (165 mg) was concentrated under vacuum. A fraction (36 mg) was removed and analyzed by reversed-phase preparative HPLC (Sunfire). Purified at 19x150mm, 10μm using 20-80% acetonitrile / water (10mM NH4HCO3), 20mL / min, RT, to give the title compound (18.64mg, 15%).

[0683] 1 H NMR(400MHz,DMSO-d6)δ10.15(brs,1H),8.97(td,J=1.1,7.0Hz,1H),8.14(s,1H) ,8.12(s,1H),7.75(td,J=1.1,9.0Hz,1H),7.48(ddd,J=1.3,6.8,9.0Hz,1H),7.1 1(dt,J=1.2,6.9Hz,1H),6.21(s,1H),5.32(brs,1H),5.05(s,2H),4.09(t,J=5.8 Hz, 2H), 4.03-3.97 (m, 2H), 3.72 (t, J = 5.8Hz, 2H), 3.10-3.04 (m, 2H), 1.25 (s, 9H). LC-MS (ESI) Method 7: t R =3.23min; m / z(M+1) = 493.3

[0684] Example 65: Preparation of compound N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridin-3-ylmethyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide

[0685]

[0686] Step 1: 6-(imidazo[1,2-a]pyridin-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxylic acid ethyl ester (intermediate 48)

[0687]

[0688] Under argon atmosphere, intermediate 38 (3.00 g, 12.11 mmol) and imidazo[1,2-a]pyridine-3-carboxaldehyde (1.770 g, 12.11 mmol) were placed in a flask. Anhydrous DCM (60.5 mL) was added, followed by AcOH (0.693 mL, 12.11 mmol) and TEA (1.688 mL, 12.11 mmol). The reaction mixture was stirred at room temperature for 30 min. Then, NaBH(OAc)3 (5.13 g, 24.22 mmol) was 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 phases were combined, dried over MgSO4, and evaporated under reduced pressure. The crude product was purified by FCC with DCM / MeOH (DCM to 10% MeOH in DCM solution) to give the title compound (2.38 g, 6.97 mmol, 58% yield).

[0689] 1 H NMR (300MHz, CDCl3) δ8.37(dt,J=6.9,1.2Hz,1H),7.93(s,1H),7.64(dt,J=9.1,1.2Hz,1H),7.55(s,1H),7.21(ddd,J=9.1,6.7,1.3Hz,1H),6 .80(td,J=6.8,1.2Hz,1H),4.28(q,J=7.1Hz,2H),4.02(s,2H),3.63(s,2H),3.03-2.92(m,2H),2.83(t,J=5.8Hz,2H),1.33(t,J=7.1Hz,3H).

[0690] Step 2: Sodium 6-(imidazo[1,2-a]pyridin-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxylate (intermediate 49)

[0691]

[0692] To a solution of intermediate 48 (2.38 g, 6.97 mmol) in MeOH (69.7 mL), 1 M NaOH (6.97 mL, 6.97 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 in quantitative yield.

[0693] 1 H NMR (300MHz, DMSO-d6) δ8.48 (dt, J=6.9, 1.3Hz, 1H), 7.60-7.50 (m, 2H), 7.43 (s, 1H), 7.24 (ddd, J=9.1, 6.7, 1. 3Hz, 1H), 6.91 (td, J = 6.8, 1.2Hz, 1H), 3.99 (s, 2H), 3.57 (s, 2H), 2.85 (t, J = 5.8Hz, 2H), 2.67 (t, J = 5.8Hz, 2H).

[0694] Step 3: 6-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazo-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide (Example 65)

[0695] Intermediate 49 (0.1 g, 0.298 mmol) was dissolved in DMF (0.745 mL) and DCM (2.236 mL), followed by the addition of DIPEA (0.312 mL, 1.789 mmol) and HATU (0.227 g, 0.596 mmol). The mixture was stirred for 15 min, followed by the addition of 3-fluoro-5-(trifluoromethyl)aniline (0.053 g, 0.298 mmol). The reaction mixture was stirred at room temperature until LCMS showed complete consumption of the starting material. The reaction mixture 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 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by FC (DCM solution of 100% to 10% MeOH) to give the title compound (23 mg, 0.043 mmol, 14% yield).

[0696] 1 H NMR (300MHz, DMSO-d6) δ10.48(s,1H),8.49(d,J=6.8Hz,1H),8.18(q,J=1.8Hz ,2H),8.14(s,1H),8.07(s,1H),7.69(s,1H),7.58(d,J=9.8Hz,2H),7.46(d,J= 1.5Hz,1H),7.26(dd,J=8.6,7.2Hz,1H),6.93(t,J=6.7Hz,1H),4.05(s,2H),3. 67(s,2H),2.86(d,J=6.5Hz,2H),2.79(d,J=5.4Hz,2H),2.17(d,J=1.0Hz,3H).

[0697] LC-MS (ESI) Method 8: t R =1.69min; m / z(M+1) = 537.2

[0698] Example 66: Preparation of 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide

[0699]

[0700] Step 1: 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl ester (intermediate 50)

[0701]

[0702] Under argon atmosphere, intermediate 38 (0.73 g, 2.95 mmol) and 1H-pyrazolo[3,4-b]pyridine-5-carboxaldehyde (0.650 g, 4.42 mmol) were placed in a round-bottom flask. Anhydrous DCM (14.73 mL) was added, followed by AcOH (0.169 mL, 2.95 mmol) and TEA (0.205 mL, 1.473 mmol). The reaction mixture was stirred at room temperature for 30 min. STAB (1.249 g, 5.89 mmol) was then added, and the reaction mixture was stirred at room temperature overnight. 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 phases were combined, dried over MgSO₄, and evaporated under reduced pressure. The crude product was purified by FCC with DCM / MeOH (DCM to a DCM solution of 10% MeOH) to give the title compound (0.86 g, 2.51 mmol, 85% yield).

[0703] 1 H NMR (300MHz, DMSO-d6) δ13.60(s,1H),8.50(d,J=2.0Hz,1H),8.16(d,J=2.0Hz,1H),8.12(s,1H),8.11(d,J=1.3Hz,1H) ,4.22(q,J=7.1Hz,2H),3.82(s,2H),3.63(s,2H),2.85(d,J=5.8Hz,2H),2.75(t,J=5.7Hz,2H),1.27(t,J=7.1Hz,3H).

[0704] Step 2: 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxylate lithium (intermediate 51)

[0705]

[0706] 1 M LiOH (5.02 mL, 5.02 mmol) was added to a MeOH (24 mL) solution of intermediate 50 (0.86 g, 2.51 mmol), the reaction mixture was stirred overnight at 45 °C, and the reaction mixture was concentrated under vacuum to give the title compound (0.98 g, 3.06 mmol) in quantitative yield.

[0707] 1H NMR(300MHz,DMSO-d6)δ8.05(d,J=2.1Hz,1H),7.81(s,1H),7.72(d,J=2.1Hz,1H),7 .39(s,1H),3.65(s,2H),3.48(s,2H),2.86(d,J=5.9Hz,2H),2.65(t,J=5.8Hz,2H).

[0708] Step 3: 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide (Example 66)

[0709] Intermediate 51 (0.10 g, 0.312 mmol) was suspended in DMF (0.781 mL) and DCM (2.342 mL), followed by the addition of DIPEA (0.327 mL, 1.873 mmol) and HATU (0.297 g, 0.781 mmol). The mixture was stirred for approximately 15 min, followed by the addition of 3-(trifluoromethoxy)aniline (0.084 mL, 0.624 mmol). The mixture was stirred overnight at room temperature. The crude product was cooled and diluted with DCM, followed by the addition of water. The mixture was stirred for 15 min and phase separation was performed. The organic phase was washed with 5% citric acid, water, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure.

[0710] The crude product was purified by FCC (DCM to contain 10% MeOH in DCM) to give the title compound (7.56 mg, 0.016 mmol, 5.11% yield).

[0711] 1 H NMR(300MHz,MeOH-d4)δ8.59(s,1H),8.27(d,J=2.0Hz,1H),8.12(s,1H),7.95(s,1H),7.79(s,1H),7.59(d,J=8.2Hz ,1H),7.41(t,J=8.2Hz,1H),7.01(d,J=8.2Hz,1H),3.92(s,2H),3.75(s,2H),3.04-2.98(m,2H),2.93-2.85(m,2H).

[0712] LC-MS (ESI) Method 3: t R =2.17min; m / z(M+1) = 474.0

[0713] The following compounds were prepared by amide coupling as described in steps 1-3 of Example 66, using the corresponding commercially available aniline in step 3.

[0714]

[0715] Example 68: Preparation of 6-(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

[0716]

[0717] Step 1: 6-(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl ester (intermediate 52)

[0718]

[0719] To a solution of intermediate 38 (5 g, 20.18 mmol) and 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (3.27 g, 20.18 mmol) in DCM (101 mL), DIPEA (28.2 mL, 161 mmol) was added, followed by T3P (24.03 mL, 40.4 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM, water was added, and the mixture was stirred for 10 min. The phases were then separated, the aqueous phase was washed with DCM (3 × 50 mL), the organic phases were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by FC with DCM:MeOH (DCM to 5% MeOH) to give the title compound (1.57 g, 4.42 mmol, 22% yield).

[0720] 1 H NMR (300MHz, CDCl3) δ10.50(s,1H),8.51(d,J=2.0Hz,1H),8.16(d,J=2.0Hz,1H),8.03(s,1H),7.47(d,J=3.6Hz,1H), 6.61 (d, J = 3.6 Hz, 1H), 4.91 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 3.83 (s, 2H), 3.12 (d, J = 6.2 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H).

[0721] Step 2: Sodium 6-(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (intermediate 53)

[0722]

[0723] To a solution of intermediate 52 (1.6 g, 4.50 mmol) in MeOH (45.0 mL), 1 M NaOH (6.75 mL, 4.92 mmol) was added, and the reaction mixture was stirred at room temperature over the entire weekend. The solvent was evaporated under reduced pressure to give the title compound (1.52 g, 4.35 mmol, 97% yield).

[0724] 1 H NMR (300MHz, DMSO-d6) δ8.22(d,J=2.1Hz,1H),7.96(d,J=2.1Hz,1H),7.60(s,1H),7.56( d,J=3.0Hz,1H),6.42(d,J=3.0Hz,1H),4.76(s,2H),3.71(s,2H),3.04(t,J=5.8Hz,2H).

[0725] Step 3: 6-(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 68)

[0726] Intermediate 53 (0.1 g, 0.286 mmol) and HATU (0.218 g, 0.573 mmol) were weighed into a reaction tube purged with argon (x3). The reagents were suspended in DCM (2.147 mL) and DMF (0.716 mL). DIPEA (0.400 mL, 2.290 mmol) was then added to the reaction mixture. After stirring for 15 min, 3-(trifluoromethyl)aniline (0.036 mL, 0.286 mmol) was added. The reaction mixture was stirred at room temperature for 60 h. The crude product was transferred to a separatory funnel and washed with water (x3). The desired compound was extracted with DCM, and the organic layers were combined and washed with brine (x1). The organic layer was concentrated under vacuum, and the crude product was purified by preparative HPLC to give the desired compound as a formate. The salt was washed with a 1:1 NaHCO3 (saturated):H2O solution, and the desired compound was extracted with DCM (x3). The combined organic layers were dried with Na2SO4, filtered, and concentrated under vacuum to give the title compound (10 mg, 0.021 mmol, 7.43% yield).

[0727] 1H NMR (300MHz, DMSO-d6) δ11.93(s,1H),10.40(s,1H),8.34(d,J=2.0Hz,1H),8.20(d,J=2.4Hz,2H),8.10(d,J=2.0Hz,1H),7.97( d,J=8.5Hz,1H),7.65-7.53(m,2H),7.44(d,J=8.0Hz,1H),6.55(dd,J=3.5,1.8Hz,1H),4.86(s,2H),3.75(s,2H),2.99(s,2H).

[0728] LC-MS (ESI) Method 3: t R =3.14min; m / z(M+1) = 471.1

[0729] Example 69: Preparation of 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide

[0730]

[0731] Step 1: 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl ester (intermediate 54)

[0732]

[0733] Under argon atmosphere, intermediate 38 (3.00 g, 12.11 mmol) and imidazo[1,2-a]pyridine-3-carboxaldehyde (1.770 g, 12.11 mmol) were placed in a flask. Anhydrous DCM (60.5 mL) was added, followed by AcOH (0.693 mL, 12.11 mmol) and TEA (1.688 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, and the organic phases were combined, dried over MgSO4, and evaporated under reduced pressure. The crude product was purified by FCC with DCM / MeOH (DCM to contain 10% MeOH in DCM) to give the title compound (2.24 g, 6.56 mmol, 52% yield).

[0734] 1H NMR (300MHz, CDCl3) δ10.41(s,1H),8.35(d,J=2.0Hz,1H),8.02(d,J=2.0Hz,1H),7.94(s,1H),7.37(dd,J=3.6,1.9Hz,1H),6.50(dd,J =3.6, 1.5Hz, 1H), 4.29 (q, J = 7.1Hz, 2H), 3.88 (s, 2H), 3.73 (s, 2H), 3.05 (t, J = 5.9Hz, 2H), 2.90 (t, J = 5.8Hz, 2H), 1.34 (t, J = 7.1Hz, 3H).

[0735] Step 2: Sodium 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxylate (intermediate 55)

[0736]

[0737] To a solution of intermediate 54 (2.24 g, 6.56 mmol) in MeOH (65.6 mL), 1 M NaOH (6.56 mL, 6.56 mmol) was added, and the reaction mixture was stirred overnight at 40 °C. The solvent was evaporated under vacuum to give the title compound in quantitative yield.

[0738] 1 H NMR (300MHz, DMSO-d6) δ8.05(d,J=2.0Hz,1H),7.77(d,J=2.0Hz,1H),7.43(d,J=3.3Hz,2H),6 .29(d,J=3.0Hz,1H),3.69(s,2H),3.51(s,2H),2.88(d,J=5.8Hz,2H),2.66(t,J=5.8Hz,2H).

[0739] Step 3: 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide (Example 69)

[0740] Intermediate 55 (0.1 g, 0.298 mmol) was dissolved in DMF (0.745 mL) and DCM (2.236 mL), followed by the addition of DIPEA (0.312 mL, 1.789 mmol) and HATU (0.227 g, 0.596 mmol). The mixture was stirred for 15 min, followed by the addition of 3-(trifluoromethyl)aniline (0.045 mL, 0.358 mmol). The reaction mixture was stirred at room temperature until LCMS indicated complete consumption of the starting material or significant conversion was observed in DP. The reaction mixture was diluted with DCM and quenched with 5% citric acid. The layers were separated, and the organic layer was washed again with 5% aqueous citric acid solution (Note: the semi-solid product adhered to the glass). The combined organic layers were washed with saturated aqueous NaHCO3 solution and brine. The crude product was purified by preparative HPLC to give the title compound (18 mg, 0.039 mmol, 13% yield).

[0741] 1 H NMR (300MHz, DMSO-d6) δ11.59(s,1H),10.33(s,1H),8.19(d,J=2.0Hz,2H),8.09(s,1H),7.96(d,J=8.2Hz,1H),7.91(d,J=2.0Hz,1H),7.5 7(t,J=8.0Hz,1H),7.49-7.38(m,2H),6.42(dd,J=3.4,1.9Hz,1H),3.78(s,2H),3.62(s,2H),2.86(t,J=5.7Hz,2H),2.75(t,J=5.7Hz,2H).

[0742] LC-MS (ESI) Method 3: t R =1.93min; m / z(M+1) = 457.0

[0743] The following compounds were prepared by amide coupling as described in steps 1-3 of Example 69, using the corresponding commercially available or previously synthesized amine in step 3.

[0744]

[0745]

[0746] Example 74: Preparation of 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(4-methyl-1H-imidazo-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

[0747]

[0748] 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 56)

[0749]

[0750] 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 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 phases were then separated, the aqueous phase was washed with DCM (3 × 50 mL), the organic phases were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by (DCM to 10% MeOH in DCM) to give the title compound (362 mg, 0.715 mmol, 13.50% yield).

[0751] 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).

[0752] 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 57)

[0753]

[0754] To a solution of intermediate 56 (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 RM was stirred overnight at room temperature. Et₂O was added to RM until no more precipitation was observed, and then the precipitate was filtered off to give the title compound (0.33 g, 0.745 mmol).

[0755] 1 H 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).

[0756] Step 3: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(4-methyl-1H-imidazo-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 74)

[0757] Imidazolo[1,2-a]pyridine-3-carboxylic acid (29.3 mg, 0.181 mmol) was dissolved in anhydrous DMF (452 ​​μL) and dichloromethane (1355 μL), followed by the addition of DIPEA (252 μL, 1.445 mmol) and HATU (137 mg, 0.361 mmol). RM was stirred for 1 h, followed by the addition of intermediate 57 (80 mg, 0.181 mmol). RM was stirred overnight at room temperature. RM was cooled, diluted with DCM (15 mL), and quenched with 5% citric acid (10 mL). The phases were separated, and the organic layer was washed with saturated NaHCO3 (aq) and brine, dried over Na2SO4, and evaporated. The crude product was purified by preparative HPLC (mobile phase: ACN + 0.1% FA, H2O + 0.1% FA) to give the title compound (40 mg, 0.073 mmol, 40.2% yield).

[0758] 1 H NMR (300MHz, DMSO-d6) δ10.55(s,1H),8.96(dt,J=7.0,1.3Hz,1H),8.25-8.18(m,3H),8.14(d,J=3.8Hz,1H),8.10(d,J=1.7Hz,1H),7.7 7-7.68(m,2H),7.51-7.42(m,2H),7.10(td,J=6.9,1.2Hz,1H),5.03(s,2H),3.99(t,J=5.8Hz,2H),3.09(s,2H),2.18(d,J=1.0Hz,3H). LC-MS(ESI) Method 8:t R =2.19 min; m / z(M+1) = 550.9

[0759] Example 75: Preparation of 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazolo-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide

[0760]

[0761] Step 1: Sodium 6-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (intermediate 58)

[0762]

[0763] 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), followed by the addition of 1 M NaOH (72.3 mL, 72.3 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was dried under reduced pressure to give the title compound in quantitative yield.

[0764] 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).

[0765] Step 2: 3-((3-(tert-butyl)-1-(p-tolyl)-1H-pyrazole-5-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (intermediate 59)

[0766]

[0767] Intermediate 58 (5 g, 16.38 mmol) and HATU (12.45 g, 32.8 mmol) were weighed into a reaction tube purged with argon (x3). DCM (123 mL) and DMF (40.9 mL) were added to the reaction mixture, followed by DIPEA (22.88 mL, 131 mmol). The reaction mixture was stirred for 30 min, then 3-(tert-butyl)-1-(p-tolyl)-1H-pyrazole-5-amine (3.49 g, 15.22 mmol) was added, and the mixture was stirred until LC-MS showed complete SM consumption. Further addition of HATU and DIPEA and increasing the reaction temperature were required to obtain complete conversion. The reaction was quenched with water and then extracted with DCM (x3). The organic layers were combined and washed with a 1:1 NaCl (saturated):H2O solution, followed by washing with brine. The combined organic layers were then concentrated under vacuum, and the crude product was purified by FCC (AcOEt / DCM from 0% to 100%) to give the title compound (3.64 g, 7.36 mmol, 44.9% yield).

[0768] 1 H NMR(300MHz,DMSO-d6)δ10.01(s,1H),8.01(s,1H),7.48-7.35(m,2H),7.29-7.20(m,2H),6.33( s,1H),4.55(s,2H),3.53(t,J=5.8Hz,2H),2.70(s,2H),2.32(s,3H),1.42(s,9H),1.30(s,9H).

[0769] Step 3: N-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazole-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (intermediate 60)

[0770]

[0771] Intermediate 59 (2.27 g, 4.59 mmol) was dissolved in DCM (45.9 mL) and cooled to 0 °C. A dioxane solution of HCl (11.47 mL, 45.9 mmol) was added to the reaction mixture and stirred for 16 h. The crude product was concentrated under vacuum and prepared with Et₂O to give the title compound (1.834 g, 4.26 mmol, 93% yield).

[0772] 1H NMR(300MHz,DMSO-d6)δ10.21(s,1H),9.45(s,2H),8.20(s,1H),7.44-7.35(m,2H),7.24(d, J=8.3Hz,3H),6.33(s,1H),4.34(s,1H),3.32(s,2H),2.95(s,2H),2.31(s,3H),1.30(s,9H).

[0773] Step 4: 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazolo-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide (Example 75)

[0774] Intermediate 60 (0.1 g, 0.232 mmol) and 1H-pyrazolo[3,4-b]pyridine-5-carboxaldehyde (0.068 g, 0.464 mmol) were added to a small reaction tube and purged with argon (x3). Methanol (1.160 mL) was added to the reaction mixture, followed by acetic acid (0.040 mL, 0.696 mmol). The tube was sealed and stirred at 50 °C for 1 h. The reaction mixture was then cooled to room temperature, and STAB (80 mg, 1.275 mmol) was added. The mixture was stirred at 50 °C until LC-MS confirmed complete consumption of SM. Further addition of STAB was required to observe 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 HPLC. The purified fraction was concentrated to obtain the desired product containing formic acid. The compound was prepared with 0.1 M NaHCO3 solution to give the title compound (46 mg, 0.088 mmol, 37.7% yield).

[0775] 1 H NMR (300MHz, DMSO-d6) δ13.62(s,1H),9.97(s,1H),8.50(d,J=2.0Hz,1H),8.15(d,J=1.9Hz,1H),8.12(d,J=1.3Hz,1H),7.95(s, 1H),7.39(d,J=8.3Hz,2H),7.24(d,J=8.3Hz,2H),6.32(s,1H),3.81(s,2H),3.62(s,2H),2.73(s,4H),2.30(s,3H),1.29(s,9H).

[0776] LC-MS (ESI) Method 3: t R=1.96min; m / z(M+1)=526.2.

[0777] The compounds reported in the table below were prepared by reductive amination as described in steps 1-4 of Example 75, using the corresponding commercially available aldehyde in step 4.

[0778]

[0779] Example 77: Preparation of 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(tert-butyl)-1-methyl-1H-pyrazolo-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide

[0780]

[0781] Step 1: 3-((3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (intermediate 61)

[0782]

[0783] Intermediate 58 (1 g, 3.28 mmol) and HATU (2.491 g, 6.55 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 (4.58 mL, 26.2 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 stirred at room temperature until LC-MS confirmed complete consumption of SM. Further addition of HATU was required to observe complete conversion.

[0784] 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, and the crude product was purified by rapid column chromatography using a Puriflash instrument (0-50% AcOEt / hexane, eluting the product at 50% AcOEt) to give the title compound.

[0785] 1H 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).

[0786] Step 2: N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (intermediate 62)

[0787]

[0788] Intermediate 61 (1.13 g, 2.70 mmol) was dissolved in DCM (27.0 mL) and cooled to 0 °C. A dioxane solution of HCl (3.37 mL, 13.50 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated, and the residue was prepared with Et₂O to give the title compound in quantitative yield.

[0789] 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).

[0790] Step 3: 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(tert-butyl)-1-methyl-1H-pyrazolo-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide (Example 77)

[0791] Intermediate 62 (100 mg, 0.282 mmol) and 1H-pyrazolo[3,4-b]pyridine-5-carboxaldehyde (41.5 mg, 0.282 mmol) were added to a small reaction tube and purged with argon (x3). MeOH (1409 μL) was added to the reaction mixture, followed by ice-cold AcOH (48.6 μL, 0.845 mmol). The tube was sealed and stirred at 50 °C for 1 h. The reaction mixture was then cooled to room temperature, and STAB (80 mg, 1.268 mmol) was added. The mixture was stirred at 50 °C until LC-MS confirmed complete consumption of SM. Further addition of STAB was required to observe complete conversion. The reaction mixture was quenched with saturated NaHCO3 and transferred to a separatory funnel. 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 rapid column chromatography (0-10% MeOH / DCM) on a Puriflash instrument. The purified fractions were concentrated to give the title compound (39 mg, 0.087 mmol, 30.8% yield).

[0792] 1 H NMR (300MHz, DMSO-d6) δ13.62(s,1H),9.97(s,1H),8.51(d,J=2.0Hz,1H),8.21-8.05(m,3H),6.07(s, 1H), 3.83 (s, 2H), 3.64 (s, 2H), 3.60 (s, 3H), 2.85 (d, J = 5.5Hz, 2H), 2.76 (t, J = 5.8Hz, 2H), 1.22 (s, 9H).

[0793] LC-MS (ESI) Method 9: t R =1.90min; m / z(M+1) = 450.0

[0794] The compounds reported in the table below were prepared by reductive amination as described in steps 1-4 of Example 77, using the corresponding commercially available aldehyde in step 4.

[0795]

[0796] Example 79: Preparation of N-(5-tert-butyl-2-methyl-pyrazol-3-yl)-6-(7-methylimidazo[1,2-a]pyridine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide

[0797]

[0798] Step 1: N-(5-tert-butyl-2-methyl-pyrazol-3-yl)-6-(7-methylimidazo[1,2-a]pyridine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 79)

[0799] G was prepared according to general method from 7-methylimidazo[1,2-a]pyridine-3-carboxylic acid (22 mg, 0.124 mmol) and intermediate 62. The title compound (23 mg, 43%) was purified by reversed-phase preparative HPLC (Sunfire C1819 x 150 mm, 10 μm, 5-60% ACN / H2O (0.1% FA), 20 mL / min, RT).

[0800] 1 H NMR (400MHz, DMSO-d6) δ10.04(s,1H),8.88(d,J=7.3Hz,1H),8.19(s,1H),8.09(s,1H),7.54(s,1H),6.98(dd,J=1.7,7 .2Hz,1H),6.11-6.10(m,1H),5.02(s,2H),3.98(t,J=5.7Hz,2H),3.63(s,3H),3.05(s,2H),2.42(s,3H),1.24(s,9H).

[0801] LC-MS (ESI) Method 7: t R =3.33min; m / z(M+1) = 477.4

[0802] The compounds reported in the table below were prepared as described in step 1 of Example 79, using the corresponding commercially available carboxylic acids in step 1.

[0803]

[0804]

[0805] Example 84: Preparation of 6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0806]

[0807] Step 1: 3-((3-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (intermediate 63)

[0808]

[0809] Intermediate 58 (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). The mixture was stirred continuously at room temperature for 15 min, and then 3-(trifluoromethyl)aniline (1.964 mL, 15.72 mmol) was added. The mixture was stirred continuously at room temperature until LC-MS showed complete consumption of SM. The reaction temperature was raised to 40 °C, and HATU and 3-(trifluoromethyl)aniline were further added to obtain complete conversion. The reaction mixture 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 and 5% wt citric acid solution, washed twice with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by FC (DCM to 10% MeOH in DCM solution) to give the title compound (4.36 g, 10.22 mmol, 78% yield).

[0810] 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).

[0811] Step 2: N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (intermediate 64)

[0812]

[0813] Intermediate 63 (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).

[0814] 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).

[0815] Step 3: 6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0816] Under argon protection, intermediate 64 (0.10 g, 0.276 mmol), imidazo[1,2-a]pyrazin-3-carboxaldehyde (0.041 g, 0.276 mmol), and magnesium sulfate (0.033 g, 0.276 mmol) were placed in a round-bottom flask. Anhydrous DCM (1.378 mL) was added, followed by TEA (0.038 mL, 0.276 mmol). The reaction mixture was stirred at room temperature for 30 min, STAB (0.117 g, 0.551 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM and washed with a 1:1 mixture of saturated K2CO3 and water. The aqueous phase was extracted twice with DCM, the organic phases were combined, dried over Na2SO4, and evaporated under reduced pressure. The crude product was purified by FCC using DCM / MeOH (DCM to DCM containing 5% MeOH) to give the title compound (32 mg, 0.070 mmol, 25.4% yield).

[0817] 1 H NMR (300MHz, DMSO-d6) δ10.34(s,1H),9.07(d,J=1.5Hz,1H),8.56(dd,J=4.7,1.5Hz,1H),8.17(s,1H),8.10(s,1H),7.96(d,J=8.1Hz,1H),7.92(d ,J=4.6Hz,1H),7.82(s,1H),7.57(t,J=8.0Hz,1H),7.42(d,J=7.7Hz,1H) ,4.12(s,2H),3.68(s,2H),2.85(d,J=5.5Hz,2H),2.78(d,J=5.2Hz,2H).

[0818] LC-MS (ESI) Method 3: t R =1.85min; m / z(M+1) = 458.0

[0819] The compounds reported in the table below were prepared by reductive amination as described in steps 1-3 of Example 84, using the corresponding commercially available aldehydes in step 3.

[0820]

[0821]

[0822]

[0823] Example 90: Preparation of 6-(imidazo[1,2-a]pyrazine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0824]

[0825] Imidazolo[1,2-a]pyrazin-3-carboxylic acid (0.049 g, 0.303 mmol) was dissolved in DMF (0.689 mL) and DCM (2.067 mL), followed by the addition of DIPEA (0.289 mL, 1.654 mmol) and HATU (0.231 g, 0.606 mmol). The mixture was stirred for 15 min, and intermediate 64 (0.1 g, 0.276 mmol) was added. The reaction mixture was stirred overnight at room temperature, diluted with DCM, and water was added. The mixture was stirred for 15 min and subjected to phase separation. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by FCC (DCM to 10% MeOH in DCM solution) to give the title compound (71.64 mg, 0.152 mmol, 55% yield).

[0826] 1 H NMR(DMSO-d6,300MHz)δ10.41(s,1H),9.24(d,1H,J=1.5Hz),8.87(dd,1H,J=1.4,4.7Hz),8.33(s,1H),8.21(s,2H), 8.08(d,1H,J=4.8Hz),7.98(d,1H,J=8.8Hz),7.59(t,1H,J=7.9Hz),7.44(d,1H,J=7.7Hz),4.9-5.2(m,2H),3.98(br t,2H,J=5.4Hz),3.0-3.1(m,2H).

[0827] LC-MS (ESI) Method 4: t R =2.77min; m / z(M+1) = 471.9

[0828] The compounds reported in the table below were prepared by amide coupling as described in Example 90, using the corresponding commercially available carboxylic acids in step 1. Variations in general methods or reagents are reported in the table.

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835] Example 97: Preparation of N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0836]

[0837] Step 1: N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 65)

[0838]

[0839] 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 N,N-dimethylformamide (22.50 mL), N,N-diisopropylethylamine (2.9 mL, 16.8 mmol, 3.00 eq) was added, and the reaction 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 (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 trifluoroacetic acid (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 sodium carbonate solution (50 mL) and ethyl acetate (40 mL). The aqueous layer was extracted with ethyl acetate (30 mL), dried over magnesium sulfate, filtered through a hydrophobic glass frit, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0% to 100% ethyl acetate / cyclohexane, then 0% to 100% 3:1 ethyl acetate:ethanol / ethyl acetate) to give the title compound (500 mg, 2.69 mmol, yield 48%).

[0840] 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).

[0841] Step 2: N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide (Example 97)

[0842] HATU (61 mg, 0.160 mmol, 1.22 eq) and N,N-diisopropylethylamine (0.069 mL, 0.394 mmol, 3.00 eq) were added to a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (25 mg, 0.153 mmol, 1.16 eq) in N,N-dimethylformamide (1.50 mL, 0.394 mmol, 3.00 eq), and the reaction mixture was stirred at room temperature for 30 min. Intermediate 65 (50 mg, 0.131 mmol, 1.00 eq) was added, and the reaction mixture was heated at 40 °C overnight, then diluted with DMSO. The title compound (29.2 mg, 45%) was purified by reversed-phase preparative HPLC (Sunfire C18 19x150 mm, 10 μm, 20-80% ACN / H2O (0.1% FA), 20 mL / min, RT).

[0843] 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),9.26(dd,J=1.6,7.0Hz,1H),8.75(d,J=2.5Hz,1H),8.49(s,1H),8.22-8.22(m,1H), 8.00-7.94(m,2H),7.40(d,J=8.5Hz,1H),7.23(dd,J=4.1,7.0Hz,1H),4.89(s,2H),3.95-3.75(m,2H),3.12-2.97(m,2H).

[0844] LC-MS (ESI) Method 7: t R =4.75min; m / z(M+1) = 490.3

[0845] Example 98: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-N-(3-(4-methyl-1H-imidazo-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0846]

[0847] Step 1: 6-(tert-butyl)3-ethyl 2-amino-7-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid (intermediate 66a), 6-(tert-butyl)3-ethyl 2-amino-5-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid (intermediate 66b)

[0848]

[0849] To a mixture of tert-butyl 2-methyl-4-oxopiperidinium-1-carboxylate (10 g, 46.9 mmol) and sulfur (1.5 g, 46.9 mmol) in ethanol (94 mL), ethyl 2-cyanoacetate (5.3 g, 46.9 mmol) and TEA (6.78 mL, 67 mmol) were added and the mixture was refluxed for 4 h. The reaction mixture was cooled and the solvent was evaporated. The crude product was purified by FCC (hexane:AcOEt from 5% to 15%) to give a mixture of 13.4 g of the two regioisomers (1:1 by LCMS and NMR).

[0850] Step 2: 6-(tert-butyl)3-ethyl 7-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid (intermediate 67a), 5-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid (intermediate 67b)

[0851]

[0852] At 0 °C, isoamyl nitrite (8.25 mL, 61.2 mmol) was added dropwise to a solution of the regioisomer mixture intermediates 66a and 66b (13.9 g, 40.8 mmol) obtained after step 1 in 204 mL of THF, and the reaction mixture was heated to room temperature and stirred for 30 min. The reaction mixture was then refluxed for 6 h. The reactants were concentrated under vacuum, and the crude product was purified by FCC (95:5 to 90:10 hexane / AcOEt) to give the title compound (2.98 g) as a 1:1 mixture of regioisomer intermediates 67a and 67b.

[0853] Step 3: 7-Methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate ethyl hydrochloride (intermediate 68a) and 5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate ethyl hydrochloride (intermediate 68b).

[0854]

[0855] A mixture of two regioisomer intermediates, 67a and 67b (2.05 g, 6.30 mmol), was dissolved in Et₂O (31.5 mL), followed by the addition of a dioxane solution of 4N HCl (15.75 mL, 63.0 mmol). The reaction mixture was stirred overnight at room temperature. The solid was filtered off, and the residual solvent was evaporated under vacuum to give 1.4 g of the title compound, a mixture of regioisomers 68a and 68b.

[0856] Step 4: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate ethyl ester (intermediate 69a), 6-(imidazo[1,2-a]pyridine-3-carbonyl)-5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate ethyl ester (intermediate 69b)

[0857]

[0858] A mixture of intermediates 68a and 68b (1 g, 3.82 mmol) was dissolved in DCM (19.10 mL), DIPEA (4.00 mL, 22.92 mmol) was added, followed by T3P (4.55 mL, 7.64 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM, water was added, and the mixture was stirred for 10 min. The phases were then separated, the aqueous phase was washed with DCM (3 × 50 mL), the organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by FCC (0%–10% DCM: MeOH) to give a mixture of 0.77 g of the title compounds.

[0859] Step 5: Lithium 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (intermediate 70a) and lithium 6-(imidazo[1,2-a]pyridine-3-carbonyl)-5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (intermediate 70b)

[0860]

[0861] A mixture of intermediates 69a (550 mg, 1.489 mmol) and 69b (550 mg, 1.489 mmol) was dissolved in methanol (14.887 mL), followed by the addition of 1 M LiOH (1.489 mL, 1.489 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum to give a mixture of title compounds 70a and 70b.

[0862] Step 6: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-N-(3-(4-methyl-1H-imidazo-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 98)

[0863] A mixture of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (0.250 g, 1.037 mmol), intermediates 70a and 70b (0.3 g, 0.864 mmol), was dissolved in DMF (2.159 mL) and DCM (6.48 mL), followed by the addition of DIPEA (0.905 mL, 5.18 mmol) and HATU (0.657 g, 1.728 mmol). The reaction mixture was stirred at 45 °C until the starting material was completely converted. The reaction mixture 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 5% citric acid, water, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The mixture of regioisomers was purified by preparative HPLC to give the title compound (35 mg, 0.062 mmol, 7.18% yield) as a pure compound. 1 H-NMR spectroscopy determined the precise regioisomorphism of Example 97.

[0864] 1 H NMR(300MHz,DMSO-d6)δ10.56(s,1H),8.93(dt,J=7.0,1.2Hz,1H),8.25(s,1H) ,8.23-8.16(m,2H),8.09(d,J=2.7Hz,2H),7.77-7.67(m,2H),7.50-7.41(m,2H ),7.10(td,J=6.9,1.3Hz,1H),5.72(q,J=7.7,6.5Hz,1H),4.52(d,J=9.8Hz,1H ), 3.46 (s, 1H), 3.19-2.96 (m, 2H), 2.18 (d, J = 1.0Hz, 3H), 1.65 (d, J = 6.6Hz, 3H).

[0865] LC-MS (ESI) Method 10: t R =3.94min; m / z(M+1) = 565.1

[0866] The compounds reported in the table below were prepared by amide coupling as described in steps 1-6 of Example 98, using the corresponding commercially available arylamine in step 6. 1 H-NMR spectroscopy determined the structure of the regioisomer.

[0867]

[0868] Example 100: (R)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0869]

[0870] Step 1: (R)-2-amino-7-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tert-butyl)3-ethyl ester (intermediate 71a) and (R)-2-amino-5-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tert-butyl)3-ethyl ester (intermediate 71b)

[0871]

[0872] To a mixture of (R)-2-methyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester (4 g, 18.75 mmol) and sulfur (0.6 g, 18.75 mmol) in ethanol (37.5 mL), ethyl 2-cyanoacetate (2.12 g, 18.75 mmol) and TEA (2.71 g, 26.8 mmol) were added and the mixture was refluxed for 4 h. The reaction mixture was cooled and the solvent was evaporated. The crude product was purified by FCC (hexane: AcOEt; from 5% to 15%) to give a mixture of 4.90 g of the two isomers 71a and 71b, with a combined yield of 77% (1:1 by LCMS and NMR).

[0873] Step 2: (R)-7-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tert-butyl)3-ethyl ester (intermediate 72a) and (R)-5-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tert-butyl)3-ethyl ester (intermediate 72b)

[0874]

[0875] At 0 °C, isoamyl nitrite (2.53 g, 21.6 mmol) was added dropwise to a solution of intermediates 71a and 71b (4.90 g, 28.8 mmol) in THF (72 mL), and the reaction mixture was heated to room temperature and stirred for 30 min. The reaction mixture was then refluxed for 6 h. The reactants were concentrated under vacuum, and the crude product was purified by FCC (95:5 to 90:10 hexane:AcOEt) to give the title compound (1.06 g) as a 1:1 mixture of regioisomers.

[0876] Step 3: (R)-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride (intermediate 73a) and (R)-5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride (intermediate 73b)

[0877]

[0878] A mixture of two regioisomer intermediates, 72a and 72b (1.06 g, 3.26 mmol), was dissolved in Et₂O (16 mL), followed by the addition of a dioxane solution of 4N HCl (12.2 mL, 49.0 mmol). The reaction mixture was stirred overnight at room temperature. It was then diluted with DCM, and a 1:1 mixture of H₂O and saturated NaHCO₃ was added. The mixture was stirred for 10 min. The phases were then separated, the organic phase was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude mixture of regioisomers was separated by FCC (DCM: 5M NH₃ / MeOH 98 / 2) to obtain the following pure regioisomers:

[0879] Intermediate 73a (quantitative yield) 1 H NMR (300MHz, CDCl3) δ7.98 (d, J = 0.8Hz, 1H), 4.32 (q, J = 7.1Hz, 2H), 4.13 (q, J = 6.7Hz, 1H), 3.37 (ddd, J = 12.5, 5.6, 2.2Hz, 1H), 3.06-2.94 (m, 2H), 2.93-2.79 (m, 1H), 1.61 (s, 1H), 1.51-1.43 (m, 3H), 1.38 (t, J = 7.1Hz, 3H).

[0880] Intermediate 73b (0.32 g, 1.42 mmol, yield 87%) 1 H NMR (300MHz, CDCl3) δ7.96 (s, 1H), 4.32 (q, J = 7.1Hz, 2H), 4.10 (t, J = 1.8Hz, 2H), 3.15 (ddt, J = 17.1, 4.3, 1.3Hz, 1H) ,3.06-2.92(m,1H),2.47(ddt,J=17.0,10.1,2.2Hz,1H),1.57(s,1H),1.38(t,J=7.1Hz,3H),1.30(d,J=6.4Hz,4H).

[0881] Step 4: (R)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl ester (intermediate 74)

[0882]

[0883] Intermediate 73a (0.48 g, 2.130 mmol) and imidazo[1,2-a]pyridine-3-carboxylic acid (0.415 g, 2.56 mmol) were dissolved in DMF (5.33 mL) and DCM (15.98 mL), followed by the addition of DIPEA (1.488 mL, 8.52 mmol) and HATU (2.025 g, 5.33 mmol). The reaction mixture was stirred overnight at room temperature, diluted with DCM, and water was added, followed by stirring for 10 min. The phases were then separated, the aqueous phase was washed with DCM (3 × 50 mL), the organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by FCC with DCM:MeOH (0% to 10% MeOH) to give the title compound (0.66 g, 1.786 mmol, 84% yield).

[0884] 1 H NMR(300MHz, CDCl3)δ9.01(dt,J=7.1,1.2Hz,1H),8.03(s,1H),7.97(s,1H),7.70(dt,J=9.1,1 .2Hz,1H),7.36(ddd,J=9.1,6.8,1.3Hz,1H),6.95(td,J=6.9,1.2Hz,1H),5.76(q,J=6.7Hz,1H) ,4.67(dd,J=13.8,5.4Hz,1H),4.32(q,J=7.1Hz,2H),3.45(t,J=12.6Hz,1H),3.28(dd,J=17.1 ,3.7Hz,1H),3.07(ddd,J=17.1,12.1,4.6Hz,1H),1.70(d,J=6.7Hz,3H),1.37(t,J=7.1Hz,3H).

[0885] Step 5: (R)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate lithium (intermediate 75)

[0886]

[0887] 1 M LiOH (3.57 mL, 3.57 mmol) was added to a solution of intermediate 74 (0.66 g, 1.786 mmol) in MeOH (8.93 mL), and the reaction mixture was stirred overnight at room temperature. The solution was concentrated under vacuum to give the title compound in quantitative yield.

[0888] 1 H NMR(300MHz,DMSO-d6)δ8.85(d,J=7.0Hz,1H),8.00(s,1H),7.69(d,J=9.0H z,1H),7.57(s,1H),7.45(ddd,J=8.6,6.8,1.3Hz,1H),7.08(dd,J=7.6,6.3H z,1H),5.55(d,J=6.8Hz,1H),4.41(dd,J=14.0,5.0Hz,1H),3.38(s,1H),3. 24(d,J=17.4Hz,1H),2.92-2.75(m,1H),2.67(s,6H),1.57(d,J=6.6Hz,3H).

[0889] Step 6: (R)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 100)

[0890] Intermediate 75 (0.10 g, 0.288 mmol) and 3-(trifluoromethyl)aniline (0.072 mL, 0.576 mmol) were dissolved in DMF (0.720 mL) and DCM (2.159 mL), followed by the addition of DIPEA (0.302 mL, 1.728 mmol) and HATU (0.274 g, 0.720 mmol). The reaction mixture was stirred overnight at room temperature, diluted with DCM, and water was added. The mixture was stirred for 15 min and subjected to phase separation. The organic phase was washed with water and 5% wt citric acid solution, followed by washing twice with water. The mixture was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by FC (DCM / MeOH from 0% to 10% MeOH) to give the title compound (54.03 mg, 0.112 mmol, 38.7% yield). Non-racemic chemical reactions were carried out on reagents with known absolute configurations by inferring the specified absolute configuration.

[0891] 1H NMR (300MHz, DMSO-d6) δ10.41 (s, 1H), 8.97-8.89 (m, 1H), 8.21 (d, J = 5.7Hz, 2H) ,8.09(s,1H),7.98(d,J=8.2Hz,1H),7.73(dt,J=9.1,1.2Hz,1H),7.59(t,J=8.0 Hz,1H),7.50-7.40(m,2H),7.09(td,J=6.9,1.3Hz,1H),5.71(q,J=6.6Hz,1H), 4.57-4.47(m,1H),3.53-3.39(m,1H),3.17-2.94(m,2H),1.64(d,J=6.7Hz,3H).

[0892] LC-MS (ESI) Method 11: t R =2.14min; m / z(M+1) = 485.1

[0893] The compounds reported in the table below were prepared by amide coupling as described in steps 1-6 of Example 100, with the corresponding commercially available arylamine used in step 6.

[0894]

[0895] Example 102: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7,7-dimethyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0896]

[0897] Step 1: 6-(tert-butyl)3-ethyl 2-amino-7,7-dimethyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid (intermediate 76a) and 6-(tert-butyl)3-ethyl 2-amino-5,5-dimethyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid (intermediate 76b)

[0898]

[0899] To a mixture of tert-butyl 2,2-dimethyl-4-oxopiperidin-1-carboxylate (5 g, 22.00 mmol) and sulfur (0.705 g, 22.00 mmol) in ethanol (44.0 mL), ethyl 2-cyanoacetate (2.341 mL, 22.00 mmol) and TEA (4.38 mL, 31.5 mmol) were added and refluxed for 6 h. The solvent was evaporated and the crude product was purified by FCC (hexane:AcOEt = 95:5 to 85:15) to give the following pure regioisomers:

[0900] Intermediate 76a (0.67 g, 1.890 mmol, 8.59% yield). 1 H NMR (300MHz, CDCl3) δ5.98 (s, 2H), 4.26 (q, J = 7.1Hz, 3H), 3.64 (dd, J = 5.9, 5.1H z, 2H), 2.78 (t, J = 5.5Hz, 2H), 1.68 (s, 6H), 1.50 (s, 9H), 1.34 (t, J = 7.1Hz, 3H).

[0901] Intermediate 76b (4.27 g, 12.05 mmol, 54.8% yield). 1 ¹H NMR (300MHz, CDCl₃) δ 5.96 (s, 2H), 4.35 (d, J = 1.5Hz, 2H), 4.28 (q, J = 7.1Hz, 2H), 2.85 (s, 2H), 1.47 (s, 9H), 1.44 (s, 6H), 1.35 (t, J = 7.1Hz, 3H). (By...) 1 H-NMR spectroscopy determined its precise regioisomeric structure.

[0902] Step 2: 6-(tert-butyl)3-ethyl 7,7-dimethyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid (intermediate 77)

[0903]

[0904] At 0 °C, isoamyl nitrite (0.382 mL, 2.84 mmol) was added dropwise to a THF (9.45 mL) solution of intermediate 76a (0.67 g, 1.890 mmol). The reaction mixture was heated to room temperature and stirred for 30 min. The reaction mixture was then heated to reflux for 6 h and concentrated under vacuum. The crude product was purified by FCC with hexane:ethyl acetate (95:5 to 90:10) to give the title compound (160 mg, 0.471 mmol, 24.94% yield).

[0905] 1H NMR (300MHz, CDCl3) δ7.97 (s, 1H), 4.30 (q, J = 7.1Hz, 2H), 3.69 (t, J = 5.5Hz, 2H), 2.96 (t, J = 5.5Hz, 2H), 1.79 (s, 6H), 1.51 (s, 9H), 1.36 (t, J = 7.1Hz, 3H).

[0906] Step 3: 7,7-Dimethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride (intermediate 78)

[0907]

[0908] A solution of 4NHCl in dioxane (1.768 mL, 7.07 mmol) was added to a solution of intermediate 77 (0.16 g, 0.471 mmol) in DCM (3.93 mL), and the reaction mixture was stirred overnight at room temperature. The solid was filtered off, and the residual solvent was evaporated under vacuum to give the title compound (0.10 g, 0.363 mmol, 77% yield).

[0909] 1 H NMR (300MHz, DMSO-d6) δ9.73 (s, 2H), 8.35 (s, 1H), 4.26 (q, J = 7.1Hz, 2H), 3.4 5(t,J=6.1Hz,2H), 3.07(t,J=6.1Hz,2H), 1.69(s,6H), 1.29(t,J=7.1Hz,3H).

[0910] Step 4: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl ester (intermediate 79)

[0911]

[0912] Intermediate 78 (0.10 g, 0.363 mmol) and imidazo[1,2-a]pyridine-3-carboxylic acid (0.071 g, 0.435 mmol) were dissolved in DMF (0.906 mL) and DCM (2.72 mL), followed by the addition of DIPEA (0.317 mL, 1.813 mmol) and HATU (0.345 g, 0.906 mmol). The reaction mixture was stirred overnight at room temperature. To obtain complete conversion, the temperature was raised to 80 °C, and further addition of HATU and imidazo[1,2-a]pyridine-3-carboxylic acid was required. The reaction mixture diluted with DCM was cooled and water was added, followed by stirring for 15 min and phase separation. The organic phase was washed with 5% citric acid, water, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by FC (DCM / MeOH from 0% to 10%) to give the title compound (74 mg, 0.193 mmol, 53.2% yield).

[0913] 1 H NMR (300MHz, CDCl3) δ9.05(d,J=7.0Hz,1H),8.05(s,1H),7.96(s,1H),7.70(d,J=9.0Hz,1H),7.36(dd,J=9.0,6.8Hz,1H),6. 97(t,J=6.9Hz,1H),4.34(q,J=7.1Hz,2H),3.98(t,J=5.4Hz,2H),3.21(t,J=5.5Hz,2H),1.98(s,6H),1.38(t,J=7.1Hz,3H).

[0914] Step 5: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate lithium (intermediate 80)

[0915]

[0916] 1 M LiOH (772 μL, 0.772 mmol) was added to a MeOH (965 μL) solution of intermediate 79 (74 mg, 0.193 mmol), and the reaction mixture was stirred overnight at room temperature. The crude product was then concentrated under vacuum to give the title compound (68 mg, 0.188 mmol, 98% yield).

[0917] 1H NMR(300MHz,DMSO-d6)δ8.90(dt,J=7.0,1.3Hz,1H),7.99(s,1H),7.71(dt,J=9.0,1.2Hz,1H),7.51(s,1H ),7.48-7.38(m,1H),7.09(td,J=6.9,1.2Hz,1H),3.81(t,J=5.3Hz,2H),3.20-3.11(m,3H),1.87(s,6H).

[0918] Step 6: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7,7-dimethyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 102)

[0919] Intermediate 80 (0.065 g, 0.180 mmol) was dissolved in DMF (0.84 mL) and DCM (2 mL), followed by the addition of DIPEA (0.189 mL, 1.079 mmol) and HATU (0.171 g, 0.450 mmol). The reaction mixture was stirred for 15 min, followed by the addition of 3-(trifluoromethyl)aniline (0.058 g, 0.360 mmol) and stirring overnight at room temperature. Further addition of amine and HATU was required to obtain complete conversion. The reaction mixture was cooled, 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 5% citric acid, water, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by FC (0% to 10% DCM / MeOH) to give the title compound (29 mg, 0.058 mmol, 32.3% yield).

[0920] 1 H NMR (300MHz, DMSO-d6) δ10.43 (s, 1H), 8.93 (dt, J = 7.0, 1.2Hz, 1H), 8.24 (s, 1H),8.22(s,1H),8.05(s,1H),7.98(d,J=8.3Hz,1H),7.73(dt,J=9.1,1.2H z,1H),7.60(t,J=8.0Hz,1H),7.46(ddd,J=9.0,6.8,1.4Hz,2H),7.11(td,J =6.9, 1.3Hz, 1H), 3.88 (t, J = 5.3Hz, 2H), 3.13 (t, J = 5.2Hz, 2H), 1.93 (s, 6H).

[0921] LC-MS (ESI) Method 2: t R =2.93min; m / z(M+1) = 499.1

[0922] Example 103: 6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0923]

[0924] Example 104: 6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-5-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide - first elution

[0925]

[0926] Example 105: 6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-5-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide - second elution

[0927]

[0928] Step 1: Lithium 6-(tert-Butoxycarbonyl)-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (intermediate 81a), lithium 6-(tert-Butoxycarbonyl)-5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (intermediate 81b)

[0929]

[0930] Intermediate 67a (0.430 g, 1.32 mmol) was dissolved in MeOH (26.4 mL), followed by the addition of 1 M LiOH (5.29 mL, 5.29 mmol). The reaction mixture was stirred overnight at 40 °C. The crude product was concentrated under vacuum to give a mixture of the title compounds.

[0931] Step 2: 7-Methyl-3-((3-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (intermediate 82a) and 5-methyl-3-((3-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (intermediate 82b)

[0932]

[0933] A mixture of intermediates 81a and 81b (0.90 g, 2.96 mmol) was dissolved in DMF (7.42 mL) and DCM (22.26 mL), followed by the addition of DIPEA (2.073 mL, 11.87 mmol) and HATU (2.82 g, 7.42 mmol). The reaction mixture was stirred at room temperature for 15 min, and 3-(trifluoromethyl)aniline (0.741 mL, 5.93 mmol) was added. The mixture was stirred overnight at 40 °C. It was then diluted with DCM and water was added. The mixture was stirred for 15 min and subjected to phase separation. The organic phase was washed with water and 5% wt citric acid solution, washed twice with water and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by FC (0% to 10% MeOH in DCM / MeOH). The resulting product was prepared with pentane to give a mixture of 750 mg of the title compounds.

[0934] Step 3: 7-Methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (intermediate 83a) and 5-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (intermediate 83b)

[0935]

[0936] A mixture of intermediates 82a and 82b (750 mg, 1.70 mmol) was dissolved in DCM (20 mL) and MeOH (4 mL). A dioxane solution of 4N HCl (4.26 mL, 17.03 mmol) was then added, and the mixture was stirred overnight at room temperature. Et₂O was added until no further precipitation was observed, then the solid was filtered off, and the residual solvent was evaporated under vacuum to give a mixture of 650 mg of the title compound.

[0937] Step 4: 6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 103), 6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-5-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 104), 6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-5-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 105)

[0938] Under argon protection, a mixture of intermediates 83a and 83b (0.140 g, 0.372 mmol), imidazo[1,2-a]pyrazin-3-carboxaldehyde (0.066 g, 0.446 mmol), and magnesium sulfate (0.045 g, 0.372 mmol) was placed in a round-bottom flask. Anhydrous DCM (3.72 mL) was added, followed by TEA (0.052 mL, 0.372 mmol), and the reaction mixture was stirred at room temperature for 30 min. STAB (0.236 g, 1.115 mmol) was then added, and the reaction mixture was stirred until LC-MS indicated complete consumption of the starting material. The reaction mixture was then diluted with DCM and washed with a 1:1 mixture of saturated Na₂CO₃ and water. The aqueous phase was extracted twice with DCM, the combined organic phases were washed with brine, dried over Na₂SO₄, and evaporated under reduced pressure. The crude product was pre-purified by FCC (DCM / MeOH from 0% to 5% MeOH) to obtain a 60 mg mixture of regioisomers. The mixture was dissolved in MeOH to 11 mg / mL and then purified by preparative HPLC (Method Prep1) to give a mixture of Example 105 (3.3 mg, 0.007 mmol, yield 2%) and Examples 103 and 104, which were further separated by SFC (Method Prep2) to give Example 103 (12.9 mg, 0.027 mmol, yield 7%) and Example 104 (2.8 mg, 0.006 mmol, yield 1%).

[0939] Example 105: 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),9.06(d,J=1.5Hz,1H),8.49(dd,J=4.6,1.5 Hz,1H),8.20(s,1H),8.11(s,1H),7.98-7.93(m,1H),7.92(d,J=4.6Hz,1H),7.78 (s,1H),7.58(t,J=8.0Hz,1H),7.43(d,J=7.7Hz,1H),4.11(s,2H),3.68(s,2H),3 .17(q,J=5.6Hz,1H),3.06-2.97(m,1H),2.75-2.68(m,1H),1.15(d,J=6.6Hz,3H). LC-MS (ESI) Method 12: t R =4.23min; m / z(M+1)=472.2; ee99.3%

[0940] Example 103: 1H NMR (300MHz, DMSO-d6) δ10.34(s,1H),9.07(d,J=1.4Hz,1H),8.51(dd,J=4.7,1.5 Hz,1H),8.18(s,1H),8.14(s,1H),8.01-7.88(m,2H),7.82(s,1H),7.57(t,J=8.0 Hz,1H),7.42(d,J=7.8Hz,1H),4.26(d,J=14.4Hz,1H),4.04(d,J=14.4Hz,1H),3. 95(q,J=6.6Hz,1H),2.99-2.78(m,2H),2.76-2.62(m,2H),1.44(d,J=6.6Hz,3H).

[0941] LC-MS (ESI) Method 12: t R =4.99min; m / z(M+1)=472.2; ee100%

[0942] Example 104: 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),9.06(d,J=1.5Hz,1H),8.49(dd,J=4.6,1.5 Hz,1H),8.20(s,1H),8.11(s,1H),7.98-7.93(m,1H),7.92(d,J=4.6Hz,1H),7.78 (s,1H),7.58(t,J=8.0Hz,1H),7.43(d,J=7.7Hz,1H),4.11(s,2H),3.68(s,2H),3 .17(q,J=5.6Hz,1H),3.06-2.97(m,1H),2.74-2.68(m,1H),1.15(d,J=6.6Hz,3H).

[0943] LC-MS (ESI) Method 12: t R =3.57min; m / z(M+1)=472.2; ee98.3%.

[0944] Example 106: 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide-first eluting enantiomer

[0945]

[0946] Example 107: 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide-second eluting enantiomer)

[0947]

[0948] Step 1: 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide - first eluted enantiomer (Example 106) and 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide - second eluted enantiomer (Example 107)

[0949] Under argon atmosphere, a mixture of intermediates 83a and 83b (0.20 g, 0.531 mmol), 1H-pyrrolo[2,3-b]pyridine-5-carboxaldehyde (0.078 g, 0.531 mmol), and magnesium sulfate (0.064 g, 0.531 mmol) was placed in a round-bottom flask. Anhydrous DCM (5.31 mL) was added, followed by TEA (0.074 mL, 0.531 mmol). The reaction mixture was stirred at room temperature for 30 min, and STAB (0.337 g, 1.592 mmol) was added, with the mixture stirred at room temperature. Further addition of STAB and the aldehyde was required to obtain complete conversion of SM. The reaction mixture was diluted with DCM, and saturated NaHCO3 was added, with the mixture stirred for 15 min. The phases were separated, the aqueous phase was extracted twice with DCM, the organic phases were combined, washed with brine dried over Na2SO4, and evaporated under reduced pressure. The crude product was pre-purified by FCC (0% to 5% DCM / MeOH) to give 190 mg of an enantiomer mixture, which was then purified by chiral SFC (method pREP3) to give:

[0950] Example 106: (39 mg, 0.082 mmol, 31% yield)

[0951] 1H NMR (300MHz, DMSO-d6) δ11.57(s,1H),10.34(s,1H),8.19(d,J=2.2Hz,2H),8.12(s,1H), 7.96(d,J=8.2Hz,1H),7.91(d,J=2.0Hz,1H),7.57(t,J=8.0Hz,1H),7.48-7.38(m,2H),6 .42(dd,J=3.5,1.2Hz,1H),3.95(d,J=13.5Hz,1H),3.89(d,J=6.7Hz,1H),3.68(d,J=13. 4Hz, 1H), 3.05-2.93 (m, 1H), 2.93-2.78 (m, 1H), 2.77-2.58 (m, 2H), 1.45 (d, J = 6.5Hz, 3H).

[0952] SFC-MS (ESI) Method 13: t R =6.92min; m / z(M+1)=471.2;

[0953] Example 107: (36 mg, 0.077 mmol, 29% yield).

[0954] 1 H NMR (300MHz, DMSO-d6) δ11.57(s,1H),10.34(s,1H),8.19(d,J=2.2Hz,2H),8.12(s,1H), 7.96(d,J=8.2Hz,1H),7.91(d,J=2.0Hz,1H),7.57(t,J=8.0Hz,1H),7.48-7.38(m,2H),6 .42(dd,J=3.5,1.2Hz,1H),3.95(d,J=13.5Hz,1H),3.89(d,J=6.7Hz,1H),3.68(d,J=13. 4Hz, 1H), 3.05-2.93 (m, 1H), 2.93-2.78 (m, 1H), 2.77-2.58 (m, 2H), 1.45 (d, J = 6.5Hz, 3H).

[0955] SFC-MS (ESI) Method 13: t R =9.73 min; m / z(M+1) = 471.2

[0956] Example 109: Preparation of compound 6-(pyrazolo[1,5-a]pyrimidin-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0957]

[0958] Step 1: 3-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (intermediate 89)

[0959]

[0960] To a suspension of 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (250 mg, 0.882 mmol) in anhydrous acetonitrile (4.4 mL), 5-(trifluoromethyl)pyridine-3-amine (157 mg, 0.971 mmol) and 1-methylimidazole (0.25 mL, 3.09 mmol) were added to form a complete solution. TCFH (371 mg, 1.32 mmol) was then added, and the reaction mixture was stirred at room temperature under an argon atmosphere for 22 h. The reaction mixture was partitioned between saturated NaHCO3(aq) and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were passed through a hydrophobic glass frit and concentrated under vacuum. Purification by silica gel column chromatography (0-25% EtOAc in cyclohexane + 0.1% NEt3) gave the desired compound (265 mg, 0.62 mmol, 70%).

[0961] 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).

[0962] Step 2: N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide (intermediate 90)

[0963]

[0964] Under an argon atmosphere, TFA (0.52 mL, 6.78 mmol) was added dropwise over 5 min to a stirred solution of intermediate 89 (290 mg, 0.678 mmol) cooled on an ice / water bath in anhydrous DCM (6.78 mL). The reaction mixture was stirred for 3 h. Further TFA (0.17 mL, 2.26 mmol) 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 applied to a pretreated 5 g Isolute SCX-II column. The column 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 desired product (193 mg, 0.59 mmol, 87%).

[0965] 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).

[0966] Step 3: 6-(pyrazolo[1,5-a]pyrimidin-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide (Example 109)

[0967] G was prepared according to general method from intermediate 90 (40 mg, 0.122 mmol) and pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (17 mg, 0.104 mmol). The title compound (6 mg, 0.013 mmol, 12%) was obtained by reversed-phase preparative HPLC (Sunfire C18 19x150 mm, 10 μm, 20-80% acetonitrile / water-10 mM NH4HCO3, 20 mL / min).

[0968] LCMS (ESI): Method 6t R =3.79min, m / z[M+1]+=473.3.

[0969] 1H NMR (400MHz, DMSO-d6) δ10.66(s,1H),9.26(dd,J=1.8,7.0Hz,1H),9.13(d,J=2.3Hz,1H),8.75(dd,J=1.6,4.0Hz,1H),8.69(d,J=1.0H z,1H),8.62-8.59(m,1H),8.49(s,1H),8.25(brs,1H),7.23(dd,J=4.0,7.0Hz,1H),4.89(s,2H),3.91-3.75(m,2H),3.11-3.02(m,2H).

[0970] The compounds reported in the table below were prepared by amide coupling as described in steps 1-3 of Example 109, using the corresponding commercially available or previously synthesized carboxylic acids in step 3. Coupling agents, salt-free methods, or modifications to chromatographic purification conditions (e.g., preparative HPLC or rapid chromatography) are reported in the table.

[0971]

[0972]

[0973]

[0974]

[0975]

[0976] Example 112: Preparation of compound N-(3-(tert-butyl)isoxazol-5-yl)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0977]

[0978] Step 1: 6-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester (intermediate 91)

[0979]

[0980] To a suspension of intermediate 38 (125 mg, 0.505 mmol), 6,8-dihydro-5H-imidazolium[2,1-c][1,4]oxazine-3-carboxylate (124 mg, 0.605 mmol), and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylureonium tetrafluoroborate (232 mg, 0.722 mmol) in anhydrous DCM (2.00 mL) and DMF (2.00 mL), N,N-diisopropylethylamine (0.35 mL, 2.02 mmol) was added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 h and allowed to stand for 16 h. The reaction mixture was diluted with saturated NaHCO3 (aq), and the organic phase was washed with saturated NaCl (aq), then dried with Na2SO4 and concentrated under vacuum. The residue was purified by FCC elution with DCM-methanol-ammonia (2M; 20:1) / 0-100% to give the desired product (196 mg, 0.477 mmol, 95%).

[0981] 1 H NMR (400MHz, CDCl3) δ8.02(s,1H),7.33(s,1H),4.94(s,2H),4.88(s,2H),4.32(q,J=7.2Hz,2H),4.28( t,J=5.4Hz,2H),4.05(t,J=5.2Hz,2H),4.01(t,J=5.5Hz,2H),3.17-3.12(m,2H),1.37(t,J=7.1Hz,3H).

[0982] Step 2: 6-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (intermediate 92)

[0983]

[0984] Sodium hydroxide (68 mg, 1.71 mmol) was added to a methanol (10) and water (0.50) solution of intermediate 91 (191 mg, 0.528 mmol) and stirred at 50 °C for 3 days.

[0985] The mixture was cooled in an ice bath and 1M hydrogen chloride (1.7 mL, 1.71 mmol) was added dropwise. The solution was concentrated under vacuum to obtain a colorless solid precipitate, which was filtered and washed with acetone (2) to give the desired product (76 mg, 0.228 mmol, 43%), which was used as is in the next step.

[0986] Step 3: N-(3-(tert-butyl)isoxazol-5-yl)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 112)

[0987] Thionyl chloride (0.13 mL, 1.80 mmol) was added to intermediate 92 (30 mg, 0.0900 mmol), and the mixture was stirred overnight at room temperature. The mixture was dried under vacuum, and the residue was suspended in dried pyridine (1.0 mL). 3-tert-butylisoxazole-5-amine (19 mg, 0.135 mmol) was added, and the mixture was stirred for 1 h. The mixture was dried under vacuum, and the residue was dissolved in 9:1 DMSO:water (1.0 mL) and purified by a Sunfire C18 19x150 mm, 10 μm, 5-60% ACN / H2O (0.1% FA), 20 mL / min to give the desired product (17 mg, 0.0381 mmol, 42%).

[0988] LCMS (ESI): Method 15t R = 3.48 min, [M+H] + =456.2

[0989] 1 H NMR(400MHz,DMSO-d6)d 11.77(s,1H),8.34(s,1H),7.40(s,1H),6.37(s,1H),4.95-4.89(s,2H),4.80-4.79(m,2H), 4.14(t,J=5.1Hz,2H),4.00(t,J=5.1Hz,2H),3.91(t,J=5.4Hz,2H),3.02(s,2H),1.29(s,9H)

[0990] Example 113: Preparation of compound N-(3-(tert-butyl)isoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[0991]

[0992] Step 1: 6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl ester (intermediate 93)

[0993]

[0994] N,N-diisopropylethylamine (0.35 mL, 2.02 mmol) was added to a suspension of intermediate 38 (125 mg, 0.505 mmol), pyrazolo[1,5-a]pyrazin-3-carboxylic acid (99 mg, 0.605 mmol), and TBTU (232 mg, 0.722 mmol) in DCM (2 mL) and DMF (2 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with saturated NaHCO3 (aq), and the organic phase was washed with saturated NaCl (aq) and concentrated under vacuum. The residue was purified by silica gel chromatography on a 0-100% elution with DCM-methanol-ammonia (2 M; 20:1) to give the title compound (149 mg, 82%).

[0995] 1 H NMR(400MHz, CDCl3) δ9.48(d,J=1.5Hz,1H),8.43(dd,J=1.5,4.8Hz,1H),8.20(s,1H),8.05(d,J=4.8Hz,1H),8 .04(s,1H),4.98(s,2H),4.32(q,J=7.0Hz,2H),4.02(t,J=5.9Hz,2H),3.23-3.18(m,2H),1.38(t,J=7.0Hz,3H)

[0996] Step 2: 6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (intermediate 94)

[0997]

[0998] Sodium hydroxide (49 mg, 1.23 mmol) was added to a solution of intermediate 93 (142 mg, 0.398 mmol) in methanol (10 mL) and water (0.5 mL), and the mixture was stirred at 50 °C for 64 h. The mixture was cooled in an ice bath and 1 M aqueous hydrogen chloride solution (1.2 mL, 1.23 mmol) was added dropwise. The solution was concentrated under vacuum to give a colorless solid precipitate, which was filtered and washed with acetone (2 mL) to give the title compound (86 mg, 66%).

[0999] LCMS (ESI): Method 15t R =0.47min; m / z[M+H] + =329.2

[1000] Step 3: N-(3-tert-butyl)isoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 113)

[1001] The title compound (4 mg, 9%) was prepared according to general method I from the prior intermediate 94 (30 mg, 0.0914 mmol) and 3-tert-butylisoxazole-5-amine (19 mg, 0.137 mmol). The compound was purified by reversed-phase preparative HPLC (Sunfire C18 19x150 mm, 10 μm, 20-80% ACN / H2O (0.1% FA), 20 mL / min, RT) to give the title compound.

[1002] LCMS (ESI): Method 7t R = 3.92 min; m / z [M+H] + =451.2

[1003] 1 H NMR (400MHz, DMSO-d6) δ11.78(s,1H),9.36(d,J=1.5Hz,1H),8.93(dd,J=1.4,4.7Hz,1H),8.55(s,1H),8.34(s, 1H),8.11(d,J=4.6Hz,1H),6.37(s,1H),4.99(s,2H),3.95(t,J=5.8Hz,2H),3.07(t,J=6.0Hz,2H),1.29(s,9H)

[1004] Example 116: Preparation of compound N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[1005]

[1006] Step 1: 3-((5-(tert-butyl)-1-methyl-1H-pyrazole-3-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (intermediate 95)

[1007]

[1008] Oxaloyl chloride (0.050 mL, 0.600 mmol) was added dropwise to a CPME (1 mL) solution of 6-(tert-butyloxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (142 mg, 0.500 mmol) and DMF (0.0019 mL, 0.0250 mmol) at 20 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum, and the residue was azeotropically reacted with CPME. The residue was suspended in ACN (1 mL) and cooled to 0 °C in an ice bath. A solution of 5-tert-butyl-2-methylpyrazole-3-amine (77 mg, 0.500 mmol) and pyridine (0.081 mL, 1.00 mmol) in ACN (1 mL) was added to the mixture. The reaction mixture was heated to room temperature and stirred for 1 h. The reaction mixture was concentrated under vacuum, and the residue was partitioned between water and DCM. The combined organic phases were filtered through a hydrophobic glass frit, and the solvent was concentrated under vacuum. The residue was purified by silica gel FCC (0-50% EtOAc in cyclohexane solution) to give the desired product (186 mg, 0.444 mmol, 89%).

[1009] 1 H NMR (400MHz, CDCl3) δ7.75 (s, 1H), 6.08 (s, 1H), 4.57 (s, 2H), 3.65 (s, 3H), 3.62 (m, 2H), 2.95 (t, J = 5.4Hz, 2H), 1.47 (s, 9H), 1.26 (s, 9H).

[1010] Step 2: N-(5-tert-butyl-1-methylpyrazol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 96)

[1011]

[1012] A solution of 4N HCl in dioxane (3 mL) was added to a solution of intermediate 95 (186 mg, 0.444 mmol) in 1,4-dioxane (3 mL). The reaction mixture was stirred at room temperature for 3 h, then diluted with diethyl ether and filtered to give a white solid, which was washed with diethyl ether and dried under vacuum overnight to give the desired product, dihydrochloride (144 mg, 0.368 mmol, 83%).

[1013] 1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),9.73-9.69(m,2H),8.44(s,1H),6.16(s,1H) ,4.42(s,2H),3.70(s,3H),3.40-3.40(m,2H),3.13(t,J=5.6Hz,2H),1.29(s,9H).

[1014] Step 3: N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 116)

[1015] The title compound (7 mg, 0.015 mmol, 26%) was prepared according to General Method I from pyrazolo[1,5-a]pyrazin-3-carboxylic acid (10 mg, 0.068 mmol) and intermediate 96 (20 mg, 0.068 mmol). The compound was purified by reversed-phase preparative HPLC (Xbridge Phenyl 19x150 mm, 10 μm, 40–100% MeOH / H₂O (10 mM NH₄CO₃), 20 mL / min) to give the title compound.

[1016] LCMS (ESI): Method 7t R =3.91min, m / z[M+H]+=464.2.

[1017] 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),9.40(d,J=1.3Hz,1H),8.97(dd,J=1.4,4.7Hz,1H),8.59(s,1H),8.24(s,1H),8.1 4(d,J=4.5Hz,1H),6.47(s,1H),5.04-4.97(m,2H),3.97(t,J=5.8Hz,2H),3.88(s,3H),3.12-3.09(m,2H),1.40(s,9H).

[1018] The compounds reported in the table below were prepared by amide coupling as described in steps 1-3 of Example 116, using a commercially available or previously synthesized aldehyde in step 3. Such a method may involve minor modifications. Changes involving coupling agents are reported in the table below.

[1019]

[1020] Example 119: Preparation of compound 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(tert-pentyl)isoxazol-5-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[1021]

[1022] Step 1: 3-((3-(tert-amyl)isoxazol-5-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (intermediate 97)

[1023]

[1024] Oxaloyl chloride (55 μL, 0.635 mmol) was added dropwise to a CPME (1 mL) solution of 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (150 mg, 0.529 mmol) and DMF (2 μL, 0.0265 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum, and the residue was azeotropically reacted with CPME. The residue was suspended in ACN (2 mL) and cooled to 0 °C in an ice bath. 3-(1,1-dimethylpropyl)isoxazole-5-amine (82 mg, 0.529 mmol) and pyridine (86 μL, 1.06 mmol) were added to the mixture. The reaction mixture was heated to room temperature and stirred for 3 h. 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 reversed-phase chromatography to obtain the desired product (14 mg, 0.033 mmol; 6%).

[1025] 1 H NMR (400MHz, CDCl3) δ8.61-8.61(m,1H),7.67(s,1H),6.23(s,1H),4.51(s,2H),3.55(t,J=5.6Hz ,2H),2.88(t,J=5.6Hz,2H),1.52(q,J=7.5Hz,2H)1.36(s,9H),1.17(s,6H),0.69(t,J=7.5Hz,3H)

[1026] Step 2: N-(3-(tert-amyl)isoxazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (intermediate 98)

[1027]

[1028] A solution of 1,4-dioxane (1 mL) containing 4N hydrogen chloride (1.0 mL, 0.033 mmol) was added to a solution of intermediate 97 (14 mg, 0.0334 mmol) in 1,4-dioxane. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with diethyl ether and filtered to give a white solid, which was washed with diethyl ether and dried under vacuum to give the title compound hydrochloride in quantitative yield.

[1029] LCMS (ESI): Method 16t R = 1.04 min; m / z [M+H] + =320.1

[1030] Step 3: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(tert-amyl)isoxazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 119)

[1031] N was prepared according to general method from imidazo[1,2-a]pyridine-3-carboxylic acid (7 mg, 0.04 mmol) and intermediate 98 (assumed to be 0.0334 mmol). The reaction was quenched with water, filtered, the solid was washed with water, and dried under vacuum overnight to give the title compound (17 mg, 0.027 mmol; 81%).

[1032] LCMS (ESI): Method 7t R = 4.52 min; m / z [M+H] + =464.8.

[1033] 1 H NMR (400MHz, DMSO-d6) δ11.80(s,1H),9.01(d,J=7.1Hz,1H),8.39(s,1H),8.18(s,1H),7.78(d,J=8.8Hz,1H),7.54-7.49(m,1H),7.17-7.1 2(m,1H),6.37(s,1H),5.07(s,2H),4.03(t,J=5.6Hz,2H),3.12(t,J=5.9Hz,2H),1.66(q,J=7.4Hz,2H),1.29(s,6H),0.81(t,J=7.5Hz,3H).

[1034] Example 121: Preparation of compound N-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide

[1035]

[1036] Step 1: 3-[[6-methoxy-5-(trifluoromethyl)-3-pyridyl]carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (intermediate 99)

[1037]

[1038] Following the method described in step 1 of Example 109, intermediate 99 was prepared starting from 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (167 mg, 0.589 mmol). The reaction mixture was concentrated under vacuum, quenched with water, and filtered to give a solid, which was washed with water and dried under vacuum to give the title compound (220 mg, 0.481 mmol, 82%).

[1039] 1 H NMR(400MHz, CDCl3)δ8.46(m,1H),8.29(m,1H),7.71-7.64(m,1H),4.60(s,2H),4. 03(s,3H),3.67(t,J=5.4Hz,2H),2.99(t,J=5.7Hz,2H),2.80(s,2H),1.50(s,9H).

[1040] Step 2: N-[6-methoxy-5-(trifluoromethyl)-3-pyridyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 100)

[1041]

[1042] At 0 °C, a solution of 4N hydrogen chloride in dioxane (5.0 mL, 0.481 mmol) was added to a solution of intermediate 99 (220 mg, 0.481 mmol) in 1,4-dioxane (5 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with diethyl ether and filtered. The resulting solid was washed with diethyl ether and dried under vacuum to give the title compound, a dihydrochloride (240 mg, 0.558 mmol, 116%).

[1043] 1 H NMR (400MHz, DMSO-d6) δ10.70(s,1H),9.68(s,2H),8.81(d,J=2.1Hz,1H),8.54(d,J=2 .4Hz,1H),8.48(s,1H),4.38(m,2H),3.99(s,3H),3.35(m,2H),3.13(t,J=5.7Hz,2H).

[1044] Step 3: N-[6-methoxy-5-(trifluoromethyl)-3-pyridyl]-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 121)

[1045] To a solution of intermediate 100 (50 mg, 0.116 mmol), pyrazolo[1,5-a]pyrazin-3-carboxylic acid (19 mg, 0.116 mmol), and 1-methylimidazolium (0.074 mL, 0.930 mmol) in ACN (5.00 mL), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (49 mg, 0.174 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with water and extracted with DCM. The combined organic phases were filtered through a hydrophobic glass frit, and the solvent was concentrated under vacuum. The residue was purified by preparative HPLC (Sunfire C18 19x150 mm, 10 μm, 5-60% ACN / H2O (10 mM NH4CO3), 20 mL / min) to give the title compound (4.02 mg, 97%).

[1046] LCMS (ESI): Method 7t R =4.36min; m / z[M+H]+=503.2

[1047] 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),9.37(d,J=1.5Hz,1H),8.94(dd,J=1.4,4.7Hz,1H),8.74(d,J=2.1Hz,1H),8.56(s,1H),8.4 8(d,J=2.5Hz,1H),8.19(s,1H),8.11(d,J=4.6Hz,1H),5.00-5.00(m,2H),3.99(s,3H),3.95(t,J=5.8Hz,2H),3.07-3.07(m,2H).

[1048] Example 122: Preparation of compound N-(5-(1,1-difluoroethyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazin-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide

[1049]

[1050] Step 1: 3-[[5-(1,1-difluoroethyl)-3-pyridyl]carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (intermediate 101)

[1051]

[1052] Following the method described in step 1 of Example 109, intermediate 101 was prepared starting from 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (167 mg, 0.589 mmol). The resulting residue was ground with water and allowed to stand overnight. The solid was filtered, washed with water, and dried under vacuum to give the title compound (182 mg, 0.430 mmol, 73%).

[1053] 1 H NMR (400MHz, CDCl3) δ8.74(m,1H),8.53(s,1H),8.40(s,1H),7.71(s,1H),4.61(s,2H),3.71-3.65(m,2H),3.00(t J=5.4Hz, 2H), 1.97 (t, J=18.2Hz, 3H), 1.50 (s, 9H).

[1054] Step 2: N-[5-(1,1-difluoroethyl)-3-pyridyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 102)

[1055]

[1056] Following the method described in step 2 of Example 121, intermediate 102 was prepared starting from intermediate 101 (182 mg, 0.430 mmol). The title compound, dihydrochloride (151 mg, 0.381 mmol, 89%), was obtained.

[1057] 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),9.65(s,2H),9.15(d,J=1.9Hz,1H),8.61(s,1H),8.56 (s, 2H), 4.40 (t, J = 4.9Hz, 2H), 3.48-3.34 (m, 2H), 3.17-3.10 (m, 2H), 2.06 (t, J = 19.1Hz, 3H).

[1058] Step 3: N-(5-(1,1-difluoroethyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazin-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide (Example 122)

[1059] To a solution of intermediate 102 (50 mg, 0.126 mmol), pyrazolo[1,5-a]pyrazin-3-carboxylic acid (21 mg, 0.126 mmol), and 1-methylimidazolium (0.080 mL, 1.01 mmol) in ACN (5 mL), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (53 mg, 0.189 mmol) was added. The reaction mixture was stirred at room temperature for 30 min and then allowed to stand overnight. The reaction was quenched with water and washed with DCM. The combined organic phases were filtered through a hydrophobic glass frit and the solvent was concentrated under vacuum. The residue was purified by preparative HPLC (Xbridge Phenyl 19x150 mm, 10 μm, 20-80% MeOH / H2O (10 mM NH4CO3), 20 mL / min, RT) to give the title compound (7.5 mg, 0.0160 mmol, 13%).

[1060] LCMS (ESI): Method 7t R =3.94min; m / z[M+H]+=516.5

[1061] 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),9.36(d,J=1.4Hz,1H),8.93(dd,J=1.4,4.7Hz,1H),8.56(s,1H),8.20(s,1H),8.11(d,J =4.6Hz,1H),6.31(s,1H),4.99-4.99(m,2H),3.95(dd,J=5.8,5.8Hz,2H),3.67(s,3H),3.08-3.03(m,2H),1.33-1.21(m,4H).

[1062] Example 123: Preparation of compound N-(5-(tert-butyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazin-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide

[1063]

[1064] Step 1: 3-[(5-tert-butyl-3-pyridyl)carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (intermediate 103)

[1065]

[1066] Following the method described in step 1 of Example 109, intermediate 103 was prepared starting from 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (83 mg, 0.293 mmol). The title compound (56 mg, 0.135 mmol, 46%) was obtained.

[1067] 1 H NMR (400MHz, CDCl3) δ9.07-8.64(m,1H),8.54(s,1H),8.33(d,J=1.5Hz,1H),8.24(t,J=2.0Hz,1H) ,7.72(s,1H),4.58(s,2H),3.66(t,J=5.6Hz,2H),3.00(t,J=5.4Hz,2H),1.49(s,9H),1.33(s,9H).

[1068] Step 2: N-(5-tert-butyl-3-pyridyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 104)

[1069]

[1070] Following the method described in step 2 of Example 121, intermediate 104 was prepared starting from intermediate 103 (56 mg, 0.135 mmol). The desired product was obtained as dihydrochloride (41 mg, 0.106 mmol, 78%).

[1071] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 11.20 (s, 1H), 9.58–9.58 (m, 2H), 9.21 (d, J = 1.8 Hz, 1H), 8.78 (s, 1H), 8.67 (s, 1H), 8.65 (d, J = 1.8 Hz, 1H), 4.41 (t, J = 4.8 Hz, 2H), 3.4 (m, 2H) (under water peak), 3.14 (t, J = 5.7 Hz, 2H), 1.38 (s, 9H).

[1072] Step 3: N-(5-tert-butyl-3-pyridinyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 123)

[1073] To a solution of intermediate 104 (41 mg, 0.106 mmol), pyrazolo[1,5-a]pyrazin-3-carboxylic acid (17 mg, 0.106 mmol), and 1-methylimidazolium (0.067 mL, 0.845 mmol, 8.00 eq) in ACN (4.1 mL), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (44 mg, 0.158 mmol) was added. The reaction mixture was stirred at room temperature for 30 min and allowed to stand overnight. The reaction was quenched with water and washed with DCM. The combined organic phases were filtered through a hydrophobic glass frit, and the solvent was concentrated under vacuum to give a light brown gel. The residue was purified by preparative HPLC (Xbridge Phenyl 19x150mm, 10µm, 20-80% MeOH / H2O (10mM NH4CO3), 20mL / min) to give the title compound (48mg, 0.0677mmol, 64%).

[1074] LCMS (ESI): Method 7t R =3.94min; m / z[M+H]+=516.5

[1075] 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),9.36(d,J=1.4Hz,1H),8.93(dd,J=1.4,4.7Hz,1H),8.56(s,1H),8.20(s,1H),8.11(d,J =4.6Hz,1H),6.31(s,1H),4.99-4.99(m,2H),3.95(dd,J=5.8,5.8Hz,2H),3.67(s,3H),3.08-3.03(m,2H),1.33-1.21(m,4H).

[1076] Example 125: Preparation of compound N-(5-(difluoromethoxy)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazin-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide

[1077]

[1078] Step 1: 3-[[5-(difluoromethoxy)-3-pyridyl]carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (intermediate 105)

[1079]

[1080] Following the method described in step 1 of Example 109, intermediate 105 was prepared starting from 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (167 mg, 0.589 mmol). The desired product (179 mg, 0.421 mmol, 71%) was obtained.

[1081] 1 H NMR (400MHz, CDCl3) δ8.50-8.49(m,1H),8.24(m,3H),7.69(s,1H),6.79-6.39(t,J =73.6Hz,1H),4.61(s,2H),3.72-3.65(m,2H),2.99(t,J=5.6Hz,2H),1.50(s,9H).

[1082] Step 2: N-[5-(difluoromethoxy)-3-pyridyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; dihydrochloride (intermediate 106)

[1083]

[1084] Following the method described in step 2 of Example 121, intermediate 106 was prepared starting from intermediate 105 (179 mg, 0.421 mmol). The desired product was obtained as dihydrochloride (146 mg, 0.367 mmol, 87%).

[1085] 1 H NMR(400MHz,DMSO-d6)d 10.90(s,1H),9.70(s,2H),8.93(s,1H),8.56(s,1H),8.31(s,1H),8.27(t,J= 26.8Hz,1H),7.36(s,1H),4.38(s,2H),,3.43-3.36(m,2H),3.16-3.08(m,2H).

[1086] Step 3: N-(5-(difluoromethoxy)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazin-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide (Example 125)

[1087] TCFH (53 mg, 0.188 mmol) was added to a solution of intermediate 106 (50 mg, 0.126 mmol), pyrazolo[1,5-a]pyrazin-3-carboxylic acid (20 mg, 0.126 mmol), and 1-methylimidazole (0.080 mL, 1.00 mmol) in ACN (5 mL). The reaction mixture was stirred at room temperature for 30 min and allowed to stand overnight. The reaction was quenched with water and washed with DCM. The combined organic phases were filtered through a hydrophobic glass frit, and the solvent was concentrated under vacuum. The residue was purified by preparative HPLC (Xbridge Phenyl 19x150 mm, 10 μm, 20-80% MeOH / H2O (10 mM NH4CO3), 20 mL / min) to give the title compound (59 mg, 0.0238 mmol, 19%).

[1088] LCMS (ESI): Method 7t R =3.94min; m / z[M+H]+=516.5

[1089] 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),9.36(d,J=1.4Hz,1H),8.93(dd,J=1.4,4.7Hz,1H),8.56(s,1H),8.20(s,1H),8.11(d, J=4.6Hz,1H),6.31(s,1H),4.99-4.99(m,2H),3.95(dd,J=5.8,5.8Hz,2H),3.67(s,3H),3.08-3.03(m,2H),1.33-1.21(m,4H)

[1090] Example 126: Preparation of compound 6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-N-(5-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

[1091]

[1092] Step 1: 3-((5-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazol-3-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (intermediate 107)

[1093]

[1094] Oxaloyl chloride (0.088 mL, 1.06 mmol) was added dropwise to a CPME (2 mL) solution of 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (250 mg, 0.882 mmol) and DMF (0.0034 mL, 0.0441 mmol) at 20 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum. The residue was azeotropically reacted with CPME, and the residue was suspended in ACN (1 mL) and cooled to 0 °C in an ice bath. A CPME (1 mL) solution of 5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)isoxazole-3-amine (171 mg, 0.882 mmol) and pyridine (0.14 mL, 1.76 mmol) was added to the mixture. The reaction mixture was heated to room temperature and stirred for 1 h. The reaction mixture was concentrated under vacuum, and 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 gel column chromatography (0-100% EtOAc in cyclohexane solution) to give the title compound (255 mg, 0.555 mmol, 63%).

[1095] 1 H NMR (400MHz, CDCl3) δ9.65 (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).

[1096] Step 2: 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 108)

[1097]

[1098] At 0 °C, a solution of 4 N HCl in dioxane (3.0 M, 0.555 mmol) was added to a solution of intermediate 107 (255 mg, 0.555 mmol) 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 then diluted with diethyl ether and filtered. The resulting solid was washed with diethyl ether and dried under vacuum to give the title compound in the form of an HCl salt (190 mg, 0.480 mmol, 86%).

[1099] 1H NMR (400MHz, DMSO-d6) δ 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).

[1100] Step 3: 6-(pyrazolo[1,5-a]pyrazin-3-carbonyl)-N-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)isoxazo-3-yl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 126)

[1101] To a solution of intermediate 108 (50 mg, 0.126 mmol), pyrazolo[1,5-a]pyrazin-3-carboxylic acid (21 mg, 0.126 mmol), and 1-methylimidazolium (0.081 mL, 1.01 mmol) in ACN (2 mL), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (53 mg, 0.189 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction was then quenched with aqueous NH4Cl solution, filtered to obtain a solid, washed with water and dried under vacuum, washed with diethyl ether, filtered and dried under vacuum, and purified by preparative HPLC (Xbridge Phenyl 19x150 mm, 10 μm 40-100% MeOH / H2O (10 mM NH4CO3), 20 mL / min, RT) to give the title compound (14 mg, 0.0282 mmol, 22%).

[1102] LCMS (ESI): Method 7t R =4.42min, m / z[M+H]+=505.4

[1103] 1 H NMR (400MHz, DMSO-d6) δ11.40-11.36(s,1H),9.40(s,1H),8.96(d,J=3.8Hz,1H),8.59(s,1H),8.41(s,1H ), 8.14 (d, J = 4.5Hz, 1H), 7.12 (s, 1H), 5.03-4.98 (s, 2H), 3.98 (t, J = 4.9Hz, 2H), 3.10 (s, 2H), 1.63 (s, 6H).

[1104] Example 127: Preparation of compound 6-(imidazo[1,2-a]pyrazine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[1105]

[1106] Step 1: 3-[[5-(trifluoromethyl)-3-pyridyl]carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (intermediate 109)

[1107]

[1108] To a solution of 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (1500 mg, 5.29 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (3713 mg, 13.2 mmol), and 1-methylimidazolium (1.3 mL, 15.9 mmol) in ACN (150 mL), 5-(trifluoromethyl)pyridine-3-amine (858 mg, 5.29 mmol) was added, and the mixture was stirred overnight. The reaction mixture was diluted in ethyl acetate, washed with water and brine, dried over MgSO4, filtered, and concentrated.

[1109] The residue was purified by FCC (80 g, 0-100% EtOAc in C-Hex solution, 10 CV) to give the title compound (1866 mg, 4.37 mmol, 82%).

[1110] 1 H NMR(400MHz, CDCl3)δ8.92(m,1H),8.65(s,1H),8.60(s,1H),7.67-7.63(m,1H) ,4.62-4.57(m,2H),3.69(t,J=5.4Hz,2H),3.02(t,J=5.4Hz,2H),1.52(s,9H).

[1111] Step 2: N-[5-(trifluoromethyl)-3-pyridyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; hydrochloride (intermediate 110)

[1112]

[1113] To a solution of intermediate 109 (2612 mg, 6.11 mmol) in 1,4-dioxane (16.80 mL), 4 M HCl (38 mL, 0.153 mol) was added, and the mixture was stirred overnight at room temperature. The mixture was concentrated and then diluted in MeOH. The resulting solid was filtered off and dried to give the title compound as hydrochloride (1819 mg, 5.00 mmol, 82%).

[1114] 1H NMR(400MHz,DMSO-d6)d 10.85(s,1H),9.38(s,2H),9.22(d,J=2.3Hz,1H),8.76(d,J=1.3Hz,1H),8.66(t, J=1.9Hz,1H),8.49(s,1H),4.45(s,2H),3.45-3.41(m,2H),3.17(t,J=6.1Hz,2H).

[1115] Step 3: 6-(imidazo[1,2-a]pyrazine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide (Example 127)

[1116] Imidazolo[1,2-a]pyrazin-3-carboxylic acid (100 mg, 0.613 mmol, 1.00 eq) was heated to reflux overnight in thionyl chloride (0.89 mL, 12.3 mmol, 20.0 eq). 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.

[1117] Imidazolo[1,2-a]pyrazine-3-carboxyl chloride (111 mg, 0.611 mmol) and intermediate 110 (222 mg, 0.611 mmol) were dissolved in THF (10 mL), followed by the addition of DIPEA (0.23 mL, 1.34 mmol) and 4-(dimethylamino)pyridine (3.7 mg, 0.0306 mmol). The reaction mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure. The residue was purified by preparative HPLC (Sunfire C18 19×150 mm, 10 μm, 20-80% ACN / H2O (0.1% FA), 20 mL / min, RT) to give the title compound (3.03 mg, 1.04%).

[1118] LCMS (ESI): Method 6t R =3.79min; m / z[M+H]+=473.2.

[1119] 1 H NMR (400MHz, DMSO-d6) δ10.68(s,1H),9.25(d,J=1.6Hz,1H),9.15(d,J=2.0Hz,1H),8.89(dd,J=1.4,4. 8Hz, 1H), 8.71 (d, J = 0.9Hz, 1H), 8.61 (t, J = 1.8Hz, 1H), 8.35 (s, 1H), 8.28 (s, 1H), 8.10 (d, J = 4.6Hz, 1H).

[1120] Example 128: Preparation of compound 6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-N-(5-(trifluoromethoxy)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[1121]

[1122] Step 1: 6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-N-(5-(trifluoromethoxy)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 128)

[1123]

[1124] A mixture of intermediate 93 (40 mg, 0.117 mmol) and intermediate 86 (30 mg, 0.140 mmol) in THF (2 mL) was cooled to -30 °C, and then a solution of n-butyllithium (1.7 M pentane, 0.247 mL, 0.420 mmol) was added. The reaction mixture was stirred while the mixture was heated to room temperature. The reaction was quenched with NH4Cl (saturated aqueous solution), and the organic matter was extracted with DCM. The combined organic phases were filtered through a hydrophobic glass frit, and the solvent was concentrated under vacuum. The crude residue obtained by washing with DCM was purified to give the title compound (5.1 mg, 0.010 mmol, 8.9%).

[1125] LCMS (ESI): Method 7t R =4.04min; m / z[M+H]+=489.3

[1126] 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),9.41(d,J=1.3Hz,1H),8.99-8.94(m,2H),8.60(s,1H),8.45(d,J=2. 0Hz, 1H), 8.38 (s, 1H), 8.29 (s, 1H), 8.15 (d, J = 4.8Hz, 1H), 5.04 (s, 2H), 3.99 (t, J = 5.6Hz, 2H), 3.11 (s, 2H).

[1127] Example 146: Preparation of N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-6-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

[1128]

[1129] Step 1: 6-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl ester (intermediate 133)

[1130]

[1131] According to general method C, the crude product obtained by purification by silica gel column chromatography (0-100% EtOAc in cyclohexane solution) from 3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxaldehyde (450 mg, 2.79 mmol) and intermediate 38 (692 mg, 2.79 mmol) yielded the title compound (529 mg, 1.48 mmol, 53%).

[1132] 1 H NMR (400MHz, DMSO-d6) δ13.15(s,1H),8.46(d,J=1.7Hz,1H),8.13-8.10(m,2H),4.22(q,J=7.1Hz,2H) ,3.80(s,2H),3.63(s,2H),2.89-2.85(m,2H),2.78-2.74(m,2H),2.49(s,3H),1.27(t,J=7.1Hz,3H).

[1133] Step 2: 6-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxylic acid (intermediate 134)

[1134]

[1135] 5M NaOH (aq) (0.89 mL, 4.45 mmol) was added to a suspension of intermediate 133 (529 mg, 1.48 mmol) in MeOH (12 mL). The reaction mixture was stirred at 60 °C under a nitrogen atmosphere for 2.5 h, and then stirred at room temperature for 16 h. The reaction mixture was acidified to pH 5–6 by dropwise addition of 1M HCl (aq) and concentrated under vacuum. The residue was suspended in water, filtered, and the solid was washed with water and dried under vacuum to give the title compound (416 mg, 85%).

[1136] 1H NMR (400MHz, DMSO-d6) δ13.15(brs,1H),12.52(brs,1H),8.46(d,J=1.7Hz,1H),8.12(d,J=1.5Hz ,1H),8.07(s,1H),3.81(s,2H),3.62(s,2H),2.89-2.85(m,2H),2.79-2.74(m,2H),2.49(s,3H).

[1137] Step 3: N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-6-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 146)

[1138] The compound was prepared according to General Method I from 5-cyclopropyl-2-methylpyrazol-3-amine (14 mg, 0.100 mmol) and intermediate 134 (22 mg, 0.0670 mmol), without the addition of DMAP or DIPEA. The crude product was purified by preparative HPLC (Sunfire C1819 x 150 mm, 10 μm, 20-80% acetonitrile / water (10 mM NH4HCO3), 20 mL / min) and then lyophilized to give the title compound (9.5 mg, 32%).

[1139] LC-MS (ESI) Method 7: t R =2.58min; m / z[M+H]+=448.3.

[1140] 1 H NMR (400MHz, DMSO) δ13.17(s,1H),9.98(s,1H),8.48(d,J=2.0Hz,1H),8.13(d,J=1.6Hz,1H),8.09(s,1H),5.91(s,1H),3.83(s,2H),3. 65(s,2H),3.58(s,3H),2.85(d,J=5.1Hz,2H),2.79-2.68(m,2H),2.52(s,3H),1.84-1.77(m,1H),0.85-0.80(m,2H),0.64-0.59(m,2H).

[1141] The compounds reported in the table below were prepared by amide coupling as described in steps 1-3 of Example 146, using the corresponding commercially available amine in step 3.

[1142]

[1143] Example 149: Preparation of 6-((3-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide

[1144]

[1145] Step 1: 6-[[3-(4-methylpiperazin-1-yl)-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-5-yl]methyl]-N-[5-(trifluoromethyl)-3-pyridyl]-5,7-dihydro-4H-thieno[2,3-c]pyridin-3-carboxamide (Intermediate 135)

[1146]

[1147] K was prepared from intermediate 126 (35 mg, 0.09 mmol) and intermediate 90 (30 mg, 0.09 mmol) according to general method. The residue was purified by FCC (0-50% [75:15:10EtOAc:EtOH:7M NH3 / MeOH] in cyclohexane solution) to give the title compound.

[1148] LC-MS (ESI) method 16t R =1.86 min; m / z [MH] - =685

[1149] Step 2: 6-[[3-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-N-[5-(trifluoromethyl)-3-pyridinyl]-5,7-dihydro-4H-thieno[2,3-c]pyridin-3-carboxamide (Example 149)

[1150] TFA (0.020 mL, 0.258 mmol) was added to a mixture of intermediate 135 (59 mg, 0.0859 mmol) in DCM (2 mL). The mixture was stirred overnight at room temperature. Another portion of TFA (0.020 mL, 0.258 mmol, 3.00 eq) was added and the mixture was stirred again for 2 h. The mixture was then diluted with water, alkalized with saturated Na2CO3, and extracted with EtOAc 2x. The combined organic phases were dried over MgSO4, filtered, and concentrated. Purification by preparative HPLC (Xbridge Phenyl 19x150 mm, 10 μm, 40–100% MeOH / H2O (10 mM NH4CO3), 20 mL / min) gave the title compound (3 mg, 6%).

[1151] LC-MS (ESI) Method 7: t R =2.36min; m / z[M + H] + =557.4.

[1152] 1 H NMR (400MHz, DMSO-d6) δ12.53(s,1H),10.59(s,1H),9.12(d,J=2.1Hz,1H),8.68(s,1H),8.59(t,J=2.1Hz,1H),8.42(d,J=1.9H z,1H),8.20(d,J=1.8Hz,1H),8.16(s,1H),3.80(s,2H),3.65(s,2H),2.90(t,J=5.5Hz,2H),2.77(t,J=5.6Hz,2H),2.25(s,3H).

[1153] The compounds reported in the table below were prepared by reductive amination as described in step 1 of Example 149, using the corresponding commercially available or pre-synthesized aldehydes.

[1154]

[1155]

[1156]

[1157] Example 156: Preparation of compound N-(3-(tert-butyl)isoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrimidin-6-ylmethyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[1158]

[1159] Step 1: 6-(pyrazolo[1,5-a]pyrimidin-6-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl ester (intermediate 136)

[1160]

[1161] L was prepared according to a general method from pyrazolo[1,5-a]pyrimidine-6-carboxaldehyde (82 mg, 0.555 mmol) and intermediate 38 (125 mg, 0.505 mmol). The product (123 mg, 71%) was purified by FCC (0-100% DCM / 2M methanol-ammonia in DCM 20:1 solution).

[1162] 1H NMR (400MHz, CDCl3) δ8.66-8.65(m,1H),8.55(d,J=2.4Hz,1H),8.12(d,J=2.5Hz,1H),7.96(s,1H),6.71(dd,J=0.9,2 .3Hz,1H),4.30(q,J=7.1Hz,2H),3.78-3.73(m,4H),3.06-3.01(m,2H),2.88(t,J=5.8Hz,2H),1.35(t,J=7.0Hz,3H).

[1163] Step 2: 6-(pyrazolo[1,5-a]pyrimidin-6-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (intermediate 137)

[1164]

[1165] Following the method for intermediate 94, starting from intermediate 136 (120 mg, 0.350 mmol), the desired product (102 mg, 93%) was obtained.

[1166] LCMS (ESI) Method 15: t R =0.71min; m / z[M+H]+=315.2

[1167] Step 3: N-(3-tert-butyl)isoxazo-5-yl)6-(pyrazolo[1,5-a]pyrimidin-6-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 156)

[1168] The title compound (4 mg, 10%) was prepared according to General Method I from intermediate 137 (30 mg, 0.095 mmol) and 3-tert-butylisoxazole-5-amine (20 mg, 0.143 mmol). The compound was purified by preparative HPLC (Sunfire C1819 x 150 mm, 10 μm, 20-80% ACN / H2O (10 mM NH4CO3), 20 mL / min) to give the title compound.

[1169] LCMS (ESI): Method 7t R = 3.15 min, m / z [M+H] + =437.2

[1170] 1H NMR (400MHz, DMSO-d6) δ11.71(s,1H),9.08(d,J=1.1Hz,1H),8.59(d,J=2.1Hz,1H),8.24(s,1H),8.22(d,J=2.3Hz,1H),6.7 3(dd,J=0.8,2.3Hz,1H),6.35(s,1H),3.79(s,2H),3.72(s,2H),2.92(t,J=6.3Hz,2H),2.81(t,J=5.8Hz,2H),1.28(s,9H).

[1171] Example 157: Preparation of compound (R)-N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

[1172]

[1173] Step 1: (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 138)

[1174]

[1175] The preparation was carried out according to step 1 of Example 47, starting from 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (350 mg, 1.24 mmol) and intermediate 14 (355 mg, 1.24 mmol). Purification by FCC (0-10% DCM solution of 2M NH3 / MeOH) yielded the title compound (580 mg, 84%).

[1176] 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)

[1177] Step 2: (R)-N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 139)

[1178]

[1179] To a solution of intermediate 138 (576 mg, 1.04 mmol) in anhydrous DCM (10.4 mL) (stirred on an ice / water bath under argon atmosphere), TFA (1.6 mL, 20.8 mmol) was added dropwise over 5 min. The reaction mixture was stirred for 1.5 h and concentrated under vacuum. The residue was dissolved in MeOH and applied to a MeOH-pretreated 20 g Isolute SCX-II column. The column 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 (356 mg, 75%).

[1180] 1 H 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)

[1181] Step 3: (R)-N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 157)

[1182] The title compound (34 mg, 45%) was prepared according to general method J from intermediate 139 (59 mg, 0.130 mmol) and 3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxaldehyde (20 mg, 0.124 mmol). The compound was purified by preparative HPLC (Xbridge Phenyl 19 × 150 mM, 10 μM 40–100%, methanol / water (10 mM NH4HCO3), 20 mL / min, RT) to give the title compound.

[1183] LCMS (ESI): Method 7t R =2.18min; m / z[M+H]+=598.4

[1184] 1 H NMR (400MHz, DMSO) δ13.17 (s, 1H), 10.32 (s, 1H), 8.49 (d, J = 2.0Hz, 1H), 8.15-8.10 (m, 3H),7.94(s,1H),7.33(s,1H),3.84(s,2H),3.70(d,J=13.6Hz,1H),3.66(s,2H),3.57( d,J=13.7Hz,1H),2.93-2.87(m,2H),2.81-2.65(m,4H),2.63-2.55(m,1H),2.49-2.43( m,1H),2.31(dd,J=5.7,7.8Hz,1H),2.09(s,6H),1.93-1.82(m,1H),1.68-1.59(m,1H).

[1185] The compounds reported in the table below were prepared by reductive amination as described in steps 1-3 of Example 157, using the corresponding commercially available or previously synthesized aldehyde in step 3.

[1186]

[1187]

[1188]

[1189] Example 162: Preparation of (R)-N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(5-methylimidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

[1190]

[1191] Step 1: (R)-N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(5-methylimidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 162)

[1192] H was prepared according to general method from intermediate 139 (40 mg, 0.0884 mmol) and lithium 5-methylimidazo[1,2-a]pyridine-3-carboxylate (16 mg, 0.0884 mmol). The title compound (22 mg, 39%) was obtained by reversed-phase preparative HPLC (Xbridge Phenyl 19x150 mm, 10 μm, 40-100%, MeOH / water (10 mM NH4HCO3), 20 mL / min, RT).

[1193] LC-MS (ESI) Method 7: t R = 2.55 min; m / z [M+H] + =611.3.

[1194] 1 H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.-7-8.21(m,1H),8.12(s,1H),7.-6-7.93(m,2H),7.-4-7 .60(m,1H),7.39(dd,J=6.9,8.9Hz,1H),7.35(s,1H),6.91(s,1H),4.98(s,2H),3.89(s,2H),3.7 1(d,J=13.6Hz,1H),3.58(d,J=13.6Hz,1H),3.04(s,2H),2.-4-2.69(m,2H),2.-5-2.58(m,1H),2 .-9-2.43(m,1H),2.32(dd,J=5.6,7.5Hz,1H),2.09(s,6H),1.-0-1.83(m,1H),1.-8-1.59(m,1H).

[1195] Example 163: Preparation of compound 6-[(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl]-N-[3-(2-pyrrolidine-1-ylethoxy)-5-(trifluoromethyl)phenyl]-5,7-dihydro-4H-thieno[2,3-c]pyridin-3-carboxamide

[1196]

[1197] Step 1: 3-[[3-(2-pyrrolidine-1-ylethoxy-5-(trifluoromethyl)phenyl]carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (intermediate 140)

[1198]

[1199] M was prepared according to general methods from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (190 mg, 0.671 mmol) and intermediate 18 (193 mg, 0.704 mmol). The residue was purified by FCC (0-100% EtOAc in cyclohexane solution, then 0-20% 7N NH3 in EtOAc solution). The residue was dissolved in MeOH and loaded onto an SCX column, washed with MeOH. The compound was released using 7N NH3 in MeOH. The solution was concentrated under reduced pressure.

[1200] 1 H NMR (400MHz, CDCl3) δ7.69(s,1H),7.58(s,1H),7.37(s,1H),6.93(s,1H),4.62(s,2H),4.16(dd,J=5.8,5.8Hz, 2H),3.71-3.64(m,2H),3.02-2.96(m,2H),2.95-2.88(m,2H),2.80(s,9H),2.66-2.61(m,4H),1.84-1.78(m,4H)

[1201] Step 2: N-[3-(2-pyrrolidine-1-ylethoxy)-5-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 141)

[1202]

[1203] Following the method of intermediate 139, starting from intermediate 140 (60 mg, 0.111 mmol), the desired product (44 mg, 90% yield) was obtained.

[1204] 1 H NMR (400MHz, CDCl3) δ7.74(s,1H),7.63(s,1H),7.55(s,1H),7.34(s,1H),6.93(s,1H),4.16(t,J=5. 8Hz,2H),4.06(s,2H),3.13(t,J=5.9Hz,2H),2.94-2.90(m,4H),2.66-2.61(m,4H),1.84-1.80(m,4H)

[1205] Step 3: 6-[(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl]-N-[3-(2-pyrrolidine-1-ylethoxy)-5-(trifluoromethyl)phenyl]-5,7-dihydro-4H-thieno[2,3-c]pyridin-3-carboxamide (Example 163)

[1206] The title compound (15 mg, 0.0910 mmol) was prepared according to general method J from intermediate 141 (40 mg, 0.0910 mmol) and 3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxaldehyde (15 mg, 0.0910 mmol). The compound was purified by reversed-phase preparative HPLC (Xbridge Phenyl 19x150 mm, 10 μm, 40-100% MeOH / H2O (10 mM NH4CO3), 20 mL / min, RT) to give the title compound (15 mg, 28%).

[1207] LCMS (ESI): Method 7t R = 2.64 min, m / z [M+H] + =585.2

[1208] 1 H NMR (400MHz, DMSO) δ13.17(s,1H),10.28(s,1H),8.49(d,J=2.0Hz,1H),8.14(d,J=1.9Hz,1H),8.10(s,1H),7.76(s,1H),7.65 (s,1H),6.98(s,1H),4.14(t,J=5.8Hz,2H),3.84(s,2H),3.66(s,2H),2.91-2.87(2H,m),2.84-2.77(4H,m)1.72-1.68(m,4H).

[1209] The compounds reported in the table below were prepared by reductive amination as described in steps 1-3 of Example 163, using the corresponding commercially available or previously synthesized aldehyde in step 3.

[1210]

[1211] Example 165: Preparation of 6-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridine-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[1212]

[1213] Step 1: 6-[6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester (intermediate 142)

[1214]

[1215] M was prepared from intermediate 38 (405 mg, 1.6 mmol) and intermediate 113 (851 mg, 1.6 mmol) according to the general method. The residue was purified by FCC (0-100% EtOAc in cyclohexane solution, followed by 0-100% MeOH in EtOAc solution) to give the desired product (330 mg, 45%).

[1216] 1 H NMR (400MHz, CDCl3) δ8.52(d,J=1.8Hz,1H),8.03(s,1H),7.89(s,1H),7.57(d,J=9.6Hz,1H),7.25(m,1H),5.01(s,2 H), 4.32 (q, J = 7.1Hz, 2H), 4.09 (m, 2H), 3.24-3.14 (m, 6H), 2.61 (t, J = 4.7Hz, 4H), 2.37 (s, 3H), 1.38 (t, J = 7.1Hz, 3H).

[1217] Step 2: 6-[6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (intermediate 143)

[1218]

[1219] Following the method of step 2 in Example 140, starting from intermediate 142 (330 mg, 0.728 mmol), the crude product was washed with MeOH, and the combined organic phases were evaporated to give the title compound (310 mg, 100%).

[1220] 1 H NMR(400MHz,MeOH-d4)δ8.46(d,J=1.8Hz,1H),8.00(s,1H),7.93(s,1H),7.60(d,J=9.6Hz,1H),7.52(dd,J= 2.3, 9.6Hz, 1H), 5.03 (s, 2H), 4.07 (t, J = 5.7Hz, 2H), 3.19 (t, 5.4Hz, 2H), 3.07 (t, J = 4.7Hz, 4H), 2.68 (s, 3H).

[1221] Step 3: 6-[6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl]-N-[5-(trifluoromethyl)-3-pyridyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 165)

[1222] N was prepared by general method from 5-(trifluoromethyl)pyridine-3-amine (19 mg, 0.118 mmol) and intermediate 143 (assumed 50% purity, 100 mg, 0.118 mmol). The residue was purified by preparative HPLC (Xbridge Phenyl 19 × 150 mm, 10 μM 40–100% MeOH / H2O (10 mM NH4CO3), 20 mL / min, RT) to give the title compound (13 mg, 19% yield).

[1223] LC-MS (ESI) Method 7: t R =2.70min; m / z[M + H] + =570.4.

[1224] 1 H NMR (400MHz, DMSO) δ10.66(s,1H),9.15(d,J=2.1Hz,1H),8.70(s,1H),8.61(t,J=2.1Hz,1H),8.41(d,J=1.9Hz,1H),8.27(s,1H),8 .03(s,1H),7.61(d,J=9.8Hz,1H),7.49(dd,J=2.3,9.8Hz,1H),5.03(s,2H),3.99(t,J=5.7Hz,2H),3.08(m,6H),2.51(m,4H-under DMSO peak),2.24(s,3H).

[1225] Example 166: Preparation of 6-(6-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[1226]

[1227] Step 1: 6-[(2-aminopyrimidin-5-yl)methyl]-N-(5-isobutyl-2-methyl-pyrazol-3-yl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (intermediate 144)

[1228]

[1229] H was prepared according to general method from 6-bromoimidazolo[1,2-a]pyridine-3-carboxylic acid (406 mg, 1.68 mmol) and intermediate 64 (550 mg, 0.40 mmol). The reactants were diluted with aqueous NH4Cl solution and filtered to give a solid, which was dried under vacuum. The solid was washed with MeOH to give the title compound (533 mg, 57%).

[1230] 1 H NMR (400MHz, DMSO-d6) δ10.46(s,1H),9.17(s,1H),8.27(s,2H),8.22(s,1H),8.04(d,J=8.1Hz,1H),7.79(d ,J=9.6Hz,1H),7.68-7.61(m,2H),7.49(d,J=7.8Hz,1H),5.09(s,2H),4.06-3.99(m,2H),3.16-3.10(m,2H)

[1231] Step 2: 6-(6-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 166)

[1232] Intermediate 144 (35 mg, 0.0637 mmol) and Pd-PEPPSI(TM)-IPent catalyst (5.1 mg, 6.37 μmol) were packed into a nitrogen-purged microwave tube. Tetrahydrofuran (2.0 mL) was added, the solution was degassed, and 2 M sodium tert-butoxide (0.37 mL, 0.733 mmol) and 2-methyl-2,6-diazaspiro[3.3]heptane dihydrochloride (117 mg, 0.63 mmol) were added. The reaction mixture was then microwave-heated at 120 °C for 2 h. The reaction mixture was concentrated, and the residue 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). The separated material was dissolved in EtOAc and washed with saturated NaHCO3 aqueous solution. The organic matter was concentrated and lyophilized to give the title compound (2.3 mg, 6%).

[1233] LC-MS (ESI) Method 7: t R =3.12min; m / z[M + H] + =581.2.

[1234] 1H NMR (300MHz, DMSO-d6) δ10.42(s,1H),8.22(s,2H),8.07(d,J=1.8Hz,1H),8.01-7.98(m,2H),7.63-7.58(m,2H),7.46(d,J=7.4Hz,1 H),6.98(dd,J=2.3,9.5Hz,1H),5.01(s,2H),3.98(dd,J=5.5,5.5Hz,2H),3.89(s,4H),3.28(s,4H),3.08-3.06(m,2H),2.20(s,3H).

[1235] Example 167: Preparation of 6-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

[1236]

[1237] Step 1: 6-[6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)imidazo[1,2-a]pyridin-3-carbonyl]-N-[3-(trifluoromethyl)phenyl]-5,7-dihydro-4H-thieno[2,3-c]pyridin-3-carboxamide (Example 167)

[1238] Intermediate 144 (150 mg, 0.273 mmol) was added to a solution of DMF (1.5 mL) and water (0.5 mL) with 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (79 mg, 0.355 mmol), K₂CO₃ (45 mg, 0.328 mmol), and Pd(dppf)Cl₂·DCM (3.4 mg, 4.10 μmol). The reaction was heated at 100 °C for 4 h under nitrogen protection. Water was added to the mixture, followed by extraction with DCM. The organic phase was separated, passed through a hydrophobic glass frit, and concentrated under vacuum. The residue was purified by FCC (0-20% MeOH in DCM solution) to give the title compound (75 mg, 49%).

[1239] LC-MS (ESI) Method 7: t R =3.29min; m / z[M + H] + =566.3.

[1240] 1H NMR (400MHz, DMSO-d6) δ10.42(s,1H),8.91(s,1H),8.22(s,2H),8.12(s,1H),8.00(d,J=8.9Hz,1H),7.72-7.70(m,2H),7.60(t,J=8.0Hz,1 H), 7.45 (d, J = 7.7Hz, 1H), 6.34 (t, J = 3.6Hz, 1H), 5.05 (s, 2H), 4.00 (t, J = 5.6Hz, 2H), 3.10-3.04 (m, 4H), 2.60 (t, J = 5.6Hz, 2H), 2.30 (s, 3H).

[1241] Example 168; N-(3-(tert-butyl)isoxazo-5-yl)-6-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[1242]

[1243] Step 1: 3-[(5-tert-butylisoxazol-3-yl)carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (intermediate 145)

[1244]

[1245] Following the method of intermediate 95, starting from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (142 mg, 0.500 mmol) and 3-amino-5-tert-butylisoxazole (70 mg, 0.500 mmol), the title compound (164 mg, 0.404 mmol, 81%) was obtained.

[1246] 1 H NMR (400MHz, CDCl3)d 10.84(s,1H),8.10(s,1H),6.88(s,1H),4.67-4.62(m,2H),3.68(t,J=4.9Hz,2H),3.03(t,J=5.8Hz,2H),1.42(s,9H),1.37(s,9H).

[1247] Step 2: N-(3-tert-butylisoxazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (intermediate 146)

[1248]

[1249] Following the method for intermediate 86, starting from intermediate 145 (100 mg, 0.247 mmol), the title compound (56 mg, 0.162 mmol, 66%) was obtained.

[1250] 1 H NMR(400MHz,DMSO-d6)d 11.93(s,1H),9.65-9.60(m,2H),8.52(s,1H),6.41(s,1H),4.47-4.38(m,2H),3.40(m,2H),3.20-3.12(m,2H),1.33(s,9H).

[1251] Step 3: N-(3-(tert-butyl)isoxazol-5-yl)-6-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 168)

[1252] According to the method in step 3 of Example 122, intermediate 113 (107 mg, 0.161 mmol) and intermediate 146 (55 mg, 0.161 mmol) were prepared. The residue was purified by preparative HPLC (Sunfire C18 19x150 mm, 10 μm, 5-60% ACN / H2O (0.1% FA), 20 mL / min, RT) and eluted on an SCX column with 1N NH3 in methanol to give the title compound (9 mg, 10%).

[1253] LC-MS (ESI) Method 7: t R =2.88min; m / z[M + H] + =548.5.

[1254] 1 H NMR(400MHz,DMSO-d6)d 11.78(s,1H),8.41(d,J=1.8Hz,1H),8.36(s,1H),8.03(s,1H),7.62(d,J=9.8Hz,1H),7.49(dd,J=2.3,9.8Hz,1H) ,6.39(s,1H),5.02(s,2H),3.98(t,J=5.6Hz,2H),3.09-3.08(m,6H),2.57-2.55(m,2H),2.29(s,3H),1.30(s,9H).

[1255] Example 169: Preparation of 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide

[1256]

[1257] Step 1: 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide (Example 169)

[1258] Following the method in step 3 of Example 1, starting from 1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-amine (145 mg, 0.879 mmol) and intermediate 54 (100 mg, 0.293 mmol), the desired product (44 mg, 0.095 mmol, 11%) was obtained.

[1259] LC-MS (ESI) Method 1: t R =0.88min; m / z[M + H] + =461.1.

[1260] 1 H NMR(ACN-d3,400MHz)δ9.60(br s,1H),8.97(br s,1H),8.23(s,1H),7.92(s,1H),7.83(s,1H),7.36(br s,1H),7.09(s,1H),6.46(br s,1H),3.88(s,3H),3.80(s,2H),3.66(s,2H),2.91(br t,2H,J=5.6Hz),2.79(t,2H,J=5.8Hz)

[1261] Example 170: Preparation of 6-(6-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[1262]

[1263] Step 1: 6-(6-hydroxyimidazo[1,2-a]pyridine-3-carbonyl)-N-[3-(trifluoromethyl)phenyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (intermediate 147)

[1264]

[1265] The title compound (169 mg, 0.347 mmol, 56%) was obtained from 6-hydroxyimidazo[1,2-a]pyridine-3-carboxylic acid (110 mg, 0.617 mmol) and intermediate 64 (202 mg, 0.617 mmol) according to the method of Example 90.

[1266] 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),9.79(s,1H),8.59(d,J=2.0Hz,1H),8.22(d,J=4.4Hz,2H),8.00-7.96(m,2H),7. 63-7.58(m,2H),7.45(d,J=7.9Hz,1H),7.17(dd,J=2.4,9.5Hz,1H),5.02(s,2H),4.01-3.96(m,2H),3.09-3.06(m,2H).

[1267] Step 2: 6-(6-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 170)

[1268] To a DMF (2.0 mL) solution of intermediate 147 (109 mg, 0.224 mmol), K₂CO₃ (77 mg, 0.560 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (46 mg, 0.246 mmol) were added, and the mixture was heated to 85 °C and stirred for 6 h. The reaction mixture was diluted in EtOAc and washed with water, water:saturated brine 1:1, dried over MgSO₄, filtered, and concentrated. The residue was purified by preparative HPLC (Xbridge Phenyl 19x150 mm, 10 μm, 40–100% MeOH / H₂O (10 mM NH₄CO₃), 20 mL / min) to give the title compound (20 mg, 14%).

[1269] LC-MS (ESI) Method 7: t R =3.22min; m / z[M + H] + =600.5.

[1270] 1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.63(d,J=2.1Hz,1H),8.22(s,2H),8.09(s, 1H),7.99(d,J=8.5Hz,1H),7.67(d,J=9.7Hz,1H),7.60(dd,J=8.0,8.0Hz,1H),7.4 5(d,J=7.7Hz,1H),7.30(dd,J=2.4,9.7Hz,1H),5.04(s,2H),4.12(t,J=5.6Hz,2H) ,3.99(t,J=5.6Hz,2H),3.59(t,J=4.6Hz,3H),3.08(s,2H),2.74(t,J=5.6Hz,2H).

[1271] Example 171: Preparation of N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[1272]

[1273] Step 1: 3-[[4-[(dimethylamino)methyl]-3-(trifluoromethyl)phenyl]carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (intermediate 148)

[1274]

[1275] N was prepared according to the general method from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (96 mg, 0.339 mmol) and intermediate 27 (74 mg, 0.339 mmol). The crude residue was purified by FCC (0-6% 2M NH3 / MeOH in DCM) to give the title compound (121 mg, 0.250 mmol, 73%).

[1276] 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),8.15-8.13(m,2H),7.97(d,J=8.5Hz,1H),7.68(d,J=8.5H z,1H),4.59(s,2H),3.60-3.55(m,2H),3.50(s,2H),2.88-2.82(m,2H),2.19(s,6H),1.43(s,9H)

[1277] Step 2: N-[4-[(dimethylamino)methyl]-3-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 149)

[1278]

[1279] Following the method of intermediate 139, starting from intermediate 148 (121 mg, 0.250 mmol), the title compound (78 mg, 81%) was obtained.

[1280] 1 H NMR (400MHz, DMSO) δ10.28(s,1H),8.14(d,J=2.1Hz,1H),8.04(s,1H),7.97(dd,J=1.8,8.5Hz,1H), 7.67(d,J=8.5Hz,1H),3.87(s,2H),3.48(s,2H),2.92-2.87(m,2H),2.77-2.71(m,2H),2.17(s,6H)

[1281] Step 3: N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 171)

[1282] Following the method of step 3 in Example 125, the title compound (11 mg, 27%) was obtained from pyrazolo[1,5-a]pyrazin-3-carboxylic acid (12 mg, 0.0756 mmol) and intermediate 149 (29 mg, 0.0756 mmol).

[1283] LC-MS (ESI) Method 7: t R =4.41min; m / z[M + H] + =529.2

[1284] 1 H NMR(400MHz,DMSO-d6)d 10.38-10.36(m,1H),9.37(d,J=1.5Hz,1H),8.93(dd,J=1.4,4.7Hz,1H),8.56(s,1H),8.20-8.10(m,3H),7. 99(dd,J=1.9,8.5Hz,1H),7.72-7.68(m,1H),4.99(s,2H),3.95(t,J=5.7Hz,2H),3.06(s,2H),2.19(s,6H).

[1285] Example 172: Preparation of N-(3-(morpholinomethyl)-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[1286]

[1287] Step 1: 3-[[3-(morpholinomethyl)-5-(trifluoromethyl)phenyl]carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (intermediate 150)

[1288]

[1289] Following the method of intermediate 89, the desired product (370 mg, 58%) was obtained starting from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (327 mg, 1.15 mmol) and intermediate 12 (300 mg, 1.15 mmol).

[1290] 1 H NMR (400MHz, CDCl3)d 7.85(s,1H),7.79(s,1H),7.65(s,1H),7.37(s,1H),5.30(s,2H),4.61(s,2H),3.74- 3.64(m,6H),3.53(s,2H),3.00(t,J=5.7Hz,2H),2.46(t,J=4.4Hz,4H),1.51(s,9H).

[1291] Step 2: N-[3-(morpholinomethyl)-5-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide dihydrochloride (intermediate 151)

[1292]

[1293] Following the method for intermediate 90, starting from intermediate 150 (350 mg, 0.666 mmol), the title compound (314 mg, 94.6%) was obtained.

[1294] 1H NMR(400MHz,DMSO-d6)d 11.51(s,1H),10.87(s,1H),9.81-9.73(m,2H),8.57(s,1H),8.35(s,1H),8.26(s,1H),7.92(s,1H),4.52-4.40(m,4 H), 4.00 (d, J = 11.9Hz, 2H), 3.86 (t, J = 11.6Hz, 2H), 3.45-3.37 (m, 2H), 3.31 (d, J = 12.1Hz, 2H), 3.18 (t, J = 5.4Hz, 4H).

[1295] Step 3: N-[3-(morpholinomethyl)-5-(trifluoromethyl)phenyl]-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 172)

[1296] The title compound was prepared according to method M from pyrazolo[1,5-a]pyrazin-3-carboxylic acid (49 mg, 0.301 mmol) and intermediate 151 (150 mg, 0.301 mmol). The compound was obtained by grinding with Et2O (90 mg, 49%).

[1297] LC-MS (ESI) Method 7: t R =3.05min; m / z[M + H] + =571.2

[1298] 1 H NMR(400MHz,DMSO-d6)d 10.44(s,1H),9.41(d,J=1.5Hz,1H),8.97(dd,J=1.4,4.7Hz,1H),8.60(s,1H),8.27(s,1H),8.19(s,1H),8.15(d,J=4.8Hz,1H ),8.01(s,1H),7.41(s,1H),5.04-5.01(m,2H),3.99(dd,J=5.7,5.7Hz,2H),3.62(d,J=20.2Hz,6H),3.11(s,2H),2.46(s,4H).

[1299] Example 173: Preparation of 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridazin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

[1300]

[1301] Step 1: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridazin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 173)

[1302] At -78 °C, lithium bis(trimethylsilyl)amino (1 M THF solution, 0.32 mL, 0.318 mmol) was added dropwise over 2 min to a stirred suspension of 5-(trifluoromethyl)pyridazin-3-amine (33 mg, 0.202 mmol) in THF (0.5 mL). The reaction mixture was stirred for 1.5 h, and then a suspension of 6-(imidazo[1,2-a]pyridin-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridin-3-carboxyl chloride (obtained from intermediate 40 (acid form) according to step H) (50 mg, 0.145 mmol) in DCM (1.2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NH4Cl(aq), and the aqueous phase was extracted with DCM. The organic phase was passed through a hydrophobic glass frit and concentrated under vacuum. The title compound (6 mg, 8%) was purified by preparative HPLC (Luna Phenyl-Hexyl 21.2 x 150 mm, 10 μm, 40-100% MeOH / water (0.1% FA) 20 mL / min, RT).

[1303] LC-MS (ESI) Method 7: t R =3.37min; m / z[M + H] + =473.2

[1304] 1 H NMR (400MHz, DMSO-d6) δ11.72(s,1H),9.39(d,J=1.6Hz,1H),8.89(td,J=1.1,7.0Hz,1H),8.62(dd,J=0.8,2.0Hz,1H),8.47(s,1H),8.07(s,1H) ,7.66(td,J=1.1,9.0Hz,1H),7.40(ddd,J=1.3,6.8,9.0Hz,1H),7.03(d t,J=1.2,6.9Hz,1H),4.97(s,2H),3.94-3.89(m,2H),3.07-3.02(m,2H)

[1305] Example 174: Preparation of 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide

[1306]

[1307] Step 1: 3-((3-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (intermediate 152)

[1308]

[1309] Following the method in step 4 of Example 1, the title compound (153 mg, 0.332 mmol, 38%) was obtained starting from 4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tert-butyl)3-ethyl ester (271 mg, 0.871 mmol) and N-3-fluoro-5-(trifluoromethoxy)aniline (600 mg, 2.61 mmol).

[1310] Step 2: N-(3-fluoro-5-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide (intermediate 153)

[1311]

[1312] Following the method of intermediate 139, starting from intermediate 152 (303 mg, 0.658 mmol), the title compound (80 mg, 0.222 mmol, 34%) was obtained.

[1313] Step 3: 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide (Example 174)

[1314] Following method K, starting from 1H-pyrazolo[3,4-b]pyridine-5-carboxaldehyde (36 mg, 0.244 mmol) and intermediate 153 (80 mg, 0.222 mmol), the title compound (15 mg, 0.031 mmol, 14%) was obtained.

[1315] LC-MS (ESI) Method 7: t R =5.16 min; m / z(M+1) = 492.3

[1316] 1H NMR(ACN-d3,400MHz)δ11.47(bs,1H),8.79(br s,1H),8.54(d,1H,J=2.0Hz),8.12(d,1H,J=2.0Hz),8.04(s,1H),7.86(s,1H),7.5-7.6(m,2H),6.84(br d,1H,J=8.6Hz),3.84(s,2H),3.69(s,2H),2.93(br t,2H,J=5.8Hz),2.81(t,2H,J=5.8Hz)

[1317] Example 175: Preparation of N-(5-(tert-butyl)isoxazol-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

[1318]

[1319] Step 1: 3-((5-(tert-butyl)isoxazol-3-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (intermediate 154)

[1320]

[1321] Following the method of intermediate 95, starting from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (142 mg, 0.500 mmol) and 3-amino-5-tert-butylisoxazole (70 mg, 0.500 mmol), the title compound (164 mg, 0.404 mmol, 81%) was obtained.

[1322] 1 H NMR (400MHz, CDCl3)d 10.84(s,1H),8.10(s,1H),6.88(s,1H),4.67-4.62(m,2H),3.68(t,J=4.9Hz,2H),3.03(t,J=5.8Hz,2H),1.42(s,9H),1.37(s,9H).

[1323] Step 2: N-(5-tert-butylisoxazol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (intermediate 155)

[1324]

[1325] Following the method for intermediate 86, the title product was obtained starting from intermediate 154 (164 mg, 0.404 mmol, 1.00 eq).

[1326] 1 ¹H NMR (400MHz, DMSO-d⁶) d 11.32 (s, 1H), 9.65–9.56 (m, 2H), 8.49 (s, 1H), 6.74 (s, 1H), 4.42 (s, 2H), 3.39 (m, 2H under water peak), 3.15 (t, J = 5.8 Hz, 2H), 1.37 (s, 9H).

[1327] Step 3: N-(5-(tert-butyl)isoxazol-3-yl)-6-(pyrazolo[1,5-a]pyrazin-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 175)

[1328] The compound was prepared according to method N from intermediate 155 (52 mg, 0.152 mmol) and pyrazolo[1,5-a]pyrazin-3-carboxylic acid (25 mg, 0.152 mmol). Purification was achieved by washing with DMSO, followed by washing with water and drying before further washing with DCM, to give the title compound (28.39 mg, 40.26%).

[1329] LC-MS (ESI) Method 6: t R =4.20min; m / z[M + H] + =451.4

[1330] 1 H NMR (400MHz, DMSO-d6) δ11.22-11.19(s,1H),9.41-9.39(d,J=1.46Hz,1H),8.97(dd,J=1.4,4.7Hz,1H),8.59(s,1H),8. 38(s,1H),8.14(d,J=4.5Hz,1H),6.75(s,1H),5.02-5.00(s,2H),4.01-3.95(t,J=5.7Hz,2H),3.10(s,2H),1.37(s,9H).

[1331] Example 176: Preparation of compound N-(4-chloro-3-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[1332]

[1333] Step 1: 3-((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (intermediate 156)

[1334]

[1335] Following the method of step 1 in Example 47, the crude residue obtained by purification by FCC (0-50% EtOAc in cyclohexane solution) from 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (200 mg, 0.706 mmol) and 4-chloro-3-(trifluoromethyl)aniline (138 mg, 0.706 mmol) yielded the title compound (231 mg, 0.501 mmol, 71%).

[1336] 1 H NMR (400MHz, DMSO-d6) δ10.49(s,1H),8.32(d,J=2.4Hz,1H),8.18(s,1H),8.04(dd,J=2.3,8.8Hz, 1H), 7.71 (d, J = 8.8Hz, 1H), 4.60 (s, 2H), 3.59 (t, J = 5.6Hz, 2H), 2.86 (t, J = 5.6Hz, 2H), 1.44 (s, 9H).

[1337] Step 2: N-[4-chloro-3-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 157)

[1338]

[1339] Following the method for intermediate 96, starting from intermediate 156 (230 mg, 0.499 mmol), the title compound (180 mg, 0.454 mmol, 91%) was obtained.

[1340] 1 H NMR (400MHz, DMSO-d6) δ10.48(s,1H),8.33(d,J=2.5Hz,1H),8.13(s,1H),8.05(dd,J=2.4,8.8Hz, 1H), 7.71 (d, J = 8.8Hz, 1H), 4.11 (s, 1H), 3.97 (s, 2H), 2.98 (t, J = 5.8Hz, 2H), 2.81 (t, J = 5.6Hz, 2H).

[1341] Step 3: N-(4-chloro-3-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 176)

[1342] Following the method of step 3 in Example 121, the title compound (4.39 mg, 1.64%) was obtained from pyrazolo[1,5-a]pyrazin-3-carboxylic acid (81 mg, 0.499 mmol) and intermediate 157 (180 mg, 0.499 mmol).

[1343] LC-MS (ESI) Method 6: t R =4.78min; m / z[M + H] + =506.2

[1344] 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),9.37(d,J=1.5Hz,1H),8.94(dd,J=1.4,4.7Hz,1H),8.56(s,1H),8.33(d,J=2.4Hz,1H),8.22 (s, 1H), 8.11 (d, J = 4.8Hz, 1H), 8.05 (dd, J = 2.5, 8.8Hz, 1H), 7.72 (d, J = 8.9Hz, 1H), 5.00 (s, 2H), 3.95 (t, J = 5.6Hz, 2H), 3.06 (s, 2H).

[1345] Example 177: Preparation of 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[1346]

[1347] Step 1: 3-[[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (intermediate 158)

[1348]

[1349] Following the method of step 1 in Example 109, the title compound (516 mg, 0.984 mmol, 93%) was obtained from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (300 mg, 1.06 mmol) and 3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)aniline (275 mg, 1.06 mmol).

[1350] 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),8.14(s,1H),7.61-7.56(m,2H),6.94(s,1H),4.60(s,2H),3.66-3. 57(t,2H),3.21(t,J=4.9Hz,4H),2.86(t,J=5.7Hz,2H),2.47(t,J=5.0Hz,4H),2.24(s,3H),1.44(s,9H).

[1351] Step 2: N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 159)

[1352]

[1353] Following the procedure for intermediate 86, starting with intermediate 158 (515 mg, 0.982 mmol), the obtained residue was diluted in MeOH, washed through an SCX column (5 g, eluted with 1 N NH3 / MeOH) and concentrated to give the title compound (430 mg, 1.01 mmol, 103%).

[1354] 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),8.18(s,1H),7.62(s,1H),7.58(s,1H),6.94(s,1H),4. 14(s,3H),3.22(t,J=5.71Hz,4H),3.15(t,J=6.43Hz,2H),2.93(t,J=5.3Hz,2H),2.25(s,3H).

[1355] Step 3: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 177)

[1356] Starting from imidazo[1,2-a]pyridine-3-carboxylic acid (79 mg, 0.490 mmol) and intermediate 159 (208 mg, 0.490 mmol) according to the universal method M, the crude product was purified by preparative HPLC (Sunfire C18 19x150 mm, 10 μm 20-80% ACN / H2O (10 mM NH4CO3), 20 mL / min, RT) to give the title compound (49 mg, 17.59%).

[1357] LC-MS (ESI) Method 7: t R =2.84min; m / z[M + H] + =569.2

[1358] 1 H NMR (400MHz, DMSO-d6) δ10.20 (s, 1H), 8.98 (d, J = 7.0Hz, 1H), 8.19 (s, 1H), 8. 15(s,1H),7.75(d,J=8.9Hz,1H),7.62(s,1H),7.59(s,1H),7.51-7.45(m,1H ),7.13-7.09(m,1H),6.95(s,1H),5.06-5.02(m,2H),4.00(t,J=5.6Hz,2H), 3.22(t,J=4.9Hz,4H), 3.09(t,J=6.5Hz,2H), 2.50-2.45(m,4H), 2.25(s,3H).

[1359] The compounds reported in the table below were prepared by amide coupling as described in steps 1-3 of Example 177, using the corresponding commercially available carboxylic acid in step 3.

[1360]

[1361] Example 179: Preparation of N-(3-(tert-amyl)isoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

[1362]

[1363] Step 1: 3-((3-(tert-amyl)isoxazol-5-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (intermediate 160)

[1364]

[1365] The title compound (14 mg, 6%) was obtained from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (150 mg, 0.529 mmol) and 3-(1,1-dimethylpropyl)isoxazole-5-amine (82 mg, 0.529 mmol) according to the method of intermediate 95.

[1366] 1 H NMR (400MHz, CDCl3) δ8.61-8.61(m,1H),7.67(s,1H),6.23(s,1H),4.51(s,2H),3.55(t,J=5.6Hz ,2H),2.88(t,J=5.6Hz,2H),1.52(q,J=7.5Hz,2H)1.36(s,9H),1.17(s,6H),0.69(t,J=7.5Hz,3H)

[1367] Step 2: N-(3-(tert-amyl)isoxazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (intermediate 161)

[1368]

[1369] Following the method for intermediate 86, the title compound (17 mg, assumed quantification) was obtained from intermediate 160 (14 mg, 0.0334 mmol) via precipitation from Et2O.

[1370] LC-MS (ESI) Method 16: t R =1.04min; m / z[M + H] + =320.1

[1371] Step 3: N-(3-(tert-amyl)isoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 179)

[1372] Following the method in step 3 of Example 121, a crude product was obtained from intermediate 161 (52 mg, 0.146 mmol) and pyrazolo[1,5-a]pyrazin-3-carboxylic acid (24 mg, 0.146 mmol). The crude product was purified by SFC (TORUS-2PIC 20x250 mm, 5 μm, 5-15% MeOH (0.1% DEA) / CO2, 100 mL / min, 120 bar, 40°C, DAD 260 nm) to obtain the title compound (15 mg, 23%).

[1373] LC-MS (ESI) Method 7: tR =4.45min; m / z[M + H] + =465.6

[1374] 1 H NMR (400MHz, DMSO-d6) δ11.76-11.76(s,1H),9.36(d,J=1.4Hz,1H),8.93(dd,J=1.4,4.7Hz,1H),8.55(s,1H),8.34(s,1H),8.11(d,J=4.8H z,1H),6.32(s,1H),4.99-4.99(s,2H),3.95(t,J=5.8Hz,2H),3.07-3.07(m,2H),1.62(q,J=7.4Hz,2H),1.25(s,6H),0.77(t,J=7.5Hz,3H).

[1375] Example 180: Preparation of compound N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[1376]

[1377] Step 1: 6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (intermediate 162)

[1378]

[1379] Pyrazolo[1,5-a]pyrazin-3-carboxylic acid (0.083 g, 0.507 mmol) was added to a flask, followed by DMF (1.491 mL). Then DIPEA (0.195 mL, 1.115 mmol) was added. After 5 min, HATU (0.212 g, 0.558 mmol) was added, and the solution was stirred at room temperature for 30 min. Then intermediate 36 (0.1 g, 0.507 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. The RM was poured onto ice, and the solid was filtered through a Schoutt funnel to give the title compound (0.153 g, 0.447 mmol, 88%).

[1380] 1H NMR(300MHz,DMSO-d6)δ9.33(d,J=1.4Hz,1H),8.91(dd,J=4.7,1.5Hz,1H),8.54(s,1H),8.25 (s,1H),8.08(d,J=4.7Hz,1H),4.95(s,2H),3.93(t,J=5.8Hz,2H),3.78(s,3H),3.03(s,2H).

[1381] Step: N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 180)

[1382] Following the method of step 1 in Example 128, starting with intermediate 162 (50 mg, 0.146 mmol) and intermediate 112 (33 mg, 0.175 mmol), the crude product was purified by SFC (YMC Amylose-C MeOH TORUS-2PIC 20x250 mm, 5 μm 15-25% MeOH (0.1% DEA) / CO2, 100 mL / min, 120 bar, 40°C, DAD 260 nm) to give the title compound (15 mg, 21%).

[1383] LC-MS (ESI) Method 7: t R =3.74min; m / z[M + H] + =502.5

[1384] 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),9.37(d,J=1.5Hz,1H),8.94(dd,J=1.4, 4.7Hz,1H),8.56(s,1H),8.20(s,1H),8.16(d,J=2.0Hz,1H),8.11(d,J=4.6Hz ,1H),8.01(dd,J=1.7,8.6Hz,1H),7.74(d,J=8.5Hz,1H),5.00-5.00(m,2H),4 .65(s,2H),3.95(dd,J=5.8,5.8Hz,2H),3.07-3.05(m,2H),2.58-2.55(m,1H).

[1385] Example 181: Preparation of compound 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-morpholino-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[1386]

[1387] Step 1: 3-[[3-morpholino-5-(trifluoromethyl)phenyl]carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (intermediate 163)

[1388]

[1389] Following the method of intermediate 89, starting from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (300 mg, 1.06 mmol) and 3-morpholino-5-(trifluoromethyl)aniline (261 mg, 1.06 mmol), the title compound (489 mg, 0.956 mmol, 90%) was obtained.

[1390] 1 H NMR(400MHz,DMSO-d6)d 10.21(s,1H),8.14(s,1H),7.63(s,1H),7.59(s,1H),6.96(s,1H),4.60(s,2H),3.77(t,J=4 .8Hz, 4H), 3.59 (t, J = 5.8Hz, 2H), 3.19 (t, J = 4.8Hz, 4H), 2.85 (t, J = 5.6Hz, 2H), 1.44 (s, 9H).

[1391] Step 2: N-[3-morpholino-5-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 164)

[1392]

[1393] Following the method for intermediate 86, starting from intermediate 163 (489 mg, 0.956 mmol), the title compound (404 mg, 0.982 mmol, quantitative yield) was obtained.

[1394] 1 H NMR(400MHz,DMSO-d6)d 10.16(s,1H),8.05(s,1H),7.64(s,1H),7.59(s,1H),6.95(s,1H),3.90(s,2H),3.7 7(t,J=4.8Hz,4H),3.20-3.16(m,4H),2.92(t,J=5.6Hz,2H),2.76(t,J=5.5Hz,2H).

[1395] Step 3: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-morpholino-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 181)

[1396] Starting from intermediate 164 (196 mg, 0.476 mmol) and imidazo[1,2-a]pyridine-3-carboxylic acid (77 mg, 0.476 mmol) according to general method M, the crude product was purified by FCC (25 g, 0-50% cyclohexane solution of 3:1 EtOAc:EtOH) to give the title compound (162 mg, 60%).

[1397] LC-MS (ESI) Method 7: t R =3.97min; m / z[M + H] + =556.2

[1398] 1 H NMR (400MHz, DMSO-d6) δ10.23(s,1H),8.97(d,J=6.9Hz,1H),8.19(s,1H),8.15(s,1H),7.75(d,J=9.0Hz,1H),7.64(s,1H),7.60(s,1H),7.51-7 .45(m,1H),7.13-7.10(m,1H),6.97(s,1H),5.04(s,2H),3.99(t,J=5.6 Hz, 2H), 3.77 (t, J = 4.8 Hz, 4H), 3.22-3.16 (m, 4H), 3.09 (t, J = 5.8 Hz, 3H).

[1399] The compounds reported in the table below were prepared by amide coupling as described in steps 1-3 of Example 181, using the corresponding commercially available or previously synthesized carboxylic acids in step 3.

[1400]

[1401] Example 183: Preparation of compound N-(3-isobutylisoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[1402]

[1403] Step 1: 3-[(3-isobutylisoxazol-5-yl)carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (intermediate 165)

[1404]

[1405] The title compound (226 mg, 0.557 mmol, 63%) was obtained from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (250 mg, 0.882 mmol) and 3-isobutylisoxazol-5-amine according to the method of intermediate 95.

[1406] 1 H NMR (400MHz, CDCl3) δ8.63-8.62(s,1H),7.76(s,1H),6.31(s,1H),4.64(s,2H),3.68(t,J=5.6Hz,2H),3.01(t, J=5.4Hz,2H),2.51(d,J=7.1Hz,2H),2.05-1.96(m,1H),1.61(s,4H),1.49(s,9H),0.99-0.96(d,J=6.7Hz,6H).

[1407] Step 2: N-(3-isobutylisoxazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 166)

[1408]

[1409] Following the steps of intermediate 96, starting from intermediate 165 (226 mg, 0.557 mmol), the title compound (143 mg, 0.418 mmol, 75%) was obtained.

[1410] 1 H NMR (400MHz, DMSO-d6) δ 8.52 (s, 1H), 6.31 (s, 1H), 4.41 (s, 2H), 3.15 (t, J = 5.2Hz, 2H), 2.51 (d, J = 7.0Hz, 2H), 2.05-1.96 (m, 1H), 0.97 (d, J = 6.6Hz, 6H).

[1411] Step 3: N-(3-isobutylisoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 183)

[1412] Following the method of step 3 in Example 121, starting from intermediate 166 (52 mg, 0.152 mmol) and the obtained pyrazolo[1,5-a]pyrazin-3-carboxylic acid (25 mg, 0.152 mmol), the residue was purified by preparative HPLC (Sunfire C183 x 50 mm, 3 μm 5-95% ACN / H2O (10 mM NH4CO3), 1.7 mL / min, RT) to give the title compound (13.16 mg, 19.21%).

[1413] LC-MS (ESI) Method 17: t R =4.26min; m / z[M + H] + =451.4

[1414] 1 H NMR (400MHz, DMSO-d6) δ11.77-11.77(m,1H),9.36(d,J=1.4Hz,1H),8.93(dd,J=1.4,4.7Hz,1H),8.56(s,1H),8.34(s,1H),8.11(d,J=4.8Hz,1 H), 6.27 (s, 1H), 4.99-4.99 (m, 2H), 3.94 (t, J = 5.8Hz, 2H), 3.10-3.05 (m, 2H), 2.47 (d, J = 7.2Hz, 2H), 2.01-1.93 (m, 1H), 0.94 (d, J = 6.5Hz, 6H).

[1415] Example 184: Preparation of compound N-(3-cyano-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[1416]

[1417] Step 1: 3-((3-cyano-5-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (intermediate 167)

[1418]

[1419] Following the method of step 1 in Example 47, the title compound (704 mg, 1.56 mmol) was obtained by precipitation in water, starting from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (500 mg, 1.76 mmol) and 3-amino-5-(trifluoromethyl)benzyl nitrile (345 mg, 1.85 mmol).

[1420] 1 H NMR(400MHz, CDCl3)δ8.68(s,1H),8.33-8.32(s,1H),8.17-8.15(s,1H),7.64(s, 2H), 4.58-4.56 (m, 2H), 3.69 (t, J = 5.6Hz, 2H), 3.01 (t, J = 5.4Hz, 3H), 1.57 (s, 9H).

[1421] Step 2: N-(3-cyano-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 168)

[1422]

[1423] Following the procedure for intermediate 86, the title product was obtained by precipitation with Et2O, starting from intermediate 167 (704 mg, 1.56 mmol), as an HCl salt (596 mg, 1.54 mmol, 99%).

[1424] 1 H NMR (400MHz, DMSO-d6) δ11.00 (s, 1H), 9.60-9.52 (m, 2H), 8.55 (d, J = 9.1Hz, 3H), 8.10 (s, 1H), 4.44 (s, 2H), 3.43 (t, J = 5.8Hz, 2H), (t, J = 5.8Hz, 2H).

[1425] Step 3: N-(3-cyano-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 184)

[1426] Following the method of step 3 in Example 121, the title compound (63 mg, 0.126 mmol, 59%) was obtained by precipitation from water, starting from intermediate 168 (75 mg, 0.213 mmol) and pyrazolo[1,5-a]pyrazine-3-carboxylic acid (35 mg, 0.213 mmol).

[1427] LC-MS (ESI) Method 6: tR =4.44min; m / z[M + H] + =497.5

[1428] 1 H NMR(400MHz,DMSO-d6)d 10.72(s,1H),9.41(s,1H),8.97(d,J=3.5Hz,1H),8.61(s,1H),8.52-8.47(m,2H),8.30( s,1H),8.15(d,J=4.0Hz,1H),8.09(s,1H),5.04-5.00(m,2H),4.00(s,2H),3.11(s,2H).

[1429] Example 185: Preparation of 6-(imidazo[1,2-a]pyridine-3-carbonyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[1430]

[1431] Step 1: 6-(tert-butyl)3-ethyl 2-amino-4-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid (intermediate 169)

[1432]

[1433] To a solution of tert-butyl 3-methyl-4-oxo-piperidin-1-carboxylate (5000 mg, 23.4 mmol) in ethanol (50 mL), ethyl cyanoacetate (2.5 mL, 23.4 mmol), sulfur (750 mg, 23.4 mmol), and TEA (4.7 mL, 33.5 mmol) were added. The reaction mixture was heated under reflux for 90 min. After cooling to room temperature and filtration, the residue was purified by FCC (0-50% EtOAc in cyclohexane solution) and prepared with cyclohexane to give the title compound (2540 mg, 7.46 mmol, 32%).

[1434] 1 H NMR (400MHz, CDCl3) δ6.08-6.01(s,2H),4.89-4.59(m,1H),4.36-4.22(m,2H),4.14-3. 91(m,2H),3.34-2.96(m,2H),1.49(s,9H),1.36(t,J=7.1Hz,3H),1.17(d,J=6.8Hz,3H).

[1435] Step 2: 4-Methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tert-butyl)3-ethyl ester (intermediate 170)

[1436]

[1437] At -5 °C, concentrated HCl (0.50 mL, 0.587 mmol) was added to a suspension of intermediate 169 (200 mg, 0.587 mmol) in 1,4-dioxane (2 mL), followed by the dropwise addition of a solution of sodium nitrite (45 mg, 0.646 mmol) in 0.2 mL of water. The reaction mixture was stirred at -5 °C for 1 h, and then added to a 50% phosphoric acid solution (1.0 mL, 17.2 mmol) and Et₂O (1 mL). The reaction mixture was heated to room temperature and stirred for 45 min. The reaction mixture was poured onto ice and extracted with DCM. The organic phase was filtered through a hydrophobic glass frit, and the solvent was concentrated under vacuum. The residue was purified by FCC (0-50% EtOAc in cyclohexane solution) to give the title compound (90 mg, 0.277 mmol, 47%).

[1438] 1 H NMR (400MHz, CDCl3)d 7.99(s,1H),5.13-4.86(m,1H),4.35-4.27(m,2H),4.23-4.02(m,2H),3.53-3.47(m ,1H),3.18-3.06(m,1H),1.42(s,9H),1.36(t,J=7.1Hz,3H),1.22(d,J=6.8Hz,3H).

[1439] Step 3: Ethyl 4-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (intermediate 171)

[1440]

[1441] Following the method for intermediate 86, starting from intermediate 170 (90 mg, 0.277 mmol), the title compound (60 mg, 0.229 mmol, 83%) was obtained.

[1442] 1 H NMR (400MHz, DMSO-d6)d 9.45-9.45(m,2H),8.37(s,1H),4.44(d,J=15.9Hz,1H),4.37-4.28(m,3H),3.61-3.54(m,1H),1.35(dd,J=7.1,7.1Hz,6H).

[1443] Step 4: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-4-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl ester (intermediate 172)

[1444]

[1445] Following the method of step 3 in Example 121, the title compound (73 mg, 0.178 mmol, 78%) was obtained by starting with intermediate 171 (60 mg, 0.229 mmol) and imidazo[1,2-a]pyridine-3-carboxylic acid (37 mg, 0.229 mmol).

[1446] 1 H NMR (400MHz, CDCl3)d 8.94(d,J=6.8Hz,1H),7.96(s,1H),7.92(s,1H),7.61(d,J=9.1Hz,1H),7.31-7.25(t,J=7.2Hz,1H),5.36(d,J=16.4Hz,1H),4.63-4. 48(m,2H),4.28-4.21(m,2H),3.55(d,J=3.5Hz,1H),3.42(d,J=11.1Hz,1H),1.32-1.26(d,J=7.1Hz,1H),1.26-1.21(d,J=6.7Hz,3H).

[1447] Step 4: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 185)

[1448] At -40 °C, a 1.7 M tert-butyllithium solution in pentane (0.35 mL, 3.77 mmol) was added dropwise to a THF (3 mL) solution of intermediate 172 (73 mg, 0.198 mmol) and 3-(trifluoromethyl)aniline (0.030 mL, 0.237 mmol). The reaction mixture was heated to room temperature and stirred overnight. The reaction was carefully quenched with aqueous NH4Cl and extracted with DCM. The organic phase was filtered through a hydrophobic glass frit and the solvent was concentrated under vacuum. The residue was purified by preparative HPLC (Sunfire C18 19 × 150 mm, 10 μm, 20-80% ACN / H2O (10 mM NH4CO3), 20 mL / min, RT) to give the title compound (19 mg, 0.0386 mmol, 20%).

[1449] LC-MS (ESI) Method 6: t R=4.79min; m / z[M + H] + =485.5

[1450] 1 H NMR(400MHz,DMSO-d6)d 10.48(s,1H),8.96(d,J=7.0Hz,1H),8.21(s,1H),8.16(d,J=9.3Hz,2H),8.00(d,J=8.2Hz,1H),7.75(m,1H),7.60(t,J=8.0Hz,1H ),7.51-7.45(m,2H),7.13-7.09(m,1H),5.32(d,J=16.7Hz,1H),4.33(d,J=12.3Hz,1H),3.58-3.56(m,3H),1.18(d,J=6.8Hz,3H).

[1451] Example 186: Preparation of 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethoxy)pyridine-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide

[1452]

[1453] Step 1: 3-((5-(trifluoromethoxy)pyridin-3-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (intermediate 173)

[1454]

[1455] Following the method of intermediate 89, the title compound (100 mg, 0.226 mmol, 76%) was obtained by precipitation from water, starting from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (85 mg, 0.298 mmol) and intermediate 86 (64 mg, 0.298 mmol).

[1456] 1 H NMR (400MHz, CDCl3)d 8.55 (s, 1H), 8.33 (s, 2H), 8.04 (m, 1H), 7.68 (s, 1H), 4.62 (s, 2H), 3.68 (t, J = 5.3Hz, 2H), 3.00 (t, J = 5.7Hz, 2H), 1.50 (s, 9H).

[1457] Step 2: N-(5-(trifluoromethoxy)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide (intermediate 174)

[1458]

[1459] Following the method for intermediate 86, starting from intermediate 173 (100 mg, 0.226 mmol), the title compound (78 mg, 0.205 mmol, 91%) was obtained.

[1460] 1 H NMR(400MHz,DMSO-d6)d 10.92(s,1H),9.64(s,2H),9.04(d,J=2.0Hz,1H),8.56(s,1H),8.44(m,2H),4.43(t,J=4.8Hz,2H),3.41(m,2H),3.17(t,J=5.8Hz,2H).

[1461] Step 3: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethoxy)pyridine-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 186)

[1462] Following the method of step 3 in Example 121, the title compound (22 mg, 0.0445 mmol, 44%) was obtained by preparative HPLC starting from intermediate 174 (38 mg, 0.100 mmol) and imidazo[1,2-a]pyridine-3-carboxylic acid (16 mg, 0.100 mmol).

[1463] LC-MS (ESI) Method 7: t R =3.54min; m / z[M + H] + =488.5

[1464] 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.98(d,J=7.0Hz,1H),8.92(d,J=2.0Hz,1H),8.41(d,J=2.3Hz,1H),8.35(s,1H),8.26 (s,1H),8.15(s,1H),7.75(d,J=9.0Hz,1H),7.50-7.45(m,1H),7.12(m,1H),5.04(s,2H),4.00(t,J=5.6Hz,2H),3.10(m,2H).

[1465] Example 187: Preparation of N-(3-(hydroxymethyl)-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

[1466]

[1467] Step 1: 3-[[3-(hydroxymethyl)-5-(trifluoromethyl)phenyl]carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (intermediate 175)

[1468]

[1469] Following the method of intermediate 89, starting from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (300 mg, 1.06 mmol) and [3-amino-5-(trifluoromethyl)phenyl]methanol (241 mg, 1.06 mmol), the title compound (414 mg, 0.907 mmol, 86%) was obtained.

[1470] 1 H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.19(s,1H),8.07(s,1H),7.98(s,1H),7.37(s,1H),5.46 (t,J=5.7Hz,1H),4.64-4.57(m,4H),3.59(t,J=5.8Hz,2H),2.87(t,J=5.6Hz,2H),1.45(s,9H).

[1471] Step 2: N-[3-(hydroxymethyl)-5-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; hydrochloride (intermediate 176)

[1472]

[1473] Following the method for intermediate 86, starting from intermediate 175 (414 mg, 0.907 mmol), the title compound (344 mg, 0.876 mmol, 97%) was obtained.

[1474] 1H NMR(400MHz,DMSO-d6)d 10.49(s,1H),8.41(s,1H),8.20(s,1H),8.02(d,J=6.1Hz,1H),7.63-7.59(m ,2H),4.06(s,2H),3.19(s,2H),3.07(t,J=5.8Hz,2H),2.88(t,J=5.6Hz,2H).

[1475] Step 3: N-[3-(hydroxymethyl)-5-(trifluoromethyl)phenyl]-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 187)

[1476] Following the method of step 3 in Example 121, the title compound (13 mg, 0.0259 mmol, 6.0%) was obtained by starting with intermediate 176 (169 mg, 0.429 mmol) and pyrazolo[1,5-a]pyrazin-3-carboxylic acid (70 mg, 0.429 mmol).

[1477] LC-MS (ESI) Method 6: t R =3.84min; m / z[M + H] + =502.4

[1478] 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),9.37(d,J=1.4Hz,1H),8.94(dd,J=1.4,4.7Hz,1H),8.56(s,1H),8.22(s,1H),8.12-8.08(m,2H) ,7.99(s,1H),7.38(s,1H),5.46(t,J=5.7Hz,1H),5.09-4.89(m,2H),4.60(d,J=5.5Hz,2H),3.96(t,J=5.8Hz,2H),3.10-3.02(m,2H).

[1479] Compared with the newly synthesized compound, it is characterized by:

[1480] - Acylamino group substituted at the α-position relative to sulfur, forming a thiophene ring (Example C1)

[1481] Simultaneously, the amide-substituted thiophene ring linked at the α-position relative to sulfur and the hy-substituted pyridine ring linked to the nitrogen at the 5-position are connected via spacer groups (Example C2).

[1482] Example C1: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide

[1483]

[1484] Step 1: Methyl 6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (intermediate 84)

[1485]

[1486] Imidazolo[1,2-a]pyridine-3-carboxylic acid (153 mg, 0.941 mmol), methyl 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylic acid hydrochloride (200 mg, 0.856 mmol), and TBTU (412 mg, 1.284 mmol) were dissolved in 6 mL of 1:1 DCM / DMF, followed by the dissolution of N-ethyl-N-isopropylpropyl-2-amine (598 μL, 3.42 mmol). The solution was stirred at room temperature for 1 h. T...

Claims

1. Compounds of formula (I) (I) in Rx, Ry, and Rz are independently H or -(C1-C4) alkyl; L is selected from -C(O)- and -CH2-; Hy is a bicyclic heteroaryl group, optionally substituted with at least one substituent selected from -(C1-C4)alkyl, halogen atom, cyano, -O-(C1-C4)alkyl, -O-(C1-C4)alkylene-OH, -O-(C1-C4)alkylene-O-(C1-C4)alkyl, -O-(C1-C4)alkylene-heterocyclic alkyl, -(C1-C4)alkylene-NR4R5, -(C1 -C6) haloalkyl and heterocyclic alkyl, optionally substituted with one or more -(C1-C4) alkyl groups, or Hy is a bicyclic semi-saturated heteroaryl group, wherein the semi-saturated heteroaryl group is selected from 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl and 5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-3-yl; R1 is selected from: - Het is a heteroaryl group, optionally substituted with one or more substituents selected from -(C1-C4)alkyl, -(C1-C4)haloalkyl, cycloalkyl optionally substituted with one or more -(C1-C6)haloalkyl, -O-(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -(C1-C4)alkylene-OH, -(C1-C4)alkylene-NR4R5, heterocycloalkyl, -(C1-C4)alkylene-aryl, and aryl, wherein the aryl group is optionally substituted with one or more groups selected from -(C1-C4)alkyl and halogen atoms, and - X (X) in R2 is H or selected from -O(C1-C4) haloalkyl, halogen atom and -(C1-C4) haloalkyl; R3 is H or selected from halogen atoms, cyano groups, heterocyclic alkyl groups optionally substituted with one or more -(C1-C4)alkyl groups, -(C1-C4)alkylene-heterocyclic alkyl groups, and -(C1-C4)alkylene-heterocyclic alkyl-(CH2) groups. n -NR4R5, -(C1-C4)alkylene-NR4R5, -(C1-C4)alkylene-NR4R6, -O(C1-C4)alkyl, -O(C1-C4)haloalkyl, -O-(C1-C4)alkylene-OH, heteroaryl groups optionally substituted with -(C1-C4)alkyl, -O-(C1-C4)alkylene-NR4R5, -O-(C1-C4)alkylene-O-(C1-C4)alkyl, -O-(C1-C4)alkylene-heterocyclic alkyl and -O-heterocyclic alkyl, wherein each of the heterocyclic alkyl groups is optionally substituted with one or more groups selected from -(C1-C4)alkyl, oxo, halogen atom, -C(O)-(C1-C4)alkyl and heterocyclic alkyl; n is 0, 1, or 2; R4 is H or -(C1-C4) alkyl; R5 is H or -(C1-C4) alkyl; R6 is selected from -heterocyclic alkyl, -(C1-C4)alkylene-O-(C1-C4)alkyl and -(C1-C4)alkylene-OH; 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. 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 (Ia) according to claim 2, wherein L is -CH2-, said compound being represented by formula (Iaa). (Iaa) 。 4. The compound of formula (Iaa) according to claim 3, selected from at least one of the following: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazo-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide; 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide 6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; 6-((1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; 6-(imidazo[1,2-b]pyridazine-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(pyrazolo[1,5-a]pyrimidin-6-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-5-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-5-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; (R)-N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)-6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; (R)-6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; (R)-N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)-N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-6-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(2-(pyrrolidine-1-yl)ethoxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(2-(pyrrolidine-1-yl)ethoxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; and 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide.

5. The compound of formula (Ia) according to claim 2, wherein L is -C(O)-, said compound is represented by formula (Iab). (Iab).

6. The compound of formula (Iab) according to claim 5, selected from at least one of the following: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethoxy)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(pyrrolidine-1-ylmethyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-((dimethylamino)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(morpholinomethyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(2-(pyrrolidine-1-yl)ethoxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; (S)-N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)-N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-((4-(dimethylamino)piperidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-((6-oxa-1-azaspiro[3.3]hept-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-((2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-((3-fluoropyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-(azacyclobutane-1-ylmethyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((methyl(oxecyclobutane-3-yl)amino)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-(oxecyclobutane-3-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-((3-((dimethylamino)methyl)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(((2-hydroxyethyl)(methyl)amino)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-((4-acetylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methyl-3-oxopiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(piperidin-1-ylmethyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(((2-methoxyethyl)(methyl)amino)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(2-(4-methylpiperazin-1-yl)ethoxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((1-methylpyrrolidine-3-yl)oxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(4-methyl-1H-imidazo-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyrazine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-b]pyridazine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-N-(3-(4-methyl-1H-imidazo-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; (R)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; (R)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-N-(3-(4-methyl-1H-imidazo-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7,7-dimethyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; (R)-N-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-cyano-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(6-((dimethylamino)methyl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(6-(2-hydroxyethoxy)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; (R)-N-(3-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(5-methylimidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(6-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(6-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-(morpholinomethyl)-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazin-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-morpholino-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-morpholino-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-cyano-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; and N-(3-(hydroxymethyl)-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide.

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 -C(O)-, said compound is represented by formula (Ibb). (Ibb) 。 9. The compound of formula (Ibb) according to claim 8, selected from at least one of the following: N-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazol-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(6-(trifluoromethyl)pyrimidin-4-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(4-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(4-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(5-(tert-butyl)isoxazol-3-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)isoxazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-cyclobutyl-1-methyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-isopropyl-1-methyl-1H-pyrazole-5-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(2-(tert-butyl)pyridin-4-yl)-6-(imidazo[1,2-a]pyridin-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide; N-(3-(tert-butyl)-1-isopropyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(1-methyl-3-propyl-1H-pyrazole-5-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(1-benzyl-3-(tert-butyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-ethyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-isobutyl-1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(4-(tert-butyl)oxazol-2-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-(2-hydroxyethyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(7-methylimidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(6-methylimidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(6-fluoroimidazolo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(6-chloroimidazolo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide; 6-(pyrazolo[1,5-a]pyrimidin-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; 6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridine-3-yl)-4,5,6,7-tetrahydrothienozo[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)isoxazol-5-yl)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)isoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazin-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(1-methyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(5-(1,1-difluoroethyl)pyridin-3-yl)-6-(imidazo[1,2-a]pyridin-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(5-(tert-butyl)pyridin-3-yl)-6-(imidazo[1,2-a]pyridin-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; N-(5-(difluoromethoxy)pyridin-3-yl)-6-(imidazo[1,2-a]pyridin-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(tert-pentyl)isoxazol-5-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothienozo[2,3-c]pyridin-3-carboxamide; N-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazin-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; N-(5-(1,1-difluoroethyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazin-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; N-(5-(tert-butyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazin-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; 6-(pyrazolo[1,5-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(5-(difluoromethoxy)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazin-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; 6-(pyrazolo[1,5-a]pyrazin-3-carbonyl)-N-(5-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyrazin-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide; 6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-N-(5-(trifluoromethoxy)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide; N-(2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-yl)-6-(imidazo[1,2-a]pyridin-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; 6-(5-methoxypyrazolo[1,5-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyrazolo[5,1-b]thiazolyl-7-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-carboxamide; 6-(7-methoxyimidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridine-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(7-Fluorimidazolo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridine-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-6-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridine-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)isoxazol-5-yl)-6-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridazin-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide; N-(5-(tert-butyl)isoxazol-3-yl)-6-(pyrazolo[1,5-a]pyrazin-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-amyl)isoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazin-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-isobutylisoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazin-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; and 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethoxy)pyridine-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxamide.

10. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 9, which is 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, wherein the medicament is used to prevent and / or treat 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 (IPF).

Images