TETRAHYDROTHIENO PYRIDINE DERIVATIVES AS DDRs INHIBITORS

Abstract

This invention relates to compounds that inhibit discoid domain receptors (DDR inhibitors), methods for preparing such compounds, pharmaceutical compositions containing such compounds, and their therapeutic uses. The compounds of this invention are applicable, for example, to the treatment of many conditions related to the DDR mechanism.

Description

Technical field

[0001] The present invention relates to compounds (DDR inhibitors) that inhibit discoidin domain receptors (DDR inhibitors), methods for preparing such compounds, pharmaceutical compositions containing such compounds and their therapeutic use.

[0002] The compounds of the present invention are useful, for example, in the treatment of a number of disorders associated with DDR mechanisms.

Prior technology

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

[0004] DDR is a unique receptor among other members of the RTK superfamily, wherein DDR is activated by collagen, while other members of the RTK superfamily are usually activated by soluble peptide-like growth factors (see Vogel, W. (1997 ) Mol. Cell 1, 13-23; Shrivastava A. Mol Cell. 1997; 1:25-34.). Furthermore, DDR is also an unusual RTK because it forms a ligand-independent stable dimer that is not covalently linked (see Noordeen, N. A. (2006) J. Biol. Chem. 281, 22744-22751; Mihai C. J Mol Biol. 2009; 385:432-445).

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

[0006] The DDR receptor family has been found to be involved in a range of fibrotic diseases, such as pulmonary fibrosis, and especially idiopathic pulmonary fibrosis (IPF). Dr. Vogel's research group first presented evidence that DDR1 deletion has a protective role in pulmonary fibrosis in 2006 (see Avivi-Green C, Am J Respir Crit Care Med 2006;174:420-427). The authors demonstrate that DDR1 knockout mice are largely protected from bleomycin (BLM)-induced injury. Furthermore, myofibroblast expansion and apoptosis were much lower in these animals compared to their wild-type counterparts. Absence of inflammation in knockout mice was confirmed by lavage cell count and interleukin ELISA. These results indicate that DDR1 expression is a prerequisite for the development of lung inflammation and fibrosis.

[0007] 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). demonstrated that DDR2 plays a key role in inducing fibrosis and angiogenesis in the lung, specifically DDR2 cooperates with transforming growth factor (TGF)-β to induce myofibroblastic differentiation. Furthermore, it was shown that treatment of injured mice with specific siRNA against DDR2 exhibited therapeutic efficacy on pulmonary fibrosis. In a second publication, Jia et al. showed that mice lacking DDR2 were protected from bleomycin-induced lung fibrosis (see Jia S, Am J Respir Cell Mol Biol 2018;59:295-305) . In addition, DDR2-knockout fibroblasts were significantly more prone to apoptosis than wild-type fibroblasts, supporting the paradigm that resistance of fibroblasts to apoptosis is critical for fibrosis progression.

[0008] Several compounds have been described in the literature as DDR1 or DD2 antagonists.

[0009] WO2016064970 (Guangzhou) discloses tetrahydroisoquinoline-7-formamide as a selective DDR1 inhibitor, suitable for preventing and treating inflammation, liver fibrosis, renal fibrosis, pulmonary fibrosis, skin scars, arteries Therapeutic agent for atherosclerosis and cancer.

[0010] It is worth noting that antagonism of DDR receptors may be useful in the treatment of fibrosis and diseases, disorders and conditions caused by fibrosis, and that even more antagonism of both receptors DDR1 and DDR2 may be useful in the treatment of such diseases, disorders and diseases are particularly effective.

[0011] Several efforts have been made over the past few years to develop novel DDR1 and DDR2 receptor antagonists useful in the treatment of certain diseases, and some of these compounds have also demonstrated efficacy in humans.

[0012] Regardless of the prior art cited above, it remains possible to develop selective inhibitors of both receptors DDR1 and DDR2, which are useful in the treatment of diseases or conditions associated with dysregulation of DDR receptors in the respiratory field, specifically In other words, idiopathic pulmonary fibrosis (IPF), administered by the inhalation route, and characterized by a good inhalation profile, which corresponds to good lung activity, good lung storage and low metabolic stability, so that systemic exposure and related safety issues are minimized.

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

Content of invention

[0014] In the first aspect, the present invention relates to a compound of formula (I) (I) wherein Rx, Ry and Rz are independently H or -(C1-C4) alkyl; L is selected from -C( O )- and -CH2-groups; Hy is a bicyclic heteroaryl group optionally substituted by at least one substituent selected from the group consisting of: -(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-heterocycloalkyl, -(C1-C4) alkylene-NR4R5, -(C1-C6) haloalkyl and optionally one or more -(C1-C4) alkane R is a heterocycloalkyl group substituted with a radical, or Hy is a bicyclic semi-saturated heteroaryl group; R1 is selected from the group consisting of: - Het is a heteroaryl group optionally substituted with one or more substituents selected from the group consisting of : -(C1-C4)alkyl, -(C1-C4)haloalkyl, cycloalkyl optionally substituted by 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 is optionally substituted by one or more groups selected from -(C1-C4)alkyl and halogen atoms, and-X(X) wherein R2 is H or is selected from the group consisting of: -O(C1-C4) haloalkyl, halogen atom, -O-cycloalkyl and -(C1-C4) haloalkyl; R3 is H or is selected from the group consisting of Constituent groups: halogen atom, cyano group, heterocycloalkyl group optionally substituted by one or more -(C1-C4) alkyl groups, -(C1-C4) alkylene-heterocycloalkyl group, -(C1 -C4)alkylene-heterocycloalkyl-(CH2)n-NR4R5, -(C1-C4)alkylene-NR4R5, -(C1-C4)alkylene-NR4R6,-O(C1-C4) Alkyl, -O(C1-C4)haloalkyl, -O-(C1-C4)alkylene-OH, heteroaryl optionally substituted with -(C1-C4)alkyl, -O-( C1 -C4)alkylene-NR4R5, -O-(C1-C4)alkylene-O-(C1-C4)alkyl, -O-(C1-C4)alkylene-heterocycloalkyl and - O-heterocycloalkyl, wherein each of the heterocycloalkyl is optionally selected from one or more groups selected from -(C1-C4)alkyl, pendant oxy group, halogen atom, -C(O)-( C1-C4) alkyl and heterocycloalkyl groups are substituted; n is 0, 1 or 2; R4 is H or -(C1-C4) alkyl; R5 is H or -(C1-C4) alkyl; R6 is selected from the group consisting of: -heterocycloalkyl, -(C1-C4) alkylene-O-(C1-C4) alkyl and -(C1-C4) alkylene-OH; and its pharmaceutical acceptable salt.

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

[0016] In a third aspect, the present invention relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof substances, which are used as medicines.

[0017] In another aspect, the present invention relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof or a medicine comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof Compositions for the prevention and / or treatment of disorders, diseases or conditions associated with dysregulation of DDR.

[0018] In another aspect, the present invention relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof or a medicine comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof Compositions for preventing and / or treating fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0019] In another aspect, the present invention relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof or to a compound comprising formula (I) and a pharmaceutically acceptable salt thereof A pharmaceutical composition for preventing and / or treating idiopathic pulmonary fibrosis (IPF).

Implementation

[0020] definition

[0021] Unless otherwise specified, the compounds of formula (I) of the present invention are also intended to include their stereoisomers, tautomers or pharmaceutically acceptable salts or solvates.

[0022] Unless otherwise specified, the compounds of formula (I) of the present invention are also intended to include formulas (Ia), (Iaa), (Iab), (Iaa'), (Iab'), (Ib), (Iba), (Ibb) compound.

[0023] As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of compounds of formula (I), wherein the parent compound is suitably prepared by using any base known to be expected to be pharmaceutically acceptable. Alternatively the acid is modified by converting either a free acid group or a free base (if present) into the corresponding addition salt.

[0024] Accordingly, suitable examples of such salts may include mineral or organic acid addition salts having a basic residue such as an amine group as well as mineral or organic base addition salts having an acidic residue such as a carboxyl group.

[0025] Cations of inorganic bases which may be suitably used in the preparation of salts include ions of alkali or alkaline earth metals such as potassium, sodium, calcium or magnesium.

[0026] The salt obtained by reacting the main compound acting as a base with an inorganic or organic acid to form a salt includes, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, acetic acid, oxalic acid, Salts of maleic acid, fumaric acid, succinic acid and citric acid.

[0027] The term "solvate" means a physical association of a compound of the present invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, solvates will be capable of isolation, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules.

[0028] The term "stereoisomer" refers to isomers of identical constitution which differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

[0029] The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are not superimposable.

[0030] The symbols "R" and "S" represent the configuration of substituents around the chiral carbon atom. The isomeric descriptors "R" and "S" are used as described herein to indicate the atomic configuration relative to the core molecule and are intended as described in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)) Used as defined in .

[0031] The term "diastereomer" refers to a stereoisomer that is not a mirror image.

[0032] The term "racemate" or "racemic mixture" refers to a composition consisting of equimolar amounts of two enantiomer species, wherein the composition lacks optical activity.

[0033] The term "tautomer" refers to each of two or more isomers of a compound that exist together in equilibrium and are readily separated by atoms or groups in the molecule. Migrating and swapping.

[0034] The term "halogen" or "halogen atom" or "halo" as used herein includes fluorine, chlorine, bromine and iodine atoms.

[0035] The term "(Cx-Cy)alkyl" wherein x and y are integers refers to a straight or branched chain alkyl group having x to y carbon atoms. Thus, when x is 1 and y is 4, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl and tertiary butyl.

[0036] The term "(Cx-Cy)alkylene" wherein x and y are integers refers to a Cx-Cy alkyl group having a total of two unsaturated valences, such as a divalent methylene group.

[0037] The term "(Cx-Cy)alkylene-OH" refers to an alkylene group attached to an OH group.

[0038] The term "(Cx-Cy)alkylene-aryl" refers to an alkylene group attached to an aryl group.

[0039] The term "O(Cx-Cy)alkyl" wherein x and y are integers refers to a "(Cx-Cy)alkyl" group as defined above wherein a carbon atom is attached to an oxygen atom.

[0040] The term "(Cx-Cy)haloalkyl" wherein x and y are integers refers to a "(Cx-Cy)alkyl" group as defined above, wherein one or more hydrogen atoms are replaced by one One or more halogen atoms which may be the same or different are substituted. Examples of such "(Cx-Cy)haloalkyl" may thus include halogenated, polyhalogenated and fully halogenated alkyl groups wherein all hydrogen atoms are replaced by halogen atoms, eg trifluoromethyl.

[0041] The term "O(Cx-Cy)haloalkyl" wherein x and y are integers refers to a "(Cx-Cy)haloalkyl" group as defined above, wherein the carbon atom is attached to Oxygen atom.

[0042] Examples of such "O(Cx-Cy)haloalkyl" may thus include halogenated, polyhalogenated and fully halogenated O-alkyl groups in which all hydrogen atoms are replaced by halogen atoms, such as trifluoromethoxy.

[0043] The term "aryl" refers to a monocyclic carbocyclic ring system having 6 ring atoms, wherein the ring is aromatic. Examples of suitable aryl monocyclic ring systems include, for example, phenyl.

[0044] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic group containing one or more heteroatoms selected from S, N, and O, and includes having two such monocyclic rings, or one such A group of monocyclic and one monocyclic aryl rings fused via a common bond.

[0045] The term "semisaturated heteroaryl" refers to a bicyclic group containing one or more heteroatoms selected from S, N and O, and includes a monocyclic heteroaryl group fused to a monocyclic heterocycloalkyl ring base. Examples of suitable half-saturated heteroaryl groups include, for example, 5,6-dihydro-8H-imidazo[2,1-c][1,4]-3-yl, 5,6,7,8-tetrahydro imidazo[1,2-a]pyridin-3-yl and 5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-3-yl.

[0046] The term "heterocycloalkyl" refers to a saturated monocyclic or bicyclic ring system having 3 to 12 ring atoms containing one or more heteroatoms selected from N, S or O. Examples of heterocycloalkyl include piperidinyl, pyrrolidinyl, linyl and piperidinyl. The heterocycloalkyl group may be further optionally substituted at available positions in the ring, ie, on carbon atoms or on available heteroatoms for substitution. Substitution may be on a carbon atom including spiro substitution, forming a bicyclic ring system in which two heterocycloalkyl rings or a heterocycloalkyl and a cycloalkyl ring are joined through a single carbon atom. Substitution can also be on two adjacent carbon atoms forming an additional fused 4 to 6 membered heterocycloalkyl ring. Examples of spirocycles include and are not limited to, for example, 6-methyl-2,6-diazaspiro[3.3]heptyl, 6-oxa-1-azaspiro[3.3]heptyl; and 2-methyl -2,8-diazaspiro[4.5]decyl. In addition, the heterocycloalkyl group may be a diazabicyclo, an azabicyclo or a cyclic carbonate. Examples of diazabicyclo include and 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[2.2.1]heptane-5-yl; examples of suitable cyclic carbonates include for example 1, 3-dioxolan-2-one and 4-methyl-1,3-dioxol-2-one.

[0047] The term "heterocycloalkyl(Cx-Cy)alkyl" refers to a heterocycloalkyl group attached to a "(Cx-Cy)alkyl" group as defined above.

[0048] The term "O-heterocycloalkyl" refers to a heterocycloalkyl group attached to an oxygen atom.

[0049] The term "(Cx-Cy)alkylene-heterocycloalkyl" refers to a heterocycloalkyl ring attached to an alkylene group both as defined above.

[0050] The term "O-(Cx-Cy)alkylene-OH" refers to a "(Cx-Cy)alkylene-OH" group as defined above, wherein the alkylene group is attached to an oxygen atom.

[0051] The term "O-(Cx-Cy)alkylene-O-(Cx-Cy)alkyl" refers to "(Cx-Cy)alkyl" as defined above, wherein the alkyl group is connected via an oxygen atom to "-O-(Cx-Cy)alkyl" as defined above.

[0052] The term "O-(Cx-Cy)alkylene-heterocycloalkyl" refers to a (Cx-Cy)alkylene-heterocycloalkyl group as defined above attached to an oxygen atom.

[0053] The term "-C(O)-(Cx-Cy)alkyl" refers to a "(Cx-Cy)alkyl" group as defined above, wherein the alkyl group is attached to a -C(O)- group.

[0054] The term "(Cx-Cy)alkylene-heterocycloalkyl-(CH2)n-NRxRy" refers to a compound as defined above directly attached to a "(Cx-Cy)alkylene" as defined above. defined heterocycloalkyl. The heterocycloalkyl is further linked to the nitrogen NRxRy, where x and y are integers, via -(CH2)n- (where n is an integer). The term "(Cx-Cy)alkylene-NRxRy" refers to a "(Cx-Cy)alkylene" as defined above attached to nitrogen NRxRy, where x and y are integers.

[0055] The term "O-(Cx-Cy)alkylene-NRxRy" refers to an "O-(Cx-Cy)alkylene" as defined above attached to NRxRy (where x and y are integers).

[0056] The term "O-(Cx-Cy)alkylene-O-(Cx-Cy)alkyl" refers to an "O-(Cx-Cy)alkylene" as described above attached via an oxygen atom "(Cx-Cy)alkyl" as defined above.

[0057] A bond pointing to a wavy or curved line, such as the bond depicted as the point of attachment of a moiety or substituent to a core or backbone structure as used in structural formulas herein.

[0058] When referring to a substituent, a dash ("-") not between two letters, words or symbols is meant to indicate the point of attachment of such substituent.

[0059] Carbonyl is preferably represented herein as -C(O)-, as an alternative to other common representations such as -CO-, -(CO)- or -C(=O)-.

[0060] Whenever a basic amine group is present in a compound of formula (I), a physiologically acceptable anion may be present selected from the group consisting of chloride, bromide, iodide, trifluoroacetate, formate , sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzene Formate, p-toluenesulfonate, pamoate and naphthalene disulfonate. Likewise, in the presence of acid groups, corresponding physiological cationic salts may also be present, including, for example, alkali metal or alkaline earth metal ions.

[0061] The term "half-maximal inhibitory concentration" (IC50) indicates the concentration of a particular compound or molecule required to obtain 50% inhibition of a biological process in vitro.

[0062] The term "Ki" indicates 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.

[0063] As indicated above, the present invention refers to a series of compounds represented by general formula (I) as described in detail below, which have inhibitory activity on the receptors DDR1 and DDR2. Antagonizing the receptors DDR1 and DDR2 may be particularly effective in the treatment of those diseases in which DDR receptors play a role, such as fibrosis and fibrosis-related diseases, disorders and conditions.

[0064] Indeed, as detailed in the experimental section below, the compounds of formula (I) of the present invention are capable of acting in a substantial and efficient manner as antagonists of both DDR1 and DDR2 receptors. In particular, Table 6 below shows, for the compounds of the invention, the affinity for DDR1 and DDR2 receptors and the inhibitory activity against DDR1 and DDR2 receptors in terms of both binding (expressed as Ki) and cell-based assays (expressed as IC50 ) below about 80 nM respectively. This demonstrates that the compound of formula (I) is capable of antagonizing both isoforms of the DDR receptor, which are mainly involved in fibrosis and the diseases resulting from fibrosis. Thus, compounds of formula (I) are useful in the treatment of fibrosis, especially pulmonary fibrosis, when DDR1 and DDR2 are involved.

[0065] As indicated in the same experimental part of Table 7, contrary to compound C1, characterized in that the -C(O)NH- group is substituted at the alpha position relative to sulfur, rather than as in Example 1 of the present invention Beta position, the presence of the above-mentioned substitutions at the beta position in the compounds of the invention unexpectedly and significantly determines an associated increase in inhibitory activity at the DDR1 and DDR2 receptors.

[0066] As other evidence, contrary to compound C2, it is characterized in that in Example 1 of the present invention, -C(O)NH- is simultaneously substituted for the thienyl ring linked at the α position relative to sulfur, and Hy The group replaces the tetrahydropyridyl ring bonded to the nitrogen via a spacer at the 5 position, the presence of the -C(O)NH- group replaces the thienyl ring bonded at the β position relative to the sulfur and Hy groups, at Substitution of the tetrahydropyridyl ring to the nitrogen at the 6-position via a spacer bonded to the nitrogen, compounds in the present invention unexpectedly and remarkably establishes an associated increase in inhibitory activity at the DDR1 and DDR2 receptors.

[0067] Advantageously, the compounds of the present invention are extremely potent and can be administered in humans at lower doses relative to compounds of the prior art, thereby reducing adverse events that typically occur when higher doses of the drug are administered.

[0068] In addition to being particularly potent in its inhibitory activity on the two receptors DDR1 and DDR2, the compounds of the invention are also characterized by a good inhalation profile, which allows effective action on the lung compartment and at the same time has a low metabolism Stability, which minimizes pitfalls associated with systemic exposure, such as safety and tolerability issues.

[0069] Thus, the compounds of the present invention are especially appreciated by those skilled in the art in looking at suitable and effective compounds useful in the treatment of fibrosis, idiopathic pulmonary fibrosis in particular, administered by the inhalation route and characterized Due to the good inhalation profile, which corresponds to good activity on the lungs, good lung storage and low metabolic stability, this minimizes systemic exposure and associated safety concerns.

[0070] Therefore, in one aspect, the present invention relates to a compound of general formula (I) (I) wherein Rx, Ry and Rz are independently H or -(C1-C4) alkyl; L is selected from- A group consisting of C (O)- and -CH2-; Hy is a bicyclic heteroaryl group optionally substituted by at least one substituent selected from the group consisting of: -(C1-C4) alkyl, halogen atom, cyano , -O-(C1-C4)alkyl, -O-(C1-C4)alkylene-OH, -O-(C1-C4)alkylene-O-(C1-C4)alkylene, -O -(C1-C4) alkylene-heterocycloalkyl, -(C1-C4) alkylene-NR4R5, -(C1-C6) haloalkyl and optionally one or more -(C1-C4 ) alkyl substituted heterocycloalkyl, or Hy is bicyclic semisaturated heteroaryl; R1 is selected from the group consisting of: - Het is heterocyclyl optionally substituted with one or more substituents selected from the group consisting of Aryl: -(C1-C4)alkyl, -(C1-C4)haloalkyl, cycloalkyl optionally substituted by 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 is optionally substituted by one or more groups selected from -(C1-C4)alkyl and halogen atoms, and-X(X) Wherein R2 is H or is selected from the group consisting of the following: -O(C1-C4) haloalkyl, halogen atom, -O-cycloalkyl and -(C1-C4) haloalkyl; R3 is H or selected A group consisting of the following: halogen atom, cyano group, heterocycloalkyl group optionally substituted by one or more -(C1-C4)alkyl groups, -(C1-C4)alkylene-heterocycloalkyl group, - (C1-C4)alkylene-heterocycloalkyl-(CH2)n-NR4R5, -(C1-C4)alkylene-NR4R5,-(C1-C4)alkylene-NR4R6,-O(C1- C4) alkyl, -O(C1-C4) haloalkyl, -O-(C1-C4) alkylene-OH, heteroaryl optionally substituted with -(C1-C4) alkyl, -O -(C1-C4)alkylene-NR4R5, -O-(C1-C4)alkylene-O-(C1-C4)alkyl, -O-(C1-C4)alkylene-heterocycloalkyl and -O-heterocycloalkyl, wherein each of the heterocycloalkyl groups is optionally selected from one or more groups selected from -(C1-C4)alkyl, pendant oxy, halogen atom, -C(O) - (C1-C4) alkyl and heterocycloalkyl group substitution; n is 0, 1 or 2; R4 is H or -(C1-C4) alkyl; R5 is H or -(C1-C4) alkane R6 is selected from the group consisting of: -heterocycloalkyl, -(C1-C4) alkylene-O-(C1-C4) alkyl and -(C1-C4) alkylene-OH; and Pharmaceutically acceptable salts.

[0071] In an especially preferred embodiment, the present invention relates to a compound of general formula (I), wherein R1 is X', and the compound is represented by formula (Ia): (X') (Ia) wherein Rx, Ry, Rz, L, Hy, R2 and R3 are as defined above.

[0072] In an especially preferred embodiment, the present invention refers to a compound of formula (Ia), wherein L is -CH2-, the compound is represented by formula (Iaa): (Iaa) wherein Rx, Ry, Rz, Hy, R2 and R3 are as defined above.

[0073] In a preferred embodiment, the present invention relates to a compound of formula (Iaa), wherein Hy is selected from the group consisting of: imidazo[1,2-a]pyridin-3-yl, 1H-pyrrole A[2,3-b]pyridin-5-yl, imidazo[1,2-a]pyr-3-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrrole A[2,3-b]pyridin-4-yl, pyrazolo[1,5-a]pyrimidin-6-yl, 3-methyl-1H-pyrazolo[3,4-b]pyridine-5 -yl and imidazo[1,2-b]pyrid-3-yl.

[0074] In another preferred embodiment, the present invention refers to a compound of formula (Iaa), wherein R2 is trifluoromethyl and trifluoromethoxy.

[0075] In another particularly preferred embodiment, the present invention refers to a compound of formula (Iaa), wherein R3 is H or is selected from the group consisting of: 4-methyl-1H-imidazol-1-yl, 3-(dimethylamino)pyrrolidin-1-yl, 2-(pyrrolidin-1-yl)ethoxy and fluorine.

[0076] In another preferred embodiment, the present invention relates to a compound of formula (Iaa), wherein Hy is selected from the group consisting of: 1H-pyrazolo[3,4-b]pyridin-5-yl and 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl, R2 is selected from the group consisting of trifluoromethoxy and trifluoromethyl, R3 is H or is selected from the following Composition group: fluorine, (R)-N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl and 2-(pyrrolidin-1-yl)ethoxy.

[0077] According to a preferred embodiment, the present invention relates to at least one of the compounds of formula (Iaa) listed in Table 1 below and pharmaceutically acceptable salts thereof. These compounds have specific activities on receptors DDR1 and DDR2, as shown in Table 6. Table 1: List of compounds of formula (Iaa) Example number structure Chemical Name 65 6-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzene base)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 66 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethoxy)phenyl)-4,5,6,7- Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 67 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6 ,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 69 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro Thieno[2,3-c]pyridine-3-carboxamide 72 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethoxy)phenyl)-4,5,6,7-tetra Hydrothieno[2,3-c]pyridine-3-carboxamide 73 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6, 7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 84 6-(imidazo[1,2-a]pyr-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2 ,3-c]pyridine-3-carboxamide 85 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetra Hydrogenthieno[2,3-c]pyridine-3-carboxamide 86 6-((1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro Thieno[2,3-c]pyridine-3-carboxamide 87 6-(imidazo[1,2-b]pyrid-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2 ,3-c]pyridine-3-carboxamide 88 6-(pyrazolo[1,5-a]pyrimidin-6-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[ 2,3-c]pyridine-3-carboxamide 89 6-(pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[ 2,3-c]pyridine-3-carboxamide 103 6-(imidazo[1,2-a]pyr-3-ylmethyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetra Hydrothieno[2,3-c]pyridine-3-carboxamide 104 6-(imidazo[1,2-a]pyr-3-ylmethyl)-5-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetra Hydrothieno[2,3-c]pyridine-3-carboxamide 105 6-(imidazo[1,2-a]pyr-3-ylmethyl)-5-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetra Hydrothieno[2,3-c]pyridine-3-carboxamide 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]pyridine-3-carboxamide 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]pyridine-3-carboxamide 157 (R)-N-(3-((3-(Dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-((3-methyl Base-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 158 (R)-6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-((3-(dimethylamino)pyrrolidine-1 -yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 159 (R)-6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-((3-(dimethylamino)pyrrolidin-1- Base)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 160 (R)-N-(3-((3-(Dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1 ,2-a]pyr-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 161 (R)-N-(3-((3-(Dimethylamino)pyrrolidin-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 163 6-((3-Methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(2-(pyrrolidin-1-yl)ethoxy )-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 164 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(2-(pyrrolidin-1-yl)ethoxy)-5-( Trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 174 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethoxy)phenyl)-4,5, 6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide

[0078] In another preferred embodiment, the present invention refers to a compound of formula (Ia), wherein L is -C(O)-, the compound is represented by the following formula (Iab): (Iab) wherein Rx, Ry, Rz, Hy, R2 and R3 are as defined above.

[0079] In a preferred embodiment, the present invention refers to a compound of formula (Iab), wherein Hy is selected from the group consisting of: imidazo[1,2-a]pyridin-3-yl, 1H-pyrrole A[2,3-b]pyridin-5-yl, imidazo[1,2-a]pyr-3-yl, 1H-pyrazolo[3,4-b]pyridin-yl, pyrazolo[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]-3-yl, imidazo[1,2-b]pyridine-3,6-((dimethylamino)methyl)imidazo[1,2-a]pyridine - 3-yl, 4-methylpiper-1-yl) imidazo[1,2-a]pyridin-3-yl, 5-methylimidazo[1,2-a]pyridin-3-yl, 6 -Methyl-2,6-diazaspiro[3.3]heptane-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-tetra Hydropyridine-4-yl)imidazo[1,2-a]pyridin-3-yl, 6-(2-(N-olyl)ethoxy)imidazo[1,2-a]pyridine-3- base, 2-(N-olyl)ethoxy)imidazo[1,2-a]pyridin-3-yl and pyrazolo[1,5-a]pyr-3-yl.

[0080] In another preferred embodiment, the present invention refers to a compound of formula (lab), wherein R2 is selected from the group consisting of trifluoromethyl and trifluoromethoxy.

[0081] In another particularly preferred embodiment, the present invention refers to a compound of formula (Iab), wherein R3 is H or is selected from the group consisting of: 4-methyl-1H-imidazol-1-yl, Fluorine, pyrrolidin-1-ylmethyl, (dimethylamino)methyl, 3-((N-olyl)methyl), 2-(N-olyl)ethoxy, 4-(di Methylamino)piperidin-1-yl)methyl, 3-(dimethylamino)pyrrolidin-1-yl)methyl, 6-oxa-1-azaspiro[3.3]heptane- 1-yl)methyl, 2-(dimethylamino)ethoxy, 2-(pyrrolidin-1-yl)ethoxy, (2-hydroxyethyl)(methyl)amino)methyl , 2-oxa-5-azabicyclo[2.2.1]heptane-5-yl, (2-methoxyethyl)(methyl)amino)methyl, (4-acetylpiper- 1-yl) methyl, (4-methyl-3-side oxypiper-1-yl) methyl, (piperidin-1-yl) methyl, (3-fluoropyrrolidin-1-yl) methyl Base, azetidin-1-ylmethyl, methyl(oxetan-3-yl)amino)methyl, (4-(oxetan-3-yl)piper-1-yl ) methyl, (3-((dimethylamino)methyl)pyrrolidin-1-yl)methyl, 2-(4-methylpiper-1-yl)ethoxy, 3-(dimethyl Amino)pyrrolidine-1-carbonyl, cyano, 4-methylpiper-1-yl, N-olyl, hydroxymethyl, (4-methylpiper-1-yl)methyl and (1- methylpyrrolidin-3-yl)oxyl group.

[0082] In another particularly preferred embodiment, the present invention refers to a compound of formula (lab), wherein Hy is selected from the group consisting of: 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-di Azaspiro[3.3]heptane-2-yl)imidazo[1,2-a]pyridin-3-yl, 6-(1-methyl-1,2,3,6-tetrahydropyridine-4- Base) imidazo[1,2-a]pyridin-3-yl, 6-(4-methylpiper-1-yl)imidazo[1,2-a]pyridin-3-yl and 6-(2- (N-olyl)ethoxy)imidazo[1,2-a]pyridin-3-yl, R2 is trifluoromethyl, and R3 is H.

[0083] According to a preferred embodiment, the present invention refers to at least one of the compounds of formula (Iab) listed in Table 2 and pharmaceutically acceptable salts thereof. Table 2: List of compounds of formula (lab) Example number structure Chemical Name 1 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methylpiper-1-yl)methyl)-5-(trifluoromethyl)phenyl )-4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 7 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3 -c]pyridine-3-carboxamide 8 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydrothieno[2, 3-c]pyridine-3-carboxamide 10 N-(3-fluoro-5-(trifluoromethoxy)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiophene A[2,3-c]pyridine-3-carboxamide 11 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl)phenyl)-4,5 ,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 19 N-(3-((dimethylamino)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4, 5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 20 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((N-olyl)methyl)-5-(trifluoromethyl)phenyl)-4,5 ,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide twenty four 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(2-(N-olyl)ethoxy)-5-(trifluoromethyl)phenyl)- 4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 25 N-(3-(2-(Dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl) -4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 26 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(2-(pyrrolidin-1-yl)ethoxy)-5-(trifluoromethyl)phenyl )-4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 44 (S)-N-(3-((3-(Dimethylamino)pyrrolidin-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 45 (R)-N-(3-((3-(Dimethylamino)pyrrolidin-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 46 N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno [2,3-c]pyridine-3-carboxamide 48 N-(3-((4-(dimethylamino)piperidin-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 49 N-(3-((6-Oxa-1-azaspiro[3.3]heptane-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 50 N-(3-((2-oxa-5-azabicyclo[2.2.1]heptane-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 51 N-(3-((3-fluoropyrrolidin-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 52 N-(3-(azetidin-1-ylmethyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)- 4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 53 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((methyl(oxetan-3-yl)amino)methyl)-5-(trifluoro Methyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 54 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-(oxetan-3-yl)piper-1-yl)methyl)-5- (Trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 55 N-(3-((3-((dimethylamino)methyl)pyrrolidin-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 56 N-(3-((3-(dimethylamino)pyrrolidin-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 57 N-(3-(((2-hydroxyethyl)(methyl)amino)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine -3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 58 N-(3-((4-acetylpiper-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 59 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methyl-3-oxopiper-1-yl)methyl)-5-(tri Fluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 60 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(piperidin-1-ylmethyl)-5-(trifluoromethyl)phenyl)-4,5 ,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 61 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(((2-methoxyethyl)(methyl)amino)methyl)-5-(tri Fluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 62 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(2-(4-methylpiper-1-yl)ethoxy)-5-(trifluoromethyl )phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 63 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((1-methylpyrrolidin-3-yl)oxy)-5-(trifluoromethyl)benzene base)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 68 6-(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2 ,3-c]pyridine-3-carboxamide 74 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl) -4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 90 6-(imidazo[1,2-a]pyr-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3 -c]pyridine-3-carboxamide 91 6-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[ 2,3-c]pyridine-3-carboxamide 92 6-(imidazo[1,2-b]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3 -c]pyridine-3-carboxamide 93 6-(pyrazolo[1,5-a]pyr-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2, 3-c]pyridine-3-carboxamide 94 6-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2, 3-c]pyridine-3-carboxamide 95 6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6, 7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 96 6-(5,6-Dihydro-8H-imidazo[2,1-c][1,4]-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5 ,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 97 N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-4,5,6,7-tetrahydrothiophene A[2,3-c]pyridine-3-carboxamide 98 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl yl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 100 (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 101 (R)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5- (Trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 102 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 130 (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 131 N-(3-cyano-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiophene A[2,3-c]pyridine-3-carboxamide 135 6-(6-((Dimethylamino)methyl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5 ,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 136 6-(6-(4-methylpiper-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5 ,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 137 6-(6-(2-Hydroxyethoxy)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6, 7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 138 6-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5, 6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 139 6-(7-(2-(N-olyl)ethoxy)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4 ,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 162 (R)-N-(3-((3-(Dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(5-methyl Imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 166 6-(6-(6-Methyl-2,6-diazaspiro[3.3]heptane-2-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3- (Trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 167 6-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(tri Fluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 170 6-(6-(2-(N-olyl)ethoxy)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4 ,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 172 N-(3-((N-olyl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyr-3-carbonyl)-4, 5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 177 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(4-methylpiper-1-yl)-5-(trifluoromethyl)phenyl)-4, 5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 178 N-(3-(4-methylpiper-1-yl)-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyr-3-carbonyl)-4 ,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 181 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(N-olyl)-5-(trifluoromethyl)phenyl)-4,5,6,7 -Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 182 N-(3-(N-olyl)-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyr-3-carbonyl)-4,5,6, 7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 184 N-(3-cyano-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyr-3-carbonyl)-4,5,6,7-tetrahydro Thieno[2,3-c]pyridine-3-carboxamide 187 N-(3-(hydroxymethyl)-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyr-3-carbonyl)-4,5,6,7 -Tetrahydrothieno[2,3-c]pyridine-3-carboxamide

[0084] In another preferred embodiment, the present invention refers to a compound of formula (I), wherein R1 is X'', and the compound is represented by formula (Ia'): (X'')(Ia') wherein Hy, R2 and R3 are as defined above.

[0085] In another preferred embodiment, the present invention refers to a compound of formula (Ia'), wherein L is -CH2-, the compound is represented by formula (Iaa'): (Iaa') wherein Hy, R2 and R3 are as defined above.

[0086] In an especially preferred embodiment, the present invention relates to a compound of general formula (Iaa'), wherein R2 is trifluoromethyl.

[0087] In another particularly preferred embodiment, the present invention relates to a compound of general formula (Iaa''), wherein R3 is methoxy.

[0088] In another preferred embodiment, the present invention relates to a compound of general formula (Iaa'), wherein Hy is 1H-pyrrolo[2,3-b]pyridin-5-yl.

[0089] According to a preferred embodiment, the present invention relates to compounds of formula (Iaa') listed in Table 3a below and pharmaceutically acceptable salts thereof. This compound has specific activity on receptors DDR1 and DDR2, as shown in Table 6. Table 3a: List of compounds of formula (Iaa') Example number structure Chemical Name 71 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(4-methoxy-3-(trifluoromethyl)phenyl)-4,5, 6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide

[0090] In another preferred embodiment, the present invention refers to a compound of formula (Ia'), wherein L is -CO, and the compound is represented by the following formula (Iab'): (Iab') wherein Hy, R2 and R3 are as defined above.

[0091] In an especially preferred embodiment, the present invention relates to a compound of general formula (lab'), wherein R2 is trifluoromethyl.

[0092] In another particularly preferred embodiment, the present invention refers to a compound of formula (Iab'), wherein R3 is selected from the group consisting of: methoxy group, (tetrahydrofuran-3-yl) oxygen group, ( 4-methylpiper-1-yl)methyl, oxetan-3-yloxy, pyrrolidin-1-ylmethyl, (N-olyl)methyl, oxetan-3-yl Methoxy, 2-methoxyethoxy, (dimethylamino)methyl, 2-hydroxyethoxy, (1-methylpiperidin-4-yl)oxy, hydroxymethyl, chlorine and (1-methylpyrrolidin-3-yl)oxy.

[0093] In another preferred embodiment, the present invention relates to a compound of general formula (lab'), wherein Hy is pyrazolo[1,5-a]pyr-3-yl, and R3 is selected from the following composition Groups: hydroxymethyl, (dimethylamino)methyl and chlorine, and R2 is trifluoromethyl.

[0094] According to another preferred embodiment, the present invention refers to at least one of the compounds of formula (lab') and pharmaceutically acceptable salts thereof listed in Table 3b below. These compounds have specific activities on receptors DDR1 and DDR2, as shown in Table 6. Table 3b: List of compounds of formula (lab') Example number structure Chemical Name 4 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(4-methoxy-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro Thieno[2,3-c]pyridine-3-carboxamide 12 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(4-((tetrahydrofuran-3-yl)oxy)-3-(trifluoromethyl)phenyl)-4, 5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 13 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(4-(oxetan-3-yl)-3-(trifluoromethyl)phenyl)-4,5 ,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 14 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(4-(oxetan-3-ylmethoxy)-3-(trifluoromethyl)phenyl)- 4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 15 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(4-(2-methoxyethoxy)-3-(trifluoromethyl)phenyl)-4,5 ,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 16 N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6 ,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 18 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(4-((4-methylpiper-1-yl)methyl)-3-(trifluoromethyl)phenyl )-4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide twenty two 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(4-(pyrrolidin-1-ylmethyl)-3-(trifluoromethyl)phenyl)-4,5 ,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide twenty three 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(4-((N-olyl)methyl)-3-(trifluoromethyl)phenyl)-4,5 ,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 27 N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4, 5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 31 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(4-((1-methylpyrrolidin-3-yl)oxy)-3-(trifluoromethyl)benzene base)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 32 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)benzene base)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 132 N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7- Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 171 N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyr-3-carbonyl)-4 ,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 176 N-(4-chloro-3-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyr-3-carbonyl)-4,5,6,7-tetrahydrothiophene A[2,3-c]pyridine-3-carboxamide 180 N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyr-3-carbonyl)-4,5,6,7 -Tetrahydrothieno[2,3-c]pyridine-3-carboxamide

[0095] In an especially preferred embodiment, the present invention refers to a compound of formula (I), wherein R1 is Het, and the compound is represented by formula (Ib): (Ib) wherein L is selected from -C (O) The group consisting of - and -CH2-; Hy is a bicyclic heteroaryl group optionally substituted by at least one substituent selected from the group consisting of: -(C1-C4) alkyl, halogen atom and -(C1-C6) Haloalkyl; Het is heteroaryl optionally substituted with one or more substituents selected from the group consisting of: -(C1-C4)alkyl, -(C1-C4)haloalkyl, ring Alkyl, -O-(C1-C4) haloalkyl, -(C1-C4) alkylene-OH, -(C1-C4) alkylene-aryl, optionally selected from one or more - an aryl group substituted with a (C1-C4) alkyl group and a halogen atom; and a pharmaceutically acceptable salt thereof.

[0096] In an especially preferred embodiment, the present invention refers to a compound of formula (Ib), wherein L is -CH2-, the compound is represented by formula (Iba): (Iba) wherein Rx, Ry, Rz, Hy and Het are as defined above.

[0097] In a preferred embodiment, the present invention refers to a compound of formula (Iba), wherein Hy is selected from the group consisting of: 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]pyridine-3-yl, (4 -Methylpiper-1-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl, pyrazolo[1,5-a]pyr-3-yl, 7H-pyrrolo[2 , 3-d]pyrimidin-4-yl and 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl.

[0098] In another preferred embodiment, the present invention refers to a compound of formula (Iba), wherein Het is selected from the group consisting of: 3-(tertiary butyl)-1-methyl-1H-pyridine Azol-5-yl, 3-cyclopropyl-1-methyl-1H-pyrazol-5-yl, 3-(tertiary butyl)isoxazol-5-yl, 5-cyclopropylisoxazol-3 -yl, 5-(trifluoromethyl)pyridin-3-yl, 5-(tertiary butyl)isoxazol-3-yl, 1-methyl-5-(trifluoromethyl)-1H-pyrazole - 3-yl and 3-(tertiary butyl)-1-(p-tolyl)-1H-pyrazol-5-yl.

[0099] In another preferred embodiment, the present invention refers to a compound of formula (Iba), wherein Hy is selected from the group consisting of: 3-(4-methylpiper-1-yl)-1H-pyridine Azolo[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]pyr-3-yl, pyrazolo[1,5-a]pyridine -3-yl and 7H-pyrrolo[2,3-d]pyrimidin-4-yl, and Het is 5-(trifluoromethyl)pyridin-3-yl.

[0100] According to a preferred embodiment, the present invention relates to at least one of the compounds of formula (Iba) listed in Table 4 below and pharmaceutically acceptable salts thereof. Table 4: List of compounds of formula (Iba) Example number structure Chemical Name 70 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-(tertiary butyl)-1-methyl-1H-pyrazol-5-yl )-4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 75 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(tertiary butyl)-1-(p-tolyl)-1H-pyrazole -5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 76 6-((1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)-N-(3-(tertiary butyl)-1-(p-tolyl)-1H-pyrazole- 5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 77 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(tertiary butyl)-1-methyl-1H-pyrazole-5- base)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 78 N-(3-(tertiary butyl)-1-methyl-1H-pyrazol-5-yl)-6-((3-methyl-1H-pyrazolo[3,4-b]pyridine- 5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 133 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(tertiary butyl)isoxazol-5-yl)-4,5,6 ,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 134 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(5-(tertiary butyl)isoxazol-3-yl)-4,5,6 ,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 146 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 147 N-(3-(tertiary butyl)isoxazol-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 148 N-(5-cyclopropylisoxazol-3-yl)-6-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-4,5 ,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 149 6-((3-(4-Methylpiper-1-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(5-(trifluoromethyl )pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 150 6-((3-Methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4 ,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 151 6-(1H-pyrazolo[3,4-b]pyridin-5-ylmethyl)-N-[5-(trifluoromethyl)-3-pyridyl]-5,7-dihydro-4H -Thieno[2,3-c]pyridine-3-carboxamide 152 6-(Pyrazolo[1,5-a]pyrimidin-6-ylmethyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydro Thieno[2,3-c]pyridine-3-carboxamide 153 6-(imidazo[1,2-a]pyr-3-ylmethyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiophene A[2,3-c]pyridine-3-carboxamide 154 6-(pyrazolo[1,5-a]pyr-3-ylmethyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydro Thieno[2,3-c]pyridine-3-carboxamide 155 6-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7 -Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 156 N-(3-(tertiary butyl)isoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrimidin-6-ylmethyl)-4,5,6,7-tetra Hydrothieno[2,3-c]pyridine-3-carboxamide 169 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]pyridine-3-carboxamide

[0101] In an especially preferred embodiment, the present invention refers to a compound of formula (Ib), wherein L is -C(O)-, the compound is represented by formula (Ibb): (Ibb) wherein Rx, Ry , Rz, Hy and Het are as defined above.

[0102] In a preferred embodiment, the present invention refers to a compound of formula (Ibb), wherein Hy is selected from the group consisting of: imidazo[1,2-a]pyridin-3-yl, 6-methyl Imidazo[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]pyr-3-yl, pyrazolo[1,5-a]pyrimidin-3-yl, 5,6-dihydro-8H-imidazo[2,1-c][1,4]- 3-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine- 3-yl, pyrazolo[1,5-a]pyridin-3-yl, (4-methylpiper-1-yl)imidazo[1,2-a]pyridin-3-yl, 5-methoxy Pyrazolo[1,5-a]pyridin-3-yl, pyrazolo[5,1-b]thiazol-7-yl, 7-methoxyimidazo[1,2-a]pyridine-3 -yl, 1-methyl-1H-imidazo[1,2-b]pyrazol-7-yl and imidazo[1,2-a]pyr-3-yl.

[0103] In another preferred embodiment, the present invention refers to a compound of formula (Ibb), wherein Het is selected from the group consisting of: 3-(tertiary butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl, 3-(tertiary butyl)-1-methyl-1H-pyrazol-5-yl, 3-(tertiary butyl)-1-(4-fluorophenyl) - 1H-pyrazol-5-yl, 3-(tertiary butyl)-1-phenyl-1H-pyrazol-5-yl, 5-(1,1,1-trifluoro-2-methylpropane -2-yl) isoxazol-3-yl, 2-(trifluoromethyl)pyridin-4-yl, 6-(trifluoromethyl)pyrimidin-4-yl, 6-(trifluoromethyl)pyrimidine- 4-yl, 4-(trifluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-3-yl, 5-(tertiary butyl)isoxazol-3-yl, 3-( Tertiary butyl)isoxazol-5-yl, 4-(tertiary butyl)azol-2-yl, 3-cyclobutyl-1-methyl-1H-pyrazol-5-yl, 6-fluoroimidazole A[1,2-a]pyridin-3-yl, 6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl, 6-chloroimidazo[1,2-a]pyridine - 3-yl, 3-isopropyl-1-methyl-1H-pyrazol-5-yl, 4-(trifluoromethyl)pyrimidin-2-yl, 2-(tertiary butyl)pyridine-4 -yl, 3-(tertiary butyl)-1-isopropyl-1H-pyrazol-5-yl, 1-methyl-3-propyl-1H-pyrazol-5-yl, 3-(tri tertiary butyl)-1-(2-hydroxyethyl)-1H-pyrazol-5-yl, 3-(tertiary butyl)-1-(2,2,2-trifluoroethyl)-1H- Pyrazol-5-yl, 1-benzyl-3-(tertiary butyl)-1H-pyrazol-5-yl, 3-(tertiary butyl)-1-ethyl-1H-pyrazole- 5-yl, 3-isobutyl-1-methyl-1H-pyrazol-5-yl, 1-methyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazole- 5-yl, 5-(1,1-difluoroethyl)pyridin-3-yl, 5-(tertiary butyl)-1-methyl-1H-pyrazol-3-yl, 5-(difluoro Methoxy)pyridin-3-yl, 3-(tertiary pentyl)isoxazol-5-yl, 6-methoxy-5-(trifluoromethyl)pyridin-3-yl, 5-(tertiary Butyl)pyridin-3-yl, 2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-yl, (trifluoromethyl)pyridine-3-yl, 3 -Isobutylisoxazol-5-yl, trifluoromethoxy)pyridin-3-yl and 5-(trifluoromethoxy)pyridin-3-yl.

[0104] In another preferred embodiment, the present invention refers to a compound of formula (Ibb), wherein Hy is selected from the group consisting of: pyrazolo[1,5-a]pyr-3-yl and 6 -(4-methylpiper-1-yl)imidazo[1,2-a]pyridin-3-yl, Het is selected from the group consisting of 5-(trifluoromethyl)pyridin-3-yl, 3 -(tertiary butyl)isoxazol-5-yl, 5-(tertiary butyl)-1-methyl-1H-pyrazol-3-yl, 6-methoxy-5-(trifluoromethyl ) pyridin-3-yl, 5-(1,1-difluoroethyl)pyridin-3-yl, 5-(tertiary butyl)pyridin-3-yl, 5-(difluoromethoxy)pyridine- 3-yl, 5-(1,1,1-trifluoro-2-methylprop-2-yl) isoxazol-3-yl, 5-(trifluoromethoxy)pyridin-3-yl, 5- (tertiary butyl)isoxazol-3-yl, 3-(tertiary pentyl)isoxazol-5-yl and 3-isobutylisoxazol-5-yl.

[0105] According to a preferred embodiment, the present invention refers to at least one of the compounds of formula (Ibb) and pharmaceutically acceptable salts thereof listed in Table 5 below. These compounds have specific activities on receptors DDR1 and DDR2, as shown in Table 6. Table 5: List of compounds of formula (Ibb) Example number structure Chemical Name 2 N-(3-(tertiary 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 3 N-(3-(tertiary 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 5 N-(3-(tertiary butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl) -4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 6 N-(3-(tertiary 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 9 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl )-4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 17 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-4,5,6,7-tetrahydrothieno[ 2,3-c]pyridine-3-carboxamide twenty one 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(6-(trifluoromethyl)pyrimidin-4-yl)-4,5,6,7-tetrahydrothieno[ 2,3-c]pyridine-3-carboxamide 28 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[ 2,3-c]pyridine-3-carboxamide 29 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(4-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydrothieno[ 2,3-c]pyridine-3-carboxamide 30 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(4-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydrothieno[ 2,3-c]pyridine-3-carboxamide 33 N-(5-(tertiary butyl)isoxazol-3-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno [2,3-c]pyridine-3-carboxamide 34 N-(3-(tertiary butyl)isoxazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno [2,3-c]pyridine-3-carboxamide 35 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 36 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4,5,6,7 -Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 37 N-(2-(tertiary butyl)pyridin-4-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[ 2,3-c]pyridine-3-carboxamide 38 N-(3-(tertiary 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 39 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(1-methyl-3-propyl-1H-pyrazol-5-yl)-4,5,6,7- Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 40 N-(3-(tertiary 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 41 N-(1-Benzyl-3-(tertiary butyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5 ,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 42 N-(3-(tertiary 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 43 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-isobutyl-1-methyl-1H-pyrazol-5-yl)-4,5,6,7 -Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 47 N-(4-(tertiary butyl)azol-2-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[ 2,3-c]pyridine-3-carboxamide 64 N-(3-(tertiary 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 79 N-(3-(tertiary butyl)-1-methyl-1H-pyrazol-5-yl)-6-(7-methylimidazo[1,2-a]pyridine-3-carbonyl)- 4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 80 N-(3-(tertiary butyl)-1-methyl-1H-pyrazol-5-yl)-6-(6-methylimidazo[1,2-a]pyridine-3-carbonyl)- 4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 81 N-(3-(tertiary butyl)-1-methyl-1H-pyrazol-5-yl)-6-(6-fluoroimidazo[1,2-a]pyridine-3-carbonyl)-4 ,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 82 N-(3-(tertiary butyl)-1-methyl-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)imidazo[1,2-a]pyridine-3 -carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 83 N-(3-(tertiary butyl)-1-methyl-1H-pyrazol-5-yl)-6-(6-chloroimidazo[1,2-a]pyridine-3-carbonyl)-4 ,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 99 N-(3-(tertiary 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 108 6-(pyrazolo[1,5-a]pyr-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno [2,3-c]pyridine-3-carboxamide 109 6-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno [2,3-c]pyridine-3-carboxamide 110 6-(5,6-Dihydro-8H-imidazo[2,1-c][1,4]-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)- 4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 111 6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5 ,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 112 N-(3-(tertiary butyl)isoxazol-5-yl)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]-3-carbonyl) -4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 113 N-(3-(tertiary butyl)isoxazol-5-yl)-6-(pyrazolo[1,5-a]pyr-3-carbonyl)-4,5,6,7-tetrahydrothiophene A[2,3-c]pyridine-3-carboxamide 114 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(1-methyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazole-5- base)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 115 N-(5-(1,1-difluoroethyl)pyridin-3-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetra Hydrothieno[2,3-c]pyridine-3-carboxamide 116 N-(5-(tertiary butyl)-1-methyl-1H-pyrazol-3-yl)-6-(pyrazolo[1,5-a]pyr-3-carbonyl)-4,5 ,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 117 N-(5-(tertiary butyl)pyridin-3-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[ 2,3-c]pyridine-3-carboxamide 118 N-(5-(difluoromethoxy)pyridin-3-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno [2,3-c]pyridine-3-carboxamide 119 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(tertiary pentyl)isoxazol-5-yl)-4,5,6,7-tetrahydrothieno [2,3-c]pyridine-3-carboxamide 120 6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5 ,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 121 N-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyr-3-carbonyl)-4,5,6, 7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 122 N-(5-(1,1-difluoroethyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyr-3-carbonyl)-4,5,6,7- Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 123 N-(5-(tertiary butyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyr-3-carbonyl)-4,5,6,7-tetrahydrothieno [2,3-c]pyridine-3-carboxamide 124 6-(pyrazolo[1,5-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno [2,3-c]pyridine-3-carboxamide 125 N-(5-(difluoromethoxy)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyr-3-carbonyl)-4,5,6,7-tetrahydrothiophene A[2,3-c]pyridine-3-carboxamide 126 6-(pyrazolo[1,5-a]pyr-3-carbonyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazole-3- base)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 127 6-(imidazo[1,2-a]pyr-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[ 2,3-c]pyridine-3-carboxamide 128 6-(pyrazolo[1,5-a]pyr-3-carbonyl)-N-(5-(trifluoromethoxy)pyridin-3-yl)-4,5,6,7-tetrahydrothiophene A[2,3-c]pyridine-3-carboxamide 129 N-(2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl) -4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 140 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 141 6-(pyrazolo[5,1-b]thiazole-7-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno [2,3-c]pyridine-3-carboxamide 142 6-(7-Methoxyimidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7- Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 143 6-(1-Methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6 ,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 144 6-(7-fluoroimidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydro Thieno[2,3-c]pyridine-3-carboxamide 145 N-(5-(tertiary butyl)-1-methyl-1H-pyrazol-3-yl)-6-(6-(4-methylpiper-1-yl)imidazo[1,2- a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 165 6-(6-(4-methylpiper-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridine-3-yl)- 4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 168 N-(3-(tertiary butyl)isoxazol-5-yl)-6-(6-(4-methylpiper-1-yl)imidazo[1,2-a]pyridine-3-carbonyl) -4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide 173 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridine-3-yl)-4,5,6,7-tetrahydrothieno[ 2,3-c]pyridine-3-carboxamide 175 N-(5-(tertiary butyl)isoxazol-3-yl)-6-(pyrazolo[1,5-a]pyr-3-carbonyl)-4,5,6,7-tetrahydrothiophene A[2,3-c]pyridine-3-carboxamide 179 N-(3-(tertiary pentyl)isoxazol-5-yl)-6-(pyrazolo[1,5-a]pyr-3-carbonyl)-4,5,6,7-tetrahydrothiophene A[2,3-c]pyridine-3-carboxamide 183 N-(3-isobutylisoxazol-5-yl)-6-(pyrazolo[1,5-a]pyr-3-carbonyl)-4,5,6,7-tetrahydrothieno[2 ,3 -c]pyridine-3-carboxamide 186 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethoxy)pyridin-3-yl)-4,5,6,7-tetrahydrothieno [2,3-c]pyridine-3-carboxamide

[0106] In another preferred embodiment, the present invention refers to a compound of formula (I), wherein Rx, Ry and Rz are H.

[0107] In another preferred embodiment, the present invention refers to a compound of formula (I), wherein Rx is H, Ry is methyl, and Rz is H.

[0108] In another preferred embodiment, the present invention refers to a compound of formula (I), wherein Rx is methyl, Ry is H, and Rz is H.

[0109] In another preferred embodiment, the present invention refers to a compound of formula (I), wherein Rx is H, Ry is methyl, and Rz is methyl.

[0110] It is to be clearly understood that any compound of the invention may be covered by more than one general formula. By way of example, but not limitation, compounds where R1 is X' can be encompassed by both formula (Ia) and formula (Iab).

[0111] Compounds of the present invention, including all compounds listed above, can be prepared from readily available starting materials using the following general methods and procedures or by using slightly modified procedures readily available to those of ordinary skill in the art Substance preparation. 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 may be obtained using the methods described herein or by using other known methods, Reagents and starting materials were obtained. Where typical or preferred process conditions (ie, reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Although optimal reaction conditions may vary with the particular reactants or solvent used, such conditions can be readily determined by one skilled in the art by routine optimization procedures.

[0112] In some cases, generally known protecting groups (PG) can be used when necessary to mask or protect sensitive or reactive moieties according to general principles of chemical methods (Protective group in organic syntheses, 3rd edition. T. W. Greene, P.G.M. Wuts).

[0113] It has been unexpectedly found that the compounds of formula (I) of the present invention effectively inhibit both the receptors DDR1 and DDR2. Advantageously, inhibition of receptors DDR1 and DDR2 can lead to effective treatment of diseases or conditions involving DDR receptors.

[0114] In this regard, it has now been found that the compounds of formula (I) according to the invention have an antagonist drug potency of less than 80 nM expressed in the form of a constant Ki for inhibition of DDR1 and DDR2, as shown in the experimental part of the present invention. Preferably, the Ki of the compound of the present invention for DDR1 and DDR2 is lower than 50 nM. Even more preferably, the compounds of the invention have a Ki of less than 25 nM for DDR1 and DDR2.

[0115] In addition, it has been found that the affinity of the compounds of formula (I) of the present invention for the DDR1 and DD2 receptors and the inhibitory activity against the DDR1 and DDR2 receptors are both in binding (expressed as Ki) and cell-based assays (expressed as IC50) were lower than about 80 nM, respectively, as demonstrated in this experimental section. Preferably, the Ki and / or IC50 of the compounds of the present invention on DDR1 and DDR2 receptors are lower than 50 nM. Even more preferably, the compounds of the invention have a Ki and / or IC50 of less than 25 nM for DDR1 and DDR2 receptors.

[0116] In one aspect, the invention refers to a compound of formula (I) according to any one of the embodiments disclosed above, for use as a medicament.

[0117] In a preferred embodiment, the present invention relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof, which are used in the treatment of diseases, diseases or conditions related to the disorder of DDR.

[0118] In another aspect, the present invention relates to the use of a compound of formula (I) as described above for the manufacture of a medicament for the treatment of a disorder associated with a dysregulation of DDR.

[0119] In a preferred embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for preventing and / or treating diseases and diseases related to DDR receptor mechanism or symptoms. In one embodiment, the invention relates to a compound of formula (I) suitable for the prevention and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0120] As used herein, the term "fibrosis" or "fibrotic disorder" refers to a disorder associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased recruitment of fibroblasts and include (but not limited to) fibrosis of individual organs or tissues such as heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal, and digestive tract.

[0121] Preferably, the compound of formula (I) as described above is suitable for the treatment and / or prevention of fibrosis, such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, renal fibrosis, Ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

[0122] More preferably, the compound of formula (I) as described above is used for the treatment of idiopathic pulmonary fibrosis (IPF).

[0123] In one aspect, the present invention also relates to a method for the prevention and / or treatment of a disorder associated with the DDR receptor mechanism, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of Compounds of formula (I) described.

[0124] In another aspect, the present invention relates to the use of a compound of formula (I) as described above for the treatment of disorders associated with the DDR receptor mechanism.

[0125] In another aspect, the present invention relates to the use of a compound of formula (I) as described above for the manufacture of a medicament for the treatment of disorders associated with the DDR receptor mechanism.

[0126] In another aspect, the invention relates to a method for preventing and / or treating a disorder or condition associated with a dysregulation of DDR receptors 1 and 2, the method comprising administering to a patient in need of such treatment A therapeutically effective amount of a compound of formula (I) as described above.

[0127] In another aspect, the present invention relates to the use of a compound of formula (I) as described above for the treatment of a disorder, disease or condition associated with a dysregulation of DDR receptors 1 and 2.

[0128] As used herein, a "safe and effective amount" of a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically active agent means that the compound is sufficient to treat the patient's condition but low enough to avoid severe The amount of side effects can still be determined routinely by those skilled in the art.

[0129] Compounds of formula (I) may be administered once or according to a dosing regimen in which multiple doses are administered at different time intervals within a given period of time. Typical daily dosages will vary depending on the particular route of administration chosen.

[0130] The present invention also relates to a pharmaceutical composition comprising a mixture of a compound of formula (I) according to any one of its specific examples and at least one or more pharmaceutically acceptable carriers or excipients .

[0131] In one embodiment, the present invention relates to a pharmaceutical composition in which a compound of formula (I) is mixed with one or more pharmaceutically acceptable carriers or excipients, such as described in Remington's Pharmaceutical Sciences Handbook, No. Those pharmaceutical compositions in Edition XVII, Mack Pub., N.Y., U.S.A.

[0132] The compounds of the present invention and their pharmaceutical compositions can be administered according to the needs of the patient, such as orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion) and by inhalation. Finish.

[0133] Preferably, the compounds of the invention are administered orally or by inhalation.

[0134] In a preferred embodiment, the pharmaceutical composition comprising the compound of formula (I) is a solid oral dosage form, such as tablets, capsules, capsules, sachets, granules, buccal tablets and bulk powder.

[0135] In one embodiment, the pharmaceutical composition comprising the compound of formula (I) is a lozenge.

[0136] The compounds of the present invention may be administered alone or in combination with: various pharmaceutically acceptable carriers; diluents (such as sucrose, mannitol, lactose, starch); and known excipients, including suspending agents, Solubilizers, buffers, binders, disintegrants, preservatives, coloring agents, flavoring agents, lubricants and similar agents.

[0137] In another embodiment, the pharmaceutical composition comprising the compound of formula (I) is a liquid oral dosage form, such as aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs. Such liquid dosage forms may also contain suitable known inert diluents, such as water; and suitable known excipients, such as preservatives, wetting agents, sweeteners, flavoring agents, and agents for emulsifying and / or suspending the product. Reagents for inventive compounds.

[0138] In another embodiment, the pharmaceutical composition comprising the compound of formula (I) is an inhalable preparation, such as an inhalable powder, a propellant-containing metered-dose aerosol or a propellant-free inhalable formulation.

[0139] For administration in dry powder form, single-dose or multi-dose inhalants known from the prior art may be utilized. In that case the powder may be filled in gelatin, plastic or other capsules, cartridges or blister packs or in reservoirs.

[0140] Diluents or carriers that are chemically inert to the compounds of the invention (eg, lactose or any other additive suitable for improving the respirable fraction) may be added to the powdered compounds of the invention.

[0141] Inhalation sprays containing a propellant gas such as a hydrofluoroalkane may contain the compound of the invention in solution or in dispersed form. Propellant driven formulations may also contain other ingredients such as co-solvents, stabilizers and optionally other excipients.

[0142] Propellant-free inhalable formulations comprising the compounds of the present invention may be in the form of solutions or suspensions in aqueous, alcoholic or hydroalcoholic media, and they may be sprayed by spray or ultrasonic nebulizers known from the prior art. Or delivered with a soft mist nebulizer.

[0143] Compounds of the invention may be administered as the sole active agent or in combination with other pharmaceutically active ingredients.

[0144] The dosage of the compounds of this invention will depend on various factors including, inter alia, the particular disease being treated, the severity of the symptoms, the route of administration and the like.

[0145] The invention also relates to a device comprising a pharmaceutical composition comprising a compound of formula (I) according to the invention in the form of a single or multi-dose dry powder inhaler or a metered dose inhaler.

[0146] All the preferred groups or specific examples described above for the compound of formula (I) may be combined with each other and the details apply mutatis mutandis.

[0147] Compounds of the present invention, including all compounds listed above, can be prepared from readily available starting materials using the following general methods and procedures or by using slightly modified procedures readily available to those of ordinary skill in the art. Substance preparation. 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 may be obtained using the methods described herein or by using other known methods, Reagents and starting materials were obtained. Where typical or preferred process conditions (ie, reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Although optimal reaction conditions may vary with the particular reactants or solvent used, such conditions can be readily determined by one skilled in the art by routine optimization procedures.

[0148] Accordingly, the methods depicted below and reported in the following schemes should not be considered as limiting the scope of synthetic methods that can be used to prepare compounds of the invention.

[0149] Compounds of formula (I), including all compounds or at least one listed herein, can generally be prepared using generally known methods according to the procedures outlined in detail in the schemes presented below.

[0150] In the first embodiment of the present invention, the compound of formula (I), wherein R1, Rx, Ry, Rz, L and Hy are as defined above, can be prepared as described in Scheme 1.

[0151] Compounds of formula (I) can be prepared according to Scheme 1 described below, providing at least one non-limiting synthetic route for the preparation of all of the Examples. Process 1

[0152] According to Scheme 1, intermediate III can be synthesized after a one-step synthesis starting from intermediate II under suitable ester formation conditions in the presence of an alkylating agent such as methyl iodide in the presence of an inorganic base such as cesium carbonate , in a suitable organic solvent such as DMF, and at a temperature usually around room temperature, for a period ranging from several hours to overnight. Intermediate III can be converted to intermediate IV by deprotecting the BOC protected amine under acidic conditions such as concentrated aqueous hydrogen chloride or hydrogen chloride in dioxane in a suitable solvent such as ethanol or diethyl ether at room temperature .

[0153] Intermediate V can be synthesized after a one-step synthesis starting from intermediate IV and the appropriate carboxylic acid under suitable amide coupling conditions in the presence of reagents to activate the carboxylic acid complex such as TBTU or HATU or T3P , in the presence of an inorganic base such as DIPEA or TEA, in a suitable organic solvent such as DCM or DMF, and at a temperature usually around room temperature. Direct amidation (transamidation) of esters can be carried out between intermediate V and intermediates XII or XIII to use e.g. butyllithium as promoter in a suitable organic solvent as THF or dioxane, in - At temperatures ranging from 78°C to room temperature for several hours, compounds of formula (I) are obtained. In a different method, intermediate V can be converted to intermediate VI by hydrolysis under basic conditions in a suitable solvent such as aqueous sodium hydroxide, eg methanol, at room temperature for several hours. Sequentially, intermediates VI and intermediates XII or XIII are used under suitable amide coupling conditions in the presence of reagents that activate carboxylic acid complexes such as TBTU or HATU or T3P, for use in organic compounds such as DIPEA or TEA The amine is reacted in the presence of a base in a suitable organic solvent, such as DCM or DMF, and typically at about room temperature for a period ranging from a few hours to overnight.

[0154] Alternatively, the compound of formula (I) can be prepared via amidation, starting from intermediate VI in the presence of TCFH and 1-methylimidazole, to obtain a solvent such as DMF at RT with the appropriate Transiently activated acyl imidazolinium intermediates for amine XII or XIII reactions. In a different approach, compounds of formula (I) can be obtained starting from intermediate VI in the presence of a suitable chlorinating agent such as POCl3 or thionyl chloride in a solvent such as pyridine at 5°C to give the corresponding Acyl chlorides which are directly treated with the appropriate amine XII or XIII in Py at RT.

[0155] The compound of formula (I) can also be formed via an acyl chloride, starting from intermediate VI in the presence of thionyl chloride at 50° C., followed by the presence of a suitable base such as LiHMDS, Reaction with XXIII in a suitable solvent such as DCM at a temperature of -78 °C.

[0156] Intermediate VI can be converted to Intermediate X following the conditions described above, undergoes amide coupling with Intermediate XIV, and can then be converted to a compound of Formula (I) at room temperature under suitable deprotection Deprotection of silyl groups is carried out in a suitable solvent such as MeOH or THF under conditions such as HCl or TFA.

[0157] In a different approach, intermediate VII can be prepared from intermediate VI by amide coupling using intermediate XII following the conditions described above, and sequentially undergoes removal of the BOC-protected amine following the conditions reported above. Protection, and the final methylation application of Eschweiler-Clarke reaction conditions, to obtain the compound of formula (I). In a different method, 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 prepared by using a suitable reducing agent such as Na( OAc)3BH or NaCNBH3 are transferred to compounds of formula (I) with the appropriate alkylamine using reductive amination conditions.

[0158] In another embodiment, compounds of formula (I) can be prepared according to Schemes 2a and 2b. Process 2a Process 2b

[0159] According to Scheme 2a, the mixture of intermediates IIIa and IVa can be obtained using a suitable sulfur source (such as sulfur) in a suitable solvent (such as EtOH) at reflux using ethyl 2-cyanoacetate Preparation from intermediate IIa followed by Wald multicomponent cyclization conditions. Mixtures of intermediates VIIa and VIIIa can be obtained using a suitable diazotizing agent, such as isoamyl nitrite or isopropyl nitrite, in a suitable solvent, such as THF or acetonitrile, at temperatures ranging from 0 °C to reflux, Deamination conditions are applied to the mixture of intermediates IIIa and IVa followed by deprotection of the BOC group under acidic conditions such as concentrated hydrochloric acid or hydrochloric acid in dioxane in a suitable solvent such as ethanol or diethyl ether at room temperature. Mixtures of intermediates IXa and Xa can be prepared from mixtures of intermediates VIIa and VIIIa with appropriate carboxylic acids in the presence of carboxylic acid complex activating reagents such as TBTU or HATU or T3P, in the presence of organic bases such as DIPEA or TEA, in the presence of organic bases such as DIPEA or TEA, in the presence of DCM or It is prepared in a suitable organic solvent in DMF and using amide coupling conditions at temperatures typically around RT. Mixtures of intermediates Xa and IXa can be hydrolyzed using a suitable inorganic base, such as aqueous NaOH or LiOH, in a suitable solvent, such as MeOH or EtOH, at room temperature, followed by intermediates XIIa and XIa as described above with the appropriate Amide Coupling Conditions on Mixtures of Amines XIIIa or XIVa. Compounds of formula (I) can be isolated from a mixture of intermediates XVIa and XVa using a suitable stationary phase such as silica gel on a column using a suitable mobile phase such as water / acetonitrile or DCM / MeOH or hexane / AcOEt chromatography. In a different method, mixtures of intermediates Va and Via can be converted to mixtures of intermediates XVIIa and XVIIIa by applying hydrolysis conditions using a suitable inorganic base such as NaOH in a suitable solvent such as EtOH at room temperature. A mixture of intermediates XVIIa and XVIIIa can be converted to a mixture of intermediates XIXa and XXIIa following the amide coupling following the conditions described above followed by deprotection of the BOC group using the conditions described above. Mixtures of intermediates XXVIa and XXVa can be prepared using the appropriate aldehyde XXIIIa with a suitable reducing agent such as Na(OAc)3BH or NaCNBH3 in a suitable solvent such as DCM or EtOH in an acid such as acetic acid and a complexing agent such as It is obtained by reductive amination at room temperature in the presence of titanium isopropoxide.

[0160] In another embodiment, the compound of formula (I) can be prepared according to Scheme 3. Process 3

[0161] According to Scheme 3, intermediate XXVIIIa can be subjected to a Gwald multicomponent cyclization with ethyl 2-cyanoacetate in a suitable solvent such as EtOH at reflux using a suitable sulfur source such as sulfur Compound IIa was obtained using suitable mobile phases such as water / acetonitrile or DCM / MeOH or hexane / AcOEt, followed by appropriate column chromatography using an appropriate stationary phase such as silica gel. Intermediate XXVIIIa can be deaminated, followed by BOC deprotection, amidation with the appropriate acid, hydrolysis of the ethyl ester and final amidation with the appropriate amine XIIIa or XIVa following the conditions described in Scheme 2b to convert to Compounds of formula (I).

[0162] In another preferred embodiment, the compound of formula (I) can be prepared according to Scheme 4. Process 4

[0163] According to Scheme 4, intermediate IIIb can be synthesized after a step starting from intermediate IIb under suitable ester formation conditions in the presence of an alkylating agent such as methyl iodide in the presence of an inorganic base such as cesium carbonate , in a suitable organic solvent such as DMF, and at a temperature typically around RT, for a time ranging from a few hours to overnight. Intermediate IIIb can be converted to intermediate IVb by removal of the bound BOC in a suitable solvent such as ethanol or diethyl ether in acidic conditions such as concentrated hydrochloric acid or a solution containing hydrochloric acid in dioxane at room temperature The protecting group of the protected amine; and then by using a suitable reducing agent such as Na(OAc)3BH or NaCNBH3 in the presence of a suitable aldehyde, in a suitable solvent such as DCM or EtOH, in a solution such as acetic acid Conversion to intermediate Vb was carried out by applying reductive amination conditions in the presence of acid at room temperature. The compound of formula (I) can be hydrolyzed in a suitable solvent such as MeOH or EtOH, using a suitable base such as NaOH or LiOH to hydrolyze the intermediate Vb, followed by a carboxyl group such as TBTU or HATU or T3P under suitable amide coupling conditions. It is obtained by coupling with the appropriate intermediate XIIb or XIIIb amide in the presence of an acid complex, in the presence of an organic base such as DIPEA or TEA, in a suitable organic solvent such as DCM or DMF, and at temperatures usually around RT. Alternatively, compounds of formula (I) can be obtained from intermediate VIb in a solvent such as pyridine at 5°C in the presence of a suitable chlorinating agent such as acetyl chloride or thionyl chloride, to give the corresponding acyl chloride compounds, which can be directly treated with the appropriate amine XIIb or XIIIb in Py at room temperature.

[0164] In a different manner, intermediate VIIb can be prepared from intermediate IIb by amide coupling following the conditions described above, or by reacting intermediate IIb in the presence of TCFH and 1-methylimidazole to obtain A transiently activated acyl imidazolinium intermediate that can be reacted with the appropriate amine XIIb or XIIIb in a suitable solvent such as DMF at RT. Compounds of formula (I) can be prepared from intermediate VIIb after deprotection of the BOC group, followed by amide coupling, applying suitable conditions and appropriate carboxylic acids as described above.

[0165] Alternatively, intermediate VIIIb can be converted to intermediate IXb by reductive amination with an appropriate SEM-protected aldehyde following the appropriate conditions described above. It will be clear to those skilled in the art that where the aldehyde contains moieties that may interfere with the reaction, such moieties will need to be protected. Applying SEM deprotection conditions to intermediate IXb using a suitable acid such as acetic acid in a suitable solvent such as DMF at room temperature can afford compounds of formula (I).

[0166] In a different method, intermediate VIIIb can be converted to intermediate Xb by amide coupling following the conditions described above, wherein intermediate XIb can be obtained by using a solvent such as potassium carbonate in a suitable solvent such as DMF Alkylation with a suitable inorganic base with a suitable haloalkyl group such as chloroethylline is converted to a compound of formula (I). Alternatively, the compound of formula (I) can be obtained from intermediate Xb, applying Suzuki coupling conditions, using a suitable inorganic base (such as potassium carbonate or sodium carbonate), a suitable catalyst (such as Pd(dppf)Cl ), at 100° C. In a suitable organic solvent such as DMF or DMA, using a suitable boron reagent such as 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborine Pentan-2-yl)-1,2,3,6-tetrahydropyridine.

[0167] Alternatively, compounds of formula (I) may be obtained from intermediate VIIa using the amide coupling conditions described above, with the appropriate acid. Alternatively, compounds of formula (I) can be prepared from intermediate VIIIb using an appropriate aldehyde with a suitable reducing agent such as Na(OAc)3BH or NaCNBH3 in a suitable solvent such as DCM or EtOH in a solution such as acetic acid The reductive amination is carried out in the presence of an acid and at room temperature using a complexing agent such as titanium isopropoxide.

[0168] Various aspects of the invention described in this application are illustrated by the following examples which do not limit the invention in any way. Preparation of intermediates and examples

[0169] Chemical names of compounds were generated by PerkinElmer ChemDraw Professional 19.1.1.21 using Structure To Name Place IUPAC Name. All reagents whose synthesis is not described in the Experimental Section are commercially available, are known compounds, or can be formed from known compounds by known methods by those skilled in the art.

[0170] In subsequent procedures, some of the starting materials were identified via "Intermediate" or "Example" numbers with indications to the step numbers. This compound number is provided only to assist those skilled in the art.

[0171] "Similar or analogous" procedures mean that such procedures may involve minor variations in, for example, reaction temperatures, amounts of reagents / solvents, reaction times, work-up conditions, or chromatographic purification conditions. Abbreviation meaning

[0172] ACN=acetonitrile; EtO=diethyl ether; DCM=dichloromethane; DMF=N,N-dimethylformamide; CPME=cyclopentyl methyl 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 = tert-butyl dicarbonate; HATU = (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridine-3 -yl)methyliminium hexafluorophosphate; TBTU = 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate; T3P = propane phosphate Anhydride; HOBt = 1-hydroxybenzotriazole hydrate; TCFH = chloro-N,N,N',N'-tetramethylformamidine hexafluorophosphate; n-BuLi = n-butyllithium; XPhos Pd G3 = (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] Palladium(II) mesylate; Xphos Pd G2 = chloro(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 = flash column chromatography; MeOH-d4 = deuterated methanol; DMSO-d6 = deuterated dimethyl sulfide; CDCl3 = deuterated chloroform; ACN-d3 = deuterated acetonitrile; NMR = nuclear magnetic resonance; Phase chromatography / mass spectrometry; ESI = electrospray ionization; preparative HPLC = preparative high performance liquid chromatography; SCX = solid cation exchange; SM = starting material; DP = desired product; wt = weight; e.e. = pairs Enantiomeric excess; SEM-Cl = 2-(trimethylsilyl)ethoxymethyl chloride; PyBOP = benzotriazol-1-yl-oxy-para-pyrrolidinyl-phosphonium hexafluorophosphate ; Pd2(dba)3 = ginseng (dibenzylideneacetone) dipalladium (0); 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(diphenylphosphine base) complex of ferrocene]dichloropalladium(II) and dichloromethane; BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; XantPhos = 4,5- Bis(diphenylphosphino)-9,9-dimethyldibenzopyran. General Experimental Details NMR Characterization:

[0173] 1H NMR spectra were recorded on a Varian MR-400 spectrometer operating at 400 MHZ (proton frequency), equipped with a self-protected Z-gradient coil for reverse detection 5 mm 1H / nX broadband probe, deuterium digitally locked channel Unit, quadrature digit detection unit with transmitter offset frequency shift or on Bruker Avance III HD 400 MHz or Bruker Fourier 300 MHz. Chemical shifts are reported as delta 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 double triplet, m = multiplet, br = broad, nd = not determined).

[0174] In some cases, the signal NH from an amide bond or an amine bond (exchangeable proton) is not visible.

[0175] In a few cases, some signals can be hidden under the water signal or under the signal of DMSO or other residual solvents. LC / UV / MS analysis method

[0176] Estimated LC / MS retention times are subject to an experimental error of ± 0.5 min.

[0177] Method 1: Acquity CSH C18 column 50mm x 2.1mm 1.7µm, maintained at 40°C; mobile phase: eluting agent B (ACN / water 95:5 +0.05% HCOOH) in eluting agent A (water / ACN 95:5 +0.05% HCOOH) from 1% to 99.9% within 3.5 minutes. Flow rate: 1 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters PDA + Waters QDA.

[0178] Method 2: Kinetex® XB-C18 column, 4.6x50 mm, 2.6 µm maintained at 25°C. Mobile phase: water (0.1% formic acid) in ACN (0.1% formic acid), 70% to 5% in 3.90 min; flow rate: 1.0 mL / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus.

[0179] Method 3: Kinetex® XB-C18 column, 4.6x50 mm, 2.6 µm maintained at 25°C. Mobile phase: water (0.1% formic acid) in ACN (0.1% formic acid), 80% to 5% in 3.90 min; flow rate: 1.0 mL / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus.

[0180] Method 4: Kinetex® XB-C18 column, 4.6x50 mm, 2.6 µm maintained at 25°C. Mobile phase: water (0.1% formic acid) in ACN (0.1% formic acid), 70% to 5% in 3.90 min; flow rate: 1.0 mL / min; wavelength: 190-350 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC mass spectrometer.

[0181] 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), 5% to 95% in 5.6 min; flow rate: 0.4 mL / min; wavelength: 100-800 nm DAD. Acquity UPLC with PDA detector and ZQ mass spectrometer.

[0182] Method 6: Acquity UPLC BEH Shield RP18 column, 100 x 2.1 mm, 1.72 µm (Plus shield), maintained at 40°C. Mobile phase: ACN / water + 10 nM ammonium bicarbonate, 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.

[0183] Method 7: Acquity UPLC HSS C18 column, 100 x 2.1 mm, 1.8 µm (Plus protective cartridge), maintained at 40°C. Mobile phase: ACN (0.1% formic acid) in water (0.1% formic acid), 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.

[0184] Method 8: Kinetex® XB-C18 column, 4.6x50 mm, 2.6 µm maintained at 25°C. Mobile phase: water (0.1% formic acid) in ACN (0.1% formic acid), 90% to 5% in 3.90 min; flow rate: 1.0 mL / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus.

[0185] Method 9: Kinetex® XB-C18 column, 4.6x50 mm, 2.6 µm maintained at 25°C. Mobile phase: water (0.1% formic acid) in ACN (0.1% formic acid), 90% to 5% in 3.90 min; flow rate: 1.0 mL / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus.

[0186] Method 10: Gemini-NX C18 column, 4.6x150 mm, 3 µm maintained at 35°C. Mobile phase: water (0.1% formic acid) in ACN (0.1% formic acid), 80% to 5% in 8.50 min; flow rate: 1.0 mL / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus.

[0187] Method 11: Gemini-NX C18 column, 4.6x150 mm, 3 µm maintained at 35°C. Mobile phase: water (0.1% formic acid) in ACN (0.1% formic acid), 65% to 5% in 8.50 min; flow rate: 1.0 mL / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus.

[0188] 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, 1 wavelength: 254 nm. Waters / Thar SFC system with Waters SQD.

[0189] 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.

[0190] Method 14: Agilent Zorbax column 4.6x50 mm, 3.5 µm maintained at 40°C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid), 40% to 100% in 2 min. Flow rate: 3.0 mL / min. Wavelength: 210-400 nm DAD. Waters 2795 / 2695 separation module + Waters DAD + Micromass ZQ, single quadrupole LC-MS.

[0191] 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), 8% to 97% in 1.5 min; flow rate: 0.8 mL / min; wavelength: 210-400 nm DAD. Acquity H-Class UPLC with PDA detector and QDa.

[0192] Method 16: Waters Sunfire C18 column, 4.6x50 mm, 3.5 µm maintained at 40°C. Mobile phase MeCN in water + 10 mM ammonium bicarbonate, 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.

[0193] Method 17: Agilent Zorbax column 4.6x50 mm, 3.5 µm maintained at 40°C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid), 5% to 95% in 2 min. Flow rate: 3.0 mL / min. Wavelength: 210-400 nm DAD. Waters 2795 / 2695 separation module + Waters DAD + Micromass ZQ, single quadrupole LC-MS. LC / SFC chiral preparative method

[0194] Preparation method 1: Separation operation (Gilson Pump 333; Gilson 151; Gilson Valvemate 6 position) was carried out on the Gilson Prepare LC system using a Lux C1 (21.2mm x 250 mm, 5um) column with a temperature of 21mL / min Isocratic operation (90 / 10 ACN:i-PrOH, 0.2% v / v NH3), column maintained at room temperature; wavelength: 210nm.

[0195] Preparation method 2: the SFC-MS separation operation system is carried out on the Gilson Preparative LC system (Gilson Pump-333; Gilson 151; Gilson Valvemate 6 position) using AmyC (20mm x 250 mm, 5um) column, with 50 Isocratic operation at mL / min (70 / 30 MeOH:CO2, 0.2% v / v NH3, 125 Bar back pressure), column maintained at 40°C; wavelength: 210nm.

[0196] Preparation method 3: the SFC-MS separation operation system is carried out on a Gilson Preparative LC system (Gilson Pump-333; Gilson 151; Gilson Valvemate 6 position) using a Lux A1 (21.2mm x 250 mm, 5um) column with a Isocratic operation at 50mL / min (40 / 60 MeOH:CO2, 0.2% v / v NH3, 100Bar back pressure), column maintained at 40°C; wavelength: 210nm.

[0197] Where the preparation of starting materials is not described, such are commercially available, known in the literature or can be readily obtained by those skilled in the art using standard procedures. All solvents were purchased from commercial sources and used without additional purification.

[0198] Compounds were purified by reverse phase HPLC using Waters Fractionlynx preparative HPLC system (2525 pumps, 2996 / 2998 UV / VIS detector, 2767 liquid handler) or Gilson preparative HPLC system (322 pumps, 155 UV / VIS detectors) detector, GX-281 liquid disposer) or equivalent system, both in alkaline conditions (ACN+0.1%NH3, H2O+0.1%NH3) and in acidic conditions (ACN+0.1% HCOOH, H2O+0.1%HCOOH ), in the latter case, the residual fractions (identified by TLC and / or LCMS analysis) containing the desired product were combined and the solvent was removed under reduced pressure or lyophilized; or alternatively by SCX (NH) extraction.

[0199] Specific details of the conditions used in some examples, including columns, solvents, gradients and modifiers (acidic or basic), are provided and are provided for assistance only. When specific conditions are not provided, they can be readily optimized by one skilled in the art.

[0200] Thin layer chromatography was performed on Merck silica gel 60 F254 TLC plates. Preparative thin layer chromatography (pTLC) was performed using Uniplate 1000 micron or 500 micron silica gel discs. Flash chromatography was performed on an Interchim PuriFlash 450 and 520Plus or an equivalent MPLC using a Biotage SP1 purification system or using prepacked silica cartridges. General Synthesis Procedure General Procedure A

[0201] Sodium hydride (60% in mineral oil, 1.10 equiv) was added to a stirred solution of the desired alcohol (1.20 equiv) in ACN (0.5M concentration) under an inert atmosphere. The reaction mixture was stirred for 1 hour, then the desired aryl-fluoride (1.00 equiv) was added in one portion. The reaction mixture was stirred at room temperature until LCMS indicated consumption of starting material. 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 frit and concentrated in vacuo. General procedure B

[0202] The desired aryl-nitro group (1.00 equiv) and iron powder (5.00 equiv) were combined in acetic acid (0.3M concentration) and methanol (0.3M concentration). The reaction mixture was stirred at 50 °C until LCMS indicated consumption of starting material. 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 frit and concentrated in vacuo. General program C

[0203] To a solution of the desired aldehyde (1.00 equiv) in DCM (0.1 M concentration) was added the desired amine (1.10 equiv), titanium(IV) isopropoxide (2.00 equiv) and acetic acid (3.00 equiv). The reaction mixture was stirred at room temperature for 1 h. Sodium triacetyloxyborohydride (2.00 equiv) was added and the reaction mixture was stirred at room temperature until LCMS indicated consumption of starting material. The reaction mixture was partitioned between DCM and saturated NaHCO3 (aq), and the mixture was filtered through a bed of celite. The aqueous phase was extracted with 2xDCM and the combined organic phases were washed with saturated aqueous NaCl (aq), passed through a hydrophobic frit and concentrated in vacuo. General procedure D

[0204] To palladium (10% on carbon) (10 wt%) was added a solution of the desired nitro-aryl (1.00 equiv) in EtOH (0.1 M concentration). The flask was evacuated and purged with argon (x3), then evacuated and purged with hydrogen (x3). The reaction mixture was stirred at room temperature until LCMS indicated consumption of starting material. The reaction mixture was diluted with DCM and filtered through celite. The filter cake was washed with DCM, and the combined filtrates were concentrated in vacuo. General procedure E

[0205] To a solution of the desired phenol (1.00 equiv) in DMF (0.2M concentration) was added the desired alkyl halide (1.20 equiv) followed by cesium carbonate (2.00 equiv). The mixture was stirred at 80 °C until LCMS indicated consumption of starting material. The reaction mixture was diluted with water and extracted with DCM (x2). The organic phases were combined and concentrated. General procedure F

[0206] To a solution of the desired nitro-aryl group (1.00 eq) in ethanol (0.1 M concentration) was added sequentially 1-methyl-1,4-cyclohexadiene (30.0 eq) under a nitrogen atmosphere and palladium on carbon (10%) (1.00 equiv), and the reaction mixture was stirred at 80 °C until LCMS indicated consumption of starting material. The reaction mixture was cooled to room temperature and filtered through a pad of Celite, which was washed with EtOH and AcOEt. The filtrate was concentrated under reduced pressure. General procedure G

[0207] To a mixture of the desired carboxylic acid sodium salt or acid (1.00 equiv) and HATU (1.20 to 2.00 equiv) in DMF / DCM (0.1 M concentration) was added DIPEA (3.00 to 8.00 equiv). The reaction mixture was stirred at room temperature for 15 min before addition of the desired amine (1.00 to 2.00 equiv). The reaction mixture was stirred at room temperature until LCMS indicated consumption of starting material and then concentrated. General procedure H

[0208] 6-(imidazo[1,2-a]pyridine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (1.00 equivalent ) was suspended in thionyl chloride (10.0 equiv) and the reaction mixture was stirred at 50 °C for 20 min. Another portion of thionyl chloride (10.0 equiv) was added and the reaction mixture was stirred at 50°C for 30 minutes. The reaction mixture was concentrated in vacuo to afford 6-(imidazo[1,2-a]pyridine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine as a white solid -3-Formyl chloride. To a solution of the desired aniline (1.00 equiv) and TEA (3.00 equiv) in DCM (0.1 M concentration) was added 6-(imidazo[1,2-a]pyridine-3-carbonyl)-5,7-bis Hydrogen-4H-thieno[2,3-c]pyridine-3-formyl chloride (1.30 equiv). The reaction mixture was stirred at room temperature until LCMS indicated consumption of starting material and then concentrated in vacuo. General Procedure I

[0209] The desired carboxylic acid (1.00 equiv) was suspended in thionyl chloride (0.21 mL, 2.93 mmol, 30.0 equiv), 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 re-concentrated to give the intermediate acyl chloride. To a solution of the desired aniline (1.00 equiv) and DMAP (0.20 equiv) in pyridine (0.1 M concentration) was added acyl chloride followed by DIPEA (3.00 equiv). The reaction mixture was stirred at 40 °C until LCMS indicated consumption of starting material and then concentrated in vacuo. General procedure J

[0210] To a solution of the desired aldehyde (1.00 equiv) in DCM (0.1 M concentration) was added the desired amine (1.10 equiv), titanium(IV) isopropoxide (2.00 equiv) and acetic acid (3.00 equiv). The reaction mixture was stirred at room temperature for 1 h. Sodium triacetyloxyborohydride (2.00 equiv) was added and the reaction mixture was stirred at room temperature until LCMS indicated consumption of starting material. The residue was loaded onto an Isolute SCX-II cartridge, washed with MeOH, then released with 2M NH3 / MeOH. The eluate was concentrated under vacuum. General procedure K

[0211] To a solution of the desired amine (1.00 equiv) and desired aldehyde (1.00 equiv) in MeOH (0.03 M concentration) was added titanium(IV) isopropoxide (3.00 equiv) and refluxed for 2 h. The reaction was cooled to room temperature and NaBH3CN (2.50 equiv) was added and stirring was continued at room temperature overnight. The reaction was quenched with water, filtered through celite and concentrated under vacuum. General program L

[0212] To the desired aldehyde (1.00 equivalents) and N-[3-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-6- To a mixture of the hydrochloride salt of onium-3-carboxamide (1.00 eq) in MeOH (0.075 M concentration) was added acetic acid (9.86 eq) and the reaction mixture was stirred at 65 °C for 90 min. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was suspended in DCM (0.025 M concentration) and sodium triacetyloxyborohydride (3.50 equiv) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM and treated with a 10% solution of KHSO4 (aq). After stirring for 15 min, the mixture was basified with saturated aqueous Na2CO3 (aq) and the layers were separated. The aqueous layer was extracted with DCM and the combined organic extracts were filtered through a hydrophobic frit and concentrated in vacuo. General Program M

[0213] To a solution of the desired carboxylic acid (1.10 equiv) in DMF (0.1 M concentration) was added DIPEA (3.00 equiv) and HATU (1.20 equiv). The reaction mixture was stirred at room temperature for 30 minutes. Subsequently, N-[3-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (1.00 equivalent ), and the reaction mixture was stirred overnight at 40 °C. The reaction mixture was cooled to room temperature and concentrated. General ProgramN To a solution of the desired acid (1.00 equiv), desired amine (1.00 to 1.30 equiv) and 1-methylimidazole (3.50 equiv) in ACN (0.2M concentration) was added TCFH (1.20 to 1.50 equiv) . The reaction mixture was stirred at room temperature until LCMS indicated consumption of starting material and partitioned between saturated NaHCO3 (aq) and EtOAc. The phases were separated, the aqueous phase was extracted with 2xEtOAc and the combined org. phases were passed through a hydrophobic frit and concentrated in vacuo.

[0215] Preparation of 4-((tetrahydrofuran-3-yl)oxy)-3-(trifluoromethyl)aniline-Intermediate 1 Step 1: 3-(4-nitro-2-(trifluoromethyl) Phenoxy (Intermediate 2) was prepared according to general procedure A from 3-hydroxytetrahydrofuran (0.53 g, 6.00 mmol) and 2-fluoro-5-nitrobenzene trifluoride (0.69 mL, 5.00 mmol) to afford the title compound (1.52g, 99%).¹H NMR (400 MHz, CDCl3) δ 8.52 (d,J=3.0 Hz, 1H), 8.42 (dd,J=3.0, 9.0 Hz, 1H), 7.03 (d,J=9.0 Hz, 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)

[0216] Step 2: 4-((Tetrahydrofuran-3-yl)oxy)-3-(trifluoromethyl)aniline (Intermediate 1) From Intermediate 2 (1.52 g, 5.48 mmol) according to general procedure B preparation. The residue was loaded onto an Isolute SCX-II cartridge, washed with DCM / MeOH, then released with 2M NH3 / MeOH. The eluate was concentrated to give the title compound (1.10 g, 75%). ¹H NMR (400 MHz, CDCl3) δ 6.91 (d,J=2.0 Hz, 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).

[0217] The intermediates reported in the table below were prepared via aromatic nucleophilic substitution as described for Intermediate 1, Steps 1-2, using the corresponding commercially available alcohols in Step 1. Intermediate number structure step 1 SM volume (Yield) step 2 final product volume (Yield) material 3 0.69 mL, 5.00 mmol (1.37g, 99%) 940mg (73%) ¹H NMR (400 MHz, CDCl 3 ) δ 6.91 (m, 1H), 6.76 - 6.70 (m, 1H), 6.40 (d, J=8.6 Hz, 1H), 5.20 - 5.11 (m, 1H), 4.92 (t, 2H), 4.78 (t, 9H), 3.60 (s, 2H) 4 0.69 mL, 5.00 mmol (1.5g, 99%) 1.27g (78%) ¹H NMR (400 MHz, CDCl 3 ) δ 6.91 - 6.84 (m, 2H), 6.81 - 6.77 (m, 1H), 4.85 (t, J=6.9Hz, 2H), 4.57 (t, J=6.1Hz, 2H), 4.19 (d, J= 6.8 Hz, 2H), 3.59 (bs, 2H), 3.50 - 3.39 (m, 1H) 5 0.69 mL, 5.00 mmol (quantitative yield) 940mg (66%) LC-MS (ESI): Method 13 t R = 0.88 min; m / z(M+1) = 236 6 0.69 mL, 5.00 mmol (1.45g, quantitative) 1.45g (84%) LC-MS (ESI): Method 13 t R = 0.63 min; m / z(M+1) = 261 7 0.69 mL, 5.00 mmol (1.49g, 88%) 1.34g (quantitative) ¹H NMR (400 MHz, CDCl 3 ) δ 6.92 - 6.74 (m, 3H), 4.33 (s, 1H), 2.67 (br s, 2H), 2.35 (br s, 2H), 2.30 (s, 3H), 2.03-1.83 (m, 4H)

[0218] Preparation of 2-(4-amino-2-(trifluoromethyl)phenoxy)ethan-1-ol-intermediate 8 step 1 - 2-(4-nitro-2-(trifluoromethyl) yl)phenoxy)ethan-1-ol (intermediate 9) was mixed with 2-fluoro-5-nitrobenzene trifluoride (0.69 mL, 5.00 mmol, 1.00 equiv), potassium tertiary butoxide ( 1.23 g, 11.0 mmol, 2.20 equiv) and ethylene glycol (11 mL, 0.200 mol, 40.0 equiv) 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 onto 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%). ¹H NMR (400 MHz, CDCl3) δ 8.52 (d, J=2.5 Hz, 1H), 8.43 (dd, J=2.8, 9.1 Hz, 1H), 7.13 (d, J=9.1 Hz, 1H), 4.30 (t , J=4.3 Hz, 2H), 4.08 - 4.02 (m, 2H), 2.02 (t, J=6.5 Hz, 1H).

[0219] Step 2 - 2-(4-Amino-2-(trifluoromethyl)phenoxy)ethan-1-ol (Intermediate 8) Intermediate 9 (1.16 g, 4.62 mmol) to obtain the title compound (0.98 g, 89%). ¹H NMR (400 MHz, CDCl3) δ 6.89 (m, 1H), 6.85 (m, 1H), 6.81 - 6.76 (m, 1H), 4.07 (t, J=4.5 Hz, 2H), 3.92 (t, J = 4.5Hz, 2H), 3.55 (s, 2H).

[0220] Preparation of 3-((dimethylamino)methyl)-5-(trifluoromethyl)aniline (intermediate 10) step 1 - N,N-dimethyl-1-(3-nitro -5-(Trifluoromethyl)phenyl)methanamine (Intermediate 11) was synthesized from 3-nitro-5-(trifluoromethyl)benzaldehyde (200 mg, 0.913 mmol) and dimethyl Amine (2M solution in THF, 0.50 mL, 1.00 mmol) was prepared. Purification by silica gel column chromatography (12 g cartridge, 0 - 2.5% 2 M NH3 in MeOH in DCM) afforded the title compound (84 mg, 37%). ¹H NMR (400 MHz, CDCl3) δ 8.41 - 8.37 (m, 2H), 7.95 (s, 1H), 3.58 (s, 2H), 2.29 (s, 6H)

[0221] Step 2 - 3-((Dimethylamino)methyl)-5-(trifluoromethyl)aniline (Intermediate 10) From Intermediate 11 (84 mg, 0.338 mmol) according to General Procedure D Preparation afforded the title compound (67 mg, 91%). ¹H NMR (400 MHz, CDCl3) δ 6.93 (s, 1H), 6.82 (s, 1H), 6.80 (s, 1H), 3.82 (s, 2H), 3.36 (s, 2H), 2.24 - 2.24 (m, 6H)

[0222] The intermediates reported in the table below were prepared via aromatic nucleophilic substitution as described for intermediate 10, steps 1-2, in step 1 using the corresponding commercially available amines. Intermediate number structure step 1 SM amount (Yield) step 2 Product amount (yield) material 12 150 mg, 0.685 mmol (197mg, 99%) 134mg (98%) ¹H NMR (400 MHz, CDCl 3 ) δ 6.95 (s, 1H), 6.84 (s, 2H), 6.79 (s, 1H), 3.82 (s, 2H), 3.74 - 3.69 (m, 4H), 3.44 - 3.43 (m, 2H), 2.46 - 2.43 (m, 4H) 13 750 mg, 3.42 mmol (707 mg, 65%) 638mg (99%) ¹H NMR (400 MHz, CDCl 3 ) δ 6.94 (s, 1H), 6.84 (s, 1H), 6.78 (s, 1H), 3.82 (s, 2H), 3.57 (d, J=13.2 Hz, 1H), 3.50 (d, J=13.2 Hz , 1H), 2.83 - 2.68 (m, 3H), 2.53 - 2.45 (m, 1H), 2.31 (dd, J=6.7, 8.3 Hz, 1H), 2.20 (s, 6H), 2.04 - 1.94 (m, 1H ), 1.77 - 1.68 (m, 1H) 14 750 mg, 3.42 mmol (786 mg, 72%) 710mg (99%) ¹H NMR (400 MHz, CDCl 3 ) δ 6.94 (s, 1H), 6.84 (s, 1H), 6.77 (s, 1H), 3.81 (s, 2H), 3.58 (d, J=13.2 Hz, 1H), 3.50 (d, J=13.3 Hz , 1H), 2.83 - 2.69 (m, 3H), 2.53 - 2.45 (m, 1H), 2.31 (dd, J=6.8, 8.3 Hz, 1H), 2.20 (s, 6H), 2.05 - 1.95 (m, 1H ), 1.77 - 1.68 (m, 1H)

[0223] Preparation of 3-(2-(N-olyl)ethoxy)-5-(trifluoromethyl)aniline (intermediate 15) step 1 - 4-(2-(3-nitro-5- (Trifluoromethyl)phenoxy)ethyl)line (Intermediate 16) was prepared according to general procedure E from 4-(2-chloroethyl)line hydrochloride (431 mg, 2.32 mmol). The residue was purified by silica gel column chromatography (40 g cartridge, 0-100% AcOEt in cyclohexane) to afford the title compound (0.6 g, 97%). ¹H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J=2.5 Hz, 2H), 7.81 (s, 1H), 4.34 (dd, J=5.6, 5.6 Hz, 2H), 3.58 (dd, J= 4.6, 4.6 Hz, 4H), 2.74 (dd, J=5.6, 5.6 Hz, 2H), 2.52 (s, 4H), 2.51 (ddd, J=5.5, 5.5, 4.3 Hz, 4H).

[0224] Step 2 - 3-(2-(N-olyl)ethoxy)-5-(trifluoromethyl)aniline (Intermediate 15) From Intermediate 16 (100 mg, 0.312 mmol) to afford the title compound (84 mg, 93%) which was used without further purification. ¹H NMR (400 MHz, CDCl3) δ 6.52 (d, J=9.5 Hz, 2H), 6.36 (t, J=2.0 Hz, 1H), 4.09 (t, J=5.6 Hz, 2H), 3.83 (s, 2H ), 3.75 - 3.72 (m, 4H), 2.79 (t, J=5.7 Hz, 2H), 2.59 - 2.55 (m, 4H).

[0225] The intermediates reported in the table below were prepared via nucleophilic substitution as described for intermediate 15, steps 1-2, in step 1 using the corresponding commercially available alkyl chlorides. Intermediate number structure step 1 SM amount (Yield) step 2 Product amount (yield) material 17 250 mg, 1.74 mmol (346mg, 82%) 305mg (93%) ¹H NMR (400 MHz, CDCl 3 ) δ 6.54 (s, 1H), 6.51 (s, 1H), 6.37 (t, J=2.0 Hz, 1H), 4.06 - 4.03 (m, 2H), 3.81 (s, 2H), 2.72 (t, J= 5.6 Hz, 2H), 2.33 (s, 6H). 18 296 mg, 1.74 mmol (305 mg, 93%) 313mg (90%) ¹H NMR (400 MHz, CDCl 3 ) δ 6.55 (s, 1H), 6.50 (s, 1H), 6.37 (d, J=2.0 Hz, 1H), 4.10 - 4.06 (m, 2H), 3.81 (s, 2H), 2.91 - 2.86 (m, 2H), 2.64 - 2.58 (m, 4H), 1.83 - 1.79 (m, 4H). 19 378 mg, 1.52 mmol (544 mg, 89%) 410mg (80%) ¹H NMR (400 MHz, CDCl 3) δ 6.53 (s, 1H), 6.51 (s, 1H), 6.36 - 6.34 (m, 1H), 4.10 - 4.06 (m, 2H), 3.86 (s, 2H), 3.47 - 3.42 (m, 4H), 2.80 (t, J=5.6 Hz, 2H), 2.54 - 2.49 (m, 4H), 1.47 (s, 9H).

[0226] Preparation of 4-(pyrrolidin-1-ylmethyl)-3-(trifluoromethyl)aniline (intermediate 20) step 1 - 3-(trifluoromethyl)-4-vinylaniline (intermediate Substance 21) 4-bromo-3-(trifluoromethyl)aniline (2.50 g, 10.4 mmol, 1.00 equiv), XPhos (497 mg, 1.04 mmol, 0.100 equiv), XPhos Pd G2 (410 mg, 0.521 mmol, 0.05 eq) and K3PO4 (5.53 g, 26.0 mmol, 2.50 eq) were suspended in 1,4-dioxane (45.00 mL) and water (5.00 mL) and bubbled with argon for 10 min under sonication. Tetramethylethylene glycol vinylate (2.1 mL, 12.5 mmol, 1.20 equiv) was added and the reaction mixture was stirred at 80 °C under 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 in vacuo. The residue was purified by silica gel column chromatography (80 g cartridge, 0-30% AcOEt in cyclohexane) to afford the title compound (1.12 g, 57%). ¹H NMR (400 MHz, CDCl3) δ 7.48 (d, J=8.5 Hz, 1H), 7.04 - 6.93 (m, 1H), 6.91 (d, J=2.5 Hz, 1H), 6.78 (dd, J=2.5, 8.5 Hz, 1H) 5.58 (d, J=17.5 Hz, 1H), 5.22 (dd, J=1.0, 11.0 Hz, 1H), 3.87 (s, 2H).

[0227] Step 2 - (3-(trifluoromethyl)-4-vinylphenyl)carbamate tertiary butyl ester (intermediate 22) at room temperature to intermediate 21 (1.12 g, 5.98 mmol, 1.00 equiv) in toluene (12.00 mL) was added Boc2O (1.7 mL, 7.48 mmol, 1.25 equiv). 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 cartridge, 0-20% AcOEt in cyclohexane) to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=2.0 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.08 - 6.97 (m , 1H), 6.59 (s, 1H), 5.67 (d, J=17.5 Hz, 1H), 5.35 - 5.29 (m, 1H), 1.53 (s, 9H).

[0228] Step 3 - tertiary butyl (4-formyl-3-(trifluoromethyl)phenyl)carbamate (intermediate 23) made intermediate 22 (1.72 g, 5.99 mmol, 1.00 equiv) in DCM (60.00 mL) was passed through O3 / O2 for 45 min to give a green reaction mixture. DMSO (440 uL, 5.99 mmol, 1.00 equiv) was added and the reaction mixture was allowed to warm to room temperature while bubbling with argon. The reaction mixture was concentrated under vacuum and the residue was purified by silica gel FCC (80 g cartridge, 0-20% AcOEt in cyclohexane) to afford the crude title compound (1.19 g, 39%). ¹H NMR (400 MHz, CDCl3) δ 10.27 (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).

[0229] Step 4 - (tert-butyl 4-(pyrrolidin-1-ylmethyl)-3-(trifluoromethyl)phenyl)carbamate (Intermediate 24) Intermediate according to General Procedure C 23 (298 mg, 1.03 mmol) and pyrrolidine (0.095 mL, 1.13 mmol) to give the title compound (317 mg, 89%). ¹H NMR (400 MHz, CDCl3) δ 7.69 (d, J=8.5 Hz, 1H), 7.65 (d, J=2.0 Hz, 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)

[0230] Step 5 - 4-(Pyrrolidin-1-ylmethyl)-3-(trifluoromethyl)aniline (Intermediate 20) To Intermediate 24 (315 mg, 0.915 mmol, 1.00 equiv) in MeOH ( 6.10 mL) in dioxane (1.5 mL, 6.00 mmol, 6.56 eq) containing 4 M HCl was added. The reaction mixture was stirred at room temperature for 66 hours. The reaction mixture was evaporated under vacuum to afford the hydrochloride salt of the title compound in quantitative yield. ¹H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.66 (d, J=9.0 Hz, 1H), 6.98 (d, J=2.5 Hz, 1H), 6.87 (dd, J=2.0, 8.5 Hz, 1H), 4.28 (d, 2H), 3.43 - 3.36 (m, 2H), 3.11 - 3.02 (m, 2H), 2.03 - 1.88 (m, 4H)

[0231] The intermediates reported in the table below were prepared via reductive amination as described for intermediate 20, steps 1-5, in step 4 using the corresponding commercially available amines. Intermediate number structure step 4 SM amount (Yield) step 5 Product amount (yield) material 25 298 mg, 1.03 mmol (323mg, 87%) Quantitative yield ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.83 (s, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 6.90 (dd, J=1.4, 8.3 Hz, 1H), 3.92 - 3.85 (m, 4H), 3.25 - 3.20 (m, 2H), 3.12 - 3.06 (m, 2H).

[0232] The intermediates reported in the table below were prepared via Suzuki coupling as described for intermediate 24, steps 1-5, in step 1 using the corresponding commercially available aryl bromide. Modifications of the catalysts are reported in the table below. Intermediate number structure step 1 SM amount (Yield) step 5 Product amount (yield) material 26 2.50g, 10.4 mmol (1.54g, 79%) XPhos Pd G3 replaces XPhos Pd G2 140mg (90%) ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.64 (s, 1H), 7.12 (s, 1H), 6.98 (s, 1H), 6.96 (s, 1H), 4.27 (d, J=6.0 Hz, 2H), 3.37 - 3.31 (m, 2H) , 3.07 - 2.98 (m, 2H), 2.03 - 1.96 (m, 2H), 1.91 - 1.86 (m, 2H)

[0233] Preparation of 4-(pyrrolidin-1-ylmethyl)-3-(trifluoromethyl)aniline (intermediate 27) step 1-N,N-dimethyl-1-(4-nitro- 2-(Trifluoromethyl)phenyl)methanamine (Intermediate 28) was prepared from 4-nitro-2-(trifluoromethyl)benzaldehyde (125 mg, 0.570 mmol) and dimethylamine according to general procedure C (2M solution in THF, 0.31 mL, 0.628 mmol) was prepared to afford the title compound (132 mg, 93%). ¹H NMR (400 MHz, CDCl3) δ 8.50 (d, J=2.2 Hz, 1H), 8.38 (dd, J=2.3, 8.6 Hz, 1H), 8.10 (d, J=8.6 Hz, 1H), 3.68 (s , 2H), 2.30 (s, 6H)

[0234] Step 2 - 4-((Dimethylamino)methyl)-3-(trifluoromethyl)aniline (Intermediate 27) From Intermediate 28 (132 mg, 0.532 mmol) according to General Procedure D Preparation afforded the title compound (104 mg, 90%). ¹H NMR (400 MHz, CDCl3) δ 7.45 (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).

[0235] Preparation of 3-(3-amino-5-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (intermediate 29) 3-(3-nitro-5-(trifluoromethyl) Tributylphosphine (0.90 mL, 3.62 mmol, 1.50 equiv) and diisopropyl azodicarboxylate (0.71 mL , 3.62 mmol, 1.50 equiv) in THF (10 mL) was stirred at 0°C for 20 minutes, then 3-nitro-5-(trifluoromethyl)phenol (500 mg, 2.41 mmol, 1.00 equiv) and N-Boc-3-pyrrolidinol (678 mg, 3.62 mmol, 1.50 equiv) in THF (10 mL). The reaction mixture was stirred at room temperature for 3 days, and then concentrated under vacuum. The crude material was purified by silica gel column chromatography (25 g cartridge, 0-100% AcOEt in cyclohexane) to afford the title compound (367 mg, 67% yield). ¹H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.89 - 7.86 (m, 1H), 7.44 (d, J=4.8 Hz, 1H), 5.05 - 4.94 (m, 2H), 3.74 - 3.49 ( m, 5H), 2.22 - 2.21 (m, 2H), 1.48 (s, 9H)

[0236] tertiary butyl 3-(3-amino-5-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (intermediate 29) From intermediate 30 (300 mg, 0.805 mmol) preparation. Purification by reverse phase preparative HPLC (Sunfire® C18 19x150 mm, 10um 40-100% ACN / H2O (0.1% FA), 20mL / min, RT) afforded the title compound (170 mg, 61%). ¹H NMR (400 MHz, CDCl3) δ 6.52 (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).

[0237] Preparation of 3-(tertiary butyl)-1-(2-((tertiary butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-5-amine (intermediate 31) Step 1 - 4,4-Dimethyl-3- A solution of valeronitrile (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 heated at 90 °C under nitrogen atmosphere Stir for 23 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residual oily solid was tritiated under cyclohexane (30 mL), the solvent was decanted and the residue was dried under vacuum to give the title compound (7.082 g, 97%). ¹H NMR (400 MHz, CDCl3) δ 5.43 (s, 1H), 4.02 - 3.95 (m, 4H), 3.64 (brs, 2H), 1.25 (s, 9H).

[0238] Step 2 - 3-(tertiary butyl)-1-(2-((tertiary butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-5-amine (intermediate 31) To a solution of intermediate 32 (7.08 g, 38.6 mmol) in DMF (63.00 mL) stirred at room temperature under nitrogen atmosphere was added imidazole (7.89 g, 0.116 mol). Tertiary-butyl-chloro-dimethyl-silane (8.74 g, 58.0 mmol) was added in 3 portions, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was cooled with an ice / water bath and saturated NH4Cl(aq) (60 mL) was added slowly. DCM (70 mL) was added, and the aqueous phase was diluted with water (100 mL). The aqueous phase was extracted with 3xDCM and the combined organic phases were washed with 3x5% LiCl(aq), dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum and purified by silica gel column chromatography (AcOEt / cyclohexane, 0% to 50%) to afford the title compound (8.905 g, 77%). ¹H NMR (400 MHz, CDCl3) δ 5.36 (s, 1H), 4.07 (t, J=4.7 Hz, 2H), 3.90 (t, J=4.7 Hz, 2H), 3.85 (s, 2H), 1.25 (s , 9H), 0.83 (s, 9H), -0.04 (s, 6H).

[0239] Preparation of 3-(dimethoxymethyl)-5-(trifluoromethyl)aniline (intermediate 33) step 1 - 1-(dimethoxymethyl)-3-nitro-5- (Trifluoromethyl)benzene (Intermediate 34) To a solution of 3-nitro-5-(trifluoromethyl)benzaldehyde (2.00 g, 9.13 mmol, 1.00 equiv) in MeOH (25.00 mL) was added mono Hydrated p-toluenesulfonic acid (864 mg, 4.54 mmol, 0.498 equiv) and trimethyl orthoformate (2.9 mL, 26.5 mmol, 2.90 equiv). The reaction mixture was stirred at 65°C for 66 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was partitioned between AcOEt and saturated aqueous Na2CO3(aq), and the aqueous phase was extracted with 2xAcOEt. Drying (Na2SO4) combined organic extracts and evaporation of the solvent in vacuo afforded the title compound in quantitative yield (2.42 g). 1H NMR (400 MHz, CDCl3) δ 8.53 (1H, s), 8.47 (1H, s), 8.08 (1H, s), 5.53 (1H, s), 3.37 (6H, s)

[0240] Step 2 - 3-(Dimethoxymethyl)-5-(trifluoromethyl)aniline (Intermediate 33) To Intermediate 34 (3.18 g, 12.0 mmol, 1.00 equiv) in MeOH (15.00 mL ) and acetic acid (15.00 mL) was added iron powder (3.35 g, 60.0 mmol, 5.00 equiv). The reaction mixture was stirred vigorously at room temperature for 4 h. The reaction mixture was taken up from 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 2xEt2O. The combined organic phases were washed with brine, dried (Na2SO4) and evaporated in vacuo to give the title compound (1.80 g, 64%). 1H NMR (400 MHz, CDCl3) δ 7.10 (1H, s), 6.92 (1H, s), 6.84 (1H, s), 5.32 (1H, s), 4.83 2H, br s), 3.32 (6H, s) .

[0241] Preparation of 5-(trifluoromethoxy)pyridin-3-amine hydrochloride (intermediate 86) step 1; N-[5-(trifluoromethoxy)-3-pyridyl]amino Tertiary butyl formate (intermediate 87) was combined with tertiary butyl carbamate (102 mg, 0.868 mmol), XantPhos (63 mg, 0.108 mmol), ginseng(dibenzylideneacetone)dipalladium(0)- A mixture of 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 hour. The reaction mixture was cooled to room temperature, filtered through a pad of celite, then the pad was washed with dioxane, and the combined organic phases were concentrated in vacuo. The residue was purified by silica gel column chromatography (0-100%, EtOAc / cyclohexane), followed by drying in vacuo overnight to afford the title compound (115 mg, 0.413 mmol, 57%). ¹H NMR (400 MHz, CDCl3) δ 8.33 (d, J=2.3 Hz, 1H), 8.23 ​​- 8.21 (m, 1H), 8.07 (s, 1H), 7.04 (s, 1H), 1.54 (s, 9H) .

[0242] Step 2; 5-(Trifluoromethoxy)pyridin-3-amine hydrochloride (Intermediate 86) To Intermediate 87 (115 mg, 0.413 mmol) in 1,4-dioxane (3 ml) To the solution in dioxane (3.0 ml, 0.413 mmol) containing hydrogen chloride 4N was added. 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 in vacuo to give the title compound (60 mg, 0.280 mmol, 68%). ¹H NMR (400 MHz, 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).

[0243] Preparation of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-3-carboxylic acid (Intermediate 88) Imidazo[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 before degassing and platinum(IV) oxide (22 mg, 0.0969 mmol) was added, followed by hydrogenation. After 2 hours under an atmosphere of hydrogen, water (1.00 ml) was added and the reaction was allowed to stir overnight. The reaction mixture was filtered through celite to remove the catalyst and concentrated under reduced pressure to give the desired product (100 mg, 97.58%). ¹H NMR (400 MHz, DMSO-d6) d 13.09 (s, 1H), 8.78 (s, 1H), 7.71 (s, 1H), 4.18 (t, J=6.0 Hz, 2H), 3.39 - 3.31 (m, 2H), 2.05 - 1.99 (m, 2H).

[0244] Preparation of (R)-(3-amino-5-(trifluoromethyl)phenyl)(3-(dimethylamino)pyrrolidin-1-yl)methanone (intermediate 111) to 3-Amino-5-(trifluoromethyl)benzoic acid (205 mg, 1.00 mmol), (R)-(+)-3-(dimethylamino)pyrrolidine (0.38 mL, 3.00 mmol) and To a solution of TEA (0.42 mL, 3.00 mmol) in DCM (5.00 mL) and DMF (5.00 mL) was added PyBOP (781 mg, 1.50 mmol). The reaction mixture was stirred for 2 h, partially concentrated in vacuo and the residue was partitioned between saturated NaCl(aq) and EtOAc. The aqueous phase was extracted with EtOAc and the organic extracts were washed with sat. NaCl (aq), dried (Na2SO4) and concentrated in vacuo. Purification by FCC (0-10% 2M NH3 / MeOH in DCM) afforded the desired product (290 mg, 87%). ¹H NMR (400 MHz, DMSO-d6) δ 6.90 (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 )

[0245] Preparation of [4-amino-2-(trifluoromethyl)phenyl]methanol (intermediate 112) to [4-nitro-2-(trifluoromethyl)phenyl]methanol at 75°C (1000 mg, 4.52 mmol) and NH4Cl (121 mg, 2.26 mmol) in EtOH (50 mL) and water (50 mL) were added iron powder (2526 mg, 45.2 mmol), and the reaction mixture was stirred for 30 minutes . The reaction mixture was filtered through a pad of celite. The combined filtrates were concentrated in vacuo, redissolved in 2:1 DCM / cyclohexane and filtered, and the combined filtrates were evaporated to give the title compound (800 mg, 4.19 mmol, 93%). ¹H NMR (400 MHz, CDCl3) δ 7.40 (d, J=8.1 Hz, 1H), 6.93 (d, J=2.3 Hz, 1H), 6.82 (dd, J=2.4, 8.2 Hz, 1H), 4.72 (s , 2H), 3.90 - 3.84 (s, 2H), 1.70 (s, 1H).

[0246] Preparation of 6-(4-methylpiperone-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (intermediate 113) step 1; 6-(4-methylpiperone-1-yl) -1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid methyl ester (intermediate 114) to 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (807 mg, 3.00 mmol) in toluene (10 mL) was added Pd2(dba)3 (275 mg, 0.300 mmol), BINAP (560 mg, 0.900 mmol) and sodium tertiary butoxide (403 mg, 4.20 mmol) . The reaction mixture was sparged with nitrogen, then 1-methylpiperene (0.37 mL, 3.30 mmol) was added and the reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was cooled to room temperature and filtered through a pad of celite followed by washing with MeOH. The combined organic phases were concentrated in vacuo and the residue was purified by FCC (0-100% EtOAc / cyclohexane, then 0-100% MeOH / EtOAc). The material was used in the next step without further purification.

[0247] Step 2; 6-(4-methylpiper-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (intermediate 113) was dissolved in LiOH (314 mg, 13.1 mmol) in water (1 mL) was added intermediate 114 (1200 mg, 4.37 mmol) in THF (1 mL). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was concentrated in vacuo. The residue was washed with water and the aqueous phase was adjusted to pH 7 with 1M HCl(aq) and washed with DCM. The aqueous fractions were concentrated in vacuo to give a mixture of product and inorganic salt. The material was used in the next step without further purification.

[0248] Preparation of 7-(2-methoxyethoxy) imidazo[1,2-a]pyridine-3-carboxylic acid (intermediate 115) step 1 - 7-hydroxyimidazo[1,2-a ]pyridine-3-carboxylic acid ethyl ester (intermediate 116) To a solution of 2-aminopyridin-4-ol (400 mg, 3.63 mmol) in EtOH (12 mL) was added 2-chloro-3-oxo yl-propionate ethyl ester (547 mg, 3.63 mmol), and the mixture was heated to 80 °C and stirred overnight. The mixture was concentrated and the residue was triturated in EtOAc, the solid was collected and purified by silica FCC (25 g, 0-10% MeOH in DCM, 10 CV) followed by concentration to give the title compound (367 mg, 1.78 mmol, 49%). ¹H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 9.19 (d, J=8.0 Hz, 1H), 8.67 (s, 1H), 7.25 - 7.18 (m, 2H), 4.44 - 4.38 ( m, 2H), 1.39 - 1.35 (m, 3H).

[0249] Step 2 - Ethyl 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Intermediate 117) to Intermediate 116 (365 mg, 1.77 mmol , 1.00 equiv) in DMF (6.00 mL) were added KCO (367 mg, 2.66 mmol, 1.50 equiv) and 2-bromoethylmethyl ether (0.18 mL, 1.95 mmol, 1.10 equiv) and the mixture was heated to 85°C and stirred overnight. The reaction mixture was diluted in EtOAc and washed with water, water / brine 1:1, brine, dried over MgSO4, filtered and concentrated to give the title compound (202 mg, 0.764 mmol, 43%). ¹H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J=7.7 Hz, 1H), 8.17 (s, 1H), 7.24 (d, J=2.3 Hz, 1H), 6.97 (dd, J=2.6, 7.7 Hz, 1H), 4.38 - 4.25 (m, 4H), 3.74 - 3.71 (m, 2H), 1.35 (t, J=7.1 Hz, 3H).

[0250] Step 3 - 7-(2-Methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate 115) to Intermediate 117 (200 mg, 0.757 mmol, 1.00 eq) in THF (4 mL) was added a solution of LiOH monohydrate (79 mg, 1.89 mmol, 2.50 eq) in water (1 mL) and the mixture was stirred at room temperature overnight. The reaction was then heated to 50 °C for 1 hour. The reaction mixture was acidified to pH 2 with 2M aqueous HCl and extracted with EtOAc, the organic layer was washed with brine, dried and concentrated. 18 mg of solid were recovered. The aqueous layer was concentrated, then triturated with MeOH and concentrated to afford the title compound (178 mg, quantitative yield). ¹H NMR (400 MHz, DMSO-d6) δ 9.23 - 9.21 (m, 1H), 8.52 (s, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.20 (dd, J=2.5, 7.7 Hz, 1H), 4.37 - 4.33 (m, 2H), 3.76 - 3.72 (m, 2H), 3.35 - 3.34 (m, 3H).

[0251] The intermediates reported in the table below were prepared via nucleophilic substitution as described for intermediate 115, steps 1-3, in step 2 using the corresponding commercially available alkyl chlorides. Such procedures may involve minor changes. Intermediate number structure step 2 SM amount (Yield) step 3 Product amount (yield) material 118 4-(2-Chloroethyl)line: 180 mg, 1.2 mmol Intermediate 116: 225 mg, 1.1 mmol (182g, 52%) 163mg (quantitative) ¹H NMR (400 MHz, DMSO-d 6 ) δ 11.96 - 11.81 (s, 1H), 9.25 - 9.21 (d, 1H), 8.45 - 8.41 (s 1H), 7.40 - 7.37 (d, 1H), 7.18 - 7.13 (dd 1H), 4.70 - 4.65 (t , 2H), 4.01 - 3.96 (m, 4H), 3.66 - 3.60 (t, 4H)

[0252] The intermediates reported in the table below were prepared as described for intermediate 115, steps 1-3, using the corresponding commercially available aminopyridin-alcohol in step 1 and applying the corresponding electrophile in step 2. Such procedures may involve minor changes. Intermediate number structure step 1 SM amount (Yield) step 2 SM amount (Yield) step 3 Product amount (yield) material 119 6-aminopyridin-3-ol: 1.00 g, 9.1 mmol 2-Chloro-3-oxo-propionic acid ethyl ester: 1.37 g, 9.08 mmol (0.90g, 48%) Product Step 1: 100 mg, 0.485 mmol Ethyl carbonate: 47 mg, 0.533 mmol (92mg 76%) 80mg (quantitative) ¹H NMR (400 MHz, DMSO-d 6) δ 8.88 (d, J=2.1 Hz, 1H), 8.23 ​​(s, 1H), 7.76 (d, J=9.7 Hz, 1H), 7.41 (dd, J=2.5, 9.7 Hz, 1H), 4.99 (t , J=5.5 Hz, 1H), 4.38 (q, J=7.1 Hz, 2H), 4.08 (t, J=4.8 Hz, 2H), 3.81 - 3.76 (m, 2H), 1.36 (t, J=7.2 Hz , 3H)

[0253] Preparation of 6-((dimethylamino)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid (intermediate 120) step 1; 6-(hydroxymethyl)imidazo[ 1,2-a] Ethyl pyridine-3-carboxylate (intermediate 121) was dissolved in 2-amino-5-pyridinemethanol (0.50 g, 4.03 mmol) and potassium (Z)-2-chloro- To a suspension of 3-ethoxy-3-oxo-prop-1-ene-1-olate (1.52 g, 8.06 mmol) in EtOH (5.0 mL) was added dropwise sulfuric acid (0.21 mL, 4.03 mmol ). The reaction mixture was stirred at 20 °C for 15 minutes 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 afford the title product (645 mg, 73%). ¹H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 8.27 - 8.26 (m, 1H), 7.68 (d, J=9.3 Hz, 1H), 7.45 (dd, J=1.6, 9.2 Hz, 1H) , 4.77 (s, 2H), 4.41 (q, J=7.2 Hz, 2H), 2.63 (s, 1H), 1.43 (t, J=7.2 Hz, 3H).

[0254] Step 2; Ethyl 6-formylimidazo[1,2-a]pyridine-3-carboxylate (Intermediate 122) to Intermediate 121 (460 mg, 2.09 mmol) in DCM (25 mL) To the mixture in was added manganese(IV) oxide (1816 mg, 20.9 mmol) and the reaction was stirred at room temperature for 3 days. The reaction mixture was filtered through celite and washed with DCM. The filtrate was concentrated under reduced pressure to obtain the title compound (414 mg, 91%). ¹H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 9.85 (s, 1H), 8.38 (s, 1H), 7.92 (d, J=9.7 Hz, 1H), 7.81 (d, J=9.3 Hz , 1H), 4.47 (q, J=7.2 Hz, 2H), 1.46 (t, J=7.1 Hz, 3H)

[0255] Step 3; Ethyl 6-((dimethylamino)methyl)imidazo[1,2-a]pyridine-3-carboxylate (intermediate 123) to intermediate 122 (210 mg, 0.962 mmol) in THF (2.5 mL) was added 2M dimethylamine (2.2 mL, 4.33 mmol). The reaction mixture was stirred at RT for 16 hours. 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 hours. The reaction mixture was diluted with water (10 mL) and adjusted to pH 8-9 by addition of saturated NaHCO 3 (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 afford the title compound (114 mg, 61%). ¹H NMR (400 MHz, CDCl3) δ 9.23 (s, 1H), 8.29 - 8.28 (m, 1H), 7.72 - 7.69 (m, 1H), 7.52 - 7.48 (m, 1H), 4.42 (q, J=7.2 Hz, 2H), 3.56 (s, 2H), 2.33 (s, 6H), 1.43 (t, J=7.2 Hz, 3H)

[0256] Step 4: 6-((Dimethylamino)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate 120) was dissolved in 2 M NaOH (1.2 mL, 2.36 mmol) To a solution in MeOH (4.50 mL) was added intermediate 123 (144 mg, 0.582 mmol) and the resulting mixture was stirred at room temperature for three days. The reaction mixture was concentrated. The pH was acidified to pH 2 with 2M aqueous HCl and concentrated under reduced pressure to afford the title compound which was used in the next step without purification (quantitative yield). ¹H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.58 (s, 1H), 8.56 (s, 1H), 8.08 (dd, J=1.5, 9.3 Hz, 1H), 8.03 (dd, J=0.7, 9.3 Hz, 1H), 4.57 - 4.53 (m, 2H), 2.79 (s, 3H), 2.78 (s, 3H)

[0257] Preparation of pyrazolo[1,5-a]pyroxet-3-carbaldehyde (intermediate 124) step 1; pyrazolo[1,5-a]pyroxet-3-ylmethanol (intermediate 125) To a solution of pyrazolo[1,5-a]pyridine-3-carboxylic acid (130 mg, 0.797 mmol) in THF (20 mL) cooled to 0°C was added isobutyl chloroformate (0.12 mL, 0.956 mmol) and 4-methylline (0.11 mL, 0.956 mmol). 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 and the organics were extracted with EtOAc before concentration under reduced pressure to give the desired product (50 mg, 42%) which was used directly in the next step without purification.

[0258] Step 2; Pyrazolo[1,5-a]pyrox-3-carbaldehyde (Intermediate 124) Intermediate 125 (60 mg, 0.402 mmol) was dissolved in THF (5.0 mL) and manganese oxide was added (IV) (350 mg, 4.02 mmol), then stirred at reflux for 2 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure to afford the title compound (30 mg, 51%). ¹H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 9.72 (d, J=1.2 Hz, 1H), 8.51 (dd, J=1.5, 4.7 Hz, 1H), 8.49 (s, 1H), 8.22 (d, J=4.4 Hz, 1H).

[0259] Preparation of 3-(4-methylpiper-1-yl)-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-5-carbaldehyde (Intermediate 126) Step 1; 3-Bromo-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-5-carboxylic acid methyl ester (Intermediate 127 ) Dissolve methyl 3-bromo-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (512 mg, 2.00 mmol) in DMF (6.0 mL) and cool to 0 °C, followed by NaH ( 60%, 96 mg, 2.40 mmol), then SEM-Cl (0.71 mL, 4.00 mmol, 2.00 equiv) was added and stirred at room temperature for 3 hours. The reaction mixture was diluted with water, 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) to afford the title compound (513 mg, 66%). ¹H NMR (400 MHz, CDCl3) δ 9.21 (d, J=2.0 Hz, 1H), 8.63 (d, J=2.0 Hz, 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)

[0260] Step 2; 3-(4-methylpiper-1-yl)-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-5 -Methyl carboxylate (Intermediate 128) Intermediate 127 (200 mg, 0.518 mmol), Cs2CO3 (253 mg, 0.777 mmol), 1-methylpiperene (0.29 mL, 2.59 mmol) and XantPhos (45 mg, 0.0777 mmol) in 1,4-dioxane (4 mL) was degassed under N2, then Pd2(dba)3 (24 mg, 0.0259 mmol) was added, the tube was capped and the mixture was stirred at 100 °C overnight. The mixture was concentrated to dryness. The residue was purified by FCC (0-50% [75:15:10 EtOAc:EtOH:7M NH3 / MeOH] in cyclohexane) to afford the title compound (133 mg, 63%). ¹H NMR (400 MHz, CDCl3) δ 9.08 (d, J=2.0 Hz, 1H), 8.72 (d, J=2.0 Hz, 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)

[0261] Step 3; [3-(4-methylpiperone-1-yl)-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine- 5-yl]methanol (Intermediate 129) A 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 RT. The reaction mixture was quenched with water followed by 0.5 mL NaOH 2N. The mixture was stirred for 10 min, then MgSO4 was added. The mixture was filtered and concentrated to dryness to afford (45 mg, 100%) which was used in the next step without purification.

[0262] Step 4; 3-(4-methylpiper-1-yl)-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-5 -Formaldehyde (Intermediate 126) Following Intermediate 125 starting from Intermediate 129 (45 mg, 0.119 mmol) in 2-methyl-THF (1.0 mL) at 50 °C gave the title compound 2 h (35 mg, 78%) and was used directly in the next step without purification.

[0263] Preparation of 2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-amine (intermediate 130) step 1: 4-amino-N-methoxy- N-Methyl-6-(trifluoromethyl)picolinamide (Intermediate 131) was prepared from 4-amino-6-(trifluoromethyl)picolinic acid (445 mg, 2.16 mmol) and Preparation of N,O-dimethylhydroxylamine hydrochloride (232 mg, 2.37 mmol). Purification by silica FCC (80 g cartridge, 0-50% EtOAc in cyclohexane (+0.1% NEt3)) afforded the title compound (369 mg, 68%). ¹H NMR (400 MHz, DMSO-d6) δ 6.96 (d, J=2.1 Hz, 1H), 6.84 - 6.78 (m, 3H), 3.67 (s, 3H), 3.24 (s, 3H)

[0264] Step 2: 4-Amino-6-(trifluoromethyl)pyridinecarbaldehyde (Intermediate 132) to a stirred solution of Intermediate 131 (308 mg, 1.24 mmol) in THF (4.82 mL) (in (cooled in an ice / water bath) was added LiAlH4 (2M in THF, 0.62 mL, 1.24 mmol) dropwise, 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 allowed to warm 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 in vacuo to afford the title compound (252 mg, >100%) which was used in the next step without purification. LC-MS (ESI) Method 12: tR = 0.95 min; m / z (M+1) = 191

[0265] Step 3: 2-((Dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-amine (Intermediate 130) From Intermediate 132 (126 mg , 0.663 mmol) and dimethylamine (2M solution in THF) (0.33 mL, 0.663 mmol). Purification by silica FCC (12 g cartridge, 0-8% 2M NH3 / MeOH in DCM) afforded the title compound (65 mg, 44%). ¹H NMR (400 MHz, DMSO-d6) δ 6.78 - 6.77 (m, 2H), 6.49 (s, 2H), 3.34 (s, 2H), 2.18 (s, 6H).

[0266] Example 1; Preparation of 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methylpiper-1-yl)methyl)-5- (Trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide Example 1 Step 1; 4,7-Dihydrothieno [2,3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tertiary butyl) 3-methyl ester (intermediate 35) converts 6-(tertiary 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 (volume: 15 ml ), followed by the addition of CH3I (0.413 ml, 6.61 mmol) in one portion. The solution was stirred overnight at RT. The reaction mixture was diluted with Et2O (20 mL), 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 material was purified by direct phase FCC (silica, gradient n-heptane:AcOEt from 100:0 to 80:20) to provide the title compound (1.21 g, 4.07 mmol, 92% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.98 (s, 1H) 4.62 (br s, 2H) 3.84 (s, 1H) 3.67 (t, J=5.70 Hz, 1H) 2.99 (br t, J=5.48 Hz, 1H) 1.49 (s, 1H)

[0267] Step 2; 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid methyl ester hydrochloride (intermediate 36) Intermediate 35 (1.21 g, 4.07 mmol) was dissolved in concentrated HCl (7 ml, 230 mmol) and the reaction was stirred at RT for 10 min. Ethanol was then added under the reaction and the solvent was evaporated under reduced pressure until the title compound (0.921 g, 3.94 mmol, 97% yield) was obtained. The compound was used in the next step without further purification.

[0268] Step 3; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid Methyl ester (Intermediate 37) Imidazo[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) Dissolved in 6 mL DCM / DMF 1:1, then added DIPEA (0.598 ml, 3.42 mmol) in one portion. The solution was stirred at room temperature for 1 hour. The crude material was diluted with DCM (10 mL), then washed with a saturated solution of NH4Cl (2x 15 mL) and a saturated solution of NaHCO3 (2x15 mL). The organic phase was dried over Na2SO4, filtered and concentrated to dryness. The crude material was filtered by reverse phase FCC (C18 column, gradient A:B, 100:0 to 0:100, eluent A: H2O:ACN:HCOOH 95:5:0.1, eluent B:H2O:ACN: HCOOH 5:95:0.1) to afford the title compound (155.2 mg, 0.455 mmol, 53.1 % yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.05 - 9.10 (m, 1H) 8.04 (s, 1H) 7.99 - 8.03 (m, 1H) 7.81 (d,J=8.99 Hz, 1H) 7.42 - 7.50 (m, 1H) ) 7.04 (t,J=6.91 Hz, 1H) 5.03 (s, 2H) 4.09 (t,J=5.81 Hz, 2H) 3.87 (s, 3H) 3.22 (br t,J=5.59 Hz, 2H)

[0269] Step 4: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methylpiper-1-yl)methyl)-5-( Trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 1) 3-((4- Methylpiperone-1-yl)methyl)-5-(trifluoromethyl)aniline (84 mg, 0.308 mmol) was dissolved in anhydrous THF (volume: 6 ml, ratio: 1.500), and the mixture was dissolved in - Stirred at 78°C for 15 min, then added n-BuLi 2.5M / hexane (0.098 ml, 0.246 mmol) dropwise within 5 min and the solution was stirred at -78°C for 1 h. A solution of Intermediate 37 (42 mg, 0.123 mmol) in THF (volume: 6 ml) was added dropwise for 10 min, then the temperature was increased at room temperature and the reaction was stirred for another 1 h. 10 mL of water was added onto the solution and the solvent was evaporated. The crude material was filtered by reverse phase FCC (C18 column, gradient A:B, 100:0 to 0:100, wherein eluent A=HO:ACN:HCOOH 95:5:0.1 and eluent B=HO:ACN :HCOOH 5:95:0.1) to afford the title compound (32 mg, 0.055 mmol, 45% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.34 (s, 1H), 8.93 (d, J=6.80 Hz, 1H), 8.18 (s, 1H), 8.10 (s, 2H), 7.90 (s, 1H ), 7.70 (d, J=8.99 Hz, 1H), 7.44 (br t, J=7.80 Hz, 1H), 7.30 (s, 1H), 7.07 (t, J=6.72 Hz, 1H), 4.99 (br s , 2H), 3.95 (br t, J=5.59 Hz, 2H), 3.28 (s, 2H), 3.01 - 3.10 (m, 2H), 2.27 - 2.43 (m, 8H), 2.15 (br s, 3H) LC - MS (ESI) method 1: tR = 0.92 min; m / z (M+1) = 583.2.

[0270] Example 2; Preparation of N-(3-(tertiary 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 Step 1; 4,5,6,7-tetrahydrothiophene [2,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride (intermediate 38) to 4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-di To a solution of 6-(tert-butyl) 3-ethyl carboxylic acid (4.88 g, 15.67 mmol) in Et2O (volume: 78 ml) was added 4N HCl in dioxane (19.59 ml, 78 mmol) and the reaction The mixture was stirred overnight at RT. The solid was isolated and dried under reduced pressure to afford the title compound (3.58 g, 14.45 mmol, 92% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 2H), 8.31 (s, 1H), 4.35 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.39 - 3.34 (m, 2H), 3.07 (t, J = 6.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H).

[0271] 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) 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 every other week. The crude material 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 (3x50 mL), the combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by direct phase FCC (silica, gradient DCM:MeOH, 100:0 to 90:10) to afford the title compound (1.75 g, 4.92 mmol, 87% yield). 1H NMR (300 MHz, CDCl3) δ 9.03 (dt, J = 7.0, 1.2 Hz, 1H), 8.03 (d, J = 0.8 Hz, 1H), 7.98 (s, 1H), 7.72 (dt, J = 9.0, 1.2 Hz, 1H), 7.38 (ddd, J = 9.0, 6.8, 1.3 Hz, 1H), 6.97 (td, J = 6.9, 1.3 Hz, 1H), 5.01 (d, J = 1.8 Hz, 2H), 4.32 ( q, J = 7.1 Hz, 2H), 4.08 (t, J = 5.8 Hz, 2H), 3.20 (tt, J = 5.9, 1.7 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H).

[0272] Step 3; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid Sodium (Intermediate 40) To a solution of Intermediate 39 (1.75 g, 4.92 mmol) in MeOH (49.2 ml) was added 1M NaOH (4.92 ml, 4.92 mmol) and the reaction mixture was stirred at room temperature every other week. The solvent was evaporated under reduced pressure to afford the title compound in quantitative yield. 1H NMR (300 MHz, DMSO-d6) δ 8.98 - 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, 1.3 Hz, 1H), 4.93 (s, 2H), 3.92 (t, J = 5.8 Hz, 2H), 3.12 (t, 5.8 Hz, 2H).

[0273] Step 4; N-(3-(tertiary 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) From sodium intermediate 40 (100 mg, 0.286 mmol) and 3-(tertiary butyl)-1-(p-tolyl)-1H-pyrazol-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 minutes and the phases were separated. The organic phase was washed with 5% citric acid, water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford the title compound (23.1 mg, 0.043 mmol, 15% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.94 (dt, J = 7.0, 1.2 Hz, 1H), 8.10 (s, 1H), 8.04 (s, 1H), 7.73 (dt, J = 9.0, 1.2 Hz, 1H), 7.46 (ddd, J = 9.0, 6.8, 1.3 Hz, 1H), 7.43 - 7.36 (m, 2H), 7.25 (d, J = 8.2 Hz, 2H), 7.09 (td , J = 6.9, 1.3 Hz, 1H), 6.34 (s, 1H), 4.98 (s, 2H), 3.93 (t, J = 5.6 Hz, 2H), 2.92 (s, 2H), 2.31 (s, 3H) , 1.30 (s, 9H). LC-MS (ESI) method 2: tR = 2.18 min; m / z (M+1) = 539.0.

[0274] The compounds reported in the table below were prepared via amide group coupling as described in Example 2, Steps 1-4, applying the corresponding commercially available or previously synthesized amine in Step 4. Modifications of coupling reagents (eg, HATU instead of T3P), salt release, or chromatographic purification conditions (eg, preparative HPLC or flash chromatography) are reported in the table. For Example 44 and Example 45, absolute configuration was assigned by inference, non-racemic chemistry was performed on reagents of known absolute configuration. Example number structure General procedure - Reagent volume Product amount (yield) Purification method material 3 General procedure G Amine: 43.9 mg (1.0 equiv) Intermediate 40: 100 mg (1.0 equiv) 21.7mg (16%) Preparative HPLC 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.03 (s, 1H), 8.95 (dt, J = 7.0, 1.2 Hz, 1H), 8.17 (s, 1H), 8.13 (s, 1H), 7.73 (dt, J = 9.1, 1.2 Hz, 1H) , 7.46 (ddd, J = 9.1, 6.8, 1.3 Hz, 1H), 7.09 (td, J = 6.9, 1.3 Hz, 1H), 6.09 (s, 1H), 5.02 (s, 2H), 3.97 (t, J = 5.7 Hz, 2H), 3.62 (s, 3H), 3.05 (s, 2H), 1.23 (s, 9H). LC-MS (ESI): Method 3 t R = 2.80 min; m / z (M+1) = 463. 4 General procedure G Amine: 54.7 mg, 0.286 mmol) Intermediate 40: 100 mg (1.0 equiv) 18.8mg (13%) Preparative HPLC 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.21 (s, 1H), 8.96 (dt, J = 7.0, 1.3 Hz, 1H), 8.14 (d, J = 5.3 Hz, 2H), 8.07 (d, J = 2.6 Hz, 1H), 7.94 (dd , J = 9.1, 2.7 Hz, 1H), 7.73 (dt, J = 9.0, 1.2 Hz, 1H), 7.46 (ddd, J = 8.8, 6.8, 1.3 Hz, 1H), 7.27 (d, J = 9.2 Hz, 1H), 7.10 (td, J = 6.9, 1.4 Hz, 1H), 5.02 (s, 2H), 3.98 (t, J = 5.7 Hz, 2H), 3.87 (s, 3H), 3.07 (s, 2H). LC-MS (ESI): Method 3 t R = 2.80 min; m / z (M+1) = 463. 5 General procedure G Amine: 0.067 g, 0.286 mmol) Intermediate 40: 100 mg (1.0 equiv) 4mg (3%) Preparative HPLC 1 H NMR (400 MHz, MeOH-d 4 ) δ 8.96 (d, J = 6.9 Hz, 1H), 8.06 (s, 1H), 7.89 (s, 1H), 7.69 (d, J = 9.1 Hz, 1H), 7.53 (t, J = 6.5 Hz, 2H ), 7.22 (t, J = 8.7 Hz, 2H), 7.11 (t, J = 7.1 Hz, 1H), 6.39 (s, 1H), 5.04 (s, 2H), 4.04 (t, J = 5.8 Hz, 2H ), 3.02 (s, 2H), 1.36 (s, 9H). LC-MS (ESI): Method 2 t R = 2.05 min; m / z (M+1) = 543.2 6 General procedure G Amine: 61.6 mg, 0.286 mmol) Intermediate 40: 100 mg (1.0 equiv) 9.8mg (7%) Preparative HPLC + with NaHCO 3 solution washing 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.11 (s, 1H), 8.95 (dt, J = 7.0, 1.2 Hz, 1H), 8.11 (s, 1H), 8.06 (s, 1H), 7.77 - 7.69 (m, 1H), 7.57 - 7.43 ( m, 5H), 7.36 - 7.29 (m, 1H), 7.10 (td, J = 6.9, 1.3 Hz, 1H), 6.37 (s, 1H), 5.00 (s, 2H), 3.94 (t, J = 5.6 Hz , 2H), 2.93 (s, 2H), 1.32 (s, 9H). LC-MS (ESI): Method 3 t R = 2.44 min; m / z (M+1) = 525.2 7 General procedure G Amine: 0.036 mL, 0.286 mmol) Intermediate 40: 100 mg (1.0 equiv) 23mg (17%) Preparative HPLC 1 H NMR (300 MHz, MeOH-d 4 ) δ 8.98 (dt, J = 7.1, 1.2 Hz, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 8.06 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.69 (dt, J = 9.1, 1.2 Hz, 1H), 7.53 (ddt, J = 10.4, 4.1, 2.1 Hz, 2H), 7.41 (d, J = 7.8 Hz, 1H), 7.11 (td, J = 6.9, 1.2 Hz, 1H), 5.08 (s, 2H), 4.10 (t, J = 5.8 Hz, 2H), 3.18 (t, J = 6.0 Hz, 2H). LC-MS (ESI): Method 2 t R = 1.96 min; m / z (M+1) = 471. 8 General procedure G Amine: (0.046 mL, 0.344 mmol) Intermediate 40: 100 mg (1.0 equiv) 35mg (25%) Preparative HPLC 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.36 (s, 1H), 8.96 (dt, J = 7.0, 1.2 Hz, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 7.89 (s, 1H), 7.78 - 7.65 (m, 2H), 7.53 - 7.40 (m, 2H), 7.15 - 7.02 (m, 2H), 5.02 (s, 2H), 3.98 (t, J = 5.8 Hz, 2H), 3.06 (s, 2H). LC-MS (ESI): Method 4 t R = 2.46 min; m / z (M+1) = 487.0 9 General procedure G Amine: (0.083 g, 0.429 mmol) Intermediate 40: 100 mg (1.0 equiv) T3P: 2.0 equivalent 36mg (25%) Preparative HPLC 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.35 (s, 1H), 8.95 (dt, J = 7.0, 1.2 Hz, 1H), 8.36 (s, 1H), 8.13 (s, 1H), 7.73 (dt, J = 9.0, 1.2 Hz, 1H) , 7.46 (ddd, J = 8.8, 6.8, 1.3 Hz, 1H), 7.14 - 7.05 (m, 2H), 5.02 (s, 2H), 3.97 (t, J = 5.7 Hz, 2H), 3.07 (s, 2H ), 1.58 (s, 6H). LC-MS (ESI): Method 3 t R = 2.35 min; m / z (M+1) = 504.1 10 General procedure G Amine (0.059 mL, 0.429 mmol) Intermediate 40: 75 mg 12.7mg (12%) Preparative HPLC 1H NMR (300 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.96 (d, J = 7.1 Hz, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 7.78 - 7.64 (m, 3H), 7.46 (ddd, J = 8.8, 6.8, 1.3 Hz, 1H), 7.15 - 7.01 (m, 2H), 5.02 (s, 2H), 3.98 (t, J = 5.8 Hz, 2H), 3.07 (s, 2H)LC-MS (ESI)：方法2tR= 2.13 min；m / z (M+1) = 505.0 11 General procedure G Amine (Intermediate 26) (118 mg, 0.420 mmol) Intermediate 40: 140 mg, 0.420 mmol 8mg 4% reverse phase FCC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.36 (s, 1H), 8.96 (td, J=1.0, 7.0 Hz, 1H), 8.22 (s, 1H), 8.14 - 8.11 (m, 2H), 7.95 (s, 1H), 7.73 (td, J=1.0, 9.0 Hz, 1H), 7.47 (ddd, J=1.5, 7.0, 9.0 Hz, 1H), 7.34 (s, 1H), 7.10 (dt, J=1.0, 7.0 Hz, 1H), 5.03 (s , 2H), 3.99 (t, J=6.0 Hz, 2H), 3.65 (s, 2H), 3.11 - 3.05 (m, 2H), 2.48 - 2.43 (m, 4H), 1.75 - 1.67 (m, 4H). LC-MS (ESI): Method 5 t R = 2.85 min; m / z (M+1) = 554.2 12 General procedure G Amine (Intermediate 2) (38 mg, 0.153 mmol) Intermediate 40: 51 mg (1.0 equiv) 31mg 36% filter after water quenching ¹H NMR (400 MHz, CDCl 3 ) δ 9.04 (d, J=7.0 Hz, 1H), 7.98 (s, 1H), 7.86 (dd, J=2.6, 8.9 Hz, 1H), 7.75 (s, 1H), 7.72 - 7.68 (m, 2H) , 7.66 (s, 1H), 7.40 - 7.35 (m, 1H), 6.99 - 6.92 (m, 2H), 5.02 (s, 3H), 4.12 - 4.06 (m, 3H), 4.00 - 3.93 (m, 3H) , 3.23 (t,, J= 5.7Hz, 2H), 2.23 - 2.17 (m, 2H). LC-MS (ESI): Method 6 t R = 4.39 min; m / z (M+1) = 557.3 13 General procedure G Amine (36 mg, 0.153 mmol, intermediate 3) Intermediate 40: 50 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 14mg 16% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.26 (s, 1H), 8.97 (d, J=6.9 Hz, 1H), 8.16 - 8.12 (m, 3H), 7.90 (dd, J=2.6, 9.0 Hz, 1H), 7.75 (d, J= 9.0 Hz, 1H), 7.50 - 7.45 (m, 1H), 7.13 - 7.09 (m, 1H), 6.92 (d, J=9.0 Hz, 1H), 5.43 - 5.39 (m, 1H), 5.03 - 4.94 (m , 4H), 4.56 (dd, J=5.0, 7.7 Hz, 2H), 3.99 (t, J=5.7 Hz, 2H), 3.08 - 3.07 (m, 2H) LC-MS (ESI): Method 7 t R = 3.74 min; m / z (M+1) = 543.3 14 General procedure G Amine (Intermediate 4) (43 mg, 0.153 mmol) Intermediate 40: 50 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 12mg 13% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.24 (s, 1H), 8.98 (d, J=6.9 Hz, 1H), 8.16 (d, J=7.0 Hz, 2H), 8.08 (d, J=2.6 Hz, 1H), 7.96 (dd, J =2.5, 9.0 Hz, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.50 - 7.45 (m, 1H), 7.33 (d, J=9.2 Hz, 1H), 7.13 - 7.09 (m, 1H) , 5.05 (s, 2H), 4.71 (dd, J=6.0, 8.0 Hz, 2H), 4.47 (t, J=6.1Hz, 2H), 4.32 (d, J=6.3 Hz, 2H), 3.99 (t, J=5.6 Hz, 2H), 3.46 - 3.39 (m, 1H), 3.08 (s, 2H) LC-MS (ESI): Method 6 t R = 4.27 min; m / z (M+1) = 557.4 15 General procedure G Amine (Intermediate 5) (36 mg, 0.153 mmol) Intermediate 40: 50 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 23mg 27% Preparative HPLC ¹H NMR (400 MHz, CDCl 3 ) δ 9.04 (d, J=7.0 Hz, 1H), 7.98 (s, 1H), 7.81 (dd, J=2.6, 8.9 Hz, 1H), 7.73 - 7.70 (m, 2H), 7.65 (d, J= 3.1 Hz, 2H), 7.37 (t, J=7.9, 7.9 Hz, 1H), 7.05 (d, J=8.9 Hz, 1H), 6.97 (t, J=6.7 Hz, 1H), 5.04 (s, 2H) , 4.21 (t, J=4.8 Hz, 2H), 4.10 (t, J=5.8 Hz, 2H), 3.79 (t, J=4.8 Hz, 2H), 3.47 (s, 3H), 3.23 (t, J= 5.6 Hz, 2H). LC-MS (ESI): Method 6 t R = 4.51 min; m / z (M+1) = 545. 4 16 General procedure G Amine (Intermediate 9) (34 mg, 0.153 mmol) Intermediate 40: 50 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 27mg 33% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.21 (s, 1H), 8.97 (d, J=7.0 Hz, 1H), 8.15 (d, J=3.0 Hz, 2H), 8.07 (d, J=2.6 Hz, 1H), 7.93 (dd, J =2.6, 9.0 Hz, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.50 - 7.45 (m, 1H), 7.30 (d, J=9.0 Hz, 1H), 7.13 - 7.09 (m, 1H) , 5.03 (s, 2H), 4.86 (t, , J=5.5 Hz, 1H), 4.12 (t, J = 5.0 Hz, 2H), 3.99 (t, J=5.0 Hz, 2H), 3.74 (q, J =5.2 Hz, 2H), 3.08 (s, 2H). LC-MS (ESI): Method 7 t R = 3.26 min; m / z (M+1) = 531.3 17 General procedure H Amine (25 mg, 0.153 mmol) Intermediate 40: 50 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 10mg 14% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.81 (s, 1H), 8.97 (td, J=1.0, 7.0 Hz, 1H), 8.67 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.28 (d, J=2.0 Hz , 1H), 8.15 (s, 1H), 8.00 (dd, J=2.0, 5.5 Hz, 1H), 7.75 (td, J=1.0, 9.0 Hz, 1H), 7.48 (ddd, J=1.5, 7.0, 9.0 Hz, 1H), 7.11 (dt, J=1.5, 7.0 Hz, 1H), 5.04 (s, 2H), 4.00 (t, J=5.5 Hz, 2H), 3.10 (t, J=5.5 Hz, 2H) LC-MS (ESI): Method 6 t R = 4.12 min; m / z (M+1) = 472.2 18 General procedure H Amine (63 mg, 0.153 mmol) Intermediate 40: 50 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 35mg 39% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.37 (s, 1H), 8.98 (td, J=1.0, 7.0 Hz, 1H), 8.20 (s, 1H), 8.18 (d, J=2.0 Hz, 1H), 8.15 (s, 1H), 7.98 (dd, J=2.0, 8.5 Hz, 1H), 7.75 (td, J=1.0, 9.0 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.50 - 7.45 (m, 1H), 7.11 ( dt, J=1.5, 7.0 Hz, 1H), 5.05 (s, 2H), 4.00 (t, J=5.5 Hz, 2H), 3.57 (s, 2H), 3.09 (t, J=5.5 Hz, 2H), 2.45 - 2.27 (m, 8H), 2.17 (s, 3H) LC-MS (ESI): Method 6 t R = 4.27 min; m / z (M+1) = 583.3 19 General procedure H Amine (Intermediate 17) (32 mg, 0.153 mmol) Intermediate 40: 50 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 25mg 33% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.38 (s, 1H), 8.98 (td, J=1.0, 7.0 Hz, 1H), 8.24 (s, 1H), 8.15 (s, 1H), 8.14 (s, 1H), 7.99 (s, 1H) , 7.75 (td, J=1.0, 9.0 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.35 (s, 1H), 7.11 (dt, J=1.0, 7.0 Hz, 1H), 5.05 (s, 2H ), 4.00 (t, J=5.5 Hz, 2H), 3.48 (s, 2H), 3.13 - 3.07 (m, 2H), 2.20 (s, 6H) LC-MS (ESI): Method 7 t R = 2.76 min; m / z (M+1) = 528.2 20 General procedure H Amine (Intermediate 12) (38 mg, 0.145 mmol) Intermediate 40: 50 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 38mg 47% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.40 (s, 1H), 8.98 (d, J=7.0 Hz, 1H), 8.23 ​​(s, 1H), 8.15 (s, 2H), 7.98 (s, 1H), 7.75 (td, J=1.0, 9.0 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.37 (s, 1H), 7.12 (dt, J=1.5, 7.0 Hz, 1H), 5.04 (s, 2H), 4.00 (t, J=6.0 Hz, 2H), 3.61 (t, J=4.5 Hz, 4H), 3.56 (s, 2H), 3.11 - 3.08 (m, 2H), 2.43 - 2.37 (m, 4H) LC-MS (ESI): Method 7 t R = 2.80 min; m / z (M+1) = 570.3 twenty one General procedure H Amine (25 mg, 0.153 mmol) Intermediate 40: 50 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 2.2mg 3% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6) δ 11.67 (s, 1H), 9.17 (s, 1H), 8.97 (td, J=1.0, 7.0 Hz, 1H), 8.57 (d, J=1.0 Hz, 1H), 8.54 (s, 1H), 8.15 (s, 1H), 7.75 (td, J=1.0, 9.0 Hz, 1H), 7.48 (ddd, J=1.5, 7.0, 9.0 Hz, 1H), 7.11 (dt, J=1.0, 7.0 Hz, 1H), 5.05 (s, 2H), 4.00 (t, J=6.0 Hz, 2H), 3.12 (t, J=5.5 Hz, 2H) LC-MS (ESI): Method 7 t R = 3.52 min; m / z (M+1) = 473.4 twenty two General procedure H Amine (Intermediate 24) (61 mg, 0.217 mmol) Intermediate 40: Intermediate 40 was used as acid deblocking salt via acid wash 17mg 14% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.36 (s, 1H), 8.98 (d, J=7.0 Hz, 1H), 8.20 (s, 1H), 8.17 (d, J=2.0 Hz, 1H), 8.15 (s, 1H), 7.98 (dd , J=2.0, 8.5 Hz, 1H), 7.77 - 7.71 (m, 2H), 7.50 - 7.45 (m, 1H), 7.11 (dt, J=1.0, 7.0 Hz, 1H), 5.04 (s, 2H), 4.02 - 3.97 (m, 2H), 3.71 (s, 2H), 3.10 - 3.06 (m, 2H), 2.50 - 2.45 (m, 4H), 1.76 - 1.71 (m, 4H) LC-MS (ESI): Method 7 t R = 2.70 min; m / z (M+1) = 554.3 twenty three General procedure H Amine (Intermediate 25) (64 mg, 0.217 mmol) Intermediate 40: 70 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 22mg 18% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.38 (s, 1H), 8.98 (td, J=1.0, 7.0 Hz, 1H), 8.20 - 8.18 (m, 2H), 8.15 (s, 1H), 7.99 (dd, J=2.0, 8.5 Hz, 1H), 7.76 - 7.71 (m, 2H), 7.50 - 7.46 (m, 1H), 7.11 (dt, J=1.0, 7.0 Hz, 1H), 5.03 (s, 2H), 4.00 (t, J=5.5 Hz , 2H), 3.63 - 3.59 (m, 6H), 3.11 - 3.07 (m, 2H), 2.42 - 2.37 (m, 4H). LC-MS (ESI): Method 7 t R = 2.67 min; m / z (M+1) = 570.3 twenty four General procedure H Amine (Intermediate 16) (44 mg, 0.153 mmol) Intermediate 40: 50 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 10mg 10% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.35 (s, 1H), 8.98 (d, J=7.0 Hz, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 7.78 - 7.74 (m, 2H), 7.68 (s, 1H) , 7.51 - 7.46 (m, 1H), 7.14 - 7.09 (m, 1H), 7.01 (s, 1H), 5.04 - 5.02 (m, 2H), 4.18 (t, J=5.7 Hz, 2H), 4.00 (t , J=5.6 Hz, 2H), 3.60 (t, J=4.6 Hz, 4H), 3.08 (s, 2H), 2.73 (t, J=5.6 Hz, 2H), 2.53 - 2.49 (m, 4H). LC-MS (ESI): Method 7 t R = 2.28 min; m / z (M+1) = 600 25 General procedure H Amine (Intermediate 17) (50 mg, 0.200 mmol) Intermediate 40: 65 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 23mg 20% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.35 (s, 1H), 8.98 (d, J=7.0 Hz, 1H), 8.21 - 8.15 (m, 2H), 7.78 - 7.74 (m, 2H), 7.67 (s, 1H), 7.51 - 7.45 ( m, 1H), 7.14 - 7.09 (m, 1H), 6.99 (s, 1H), 5.04 (s, 2H), 4.16 - 4.11 (m, 2H), 4.00 (t, J=5.8 Hz, 2H), 3.09 - 3.07 (m, 2H), 2.69 - 2.64 (m, 2H), 2.24 (s, 6H). LC-MS (ESI): Method 7 t R = 2.83 min; m / z (M+1) = 558 26 General procedure H Amine (Intermediate 18) (55 mg, 0.200 mmol) Intermediate 40: 65 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 48mg 39% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.35 (s, 1H), 8.98 (d, J=6.9 Hz, 1H), 8.21 (s, 1H), 8.15 - 8.15 (m, 1H), 7.78 - 7.74 (m, 2H), 7.67 (s, 1H), 7.50 - 7.46 (m, 1H), 7.14 - 7.09 (m, 1H), 7.00 (s, 1H), 5.04 - 5.02 (m, 2H), 4.16 (t, J=5.8 Hz, 2H), 4.03 - 3.98 (m, 2H), 3.08 (s, 2H), 2.83 (t, J=5.8 Hz, 2H), 2.57 - 2.51 (m, 4H), 1.73 - 1.68 (m, 4H). LC-MS (ESI): Method 7 t R = 2.95 min; m / z (M+1) = 584 27 General procedure H Amine (Intermediate 28) (55 mg, 0.200 mmol) Intermediate 40: 65 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash DIPEA replaces TEA 1.97mg 3% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.37 (s, 1H), 8.99 - 8.96 (m, 1H), 8.21 (s, 1H), 8.17 (d, J=2.5 Hz, 1H), 8.15 (s, 1H), 8.00 (dd, J= 2.0, 8.7 Hz, 1H), 7.75 (td, J=1.1, 9.0 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.50 - 7.45 (m, 1H), 7.11 (dt, J=1.2 , 6.9 Hz, 1H), 5.04 (s, 2H), 4.02 - 3.98 (m, 2H), 3.50 (s, 2H), 3.11 - 3.08 (m, 2H), 2.19 (s, 6H) LC-MS (ESI): Method 7 t R = 2.54 min; m / z (M+1) = 528 28 General procedure H Amine (16 mg, 0.096 mmol) Intermediate 40: 31 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash DIPEA replaces TEA 1.8mg 4% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.68 (s, 1H), 9.15 (d, J=2.4 Hz, 1H), 8.98 (td, J=1.1, 6.9 Hz, 1H), 8.72 - 8.70 (m, 1H), 8.63 - 8.60 (m, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.75 (td, J=1.1, 9.0 Hz, 1H), 7.51 - 7.46 (m, 1H), 7.12 (dt, J=1.2, 6.9 Hz , 1H), 5.05 (s, 2H), 4.03 - 3.98 (m, 2H), 3.13 - 3.07 (m, 2H). LC-MS (ESI): Method 7 t R = 3.42 min; m / z (M+1) = 472 29 General procedure H Amine (26 mg, 0.160 mmol) Intermediate 40: 52 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash Py replacement solvent and TEA 10.6mg 14% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 11.13 (s, 1H), 8.98 (td, J=1.1, 7.0 Hz, 1H), 8.68 (d, J=5.2 Hz, 1H), 8.51 (t, J=0.8 Hz, 1H), 8.45 (s , 1H), 8.15 (s, 1H), 7.75 (td, J=1.1, 9.1 Hz, 1H), 7.55 - 7.52 (m, 1H), 7.48 (ddd, J=1.3, 6.7, 9.1 Hz, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H), 5.05 (s, 2H), 4.01 (t, J=5.7 Hz, 2H), 3.15 - 3.09 (m, 2H). LC-MS (ESI): Method 6 t R = 4.41 min; m / z (M+1) = 472.3 30 General procedure H Amine (26 mg, 0.160 mmol) Intermediate 40: 52 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash DIPEA replaces TEA 9mg 12% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 11.32 (s, 1H), 9.09 (d, J=4.9 Hz, 1H), 9.00 (d, J=6.9 Hz, 1H), 8.38 (s, 1H), 8.28 - 8.24 (m, 1H), 7.83 - 7.79 (m, 1H), 7.72 (d, J=4.9 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.21 (t, J=7.1 Hz, 1H), 5.04 - 5.04 (m, 2H), 4.02 - 3.97 (m, 2H), 3.10 - 3.08 (m, 2H) LC-MS (ESI): Method 7 t R = 3.14 min; m / z (M+1) = 473 31 General procedure G Amine (Intermediate 6) (45 mg, 0.153 mmol) Intermediate 40: 50 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 7mg 8% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.21 (s, 1H), 8.97 (d, J=6.9 Hz, 1H), 8.15 (s, 2H), 8.07 (d, J=2.5 Hz, 1H), 7.91 (dd, J=2.6, 9.0 Hz , 1H), 7.75 (d, J=9.0 Hz, 1H), 7.50 - 7.45 (m, 1H), 7.20 (d, J=9.2 Hz, 1H), 7.13 - 7.09 (m, 1H), 5.05 - 4.96 ( m, 3H), 3.99 (t, J=5.6 Hz, 2H), 3.08 (m, 2H), 2.90 (dd, J=6.2, 10.5 Hz, 1H), 2.70-2.54 (m, 2H), 2.46 - 2.29 (m, 2H), 2.28 (s, 3H), 1.83 - 1.75 (m, 1H) LC-MS (ESI): Method 6 t R = 4.21 min; m / z (M+1) = 570 32 General procedure G Amine (Intermediate 7) (47 mg, 0.153 mmol) Intermediate 40: 50 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 19mg 20% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.20 (s, 1H), 8.97 (d, J=7.0 Hz, 1H), 8.15 (s, 2H), 8.07 (d, J=2.6 Hz, 1H), 7.91 (dd, J=2.5, 9.0 Hz , 1H), 7.75 (d, J=9.0 Hz, 1H), 7.50 - 7.45 (m, 1H), 7.32 (d, J=9.3 Hz, 1H), 7.11 (dd, J=7.0, 7.0 Hz, 1H) , 5.03 (s, 2H), 4.60 - 4.56 (m, 1H), 3.99 (t, J=5.6 Hz, 2H), 3.29 - 3.29 (m, 2H), 3.09 - 3.08 (m, 2H), 2.24 (m , 2H), 2.18 (s, 3H), 1.95 - 1.90 (m, 2H), 1.74 - 1.65 (m, 2H). LC-MS (ESI): Method 7 t R = 2.79 min; m / z (M+1) = 584 33 General Procedure I Amine (21 mg, 0.150 mmol) Intermediate 40: 49 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 3.9mg 7% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 11.18 (s, 1H), 8.99 - 8.95 (m, 1H), 8.34 (s, 1H), 8.14 (s, 1H), 7.76 - 7.73 (m, 1H), 7.50 - 7.45 (m, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H), 6.72 (s, 1H), 5.04 (s, 2H), 4.01 - 3.96 (m, 2H), 3.11 - 3.05 (m, 2H), 1.33 (s, 9H) LC-MS (ESI): Method 7 t R = 3.75 min; m / z (M+1) = 450.3 34 General Procedure I Amine (16 mg, 0.117 mmol) Intermediate 40: 38 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 4.1mg 9% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 11.78 (s, 1H), 8.97 (td, J=1.1, 6.9 Hz, 1H), 8.34 (s, 1H), 8.14 (s, 1H), 7.76 - 7.73 (m, 1H), 7.50 - 7.45 ( m, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H), 6.37 (s, 1H), 5.03 (s, 2H), 4.02 - 3.97 (m, 2H), 3.12 - 3.07 (m, 2H) , 1.29 (s, 9H) LC-MS (ESI): Method 7 t R = 3.65 min; m / z (M+1) = 450.3 35 General Procedure I Amine (19 mg, 0.124 mmol) Intermediate 40: 40 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 4.1mg 9% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.07 (s, 1H), 8.97 (td, J=1.1, 7.0 Hz, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 7.75 (td, J=1.1, 9.0 Hz, 1H) , 7.50 - 7.45 (m, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H), 6.11 (s, 1H), 5.04 (s, 2H), 4.02 - 3.97 (m, 2H), 3.63 (s , 3H), 3.45 - 3.38 (m, 1H), 3.09 - 3.04 (m, 2H), 2.28 - 2.20 (m, 2H), 2.16 - 2.09 (m, 2H), 2.01 - 1.81 (m, 2H) LC-MS (ESI): Method 7 = 3.21 min; m / z (M+1) = 461.3 36 General Procedure I Amine (30 mg, 0.213 mmol) Intermediate 40: 70 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 35mg 41% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.05 (s, 1H), 8.97 (td, J=1.1, 7.0 Hz, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 7.75 (td, J=1.1, 9.0 Hz, 1H) , 7.48 (ddd, J=1.3, 6.8, 9.0 Hz, 1H), 7.11 (dt, J=1.3, 6.9 Hz, 1H), 6.06 (s, 1H), 5.04 (s, 2H), 3.99 (t, J =5.7 Hz, 2H), 3.63 (s, 3H), 3.07 (t, J=5.4 Hz, 2H), 2.88 - 2.77 (septet, J=7.0 Hz, 1H), 1.19 (d, J=7.0 Hz, 6H) LC-MS (ESI): Method 7 = 3.08 min; m / z (M+1) = 449.3 37 General Procedure I Amine (36 mg, 0.211 mmol) Intermediate 40: 69mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 19mg 28% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.37 (s, 1H), 8.98 (td, J=1.2, 7.1 Hz, 1H), 8.41 (d, J=5.5 Hz, 1H), 8.24 (s, 1H), 8.15 (s, 1H), 7.77 - 7.74 (m, 2H), 7.63 (dd, J=1.9, 5.5 Hz, 1H), 7.48 (ddd, J=1.3, 6.8, 9.0 Hz, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H ), 5.04 (s, 2H), 4.02 - 3.97 (m, 2H), 3.11 - 3.06 (m, 2H), 1.32 (s, 9H). LC-MS (ESI): Method 6 = 4.21 min; m / z (M+1) = 460.3 38 General Procedure I Amine (38 mg, 0.210 mmol) Intermediate 40: 68 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 27.7mg 35% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.97 (td, J=1.1, 7.0 Hz, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 7.75 (td, J=1.1, 9.0 Hz, 1H) , 7.48 (ddd, J=1.3, 6.8, 9.0 Hz, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H), 6.05 (s, 1H), 5.03 (s, 2H), 4.46 - 4.35 (hept , J=6.6 Hz, 1H), 4.02 - 3.96 (m, 2H), 3.09 - 3.03 (m, 2H), 1.34 (d, J=6.6 Hz, 6H), 1.25 (s, 9H). LC-MS (ESI): Method 7 = 3.97 min; m / z (M+1) = 491.4 39 General Procedure I Amine (30 mg, 0.213 mmol) Intermediate 40: 70 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 40mg 59% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.06 (s, 1H), 8.97 (td, J=1.1, 7.0 Hz, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 7.75 (td, J=1.1, 9.0 Hz, 1H) , 7.48 (ddd, J=1.3, 6.8, 9.0 Hz, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H), 6.04 (s, 1H), 5.03 (s, 2H), 3.99 (t, J =5.6 Hz, 2H), 3.63 (s, 3H), 3.10 - 3.03 (m, 2H), 2.46 (t, J=7.6 Hz, 2H), 1.65 - 1.54 (m, 2H), 0.93 (t, J= 7.4 Hz, 3H) LC-MS (ESI): Method 7 = 3.08 min; m / z (M+1) = 449.3 40 General Procedure I Amine (46.6 mg, 0.211 mmol) Intermediate 40: 69 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 39mg 44% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.21 (s, 1H), 8.97 (td, J=1.1, 7.0 Hz, 1H), 8.16 - 8.14 (m, 2H), 7.75 (td, J=1.1, 9.0 Hz, 1H), 7.48 (ddd, J=1.3, 6.8, 9.0 Hz, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H), 6.32 (s, 1H), 5.07 - 4.98 (m, 4H), 4.02 - 3.96 (m, 2H) , 3.08 - 3.04 (m, 2H), 1.26 (s, 9H). LC-MS (ESI): Method 7 = 3.97 min; m / z (M+1) = 531.3 41 General Procedure I Amine (48 mg, 0.213 mmol) Intermediate 40: 70 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 47mg 57% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.07 (s, 1H), 8.96 (td, J=1.1, 7.0 Hz, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.75 (td, J=1.1, 9.0 Hz, 1H) , 7.48 (ddd, J=1.3, 6.8, 9.0 Hz, 1H), 7.33 - 7.28 (m, 2H), 7.27 - 7.21 (m, 1H), 7.13 - 7.08 (m, 3H), 6.21 (s, 1H) , 5.28 (s, 2H), 5.01 (s, 2H), 3.97 - 3.91 (m, 2H), 2.97 - 2.91 (m, 2H), 1.26 (s, 9H). LC-MS (ESI): Method 7 = 4.12 min; m / z (M+1) = 539.3 42 General Procedure I Amine (35 mg, 0.211 mmol) Intermediate 40: 69 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 30.6mg 42% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 9.98 (s, 1H), 8.97 (td, J=1.1, 7.0 Hz, 1H), 8.17 (s, 1H), 8.14 (s, 1H), 7.75 (td, J=1.1, 9.0 Hz, 1H) , 7.48 (ddd, J=1.3, 6.8, 9.0 Hz, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H), 6.09 (s, 1H), 5.04 (s, 2H), 4.02 - 3.93 (m , 4H), 3.08 - 3.03 (m, 2H), 1.29 (t, J=7.2 Hz, 3H), 1.25 (s, 9H). LC-MS (ESI): Method 7 = 3.53 min; m / z (M+1) = 477.3 43 General Procedure I Amine (35 mg, 0.211 mmol) Intermediate 40: 69mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 30.6mg 42% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.06 (s, 1H), 8.97 (td, J=1.1, 7.0 Hz, 1H), 8.21 (s, 1H), 8.14 (s, 1H), 7.75 (td, J=1.1, 9.1 Hz, 1H) , 7.48 (ddd, J=1.3, 6.8, 9.0 Hz, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H), 6.03 (s, 1H), 5.03 (s, 2H), 3.99 (t, J =5.6 Hz, 2H), 3.63 (s, 3H), 3.10 - 3.04 (m, 2H), 2.35 (d, J=7.0 Hz, 2H), 1.92 - 1.81 (m, 1H), 0.91 (d, J= 6.7 Hz, 6H). LC-MS (ESI): Method 7 = 3.32 min; m / z (M+1) = 463.3 44 General Procedure I Amine (Intermediate 13) (147 mg, 0.513 mmol) Intermediate 40: 168mg (1.0 equivalent) Intermediate 40 was used as acid deblocking salt via acid wash 187mg 71% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.40 - 10.38 (m, 1H), 8.98 (d, J=7.0 Hz, 1H), 8.23 ​​(s, 1H), 8.15 (s, 1H), 8.13 (s, 1H), 7.95 (s, 1H) , 7.75 (td, J=1.1, 9.1 Hz, 1H), 7.48 (ddt, J=1.3, 5.3, 4.5 Hz, 1H), 7.35 (s, 1H), 7.11 (ddd, J=6.9, 6.9, 1.2 Hz , 1H), 5.06 - 5.02 (m, 2H), 4.03 - 3.97 (m, 2H), 3.71 (d, J=13.6 Hz, 1H), 3.58 (d, J=13.7 Hz, 1H), 3.10 - 3.06 ( m, 2H), 2.76 - 2.67 (m, 2H), 2.65 - 2.58 (m, 1H), 2.50 - 2.45 (m, 1H), 2.35 - 2.29 (m, 1H), 2.10 - 2.09 (m, 6H), 1.93 - 1.83 (m, 1H), 1.68 - 1.59 (m, 1H) LC-MS (ESI): Method 7 = 2.56 min; m / z (M+1) = 597.5 45 General Procedure I Amine (Intermediate 14) (160 mg, 0.555 mmol) Intermediate 40: 181 mg (1.0 equiv) Intermediate 40 was used as acid deblocking salt via acid wash 87mg 31% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.39 (s, 1H), 8.98 (td, J=1.1, 7.0 Hz, 1H), 8.23 ​​(s, 1H), 8.15 - 8.12 (m, 2H), 7.95 (s, 1H), 7.75 (td, J=1.1, 9.0 Hz, 1H), 7.48 (ddd, J=1.3, 6.8, 9.0 Hz, 1H), 7.35 (s, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H), 5.05 (s , 2H), 4.03 - 3.97 (m, 2H), 3.71 (d, J=13.7 Hz, 1H), 3.58 (d, J=13.7 Hz, 1H), 3.12 - 3.06 (m, 2H), 2.76 - 2.67 ( m, 2H), 2.65 - 2.58 (m, 1H), 2.49 - 2.44 (m, 1H), 2.35 - 2.29 (m, 1H), 2.09 (s, 6H), 1.93 - 1.83 (m, 1H), 1.68 - 1.59 (m, 1H) LC-MS (ESI): Method 7 t R = 2.58 min; m / z (M+1) = 597.4 129 General Procedure I Intermediate 130 (28 mg, 1.21 mmol) Intermediate 40: 38 mg (1.15 equiv) Intermediate 40 is used as acid. 5mg 7% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.77 (s, 1H), 8.98 (td, J=1.1, 7.0 Hz, 1H), 8.32 (s, 1H), 8.19 (d, J=1.7 Hz, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.75 (td, J=1.1, 9.0 Hz, 1H), 7.48 (ddd, J=1.3, 6.8, 9.0 Hz, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H), 5.05 (s, 2H), 4.03 - 3.97 (m, 2H), 3.58 (s, 2H), 3.14 - 3.08 (m, 2H), 2.25 (s, 6H). LC-MS (ESI) method 7:t R = 2.58 min; m / z [M+H]+ = 529.5 130 General Procedure I Intermediate 111 (44 mg, 1.47 mmol) Intermediate 40: 40 mg (0.9 equiv) Intermediate 40 is used as acid. 49mg 64% Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.52 (s, 1H), 8.98 (d, J=7.0 Hz, 1H), 8.28 (d, J=7.1 Hz, 1H), 8.24 (s, 1H), 8.16 (t, J=1.7 Hz, 1H ), 8.15 (s, 1H), 7.76 - 7.74 (m, 1H), 7.56 (d, J=3.4 Hz, 1H), 7.51 - 7.46 (m, 1H), 7.14 - 7.09 (m, 1H), 5.06 - 5.03 (m, 2H), 4.00 (t, J=5.7 Hz, 2H), 3.78 - 3.46 (m, 3H), 3.30 - 3.23 (m, 1H), 3.12 - 3.07 (m, 2H), 2.77 - 2.67 ( m, 1H), 2.21 (s, 3H), 2.13 - 2.11 (m, 3H), 2.06 - 2.01 (m, 1H), 1.83 - 1.72 (m, 1H) LC-MS (ESI) method 7:t R = 2.82 min; m / z (M+1) = 611.2.

[0275] Example 46; Preparation of N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5, 6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide step 1; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(imidazo[ 1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 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 SM conversion 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 material was purified by FCC (DCM to 10% MeOH / DCM) to afford the title compound (6 mg, 0.012 mmol, 4% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.96 (d, J = 6.9 Hz, 1H), 8.23 ​​(s, 1H), 8.13 (s, 1H), 8.01-7.91 (m, 2H), 7.73 (d, J = 9.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.10 (t, J = 6.8 Hz, 1H) , 5.03 (s, 2H), 3.98 (t, J = 5.7 Hz, 2H), 3.07 (s, 2H). LC-MS (ESI) method 2: tR = 2.21 min; m / z (M+1) = 489.0

[0276] Example 47; Preparation of N-(4-(tertiary butyl)oxazol-2-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5, 6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide Example 47 Step 1; N-(4-(tertiary butyl)oxazol-2-yl)-6-( Imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide to intermediate 40 acid form (40 mg, 0.122 mmol) and 4-tertiary-butylazol-2-amine (24 mg, 0.171 mmol) in DMF (0.60 mL) was added 1-methylimidazole (0.034 mL, 0.428 mmol), Then TCFH (51 mg, 0.183 mmol) was added. The reaction mixture was stirred at room temperature for 72 h, partitioned between saturated NaHCO 3 (aq) and DCM, and the aqueous phase was extracted with 3×DCM. The combined org. phases were washed with sat. NaCl(aq), passed through a hydrophobic frit and concentrated in vacuo. Purification by reverse phase preparative HPLC (Xbridge Phenyl 19x150 mm, 10 µm 40-100% MeOH / water (10 mM NH4HCO3), 20 mL / min, RT) afforded the title compound (1.55 mg, 2%). ¹H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.97 (td, J=1.1, 7.1 Hz, 1H), 8.28 (s, 1H), 8.14 (s, 1H), 7.74 (td, J=1.1, 9.0 Hz, 1H), 7.59 (s, 1H), 7.50 - 7.45 (m, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H), 5.03 (s, 2H), 4.01 - 3.96 (m, 2H), 3.09 - 3.04 (m, 2H), 1.23 (s, 9H). LC-MS (ESI) method 7: tR = 3.46 min; m / z (M+1) = 450.2

[0277] The compounds reported in the table below were prepared via amide group coupling as described in Example 47, Step 1, using the corresponding commercially available or previously synthesized amine in Step 1. If not DMF, specify solvent. Example number structure General Procedure - Reagent Volume Product amount (yield) Purification method material 114 General procedure G 2-Methyl-5-[1-(trifluoromethyl)cyclopropyl]pyrazol-3-amine (47 mg, 0.23 mmol): Intermediate 40: 75 mg, (1.0 equiv) 89 mg (73%) no further purification ¹H NMR (400 MHz, CDCl 3 ) δ 9.02 (d, J=6.8 Hz, 1H), 7.96 (s, 1H), 7.73 (s, 1H), 7.69 (d, J=9.1 Hz, 1H), 7.62 (s, 1H), 7.37 (t , J=7.8 Hz, 1H), 6.97 (t, J=6.8 Hz, 1H), 6.37 (s, 1H), 5.03 (s, 2H), 4.09 (t, J=5.7 Hz, 2H), 3.74 (s , 3H), 3.21 (t, J=5.1 Hz, 2H), 1.34 - 1.22 (m, 4H). LCMS (ESI): Method 7t R = 3.50 min; m / z [M+1+]+= 515.5 115 5-(1,1-difluoroethyl)pyridin-3-amine (36 mg, 0.23 mmol): Intermediate 40: 75 mg, (1.0 equiv) 61mg (54%) no further purification ¹H NMR (400 MHz, CDCl 3 ) δ 9.03 (d, J=6.6 Hz, 1H), 8.78 (s, 1H), 8.54 (s, 1H), 8.41 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 7.73 - 7.66 (m, 2H), 7.42 - 7.34 (m, 1H), 6.99 (t, J=6.7 Hz, 1H), 5.00 (s, 2H), 4.10 (t, J=5.9 Hz, 2H), 3.25 ( s, 2H), 1.99 (t, J=18.3 Hz, 3H). LCMS (ESI): Method 7t R 3.17 min; m / z [M+H+]+, = 468.4 117 5-tertiary-butylpyridin-3-amine (27 mg, 0.23 mmol): Intermediate 40: 75 mg, (1.0 equiv) 57mg (67%) Precipitation from water ¹H NMR (400 MHz, CDCl 3 ) δ 9.03 (d, J=6.8 Hz, 1H), 8.51 (d, J=2.3 Hz, 1H), 8.44 (d, J=2.0 Hz, 1H), 8.20 (t, J=2.4 Hz, 1H), 7.98 (s, 1H), 7.92 (s, 1H), 7.71 (m, 2H), 7.37 (t, J=8.8 Hz, 1H), 6.97 (t, J=6.9 Hz, 1H), 5.02 (s, 2H ), 4.10 (t, J=5.7 Hz, 2H), 3.24 (t, J=5.4 Hz, 2H), 1.38 (s, 9H). LCMS (ESI): Method 7t R = 4.07 min, m / z [M+H+]+ = 460.5 118 5-(Difluoromethoxy)pyridin-3-amine dihydrochloride amine (42 mg, 0.23 mmol): Intermediate 40: 75 mg, (1.0 equiv) 44mg (49%) Precipitation from water ¹H NMR (400 MHz, CDCl 3 ) δ 10.56 (s, 1H), 9.02 (d, J=6.8 Hz, 1H), 8.84 (m, 1H), 8.28 (s, 2H), 8.22 - 8.17 (m, 2H), 7.79 (d, J= 9.1 Hz, 1H), 7.53 (m, 1H), 7.21 - 7.12 (m, 1H), 5.08 - 5.05 (s, 2H), 4.04 (t, J=5.3 Hz, 2H), 3.17 - 3.09 (t, J =5.3 Hz, 2H). (1H deletion) LCMS (ESI): Method 7t R = 3.13 min, m / z[M+H+]+ = 470.3 131 ACN 3-Amino-5-(trifluoromethyl)benzonitrile (28 mg, 0.153 mmol): Intermediate 40: 50 mg, (1.0 equiv) 24 mg (30%) Precipitation from water ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.74 - 10.71 (m, 1H), 9.02 (d, J=6.8 Hz, 1H), 8.48 (d, J=5.8 Hz, 2H), 8.30 (s, 1H), 8.19 (s, 1H), 8.10 (s, 1H), 7.79 (d, J=9.1 Hz, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.15 (t, J=6.7 Hz, 1H), 5.12 - 5.05 (m, 2H) , 4.04 (t, J=5.7 Hz, 2H), 3.14 (t, J=5.6 Hz, 2H). LC-MS (ESI) Method 6: t R = 4.61 min; m / z [M + H] + = 496.4 132 ACN Intermediate 112 (29 mg, 0.153 mmol): Intermediate 40: 50 mg, (1.0 equiv) 7 mg (9%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.36 (s, 1H), 8.98 (m, 1H), 8.21 (s, 1H), 8.17 - 8.15 (m, 2H), 8.01 (dd, J=1.9, 8.4 Hz, 1H), 7.74 (m, 2H), 7.50 - 7.45 (m, 1H), 7.13 - 7.09 (m, 1H), 5.44 (t, J=5.6 Hz, 1H), 5.03 (s, 2H), 4.65 (d, J=5.5 Hz, 2H ), 4.00 (t, J=5.6 Hz, 2H), 3.30 - 3.28 (m, 1H), 3.19 (d, J=5.1 Hz, 1H), 3.09 (s, 2H). LC-MS (ESI) method 7:t R = 3.27 min; m / z [M + H] + = 501.5

[0278] Example 48; Preparation of compound N-(3-((4-(dimethylamino)piperidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6- (Imidazolo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide Step 1; N-(3 -(Dimethoxymethyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetra Hydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 41) was synthesized from 3-(dimethoxymethyl)-5-(trifluoromethyl)aniline (216 mg , 0.916 mmol, intermediate 42) and intermediate 40 acid form (300 mg, 0.916 mmol). The residue was tritiated under Et2O and the suspension was filtered to afford the title compound (496 mg, 0.910 mmol, 99% yield). ¹H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.98 (d, J=7.0 Hz, 1H), 8.25 - 8.19 (m, 3H), 8.07 (s, 1H), 7.76 (d, J=9.1 Hz, 1H), 7.55 - 7.49 (m, 1H), 7.39 (s, 1H), 7.15 (t, J=6.9 Hz, 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)

[0279] 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) was dissolved in DCM (5.00 mL) at room temperature to Intermediate 41 (498 mg, 0.915 mmol, 1.00 equiv) To the solution in TFA (0.50 mL, 6.53 mmol, 7.14 equiv) was added and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo to give a light brown mobile oil, which was tritiated under Et20, and the ether was decanted to afford the title compound (450 mg, 0.910 mmol, 99% yield). ¹H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 10.09 (s, 1H), 9.04 (d, J=7.0 Hz, 1H), 8.57 (s, 1H), 8.46 (s, 2H) , 8.29 (s, 1H), 8.01 (s, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.84 - 7.78 (m, 1H), 7.39 (t, J=7.0 Hz, 1H), 5.03 ( s, 2H), 4.01 - 3.96 (m, 2H), 3.14 - 3.09 (m, 2H)

[0280] 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-tetrahydrothieno[2,3-c]pyridine-3-carboxamide According to general procedure C, intermediate 42 ( 50 mg, 0.100 mmol) and N,N-dimethylpiperidin-4-amine (14 mg, 0.110 mmol). Purification by reverse phase preparative HPLC (Xbridge Phenyl 19x150 mm, 10 µm 40-100% methanol / water (10 mM NH4HCO3), 20 mL / min, RT) afforded the title compound (16 mg, 26%). ¹H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.98 (td, J=1.0, 7.0 Hz, 1H), 8.24 (s, 1H), 8.17 - 8.15 (m, 2H), 7.93 ( s, 1H), 7.75 (td, J=1.0, 9.0 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.34 (s, 1H), 7.11 (dt, J=1.0, 7.0 Hz, 1H), 5.03 (s, 2H), 4.00 (t, J=5.5 Hz, 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, 11.8 Hz, 2H). LC-MS (ESI) method 7: tR = 2.34 min; m / z (M+1) = 611.4

[0281] The compounds reported in the table below were prepared via amide group coupling as described in Example 48, Steps 1-3, using the corresponding commercially available or previously synthesized amines in Step 3. Step 3 can be performed according to the general procedure described above in the manner reported in the table above. Modifications relate to chromatographic purification conditions (eg, preparative HPLC or flash chromatography) and such changes are described. Example serial number structure SM volume Amount of purified product (yield) Purification method material 49 General program C NH2: 29 mg (0.100 mmol) Intermediate 42: 50 mg (0.100 mmol) 19mg (32%) Preparation HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.40 (s, 1H), 8.98 (td, J=1.1, 7.0 Hz, 1H), 8.24 (s, 1H), 8.15 (s, 1H), 8.14 (s, 1H), 8.00 (s, 1H) , 7.75 (td, J=1.1, 9.0 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.40 (s, 1H), 7.11 (dt, J=1.3, 6.9 Hz, 1H), 5.04 (s, 2H ), 4.87 (d, J=7.8 Hz, 2H), 4.54 (d, J=7.7 Hz, 2H), 4.00 (t, J=5.6 Hz, 2H), 3.91 (s, 2H), 3.12 - 3.07 (m , 2H), 3.03 (t, J=6.9 Hz, 2H), 2.35 (t, J=6.8 Hz, 2H) LC-MS (ESI): Method 7 t R = 2.77 min; m / z (M+1) = 582.2 50 General program C NH2: 15 mg (0.110 mmol) Intermediate 42: 50 mg (0.100 mmol) 10mg (17%) Preparation HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.39 (s, 1H), 8.98 (td, J=1.0, 7.0 Hz, 1H), 8.23 ​​(s, 1H), 8.15 (s, 1H), 8.13 (s, 1H), 8.00 (s, 1H) , 7.75 (td, J=1.1, 9.1 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.39 (s, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H), 5.04 (s, 2H ), 4.38 (s, 1H), 4.03 - 3.94 (m, 3H), 3.87 - 3.77 (m, 2H), 3.57 (dd, J=1.8, 7.5 Hz, 1H), 3.50 (s, 1H), 3.10 - 3.08 (m, 2H), 2.76 (dd, J=1.6, 9.9 Hz, 1H), 2.46 (d, J=9.8 Hz, 1H), 1.85 (dd, J=2.0, 9.5 Hz, 1H), 1.65 - 1.62 (m, 1H) LC-MS (ESI): Method 7 t R = 2.70 min; m / z (M+1) = 582 51 General program C NH2: 14 mg (0.110 mmol) Intermediate 42: 50 mg (0.100 mmol) 8.4mg (15%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6) δ 10.41 (s, 1H), 8.99 - 8.96 (m, 1H), 8.24 (s, 1H), 8.15 (s, 2H), 7.98 (s, 1H), 7.76 - 7.74 (m, 1H), 7.50 - 7.45 (m, 1H), 7.37 (s, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H), 5.32 - 5.14 (m, 1H), 5.05 (s, 2H), 4.03 - 3.97 (m, 2H), 3.76 - 3.66 (m, 2H), 3.10 (s, 2H), 2.88 - 2.78 (m, 2H), 2.73 - 2.59 (m, 1H), 2.40 - 2.34 (m, 1H), 2.26 - 2.10 ( m, 1H), 1.99 - 1.84 (m, 1H) LC-MS (ESI): Method 7 t R = 2.80 min; m / z (M+1) = 572.4 52 General program C NH2: 11 mg (0.120 mmol) Intermediate 42: 40 mg (0.080 mmol) 3.5mg (8%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.38 (s, 1H), 8.99 - 8.96 (m, 1H), 8.23 ​​(s, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.76 - 7.74 ( m, 1H), 7.50 - 7.46 (m, 1H), 7.31 (s, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H), 5.04 (s, 2H), 4.03 - 3.97 (m, 2H) , 3.61 (s, 2H), 3.18 (dd, J=7.0, 7.0 Hz, 4H), 3.12 - 3.07 (m, 2H), 2.06 - 1.98 (m, 2H) LC-MS (ESI): Method 7 t R = 2.74 min; m / z (M+1) = 540.3 53 General program C NH2: 9.8 µL (0.110 mmol) Intermediate 42: 50 mg (0.100 mmol) 1.2mg (2%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.42 (s, 1H), 9.00 - 8.96 (m, 1H), 8.24 (s, 1H), 8.18 - 8.14 (m, 2H), 7.96 (s, 1H), 7.77 - 7.73 (m, 1H), 7.51 - 7.45 (m, 1H), 7.37 (s, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H), 5.06 - 5.02 (m, 2H), 4.57 (dd, J=6.6, 6.6 Hz, 2H), 4.48 (dd, J=6.2, 6.2 Hz, 2H), 4.03 - 3.98 (m, 2H), 3.69 - 3.61 (m, 1H), 3.44 (s, 2H), 3.13 - 3.07 (m, 2H) , 2.01 (s, 3H) LC-MS (ESI): Method 7 t R = 2.75 min; m / z (M+1) = 570.3 54 General program C NH2: 13 mg (0.088 mmol) Intermediate 42: 40 mg (0.080 mmol) 14mg (28%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.40 (s, 1H), 8.98 (td, J=1.1, 6.8 Hz, 1H), 8.23 ​​(s, 1H), 8.16 - 8.14 (m, 2H), 7.95 (s, 1H), 7.75 (td, J=1.1, 9.0 Hz, 1H), 7.51 - 7.46 (m, 1H), 7.35 (s, 1H), 7.12 (dt, J=1.2, 6.9 Hz, 1H), 5.04 (s, 2H), 4.53 (t , J=6.5 Hz, 2H), 4.42 (t, J=6.1 Hz, 2H), 4.02 - 3.97 (m, 2H), 3.57 (s, 2H), 3.45 - 3.38 (m, 1H), 3.12 - 3.08 ( m, 2H), 2.49 - 2.39 (m, 4H), 2.37 - 2.24 (m, 4H) LC-MS (ESI): Method 7 t R = 2.74 min; m / z (M+1) = 625.4 55 General program C NH2: 14 mg (0.110 mmol) Intermediate 42: 50 mg (0.100 mmol) 11.5mg (19%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.39 (s, 1H), 8.99 - 8.97 (m, 1H), 8.23 ​​(s, 1H), 8.15 - 8.12 (m, 2H), 7.96 (s, 1H), 7.76 - 7.74 (m, 1H), 7.50 - 7.45 (m, 1H), 7.35 (s, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H), 5.05 (s, 2H), 4.03 - 3.97 (m, 2H), 3.69 - 3.58 ( m, 2H), 3.10 - 3.08 (m, 2H), 2.63 - 2.57 (m, 1H), 2.35 - 2.25 (m, 1H), 2.24 - 2.10 (m, 9H), 1.95 - 1.84 (m, 1H), 1.45 - 1.35 (m, 1H). Pyrrolidine CH 2 Masked by DMSO. Structure was confirmed by HSQC. LC-MS (ESI): Method 7 t R = 2.32 min; m / z (M+1) = 611.5 56 General procedure J NH2: 14 µL (0.110 mmol) Intermediate 42: 50 mg (0.100 mmol) 17mg (29%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.39 (s, 1H), 8.98 (td, J=1.0, 7.0 Hz, 1H), 8.23 ​​(s, 1H), 8.15 - 8.12 (m, 2H), 7.95 (s, 1H), 7.75 (td, J=1.0, 9.0 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.35 (s, 1H), 7.11 (dt, J=1.0, 6.9 Hz, 1H), 5.05 (s, 2H), 4.00 (t , J=5.5 Hz, 2H), 3.71 (d, J=13.5 Hz, 1H), 3.58 (d, J=13.5 Hz, 1H), 3.12 - 3.06 (m, 2H), 2.76 - 2.66 (m, 2H) , 2.65 - 2.58 (m, 1H), 2.50 - 2.45 (m, 1H), 2.35 - 2.29 (m, 1H), 2.09 (s, 6H), 1.93 - 1.83 (m, 1H), 1.68 - 1.59 (m, 1H) LC-MS (ESI): Method 6 t R = 4.24 min; m / z (M+1) = 597.5 57 General procedure J NH2: 9 µL (0.110 mmol) Intermediate 42: 50 mg (0.100 mmol) 17mg (30%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6) δ 10.39 (s, 1H), 8.98 (td, J=1.0, 7.0 Hz, 1H), 8.23 ​​(s, 1H), 8.16 - 8.12 (m, 2H), 7.95 (s, 1H), 7.75 (td, J=1.0, 9.0 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.38 (s, 1H), 7.11 (dt, J=1.0, 7.0 Hz, 1H), 5.04 (s, 2H), 4.45 (t , J=5.5 Hz, 1H), 4.02 - 3.97 (m, 2H), 3.59 (s, 2H), 3.55 (q, J=6.0 Hz, 2H), 3.11 - 3.07 (m, 2H), 2.48 (t, J=6.5 Hz, 2H), 2.20 (s, 3H) LC-MS (ESI): Method 7 t R = 2.68 min; m / z (M+1) = 558.3 58 General procedure J NH2: 15 µL (0.110 mmol) Intermediate 42: 50 mg (0.100 mmol) 9mg (16%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.41 (s, 1H), 8.98 (td, J=1.0, 7.0 Hz, 1H), 8.23 ​​(s, 1H), 8.17 - 8.15 (m, 2H), 7.98 (s, 1H), 7.75 (td, J=1.0, 9.0 Hz, 1H), 7.51 - 7.46 (m, 1H), 7.37 (s, 1H), 7.12 (dt, J=1.0, 7.0 Hz, 1H), 5.05 (s, 2H), 4.03 - 3.97 (m, 2H), 3.59 (s, 2H), 3.49 - 3.44 (m, 4H), 3.12 - 3.08 (m, 2H), 2.44 - 2.33 (m, 4H), 2.00 (s, 3H) LC-MS (ESI): Method 7 t R = 2.70 min; m / z (M+1) = 611.4 59 General procedure J NH2: 13mg (0.110 mmol) Intermediate 42: 50 mg (0.100 mmol) 13mg (twenty one%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.41 (s, 1H), 8.98 (td, J=1.1, 7.0 Hz, 1H), 8.23 ​​(s, 1H), 8.18 - 8.15 (m, 2H), 7.99 (s, 1H), 7.76 - 7.74 ( m, 1H), 7.50 - 7.46 (m, 1H), 7.38 (s, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H), 5.04 (s, 2H), 4.03 - 3.97 (m, 2H) , 3.64 (s, 2H), 3.32 - 3.27 (m, 2H), 3.12 - 3.07 (m, 2H), 3.01 (s, 2H), 2.84 (s, 3H), 2.72 - 2.67 (m, 2H) LC-MS (ESI): Method 7 t R = 3.09 min; m / z (M+1) = 597.4 60 General procedure J NH2: 11 µL (0.110 mmol) Intermediate 42: 50 mg (0.100 mmol) 20mg (34%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.39 (s, 1H), 8.98 (td, J=1.1, 6.9 Hz, 1H), 8.24 (s, 1H), 8.16 - 8.14 (m, 2H), 7.94 (s, 1H), 7.75 (td, J=1.1, 9.0 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.34 (s, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H), 5.03 (s, 2H), 4.03 - 3.97 (m, 2H), 3.52 (s, 2H), 3.12 - 3.07 (m, 2H), 2.39 - 2.33 (m, 4H), 1.57 - 1.49 (m, 4H), 1.43 - 1.41 (m, 2H) LC-MS (ESI): Method 7 t R = 2.89 min; m / z (M+1) = 568.4 61 General procedure J NH2: 12 µL (0.110 mmol) Intermediate 42: 50 mg (0.100 mmol) 22mg (38%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.39 (s, 1H), 8.98 (td, J=1.0, 6.9 Hz, 1H), 8.23 ​​(s, 1H), 8.16 - 8.13 (m, 2H), 7.95 (s, 1H), 7.75 (td, J=1.1, 9.1 Hz, 1H), 7.50 - 7.45 (m, 1H), 7.37 (s, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 1H), 5.05 (s, 2H), 4.02 - 3.98 (m, 2H), 3.60 (s, 2H), 3.49 (t, J=5.9 Hz, 2H), 3.25 (s, 3H), 3.12 - 3.07 (m, 2H), 2.57 (t, J=5.8 Hz, 2H), 2.20 (s, 3H) LC-MS (ESI): Method 7 t R = 2.82 min; m / z (M+1) = 572.3

[0282] Example 62; Preparation of 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(2-(4-methylpiper-1-yl)ethoxy )-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 62) Step 1; 4- (2-(3-(6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-methyl Amino)-5-(trifluoromethyl)phenoxy)ethyl)piperone-1-carboxylic acid tert-butyl ester (Intermediate 43) According to general procedure H, intermediate 40 was dissolved in organic solvent , followed by acidic washing to convert to its free acid form, drying over sodium sulfate and evaporation under vacuum afforded intermediate 40 as the free acid (150 mg, 0.458 mmol), which was subsequently combined with intermediate 19 (178 mg, 0.458 mmol). mmol) reaction. Purification by silica gel FCC (eluent A = 3:1 AcOEt / ethanol; eluent B = cyclohexane; gradient = 0% eluent A to 100% eluent A) afforded the title compound (210 mg, 61%). ¹H NMR (400 MHz, CDCl3) δ 9.04 (d, J=6.8 Hz, 1H), 8.12 (s, 1H), 7.98 - 7.97 (m, 1H), 7.70 (d, J=9.1 Hz, 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=5.6 Hz, 2H), 4.10 (q, J=4.5 Hz, 2H), 3.45 (t, J=5.1 Hz, 4H), 3.29 - 3.21 (m, 2H), 2.85 - 2.81 (m, 2H) , 2.53 - 2.51 (m, 4H), 1.46 (s, 9H)

[0283] Step 2; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(2-(piper-1-yl)ethoxy)-5-(tri Fluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 44) made solution intermediate 43 (70 mg, 0.10 mmol, 1.00 equiv) in MeOH (1.00 mL) was treated with 4 M HCl in dioxane (0.4 mL, 1.2 mmol, 10.0 equiv), and the resulting reaction mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Sunfire C18® 19x150 mm, 10um 5-60% ACN / H2O (0.1% TFA), 20ml / min, RT) and the residue was lyophilized to give the title compound (24.3 mg, 13.6% ). ¹H NMR (400 MHz, MeOD-d3) δ 9.16 (d, J=9.2 Hz, 1H), 8.45 (s, 1H), 8.11 (s, 1H), 7.96 (d, J=3.5 Hz, 3H), 7.76 (s, 1H), 7.61 (s, 1H), 7.50 - 7.46 (m, 1H), 7.02 (s, 1H), 5.14 - 5.12 (m, 2H), 4.28 (t, J=5.2 Hz, 2H), 4.13 (t, J=5.8 Hz, 2H), 3.32 - 3.30 (m, 4H), 3.25 - 3.16 (m, 2H), 3.04 (t, J=5.1 Hz, 2H), 2.97 (t, J=5.1 Hz , 4H)

[0284] Step 3; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(2-(4-methylpiper-1-yl)ethoxy)- 5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 62) Intermediate 44 (120 mg , 0.200 mmol, 1.00 equiv) in THF (2.00 mL) and MeOH (2.00 mL) mixture suspension by formaldehyde solution (37%, 0.037 mL, 0.501 mmol, 2.50 equiv) 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 sat. NaHCO3 (aq), the organic phase was washed with sat. NaCl (aq), dried (MgSO4) and concentrated. The residue was purified by preparative HPLC (Xbridge Phenyl® 19x150 mm, 10um 40-100% MeOH / H2O (10mM NH4CO3), 20ml / min, RT) and the residue was lyophilized to give the title compound (37.4 mg, 30.6%) . ¹H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.98 (d, J=7.0 Hz, 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=5.6 Hz, 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). LC-MS (ESI) method 7: tR = 2.88 min; m / z (M+1) = 613

[0285] Example 63: Preparation of 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-[3-(1-methylpyrrolidin-3-yl)oxy-5-( Trifluoromethyl)phenyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide Example 63 Step 1: 3-(3-(6-(Imidazole [1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamido)-5-(trifluoroform yl)phenoxy)pyrrolidine-1-carboxylate tert-butyl ester (Intermediate 45) According to General Procedure H, Intermediate 40 was prepared as described in Example 62, Step 1 (80 mg, 0.244 mmol) The unblocked salt was converted to its free acid and reacted with tertiary-butyl 3-[3-amino-5-(trifluoromethyl)phenoxy]pyrrolidine-1-carboxylate (85 mg, 0.244 mmol, mid 50) reaction. The residue was purified by silica gel FCC (AcOEt / cyclohexane, 0% to 100%, then AcOEt / EtOH 75% / 25%) to afford the title compound. ¹H NMR (400 MHz, CDCl3) δ 9.02 (d, J=6.8 Hz, 1H), 8.44 - 8.37 (m, 1H), 7.99 - 7.95 (m, 1H), 7.72 - 7.65 (m, 2H), 7.37 ( t, J=9.8 Hz, 2H), 6.97 (t, J=6.7 Hz, 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)

[0286] Step 2: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(pyrrolidin-3-yl)-5-(trifluoromethyl)phenyl) -4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 46) Intermediate 45 (90 mg, 0.137 mmol, 1.00 equiv) was dissolved in The solution in methanol (1.00 mL) was treated with 4 M HCl in dioxane (0.69 mL, 2.75 mmol, 20.0 equiv). The reaction mixture was stirred at room temperature for 30 min, and then concentrated under reduced pressure to afford the HCl salt of the title compound in quantitative yield (81 mg, quant.).

[0287] Step 3: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-[3-(1-methylpyrrolidin-3-yl)oxy-5-(trifluoro Methyl)phenyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 63) Intermediate 46 (81 mg, 0.137 mmol, 1.00 eq. ) in THF (1 mL) and MeOH (1 mL) was successively dissolved by formaldehyde solution (37%, 0.025 mL, 0.342 mmol, 2.50 equiv) and sodium cyanoborohydride (15 mg, 0.233 mmol, 1.70 equiv). Work up and stir the resulting mixture at room temperature overnight. An additional portion of MeOH (1 mL) was added until all solids had dissolved and stirring was continued at room temperature for one hour. The reaction mixture was partitioned between DCM and saturated NaHCO3 (aq). The organic layer was washed with saturated NaCl (aq), dried (Na2SO4) and concentrated in vacuo. The crude material was purified by preparative HPLC (Luna Phenyl-Hexyl® 21.2x150 mm, 10 µm 20-80% MeOH / H2O (0.1% FA), 20ml / min, RT) to afford the title compound (11 mg, 14%). ¹H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.98 (d, J=7.0 Hz, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.78 (s, 1H) , 7.75 (d, J=9.0 Hz, 1H), 7.61 (s, 1H), 7.51 - 7.45 (m, 1H), 7.14 - 7.09 (m, 1H), 6.90 (s, 1H), 5.03 (s, 2H ), 4.96 - 4.91 (m, 1H), 4.00 (t, J=5.7 Hz, 2H), 3.08 (s, 2H), 2.80 (dd, J=6.0, 10.4 Hz, 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: tR = 2.92 min; m / z (M+1) = 570

[0288] Example 64: Preparation of N-(3-(tertiary 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 Step 1: N-(3-(tertiary butane Base)-1-(2-((tertiary 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) From Intermediate 31 (254 mg, 0.855 mmol) preparation. Purification by silica gel FCC (AcOEt / cyclohexane, 0% to 100%) afforded the title compound (139 mg, 37%). ¹H NMR (400 MHz, CDCl3) δ 9.04 (d, J=7.1 Hz, 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=6.9 Hz, 1H), 6.46 (s, 1H), 5.04 (s, 2H), 4.25 (t, J=4.5 Hz, 2H), 4.12 - 4.09 (m, 2H), 3.99 (t, J=4.6 Hz, 2H), 3.28 - 3.24 (m, 2H), 1.31 (s, 9H), 0.76 (s, 9H), -0.09 (s, 6H).

[0289] Step 2: N-(3-(tertiary 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) to Intermediate 47 (146 mg, 0.241 mmol) in To a solution in MeOH (1.60 mL) and THF (0.80 mL) was added 1,4-dioxane (0.60 mL, 2.41 mmol) containing 4 M HCl solution. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction mixture was concentrated under vacuum (165 mg). A portion (36 mg) was removed and purified by reverse phase preparative HPLC (Sunfire C18® 19x150 mm, 10 µm 20-80% acetonitrile / water (10 mM NH4HCO3), 20 mL / min, RT) to give the title compound (18.64 mg , 15%). ¹H NMR (400 MHz, DMSO-d6) δ 10.15 (brs, 1H), 8.97 (td, J=1.1, 7.0 Hz, 1H), 8.14 (s, 1H), 8.12 (s, 1H), 7.75 (td, J=1.1, 9.0 Hz, 1H), 7.48 (ddd, J=1.3, 6.8, 9.0 Hz, 1H), 7.11 (dt, J=1.2, 6.9 Hz, 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=5.8 Hz, 2H), 3.10 - 3.04 (m, 2H), 1.25 (s, 9H). LC-MS (ESI) method 7: tR = 3.23 min; m / z (M+1) = 493.3

[0290] Example 65: Preparation of compound N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridin-3-ylmethyl)-4 , 5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide Example 65 Step 1; 6-(imidazo[1,2-a]pyridin-3-ylmethyl )-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl ester (intermediate 48) was prepared under argon with intermediate 38 (3.00 g, 12.11 mmol) and Imidazo[1,2-a]pyridine-3-carbaldehyde (1.770 g, 12.11 mmol) was placed in the 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 another week. Then the reaction mixture was diluted with DCM and washed with a 1:1 mixture of K2CO3 (sat) 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 material was purified via FCC using DCM / MeOH (DCM to 10% MeOH / DCM) to afford the title compound (2.38 g, 6.97 mmol, 58% yield). 1H NMR (300 MHz, CDCl3) δ 8.37 (dt, J = 6.9, 1.2 Hz, 1H), 7.93 (s, 1H), 7.64 (dt, J = 9.1, 1.2 Hz, 1H), 7.55 (s, 1H) , 7.21 (ddd, J = 9.1, 6.7, 1.3 Hz, 1H), 6.80 (td, J = 6.8, 1.2 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.02 (s, 2H), 3.63 (s, 2H), 3.03 - 2.92 (m, 2H), 2.83 (t, J = 5.8 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H).

[0291] Step 2; 6-(imidazo[1,2-a]pyridin-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- Sodium carboxylate (Intermediate 49) To a solution of Intermediate 48 (2.38 g, 6.97 mmol) in MeOH (69.7 ml) was added NaOH 1M (6.97 mL, 6.97 mmol) and the reaction mixture was stirred at room temperature every other week. The solvent was evaporated in vacuo to afford the title compound in quantitative yield. 1H NMR (300 MHz, DMSO-d6) δ 8.48 (dt, J = 6.9, 1.3 Hz, 1H), 7.60 - 7.50 (m, 2H), 7.43 (s, 1H), 7.24 (ddd, J = 9.1, 6.7 , 1.3 Hz, 1H), 6.91 (td, J = 6.8, 1.2 Hz, 1H), 3.99 (s, 2H), 3.57 (s, 2H), 2.85 (t, J = 5.8 Hz, 2H), 2.67 (t , J = 5.8 Hz, 2H).

[0292] Step 3; 6-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-( Trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 65) Intermediate 49 (0.1 g, 0.298 mmol ) was dissolved in DMF (0.745 ml) and DCM (2.236 ml), followed by addition of DIPEA (0.312 ml, 1.789 mmol) and HATU (0.227 g, 0.596 mmol). The RM was stirred for 15 minutes and then 3-fluoro-5-(trifluoromethyl)aniline (0.053 g, 0.298 mmol) was added. The reaction was stirred at room temperature until LCMS indicated consumption of starting material. The reaction mixture was 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 water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by FC (DCM 100% to 10% MeOH / DCM) to give the title compound (23 mg, 0.043 mmol, 14% yield) 1H NMR (300 MHz, DMSO-d6) δ 10.48 (s, 1H) , 8.49 (d, J = 6.8 Hz, 1H), 8.18 (q, J = 1.8 Hz, 2H), 8.14 (s, 1H), 8.07 (s, 1H), 7.69 (s, 1H), 7.58 (d, J = 9.8 Hz, 2H), 7.46 (d, J = 1.5 Hz, 1H), 7.26 (dd, J = 8.6, 7.2 Hz, 1H), 6.93 (t, J = 6.7 Hz, 1H), 4.05 (s, 2H), 3.67 (s, 2H), 2.86 (d, J = 6.5 Hz, 2H), 2.79 (d, J = 5.4 Hz, 2H), 2.17 (d, J = 1.0 Hz, 3H). LC-MS (ESI) Method 8: tR = 1.69 min; m / z (M+1) = 537.2

[0293] Example 66: Preparation of 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethoxy)phenyl)- 4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide Example 66 Step 1; 6-((1H-pyrazolo[3,4-b]pyridine- 5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl ester (intermediate 50) under argon to intermediate 38 (0.73 g, 2.95 mmol) and 1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (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. Then STAB (1.249 g, 5.89 mmol) was added and the reaction mixture was stirred at room temperature overnight. Then the reaction mixture was diluted with DCM and washed with a 1:1 mixture of K2CO3 (sat) 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 material was purified via FCC using DCM / MeOH (DCM to 10% MeOH / DCM) to afford the title compound (0.86 g, 2.51 mmol, 85% yield). 1H NMR (300 MHz, DMSO-d6) δ 13.60 (s, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 8.12 (s, 1H), 8.11 (d, J = 1.3 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.82 (s, 2H), 3.63 (s, 2H), 2.85 (d, J = 5.8 Hz, 2H), 2.75 (t, J = 5.7 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H).

[0294] Step 2; 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c ] Lithium pyridine-3-carboxylate (intermediate 51) To a solution of intermediate 50 (0.86 g, 2.51 mmol) in MeOH (24 ml) was added 1M LiOH (5.02 ml, 5.02 mmol) and stirred at 45 °C The reaction mixture was left overnight. The reaction mixture was concentrated in vacuo to afford the title compound (0.98 g, 3.06 mmol) in quantitative yield. 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, J = 2.1 Hz, 1H), 7.81 (s, 1H), 7.72 (d, J = 2.1 Hz, 1H), 7.39 (s, 1H), 3.65 (s, 2H), 3.48 (s, 2H), 2.86 (d, J = 5.9 Hz, 2H), 2.65 (t, J = 5.8 Hz, 2H).

[0295] Step 3; 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethoxy)phenyl)-4, 5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 66) 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 RM was stirred for about 15 minutes and then 3-(trifluoromethoxy)aniline (0.084 ml, 0.624 mmol) was added. And stirred RM overnight at room temperature. The crude was cooled and diluted with DCM, and water was added. The mixture was stirred for 15 minutes and the phases were separated. The organic phase was washed with 5% citric acid, water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure.

[0296] The crude material was purified via FCC (DCM to 10% MeOH / DCM) to afford the title compound (7.56 mg, 0.016 mmol, 5.11% yield). 1H NMR (300 MHz, MeOH-d4) δ 8.59 (s, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.12 (s, 1H), 7.95 (s, 1H), 7.79 (s, 1H) , 7.59 (d, J = 8.2 Hz, 1H), 7.41 (t, J = 8.2 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 3.92 (s, 2H), 3.75 (s, 2H) , 3.04 - 2.98 (m, 2H), 2.93 - 2.85 (m, 2H). LC-MS (ESI) method 3: tR = 2.17 min; m / z (M+1) = 474.0

[0297] The following compounds were prepared via amido coupling as described for Example 66, Steps 1 to 3, using the corresponding commercially available aniline in Step 3. Example number structure Intermediate 51 amount Product quantity (Yield) Purification method material 67 100mg 11.5mg (8%) Preparative HPLC (ACN, H 2 O + 0.05% NH 3 ) 1 H NMR (300 MHz, MeOH-d 4 ) δ 8.59 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 1.9 Hz, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.85 (d, J = 6.4 Hz, 2H ), 7.16 (d, J = 8.4 Hz, 1H), 3.92 (s, 2H), 3.75 (s, 2H), 3.05 - 2.97 (m, 2H), 2.88 (t, J = 5.8 Hz, 2H). LC-MS (ESI): Method 8 t R = 2.74 min; m / z (M+1) = 476.0 133 30 mg (as carboxylic acid) 5.5mg (13%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d6) δ 13.63 (s, 1H), 11.70 - 11.70 (m, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.27 (s, 1H), 8.18 (d, J=1.7 Hz, 1H), 8.13 (d, J=0.9 Hz, 1H), 6.36 (s, 1H), 3.84 (s, 2H), 3.65 (s, 2H), 2.92 - 2.87 (m, 2H), 2.77 (t, J=5.8 Hz, 2H), 1.29 (s, 9H) LC-MS (ESI): Method 7 t R = 3.02 min; m / z [M+H]+ = 437.3 134 30 mg (as carboxylic acid) 7mg (16%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d6) δ 13.62 (s, 1H), 11.11 (s, 1H), 8.53 - 8.52 (m, 1H), 8.26 (s, 1H), 8.18 (d, J=1.5 Hz, 1H), 8.13 (s, 1H), 6.70 (s, 1H), 3.84 (s, 2H), 3.65 (s, 2H), 2.88 (d, J=4.9 Hz, 2H), 2.80 - 2.74 (m, 2H ), 1.32 (s, 9H) LC-MS (ESI): Method 6 t R = 4.36 min; m / z [M+H]+ = 437.4

[0298] 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 step 1; 6-(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-4,5,6, Ethyl 7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 52) to Intermediate 38 (5 g, 20.18 mmol) and 1H-pyrrolo[2,3-b]pyridine - To a solution of 5-carboxylic acid (3.27 g, 20.18 mmol) in DCM (101 ml) was added DIPEA (28.2 ml, 161 mmol) followed by T3P (24.03 ml, 40.4 mmol) and stirred RM at room temperature overnight. The reaction mixture was diluted with DCM, water was added and this mixture was stirred for 10 min. The phases were then separated, the aqueous phase was washed with DCM (3x50 mL), the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified via FC with DCM:MeOH (DCM to 5% MeOH) to afford the title compound (1.57 g, 4.42 mmol, 22% yield). 1H NMR (300 MHz, CDCl3) δ 10.50 (s, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 8.03 (s, 1H), 7.47 (d , J = 3.6 Hz, 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).

[0299] Step 2; 6-(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- Sodium carboxylate (Intermediate 53) To a solution of Intermediate 52 (1.6 g, 4.50 mmol) in MeOH (45.0 ml) was added 1M NaOH (6.75 mL, 4.92 mmol) and the reaction mixture was stirred at room temperature every other week. The solvent was evaporated under reduced pressure to obtain the title compound (1.52 g, 4.35 mmol, 97% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.22 (d, J = 2.1 Hz, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.60 (s, 1H), 7.56 (d, J = 3.0 Hz , 1H), 6.42 (d, J = 3.0 Hz, 1H), 4.76 (s, 2H), 3.71 (s, 2H), 3.04 (t, J = 5.8 Hz, 2H).

[0300] 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) Weigh intermediate 53 (0.1 g, 0.286 mmol) and HATU in a reaction tube backfilled with argon (×3) (0.218 g, 0.573 mmol). Reagents were suspended in DCM (2.147 ml) and DMF (0.716 ml). Then DIPEA (0.400 ml, 2.290 mmol) was 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 material 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 material was purified by preparative HPLC to give the desired compound as the formate salt. The salt was washed with 1:1 NaHCO3(sat):H2O solution and the desired compound was extracted with DCM (x3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (10 mg, 0.021 mmol, 7.43% yield). 1H NMR (300 MHz, DMSO-d6) δ 11.93 (s, 1H), 10.40 (s, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 2.4 Hz, 2H), 8.10 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.65 - 7.53 (m, 2H), 7.44 (d, J = 8.0 Hz, 1H), 6.55 (dd, J = 3.5, 1.8 Hz, 1H), 4.86 (s, 2H), 3.75 (s, 2H), 2.99 (s, 2H). LC-MS (ESI) method 3: tR = 3.14 min; m / z (M+1) = 471.1

[0301] 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]pyridine-3-carboxamide Example 69 Step 1; 6-((1H-pyrrolo[2,3-b]pyridine-5-yl )methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl ester (intermediate 54) under argon to intermediate 38 (3.00 g, 12.11 mmol) and imidazo[1,2-a]pyridine-3-carbaldehyde (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 another week. Then the reaction mixture was diluted with DCM and washed with a 1:1 mixture of K2CO3 (sat) 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 material was purified via FCC using DCM / MeOH (DCM to 10% MeOH / DCM) to afford the title compound (2.24 g, 6.56 mmol, 52% yield). 1H NMR (300 MHz, CDCl3) δ 10.41 (s, 1H), 8.35 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.94 (s, 1H), 7.37 (dd , J = 3.6, 1.9 Hz, 1H), 6.50 (dd, J = 3.6, 1.5 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.88 (s, 2H), 3.73 (s, 2H) , 3.05 (t, J = 5.9 Hz, 2H), 2.90 (t, J = 5.8 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H).

[0302] Step 2; 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c] Sodium pyridine-3-carboxylate (intermediate 55) To a solution of intermediate 54 (2.24 g, 6.56 mmol) in MeOH (65.6 ml) was added NaOH 1M (6.56 ml, 6.56 mmol) and the reaction mixture was heated at 40 °C Stir overnight. The solvent was evaporated in vacuo to afford the title compound in quantitative yield. 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 3.3 Hz, 2H), 6.29 (d , J = 3.0 Hz, 1H), 3.69 (s, 2H), 3.51 (s, 2H), 2.88 (d, J = 5.8 Hz, 2H), 2.66 (t, J = 5.8 Hz, 2H).

[0303] Step 3: 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5, 6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 69) Intermediate 55 (0.1 g, 0.298 mmol) was dissolved in DMF (0.745 ml) and DCM (2.236 ml ), followed by addition of DIPEA (0.312 ml, 1.789 mmol) and HATU (0.227 g, 0.596 mmol). The RM was stirred for 15 minutes, and then 3-(trifluoromethyl)aniline (0.045 ml, 0.358 mmol) was added. The reaction was stirred at room temperature until LCMS indicated consumption of starting material or significant conversion 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 (Caution: semi-solid product stuck to the glass). The combined organic layers were washed with saturated aqueous NaHCO3 and brine. The crude product was purified via preparative HPLC to afford the title compound (18 mg, 0.039 mmol, 13% yield). 1H NMR (300 MHz, DMSO-d6) δ 11.59 (s, 1H), 10.33 (s, 1H), 8.19 (d, J = 2.0 Hz, 2H), 8.09 (s, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.49 - 7.38 (m, 2H), 6.42 (dd, J = 3.4, 1.9 Hz, 1H), 3.78 (s, 2H), 3.62 (s, 2H), 2.86 (t, J = 5.7 Hz, 2H), 2.75 (t, J = 5.7 Hz, 2H). LC-MS (ESI) method 3: tR = 1.93 min; m / z (M+1) = 457.0

[0304] The following compounds were prepared via amido coupling as described for Example 69, Steps 1-3, using the corresponding commercially available or previously synthesized amine in Step 3. Example number structure Intermediate 55 quantity Product amount (yield) Purification method material 70 100mg 10mg (7%) Preparative HPLC followed by NaHCO 3 Saturated solution washing followed by preparative TLC 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.60 (s, 1H), 9.96 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.04 (s, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.46 (d , J = 3.4 Hz, 1H), 6.42 (d, J = 3.4 Hz, 1H), 6.08 (s, 1H), 3.78 (s, 2H), 3.61 (d, J = 4.8 Hz, 5H), 2.86 (s , 2H), 2.76 (d, J = 5.5 Hz, 2H), 1.22 (s, 9H). LC-MS (ESI): Method 3 t R = 1.46 min; m / z (M+1) = 449.0 71 100mg 36mg (25%) reverse phase FCC+ Preparative TLC 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.59 (s, 1H), 10.13 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.09 - 8.00 (m, 2H), 7.97 - 7.87 (m, 2H), 7.45 (dd, J = 3.4, 2.5 Hz, 1H), 7.25 (d, J = 9.1 Hz, 1H), 6.42 (dd, J = 3.4, 1.8 Hz, 1H), 3.87 (s, 3H), 3.78 (s, 2H), 3.62 (s, 2H), 2.86 (d, J = 5.6 Hz, 2H), 2.75 (t, J = 5.6 Hz, 2H). LC-MS (ESI): Method 3 t R = 1.90 min; m / z (M+1) = 487.1 72 80mg 20mg (18%) FCC 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.59 (s, 1H), 10.29 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.06 (s, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.87 (s , 1H), 7.68 (dt, J = 8.6, 1.1 Hz, 1H), 7.51 - 7.39 (m, 2H), 7.10 - 7.00 (m, 1H), 6.42 (dd, J = 3.4, 1.8 Hz, 1H), 3.78 (s, 2H), 3.62 (s, 2H), 2.85 (d, J = 5.6 Hz, 2H), 2.76 (d, J = 5.3 Hz, 2H). LC-MS (ESI): Method 3 t R = 1.99 min; m / z (M+1) = 473.1 73 80mg 3mg (3%) Preparative HPLC 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.60 (s, 1H), 10.53 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.12 (s, 1H), 7.99 - 7.88 (m, 3H), 7.45 (d, J = 3.4 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 6.42 (d, J = 3.4 Hz, 1H), 3.78 (s, 2H), 3.62 (s, 2H), 2.90 - 2.82 (m, 2H), 2.80 - 2.70 (m, 2H). LC-MS (ESI): Method 3 t R = 2.12 min; m / z (M+1) = 475.0

[0305] Example 74: Preparation of 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-( Trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide step 1; 3-((3-(4-methyl- 1H-Imidazol-1-yl)-5-(trifluoromethyl)phenyl)aminoformyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid Tertiary butyl ester (intermediate 56) to 6-(tertiary butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (1.5 g, 5.29 mmol) and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (1.277 g, 5.29 mmol) in DCM (26.5 ml) was added DIPEA ( 5.55 ml, 31.8 mmol), followed by T3P (6.30 ml, 10.59 mmol) and stirred RM at room temperature every other week. The reaction mixture was diluted with DCM, water was added and this mixture was stirred for 10 min. The phases were then separated, the aqueous phase was washed with DCM (3x50 mL), the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified via (DCM to 10% MeOH / DCM) to afford the title compound (362 mg, 0.715 mmol, 13.50% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.19 (q, J = 1.9, 1.4 Hz, 3H), 8.07 (d, J = 1.9 Hz, 1H), 7.74 - 7.67 (m, 1H), 7.46 (t, J = 1.3 Hz, 1H), 4.60 (s, 2H), 3.58 (t, J = 5.8 Hz, 2H), 2.87 (t, J = 5.8 Hz, 2H), 2.18 (d, J = 1.0 Hz, 3H), 1.43 (s, 9H).

[0306] 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) To a solution of Intermediate 56 (0.362 g, 0.715 mmol) in DCM (3.57 ml) was added 4N HCl in dihydrochloride Alkane (0.893 ml, 3.57 mmol), and stirred RM at room temperature overnight. Et2O was added to RM until no more precipitate was observed, which was then filtered off to give the title compound (0.33 g, 0.745 mmol). 1H NMR (300 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.61 (s, 1H), 9.55 (s, 1H), 8.60 (s, 1H), 8.57 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 7.91 (s, 1H), 4.39 (s, 2H), 3.37 (m, 2H), 3.13 (m, 2H), 2.36 (d, J = 1.1 Hz, 3H).

[0307] Step 3: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoro Methyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 74) Imidazo[1,2-a]pyridine- 3-Carboxylic acid (29.3 mg, 0.181 mmol) was dissolved in dry 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). The RM was stirred for 1 h, then Intermediate 57 (80 mg, 0.181 mmol) was added. And stirred RM overnight at room temperature. The RM was allowed to cool, diluted with DCM (15ml) and quenched with 5% citric acid (10ml). The phases were separated and the organic layer was washed with saturated NaHCO3 (aq) and brine, dried over Na2SO4 and evaporated. The crude material was purified via preparative HPLC (mobile phase: ACN + 0.1% FA, H2O + 0.1% FA) to afford the title compound (40 mg, 0.073 mmol, 40.2% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.96 (dt, J = 7.0, 1.3 Hz, 1H), 8.25 - 8.18 (m, 3H), 8.14 (d, J = 3.8 Hz, 1H), 8.10 (d, J = 1.7 Hz, 1H), 7.77 - 7.68 (m, 2H), 7.51 - 7.42 (m, 2H), 7.10 (td, J = 6.9, 1.2 Hz, 1H), 5.03 (s , 2H), 3.99 (t, J = 5.8 Hz, 2H), 3.09 (s, 2H), 2.18 (d, J = 1.0 Hz, 3H). LC-MS (ESI) Method 8: tR = 2.19 min; m / z (M+1) = 550.9

[0308] Example 75: Preparation of 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(tertiary butyl)-1-(p Tolyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide Example 75 Step 1: 6-(three Butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate sodium (intermediate 58) converts 4,7-dihydrothieno[2, 3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tert-butyl) 3-ethyl ester (15 g, 48.2 mmol) was dissolved in MeOH (482 ml) followed by addition of 1M NaOH (72.3 ml , 72.3 mmol), and stirred RM overnight at room temperature. The reaction mixture was dried under reduced pressure to obtain the title compound in quantitative yield. 1H NMR (300 MHz, DMSO-d6) δ 7.46 (s, 1H), 4.49 (s, 2H), 3.51 (t, J = 5.8 Hz, 2H), 2.89 (t, J = 5.8 Hz, 2H), 1.41 (s, 9H).

[0309] Step 2; 3-((3-(tertiary butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)aminoformyl)-4,7-dihydrothieno [2,3-c]Pyridine-6(5H)-tertiary butyl carboxylate (Intermediate 59) Intermediate 58 (5 g, 16.38 mmol) and HATU (12.45 g, 32.8 mmol) were weighed into a reaction tube , backfilled with argon (×3). 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-pyrazol-5-amine (3.49 g, 15.22 mmol) was added and the reaction was stirred until LC- MS exhibited complete SM consumption. Further addition of HATU and DIPEA and increasing the reaction temperature were necessary to obtain complete conversion. The reaction was quenched by adding water, then extracted with DCM (x3). The organic layers were combined and washed with 1:1 NaCl(sat):H2O solution, followed by brine. The combined organic layers were then concentrated under vacuum and the crude material was purified via FCC (AcOEt / DCM, 0% to 100%) to afford the title compound (3.64 g, 7.36 mmol, 44.9% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.01 (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 = 5.8 Hz, 2H), 2.70 (s, 2H), 2.32 (s, 3H), 1.42 (s, 9H), 1.30 (s, 9H).

[0310] Step 3: N-(3-(tertiary butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2 ,3-c] Pyridine-3-carboxamide hydrochloride (intermediate 60) Intermediate 59 (2.27 g, 4.59 mmol) was dissolved in DCM (45.9 ml) and cooled to 0 °C. HCl in dioxane (11.47 ml, 45.9 mmol) was added to the reaction mixture and stirred for 16 hours. The crude material was concentrated in vacuo and triturated with Et2O to afford the title compound (1.834 g, 4.26 mmol, 93% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.45 (s, 2H), 8.20 (s, 1H), 7.44 - 7.35 (m, 2H), 7.24 (d, J = 8.3 Hz, 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).

[0311] Step 4: 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(tertiary butyl)-1-(p-tolyl) )-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 75) Intermediate 60 (0.1 g , 0.232 mmol) and 1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (0.068 g, 0.464 mmol) were added to a small reaction tube and backfilled with argon (x3). MeOH (1.160 ml) was added to the reaction mixture followed by acetic acid (0.040 ml, 0.696 mmol) and the tube was sealed and stirred at 50 °C for 1 h. The reaction was then cooled to rt and STAB (80 mg, 1.275 mmol) was added and the reaction was stirred at 50 °C until complete consumption of SM was confirmed by LC-MS. Further addition of STAB was necessary 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) and the combined organic layers were washed once with brine and the crude mixture was purified via HPLC. Concentration of the pure fractions gave the desired product containing formic acid. The compound was triturated with 0.1 M NaHCO3 solution to afford the title compound (46 mg, 0.088 mmol, 37.7% yield). 1H NMR (300 MHz, DMSO-d6) δ 13.62 (s, 1H), 9.97 (s, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 1.9 Hz, 1H), 8.12 (d, J = 1.3 Hz, 1H), 7.95 (s, 1H), 7.39 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.3 Hz, 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). LC-MS (ESI) method 3: tR = 1.96 min; m / z (M+1) = 526.2.

[0312] The compounds reported in the table below were prepared via reductive amination as described for Example 75, steps 1-4, in step 4 using the corresponding commercially available aldehyde. Example number structure SM amount Product amount (yield) Purification method material 76 100mg 4.5mg (4%) Preparative HPLC 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.62 (s, 1H), 9.98 (s, 1H), 8.17 (d, J = 4.6 Hz, 1H), 7.95 (s, 1H), 7.40 (d, J = 9.2 Hz, 3H), 7.25 (d , J = 7.9 Hz, 2H), 7.06 (s, 1H), 6.59 (s, 1H), 6.32 (s, 1H), 3.96 (s, 2H), 3.65 (s, 2H), 2.73 (s, 4H) , 2.31 (s, 3H), 1.29 (s, 9H). LC-MS (ESI): Method 7 t R = 2.08 min; m / z (M+1) = 525.3

[0313] Example 77: Preparation of 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(tertiary butyl)-1-methyl -1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide Step 1: 3-((3-(tertiary butane Base)-1-methyl-1H-pyrazol-5-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tertiary butyl Ester (Intermediate 61) Intermediate 58 (1 g, 3.28 mmol) and HATU (2.491 g, 6.55 mmol) were weighed into a reaction tube and backfilled 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-pyrazol-5-amine (0.502 g, 3.28 mmol) was added and the reaction mixture was stirred at room temperature until LC- The MS acknowledges the complete consumption of the SM. Further addition of HATU was necessary to observe complete conversion.

[0314] The reaction mixture was then extracted with DCM / H2O (x3), and the combined organic layers were washed with 1:1 NaCl(sat):H2O solution, followed by brine. The combined organic layers were then concentrated in vacuo and the crude material was purified via flash column chromatography using a Puriflash instrument (0-50% AcOEt / hexanes. Product eluted at 50% AcOEt) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.14 (s, 1H), 6.08 (s, 1H), 4.59 (s, 2H), 3.59 (m, 5H), 2.82 (d, J = 5.7 Hz, 2H), 1.43 (s, 9H), 1.23 (s, 9H).

[0315] Step 2: N-(3-(tertiary butyl)-1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3- c] Pyridine-3-carboxamide hydrochloride (intermediate 62) Intermediate 61 (1.13 g, 2.70 mmol) was dissolved in DCM (27.0 ml) and cooled to 0°C. HCl in dioxane (3.37 ml, 13.50 mmol) was added dropwise and the reaction was stirred at room temperature for 16 hours. The reaction mixture was then concentrated and the residue was triturated with Et2O to obtain the title compound in quantitative yield. 1H NMR (300 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.46 (s, 2H), 8.34 (s, 1H), 6.09 (s, 1H), 4.38 (s, 2H), 3.63 (s, 3H), 3.37 (t, J = 6.8 Hz, 2H), 3.07 (t, J = 6.0 Hz, 2H), 1.23 (s, 9H).

[0316] Step 3: 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(tertiary butyl)-1-methyl-1H -pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 77) Intermediate 62 (100 mg, 0.282 mmol ) and 1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (41.5 mg, 0.282 mmol) were added to a small reaction tube and backfilled with argon (x3). MeOH (1409 μl) was added to the reaction mixture followed by AcOH (48.6 μl, 0.845 mmol) and the tube was sealed and stirred at 50 °C for 1 h. The reaction was then cooled to rt and STAB (80 mg, 1.268 mmol) was added and the reaction was stirred at 50 °C until complete consumption of SM was confirmed by LC-MS. Further addition of STAB was necessary to observe complete conversion. The reaction mixture was quenched with saturated NaHCO, transferred to a separatory funnel and the desired product was extracted with DCM (x3), and the combined organic layers were washed once with brine, concentrated under vacuum and the crude mixture was subjected to flash column chromatography on a Puriflash instrument (0-10% MeOH / DCM) and concentration of the pure fractions afforded the title compound (39 mg, 0.087 mmol, 30.8 % yield). 1H NMR (300 MHz, DMSO-d6) δ 13.62 (s, 1H), 9.97 (s, 1H), 8.51 (d, J = 2.0 Hz, 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 = 5.5 Hz, 2H), 2.76 (t, J = 5.8 Hz, 2H), 1.22 ( s, 9H). LC-MS (ESI) method 9: tR = 1.90 min; m / z (M+1) = 450.0

[0317] The compounds reported in the table below were prepared via reductive amination as described for Example 77, Steps 1-4, in Step 4 using the corresponding commercially available aldehyde. Example serial number structure intermediate 62 quantity Product quantity (Yield) Purification method material 78 100mg 14mg (11%) Preparation HPLC 1 H NMR (300 MHz, MeOH-d 4 ) δ 8.56 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.02 (s, 1H), 6.13 (s, 1H), 3.96 - 3.90 (m, 2H), 3.79 - 3.73 (m, 2H), 3.70 (s, 3H), 3.00 (d, J = 5.8 Hz, 2H), 2.89 (t, J = 5.8 Hz, 2H), 2.59 (s, 3H), 1.30 (s, 9H). LC-MS (ESI): Method 8 t R = 2.34 min; m / z (M+1) = 464.2

[0318] Example 79: Preparation of N-(5-tertiary 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 Step 1: N-(5-tertiary butyl-2-methyl-pyrazole- 3-yl)-6-(7-methylimidazo[1,2-a]pyridine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3- Formamide (Example 79) Prepared according to general procedure G from 7-methylimidazo[1,2-a]pyridine-3-carboxylic acid (22 mg, 0.124 mmol) and intermediate 62. Purification by reverse phase preparative HPLC (Sunfire C18 19x150 mm, 10um 5-60% ACN / H2O (0.1% FA), 20ml / min, RT) afforded the title compound (23 mg, 43%). ¹H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.88 (d, J=7.3 Hz, 1H), 8.19 (s, 1H), 8.09 (s, 1H), 7.54 (s, 1H) , 6.98 (dd, J=1.7, 7.2 Hz, 1H), 6.11 - 6.10 (m, 1H), 5.02 (s, 2H), 3.98 (t, J=5.7 Hz, 2H), 3.63 (s, 3H), 3.05 (s, 2H), 2.42 (s, 3H), 1.24 (s, 9H). LC-MS (ESI) Method 7: tR = 3.33 min; m / z (M+1) = 477.4

[0319] The compounds reported in the table below were prepared as described for Example 79, Step 1 in which the corresponding commercially available carboxylic acid was applied. Example number structure SM amount Product amount (yield) Purification method material 80 44mg 3.3mg (6%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.04 (s, 1H), 8.77 (s, 1H), 8.19 (s, 1H), 8.07 (s, 1H), 7.65 (d, J=9.7 Hz, 1H), 7.34 (dd, J=1.7, 9.2 Hz, 1H), 6.10 (s, 1H), 5.04 - 5.00 (m, 2H), 3.98 (t, J=5.6 Hz, 2H), 3.63 (s, 3H), 3.07 - 3.04 (m, 2H), 2.34 (s, 3H), 1.24 (s, 9H) LC-MS (ESI): Method 7 t R = 3.44 min; m / z (M+1) = 477.4 81 44mg 7mg (13%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.05 (s, 1H), 9.03 (dd, J=2.1, 5.0 Hz, 1H), 8.23 ​​(s, 1H), 8.20 (s, 1H), 7.85 (dd, J=5.3, 9.9 Hz, 1H) , 7.62 (ddd, J=2.3, 7.9, 10.0 Hz, 1H), 6.10 (s, 1H), 5.04 (s, 2H), 4.01 - 3.96 (m, 2H), 3.63 (s, 3H), 3.08 - 3.07 (m, 2H), 1.24 (s, 9H) LC-MS (ESI): Method 7 t R = 3.94 min; m / z (M+1) = 481.3 82 44mg 33mg (54%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.05 (s, 1H), 9.37 (s, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 7.96 (d, J=9.4 Hz, 1H), 7.73 (dd, J=1.9, 9.4 Hz, 1H), 6.10 (s, 1H), 5.04 (s, 2H), 4.00 (t, J=5.3 Hz, 2H), 3.63 (s, 3H), 3.12 - 3.04 (m, 2H), 1.24 ( s, 9H) LC-MS (ESI): Method 7 t R = 4.70 min; m / z (M+1) = 531.3 83 44mg 33mg (54%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.05 (s, 1H), 9.05 (dd, J=0.8, 2.1 Hz, 1H), 8.19 (s, 2H), 7.81 (dd, J=0.8, 9.6 Hz, 1H), 7.55 (dd, J= 2.1, 9.5 Hz, 1H), 6.10 (s, 1H), 5.03 - 5.02 (m, 2H), 3.98 (t, J=5.7 Hz, 2H), 3.63 (s, 3H), 3.07 - 3.06 (m, 2H ), 1.24 (s, 9H). LC-MS (ESI): Method 7 t R = 4.31 min; m / z (M+1) = 497.2

[0320] Example 84: Preparation of 6-(imidazo[1,2-a]pyr-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6 ,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide Step 1: 3-((3-(trifluoromethyl)phenyl)carbamoyl)-4,7-di Hydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (Intermediate 63) 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 RM was stirred at RT for 15 min, and 3-(trifluoromethyl)aniline (1.964 ml, 15.72 mmol) was added. The RM was stirred at room temperature until LC-MS showed complete consumption of SM. Raising the reaction temperature to 40°C and further addition of HATU and 3-(trifluoromethyl)aniline were necessary to achieve complete conversion. The reaction mixture was 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 water, 5% wt citric acid solution, twice with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by FC (DCM to 10% MeOH / DCM) to afford the title compound (4.36 g, 10.22 mmol, 78% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.16 (s, 1H), 8.00 - 7.92 (m, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.47 - 7.38 (m, 1H), 4.59 (s, 2H), 3.58 (t, J = 5.8 Hz, 2H), 2.85 (t, J = 5.8 Hz, 2H), 1.43 ( s, 9H).

[0321] Step 2: N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-formamide hydrochloride (Intermediate 64) Intermediate 63 (2.82 g, 6.61 mmol) was dissolved in a minimum of DCM (6.01 ml), Et2O (60.1 ml) was added followed by 4N HCl in dioxane (16.53 ml, 66.1 mmol) And the RM was stirred overnight at room temperature. Et2O was added to the RM until no more precipitation was observed, then the solid was filtered off and the residual solvent was evaporated in vacuo to afford the title compound (2.3353 g, 6.44 mmol, 97% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.27 (s, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.95 - 7.86 (m, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.48 - 7.40 (m, 1H), 4.36 (s, 2H), 3.36 (td, J = 6.5, 5.1 Hz, 2H), 3.09 (t, J = 6.1 Hz, 2H).

[0322] Step 3: 6-(imidazo[1,2-a]pyr-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7- Intermediate 64 (0.10 g, 0.276 mmol), imidazo[1,2-a]pyridine-3-carbaldehyde (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 and STAB (0.117 g, 0.551 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with a 1:1 mixture of K2CO3 (sat) 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 material was purified via FCC using DCM / MeOH (DCM to 5% MeOH / DCM) to afford the title compound (32 mg, 0.070 mmol, 25.4% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.07 (d, J = 1.5 Hz, 1H), 8.56 (dd, J = 4.7, 1.5 Hz, 1H), 8.17 (s, 1H) , 8.10 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 4.6 Hz, 1H), 7.82 (s, 1H), 7.57 (t, J = 8.0 Hz, 1H) , 7.42 (d, J = 7.7 Hz, 1H), 4.12 (s, 2H), 3.68 (s, 2H), 2.85 (d, J = 5.5 Hz, 2H), 2.78 (d, J = 5.2 Hz, 2H) . LC-MS (ESI) method 3: tR = 1.85 min; m / z (M+1) = 458.0

[0323] The compounds reported in the table below were prepared via reductive amination as described for Example 84, Steps 1-3, in Step 3 using the corresponding commercially available aldehyde. Example number structure Intermediate 64 Quantity - Program Change Product amount (yield) Purification method material 85 100mg 69mg (55%) FCC 1 H NMR (300 MHz, DMSO-d 6 ) δ 13.62 (s, 1H), 10.34 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.19 (s, 1H), 8.17 (d, J = 1.9 Hz, 1H), 8.12 (s , 1H), 8.10 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 3.83 (s , 2H), 3.65 (s, 2H), 2.92 - 2.83 (m, 2H), 2.80 - 2.71 (m, 2H). LC-MS (ESI): Method 3 t R = 1.78 min; m / z (M+1) = 458.1 86 100mg NaBH 3 CN for STAB 44mg (35%) Preparative HPLC 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.36 (s, 2H), 8.23 ​​- 8.14 (m, 2H), 8.11 (s, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.47 - 7.39 (m, 2H), 7.08 (d, J = 4.9 Hz, 1H), 6.61 (d, J = 3.5 Hz, 1H), 3.99 (s, 2H), 3.69 (s, 2H), 2.89 (d, J = 5.6 Hz, 2H), 2.79 (d, J = 5.4 Hz, 2H). LC-MS (ESI): Method 3 t R = 1.89 min; m / z (M+1) = 457.1 87 General procedure K 53mg 26mg (36%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.35 (s, 1H), 8.59 (dd, J=1.6, 4.4 Hz, 1H), 8.20 (s, 1H), 8.15 (dd, J=1.6, 9.2 Hz, 1H), 8.11 (s, 1H) , 7.97 (d, J=8.8 Hz, 1H), 7.82 (s, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.25 (dd, J= 4.5, 9.2 Hz, 1H), 4.16 (s, 2H), 3.73 (s, 2H), 2.90 - 2.80 (m, 4H). LC-MS (ESI): Method 7 t R = 3.32 min; m / z (M+1) = 458.3 88 General program L 50mg 3.7mg (6%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.36 (s, 1H), 9.09 - 9.08 (m, 1H), 8.60 (d, J=2.1 Hz, 1H), 8.22 - 8.20 (m, 2H), 8.12 (s, 1H), 8.00 - 7.97 ( m, 1H), 7.59 (t, J=8.0 Hz, 1H), 7.45 - 7.43 (m, 1H), 6.74 (dd, J=0.9, 2.4 Hz, 1H), 3.81 (s, 2H), 3.73 (s , 2H), 2.91 (t, J=5.3 Hz, 2H), 2.82 (t, J=5.8 Hz, 2H) LC-MS (ESI): Method 7 t R = 3.47 min; m / z (M+1) = 458.3 89 General program L 50mg 6mg (9%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.35 (s, 1H), 9.11 (dd, J=1.8, 7.0 Hz, 1H), 8.58 (dd, J=1.7, 4.0 Hz, 1H), 8.25 (s, 1H), 8.20 (s, 1H) , 8.09 (s, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.05 (dd, J= 4.0, 7.0 Hz, 1H), 3.95 (s, 2H), 3.67 (s, 2H), 2.87 (t, J=5.4 Hz, 2H), 2.77 (t, J=5.6 Hz, 2H). LC-MS (ESI): Method 6 t R = 4.51 min; m / z (M+1) = 458.3

[0324] Example 90: Preparation of 6-(imidazo[1,2-a]pyridine-3-hydroxyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7 -Tetrahydrothieno[2,3-c]pyridine-3-carboxamide Dissolve imidazo[1,2-a]pyridine-3-carboxylic acid (0.049 g, 0.303 mmol) in DMF (0.689 ml) and DCM (2.067 ml), followed by 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 the phases were separated, the organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by FCC (DCM to 10% MeOH / DCM) to afford the title compound (71.64 mg, 0.152 mmol, 55% yield). 1H NMR (DMSO-d6, 300 MHz) δ 10.41 (s, 1H), 9.24 (d, 1H, J=1.5 Hz), 8.87 (dd, 1H, J=1.4, 4.7 Hz), 8.33 (s, 1H) , 8.21 (s, 2H), 8.08 (d, 1H,J=4.8 Hz), 7.98 (d, 1H,J=8.8 Hz), 7.59 (t, 1H,J=7.9 Hz), 7.44 (d, 1H, J=7.7 Hz), 4.9-5.2 (m, 2H), 3.98 (br t, 2H,J=5.4 Hz), 3.0-3.1 (m, 2H). LC-MS (ESI) method 4: tR = 2.77 min; m / z (M+1) = 471.9

[0325] The compounds reported in the table below were prepared via amido coupling as described for Example 90, using the corresponding commercially available carboxylic acids in Step 1 . General procedure changes or reagent changes are reported in the table. Example number structure Intermediate 64 quantity- program change Product amount (yield) Purification method material 91 100mg HOBt replaces HATU Replacement of DIPEA by TEA 10mg (8%) FCC 1 H NMR (300 MHz, DMSO-d 6 ) δ 13.90 (s, 1H), 10.41 (s, 1H), 8.63 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 1.3 Hz, 1H ), 8.20 (s, 2H), 7.97 (d, J = 8.2 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 4.87 (s, 2H ), 4.04 - 3.51 (m, 2H), 3.00 (s, 2H). LC-MS (ESI): Method 3 t R = 2.53 min; m / z (M+1) = 472.0 92 50mg General Program M 51mg (78%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.42 (s,1H), 8.65 (dd, J=1.5, 4.4 Hz, 1H), 8.28 (dd, J=1.5, 9.4 Hz, 1H), 8.24 - 8.19 (m, 2H), 8.09 (s, 1H), 8.00 - 7.96 (m, 1H), 7.62 - 7.57 (m, 1H), 7.47 - 7.43 (m, 1H), 7.39 (dd, J=4.4, 9.4 Hz, 1H), 5.03 - 4.72 (m, 2H), 4.04 - 3.56 (m, 2H), 3.05 - 2.98 (m, 2H). LC-MS (ESI): Method 7 t R = 4.41 min; m / z (M+1) = 472 93 50mg General Program M 38mg (58%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.42 (s, 1H), 9.37 (d, J=1.5 Hz, 1H), 8.94 (dd, J=1.5, 4.7 Hz, 1H), 8.57 (s, 1H), 8.23 ​​- 8.20 (m, 2H) , 8.11 (d, J=4.7 Hz, 1H), 8.00 - 7.98 (m, 1H), 7.63 - 7.58 (m, 1H), 7.46 - 7.44 (m, 1H), 5.00 - 4.97 (m, 2H), 3.98 - 3.93 (m, 2H), 3.07 (s, 2H) LC-MS (ESI): Method 7 t R = 4.6 min; m / z (M+1) = 472 94 50mg General Program M 38mg (58%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 )δ 10.44 - 10.40 (m, 1H), 9.26 (dd, J=1.6, 7.0 Hz, 1H), 8.75 (dd, J=1.6, 4.0 Hz, 1H), 8.49 (s, 1H), 8.23 ​​- 8.20 ( m, 2H), 8.01 - 7.97 (m, 1H), 7.62 - 7.57 (m, 1H), 7.46 - 7.43 (m, 1H), 7.22 (dd, J=4.0, 7.0 Hz, 1H), 4.89 (s, 2H), 3.96 - 3.72 (m, 2H), 3.07 - 3.00 (m, 2H) LC-MS (ESI): Method 6 t R = 4.42 min; m / z (M+1) = 472 95 50mg General Program M 37mg (57%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.41 (s, 1H), 8.22 - 8.20 (m, 2H), 8.01 - 7.98 (m, 1H), 7.63 - 7.57 (m, 1H), 7.46 - 7.43 (m, 1H), 7.29 (s, 1H ), 4.92 (s, 2H), 4.07 - 4.02 (m, 2H), 3.92 - 3.87 (m, 2H), 3.01 - 2.97 (m, 2H), 2.82 - 2.77 (m, 2H), 1.91 - 1.82 (m , 4H) LC-MS (ESI): Method 6 t R = 4.53 min; m / z (M+1) = 475 96 50mg General Program M 53mg (81%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.42 (s, 1H), 8.23 ​​- 8.21 (m, 2H), 8.01 - 7.97 (m, 1H), 7.63 - 7.58 (m, 1H), 7.52 (s, 1H), 7.47 - 7.44 (m, 1H ), 4.97 - 4.89 (m, 2H), 4.84 (s, 2H), 4.19 - 4.14 (m, 2H), 4.04 - 3.99 (m, 2H), 3.94 - 3.89 (m, 2H), 3.07 - 3.02 (m , 2H) LC-MS (ESI): Method 7 t R = 3.91 min; m / z (M+1) = 477 135 95mg Intermediate 120: 64 mg, 0.292 mmol (1.0 equiv) General Program M 0.9mg (0.06%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.41 (s, 1H), 9.69 (s, 1H), 9.11 - 9.08 (m, 1H), 8.21 (s, 2H), 8.17 (s, 1H), 7.98 (d, J=8.1 Hz, 1H) , 7.81 - 7.75 (m, 1H), 7.59 (dd, J=8.0, 8.0 Hz, 1H), 7.50 (d, J=9.6 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 5.03 ( s, 3H), 4.02 - 3.96 (m, 4H), 3.07 (s, 3H), 2.61 - 2.57 (m, 4H). LC-MS (ESI): Method 6 t R = 4.57 min; m / z [M+H]+ = 528.4 136 75mg Intermediate 113: 120 mg, 0.230 mmol (1.0 equiv, assuming 50% pure) General Program M (in room temperature) 7mg (5%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.42 (s, 1H), 8.41 (d, J=1.9 Hz, 1H), 8.22 (s, 2H), 8.03 (s, 1H), 8.00 (m, 1H), 7.61 (m, 2H), 7.51 - 7.43 (m, 2H), 5.02 (s, 2H), 3.99 (t, J=5.7 Hz, 2H), 3.08 (m, 6H), 2.50 (4H, m), 2.24 (s, 3H) LC-MS (ESI): Method 6 t R = 3.21min; m / z [M+H] + = 569.4 137 114mg Intermediate 119: 78 mg, 0.35 mmol (1.0 equiv) General Program M 59mg (32%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.42 (s, 1H), 8.63 (d, J=2.1 Hz, 1H), 8.22 (s, 2H), 8.09 (s, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.74 - 7.66 (m, 1H), 7.60 (dd, J=8.0, 8.0 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.30 (dd, J=2.5, 9.7 Hz, 1H), 5.04 (s, 2H), 4.95 (t, J=5.5 Hz, 1H), 4.04 - 3.96 (m, 4H), 3.79 - 3.73 (m, 2H), 3.09 (t, J=5.9 Hz, 2H). LC-MS (ESI) Method 6: t R = 4.22 min; m / z [M + H] + = 531.4. 138 246mg Intermediate 115: 178 mg, 0.754 mmol (1.0 equiv) General Program M 179mg (42%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.41 (s, 1H), 8.85 (d, J=7.7 Hz, 1H), 8.22 (d, J=4.1 Hz, 2H), 8.03 - 8.02 (m, 2H), 7.60 (t, J=8.0 Hz , 1H), 7.47 - 7.44 (m, 1H), 7.15 (d, J=2.3 Hz, 1H), 6.83 (dd, J=2.6, 7.7 Hz, 1H), 5.04 - 5.00 (m, 2H), 4.26 - 4.22 (m, 2H), 3.98 (t, J=5.6 Hz, 2H), 3.74 - 3.70 (m, 2H), 3.09 - 3.07 (m, 2H). LC-MS (ESI) Method 6: t R = 4.66 min; m / z [M + H] + = 545.2. 139 206mg Intermediate 118: 184 mg, 0.632 mmol (1.0 equiv) General Program M 208mg (55%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.42 (s, 1H), 8.85 (d, J=7.7 Hz, 1H), 8.22 (d, J=3.4 Hz, 2H), 8.03 - 7.97 (m, 2H), 7.60 (t, J=8.0 Hz , 1H), 7.47 - 7.44 (m, 1H), 7.16 (s, 1H), 6.82 (dd, J=2.5, 7.7 Hz, 1H), 5.04 - 5.00 (m, 2H), 4.27 - 4.24 (m, 2H ), 3.98 (t, J=5.5 Hz, 2H), 3.61 - 3.57 (m, 4H), 3.08 - 3.06 (m, 2H), 2.80 - 2.75 (m, 2H). LC-MS (ESI) Method 7: t R = 3.19 min; m / z [M + H] + = 600. 2

[0326] Example 97: Preparation of N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-4,5 ,6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide Step 1: N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6 , 7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (intermediate 65) to 6-tertiary butoxycarbonyl-5,7-dihydro-4H-thieno[2, 3-c] A solution of pyridine-3-carboxylic acid (1590 mg, 5.61 mmol, 1.00 equiv) and HATU (2560 mg, 6.73 mmol, 1.20 equiv) in N,N-dimethylformamide (22.50 mL) N,N-Diisopropylethylamine (2.9 mL, 16.8 mmol, 3.00 equiv) was added to , and the reaction mixture was stirred at room temperature for 15 minutes, after which 3-fluoro-5-(trifluoromethyl)aniline (1055 mg, 5.89 mmol, 1.05 equiv). The reaction mixture was stirred for an additional 16 hours at room temperature. Purification of the reaction mixture (ethyl acetate / cyclohexane, 0% to 100) afforded 3-((3-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydro Thieno[2,3-c]pyridine-6(5H)-carboxylic acid tert-butyl ester (1.35 g, 3.04 mmol, 1.00 eq) was dissolved in DCM (35 mL) and trifluoroacetic acid (5.0 mL, 65.9 mmol, 21.7 equiv). The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The reaction mixture was partitioned between saturated aqueous sodium carbonate (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 frit and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0% to 100% ethyl acetate / cyclohexane, followed by 0% to 100% 3:1 ethyl acetate:ethanol / ethyl acetate) to afford the title compound (500 mg, 2.69 mmol, 48% yield). ¹H NMR (400 MHz, CDCl3) δ7.80 (td, J=2.1, 10.4 Hz, 1H), 7.73 (s, 1H), 7.63 (s, 1H), 7.52 (s, 1H), 7.10 (d, J =8.3 Hz, 1H), 4.07 (s, 2H), 3.15 (t, J=5.8 Hz, 2H), 2.93 (t, J=5.7 Hz, 2H), 1.27 - 1.22 (m, 1H).

[0327] Step 2: N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-4,5,6 , 7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 97) to pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (25 mg, 0.153 mmol, 1.16 equiv) in N,N-dimethylformamide (1.50 mL) were added HATU (61 mg, 0.160 mmol, 1.22 equiv) and N,N-diisopropylethylamine (0.069 mL, 0.394 mmol, 3.00 equiv), and the reaction mixture was stirred at room temperature for 30 minutes. Intermediate 65 (50 mg, 0.131 mmol, 1.00 equiv) was added and the reaction mixture was heated at 40 overnight, then diluted with DMSO. Purification by reverse phase preparative HPLC (Sunfire C18 19x150 mm, 10um 20-80% ACN / H2O (0.1% FA), 20ml / min, RT) afforded the title compound (29.2 mg, 45%). ¹H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 9.26 (dd, J=1.6, 7.0 Hz, 1H), 8.75 (d, J=2.5 Hz, 1H), 8.49 (s, 1H) , 8.22 - 8.22 (m, 1H), 8.00 - 7.94 (m, 2H), 7.40 (d, J=8.5 Hz, 1H), 7.23 (dd, J=4.1, 7.0 Hz, 1H), 4.89 (s, 2H ), 3.95 - 3.75 (m, 2H), 3.12 - 2.97 (m, 2H). LC-MS (ESI) method 7: tR = 4.75 min; m / z (M+1) = 490.3

[0328] Example 98: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-N-(3-(4-methyl-1H-imidazol-1-yl) -5-(Trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide Example 98 Step 1: 2-Amino- 7-Methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tert-butyl) 3-ethyl ester (intermediate 66a), 2-Amino-5-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tertiary butyl ester) 3-ethyl ester ( Intermediate 66b) solution of tert-butyl 2-methyl-4-oxopiperidine-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 to the mixture and refluxed for 4 hours. The reaction mixture was cooled and the solvent was evaporated. The crude product was purified by FCC (hexane:AcOEt, 5% to 15%) to afford 13.4 g of a mixture as 2 regioisomers (1:1 by LCMS and NMR).

[0329] Step 2: 7-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tertiary butyl ester) 3-ethyl ester (Intermediate 67a), 5-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tertiary butyl) 3-ethyl ester (Intermediate 67b) To a solution of the regioisomeric mixture obtained after step 1, Intermediate 66a and Intermediate 66b (13.9 g, 40.8 mmol), in THF (204 ml) was added dropwise at 0°C Isoamyl nitrate (8.25 ml, 61.2 mmol) and the reaction mixture was warmed to RT and stirred for 30 minutes. The reaction mixture was then heated to reflux for 6 hours. The reaction was concentrated in vacuo and the crude product was purified via FCC (Hexane / AcOEt, 95:5 to 90:10) to afford a 1:1 ratio of the title compound regioisomers Intermediate 67a and Intermediate 67b (2.98 g) mixture.

[0330] Step 3: Ethyl 7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate hydrochloride (intermediate 68a) and 5- Methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride (intermediate 68b) converts the two regioisomers intermediate 67a and The mixture of intermediate 67b (2.05 g, 6.30 mmol) was dissolved in Et2O (31.5 ml), then 4N HCl in dioxane (15.75 ml, 63.0 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solid was filtered off and the residual solvent was evaporated in vacuo to give the title compound (1.4 g) as a mixture of regioisomers 68a and 68b

[0331] Step 4: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine -Ethyl 3-carboxylate (intermediate 69a), 6-(imidazo[1,2-a]pyridine-3-carbonyl)-5-methyl-4,5,6,7-tetrahydrothieno[ 2,3-c] Ethyl pyridine-3-carboxylate (Intermediate 69b) A mixture of Intermediate 68a and Intermediate 68b (1 g, 3.82 mmol) was dissolved in DCM (19.10 ml) and DIPEA (4.00 ml , 22.92 mmol), followed by T3P (4.55 ml, 7.64 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM, water was added and this mixture was stirred for 10 min. The phases were then separated, the aqueous phase was washed with DCM (3x50 mL), the combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified via FCC (DCM:MeOH, 0% to 10%) to afford 0.77 g of a mixture of title compounds.

[0332] Step 5: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine -3-Lithium carboxylate (intermediate 70a) and 6-(imidazo[1,2-a]pyridine-3-carbonyl)-5-methyl-4,5,6,7-tetrahydrothieno[2 ,3-c] Lithium pyridine-3-carboxylate (Intermediate 70b) A mixture of Intermediate 69a (550 mg, 1.489 mmol) and Intermediate 69b (550 mg, 1.489 mmol) was dissolved in methanol (14.887 mL), Then 1M LiOH (1.489 mL, 1.489 mmol) was added and the reaction was stirred at RT overnight. The reaction mixture was concentrated in vacuo to afford a mixture of title compounds 70a and 70b.

[0333] Step 6: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)- 5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 98) 3-(4-methyl Base-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (0.250 g, 1.037 mmol), a mixture of intermediates 70a and 70b (0.3 g, 0.864 mmol) were dissolved in DMF (2.159 ml) and DCM (6.48 ml) followed by DIPEA (0.905 ml, 5.18 mmol) and HATU (0.657 g, 1.728 mmol). The reaction mixture was stirred at 45°C until complete conversion of the starting material. The reaction mixture was diluted with DCM and water was added. This 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 mixture of regioisomers was purified by preparative HPLC to afford the title compound (35 mg, 0.062 mmol, 7.18% yield) as pure compound. The exact regioisomer of Example 97 was indicated by the 1H-NMR spectrum. 1H NMR (300 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.93 (dt, J = 7.0, 1.2 Hz, 1H), 8.25 (s, 1H), 8.23 ​​- 8.16 (m, 2H), 8.09 ( d, J = 2.7 Hz, 2H), 7.77 - 7.67 (m, 2H), 7.50 - 7.41 (m, 2H), 7.10 (td, J = 6.9, 1.3 Hz, 1H), 5.72 (q, J = 7.7, 6.5 Hz, 1H), 4.52 (d, J = 9.8 Hz, 1H), 3.46 (s, 1H), 3.19 - 2.96 (m, 2H), 2.18 (d, J = 1.0 Hz, 3H), 1.65 (d, J = 6.6 Hz, 3H). LC-MS (ESI) method 10: tR = 3.94 min; m / z (M+1) = 565.1

[0334] The compounds reported in the table below were prepared via amido coupling as described for Example 98, Steps 1 to 6, in Step 6 using the corresponding commercially available arylamine. Regioisomeric structures are indicated by 1H-NMR spectroscopy. Example number structure intermediate 70a+70b amount Product amount (yield) Purification method material 99 150mg 15mg (7%) Preparative HPLC 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.04 (s, 1H), 8.91 (d, J = 6.9 Hz, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.46 (dd , J = 8.8, 7.2 Hz, 1H), 7.08 (t, J = 6.8 Hz, 1H), 6.09 (s, 1H), 5.38 (d, J = 17.1 Hz, 1H), 5.11 (s, 1H), 4.63 (s, 1H), 3.62 (s, 3H), 3.19 - 3.05 (m, 1H), 2.97 (d, J = 17.0 Hz, 1H), 1.27 - 1.20 (m, 12H). LC-MS (ESI): Method 10 t R = 6.02 min; m / z (M+1) = 477. 2

[0335] Example 100: (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 Step 1: (R)-2-Amino-7-methyl-4,7-dihydrothiophene A[2,3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tert-butyl) 3-ethyl ester (intermediate 71a) and (R)-2-amino-5-methanol Base-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tertiary butyl ester) 3-ethyl ester (intermediate 71b) to (R) -2-Methyl-4-oxopiperidine-1-carboxylic acid tertiary butyl ester (4 g, 18.75 mmol) and sulfur (0.6 g, 18.75 mmol) in a mixture of ethanol (37.5 ml) were added 2 - Ethyl cyanoacetate (2.12 g, 18.75 mmol) and TEA (2.71 g, 26.8 mmol) and reflux for 4 hr. The reaction mixture was cooled and the solvent was evaporated. The crude product was purified by FCC (hexanes:AcOEt; 5% to 15%) to afford 4.90 g of a mixture of two isomers 71a and 71b in 77% combined yield (1:1 by LCMS and NMR) .

[0336] Step 2: (R)-7-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tertiary butyl ester) 3-ethyl ester (intermediate 72a) and (R)-5-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tri To a solution of Intermediate 71a, Intermediate 71b regioisomeric mixture (4.90 g, 28.8 mmol) in THF (72 ml) was added dropwise at 0 °C Isoamyl nitrite (2.53 g, 21.6 mmol) and the reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was then heated to reflux for 6 hours. The reaction was concentrated under vacuum and the crude product was purified via FCC (Hex:AcOEt, 95:5 to 90:10) to give the title compound (1.06 g) as a 1:1 mixture of regioisomers.

[0337] Step 3: (R)-Ethyl 7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate hydrochloride (intermediate 73a ) and (R)-5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride (intermediate 73b) A mixture of regioisomers Intermediate 72a Intermediate 72b (1.06 g, 3.26 mmol) was dissolved in EtO (16 ml), then 4N HCl in dioxane (12.2 ml, 49.0 mmol) was added and the reaction mixture was heated at room temperature. Stir overnight. It was then diluted with DCM, a 1:1 mixture of H2O and NaHCO3 (sat) was added and this mixture was stirred for 10 min. The phases were then separated and the organic phase was washed with water and brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material mixture of regioisomers was separated by FCC (DCM: 5M NH3 / MEOH 98 / 2) to give the following pure regioisomer: Intermediate 73a (quantitative yield) 1H NMR (300 MHz, CDCl3) δ 7.98 (d, J = 0.8 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 4.13 (q, J = 6.7 Hz, 1H), 3.37 (ddd, J = 12.5, 5.6, 2.2 Hz, 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 = 7.1 Hz, 3H). Intermediate 73b (0.32 g, 1.42 mmol, 87% yield) 1H NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 4.10 (t, J = 1.8 Hz, 2H), 3.15 (ddt, J = 17.1, 4.3, 1.3 Hz, 1H), 3.06 - 2.92 (m, 1H), 2.47 (ddt, J = 17.0, 10.1, 2.2 Hz, 1H), 1.57 (s, 1H), 1.38 (t, J = 7.1 Hz, 3H), 1.30 (d, J = 6.4 Hz, 4H).

[0338] Step 4: (R)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-4,5,6,7-tetrahydrothieno[2,3 -c] ethyl pyridine-3-carboxylate (intermediate 74) Dissolved in DMF (5.33 ml) and DCM (15.98 ml), then added 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, water was added and the mixture was stirred for 10 min. The phases were then separated, the aqueous phase was washed with DCM (3x50 mL), the combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified via FCC using DCM:MeOH (0% to 10% MeOH) to afford the title compound (0.66 g, 1.786 mmol, 84% yield). 1H NMR (300 MHz, CDCl3) δ 9.01 (dt, J = 7.1, 1.2 Hz, 1H), 8.03 (s, 1H), 7.97 (s, 1H), 7.70 (dt, J = 9.1, 1.2 Hz, 1H) , 7.36 (ddd, J = 9.1, 6.8, 1.3 Hz, 1H), 6.95 (td, J = 6.9, 1.2 Hz, 1H), 5.76 (q, J = 6.7 Hz, 1H), 4.67 (dd, J = 13.8 , 5.4 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.45 (t, J = 12.6 Hz, 1H), 3.28 (dd, J = 17.1, 3.7 Hz, 1H), 3.07 (ddd, J = 17.1, 12.1, 4.6 Hz, 1H), 1.70 (d, J = 6.7 Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H).

[0339] Step 5: (R)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-4,5,6,7-tetrahydrothieno[2,3 -c] lithium pyridine-3-carboxylate (intermediate 75) To a solution of intermediate 74 (0.66 g, 1.786 mmol) in MeOH (8.93 ml) was added 1M LiOH (3.57 ml, 3.57 mmol) and the reaction mixture Stir overnight at room temperature. The solution was concentrated in vacuo to afford the title compound in quantitative yield. 1H NMR (300 MHz, DMSO-d6) δ 8.85 (d, J = 7.0 Hz, 1H), 8.00 (s, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.57 (s, 1H), 7.45 (ddd, J = 8.6, 6.8, 1.3 Hz, 1H), 7.08 (dd, J = 7.6, 6.3 Hz, 1H), 5.55 (d, J = 6.8 Hz, 1H), 4.41 (dd, J = 14.0, 5.0 Hz, 1H), 3.38 (s, 1H), 3.24 (d, J = 17.4 Hz, 1H), 2.92 - 2.75 (m, 1H), 2.67 (s, 6H), 1.57 (d, J = 6.6 Hz, 3H ).

[0340] 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-formamide (Example 100) Intermediate 75 (0.10 g, 0.288 mmol) and 3-(trifluoromethyl) Aniline (0.072 ml, 0.576 mmol) was dissolved in DMF (0.720 ml) and DCM (2.159 ml), followed by 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. This mixture was stirred for 15 min and the phases were separated, the organic phase was washed with water, 5% wt citric acid solution and twice with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by FC (DCM / MeOH, 0% to 10% MeOH) to afford the title compound (54.03 mg, 0.112 mmol, 38.7% yield). Non-fermentative chemical reactions are performed on reactants whose absolute configuration is known by assigning an absolute configuration by inference. 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.97 - 8.89 (m, 1H), 8.21 (d, J = 5.7 Hz, 2H), 8.09 (s, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.73 (dt, J = 9.1, 1.2 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.50 - 7.40 (m, 2H), 7.09 (td, J = 6.9 , 1.3 Hz, 1H), 5.71 (q, J = 6.6 Hz, 1H), 4.57 - 4.47 (m, 1H), 3.53 - 3.39 (m, 1H), 3.17 - 2.94 (m, 2H), 1.64 (d, J = 6.7 Hz, 3H). LC-MS (ESI) Method 11: tR = 2.14 min; m / z (M+1) = 485.1

[0341] The compounds reported in the table below were prepared via amido coupling as described for Example 100, Steps 1 to 6, in Step 6 using the corresponding commercially available arylamine. Example serial number structure intermediate 75 volume Product quantity (Yield) purification method material 101 150mg 59.7mg (25%) FCC 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.58 (s, 1H), 8.93 (dd, J = 6.9, 1.2 Hz, 1H), 8.25 (s, 1H), 8.22 - 8.17 (m, 2H), 8.09 (d, J = 2.0 Hz, 2H) , 7.78 - 7.66 (m, 2H), 7.52 - 7.40 (m, 2H), 7.10 (td, J = 6.9, 1.3 Hz, 1H), 5.71 (q, J = 6.6 Hz, 1H), 4.52 (dd, J = 13.5, 4.9 Hz, 1H), 3.53 - 3.43 (m, 1H), 3.20 - 2.95 (m, 2H), 2.18 (d, J = 1.0 Hz, 3H), 1.64 (d, J = 6.6 Hz, 3H) . LC-MS (ESI): Method 3 t R = 1.56 min; m / z (M+1) = 565.1

[0342] Example 102: 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 Step 1: 2-Amino-7,7-dimethyl-4,7-dihydrothiophene [2,3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tertiary butyl) 3-ethyl ester (intermediate 76a) and 2-amino-5,5-dimethyl -4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tertiary butyl ester) 3-ethyl ester (intermediate 76b) to 2,2- To a mixture of dimethyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (5 g, 22.00 mmol) and sulfur (0.705 g, 22.00 mmol) in ethanol (44.0 ml) was added 2-cyano ethyl acetate (2.341 ml, 22.00 mmol) and TEA (4.38 ml, 31.5 mmol) and reflux for 6 hours. The solvent was evaporated and the crude material was purified by FCC (Hex:AcOEt, 95:5 to 85:15) to give the following pure regioisomer: Intermediate 76a (0.67 g, 1.890 mmol, 8.59% yield). 1H NMR (300 MHz, CDCl3) δ 5.98 (s, 2H), 4.26 (q, J = 7.1 Hz, 3H), 3.64 (dd, J = 5.9, 5.1 Hz, 2H), 2.78 (t, J = 5.5 Hz , 2H), 1.68 (s, 6H), 1.50 (s, 9H), 1.34 (t, J = 7.1 Hz, 3H). Intermediate 76b (4.27 g, 12.05 mmol, 54.8 % yield). 1H NMR (300 MHz, CDCl3) δ 5.96 (s, 2H), 4.35 (d, J = 1.5 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 2.85 (s, 2H), 1.47 (s , 9H), 1.44 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H). The exact regioisomeric structure is indicated by 1H-NMR spectroscopy.

[0343] Step 2: 7,7-dimethyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylic acid 6-(tertiary butyl ester) 3 -Ethyl ester (Intermediate 77) To a solution of Intermediate 76a (0.67 g, 1.890 mmol) in THF (9.45 ml) was added isoamyl nitrite (0.382 ml, 2.84 mmol) dropwise at 0 °C, The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was heated to reflux for 6 hours, concentrated under vacuum and the crude product was purified by FCC using hexane:AcOEt (95:5 to 90:10) to afford the title compound (160 mg, 0.471 mmol, 24.94% yield ). 1H NMR (300 MHz, CDCl3) δ 7.97 (s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.69 (t, J = 5.5 Hz, 2H), 2.96 (t, J = 5.5 Hz, 2H ), 1.79 (s, 6H), 1.51 (s, 9H), 1.36 (t, J = 7.1 Hz, 3H).

[0344] Step 3: Ethyl 7,7-dimethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate hydrochloride (intermediate 78) To a solution of intermediate 77 (0.16 g, 0.471 mmol) in DCM (3.93 ml) was added 4N HCl in dioxane (1.768 ml, 7.07 mmol) and the reaction mixture was stirred at room temperature overnight. The solid was filtered off and the residual solvent was evaporated under vacuum to afford the title compound (0.10 g, 0.363 mmol, 77% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.73 (s, 2H), 8.35 (s, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.45 (t, J = 6.1 Hz, 2H), 3.07 (t, J = 6.1 Hz, 2H), 1.69 (s, 6H), 1.29 (t, J = 7.1 Hz, 3H).

[0345] Step 4: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[2,3- c] Ethyl pyridine-3-carboxylate (Intermediate 79) 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), DIPEA (0.317 ml, 1.813 mmol) and HATU (0.345 g, 0.906 mmol) were then added. The reaction mixture was stirred overnight at room temperature. To achieve complete conversion, it was necessary to increase the temperature up to 80° C. and further addition of HATU and imidazo[1,2-a]pyridine-3-carboxylic acid. The reaction mixture was cooled, diluted with DCM and water was added, then it was stirred for 15 minutes and the phases were separated. The organic phase was washed with 5% citric acid, water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by FC (DCM / MeOH, 0% to 10%) to afford the title compound (74 mg, 0.193 mmol, 53.2% yield). 1H NMR (300 MHz, CDCl3) δ 9.05 (d, J = 7.0 Hz, 1H), 8.05 (s, 1H), 7.96 (s, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.36 (dd , J = 9.0, 6.8 Hz, 1H), 6.97 (t, J = 6.9 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.98 (t, J = 5.4 Hz, 2H), 3.21 (t , J = 5.5 Hz, 2H), 1.98 (s, 6H), 1.38 (t, J = 7.1 Hz, 3H).

[0346] Step 5: Lithium 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[2,3 -c] Pyridine-3-carboxylate (Intermediate 80) To a solution of Intermediate 79 (74 mg, 0.193 mmol) in MeOH (965 µl) was added 1M LiOH (772 µl, 0.772 mmol) and the reaction mixture Stir overnight at room temperature. The crude material was then concentrated in vacuo to afford the title compound (68 mg, 0.188 mmol, 98% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.90 (dt, J = 7.0, 1.3 Hz, 1H), 7.99 (s, 1H), 7.71 (dt, J = 9.0, 1.2 Hz, 1H), 7.51 (s, 1H), 7.48 - 7.38 (m, 1H), 7.09 (td, J = 6.9, 1.2 Hz, 1H), 3.81 (t, J = 5.3 Hz, 2H), 3.20 - 3.11 (m, 3H), 1.87 (s , 6H).

[0347] 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) 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 minutes and then 3-(trifluoromethyl)aniline (0.058 g, 0.360 mmol) was added and stirred overnight at room temperature. Further addition of amine and HATU was necessary to achieve complete conversion. The reaction mixture was cooled, diluted with DCM and water was added, it was stirred for 15 minutes and the phases were separated. The organic phase was washed with 5% citric acid, water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified via FC (DCM / MeOH, 0% to 10%) to afford the title compound (29 mg, 0.058 mmol, 32.3% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.93 (dt, J = 7.0, 1.2 Hz, 1H), 8.24 (s, 1H), 8.22 (s, 1H), 8.05 (s, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.73 (dt, J = 9.1, 1.2 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.46 (ddd, J = 9.0, 6.8 , 1.4 Hz, 2H), 7.11 (td, J = 6.9, 1.3 Hz, 1H), 3.88 (t, J = 5.3 Hz, 2H), 3.13 (t, J = 5.2 Hz, 2H), 1.93 (s, 6H ). LC-MS (ESI) method 2: tR = 2.93 min; m / z (M+1) = 499.1

[0348] Example 103: 6-(imidazo[1,2-a]pyr-3-ylmethyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4, 5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide Example 103 Example 104: 6-(imidazo[1,2-a]pyr-3-ylmethyl )-5-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide-th Isolation Example 104 Example 105: 6-(imidazo[1,2-a]pyr-3-ylmethyl)-5-methyl-N-(3-(trifluoromethyl)phenyl) - 4,5,6,7-Tetrahydrothieno[2,3-c]pyridine-3-formamide-Second Elution Example 105 Step 1: 6-(tertiary butoxycarbonyl)-7 -Lithium-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (intermediate 81a), 6-(tertiary butoxycarbonyl)-5-methyl Lithium-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 81b) Intermediate 67a (0.430 g, 1.32 mmol) was dissolved in MeOH (26.4 ml ), followed by the addition of 1M LiOH (5.29 ml, 5.29 mmol). The reaction mixture was stirred overnight at 40 °C. The crude material was concentrated in vacuo to afford a mixture of title compounds.

[0349] Step 2: 7-methyl-3-((3-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6 (5H)-Tertiary butyl carboxylate (intermediate 82a) and 5-methyl-3-((3-(trifluoromethyl)phenyl)aminoformyl)-4,7-dihydrothieno [2,3-c]Pyridine-6(5H)-tertiary butyl carboxylate (Intermediate 82b) A mixture of Intermediate 81a and Intermediate 81b (0.90 g, 2.96 mmol) was dissolved in DMF (7.42 ml) and DCM (22.26 ml) followed by DIPEA (2.073 ml, 11.87 mmol) and HATU (2.82 g, 7.42 mmol). The reaction mixture was stirred at RT for 15 min, 3-(trifluoromethyl)aniline (0.741 ml, 5.93 mmol) was added, and the mixture was stirred at 40°C overnight. It was then 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 water, 5% wt citric acid solution, twice with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by FC (DCM / MeOH, 0% to 10% MeOH). The resulting product was triturated with pentane to give 750 mg of a mixture of the title compounds.

[0350] Step 3: 7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-methyl Amide hydrochloride (intermediate 83a) and 5-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c] Pyridine-3-carboxamide hydrochloride (Intermediate 83b) A mixture of Intermediate 82a and Intermediate 82b (750 mg, 1.70 mmol) was dissolved in mi DCM (20 ml) and MeOH (4 ml), then added 4N HCl in dioxane (4.26 ml, 17.03 mmol) was added and the mixture was stirred at room temperature overnight. Et2O was added until no more precipitate was observed, then the solid was filtered off and the residual solvent was evaporated in vacuo to obtain 650 mg of a mixture of title compounds.

[0351] Step 4: 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 103), 6-(imidazo[1,2-a]pyr-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]pyr-3-ylmethyl)-5-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6, 7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 105) Intermediates 83a and 83b (0.140 g, 0.372 mmol), imidazo[1,2- a] A mixture of pyrim-3-carbaldehyde (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 minutes. STAB (0.236 g, 1.115 mmol) was then added and the reaction mixture was stirred until LC-MS showed complete consumption of starting material. Then the reaction mixture was diluted with DCM and washed with a 1:1 mixture of Na2CO3(sat) 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 material was prepurified via FCC (DCM / MeOH, 0% to 5% MeOH) to afford 60 mg of a regioisomeric mixture. The mixture was dissolved in MeOH to 11 mg / mL and then purified by preparative HPLC (Method Prep 1) to afford Example 105 (3.3 mg, 0.007 mmol, 2% yield) and Example 103 and Example 104 The mixture was further separated by SFC (method preparative 2) to obtain Example 103 (12.9 mg, 0.027 mmol, yield 7%) and Example 104 (2.8 mg, 0.006 mmol, yield 1%). Example 105: 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.06 (d, J = 1.5 Hz, 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 = 4.6 Hz, 1H), 7.78 (s, 1H), 7.58 (t, J = 8.0 Hz, 1H ), 7.43 (d, J = 7.7 Hz, 1H), 4.11 (s, 2H), 3.68 (s, 2H), 3.17 (q, J = 5.6 Hz, 1H), 3.06 - 2.97 (m, 1H), 2.75 - 2.68 (m, 1H), 1.15 (d, J = 6.6 Hz, 3H). LC-MS (ESI) Method 12: tR= 4.23 min; m / z (M+1) = 472.2; e.e. 99.3% Example 103: 1H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.07 (d, J = 1.4 Hz, 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 = 7.8 Hz, 1H), 4.26 (d, J = 14.4 Hz, 1H), 4.04 (d, J = 14.4 Hz , 1H), 3.95 (q, J = 6.6 Hz, 1H), 2.99 - 2.78 (m, 2H), 2.76 - 2.62 (m, 2H), 1.44 (d, J = 6.6 Hz, 3H). LC-MS (ESI) Method 12: tR= 4.99 min; m / z (M+1) = 472.2; e.e. 100% Example 104: 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.06 (d, J = 1.5 Hz, 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 = 4.6 Hz, 1H), 7.78 (s, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 4.11 (s, 2H), 3.68 (s, 2H), 3.17 (q, J = 5.6 Hz, 1H), 3.06 - 2.97 (m, 1H), 2.74 - 2.68 (m, 1H), 1.15 (d, J = 6.6 Hz, 3H). LC-MS (ESI) method 12: tR = 3.57 min; m / z (M+1) = 472.2; e.e. 98.3%.

[0352] 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]pyridine-3-carboxamide-first eluting enantiomer Example 106 Example 107: 6-((1H- Pyrrolo[2,3-b]pyridin-5-yl)methyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiophene [2,3-c]pyridine-3-carboxamide-second eluting enantiomer) Example 107 Step 1: 6-((1H-pyrrolo[2,3-b]pyridine-5- Base) methyl) -7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-methyl Amide-the first eluting 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]pyridine-3-carboxamide-second eluting enantiomer (Example 107) Intermediates 83a and 83b (0.20 g, 0.531 mmol), 1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (0.078 g, 0.531 mmol) and magnesium sulfate (0.064 g, 0.531 mmol) were mixed The mixture 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, and the reaction mixture was stirred at room temperature. Further addition of STAB and aldehyde was necessary to achieve complete conversion of SM. The reaction mixture was diluted with DCM, NaHCO3(sat) was added and the mixture was stirred for 15 min. The phases were separated and 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 material was prepurified via FCC (DCM / MeOH, 0% to 5%) to give 190 mg of a mixture of enantiomers, which was subsequently purified via chiral SFC (Method Prep 3) to give: Example 106:( ( s, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.48 - 7.38 (m, 2H), 6.42 (dd, J = 3.5, 1.2 Hz, 1H), 3.95 (d, J = 13.5 Hz, 1H), 3.89 (d, J = 6.7 Hz, 1H), 3.68 (d, J = 13.4 Hz, 1H), 3.05 - 2.93 (m, 1H), 2.93 - 2.78 (m, 1H), 2.77 - 2.58 (m, 2H), 1.45 (d, J = 6.5 Hz, 3H). SFC-MS (ESI) method 13: tR = 6.92 min; m / z (M+1) = 471.2; Example 107: (36 mg, 0.077 mmol, 29% yield). 1H NMR (300 MHz, DMSO-d6) δ 11.57 (s, 1H), 10.34 (s, 1H), 8.19 (d, J = 2.2 Hz, 2H), 8.12 (s, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.48 - 7.38 (m, 2H), 6.42 (dd, J = 3.5, 1.2 Hz, 1H), 3.95 (d, J = 13.5 Hz, 1H), 3.89 (d, J = 6.7 Hz, 1H), 3.68 (d, J = 13.4 Hz, 1H), 3.05 - 2.93 (m, 1H), 2.93 - 2.78 (m, 1H), 2.77 - 2.58 (m, 2H), 1.45 (d, J = 6.5 Hz, 3H). SFC-MS (ESI) Method 13: tR = 9.73 min; m / z (M+1) = 471.2

[0353] Example 109; Preparation of compound 6-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5 , 6,7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide Example 109 Step 1: 3-((5-(trifluoromethyl)pyridin-3-yl)carboxamide Base)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylic acid tertiary butyl ester (intermediate 89) to 6-(tertiary butoxycarbonyl)-4, To a suspension of 5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (250 mg, 0.882 mmol) in anhydrous acetonitrile (4.4 mL) was added 5-(trifluoroform yl) pyridin-3-amine (157 mg, 0.971 mmol) and 1-methylimidazole (0.25 mL, 3.09 mmol), causing complete dissolution. Then TCFH (371 mg, 1.32 mmol) was added and the reaction mixture was stirred at room temperature for 22 h under argon atmosphere. The reaction mixture was partitioned between saturated NaHCO3 (aq) and EtOAc, and the aqueous phase was extracted with EtOAc. The combined org. phases were passed through a hydrophobic frit and concentrated in vacuo. Purification by silica gel column chromatography (0-25% EtOAc / cyclohexane + 0.1% NEt3) afforded the desired compound (265 mg, 0.62 mmol, 70%). ¹H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.12 (d, J=2.3 Hz, 1H), 8.68 (d, J=1.0 Hz, 1H), 8.58 (t, J=1.9 Hz , 1H), 8.22 (s, 1H), 4.60 (s, 2H), 3.61 - 3.56 (m, 2H), 2.89 - 2.84 (m, 2H), 1.43 (s, 9H).

[0354] Step 2: N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-formamide (Intermediate 90) To a stirred solution of Intermediate 89 (290 mg, 0.678 mmol) in anhydrous DCM (6.78 ml) (under argon atmosphere with ice / water bath cooling) was added TFA dropwise over 5 min ( 0.52 mL, 6.78 mmol). The reaction mixture was stirred for 3 hours. Additional TFA (0.17 ml, 2.26 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in 1:1 DCM:MeOH and applied to a preconditioned 5 g Isolute SCX-II cartridge, washed with MeOH, then released with 2 M NH3 / MeOH. The 2 M NH3 / MeOH eluent was concentrated in vacuo to give the desired product (193 mg, 0.59 mmol, 87%). ¹H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.12 (d, J=2.3 Hz, 1H), 8.67 (d, J=1.0 Hz, 1H), 8.59 - 8.57 (m, 1H) , 8.12 (s, 1H), 3.88 (s, 2H), 3.17 (d, J=5.0 Hz, 1H), 2.90 (t, J=5.7 Hz, 2H), 2.78 - 2.73 (m, 2H).

[0355] Step 3: 6-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6, 7-Tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 109) From intermediate 90 (40 mg, 0.122 mmol) and pyrazolo[1,5-a ] Pyrimidine-3-carboxylic acid (17 mg, 0.104 mmol). Purification by reverse phase preparative HPLC (Sunfire C18 19x150 mm, 10 µm 20-80% acetonitrile / water - 10 mM NH4HCO3), 20 mL / min) afforded the title compound (6 mg, 0.013 mmol, 12%). LCMS (ESI): Method 6 tR = 3.79 min, m / z [M+1]+ = 473.3. ¹H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 9.26 (dd, J=1.8, 7.0 Hz, 1H), 9.13 (d, J=2.3 Hz, 1H), 8.75 (dd, J= 1.6, 4.0 Hz, 1H), 8.69 (d, J=1.0 Hz, 1H), 8.62 - 8.59 (m, 1H), 8.49 (s, 1H), 8.25 (brs, 1H), 7.23 (dd, J=4.0 , 7.0 Hz, 1H), 4.89 (s, 2H), 3.91 - 3.75 (m, 2H), 3.11 - 3.02 (m, 2H).

[0356] The compounds reported in the table below were prepared via amido coupling as described in Example 109, Steps 1-3, using the corresponding commercially available or previously synthesized carboxylic acid in Step 3. Modifications of coupling reagents, salt free bases, or chromatographic purification conditions (eg, preparative HPLC or flash chromatography) are reported in the table. Example serial number structure General procedure - Reagent volume Product quantity (Yield) Purification method material 108 General procedure G Carboxylic acid (15 mg, 0.0889 mmol): Intermediate 90: 30 mg (1.1 equivalents) DCM / DMF mixture replaced by DMF 3 mg (7%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.66 (s, 1H), 9.37 (d, J=1.4 Hz, 1H), 9.14 (d, J=2.3 Hz, 1H), 8.94 (dd, J=1.4, 4.7 Hz, 1H), 8.70 (d , J=1.0 Hz, 1H), 8.62 - 8.59 (m, 1H), 8.57 (s, 1H), 8.26 (s, 1H), 8.11 (d, J=4.6 Hz, 1H), 5.01 (s, 2H) , 3.98 - 3.93 (m, 2H), 3.11 - 3.05 (m, 2H). LCMS (ESI): Method 7t R = 3.92 min; m / z [M+H]+ = 473.4 110 General procedure G carboxylic acid (17 mg, 0.0831 mmol): Intermediate 90: 30 mg (1.1 equivalents) 20mg (50%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.65 (s, 1H), 9.14 (d, J=2.4 Hz, 1H), 8.71 - 8.69 (m, 1H), 8.62 - 8.59 (m, 1H), 8.26 (s, 1H), 7.41 (s, 1H), 4.93 (s, 2H), 4.80 (s, 2H), 4.14 (t, J=5.2 Hz, 2H), 4.00 (t, J=5.2 Hz, 2H), 3.95 - 3.91 (m, 2H), 3.07 - 3.01 (m, 2H) LCMS (ESI): Method 7t R = 3.28 min; m / z [M+H]+ = 478.5 111 General procedure G carboxylic acid (17 mg, 0.0839 mmol): Intermediate 90: 30 mg (1.1 equivalents) 25mg (61%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.65 (s, 1H), 9.13 (d, J=2.3 Hz, 1H), 8.71 - 8.69 (m, 1H), 8.61 - 8.59 (m, 1H), 8.25 (s, 1H), 7.29 (s, 1H), 4.91 (s, 2H), 4.05 (t, J=5.7 Hz, 2H), 3.90 (t, J=5.7 Hz, 2H), 3.04 - 2.99 (m, 2H), 2.82 - 2.77 (m, 2H ), 1.91 - 1.81 (m, 4H) LCMS (ESI): Method 7t R = 3.16 min; m / z [M+H]+ = 476.5 120 General procedure G carboxylic acid (100 mg, 0.598 mmol): Intermediate 90: 196 mg (1.0 equiv) 69mg (twenty four%) Preparative HPLC; Further purification (Xbridge Phenyl 19x150 mm, 10um 20-80% MeOH / H 2 O (10mM NH 4 CO 3 ), 20ml / min, RT) ¹H NMR (400 MHz, DMSO-d 6) δ 10.64 (s, 1H), 9.14 (d, J=2.4 Hz, 1H), 8.70 (d, J=1.1 Hz, 1H), 8.60 (t, J=2.2 Hz, 1H), 8.24 (s, 1H ), 7.05 (s, 1H), 6.79 (t, J=2.2 Hz, 1H), 4.89 (s, 2H), 4.00 (t, J=5.9 Hz, 2H), 3.88 (t, J=5.9 Hz, 2H ), 3.25 - 3.21 (m, 2H), 2.99 (t, J=5.5 Hz, 2H), 1.93 - 1.87 (m, 2H). LCMS (ESI): Method 7t R = 3.13; m / z [M+H]+ = 477.2 124 General procedure G carboxylic acid (66 mg, 0.40 mmol): Intermediate 90: 133 mg (1.0 equiv) 8mg (4%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.68 (s, 1H), 9.19 (d, J=2.2 Hz, 1H), 8.87 (td, J=0.9, 7.0 Hz, 1H), 8.75 (d, J=1.1 Hz, 1H), 8.65 (t , J=2.0 Hz, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 7.99 (td, J=1.0, 9.1 Hz, 1H), 7.52 (ddd, J=1.0, 6.8, 8.9 Hz, 1H), 7.14 (dt, J=1.3, 6.8 Hz, 1H), 5.00 (s, 2H), 3.97 (t, J=5.7 Hz, 2H), 3.10 (t, J=5.6 Hz, 2H). LCMS (ESI): Method 7t R = 4.22 min; m / z [M+H]+ = 472.5 140 General procedure G carboxylic acid (50 mg, 0.26 mmol): Intermediate 90: 85 mg (1.0 equiv) 15mg (12%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.66 (s, 1H), 9.15 (d, J=1.9 Hz, 1H), 8.71 (d, J=1.0 Hz, 1H), 8.68 (dd, J=0.5, 7.6 Hz, 1H), 8.60 (t , J=2.0 Hz, 1H), 8.30 (s, 1H), 8.25 (s, 1H), 7.25 (d, J=2.6 Hz, 1H), 6.77 (dd, J=2.9, 7.5 Hz, 1H), 4.96 (s, 2H), 3.92 (t, J=5.7 Hz, 2H), 3.88 (s, 3H), 3.05 (t, J=5.2 Hz, 2H). LC-MS (ESI) method 7:t R = 4.39 min; m / z [M + H] + = 502.2. 141 General Program N (ACN replaced by DMF) Carboxylic acid (50 mg, 0.260 mmol) Intermediate 90: 95 mg (1.05 equiv) 57mg (40%) Precipitation from water ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.68 (1H, s), 9.18 (1H, d, J=2.3 Hz), 8.74 (1H, d, J=1.0 Hz), 8.64 (1H, t, J=2.3 Hz), 8.44 (1H, d , J=1.3 Hz), 8.38 (1H, d, J=4.2 Hz), 8.30 (1H, s), 7.59 (1H, dd, J=1.4, 4.2 Hz), 5.04 (2H, s), 4.02 (2H , t, J=5.3 Hz), 3.10 (2H, t, J=5.3 Hz); LC-MS (ESI) Method 6: t R = 4.13 min; m / z [M + H] + = 478.2 142 General Program N (ACN replaced by DMF) Carboxylic acid (50 mg, 0.260 mmol) Intermediate 90: 95 mg (1.05 equiv) 71mg (53%) Precipitation from water ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.69 (1H, s), 9.19 (1H, d, J=2.3 Hz), 8.89 (1H, d, J=7.6 Hz), 8.75 (1H, d, J=1.0 Hz), 8.65 (1H, t , J=2.2 Hz), 8.31 (1H, s), 8.07 (1H, s), 7.17 (1H, d, J=2.5 Hz), 6.86 (1H, dd, J=2.5, 7.6 Hz), 5.07 (2H , s), 4.03 (2H, t, J=5.5 Hz), 3.94 (3H, s), 3.13 (2H, t, J=5.5 Hz). LC-MS (ESI) Method 6: t R = 4.2 min; m / z [M + H] + = 502.2 143 General Program N (ACN replaced by DMF) Carboxylic acid (43 mg, 0.260 mmol) Intermediate 90: 95 mg (1.0 equiv) 7.4mg (6%) Preparative HPLC ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.65 (s, 1H), 9.14 (d, J=2.4 Hz, 1H), 8.69 (s, 1H), 8.61 - 8.60 (m, 1H), 8.25 - 8.24 (m, 1H), 7.90 (d, J=1.1 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 7.30 (dd, J=1.2, 2.2 Hz, 1H), 4.94 (s, 2H), 3.95 - 3.90 (m, 2H), 3.84 (s, 3H), 3.06 - 3.03 (m, 2H). LC-MS (ESI) Method 6: t R = 3.85 min; m / z [M + H] + = 475.5 144 General Program N (ACN replaced by DMF) Carboxylic acid (47 mg, 0.260 mmol): Intermediate 90: 95 mg (1.0 equiv) 47mg (36%) Precipitation from water ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.66 (s, 1H), 9.15 (d, J=2.3 Hz, 1H), 9.02 (dd, J=5.8, 7.5 Hz, 1H), 8.71 (d, J=1.1 Hz, 1H), 8.61 (t , J=1.9 Hz, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 7.65 (dd, J=2.2, 9.7 Hz, 1H), 7.20 - 7.15 (m, 1H), 5.04 (s, 2H), 4.02 - 3.98 (m, 2H), 3.12 - 3.09 (m, 2H). LC-MS (ESI) Method 6: t R = 4.24 min; m / z [M + H] + = 490.2

[0357] Example 112; Preparation of compound N-(3-(tertiary butyl) isoxazol-5-yl)-6-(5,6-dihydro-8H-imidazo[2,1-c] [1,4]㗁𠯤-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide Example 112 Step 1; 6-(6, 8-Dihydro-5H-imidazo[2,1-c][1,4]㗁𠯤-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3 - ethyl carboxylate (intermediate 91) to intermediate 38 (125 mg, 0.505 mmol), 6,8-dihydro-5H-imidazo[2,1-c][1,4]㗁𠯤-3- Carboxylate hydrochloride (124 mg, 0.605 mmol) and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyltetrafluoroborate (232 mg, 0.722 mmol) To a suspension in dry DCM (2.00 ml) and DMF (2.00 ml) was added N,N-diisopropylethylamine (0.35 mL, 2.02 mmol). The reaction mixture was stirred at room temperat...

Claims

1. A compound of formula (I), wherein Rx, Ry, and Rz are independently H or -(C1-C4)alkyl; L is selected from the group consisting of -C(O)- and -CH2-; Hy is a bicyclic heteroaryl group substituted with at least one substituent selected from the group consisting of: -(C1-C4)alkyl, halogen atom, cyano, -O-(C1-C4)alkyl, -O-(C1-C4)alkyl-OH, -O-(C1-C4)alkyl-O-(C1-C4)alkyl, -O-(C1-C4)alkyl-heterocyclic alkyl, -(C1-C4)alkyl-NR4R5, -(C1-C6)haloalkyl, and heterocyclic alkyl substituted with one or more -(C1-C4)alkyl groups, or Hy is a bicyclic semi-saturated heteroaryl group; R1 is selected from the group consisting of: - Het is a heteroaryl group substituted with one or more substituents selected from the group consisting of: -(C1-C4)alkyl, -(C1-C4)haloalkyl, cycloalkyl substituted with one or more -(C1-C6)haloalkyl, -O-(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -(C1-C4)epylalkyl-OH, -(C1-C4)epylalkyl-NR4R5, heterocycloalkyl, -(C1-C4)epylalkyl-aryl and aryl, wherein the aryl group is substituted with one or more groups selected from the group consisting of: -(C1-C4)alkyl and halogen atom, and -X (X) wherein R2 is H or selected from the group consisting of: -O(C1-C4)haloalkyl, halogen atom, -O-cycloalkyl and -(C1-C4)haloalkyl; R3 is H or selected from the following groups: halogen atom, cyano group, heterocyclic alkyl group substituted with one or more -(C1-C4)alkyl groups, -(C1-C4)-alkyl-heterocyclic alkyl group, -(C1-C4)-alkyl-heterocyclic alkyl group -(CH2)n-NR4R5, -(C1-C4)-alkyl-NR4R5, -(C1-C4)-alkyl-NR4R6, -O(C1-C4)alkyl group, -O(C1-C4)haloalkyl group, -O-(C1-C4) The heterocyclic alkyl group is substituted with -(C1-C4)alkyl, -O-(C1-C4)-alkyl-NR4R5, -O-(C1-C4)-alkyl-O-(C1-C4)alkyl, -O-(C1-C4)-alkyl-heterocyclic alkyl, and -O-heterocyclic alkyl, wherein each of the heterocyclic alkyl groups is substituted with one or more groups selected from -(C1-C4)alkyl, oxy-group, 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 the group consisting of -heterocyclic alkyl, -(C1-C4)-alkyl-O-(C1-C4)alkyl, and -(C1-C4)-alkyl-OH;And its pharmaceutically acceptable salts, wherein the term "heteroaryl" means a monocyclic or bicyclic aromatic group containing one or more heteroatoms selected from S, N, and O, and includes groups having two such monocyclic rings, or one such monocyclic ring and one monocyclic aryl ring, fused by a common bond; the term "semi-saturated heteroaryl" means 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; the term "heterocyclic alkyl" means a saturated monocyclic or bicyclic ring system having 3 to 12 ring atoms containing one or more heteroatoms selected from N, S, or O; the term "aryl" means a monocyclic carbocyclic system having 6 ring atoms, wherein the ring is aromatic.

2. The compound of formula (I) as claimed in claim 1, wherein, R1 is X' (X'). The compound is represented by formula (Ia): (Ia).

3. The compound of formula (Ia) as claimed in claim 2, wherein, L is -CH2-, and the compound is represented by formula (Iaa): (Iaa).

4. The compound of formula (Iaa) as claimed in item 3 is selected from at least one of the following: 6-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazo-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-methylamine; 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-methylamine; 6-((1H-pyrrolo[3,4-b]pyridin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-methylamine; 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-methylamine; 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-methylamine; 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide; 6-(imidazo[1,2-a]pyr-3-ylmethyl)-N-(3-(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-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxamide; 6-((1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-methylamine; 6-(imidazo[1,2-b]ta-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-methylamine; 6-(pyrazolo[1,5-a]pyrimidin-6-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-methylamine; 6-(pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-methylamine; 6-(imidazo[1,2-a]pyrazol-3-ylmethyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-methylamine;6-(imidazo[1,2-a]pyridine-3-ylmethyl)-5-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-methylamine; 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-methylamine; (R)-N-(3-((3-(dimethylamino)pyrrolidin-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]pyridin-3-methylamine; (R)-6-((1H-pyrazolo[3,4-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-methylamine; (R)-6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-((3-(dimethylamino)pyrrolodin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-methylamine; (R)-N-(3-((3-(dimethylamino)pyrrolodin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyr-3-ylmethyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-methylamine; (R)-N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrimidin-6-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-methylamine; 6-((3-methyl-1H-pyrazolo[3,4-b]pyridine-5-yl)methyl)-N-(3-(2-(pyrrolidin-1-yl)ethoxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-methylamine; 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(2-(pyrrolidin-1-yl)ethoxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-methylamine; and 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-methylamine.

5. The compound of formula (Ia) as claimed in claim 2, wherein, L is -C(O)-, and the compound is represented by the formula (Iab): (Iab).

6. The compound of formula (Iab) as claimed in item 5 is selected from at least one of the following: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methylpiper-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxymethylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxymethylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; N-(3-fluoro-5-(trifluoromethoxy)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; N-(3-((dimethylamino)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((N-linyl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(2-(N-linyl)ethoxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(2-(pyrrolidin-1-yl)ethoxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; (S)-N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-methylamine;(R)-N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-methylamine; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-methylamine; N-(3-((4-(dimethylamino)piperidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-methylamine; N-(3-((6-oxo-1-azaspiro[3.3]heptane-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-methylamine; N-(3-((2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-methylamine; N-(3-((3-fluoropyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-methylamine; N-(3-(azacyclobutane-1-ylmethyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-methylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((methyl(oxocyclobutane-3-yl)amino)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-methylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-(oxocyclobutanol-3-yl)piperidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-methylamine; N-(3-((3-((dimethylamino)methyl)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-methylamine; N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-methylamine;N-(3-(((2-hydroxyethyl)(methyl)amino)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-methylamine; N-(3-((4-acetylopirox-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-methylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methyl-3-sideoxypiperidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-methylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(piperidin-1-ylmethyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-methylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(((2-methoxyethyl)(methyl)amino)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-methylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(2-(4-methylpiperyl-1-yl)ethoxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-methylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((1-methylpyrrolidin-3-yl)oxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 6-(1H-pyrrolideno[2,3-b]pyridine-5-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(4-methyl-1H-imidazo-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyr-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 6-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-b]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine;6-(pyrazolo[1,5-a]pyr-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxylamine; 6-(pyrazolo[1,5-a]pyrimidin-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxylamine; 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-carboxylamine; 6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; N-(3-fluoro-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 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-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; (R)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; (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-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7,7-dimethyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; (R)-N-(3-(3-(dimethylamino)pyrrolidin-1-carbonyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; N-(3-cyano-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 6-(6-((dimethylamino)methyl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine;6-(6-(4-methylpiper-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 6-(6-(2-hydroxyethoxy)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 6-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 6-(7-(2-(N-α-linyl)ethoxy)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-methylamine; (R)-N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(5-methylimidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-methylamine; 6-(6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxylamine; 6-(6-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxylamine; 6-(6-(2-(N-α-linyl)ethoxy)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; N-(3-((N-α-linyl)methyl)-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(4-methylpiper-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; N-(3-(4-methylpiper-1-yl)-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine;6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(N-α-linyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; N-(3-(N-α-linyl)-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; N-(3-cyano-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridin-3-carbonyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-methylamine; and N-(3-(hydroxymethyl)-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-methylamine.

7. The compound of formula (I) as claimed in claim 1, wherein, R1 is Het, and the compound is represented by formula (Ib): (Ib).

8. The compound of formula (Ib) as claimed in claim 7, wherein, L is -C(O)-, and the compound is represented by formula (Ibb): (Ibb).

9. The compound of formula (Ibb) as claimed in claim 8, wherein it is selected from at least one of the following: N-(3-(tributyl)-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-carboxylamine; N-(3-(tributyl)-1-methyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; N-(3-(tributyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; N-(3-(tributyl)-1-phenyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(1,1,1-trifluoro-2-methylpropyl-2-yl)isozol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(6-(trifluoromethyl)pyrimidin-4-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(4-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(4-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; N-(5-(tributyl)isoazol-3-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; N-(3-(tributyl)isoazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine;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-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; N-(2-(tert-butyl)pyridine-4-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; 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-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(1-methyl-3-propyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; N-(3-(tributyl)-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-carboxylamine; N-(1-benzyl-3-(tributyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; N-(3-(tributyl)-1-ethyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-isobutyl-1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; N-(4-(tributyl)azol-2-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; N-(3-(tributyl)-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-carboxylamine; N-(3-(tributyl)-1-methyl-1H-pyrazol-5-yl)-6-(7-methylimidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine;N-(3-(tri-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-carboxylamine; N-(3-(tri-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(6-fluoroimidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxylamine; N-(3-(tri-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-carboxylamine; N-(3-(tri-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(6-chloroimidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxylamine; N-(3-(tributyl)-1-methyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridin-3-carbonyl)-7-methyl-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; 6-(pyrazoleno[1,5-a]pyr-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; 6-(pyrazoleno[1,5-a]pyrimidine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; 6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]pyrido-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-methylamine; 6-(5,6,7,8-tetrahydrothieno[1,2-a]pyridin-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-methylamine; N-(3-(tributyl)isoazol-5-yl)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4] N-(3-(tributyl)isoazol-5-yl)-6-(pyrazolo[1,5-a]pyrazol-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxylamine; N-(3-(tributyl)isoazol-5-yl)-6-(pyrazolo[1,5-a]pyrazol-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxylamine; 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-carboxylamine;N-(5-(1,1-difluoroethyl)pyridin-3-yl)-6-(imidazo[1,2-a]pyridin-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; N-(5-(tributyl)-1-methyl-1H-pyrazol-3-yl)-6-(pyrazoleno[1,5-a]pyrazol-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; N-(5-(tributyl)pyridin-3-yl)-6-(imidazo[1,2-a]pyridin-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; N-(5-(difluoromethoxy)pyridin-3-yl)-6-(imidazo[1,2-a]pyridin-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; 6-(imidazo[1,2-a]pyridin-3-carbonyl)-N-(3-(tripentyl)isoazol-5-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; 6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; N-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazo-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxylamine; N-(5-(1,1-difluoroethyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazo-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxylamine; N-(5-(tributyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazo-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxylamine; 6-(pyrazolo[1,5-a]pyridin-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; N-(5-(difluoromethoxy)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyr-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; 6-(pyrazolo[1,5-a]pyr-3-carbonyl)-N-(5-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoazol-3-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-methylamine;6-(pyrazolo[1,5-a]pyridine-3-carbonyl)-N-(5-(trifluoromethoxy)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; N-(2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-yl)-6-(imidazo[1,2-a]pyridin-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 6-(5-methoxypyrazolo[1,5-a]pyridin-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 6-(pyrazolo[5,1-b]thiazolyl-7-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; 6-(7-methoxyimidazo[1,2-a]pyridin-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; 6-(1-methyl-1H-imidazo[1,2-b]pyrazololyl-7-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; 6-(7-Fluorimidozolo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; N-(5-(tributyl)-1-methyl-1H-pyrazol-3-yl)-6-(6-(4-methylpiperazol-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 6-(6-(4-methylpiperazo-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-carboxyamine; N-(3-(tributyl)isoazo-5-yl)-6-(6-(4-methylpiperazo-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxyamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridine-3-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; N-(5-(tributyl)isoazol-3-yl)-6-(pyrazol[1,5-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine;N-(3-(tripentyl)isoazol-5-yl)-6-(pyrazolo[1,5-a]pyrazol-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; N-(3-isobutylisoazol-5-yl)-6-(pyrazolo[1,5-a]pyrazol-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; and 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethoxy)pyridine-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine.

10. A pharmaceutical composition comprising a compound of formula (I) of any one of claims 1 to 9 and a mixture of one or more pharmaceutically acceptable carriers or excipients.

11. The pharmaceutical composition of claim 10, administered by inhalation.

12. The compound of formula (I) of any one of claims 1 to 9 or the pharmaceutical composition of claim 10 or 11 is used as a pharmaceutical preparation.

13. A compound or pharmaceutical composition of formula (I) of claim 12, which is used for the prevention and / or treatment of diseases, conditions or symptoms associated with discoid domain receptor dysregulation.

14. A compound or pharmaceutical composition of formula (I) of claim 12, which is used for the prevention and / or treatment of fibrosis and / or diseases, conditions or symptoms involving fibrosis.

15. A compound or pharmaceutical composition of formula (I) of claim 14, which is used for the prevention and / or treatment of fibrosis, including pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, kidney fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

16. A compound or pharmaceutical composition of formula (I) of claim 15, which is used for the prevention and / or treatment of idiopathic pulmonary fibrosis (IPF).

17. A method for preparing a compound of formula (I) comprising the steps of: a) amide coupling of intermediate IIb to obtain intermediate VIIb, wherein R1 is as defined below; b) deprotecting the BOC group of intermediate VIIb to obtain intermediate VIIIb, wherein R1 is as defined below; c) amide coupling of intermediate VIIIb with a suitable acid to obtain a compound of formula (I); wherein the compound of formula (I) is: (I) wherein Rx, Ry and Rz are independently H; L is selected from the group consisting of -C(O)- and -CH2-; Hy is a bicyclic heteroaryl group substituted with at least one substituent selected from the group consisting of: -(C1-C4)alkyl, halogen atom, cyano, -O-(C1-C4)alkyl, -O-(C1-C4)alkyl-OH, -O-(C1-C4)alkyl-O-(C1-C4)alkyl, -O-(C1-C4)alkyl-heterocyclic alkyl, -(C1-C4)alkyl-NR4R5, -(C1-C6) haloalkyl and heterocyclic alkyl substituted with one or more -(C1-C4)alkyl groups, or Hy is a bicyclic semi-saturated heteroaryl group; R1 is selected from the group consisting of: - Het is a heteroaryl group substituted with one or more substituents selected from the group consisting of: -(C1-C4)alkyl, -(C1-C4)haloalkyl, cycloalkyl substituted with one or more -(C1-C6)haloalkyl, -O-(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -(C1-C4)epylalkyl-OH, -(C1-C4)epylalkyl-NR4R5, heterocycloalkyl, -(C1-C4)epylalkyl-aryl and aryl, wherein the aryl group is substituted with one or more groups selected from the group consisting of: -(C1-C4)alkyl and halogen atom, and -X (X) wherein R2 is H or selected from the group consisting of: -O(C1-C4)haloalkyl, halogen atom, -O-cycloalkyl and -(C1-C4)haloalkyl;R3 is H or selected from the following groups: halogen atom, cyano group, heterocyclic alkyl group substituted with one or more -(C1-C4)alkyl groups, -(C1-C4)-alkyl-heterocyclic alkyl group, -(C1-C4)-alkyl-heterocyclic alkyl group -(CH2)n-NR4R5, -(C1-C4)-alkyl-NR4R5, -(C1-C4)-alkyl-NR4R6, -O(C1-C4)alkyl group, -O(C1-C4)haloalkyl group, -O-(C1-C4) The heterocyclic alkyl group is substituted with -(C1-C4)alkyl, -O-(C1-C4)-alkyl-NR4R5, -O-(C1-C4)-alkyl-O-(C1-C4)alkyl, -O-(C1-C4)-alkyl-heterocyclic alkyl, and -O-heterocyclic alkyl, wherein each of the heterocyclic alkyl groups is substituted with one or more groups selected from -(C1-C4)alkyl, oxy-group, 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 the group consisting of -heterocyclic alkyl, -(C1-C4)-alkyl-O-(C1-C4)alkyl, and -(C1-C4)-alkyl-OH; or a pharmaceutically acceptable salt thereof, wherein the term "heteroaryl" means a monocyclic or bicyclic aromatic group containing one or more heteroatoms selected from S, N, and O, and includes groups having two such monocyclic rings, or one such monocyclic ring and one monocyclic aryl ring, fused by a common bond; the term "semi-saturated heteroaryl" means 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; The term "heterocyclic alkyl" refers to a saturated monocyclic or bicyclic ring system having 3 to 12 ring atoms, containing one or more heteroatoms selected from N, S, or O; the term "aryl" refers to a monocyclic carbocyclic system having 6 ring atoms, wherein the ring is aromatic.

18. As in request item 17, wherein, Step a) is the following reaction: wherein Het, R1, R2, and R3 are as defined in claim 1, and wherein the reaction is carried out in the presence of chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) and 1-methylimidazolium to obtain a transiently activated acetylidene imidazoline intermediate that can react with a suitable amine XIIb or XIIIb at room temperature in a solvent such as N,N-dimethylformamide (DMF).

19. The method as described in claim 17 or 18, wherein, The amide coupling in step c) is carried out in the presence of (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylammonium hexafluorophosphate (HATU).

20. As in request item 19, wherein, The amount of (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylammonium hexafluorophosphate (HATU) is 1.20 to 2.00 equivalents.

21. As in request item 17, wherein, The amide coupling in step c) is carried out in a solvent of N,N-dimethylformamide / dichloromethane (DMF / DCM).

22. As in request item 21, wherein, The concentration of the solvent is 0.1M.

23. As in request item 17, wherein, The amide coupling in step c) is carried out by adding N,N-diisopropylethylamine (DIPEA), stirring at room temperature, and then adding amine XIIIb, wherein amine XIIIb is Het-NH2, and Het is as defined in claim 1.

24. As in request item 23, wherein, The amount of N,N-diisopropylethylamine (DIPEA) added is from 3.00 to 8.00 equivalents.

25. The method for preparing compound of formula (I) as claimed in claim 17, wherein, The compound of formula (I) is represented by formula (Ib), where R1 is Het: (Ib).

26. The method for preparing the compound of formula (Ib) as claimed in claim 25, wherein, L is -C(O)-, and the compound is represented by formula (Ibb): (Ibb).

27. The method for preparing a compound of formula (Ibb) as claimed in claim 26, wherein, The compound of formula (Ibb) is selected from at least one of the following: N-(3-(tributyl)-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-carboxylamine; N-(3-(tributyl)-1-methyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; N-(3-(tributyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; N-(3-(tributyl)-1-phenyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoazol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(6-(trifluoromethyl)pyrimidin-4-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(4-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(4-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; N-(5-(tributyl)isoazol-3-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; N-(3-(tributyl)isoazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine;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-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; N-(2-(tert-butyl)pyridine-4-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; 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-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(1-methyl-3-propyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; N-(3-(tributyl)-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-carboxylamine; N-(1-benzyl-3-(tributyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; N-(3-(tributyl)-1-ethyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-isobutyl-1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; N-(4-(tributyl)azol-2-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine; N-(3-(tributyl)-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-carboxylamine; N-(3-(tributyl)-1-methyl-1H-pyrazol-5-yl)-6-(7-methylimidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylamine;N-(3-(tri-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-carboxylamine; N-(3-(tri-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(6-fluoroimidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxylamine; N-(3-(tri-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-carboxylamine; N-(3-(tri-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(6-chloroimidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxylamine; 6-(pyrazolo[1,5-a]pyrazin-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; 6-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; 6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]pyrazin-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; 6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridine-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxylamine; N-(3-(tributyl)isoazol-5-yl)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]isopheno-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxylamine; N-(3-(tributyl)isoazol-5-yl)-6-(pyrazolo[1,5-a]pyrazol-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxylamine; 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-carboxylamine; N-(5-(1,1-difluoroethyl)pyridin-3-yl)-6-(imidazo[1,2-a]pyridin-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-methylamine;N-(5-(tri-butyl)-1-methyl-1H-pyrazol-3-yl)-6-(pyrazolo[1,5-a]pyrazol-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxylamine; N-(5-(tri-butyl)pyridine-3-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxylamine; N-(5-(difluoromethoxy)pyridine-3-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(tripentyl)isoazol-5-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; 6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-3-carbonyl)-N-(5-(trifluoromethyl)pyridine-3-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridine-3-carboxylamine; N-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazo-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxylamine; N-(5-(1,1-difluoroethyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazo-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxylamine; N-(5-(tributyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazo-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-carboxylamine; 6-(pyrazolo[1,5-a]pyridin-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-methylamine; N-(5-(difluoromethoxy)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyridin-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-methylamine; 6-(pyrazolo[1,5-a]pyrazo-3-carbonyl)-N-(5-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoazol-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-methylamine; 6-(imidazo[1,2-a]pyrazo-3-carbonyl)-N-(5-(trifluoromethyl)pyridine-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-methylamine; 6-(pyrazolo[1,5-a]pyridine-3-carbonyl)-N-(5-(trifluoromethoxy)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridin-3-methylamine;N-(2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-yl)-6-(imidazo[1,2-a]pyridin-3-carbonyl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; 6-(5-methoxypyrazolo[1,5-a]pyridin-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; 6-(pyrazolo[5,1-b]thiazolyl-7-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiopheneno[2,3-c]pyridin-3-carboxylamine; 6-(7-methoxyimidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiophenenozo[2,3-c]pyridine-3-carboxylamine; 6-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiophenenozo[2,3-c]pyridine-3-carboxylamine; 6-(7-fluoroimidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiophenenozo[2,3-c]pyridine-3-carboxylamine; N-(5-(tributyl)-1-methyl-1H-pyrazol-3-yl)-6-(6-(4-methylpiperazol-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxylamine; 6-(6-(4-methylpiperazol-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-carboxylamine; N-(3-(tributyl)isoazol-5-yl)-6-(6-(4-methylpiperazol-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxylamine; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridine-3-yl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxylamine; N-(5-(tri-butyl)isoazol-3-yl)-6-(pyrazolo[1,5-a]pyrazol-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-methylamine; N-(3-(tri-pentyl)isoazol-5-yl)-6-(pyrazolo[1,5-a]pyrazol-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-methylamine;N-(3-isobutylisoazol-5-yl)-6-(pyrazolo[1,5-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothiopheno[2,3-c]pyridine-3-carboxylamine; 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-carboxylamine.

28. An intermediate compound of formula VIIb, wherein R1 is as defined in claim 17.

29. An intermediate compound of formula VIIIb, wherein R1 is as defined in claim 17.

30. Use of the intermediate compound VIIb of claim 28 for the preparation of a compound of formula (I), wherein Rx, Ry, Rz, L, Hy, and R1 are as defined in claim 17.

31. Use of the intermediate compound VIIIb of claim 29 for the preparation of a compound of formula (I), wherein Rx, Ry, Rz, L, Hy, and R1 are as defined in claim 17.

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