Tetrahydrothienopyridine derivatives as DDR inhibitors

Abstract

The present invention relates to compounds of general formula (I) that inhibit discoidin domain receptors (DDR inhibitors), processes for the preparation of such compounds, pharmaceutical compositions containing them and their therapeutic use. The compounds of the invention may, for example, be useful in the treatment of a number of disorders associated with the DDR mechanism. JPEG2024512595000369.jpg5173

Description

[Technical Field]

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

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

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

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

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

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

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

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

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

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

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

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

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

[0014] Summary of the Invention In a first aspect, the present invention provides a compound of formula (I): [ka] [During the ceremony, 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 optionally substituted with at least one substituent selected from the group consisting of -(C1-C4)alkyl, halogen, 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 heterocycloalkyl optionally substituted with one or more -(C1-C4)alkyl, or Hy is a bicyclic semi-saturated heteroaryl; R1: - Het is heteroaryl optionally substituted with one or more substituents selected from the group consisting of -(C1-C4)alkyl, -(C1-C4)haloalkyl, cycloalkyl optionally substituted with one or more -(C1-C6)haloalkyl, -O-(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -(C1-C4)alkylene-OH, -(C1-C4)alkylene-NR4R5, heterocycloalkyl, -(C1-C4)alkylene-aryl and aryl, wherein the aryl is optionally substituted with one or more groups selected from -(C1-C4)alkyl and halogen atoms, and - X [ka] wherein: R2 is H or selected from the group consisting of -O(C1-C4)haloalkyl, halogen atoms, -O-cycloalkyl, and -(C1-C4)haloalkyl; R3 is H or a halogen atom, cyano, heterocycloalkyl optionally substituted with one or more -(C1-C4)alkyl, -(C1-C4)alkylene-heterocycloalkyl, -(C1-C4)alkylene-heterocycloalkyl-(CH2) nselected from the group consisting of —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 said heterocycloalkyls is optionally substituted with one or more groups selected from —(C1-C4)alkyl, oxo, halogen atoms, —C(O)—(C1-C4)alkyl, and heterocycloalkyl; n is 0, 1 or 2; R4 is H or -(C1-C4)alkyl; R5 is H or -(C1-C4)alkyl; R6 is -heterocycloalkyl, -(C1-C4)alkylene-O-(C1-C4)alkyl, and -(C1-C4) alkylene-OH. and pharmaceutically acceptable salts thereof.

[0015] In a second aspect, the present invention relates to pharmaceutical compositions comprising compounds of formula (I) and pharmaceutically acceptable salts thereof in admixture with one or more pharmaceutically acceptable carriers or 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 for use as a medicament.

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

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

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

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

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

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

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

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

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

[0026] The term "solvate" refers to 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 some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate may be isolated. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules.

[0027] The term "stereoisomer" refers to isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

[0028] The term "enantiomers" refers to a pair of molecular species that are mirror images of each other and are not superimposable.

[0029] The symbols "R" and "S" represent the configuration of substituents around a chiral carbon atom. The isomeric descriptors "R" and "S" are used herein as defined and are intended to be used as defined in the literature to denote atomic configurations relative to a core molecule (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).

[0030] The term "diastereomers" refers to stereoisomers that are not mirror images.

[0031] The terms "racemate" or "racemic mixture" refer to a composition consisting of equimolar amounts of two enantiomeric species, devoid of optical activity.

[0032] The term "tautomer" refers to each of two or more isomers of a compound that exist together in equilibrium and are readily interconverted by shifting an atom or group within the molecule.

[0033] As used herein, the term "halogen" or "halogen atom" or "halo" includes fluorine, chlorine, bromine, and iodine atoms.

[0034] The term “(C x -C y ")Alkyl" (where x and y are integers) refers to a straight or branched chain alkyl group having x to y carbon atoms. Thus, when x is 1 and y is 4, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl.

[0035] The term “(C x -C y ) alkylene" (where x and y are integers) refers to a C alkylene having a total of two unsatisfied valences, such as a divalent methylene radical. x -C y It refers to an alkyl group.

[0036] The term “(C x -C y ) Alkylene-OH" refers to an alkylene bonded to an OH group.

[0037] The term “(C x -C y )Alkylene-aryl" refers to an alkylene linked to an aryl group.

[0038] The term “O(C x -C y ) alkyl" (where x and y are integers) is a group in which a carbon atom is bonded to an oxygen atom and is a group as defined above as "(C x -C y ) alkyl group.

[0039] The term “(C x -C y)haloalkyl" (where x and y are integers) refers to a "(C )haloalkyl" as defined above in which one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different. x -C y ) alkyl group. x -C y Examples of "haloalkyl" groups may thus include halogenated, poly-halogenated and fully halogenated alkyl groups in which all hydrogen atoms have been replaced with halogen atoms, such as trifluoromethyl.

[0040] The term “O(C x -C y )haloalkyl" (where x and y are integers) refers to a group in which a carbon atom is attached to an oxygen atom and the carbon atom is a group as defined above as "(C x -C y )haloalkyl group.

[0041] The “O(C x -C y Examples of "haloalkyl" groups may thus include halogenated, poly-halogenated and fully halogenated O-alkyl groups in which all hydrogen atoms have been replaced with halogen atoms, such as trifluoromethoxy.

[0042] The term "aryl" refers to a monocyclic carbocyclic ring system having 6 ring atoms that is aromatic. Examples of suitable aryl monocyclic ring systems include, for example, phenyl.

[0043] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic group containing one or more heteroatoms selected from S, N, and O, and refers to a group having two such monocyclic rings or one such monocyclic ring and one monocyclic aryl ring fused through a common bond.

[0044] The term "semi-saturated heteroaryl" refers to a bicyclic group containing one or more heteroatoms selected from S, N, and O, including a monocyclic heteroaryl fused to a monocyclic heterocycloalkyl ring. Examples of suitable semi-saturated heteroaryls include, for example, 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl, and 5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-3-yl.

[0045] The term "heterocycloalkyl" refers to a saturated monocyclic or bicyclic ring system of 3 to 12 ring atoms containing one or more heteroatoms selected from N, S, or O. Examples of heterocycloalkyl include piperazinyl, pyrrolidinyl, morpholinyl, and piperidinyl. The heterocycloalkyl may be further optionally substituted on any available ring atom, i.e., on any available carbon atom or heteroatom. Substitution may occur on a carbon atom, including spirodisubstitution, in which two heterocycloalkyl rings or one heterocycloalkyl and one cycloalkyl ring form a bicyclic ring system linked through a single carbon atom. Substitution may also occur on two adjacent carbon atoms to form an additional fused 4- to 6-membered heterocycloalkyl ring. Examples of spirocyclic rings include, but are not limited to, 6-methyl-2,6-diazaspiro[3.3]heptanyl, 6-oxa-1-azaspiro[3.3]heptanyl, and 2-methyl-2,8-diazaspiro[4.5]decanyl. Furthermore, the heterocycloalkyl can be a diazabicyclo ring, an azabicyclo ring, or a cyclic carbonate. Examples of diazabicyclo rings include, but are not limited to, 5-methyl-2,5-diazabicyclo[2.2.1]heptanyl and 6-methyl-3,6-diazabicyclo[3.2.2]nonanyl; examples of azabicyclo rings include, but are not limited to, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl; examples of suitable cyclic carbonates include, but are not limited to, 1,3-dioxalan-2-one and 4-methyl-1,3-dioxol-2-one.

[0046] The term "heterocycloalkyl (Cx -C y ) alkyl" means "(C ) alkyl" as defined above. x -C y (a) a heterocycloalkyl group bonded to a "(a)-(a)-(a)-alkyl" group;

[0047] The term "O-heterocycloalkyl" refers to a heterocycloalkyl attached to an oxygen atom.

[0048] The term “(C x -C y ")Alkylene-heterocycloalkyl" refers to a heterocycloalkyl ring bonded to an alkylene group, both as defined above.

[0049] The term “O-(C x -C y ) alkylene-OH" refers to a group in which alkylene is bonded to an oxygen atom and is defined as "(C x -C y ) alkylene-OH group.

[0050] The term “O-(C x -C y ) alkylene-O-(C x -C y ) alkyl" means an alkyl group defined above as "-O-(C x -C y ) alkyl" and is bonded to "(C ) alkyl" as defined above. x -C y ) alkyl.

[0051] The term “O-(C x -C y )Alkylene-heterocycloalkyl" refers to a heterocycloalkyl group as defined above attached to an oxygen atom. x -C y ) alkylene-heterocycloalkyl.

[0052] The term “-C(O)-(C x -C y "(C(O)-alkyl" refers to a "(C(O)-alkyl" as defined above, where the alkyl is attached to a -C(O)- group. x -C y) alkyl group.

[0053] The term “(C x -C y ) alkylene-heterocycloalkyl-(CH2) n -NR x R y " is defined above as "(C x -C y Heterocycloalkyl refers to a heterocycloalkyl as defined above directly bonded to a -(CH) alkylene. n - (where n is an integer) via nitrogen NR x R y (where x and y are integers). x -C y ) Alkylene-NR x R y " is nitrogen NR x R y (where x and y are integers) x -C y ) alkylene.

[0054] The term “O-(C x -C y ) Alkylene-NR x R y " is NR x R y (where x and y are integers) x -C y ) alkylene.

[0055] The term “O-(C x -C y ) alkylene-O-(C x -C y ) alkyl” refers to a group defined above as “O—(C x -C y ) alkylene x -C y ) alkyl.

[0056] The structural formula used here is [ka] A bond pointing to a wavy or serpentine line, such as indicates a bond that is the point of attachment of the moiety or substituent to the core or backbone structure.

[0057] When referring to a substituent, a dash (“-”) that is not between two letters, words or symbols is meant to represent a point of attachment for such substituent.

[0058] Carbonyl groups herein are preferably represented as -C(O)- as an alternative to other common representations such as -CO-, -(CO)- or -C(=O)-.

[0059] When a basic amino group is present in the compound of formula (I), a physiologically acceptable anion selected from chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate and naphthalenedisulfonate may be present. Similarly, when an acidic group is present, the corresponding physiological cation salts, for example, containing alkali or alkaline earth metal ions, may also be present.

[0060] The term "half maximal inhibitory concentration" (IC 50 ) indicates the concentration of a particular compound or molecule required to inhibit a biological process by 50% in vitro.

[0061] The term "Ki" refers to 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.

[0062] As mentioned above, the present invention provides compounds of the general formula (I) detailed below, which have inhibitory activity against the receptors DDR1 and DDR2. Antagonizing the receptors DDR1 and DDR2 can be particularly effective in treating diseases in which DDR receptors play a role, such as fibrosis and diseases, disorders and conditions associated with fibrosis.

[0063] In particular, as detailed in the experimental section below, the compounds of formula (I) of the present invention can act as both DDR1 and DDR2 receptor antagonists in a substantial and effective manner. In particular, Table 6 below shows that for the compounds of the present invention, both the affinity to either DDR1 or DDR2 receptors and the inhibitory activity to either DDR1 or DDR2 receptors are measured by binding (expressed as Ki) and cell-based assays (IC 50 The results show that the ATP concentration (represented by 1000 kJ / mL) is less than about 80 nM. This confirms that the compound of formula (I) can antagonize two isoforms of DDR receptors, which are primarily involved in fibrosis and diseases caused by fibrosis. Therefore, the compound of formula (I) can be used to treat fibrosis, particularly pulmonary fibrosis, in which DDR1 and DDR2 are involved.

[0064] As shown in the same experimental section, Table 7, the data show that, contrary to compound C1, which is characterized by a -C(O)NH- group substitution at the alpha position relative to sulfur, rather than at the beta position as in Example 1 of the present invention, the presence of the substitution at the beta position in the compounds of the present invention unexpectedly and significantly determines an associated increase in inhibitory activity of the DDR1 and DDR2 receptors.

[0065] As further evidence, contrary to compound C2, which is characterized by a -C(O)NH- group substituting the thienyl ring bonded at the alpha position to the sulfur and a Hy group substituting the tetrahydropyridyl ring bonded via a spacer to the nitrogen at the 5-position, in Example 1 of the present invention, the presence of a -C(O)NH- group substituting the thienyl ring bonded at the beta position to the sulfur and a Hy group substituting the tetrahydropyridyl ring bonded via a spacer to the nitrogen at the 6-position unexpectedly and significantly determines in the compounds of the present invention an associated increase in inhibitory activity against the DDR1 and DDR2 receptors.

[0066] The compounds of the present invention advantageously have extremely high potency and can be administered to humans at lower doses than prior art compounds, thereby reducing the adverse events typically associated with the administration of high doses of drugs.

[0067] In addition to their remarkably potent inhibitory activity against both DDR1 and DDR2 receptors, the compounds of the present invention are also characterized by a favorable inhalation profile that allows them to act effectively in the pulmonary region, and at the same time, by low metabolic stability that can minimize the disadvantages associated with systemic exposure, such as safety and tolerability issues.

[0068] Therefore, the compounds of the present invention will be particularly appreciated by those skilled in the art when searching for suitable and effective compounds useful in the treatment of fibrosis, particularly idiopathic pulmonary fibrosis, that are administered by the inhalation route and are characterized by a good inhalation profile corresponding to good pulmonary activity, good pulmonary retention and low metabolic stability that minimizes systemic exposure and associated safety issues.

[0069] Thus, in one aspect, the present invention provides a compound of general formula (I) [ka] [During the ceremony, 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 optionally substituted with at least one substituent selected from the group consisting of -(C1-C4)alkyl, halogen, 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 heterocycloalkyl optionally substituted with one or more -(C1-C4)alkyl, or Hy is a bicyclic semi-saturated heteroaryl; R1: - Het is heteroaryl optionally substituted with one or more substituents selected from the group consisting of -(C1-C4)alkyl, -(C1-C4)haloalkyl, cycloalkyl optionally substituted with one or more -(C1-C6)haloalkyl, -O-(C1-C4)haloalkyl, -O-(C1-C4)alkyl, -(C1-C4)alkylene-OH, -(C1-C4)alkylene-NR4R5, heterocycloalkyl, -(C1-C4)alkylene-aryl and aryl, wherein the aryl is optionally substituted with one or more groups selected from -(C1-C4)alkyl and halogen atoms, and - X [ka] wherein: R2 is H or selected from the group consisting of -O(C1-C4)haloalkyl, halogen atoms, -O-cycloalkyl, and -(C1-C4)haloalkyl; R3 is H or a halogen atom, cyano, heterocycloalkyl optionally substituted with one or more -(C1-C4)alkyl, -(C1-C4)alkylene-heterocycloalkyl, -(C1-C4)alkylene-heterocycloalkyl-(CH2) n selected from the group consisting of —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 said heterocycloalkyls is optionally substituted with one or more groups selected from —(C1-C4)alkyl, oxo, halogen atoms, —C(O)—(C1-C4)alkyl, and heterocycloalkyl; 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 pharmaceutically acceptable salts thereof.

[0070] In a particularly preferred embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a cancer treatment, ... [ka] Formula (Ia) [ka] wherein Rx, Ry, Rz, L, Hy, R2, and R3 are as defined above. The present invention relates to compounds of general formula (I) represented by:

[0071] In a particularly preferred embodiment, the present invention provides a compound of formula (Iaa) wherein L is —CH— [ka] wherein Rx, Ry, Rz, Hy, R2, and R3 are as defined above. The present invention relates to compounds of formula (Ia) represented by:

[0072] In a preferred embodiment, the present invention relates to compounds of formula (Iaa), wherein Hy is selected from the group consisting of imidazo[1,2-a]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, imidazo[1,2-a]pyrazin-3-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, pyrazolo[1,5-a]pyrimidin-6-yl, 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl and imidazo[1,2-b]pyridazin-3-yl.

[0073] In other preferred embodiments, the present invention relates to compounds of formula (Iaa) wherein R2 is trifluoromethyl and trifluoromethoxy.

[0074] In another particularly preferred embodiment, the present invention relates to compounds of formula (Iaa) wherein R3 is H or selected from the group consisting of 4-methyl-1H-imidazol-1-yl, 3-(dimethylamino)pyrrolidin-1-yl, 2-(pyrrolidin-1-yl)ethoxy and fluorine.

[0075] In a further preferred embodiment, the present invention relates to compounds 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, and R3 is H or selected from the group consisting of fluorine, (R)—N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl and 2-(pyrrolidin-1-yl)ethoxy.

[0076] According to a preferred embodiment, the present invention relates to at least one compound of formula (Iaa) and its pharmaceutically acceptable salts as listed in Table 1 below. These compounds are particularly active on the receptors DDR1 and DDR2, as shown in Table 6.

[0077] [Table 1] [Table 2] [Table 3] [Table 4]

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

[0079] In a preferred embodiment, the present invention provides a compound wherein Hy is imidazo[1,2-a]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, imidazo[1,2-a]pyrazin-3-yl, 1H-pyrazolo[3,4-b]pyridin-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]oxazin-3-yl, imidazo[1,2-b]pyridazine-3,6-((dimethylamino)methyl)imidazo[1,2-a]pyridin-3-yl, 4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-3-yl, 5-methylimidazo 2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl, 6-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl, 2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl, and pyrazolo[1,5-a]pyrazin-3-yl.

[0080] In another preferred embodiment, the present invention relates to compounds of formula (Iab) wherein R2 is selected from the group consisting of trifluoromethyl and trifluoromethoxy.

[0081] In another particularly preferred embodiment, the present invention provides an imidin-1-yl compound wherein R3 is H or 4-methyl-1H-imidazol-1-yl, fluorine, pyrrolidin-1-ylmethyl, (dimethylamino)methyl, 3-(morpholinomethyl), 2-morpholinoethoxy, 4-(dimethylamino)piperidin-1-yl)methyl, 3-(dimethylamino)pyrrolidin-1-yl)methyl, 6-oxa-1-azaspiro[3.3]heptan-1-yl)methyl, 2-(dimethylamino)ethoxy, 2-(pyrrolidin-1-yl)ethoxy, (2-hydroxyethyl)(methyl)amino)methyl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, (2-methoxyethyl)(methyl)amino)methyl, (4-acetylpiperazin-1-yl )methyl, (4-methyl-3-oxopiperazin-1-yl)methyl, (piperidin-1-yl)methyl, (3-fluoropyrrolidin-1-yl)methyl, azetidin-1-ylmethyl, methyl(oxetan-3-yl)amino)methyl, (4-(oxetan-3-yl)piperazin-1-yl)methyl, (3-((dimethylamino)methyl)pyrrolidin-1-yl)methyl, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(dimethylamino)pyrrolidine-1-carbonyl, cyano, 4-methylpiperazin-1-yl, N-morpholinyl, hydroxymethyl, (4-methylpiperazin-1-yl)methyl and (1-methylpyrrolidin-3-yl)oxy.

[0082] In another particularly preferred embodiment, the present invention relates to compounds 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-diazaspiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridin-3-yl, 6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl, 6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-3-yl and 6-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl; R2 is trifluoromethyl; and R3 is H.

[0083] According to a preferred embodiment, the present invention relates to at least one compound of formula (Iab) and pharmaceutically acceptable salts thereof as listed in Table 2 below.

[0084] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16]

[0085] In a further preferred embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a cancer treatment, ... [ka] Formula (Ia') [ka] wherein Hy, R2, and R3 are as defined above. The present invention relates to compounds of formula (I) represented by:

[0086] In a further preferred embodiment, the present invention provides a compound of formula (Iaa') wherein L is -CH2-. [ka] wherein Hy, R2, and R3 are as defined above. The present invention relates to compounds of formula (Ia'), which are represented by:

[0087] In a particularly preferred embodiment, the present invention relates to compounds of general formula (Iaa'), wherein R2 is trifluoromethyl.

[0088] In another particularly preferred embodiment, the present invention relates to compounds of general formula (Iaa''), wherein R3 is methoxy.

[0089] In a further preferred embodiment, the invention relates to compounds of general formula (Iaa'), wherein Hy is 1H-pyrrolo[2,3-b]pyridin-5-yl.

[0090] According to a preferred embodiment, the present invention relates to compounds of formula (Iaa') and their pharmaceutically acceptable salts as listed in Table 3a below, which are particularly active at the receptors DDR1 and DDR2, as shown in Table 6.

[0091] [Table 17]

[0092] In a further preferred embodiment, the present invention provides a compound of formula (Iab') wherein L is -CO. [ka] wherein Hy, R2, and R3 are as defined above. The present invention relates to a compound of formula (Ia'), represented by:

[0093] In a particularly preferred embodiment, the present invention relates to compounds of general formula (Iab'), wherein R2 is trifluoromethyl.

[0094] In another particularly preferred embodiment, the present invention relates to compounds of general formula (Iab'), wherein R3 is selected from the group consisting of methoxy, (tetrahydrofuran-3-yl)oxy, (4-methylpiperazin-1-yl)methyl, oxetan-3-yloxy, pyrrolidin-1-ylmethyl, morpholinomethyl, oxetan-3-ylmethoxy, 2-methoxyethoxy, (dimethylamino)methyl, 2-hydroxyethoxy, (1-methylpiperidin-4-yl)oxy, hydroxymethyl, chlorine and (1-methylpyrrolidin-3-yl)oxy.

[0095] In another preferred embodiment, the present invention relates to compounds of general formula (Iab'), wherein Hy is pyrazolo[1,5-a]pyrazin-3-yl, R3 is selected from the group consisting of hydroxymethyl, (dimethylamino)methyl and chlorine, and R2 is trifluoromethyl.

[0096] According to a further preferred embodiment, the present invention relates to at least one compound of formula (Iab') listed in Table 3b below and its pharmaceutically acceptable salts. These compounds are particularly active on the receptors DDR1 and DDR2, as shown in Table 6.

[0097] [Table 18] [Table 19] [Table 20]

[0098] In a particularly preferred embodiment, the present invention provides a compound of formula (Ib) wherein R1 is Het [ka] [During the ceremony, L is selected from the group consisting of -C(O)- and -CH2-; Hy is a bicyclic heteroaryl optionally substituted with at least one substituent selected from the group consisting of -(C1-C4)alkyl, halogen, 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, cycloalkyl, -O-(C1-C4)haloalkyl, -(C1-C4)alkylene-OH, -(C1-C4)alkylene-aryl, aryl optionally substituted with one or more groups selected from -(C1-C4)alkyl and halogen atoms. and pharmaceutically acceptable salts thereof.

[0099] In a particularly preferred embodiment, the present invention provides a compound of formula (Iba) wherein L is —CH— [ka] wherein Rx, Ry, Rz, Hy and Het are as defined above. The present invention relates to compounds of formula (Ib) represented by:

[0100] In a preferred embodiment, the present invention relates to compounds 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]pyrazin-3-yl, (4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl, pyrazolo[1,5-a]pyrazin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl and 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl.

[0101] In another preferred embodiment, the present invention relates to compounds of formula (Iba), wherein Het is selected from the group consisting of 3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl, 3-cyclopropyl-1-methyl-1H-pyrazol-5-yl, 3-(tert-butyl)isoxazol-5-yl, 5-cyclopropylisoxazol-3-yl, 5-(trifluoromethyl)pyridin-3-yl, 5-(tert-butyl)isoxazol-3-yl, 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl and 3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl.

[0102] In another preferred embodiment, the invention relates to compounds of formula (Iba), wherein Hy is selected from the group consisting of 3-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl, 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-5-ylmethyl, pyrazolo[1,5-a]pyrimidin-6-yl, imidazo[1,2-a]pyrazin-3-yl, pyrazolo[1,5-a]pyrazin-3-yl and 7H-pyrrolo[2,3-d]pyrimidin-4-yl; and Het is 5-(trifluoromethyl)pyridin-3-yl.

[0103] According to a preferred embodiment, the present invention relates to at least one compound of formula (Iba) and pharmaceutically acceptable salts thereof as listed in Table 4 below.

[0104] [Table 21] [Table 22] [Table 23] [Table 24]

[0105] In a particularly preferred embodiment, the present invention provides a compound of formula (Ibb) wherein L is —C(O)— [ka] wherein Rx, Ry, Rz, Hy and Het are as defined above. The present invention relates to compounds of formula (Ib) represented by:

[0106] In a preferred embodiment, the present invention provides a compound wherein Hy is imidazo[1,2-a]pyridin-3-yl, 6-methylimidazo[1,2-a]pyridin-3-yl, 6-methylimidazo[1,2-a]pyridin-3-yl, 6-fluoroimidazo[1,2-a]pyridin-3-yl, 6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl, 6-chloroimidazo[1,2-a]pyridin-3-yl, pyrazolo[1,5-a]pyrazin-3-yl, pyrazolo[1,5-a]pyrimidin-3-yl, 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl, 5,6,7,8-tetra ... The present invention relates to a compound of formula (Ibb) selected from the group consisting of pyrazolo[1,2-a]pyridin-3-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-3-yl, pyrazolo[1,5-a]pyridin-3-yl, (4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-3-yl, 5-methoxypyrazolo[1,5-a]pyridin-3-yl, pyrazolo[5,1-b]thiazol-7-yl, 7-methoxyimidazo[1,2-a]pyridin-3-yl, 1-methyl-1H-imidazo[1,2-b]pyrazol-7-yl and imidazo[1,2-a]pyrazin-3-yl.

[0107] In another preferred embodiment, the present invention relates to a compound in which Het is 3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl, 3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl, 3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl, 3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl, 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl, 2-(trifluoromethyl)-2- ... Methyl)pyridin-4-yl, 6-(trifluoromethyl)pyrimidin-4-yl, 6-(trifluoromethyl)pyrimidin-4-yl, 4-(trifluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-3-yl, 5-(tert-butyl)isoxazol-3-yl, 3-(tert-butyl)isoxazol-5-yl, 4-(tert-butyl)oxazol-2-yl, 3-cyclobutyl-1-methyl-1H-pyrazol-5-yl, 6-fluoroimidazo[1 ,2-a]pyridin-3-yl, 6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl, 6-chloroimidazo[1,2-a]pyridin-3-yl, 3-isopropyl-1-methyl-1H-pyrazol-5-yl, 4-(trifluoromethyl)pyrimidin-2-yl, 2-(tert-butyl)pyridin-4-yl, 3-(tert-butyl)-1-isopropyl-1H-pyrazol-5-yl, 1-methyl-3-propyl-1H-pyrazol-5-yl, 3-(tert-butyl) 1-(2-hydroxyethyl)-1H-pyrazol-5-yl, 3-(tert-butyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl, 1-benzyl-3-(tert-butyl)-1H-pyrazol-5-yl, 3-(tert-butyl)-1-ethyl-1H-pyrazol-5-yl, 3-isobutyl-1-methyl-1H-pyrazol-5-yl, 1-methyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl, 5-(1,The present invention relates to a compound of formula (Ibb) selected from the group consisting of 1-difluoroethyl)pyridin-3-yl, 5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl, 5-(difluoromethoxy)pyridin-3-yl, 3-(tert-pentyl)isoxazol-5-yl, 6-methoxy-5-(trifluoromethyl)pyridin-3-yl, 5-(tert-butyl)pyridin-3-yl, 2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-yl, (trifluoromethyl)pyridazin-3-yl, 3-isobutylisoxazol-5-yl, trifluoromethoxy)pyridin-3-yl and 5-(trifluoromethoxy)pyridin-3-yl.

[0108] In another preferred embodiment, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: Hy is selected from the group consisting of pyrazolo[1,5-a]pyrazin-3-yl and 6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-3-yl; and Het is selected from the group consisting of 5-(trifluoromethyl)pyridin-3-yl, 3-(tert-butyl)isoxazol-5-yl, 5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl, 6-methoxy-5-(trifluoromethyl)pyridin-3-yl, 5-(1,1-difluoroethoxy) ...(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-3-yl;

[0023] The present invention relates to a compound of formula (Ibb), wherein the compound is selected from the group consisting of 5-(trifluoromethoxy)pyridin-3-yl, 5-(tert-butyl)pyridin-3-yl, 5-(difluoromethoxy)pyridin-3-yl, 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl, 5-(trifluoromethoxy)pyridin-3-yl, 5-(tert-butyl)isoxazol-3-yl, 3-(tert-pentyl)isoxazol-5-yl and 3-isobutylisoxazol-5-yl.

[0109] According to a preferred embodiment, the present invention relates to at least one compound of formula (Ibb) and its pharmaceutically acceptable salts as listed in Table 5 below. These compounds are particularly active on the receptors DDR1 and DDR2, as shown in Table 6.

[0110] [Table 25] [Table 26] [Table 27] [Table 28] [Table 29] [Table 30] [Table 31] [Table 32] [Table 33] [Table 34] [Table 35]

[0111] In another preferred embodiment, the present invention relates to compounds of formula (I), wherein Rx, Ry and Rz are H.

[0112] In another preferred embodiment, the present invention relates to compounds of formula (I) wherein Rx is H, Ry is methyl and Rz is H.

[0113] In another preferred embodiment, the present invention relates to compounds of formula (I) wherein Rx is methyl, Ry is H and Rz is H.

[0114] In another preferred embodiment, the present invention relates to compounds of formula (I) wherein Rx is H, Ry is methyl and Rz is methyl.

[0115] It is clearly understood that any compound of the present invention may fall within more than one general formula. By way of example and not limitation, a compound having R1 equal to X' may fall within both Formula (Ia) and Formula (Iab).

[0116] The compounds of the present invention, including all of the compounds listed above, can be prepared from readily available starting materials according to the following general methods and procedures, or using slightly modified procedures readily available to those of ordinary skill in the art. While specific embodiments of the invention may be shown or described herein, those of ordinary skill in the art will recognize that all embodiments or aspects of the invention can be obtained using the methods described herein or using other known methods, reagents, and starting materials. Even when typical or preferred process conditions (i.e., reaction temperature, time, molar concentrations of reactants, solvent, pressure, etc.) are shown, other process conditions can also be used unless specifically stated otherwise. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be readily determined by one of ordinary skill in the art by routine optimization procedures.

[0117] In some cases, when it is necessary to mask or protect sensitive or reactive moieties, commonly known protecting groups (PG) can be used in accordance with general principles of chemistry (Protective groups in organic syntheses, 3rd ed. T.W. Greene, P.G.M. Wuts).

[0118] It has surprisingly been found that the compounds of formula (I) of the present invention effectively inhibit both the receptors DDR1 and DDR2. Advantageously, the inhibition of the receptors DDR1 and DDR2 can result in the effective treatment of diseases or conditions in which the DDR receptors are involved.

[0119] In this regard, as shown in the experimental section, the compounds of formula (I) of the present invention have been found to have antagonistic potency, expressed as an inhibition constant Ki, for DDR1 and DDR2 of less than 80 nM. Preferably, the compounds of the present invention have Ki for DDR1 and DDR2 of less than 50 nM. Even more preferably, the compounds of the present invention have Ki for DDR1 and DDR2 of less than 25 nM.

[0120] Furthermore, as shown in the experimental section, the affinity for either DDR1 or DDR2 receptors and the inhibitory activity against either DDR1 or DDR2 receptors were measured by binding (expressed as Ki) and cell-based assays (IC 50 Preferably, the compounds of the present invention have a K i and / or IC for the DDR1 and DDR2 receptors of less than 50 nM. 50 Even more preferably, the compounds of the present invention have a Ki and / or IC for DDR1 and DDR2 receptors of less than 25 nM. 50 It has.

[0121] In one aspect, the invention relates to a compound of formula (I) according to any of the above embodiments for use as a medicament.

[0122] In a preferred embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof for use in the treatment of diseases, disorders or conditions associated with dysregulation of the DDR.

[0123] In another aspect, the present invention relates to the use of a compound of formula (I) as defined above in the manufacture of a medicament for the treatment of a disorder associated with dysregulation of the DDR.

[0124] In a preferred embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the prevention and / or treatment of a disease, disorder or condition associated with the DDR receptor mechanism. In certain embodiments, the present invention relates to a compound of formula (I) useful for the prevention and / or treatment of fibrosis and / or a disease, disorder or condition involving fibrosis.

[0125] As used herein, the term "fibrosis" or "fibrotic disorder" refers to a condition associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased recruitment of fibroblasts, including, but not limited to, fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and gastrointestinal tract.

[0126] Preferably, the compounds of formula (I) above are useful for the treatment and / or prevention of fibrosis such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

[0127] More preferably, the compounds of formula (I) above are for the treatment of idiopathic pulmonary fibrosis (IPF).

[0128] In one embodiment, the present invention also relates to a method for preventing and / or treating disorders associated with the DDR receptor mechanism, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) above.

[0129] In a further aspect, the present invention relates to the use of compounds of formula (I) as defined above for the treatment of disorders associated with the DDR receptor mechanism.

[0130] In another aspect, the present invention relates to the use of a compound of formula (I) as defined above in the manufacture of a medicament for the treatment of a disorder associated with the DDR receptor mechanism.

[0131] In a further aspect, the present invention relates to a method for preventing and / or treating disorders or conditions associated with dysregulation of DDR receptors 1 and 2, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) as defined above.

[0132] In a further aspect, the present invention relates to the use of compounds of formula (I) as defined above for the treatment of diseases, disorders or conditions in which dysregulation of DDR receptors 1 and 2 is involved.

[0133] As used herein, a "safe and effective amount" in connection with a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically active agent means an amount of the compound that is sufficient to treat the patient's condition but low enough to avoid serious side effects, such an amount can be determined routinely by one of ordinary skill in the art.

[0134] The compounds of formula (I) may be administered in a single or multiple dose regimen administered at varying intervals over a period of time. Typical daily doses may vary depending on the route of administration selected.

[0135] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) according to any of the embodiments in admixture with at least one or more pharmaceutically acceptable carriers or excipients.

[0136] In certain embodiments, the present invention relates to pharmaceutical compositions comprising a compound of Formula (I) in admixture with one or more pharmaceutically acceptable carriers or excipients, such as those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA.

[0137] Administration of the compounds of the present invention and pharmaceutical compositions thereof can be achieved, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion) and by inhalation, depending on the needs of the patient.

[0138] Preferably, the compounds of the present invention are administered orally or by inhalation.

[0139] In certain preferred embodiments, the pharmaceutical compositions comprising the compounds of Formula (I) are solid oral dosage forms such as tablets, gelcaps, capsules, caplets, granules, lozenges, and bulk powders.

[0140] In certain embodiments, the pharmaceutical composition comprising a compound of Formula (I) is a tablet.

[0141] The compounds of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (e.g., sucrose, mannitol, lactose, starch) and known additives, including suspending agents, solubilizing agents, buffers, binders, disintegrating agents, preservatives, coloring agents, flavoring agents, lubricants, and the like.

[0142] In a further embodiment, the pharmaceutical compositions comprising the compounds of formula (I) are liquid oral dosage forms, such as aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs. Such liquid dosage forms may also contain suitable known inert diluents, such as water, and suitable known additives, such as preservatives, wetting agents, sweeteners, flavoring agents, and agents for emulsifying and / or suspending the compounds of the present invention.

[0143] In a further embodiment, the pharmaceutical composition comprising a compound of formula (I) is an inhalable formulation, such as an inhalable powder, a propellant-containing metered dose aerosol or a propellant-free inhalable formulation.

[0144] For administration as a dry powder, single or multi-dose inhalers known from the prior art may be used, in which case the powder may be filled into gelatin, plastic or other capsules, cartridges or blister packs or reservoirs.

[0145] A diluent or carrier which is chemically inert to the compound of the present invention, such as lactose or any other additive suitable for improving the inhalable fraction, may be added to the powdered compound of the present invention.

[0146] Inhalation aerosols containing a propellant gas such as a hydrofluoroalkane may contain the compounds of the invention in solution or dispersion form. Propellant-driven formulations may also contain other ingredients such as cosolvents, stabilizers and other additives as desired.

[0147] Propellant-free inhalable formulations containing the compounds of the invention may be in the form of a solution or suspension in an aqueous, alcoholic or hydroalcoholic medium and may be delivered by jet or ultrasonic nebulizers or soft mist nebulizers known from the prior art.

[0148] The compounds of the invention may be administered as the sole active agent or in combination with other pharmaceutically active ingredients.

[0149] The dosage of the compounds of the present invention will depend on a variety of factors, including, inter alia, the particular disease being treated, the severity of the condition, the route of administration, and the like.

[0150] The present invention also relates to a device containing a pharmaceutical composition comprising a compound of formula (I) of the present invention in the form of a single or multi-dose dry powder inhaler or a metered dose inhaler.

[0151] All preferred groups or embodiments described above for compounds of formula (I) may be equally applied in combination with one another mutatis mutandis.

[0152] The compounds of the present invention, including all of the compounds listed above, can be prepared from readily available starting materials according to the following general methods and procedures, or using slightly modified procedures readily available to those of ordinary skill in the art. While specific embodiments of the present invention are shown or described herein, those of ordinary skill in the art will recognize that all embodiments or aspects of the present invention can be practiced using the methods described herein or using other known methods, reagents, and starting materials. Where typical or preferred process conditions (i.e., reaction temperatures, times, molar concentrations of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be readily determined by one of ordinary skill in the art by routine optimization procedures.

[0153] Therefore, the processes set forth below and in the following schemes should not be construed as limiting the scope of synthetic methods available for preparing the compounds of the present invention.

[0154] Compounds of formula (I), including at least one or all of the compounds listed above, can generally be prepared by the procedures detailed in the schemes below, using generally known methods.

[0155] In a first embodiment of the present invention, compounds of formula (I), wherein R1, Rx, Ry, Rz, L and Hy are as defined above, can be prepared as described in Scheme 1.

[0156] Compounds of formula (I) can be prepared according to Scheme 1 below, which provides at least one non-limiting synthetic route for the preparation of all example compounds.

[0157] [ka] According to Scheme 1, intermediate III can be prepared in a one-step synthesis starting from intermediate II under suitable ester-forming conditions in the presence of an alkylating agent such as methyl iodide with an inorganic base such as cesium carbonate in a suitable organic solvent such as DMF and at a temperature generally around room temperature for a period ranging from several hours to overnight. Intermediate III can be converted to intermediate IV by deprotection of 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.

[0158] Intermediate V can be prepared in a single-step synthesis starting from intermediate IV and an appropriate carboxylic acid under suitable amide coupling conditions, in the presence of an agent for activating the carboxylic acid partner, such as TBTU or HATU, or T3P, in the presence of an organic base, such as DIPEA or TEA, in a suitable organic solvent, such as DCM or DMF, and generally at a temperature around room temperature. Direct ester amidation (transamination) can be carried out between intermediate V and intermediate XII or XIII using, for example, butyllithium as a promoter, in a suitable organic solvent, such as THF or dioxane, at temperatures ranging from −78° C. to room temperature for several hours to give compounds of formula (I). In a different approach, intermediate V can be converted to intermediate VI by hydrolysis under basic conditions, for example, using aqueous sodium hydroxide in a suitable solvent, such as methanol, at room temperature for several hours. Intermediate VI is subsequently reacted with intermediate XII or XIII under suitable amide coupling conditions in the presence of an agent that activates the carboxylic acid partner, such as TBTU or HATU, or T3P, followed by reaction with an amine in the presence of an organic base, such as DIPEA or TEA, in a suitable organic solvent, such as DCM or DMF, and generally at a temperature around room temperature for a period ranging from several hours to overnight.

[0159] Alternatively, compounds of formula (I) can be prepared starting from intermediate VI via amidation in the presence of TCFH and 1-methylimidazole to give a transiently activated acylimidazolinium intermediate, which can be reacted with the appropriate amine XII or XIII in a solvent such as DMF at RT. In a different approach, compounds of formula (I) can be prepared starting from intermediate VI in the presence of a suitable chlorinating reagent, such as POCl or thionyl chloride, in a solvent such as pyridine at 5°C to give the corresponding acyl chloride, which can be directly treated with the appropriate amine XII or XIII in Py at RT.

[0160] Compounds of formula (I) can also be obtained by acyl chloride formation starting from intermediate VI in the presence of thionyl chloride at 50°C, followed by reaction with XXIII in the presence of a suitable base such as LiHMDS in a suitable solvent such as DCM at a temperature of -78°C.

[0161] Intermediate VI can be converted to intermediate X by amide coupling with intermediate XIV according to the conditions described above, followed by deprotection of the silyl group in a suitable solvent such as MeOH or under suitable deprotection conditions such as HCl or TFA in THF at RT to convert intermediate X to a compound of formula (I).

[0162] In a different approach, intermediate VII can be obtained from intermediate VI by amide coupling with intermediate XII according to the conditions described above, followed by deprotection of the BOC-protected amine according to the conditions described above and final methylation using Eschweiler-Clarke reaction conditions to give compounds of formula (I). In a different approach, intermediate VII can be converted to intermediate IX by deprotection of the acetal using a suitable acid such as TFA in a suitable solvent such as DCM at room temperature. Intermediate IX can be converted to compounds of formula (I) by reductive amination using a suitable alkylamine in the presence of an acid such as acetic acid and a coordinating agent such as titanium tetrahydroisopropoxide in a suitable solvent such as DCM or EtOH at room temperature.

[0163] In other embodiments, compounds of Formula (I) can be prepared according to Schemes 2a and 2b. [ka] [ka] According to Scheme 2a, a mixture of intermediates IIIa and IVa can be prepared from intermediate IIa by Gevaert multicomponent cyclization using ethyl 2-cyanoacetate in a suitable solvent such as EtOH at reflux temperature using a suitable sulfur source, such as sulfur. A mixture of intermediates VIIa and VIIIa can be obtained by subjecting the mixture of intermediates IIIa and IVa to deamination conditions using a suitable diazotization 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, followed by deprotection of the BOC group under acidic conditions, such as concentrated hydrogen chloride or hydrogen chloride in dioxane, in a suitable solvent such as ethanol or diethyl ether at room temperature. A mixture of intermediates IXa and Xa can be prepared from a mixture of intermediates VIIa and VIIIa and an appropriate carboxylic acid by subjecting the mixture to amide coupling conditions using an organic base such as DIPEA or TEA in the presence of an agent for activating the carboxylic acid partner, such as TBTU or HATU, or T3P, in a suitable organic solvent, such as DCM or DMF, and generally at a temperature around RT. The mixture 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 subjecting a mixture of intermediates XIIa and XIa and the appropriate amine, XIIIa or XIVa, to the above-described amide coupling conditions. Compounds of formula (I) can be isolated from a mixture of intermediates XVIa and XVa by column chromatography using a suitable stationary phase, such as silica gel, and a suitable mobile phase, such as water / acetonitrile, DCM / MeOH, or Hex / AcOEt. In a different approach, a mixture of intermediates Va and VIa can be converted to a mixture of intermediates XVIIa and XVIIIa by subjecting them to 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 by amide coupling according to the conditions described above, followed by deprotection of the BOC group using the conditions described above.A mixture of intermediates XXVIa and XXVa can be obtained by reductive amination using an 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 the presence of an acid such as acetic acid and a coordinating agent such as titanium tetrahydroisopropoxide at room temperature.

[0164] In other embodiments, compounds of formula (I) can be prepared according to Scheme 3. [ka] According to Scheme 3, intermediate XXVIIIa can be obtained from compound IIa by Gevaert multicomponent cyclization conditions with ethyl 2-cyanoacetate in a suitable solvent such as EtOH at reflux temperature using a suitable sulfur source such as sulfur, followed by suitable column chromatography using a suitable stationary phase such as silica gel and a suitable mobile phase such as water / acetonitrile or DCM / MeOH or Hex / AcOEt. Intermediate XXVIIIa can be converted to compounds of formula (I) by deamination according to the conditions described in Scheme 2b, followed by BOC deprotection, amidation with a suitable acid, hydrolysis of the ethyl ester and final amidation with a suitable amine XIIIa or XIVa.

[0165] In a further preferred embodiment, compounds of formula (I) can be prepared according to Scheme 4. [ka]

[0166] According to Scheme 4, intermediate IIIb can be obtained in a one-step synthesis starting from intermediate IIb under suitable ester-forming conditions in the presence of an alkylating agent such as methyl iodide with an inorganic base such as cesium carbonate in a suitable organic solvent such as DMF and at a temperature generally around RT for a period ranging from several hours to overnight. Intermediate IIIb can be converted to intermediate IVb by deprotection of the BOC-protected amine under acidic conditions such as concentrated hydrogen chloride or hydrogen chloride in dioxane in a suitable solvent such as ethanol or diethyl ether at room temperature, followed by reductive amination conditions using a suitable reducing agent such as Na(OAc)BH or NaCNBH in the presence of a suitable aldehyde in a suitable solvent such as DCM or EtOH in the presence of an acid such as acetic acid at room temperature. Compounds of formula (I) can be obtained by hydrolysis of intermediate Vb using a suitable base such as NaOH or LiOH in a suitable solvent such as MeOH or EtOH, followed by amide coupling with the appropriate intermediate XIIb or XIIIb under suitable amide coupling conditions, in the presence of an agent that activates the carboxylic acid partner, such as TBTU, HATU, or T3P, with an organic base such as DIPEA or TEA, in a suitable organic solvent such as DCM or DMF, and generally at a temperature around RT. Alternatively, compounds of formula (I) can be obtained by starting from intermediate VIb in the presence of a suitable chlorinating agent, such as oxalyl chloride, or in a solvent such as thionylpyridine chloride, at 5° C. to give the corresponding acyl chloride, which is then directly treated with the appropriate amine XIIb or XIIIb in Py at room temperature.

[0167] In a different approach, intermediate VIIb can be prepared from intermediate VIIb by amide coupling according to the conditions described above, or by reacting intermediate IIb in the presence of TCFH and 1-methylimidazole to give a temporarily activated acylimidazolinium intermediate, which 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 by deprotection of the BOC group followed by amide coupling, applying the appropriate conditions described above with the appropriate carboxylic acid.

[0168] Alternatively, intermediate VIIIb can be converted to intermediate IXb by reductive amination using a suitable SEM-protected aldehyde according to the appropriate conditions described above. It will be apparent to those skilled in the art that if the aldehyde contains a moiety that interferes with the reaction, such a moiety must be protected. SEM deprotection conditions can be applied to intermediate IXb using a suitable acid, such as acetic acid, in a suitable solvent, such as DMF, at room temperature to give a compound of formula (I).

[0169] In a different approach, intermediate VIIIb can be converted to intermediate Xb by amide coupling with intermediate XIb according to the conditions described above, which can be converted to compounds of formula (I) by alkylation with a suitable haloalkyl, such as chloroethylmorpholine, using a suitable inorganic base, such as potassium carbonate, in a suitable solvent, such as DMF. Alternatively, compounds of formula (I) can be obtained from intermediate Xb by Suzuki coupling conditions with a suitable boron reagent, such as 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine, using a suitable inorganic base, such as potassium carbonate or sodium carbonate, a suitable catalyst, such as Pd(dppf)Cl, in a suitable organic solvent, such as DMF or DMA, at 100° C.

[0170] Alternatively, compounds of formula (I) can be obtained from intermediate VIIa by applying the above-mentioned amide coupling conditions with a suitable acid. Alternatively, compounds of formula (I) can be prepared from intermediate VIIIb by reductive amination using a suitable aldehyde with a suitable reducing agent such as Na(OAc)3BH or NaCNBH3 in a suitable solvent such as DCM or EtOH in the presence of an acid such as acetic acid and a coordinating agent such as titanium tetrahydroisopropoxide at room temperature.

[0171] Various aspects of the invention described herein are illustrated by the following examples, which are not intended to limit the invention in any way. [Example]

[0172] Preparation of Intermediates and Example Compounds Compound names were generated using Structure To Name Place IUPAC Name Name in PerkinElmer ChemDraw Professional 19.1.1.21. All reagents whose synthesis is not described in the experimental section are either commercially available or known compounds or can be prepared from known compounds by known methods by one skilled in the art.

[0173] In the methods below, some of the starting materials are identified with an "Intermediate" or "Example" number along with a step number indication, which is provided solely as an aid to those skilled in the art.

[0174] "Similar" or "subsequent" methods mean that such methods may involve minor modifications, for example, reaction temperature, amounts of reagents / solvents, reaction time, work-up conditions, or chromatographic purification conditions.

[0175] Abbreviation - Meaning ACN = acetonitrile; Et2O = 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 = di-tert-butyl dicarbonate; HATU = (dimethylamine) (3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate;TBTU=2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate;T3P=propanephosphonic anhydride;HOBt=1-hydroxybenzotriazole hydrate;TCFH=chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate;n-BuLi=n-butyllithium;XPhos Pd G3=(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate;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 sulfoxide; CDCl3 = deuterated chloroform; ACN-d3 = deuterated acetonitrile; NMR = nuclear magnetic resonance; LC-MS = liquid chromatography / mass spectrometry; ESI = electrospray ionization; Prep-HPLC = preparative high-performance liquid chromatography; SCX = solid cation exchange; SM = starting material; DP = desired product; wt = weight; ee= enantiomeric excess; SEM-Cl = 2-(trimethylsilyl)ethoxymethyl chloride; PyBOP = benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate; Pd2(dba)3 = trisdibenzylideneacetone)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(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane; BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene; XantPhos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0176] General experiment details NMR Details: 1 H NMR spectra were performed on a Varian MR-400 spectrometer or a Bruker Avance III HD 400 MHz or Bruker Fourier 300 MHz spectrometer operating at 400 MHz (proton frequency) equipped with a 5 mm 1H / nX broadband probehead with a self-shielded Z-gradient coil for reversal detection, a deuterium digital lock channel unit, and a quadrature digital detection unit with transmitter offset frequency shift. Chemical shifts are reported as δ values ​​(ppm) relative to tetramethylsilane (TMS) as the internal standard. Coupling constants (J values) are given in hertz (Hz), and multiplicities are reported using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, dt = triplet of triplets, m = multiplet, br = broad, and nd = undetermined.

[0177] In some instances, the signal NH from the amide or amine bond (exchangeable proton) is not visible.

[0178] In some cases, some signals may be masked under the water signal or under the DMSO or other residual solvent signal.

[0179] LC / UV / MS analysis method LC / MS retention times are estimated to be subject to experimental error of ±0.5 min.

[0180] Method 1: Acquity CSH C18 column, 50 mm x 2.1 mm, 1.7 μm, maintained at 40°C; Mobile phase: 1% to 99.9% of eluent B (ACN / water 95:5 + 0.05% HCOOH) in eluent A (water / ACN 95:5 + 0.05% HCOOH) within 3.5 min. Flow rate: 1 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters PDA + Waters QDA.

[0181] Method 2: Kinetex (登録商標) XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: ACN (0.1% formic acid) in water (0.1% formic acid), 70% to 5% within 3.90 min; flow rate: 1.0 mL / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus.

[0182] Method 3: Kinetex (登録商標) XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: ACN (0.1% formic acid) in water (0.1% formic acid), 80% to 5% within 3.90 min; flow rate: 1.0 mL / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus.

[0183] Method 4: Kinetex (登録商標)XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: ACN (0.1% formic acid) in water (0.1% formic acid), 70% to 5% within 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. 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.

[0184] Method 6: Acquity UPLC BEH Shield RP18 column, 100 x 2.1 mm, 1.72 μm (PlusGuard cartridge), maintained at 40°C. Mobile phase: ACN in water + 10 nM ammonium bicarbonate, 5% to 95% in 5.6 minutes. Flow rate: 0.4 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters DAD + Waters SQD2, single quadrupole UPLC-MS.

[0185] Method 7: Acquity UPLC HSS C18 column, 100 x 2.1 mm, 1.8 μm (PlusGuard cartridge), maintained at 40°C. Mobile phase: ACN (0.1% formic acid) in water (0.1% formic acid), 5% to 95% in 5.6 minutes. Flow rate: 0.4 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters DAD + Waters SQD2, single quadrupole UPLC-MS.

[0186] Method 8: Kinetex (登録商標)XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: ACN (0.1% formic acid) in water (0.1% formic acid), 90% to 5% within 3.90 min; flow rate: 1.0 mL / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus.

[0187] Method 9: Kinetex (登録商標) XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: ACN (0.1% formic acid) in water (0.1% formic acid), 90% to 5% within 3.90 min; flow rate: 1.0 mL / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Plus.

[0188] Method 10: Gemini-NX C18 column, 4.6 x 150 mm, 3 μm, maintained at 35°C. Mobile phase: ACN (0.1% formic acid) in water (0.1% formic acid), 80% to 5% within 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.

[0189] Method 11: Gemini-NX C18 column, 4.6 x 150 mm, 3 μm, maintained at 35°C. Mobile phase: ACN (0.1% formic acid) in water (0.1% formic acid), 65% to 5% within 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.

[0190] Method 12: Lux C1 column, 4.6 x 150 mm, 5 μm maintained at rt. Mobile phase: 90:10 ACN:IPA isocratic; flow rate: 1.0 mL / min, wavelength: 254 nm. Waters / Thar SFC system with Waters SQD.

[0191] 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) isocratically; flow rate: 4.0 mL / min, 125 bar backpressure; wavelength: 210-400 nm. Waters / Thar SFC system with Waters SQD.

[0192] Method 14: Agilent Zorbax column, 4.6 x 50 mm, 3.5 μm, maintained at 40°C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid), 40% to 100% within 2 min. Flow rate: 3.0 mL / min. Wavelength: 210-400 nm DAD. Waters 2795 / 2695 Separation Module + Waters DAD + Micromass ZQ, single quadrupole LC-MS.

[0193] 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.

[0194] Method 16: Waters Sunfire C18 column, 4.6 x 50 mm, 3.5 μm, maintained at 40 °C. Mobile phase: MeCN + 10 mM ammonium bicarbonate in water, 5-95% 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.

[0195] Method 17: Agilent Zorbax column 4.6 x 50 mm, 3.5 μm, maintained at 40°C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid), 5% to 95% within 2 minutes. Flow rate: 3.0 ml / min. Wavelength: 210-400 nm DAD. Waters 2795 / 2695 separation module + Waters DAD + Micromass ZQ, single quadrupole LC-MS.

[0196] LC / SFC chiral separation method Method Prep 1: Separation runs were performed on a Gilson preparative LC system (Gilson Pump 333; Gilson 151; Gilson Valvemate 6 position) using a Lux C1 (21.2 mm x 250 mm, 5 μm) column at 21 mL / min, with the column maintained at room temperature; wavelength: 210 nm, and an isocratic run (90 / 10 ACN:i-PrOH, 0.2% v / v NH).

[0197] Method Prep 2: SFC-MS separation runs were performed on a Gilson preparative LC system (Gilson Pump - 333; Gilson 151; Gilson Valvemate 6 position) using an AmyC (20 mm x 250 mm, 5 μm) column at 50 mL / min, with the column maintained at 40 °C, in an isocratic run (70 / 30 MeOH:CO, 0.2% v / v NH, 125 bar backpressure). Wavelength: 210 nm.

[0198] Method Prep 3: SFC-MS separation runs were performed on a Gilson preparative LC system (Gilson Pump - 333; Gilson 151; Gilson Valvemate 6 position) using a Lux A1 (21.2 mm x 250 mm, 5 μm) column at 50 mL / min, with the column maintained at 40 °C, in an isocratic run (40 / 60 MeOH:CO, 0.2% v / v NH, 100 bar backpressure). Wavelength: 210 nm.

[0199] When the preparation of starting materials is not described, they are either commercially available, known in the literature, or readily obtainable by one skilled in the art using standard procedures. All solvents were purchased from commercial suppliers and used without further purification.

[0200] Compounds were purified using reverse-phase HPLC under both basic (ACN + 0.1% NH3, HO + 0.1% NH3) and acidic (ACN + 0.1% HCOOH, HO + 0.1% HCOOH) conditions using a Waters Fractionlynx preparative HPLC system (2525 pump, 2996 / 2998 UV / VIS detector, 2767 liquid handler) or a Gilson preparative HPLC system (322 pump, 155 UV / VIS detector, GX-281 liquid handler) or equivalent system; in the latter case, residual fractions containing the required product (identified by TLC and / or LCMS analysis) were pooled and the solvent removed under reduced pressure or by lyophilization; or alternatively, extracted with SCX(NH).

[0201] Specific details of the conditions used, including columns, solvents, gradients, and modifiers (acidic or basic), are provided for certain examples and are provided merely as a guide; when specific conditions are not provided, they can be readily optimized by one of ordinary skill in the art.

[0202] Thin-layer chromatography was performed on Merck silica gel 60 F254 TLC plates. Preparative thin-layer chromatography (pTLC) was performed on Uniplate 1000 micron or 500 micron silica gel plates. Flash chromatography was performed on Interchim PuriFlash 450 and 520Plus or using Biotage SP1 purification systems or equivalent MPLCs using pre-packed silica gel cartridges.

[0203] General synthetic procedure General Procedure A Sodium hydride (60% in mineral oil, 1.10 equiv.) was added to a stirring solution of the required alcohol (1.20 equiv.) in ACN (0.5 M concentration) under an inert atmosphere. The reaction mixture was stirred for 1 h, then the required aryl-fluoride (1.00 equiv.) was added in one portion. The reaction mixture was stirred at room temperature until LCMS indicated consumption of the 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 under reduced pressure.

[0204] General Procedure B The required aryl-nitro (1.00 equiv.) and iron powder (5.00 equiv.) were combined in acetic acid (0.3 M) and methyl alcohol (0.3 M). The reaction mixture was stirred at 50° C. until LCMS indicated the consumption of the starting material. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in DCM and saturated Na2CO3 (水性) The combined organic phase was filtered through a hydrophobic frit and concentrated under reduced pressure.

[0205] General procedure C To a solution of the required aldehyde (1.00 equiv.) in DCM (0.1 M concentration) was added the required 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 hour. Sodium triacetoxyborohydride (2.00 equiv.) was added, and the reaction mixture was stirred at room temperature until LCMS showed the consumption of starting material. The reaction mixture was diluted with DCM and saturated NaHCO 3(水性) The mixture was partitioned between 0.1 and 1.5 mL of DCM and the mixture was filtered through a bed of Celite. The aqueous phase was extracted 2x with DCM and the combined organic phases were washed with saturated aqueous NaCl. (水性) The extract was washed with HCl, passed through a hydrophobic frit and concentrated under reduced pressure.

[0206] General Procedure D To palladium (10% on carbon) (10 wt%) was added a solution of the required nitro-aryl (1.00 equiv.) in EtOH (0.1 M concentration). The flask was evacuated and purged with argon (×3), then evacuated and purged with hydrogen (×3). The reaction mixture was stirred at room temperature until LCMS indicated consumption of the 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 under reduced pressure.

[0207] General Procedure E To a solution of the required phenol (1.00 equiv.) in DMF (0.2 M concentration) was added the required alkyl halide (1.20 equiv.), followed by cesium carbonate (2.00 equiv.). The mixture was stirred at 80° C. until LCMS showed the starting material was consumed. The reaction mixture was diluted with water and extracted with DCM (×2). The organic phases were combined and concentrated.

[0208] General Procedure F To a solution of the required nitro-aryl (1.00 equiv.) in ethanol (0.1 M concentration) under 1 atmosphere of nitrogen, 1-methyl-1,4-cyclohexadiene (30.0 equiv.) and palladium on carbon (10%) (1.00 equiv.) were added sequentially, and the reaction mixture was stirred at 80°C until LCMS showed the consumption of the 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.

[0209] General Procedure G To a mixture of the required carboxylic acid sodium salt or acid (1.00 equiv.) and HATU (1.20-2.00 equiv.) in DMF / DCM (0.1 M concentration) was added DIPEA (3.00-8.00 equiv.). The reaction mixture was stirred at room temperature for 15 minutes, followed by the addition of the required amine (1.00-2.00 equiv.). The reaction mixture was stirred at room temperature until LCMS indicated the consumption of starting material, then concentrated.

[0210] General Procedure H 6-(Imidazo[1,2-a]pyridine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (1.00 equiv.) was suspended in thionyl chloride (10.0 equiv.), and the reaction mixture was stirred at 50° C. for 20 minutes. Additional thionyl chloride (10.0 equiv.) was added, and the reaction mixture was stirred at 50° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure to give 6-(imidazo[1,2-a]pyridine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carbonyl chloride as a white solid. To a solution of the required 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-dihydro-4H-thieno[2,3-c]pyridine-3-carbonyl chloride (1.30 equiv.). The reaction mixture was stirred at room temperature until LCMS showed the consumption of starting material, and then concentrated under reduced pressure.

[0211] General Procedure I The requisite 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 reduced pressure. The residue was suspended in toluene and reconcentrated to give the intermediate acyl chloride. To a solution of the requisite aniline (1.00 equiv.) and DMAP (0.20 equiv.) in pyridine (0.1 M concentration), the acyl chloride was added, followed by DIPEA (3.00 equiv.). The reaction mixture was stirred at 40° C. until LCMS indicated consumption of the starting material, and then concentrated under reduced pressure.

[0212] General procedure J To a solution of the required aldehyde (1.00 equiv.) in DCM (0.1 M concentration) was added the required 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 hour. Sodium triacetoxyborohydride (2.00 equiv.) was added, and the reaction mixture was stirred at room temperature until LCMS showed the starting material was consumed. The residue was loaded onto an Isolute SCX-II cartridge, washed with MeOH, and then eluted with 2M NH3 / MeOH. The eluent was concentrated under reduced pressure.

[0213] General Procedure K To a solution of the required amine (1.00 equiv.) and the required 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, 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 reduced pressure.

[0214] General procedure L To a mixture of the required aldehyde (1.00 equiv.) and N-[3-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-ium-3-carboxamide hydrochloride (1.00 equiv.) in MeOH (0.075 M), acetic acid (9.86 equiv.) was added and the reaction mixture was stirred at 65° C. for 90 minutes. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in DCM (0.025 M) and sodium triacetoxyborohydride (3.50 equiv.) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM and diluted with KHSO 4 4(水性) After stirring for 15 min, the mixture was treated with a 10% solution of saturated aqueous NaCO 3(水性) The mixture was basified with HCl and the layers were separated. The aqueous layer was extracted with DCM and the combined organic extracts were passed through a hydrophobic frit and concentrated under reduced pressure.

[0215] General procedure M To a solution of the required 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. N-[3-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (1.00 equiv.) was then added, and the reaction mixture was stirred at 40° C. overnight. The reaction mixture was cooled to room temperature and concentrated.

[0216] General Procedure N To a solution of the required acid (1.00 equiv.), the required amine (1.00-1.30 equiv.), and 1-methylimidazole (3.50 equiv.) in 0.2 M ACN was added TCFH (1.20-1.50 equiv.). The reaction mixture was stirred at room temperature and saturated NaHCO 4 was added until LCMS showed the consumption of starting material. 3(水性) and EtOAc. The phases were separated, the aqueous phase extracted 2× with EtOAc and the combined organic phases passed through a hydrophobic frit and concentrated under reduced pressure.

[0217] 4-((tetrahydrofuran-3-yl)oxy)-3-(trifluoromethyl)aniline - Preparation of Intermediate 1 [ka] Step 1: 3-(4-nitro-2-(trifluoromethyl)phenoxy) (Intermediate 2) [ka] Prepared according to general procedure A from 3-hydroxytetrahydrofuran (0.53 g, 6.00 mmol) and 2-fluoro-5-nitrobenzotrifluoride (0.69 mL, 5.00 mmol) to give the title compound (1.52 g, 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)

[0218] Step 2: 4-((tetrahydrofuran-3-yl)oxy)-3-(trifluoromethyl)aniline (Intermediate 1) Prepared from Intermediate 2 (1.52 g, 5.48 mmol) according to general procedure B. The residue was loaded onto an Isolute SCX-II cartridge, washed with DCM / MeOH, and then eluted with 2M NH3 / MeOH. The eluent was concentrated to give the title compound (1.10 g, 75%). 1 H 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)

[0219] The intermediates listed in the table below were prepared via aromatic nucleophilic substitution as described for Intermediate 1, steps 1-2, applying the corresponding commercially available alcohol in step 1. [Table 36]

[0220] 2-(4-amino-2-(trifluoromethyl)phenoxy)ethan-1-ol - Preparation of Intermediate 8 [ka] Step 1 - 2-(4-nitro-2-(trifluoromethyl)phenoxy)ethan-1-ol (Intermediate 9) [ka] 2-Fluoro-5-nitrobenzotrifluoride (0.69 mL, 5.00 mmol, 1.00 equiv.), potassium tert-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) under an inert atmosphere. The reaction mixture was heated at 70° C. for 1 hour, then cooled to room temperature and added to ice / HCl. (水性) The mixture was stirred for 1 hour and filtered. The resulting solid was washed with water and dried under reduced pressure to give the title compound (1.16 g, 92%). 1 H 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)

[0221] Step 2 - 2-(4-amino-2-(trifluoromethyl)phenoxy)ethan-1-ol (Intermediate 8) Prepared according to general procedure B from intermediate 9 (1.16 g, 4.62 mmol) to give the title compound (0.98 g, 89%). 1 H 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)

[0222] Preparation of 3-((dimethylamino)methyl)-5-(trifluoromethyl)aniline (Intermediate 10) [ka] Step 1 - N,N-Dimethyl-1-(3-nitro-5-(trifluoromethyl)phenyl)methanamine (Intermediate 11) [ka] Prepared from 3-nitro-5-(trifluoromethyl)benzaldehyde (200 mg, 0.913 mmol) and dimethylamine (2 M solution in THF, 0.50 mL, 1.00 mmol) according to general procedure C. Purification by column silica gel chromatography (12 g cartridge, 0–2.5% 2 M NH in MeOH, DCM) afforded the title compound (84 mg, 37%). 1 H NMR (400 MHz, CDCl3) δ 8.41 - 8.37 (m, 2H), 7.95 (s, 1H), 3.58 (s, 2H), 2.29 (s, 6H)

[0223] Step 2 - 3-((dimethylamino)methyl)-5-(trifluoromethyl)aniline (Intermediate 10) Prepared according to general procedure D from intermediate 11 (84 mg, 0.338 mmol) to give the title compound (67 mg, 91%). 1 H 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)

[0224] The intermediates listed in the table below were prepared via aromatic nucleophilic substitution as described for Intermediate 10, steps 1-2, using the corresponding commercially available amine in step 1. [Table 37]

[0225] Preparation of 3-(2-morpholinoethoxy)-5-(trifluoromethyl)aniline (Intermediate 15) [ka] Step 1 - 4-(2-(3-nitro-5-(trifluoromethyl)phenoxy)ethyl)morpholine (Intermediate 16) [ka] Prepared from 4-(2-chloroethyl)morpholine hydrochloride (431 mg, 2.32 mmol) according to general procedure E. The residue was purified by column chromatography on silica gel (40 g cartridge, 0-100% AcOEt in cyclohexane) to give the title compound (0.6 g, 97%). 1 H 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)

[0226] Step 2 - 3-(2-morpholinoethoxy)-5-(trifluoromethyl)aniline (Intermediate 15) Prepared according to general procedure F from intermediate 16 (100 mg, 0.312 mmol) to give the title compound (84 mg, 93%) which was used without further purification. 1 H 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)

[0227] The intermediates listed in the table below were prepared via nucleophilic substitution as described in Intermediate 15, steps 1-2, using the corresponding commercially available alkyl chloride in step 1. [Table 38]

[0228] Preparation of 4-(pyrrolidin-1-ylmethyl)-3-(trifluoromethyl)aniline (Intermediate 20) [ka] Step 1 - 3-(trifluoromethyl)-4-vinylaniline (Intermediate 21) [ka] A mixture of 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 equiv.), and K3PO4 (5.53 g, 26.0 mmol, 2.50 equiv.) was suspended in 1,4-dioxane (45.00 mL) and water (5.00 mL) and purged with argon under sonication for 10 min. Vinylboronic acid pinacol ester (2.1 mL, 12.5 mmol, 1.20 equiv.) was added, and the reaction mixture was stirred at 80 °C under argon for 7 h. The reaction mixture was cooled to room temperature and partitioned between AcOEt and water, and the aqueous layer was re-extracted with AcOEt. The combined organic phase was washed with brine, dried (NaSO), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (80 g cartridge, 0-30% AcOEt in cyclohexane) to give 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)

[0229] Step 2 - tert-Butyl (3-(trifluoromethyl)-4-vinylphenyl)carbamate (Intermediate 22) [ka] To a solution of intermediate 21 (1.12 g, 5.98 mmol, 1.00 equiv.) in toluene (12.00 mL) was added BocO (1.7 mL, 7.48 mmol, 1.25 equiv.) at room temperature. The reaction mixture was stirred at 100 °C for 6 h and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (80 g cartridge, 0-20% AcOEt in cyclohexane) to give the title compound. 1 H 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)

[0230] Step 3 - tert-Butyl (4-formyl-3-(trifluoromethyl)phenyl)carbamate (Intermediate 23) [ka] A solution of intermediate 22 (1.72 g, 5.99 mmol, 1.00 equiv) in DCM (60.00 mL) was passed through O3 / O2 at -78 °C for 45 min to give a green reaction mixture. DMSO (440 μL, 5.99 mmol, 1.00 equiv) was added, and the reaction mixture was warmed to room temperature while being purged with argon. The reaction mixture was concentrated under reduced pressure, and the residue was purified by FCC on silica gel (80 g cartridge, 0-20% AcOEt in cyclohexane) to give the crude title compound (1.19 g, 39%). 1 H 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)

[0231] Step 4 - tert-Butyl (4-(pyrrolidin-1-ylmethyl)-3-(trifluoromethyl)phenyl)carbamate (Intermediate 24) [ka] Intermediate 23 (298 mg, 1.03 mmol) and pyrrolidine (0.095 mL, 1.13 mmol) were purified according to general procedure C to give the title compound (317 mg, 89%). 1 H 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)

[0232] Step 5 - 4-(pyrrolidin-1-ylmethyl)-3-(trifluoromethyl)aniline (Intermediate 20) To a solution of intermediate 24 (315 mg, 0.915 mmol, 1.00 equiv) in MeOH (6.10 mL) was added 4 M HCl in dioxane (1.5 mL, 6.00 mmol, 6.56 equiv). The reaction mixture was stirred at room temperature for 66 hours. The reaction mixture was evaporated under reduced pressure to give the hydrochloride salt of the title compound in quantitative yield. 1 H 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)

[0233] The intermediates reported in the table below were prepared using intermediate 20, reductive amination as described in steps 1-5, and the corresponding commercially available amine in step 4. [Table 39]

[0234] The intermediates reported in the table below were prepared using intermediate 24, Suzuki coupling as described in steps 1-5, and the corresponding commercially available aryl bromide in step 1. The catalyst modifications are indicated in the table below. [Table 40]

[0235] Preparation of 4-(pyrrolidin-1-ylmethyl)-3-(trifluoromethyl)aniline (Intermediate 27) [ka] Step 1 - N,N-Dimethyl-1-(4-nitro-2-(trifluoromethyl)phenyl)methanamine (Intermediate 28) [ka] Prepared according to general procedure C from 4-nitro-2-(trifluoromethyl)benzaldehyde (125 mg, 0.570 mmol) and dimethylamine (2 M solution in THF, 0.31 mL, 0.628 mmol) to give the title compound (132 mg, 93%). 1 H 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)

[0236] Step 2 - 4-((dimethylamino)methyl)-3-(trifluoromethyl)aniline (Intermediate 27) Prepared according to general procedure D from intermediate 28 (132 mg, 0.532 mmol) to give the title compound (104 mg, 90%). 1 H 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)

[0237] Preparation of 3-(3-amino-5-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (Intermediate 29) [ka] tert-Butyl 3-(3-nitro-5-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (Intermediate 30) [ka] A mixture of 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 min, followed by the dropwise addition of a mixture of 3-nitro-5-(trifluoromethyl)phenol (500 mg, 2.41 mmol, 1.00 equiv.) and N-Boc-3-pyrrolidinoline (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 reduced pressure. The crude material was purified by column chromatography on silica gel (25 g cartridge, 0–100% AcOEt in cyclohexane) to afford the title compound (367 mg, 67% yield). 1 H 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)

[0238] Tert-butyl 3-(3-amino-5-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (Intermediate 29) Prepared from intermediate 30 (300 mg, 0.805 mmol) according to general procedure F. (登録商標) Purification on a C18 19 x 150 mm, 10 μm column (40-100% ACN / H2O (0.1% FA), 20 mL / min, RT) afforded the title compound (170 mg, 61%). 1 H 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)

[0239] Preparation of 3-(tert-butyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-5-amine (Intermediate 31) [ka] Step 1 - 2-(5-amino-3-(tert-butyl)-1H-pyrazol-1-yl)ethan-1-ol (Intermediate 32) [ka] A solution of 4,4-dimethyl-3-oxopentanenitrile (5.00 g, 39.9 mmol), 2-hydroxyethylhydrazine (3.0 mL, 43.9 mmol), and concentrated HCl (37%) (0.10 mL, 1.21 mmol) was stirred at 90° C. for 23 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residual oily solid was triturated with cyclohexane (30 mL), the solvent was decanted, and the residue was dried under reduced pressure to give the title compound (7.082 g, 97%). 1 H NMR (400 MHz, CDCl3) δ 5.43 (s, 1H), 4.02 - 3.95 (m, 4H), 3.64 (brs, 2H), 1.25 (s, 9H)

[0240] Step 2 - 3-(tert-butyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-5-amine (Intermediate 31) To a solution of Intermediate 32 (7.08 g, 38.6 mmol) in DMF (63.00 mL) was added imidazole (7.89 g, 0.116 mol) under nitrogen atmosphere with stirring at room temperature. Tert-butyl-chloro-dimethyl-silane (8.74 g, 58.0 mmol) was added in three portions and the reaction mixture was stirred at room temperature for 2 hours. The mixture was cooled in an ice / water bath and saturated NH4Cl was added. (水性) (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 3x with DCM and the combined organic phase was extracted 3x with 5% LiCl (水性)The mixture was washed with HCl, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (AcOEt / cyclohexane 0% to 50%) to give the title compound (8.905 g, 77%). 1 H 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)

[0241] Preparation of 3-(dimethoxymethyl)-5-(trifluoromethyl)aniline (Intermediate 33) [ka] Step 1 - 1-(Dimethoxymethyl)-3-nitro-5-(trifluoromethyl)benzene (Intermediate 34) [ka] 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 p-toluenesulfonic acid monohydrate (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 reduced pressure. The residue was dissolved in AcOEt and saturated aqueous NaCO. 3(水性) The mixture was partitioned between 100 ml of ethyl acetate and 100 ml of ethyl acetate, and the aqueous phase was extracted 2x with AcOEt. The combined organic extracts were dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (2.42 g) in quantitative yield. 1 H 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)

[0242] Step 2 - 3-(Dimethoxymethyl)-5-(trifluoromethyl)aniline (Intermediate 33) To a solution of 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 vigorously stirred at room temperature for 4 hours. The reaction mixture was separated from the iron powder with a pipette and concentrated under reduced pressure. The filtrate was dissolved in EtO (30 mL) and saturated NaHCO 3 3(水性) and the aqueous phase was extracted 2×Et 2 O. The combined organic phases were washed with brine, dried (Na 2 SO 4 ) and evaporated under reduced pressure to give the title compound (1.80 g, 64%). 1 H 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)

[0243] Preparation of 5-(trifluoromethoxy)pyridin-3-amine hydrochloride (Intermediate 86) [ka] Step 1: tert-Butyl N-[5-(trifluoromethoxy)-3-pyridyl]carbamate (Intermediate 87) [ka] A mixture of tert-butyl carbamate (102 mg, 0.868 mmol), XantPhos (63 mg, 0.108 mmol), trisdibenzylideneacetone)dipalladium(0)-chloroform adduct (37 mg, 0.0362 mmol), and cesium carbonate (283 mg, 0.868 mmol) in 1,4-dioxane (5 mL) was degassed with nitrogen and treated with 3-bromo-5-(trifluoromethoxy)pyridine (175 mg, 0.723 mmol). The reaction was stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature and filtered through a pad of Celite, which was then washed with dioxane. The combined organic phase was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0–100%, EtOAc in cyclohexane) and then dried overnight under reduced pressure to give the title compound (115 mg, 0.413 mmol, 57%). 1 H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 2.3 Hz, 1H), 8.23 ​​- 8.21 (m, 1H), 8.07 (s, 1H), 7.04 (s, 1H), 1.54 (s, 9H)

[0244] Step 2: 5-(trifluoromethoxy)pyridin-3-amine hydrochloride (Intermediate 86) To a solution of Intermediate 87 (115 mg, 0.413 mmol) in 1,4-dioxane (3 mL) was added 4N hydrogen chloride in dioxane (3.0 mL, 0.413 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether (20 mL) and filtered to give a white solid, which was washed with ether and dried under reduced pressure to give the title compound (60 mg, 0.280 mmol, 68%). 1 H 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)

[0245] Preparation of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-3-carboxylic acid (intermediate 88) [ka] 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, followed by degassing and the addition of platinum(IV) oxide (22 mg, 0.0969 mmol), followed by hydrogenation. After 2 hours under a hydrogen atmosphere, water (1.00 ml) was added and the reaction was stirred 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%). 1 H 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)

[0246] Preparation of (R)-(3-amino-5-(trifluoromethyl)phenyl)(3-(dimethylamino)pyrrolidin-1-yl)methanone (Intermediate 111) [ka] To a solution of 3-amino-5-(trifluoromethyl)benzoic acid (205 mg, 1.00 mmol), (R)-(+)-3-(dimethylamino)pyrrolidine (0.38 mL, 3.00 mmol), and TEA (0.42 mL, 3.00 mmol) in DCM (5.00 mL) and DMF (5.00 mL) was added PyBOP (781 mg, 1.50 mmol). The reaction mixture was stirred for 2 h, partially concentrated under reduced pressure, and the residue was washed with saturated NaCl. (水性) The aqueous phase was extracted with EtOAc, and the organic extract was washed with saturated NaCl (水性) The residue was washed with HCl, dried (Na2SO4), and concentrated under reduced pressure. Purification by FCC (0-10% 2M NH3 / MeOH in DCM) gave 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)

[0247] Preparation of [4-amino-2-(trifluoromethyl)phenyl]methanol (Intermediate 112) [ka] To a solution of [4-nitro-2-(trifluoromethyl)phenyl]methanol (1000 mg, 4.52 mmol) and NHCl (121 mg, 2.26 mmol) in EtOH (50 mL) and water (50 mL) at 75 °C, iron powder (2526 mg, 45.2 mmol) was added, and the reaction mixture was stirred for 30 min. The reaction mixture was filtered through a pad of Celite. The combined filtrate was concentrated under reduced pressure, redissolved in 2:1 DCM / cyclohexane, filtered, and the combined filtrate was evaporated to give the title compound (800 mg, 4.19 mmol, 93%). 1 H 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)

[0248] Preparation of 6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate 113) [ka] Step 1: Methyl 6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carboxylate (Intermediate 114) [ka] To a solution of ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (807 mg, 3.00 mmol) in toluene (10 mL) were added Pd(dba) (275 mg, 0.300 mmol), BINAP (560 mg, 0.900 mmol), and sodium tert-butoxide (403 mg, 4.20 mmol). The reaction mixture was purged with nitrogen, and then 1-methylpiperazine (0.37 mL, 3.30 mmol) was added. The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was cooled to room temperature and filtered through a pad of Celite, which was then washed with MeOH. The combined organic phases were concentrated under reduced pressure, and the residue was purified by FCC (0-100% EtOAc in cyclohexane, followed by 0-100% MeOH in EtOAc). The material was used in the next step without further purification.

[0249] Step 2: 6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate 113) A solution of LiOH (314 mg, 13.1 mmol) in water (1 mL) was added to a solution of intermediate 114 (1200 mg, 4.37 mmol) in THF (1 mL) at 0° C. The reaction mixture was warmed to RT and stirred for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was washed with water and the aqueous phase was diluted with 1 M HCl (水性) The pH was adjusted to 7 with HCl and washed with DCM. The aqueous fraction was concentrated under reduced pressure to give a mixture of product and inorganic salts. The material was used in the next step without further purification.

[0250] Preparation of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate 115) [ka] Step 1 - Ethyl 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylate (Intermediate 116) [ka] To a solution of 2-aminopyridin-4-ol (400 mg, 3.63 mmol) in EtOH (12 mL) was added ethyl 2-chloro-3-oxo-propanoate (547 mg, 3.63 mmol) and the mixture was heated to 80° C. and stirred overnight. The mixture was concentrated, the residue triturated with EtOAc, and the solid collected and purified on silica FCC (25 g, 0-10% MeOH in DCM, 10 CV) and then concentrated to give the title compound (367 mg, 1.78 mmol, 49%). 1 H 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)

[0251] Step 2 - Ethyl 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Intermediate 117) [ka] To a solution of intermediate 116 (365 mg, 1.77 mmol, 1.00 equiv) in DMF (6.00 mL) was added KCO (367 mg, 2.66 mmol, 1.50 equiv) and 2-bromoethyl methyl 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 with EtOAc, washed with water, water / brine 1:1, brine, dried over MgSO, 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)

[0252] Step 3 - 7-(2-Methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate 115) [ka] To a solution of intermediate 117 (200 mg, 0.757 mmol, 1.00 equiv) in THF (4 mL) was added a solution of LiOH monohydrate (79 mg, 1.89 mmol, 2.50 equiv) in water (1 mL), and the mixture was stirred at room temperature overnight. The reaction was then heated at 50° C. for 1 h. The reaction mixture was acidified to pH 2 with aqueous 2 M HCl, extracted with EtOAc, and the organic layer was washed with brine, dried, and concentrated. 18 mg of a solid was recovered. The aqueous layer was concentrated, then triturated with MeOH, and concentrated to give the title compound (178 mg, quantitative yield). 1 H 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)

[0253] The intermediates reported in the table below were prepared using intermediate 115, the nucleophilic substitution described in steps 1-3, and the corresponding commercially available alkyl chloride in step 2. Such procedures may involve minor modifications. [Table 41]

[0254] The intermediates reported in the table below were prepared as described in Intermediate 115, steps 1-3, using the corresponding commercially available aminopyridin-ol in step 1 and the corresponding electrophile in step 2. Such procedures may involve minor modifications. [Table 42]

[0255] Preparation of 6-((dimethylamino)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate 120) [ka] Step 1: Ethyl 6-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylate (Intermediate 121) [ka] To a suspension of 2-amino-5-pyridinemethanol (0.50 g, 4.03 mmol) and potassium (Z)-2-chloro-3-ethoxy-3-oxo-prop-1-en-1-olate (1.52 g, 8.06 mmol) in EtOH (5.0 mL) was added sulfuric acid (0.21 mL, 4.03 mmol) dropwise at 20° C. 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 at 80° C. overnight. The solvent was concentrated under reduced pressure. The residue was dissolved in EtOAc and saturated NaHCO 3 . 3(水性) The organic layer was washed with brine, dried over MgSO, filtered, and concentrated. The residue was purified by column chromatography on silica gel (0–100% EtOAc in cyclohexane, followed by 3 / 1 EtOAc / EtOH) to give 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)

[0256] Step 2: Ethyl 6-formylimidazo[1,2-a]pyridine-3-carboxylate (Intermediate 122) [ka] To a mixture of Intermediate 121 (460 mg, 2.09 mmol) in DCM (25 mL) was added manganese(IV) oxide (1816 mg, 20.9 mmol) and the reaction was stirred at RT for 3 days. The reaction mixture was filtered through Celite and washed with DCM. The filtrate was concentrated under reduced pressure to give the title compound (414 mg, 91%). 1 H 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)

[0257] Step 3: Ethyl 6-((dimethylamino)methyl)imidazo[1,2-a]pyridine-3-carboxylate (Intermediate 123) [ka] To a solution of intermediate 122 (210 mg, 0.962 mmol) in THF (2.5 mL) was added 2 M dimethylamine (2.2 mL, 4.33 mmol). The reaction mixture was stirred for 16 h at RT. NaBHCN (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 for 2 h at 60 °C. The reaction mixture was diluted with water (10 mL) and saturated NaHCO 3(水性) The pH was adjusted to 8-9 by the addition of HCl. The aqueous layer was extracted with EtOAc, and the organic extract was washed with brine (15 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% 3:1 EtOAc:EtOH in EtOAc) to give the title compound (114 mg, 61%). 1 H 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)

[0258] Step 4: 6-((dimethylamino)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate 120) To a solution of 2M NaOH (1.2 mL, 2.36 mmol) in MeOH (4.50 mL) was added Intermediate 123 (144 mg, 0.582 mmol), and the resulting mixture was stirred at RT for 3 days. The reaction mixture was concentrated. The pH was acidified to pH 2 with 2M aqueous HCl and concentrated under reduced pressure to give 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)

[0259] Preparation of pyrazolo[1,5-a]pyrazine-3-carbaldehyde (intermediate 124) [ka] Step 1: Pyrazolo[1,5-a]pyrazin-3-ylmethanol (Intermediate 125) [ka] To a solution of pyrazolo[1,5-a]pyrazine-3-carboxylic acid (130 mg, 0.797 mmol) in THF (20 mL) was added isobutyl chloroformate (0.12 mL, 0.956 mmol) and 4-methylmorpholine (0.11 mL, 0.956 mmol) cooled to 0 °C. The reaction mixture was stirred for 2 h, then filtered to remove solid residues, and added to a solution of NaBH (45 mg, 1.20 mmol) in EtOH (5.0 mL) at 0 °C and stirred overnight. The reaction mixture was acidified with 2 N HCl, and the organic layer was extracted with EtOAc and then concentrated under reduced pressure to give the desired product (50 mg, 42%), which was used directly in the next step without purification.

[0260] Step 2: Pyrazolo[1,5-a]pyrazine-3-carbaldehyde (Intermediate 124) Intermediate 125 (60 mg, 0.402 mmol) was dissolved in THF (5.0 mL), manganese(IV) oxide (350 mg, 4.02 mmol) was added, and the mixture was stirred at reflux for 2 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give 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)

[0261] Preparation of 3-(4-methylpiperazin-1-yl)-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-5-carbaldehyde (Intermediate 126) [ka] Step 1: Methyl 3-bromo-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-5-carboxylate (Intermediate 127) [ka] Methyl 3-bromo-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (512 mg, 2.00 mmol) was dissolved in DMF (6.0 mL) and cooled to 0 °C. NaH (60%, 96 mg, 2.40 mmol) was then added, followed by SEM-Cl (0.71 mL, 4.00 mmol, 2.00 equiv.), and stirred at RT for 3 h. The reaction mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with water, dried (MgSO4), and concentrated. The solid was purified by FCC (25 g column, 0–100% EtOAc in cyclohexane) to give the title compound (513 mg, 66%). 1 H 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)

[0262] Step 2: Methyl 3-(4-methylpiperazin-1-yl)-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-5-carboxylate (Intermediate 128) [ka] A mixture of intermediate 127 (200 mg, 0.518 mmol), CsCO (253 mg, 0.777 mmol), 1-methylpiperazine (0.29 mL, 2.59 mmol), and XantPhos (45 mg, 0.0777 mmol) in 1,4-dioxane (4 mL) was degassed with N, then Pd(dba) (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 NH / MeOH] in cyclohexane) to give the title compound (133 mg, 63%). 1 H 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)

[0263] Step 3: [3-(4-methylpiperazin-1-yl)-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-5-yl]methanol (Intermediate 129) [ka] 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 at RT overnight. The reaction mixture was quenched with water followed by 0.5 mL 2N NaOH. The mixture was stirred for 10 min, and then MgSO4 was added. The mixture was filtered and concentrated to dryness to give (45 mg, 100%), which was used in the next step without purification.

[0264] Step 4: 3-(4-Methylpiperazin-1-yl)-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridine-5-carbaldehyde (Intermediate 126) Following the procedure of Intermediate 125, starting with a solution of Intermediate 129 (45 mg, 0.119 mmol) in 2-methyl-THF (1.0 mL) at 50° C. for 2 hours, the title compound (35 mg, 78%) was obtained and used directly in the next step without purification.

[0265] Preparation of 2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-amine (Intermediate 130) [ka] Step 1: 4-Amino-N-methoxy-N-methyl-6-(trifluoromethyl)picolinamide (Intermediate 131) [ka] Prepared from 4-amino-6-(trifluoromethyl)picolinic acid (445 mg, 2.16 mmol) and N,O-dimethylhydroxylamine hydrochloride (232 mg, 2.37 mmol) according to general procedure A. Purification by silica FCC (80 g cartridge, 0-50% EtOAc in cyclohexane (+0.1% NEt)) gave 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)

[0266] Step 2: 4-Amino-6-(trifluoromethyl)picolinaldehyde (Intermediate 132) [ka] To a stirred solution of Intermediate 131 (308 mg, 1.24 mmol) in THF (4.82 mL) cooled in an ice / water bath was added LiAlH (2 M 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 EtO (5 mL). Water (47 μL), 15% NaOH (水性) (47 μL) and water (141 μL) were added, and the reaction mixture was warmed to room temperature and stirred for 15 minutes. Anhydrous MgSO was added, and the reaction mixture was stirred for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (252 mg, >100%), which was used in the next step without purification. LC-MS (ESI) Method 12: t R = 0.95 min; m / z (M+1) = 191

[0267] Step 3: 2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-amine (Intermediate 130) Prepared from intermediate 132 (126 mg, 0.663 mmol) and dimethylamine (2 M solution in THF) (0.33 mL, 0.663 mmol) according to general procedure D. Purification by silica FCC (12 g cartridge, 0-8% 2 M NH / MeOH in DCM) afforded the title compound (65 mg, 44%). 1 H NMR (400 MHz, DMSO-d6) δ 6.78 - 6.77 (m, 2H), 6.49 (s, 2H), 3.34 (s, 2H), 2.18 (s, 6H)

[0268] Example 1: Preparation of 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: 6-(tert-butyl)3-methyl 4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (Intermediate 35) [ka] 6-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (1.249 g, 4.41 mmol) and cesium carbonate (2.154 g, 6.61 mmol) were dissolved in anhydrous DMF (volume: 15 mL), and then CHCl (0.413 mL, 6.61 mmol) was added in one portion. The solution was stirred at RT overnight. The reaction mixture was diluted with EtO (20 mL) and then washed with saturated NHCl (10 mL) and brine (10 mL). The organic phase was separated, dried over NaSO, filtered, and concentrated to dryness. The crude material was purified by direct-phase FCC (silica, gradient n-heptane:AcOEt 100:0 to 80:20) to give the title compound (1.21 g, 4.07 mmol, 92% yield). 1 H 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)

[0269] Step 2: Methyl 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate hydrochloride (Intermediate 36) [ka] 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 minutes. Ethanol was then added to the reaction and the solvent was evaporated under reduced pressure to give the title compound (0.921 g, 3.94 mmol, 97% yield). The compound was used in the next step without further purification.

[0270] Step 3: Methyl 6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 37) [ka] 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) were dissolved in 6 mL of DCM / DMF 1:1, and then DIPEA (0.598 mL, 3.42 mmol) was added in one portion. The solution was stirred at RT for 1 h. The crude product was diluted with DCM (10 mL) and then washed with saturated NH4Cl solution (2 × 15 mL) and saturated NaHCO3 solution (2 × 15 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to dryness. The crude material was purified by reverse-phase FCC (C18 column, gradient A:B 100:0 to 0:100, eluent A: HO:ACN:HCOOH 95:5:0.1, eluent B: HO:ACN:HCOOH 5:95:0.1) to give the title compound (155.2 mg, 0.455 mmol, 53.1% yield). 1 H 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)

[0271] Step 4: 6-(Imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 1) 3-((4-Methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)aniline (84 mg, 0.308 mmol) was dissolved in dry THF (volume: 6 ml, ratio: 1.500) under nitrogen, the mixture was stirred at −78° C. for 15 min, then 2.5 M n-BuLi in hexane (0.098 ml, 0.246 mmol) was added dropwise over 5 min, and the solution was stirred for 1 h at −78° C. A solution of intermediate 37 (42 mg, 0.123 mmol) in THF (volume: 6 ml) was added dropwise over 10 min, then the temperature was raised to rt and the reaction was stirred for a further 1 h. 10 mL of water was added to the solution and the solvent was evaporated. The crude material was purified by reversed-phase FCC (C18 column, gradient A:B 100:0 to 0:100, where eluent A = HO:ACN:HCOOH 95:5:0.1 and eluent B = HO:ACN:HCOOH 5:95:0.1) to give the title compound (32 mg, 0.055 mmol, 45% yield). 1 H 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: t R = 0.92 min; m / z (M+1) = 583.2

[0272] Example 2: Preparation of N-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Ethyl 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate hydrochloride (Intermediate 38) [ka] To a solution of 6-(tert-butyl)3-ethyl 4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (4.88 g, 15.67 mmol) in EtO (volume: 78 mL) was added 4 N HCl in dioxane (19.59 mL, 78 mmol), and the reaction mixture was stirred at RT overnight. The solid was isolated and dried under reduced pressure to give the title compound (3.58 g, 14.45 mmol, 92% yield). 1 H 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)

[0273] Step 2: Ethyl 6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 39) [ka] 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) was added DIPEA (5.92 mL, 33.9 mmol), followed by T3P (6.73 mL, 11.30 mmol), and the reaction mixture was stirred at RT over the weekend. The crude was diluted with DCM, water was added, and the mixture was stirred for 10 min. The layers were then separated, and the aqueous layer was extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was purified by direct-phase FCC (silica, gradient DCM:MeOH 100:0 to 90:10) to give the title compound (1.75 g, 4.92 mmol, 87% yield). 1 H 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)

[0274] Step 3: Sodium 6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 40) [ka] To a solution of intermediate 39 (1.75 g, 4.92 mmol) in MeOH (49.2 ml) was added 1 M NaOH (4.92 ml, 4.92 mmol), and the reaction mixture was stirred at RT over the weekend. The solvent was evaporated under reduced pressure to give the title compound in quantitative yield. 1 H 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)

[0275] Step 4: N-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 2) Prepared by general procedure G from sodium intermediate 40 (100 mg, 0.286 mmol) and 3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-amine (65.6 mg, 0.286 mmol). The crude 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 give the title compound (23.1 mg, 0.043 mmol, 15% yield). 1 H 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: t R = 2.18 minutes; m / z (M+1) = 539.0

[0276] The compounds listed in the table below were prepared by amide coupling as described in Example 2, Steps 1-4, using the corresponding commercially available or independently synthesized amine in Step 4. Modifications to the coupling agent (e.g., HATU instead of T3P), salt freebasing, or chromatographic purification conditions (e.g., preparative HPLC or flash chromatography) are noted in the table. For Examples 44 and 45, the absolute configuration was assigned by inference by subjecting reagents of known absolute configuration to non-racemizing chemistry. [Table 43] [Table 44] [Table 45] [Table 46] [Table 47] [Table 48] [Table 49] [Table 50] [Table 51] [Table 52] [Table 53] [Table 54] [Table 55] [Table 56] [Table 57] [Table 58] [Table 59] [Table 60] [Table 61] [Table 62] [Table 63]

[0277] 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 [ka] 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 POCl (0.059 mL, 0.630 mmol) was added. The reaction was stirred until conversion of SM was observed. The RM was diluted with AcOEt and added with NaHCO 3(水性) The organic phase was then dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by FCC (DCM to 10% MeOH in DCM) to give the title compound (6 mg, 0.012 mmol, 4% yield). 1 H 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: t R = 2.21 min; m / z (M+1) = 489.0

[0278] Example 47: Preparation of N-(4-(tert-butyl)oxazol-2-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: N-(4-(tert-butyl)oxazol-2-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide To a suspension of the acid form of Intermediate 40 (40 mg, 0.122 mmol) and 4-tert-butyloxazol-2-amine (24 mg, 0.171 mmol) in DMF (0.60 mL) was added 1-methylimidazole (0.034 mL, 0.428 mmol) followed by TCFH (51 mg, 0.183 mmol). The reaction mixture was stirred at RT for 72 h and then cooled to rt with saturated NaHCO. 3(水性) The combined organic phase was partitioned between saturated NaCl and DCM and the aqueous phase was extracted 3x with DCM. (水性) The residue was washed with HCl, passed through a hydrophobic frit and concentrated under reduced pressure. Purification by reverse-phase preparative HPLC (Xbridge Phenyl 19 x 150 mm, 10 μm 40-100% MeOH / water (10 mM NH4HCO3), 20 mL / min, RT) gave the title compound (1.55 mg, 2%). 1 H 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: t R = 3.46 minutes; m / z (M+1) = 450.2

[0279] The compounds listed in the table below were prepared by amide coupling as described in Example 47, Step 1, using the corresponding commercially available or independently synthesized amine in Step 1. The solvent is specified unless other than DMF. [Table 64] [Table 65]

[0280] Example 48: Preparation of compound N-(3-((4-(dimethylamino)piperidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: N-(3-(dimethoxymethyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 41) [ka] Prepared from 3-(dimethoxymethyl)-5-(trifluoromethyl)aniline (216 mg, 0.916 mmol, Intermediate 42) and the acid form of Intermediate 40 (300 mg, 0.916 mmol) according to general procedure H. The residue was triturated under EtO and the suspension filtered to give the title compound (496 mg, 0.910 mmol, 99% yield). 1 H 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)

[0281] 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) [ka] To a solution of intermediate 41 (498 mg, 0.915 mmol, 1.00 equiv) in DCM (5.00 mL) at room temperature was added TFA (0.50 mL, 6.53 mmol, 7.14 equiv), and the reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give a light brown mobile oil, which was triturated under EtO and the ether was decanted to give the title compound (450 mg, 0.910 mmol, 99% yield). 1 H 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)

[0282] 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 Prepared from intermediate 42 (50 mg, 0.100 mmol) and N,N-dimethylpiperidin-4-amine (14 mg, 0.110 mmol) according to general procedure C. Purification by reverse-phase preparative HPLC (Xbridge Phenyl 19 × 150 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: t R = 2.34 minutes; m / z(M+1)=611.4

[0283] The compounds listed in the table below were prepared by amide coupling as described in Example 48, steps 1-3, using the corresponding commercially available or independently synthesized amine in step 3. Step 3 could be carried out in a variety of ways as noted in the table, following the general procedure above. When modifications involved chromatographic purification conditions (e.g., preparative HPLC or flash chromatography), such changes were noted in the table. [Table 66] [Table 67] [Table 68] [Table 69] [Table 70] [Table 71] [Table 72]

[0284] Example 62: Preparation of 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(2-(4-methylpiperazin-1-yl)ethoxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 62) [ka] Step 1: tert-Butyl 4-(2-(3-(6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamido)-5-(trifluoromethyl)phenoxy)ethyl)piperazine-1-carboxylate (Intermediate 43) [ka] Intermediate 40 was converted to the free acid form by dissolving in an organic solvent, followed by acidic washing, drying over sodium sulfate, and evaporation under reduced pressure to give intermediate 40 as the free acid (150 mg, 0.458 mmol), which was then reacted with intermediate 19 (178 mg, 0.458 mmol) according to general procedure H. Purification by FCC on silica gel (eluent A = 3:1 AcOEt / ethanol; eluent B = cyclohexane; gradient = 0% eluent A to 100% eluent A) gave 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)

[0285] Step 2: 6-(Imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(2-(piperazin-1-yl)ethoxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 44) [ka] 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) at 20 °C, 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® 19 × 150 mm, 10 μm 5–60% ACN / HO (0.1% TFA), 20 mL / 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)

[0286] Step 3: 6-(Imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(2-(4-methylpiperazin-1-yl)ethoxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 62) A suspension of Intermediate 44 (120 mg, 0.200 mmol, 1.00 equiv) in a mixture of THF (2.00 mL) and MeOH (2.00 mL) was treated successively with formaldehyde solution (37%, 0.037 mL, 0.501 mmol, 2.50 equiv) and NaBHCN (21 mg, 0.341 mmol, 1.70 equiv), and the resulting mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with DCM and saturated NaHCO 3(水性) The organic phase was partitioned into saturated NaCl (水性) The residue was washed with HCl, dried (MgSO), and concentrated. The residue was purified by preparative HPLC (Xbridge Phenyl® 19 × 150 mm, 10 μm 40–100% MeOH / H2O (10 mM NH4CO3), 20 ml / min, RT), 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: t R = 2.88 min; m / z (M+1) = 613

[0287] 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 [ka] Step 1: tert-Butyl 3-(3-(6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamido)-5-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (Intermediate 45) [ka] Intermediate 40 (80 mg, 0.244 mmol) was converted to the free acid by deblocking the salt as described in Example 62, Step 1, and reacted with tert-butyl 3-[3-amino-5-(trifluoromethyl)phenoxy]pyrrolidine-1-carboxylate (85 mg, 0.244 mmol, Intermediate 50) according to general procedure H. The residue was purified by FCC on silica gel (AcOEt / cyclohexane 0% to 100%, followed by AcOEt / EtOH 75% / 25%) to give the title compound. 1 H 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)

[0288] Step 2: 6-(Imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 46) [ka] A solution of intermediate 45 (90 mg, 0.137 mmol, 1.00 equiv) in methyl alcohol (1.00 mL) was treated with 4 M HCl in dioxane (0.69 mL, 2.75 mmol, 20.0 equiv) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure to give the HCl salt of the title compound in quantitative yield (81 mg, quantitative).

[0289] Step 3: 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) A suspension of intermediate 46 (81 mg, 0.137 mmol, 1.00 equiv) in THF (1 mL) and MeOH (1 mL) was treated successively with formaldehyde solution (37%, 0.025 mL, 0.342 mmol, 2.50 equiv) and sodium cyanoborohydride (15 mg, 0.233 mmol, 1.70 equiv), and the resulting mixture was stirred at room temperature overnight. Additional MeOH (1 mL) was added until all solids were dissolved, and stirring was continued at room temperature for 1 h. The reaction mixture was diluted with DCM and saturated NaHCO 3(水性) The organic layer was partitioned between saturated NaCl (水性) The crude material was purified by preparative HPLC (Luna Phenyl-Hexyl (登録商標) Purification on a 21.2 x 150 mm, 10 μm column (20-80% MeOH / H2O (0.1% FA), 20 ml / min, RT) gave the title compound (11 mg, 14%). 1 H 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 = LC-MS (ESI) Method 7: t R= 2.92 minutes; m / z (M+1) = 570

[0290] Example 64: Preparation of N-(3-(tert-butyl)-1-(2-hydroxyethyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: N-(3-(tert-butyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 47) [ka] Prepared from intermediate 31 (254 mg, 0.855 mmol) according to general procedure I. Purification by FCC on silica gel (AcOEt / cyclohexane 0% to 100%) afforded the title compound (139 mg, 37%). 1 H 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)

[0291] Step 2: N-(3-(tert-butyl)-1-(2-hydroxyethyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 64) To a solution of intermediate 47 (146 mg, 0.241 mmol) in MeOH (1.60 mL) and THF (0.80 mL) was added 4 M HCl solution in 1,4-dioxane (0.60 mL, 2.41 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure (165 mg). A portion (36 mg) was separated and analyzed by reverse-phase preparative HPLC (Sunfire C18 (登録商標) Purification with 19 x 150 mm, 10 μm 20-80% acetonitrile / water (10 mM NH4HCO3), 20 mL / min, RT) gave the title compound (18.64 mg, 15%). 1 H 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: t R = 3.23 minutes; m / z (M+1) = 493.3

[0292] 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 [ka] Step 1: Ethyl 6-(imidazo[1,2-a]pyridin-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 48) [ka] 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 under argon. 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 for 30 min at room temperature. NaBH(OAc) (5.13 g, 24.22 mmol) was then added, and the reaction mixture was stirred at room temperature over the weekend. The reaction mixture was then diluted with DCM and washed with a 1:1 mixture of KCO (saturated) and water. The aqueous phase was extracted twice with DCM, and the organic phases were combined, dried over MgSO, and evaporated under reduced pressure. The crude material was purified by FCC using DCM / MeOH (DCM to 10% MeOH in DCM) to give the title compound (2.38 g, 6.97 mmol, 58% yield). 1 H 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)

[0293] Step 2: Sodium 6-(imidazo[1,2-a]pyridin-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 49) [ka] 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 RT over the weekend. The solvent was evaporated under reduced pressure to give the title compound in quantitative yield. 1 H 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)

[0294] 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 the addition of DIPEA (0.312 ml, 1.789 mmol) and HATU (0.227 g, 0.596 mmol). The RM was stirred for 15 min, followed by the addition of 3-fluoro-5-(trifluoromethyl)aniline (0.053 g, 0.298 mmol). The reaction was stirred at RT until LCMS indicated the consumption of the starting material. The reaction mixture was diluted with DCM, and water was added. The mixture was stirred for 15 min, the phases were separated, and the organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by FC (DCM 100% to 10% MeOH in DCM) to give the title compound (23 mg, 0.043 mmol, 14% yield). 1 H 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: t R = 1.69 min; m / z (M+1) = 537.2

[0295] 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 [ka] Step 1: Ethyl 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 50) [ka] 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 under argon. 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 for 30 min at rt. STAB (1.249 g, 5.89 mmol) was then added, and the reaction mixture was stirred at rt overnight. The reaction mixture was then diluted with DCM and washed with a 1:1 mixture of K2CO3 (saturated) and water. The aqueous phase was extracted twice with DCM, and the organic phases were combined, dried over MgSO4, and evaporated under reduced pressure. The crude material was purified by FCC using DCM / MeOH (DCM to 10% MeOH in DCM) to give the title compound (0.86 g, 2.51 mmol, 85% yield). 1 H 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)

[0296] Step 2: Lithium 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 51) [ka] To a solution of Intermediate 50 (0.86 g, 2.51 mmol) in MeOH (24 mL) was added 1 M LiOH (5.02 mL, 5.02 mmol), and the reaction mixture was stirred overnight at 45° C. The reaction mixture was concentrated under reduced pressure to give the title compound (0.98 g, 3.06 mmol) in quantitative yield. 1 H 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)

[0297] 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), then DIPEA (0.327 ml, 1.873 mmol) and HATU (0.297 g, 0.781 mmol) were added. The RM was stirred for approximately 15 min, then 3-(trifluoromethoxy)aniline (0.084 ml, 0.624 mmol) was added. The RM was stirred overnight at RT. The crude was cooled, diluted with DCM, and water was added. The mixture was stirred for 15 min, and the phases were separated. The organic phase was washed with 5% citric acid, water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by FCC (DCM to 10% MeOH in DCM) to give the title compound (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: t R = 2.17 minutes; m / z (M+1) = 474.0

[0298] The following compounds were prepared by amide coupling as described in Example 66, steps 1-3, applying the corresponding commercially available aniline in step 3: [Table 73]

[0299] 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 [ka] Step 1: Ethyl 6-(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 52) [ka] To a solution of intermediate 38 (5 g, 20.18 mmol) and 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (3.27 g, 20.18 mmol) in DCM (101 mL) was added DIPEA (28.2 mL, 161 mmol), followed by T3P (24.03 mL, 40.4 mmol), and the mixture was stirred at RT overnight. The reaction mixture was diluted with DCM, water was added, and the mixture was stirred for 10 min. The phases were then separated, the aqueous phase was washed with DCM (3 × 50 mL), and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by FC using DCM:MeOH (DCM to 5% MeOH) to give the title compound (1.57 g, 4.42 mmol, 22% yield). 1 H 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)

[0300] Step 2: Sodium 6-(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 53) [ka] To a solution of intermediate 52 (1.6 g, 4.50 mmol) in MeOH (45.0 ml) was added 1 M NaOH (6.75 ml, 4.92 mmol), and the reaction mixture was stirred at RT over the weekend. The solvent was concentrated under reduced pressure to give 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)

[0301] 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) Intermediate 53 (0.1 g, 0.286 mmol) and HATU (0.218 g, 0.573 mmol) were weighed into a reaction tube backfilled with argon (×3). The reagents were suspended in DCM (2.147 ml) and DMF (0.716 ml). DIPEA (0.400 ml, 2.290 mmol) was then added to the reaction mixture. After stirring for 15 minutes, 3-(trifluoromethyl)aniline (0.036 ml, 0.286 mmol) was added. The reaction mixture was stirred for over 60 hours at rt. The crude material was transferred to a separatory funnel and washed with water (×3). The desired compound was extracted with DCM, and the organic layers were combined and washed with brine (×1). The organic layer was concentrated under reduced pressure, and the crude material was purified by preparative HPLC to give the desired compound as the formate salt. The salt was separated using a 1:1 NaHCO 3(飽和) The desired compound was extracted with DCM (x3) and the combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give 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: t R = 3.14 minutes; m / z (M+1) = 471.1

[0302] 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 [ka] Step 1: Ethyl 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 54) [ka] 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 under argon. 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 for 30 min at RT. STAB (5.13 g, 24.22 mmol) was then added, and the reaction mixture was stirred at RT over the weekend. The reaction mixture was then diluted with DCM and washed with a 1:1 mixture of K2CO3 (saturated) and water. The aqueous phase was extracted twice with DCM, and the organic phases were combined, dried over MgSO4, and evaporated under reduced pressure. The crude material was purified by FCC using DCM / MeOH (DCM to 10% MeOH in DCM) to give the title compound (2.24 g, 6.56 mmol, 52% yield). 1 H 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)

[0303] Step 2: Sodium 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 55) [ka] To a solution of intermediate 54 (2.24 g, 6.56 mmol) in MeOH (65.6 ml) was added 1 M NaOH (6.56 ml, 6.56 mmol) and the reaction mixture was stirred overnight at 40° C. The solvent was evaporated under reduced pressure to give the title compound in quantitative yield. 1 H 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)

[0304] 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 the addition of DIPEA (0.312 ml, 1.789 mmol) and HATU (0.227 g, 0.596 mmol). The RM was stirred for 15 min, followed by the addition of 3-(trifluoromethyl)aniline (0.045 ml, 0.358 mmol). The reaction was stirred at RT until LCMS indicated consumption of the starting material or substantial conversion to DP. The reaction mixture was diluted with DCM and quenched with 5% citric acid. The layers were separated, and the organic layer was rewashed with 5% aqueous citric acid (Note: the semi-solid product stuck to the glass). The combined organic layers were washed with saturated aqueous NaHCO3 and brine. The crude product was purified by preparative HPLC to give 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: t R = 1.93 min; m / z (M+1) = 457.0

[0305] The following compounds were prepared by amide coupling as described in Example 69, steps 1-3, using the corresponding commercially available or independently synthesized amine in step 3. [Table 74] [Table 75]

[0306] 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 [ka] Step 1: tert-Butyl 3-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 56) [ka] To a solution of 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (1.5 g, 5.29 mmol) and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (1.277 g, 5.29 mmol) in DCM (26.5 mL) was added DIPEA (5.55 mL, 31.8 mmol) followed by T3P (6.30 mL, 10.59 mmol), and the RM was stirred at RT over the weekend. The reaction mixture was diluted with DCM, water was added, and the mixture was stirred for 10 minutes. The layers were then separated, the aqueous layer was washed with DCM (3 × 50 mL), and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was purified with (DCM to 10% MeOH in DCM) to give the title compound (362 mg, 0.715 mmol, 13.50% yield). 1 H NMR (300 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.19 (q, J = 1.9, 1.4 Hz, 3H), 8.07 (d, J = 1.9 Hz, 1H), 7.74 - 7.67 (m, 1H), 7.46 (t, J = 1.3 Hz, 1H), 4.60 (s, 2H), 3.58 (t, J = 5.8 Hz, 2H), 2.87 (t, J = 5.8 Hz, 2H), 2.18 (d, J = 1.0 Hz, 3H), 1.43 (s, 9H)

[0307] 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) [ka] To a solution of intermediate 56 (0.362 g, 0.715 mmol) in DCM (3.57 ml) was added 4 N HCl in dioxane (0.893 ml, 3.57 mmol), and the RM was stirred at RT overnight. EtO was added to the RM until no more precipitate was observed, and the precipitate was then filtered to give the title compound (0.33 g, 0.745 mmol). 1 H NMR (300 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.61 (s, 1H), 9.55 (s, 1H), 8.60 (s, 1H), 8.57 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 7.91 (s, 1H), 4.39 (s, 2H), 3.37 (m, 2H), 3.13 (m, 2H), 2.36 (d, J = 1.1 Hz, 3H)

[0308] Step 3: 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 (Example 74) Imidazo[1,2-a]pyridine-3-carboxylic acid (29.3 mg, 0.181 mmol) was dissolved in anhydrous DMF (452 ​​μl) and dichloromethane (1355 μl), then DIPEA (252 μl, 1.445 mmol) and HATU (137 mg, 0.361 mmol) were added. The RM was stirred for 1 h, then Intermediate 57 (80 mg, 0.181 mmol) was added. The RM was stirred overnight at RT. The RM was cooled, diluted with DCM (15 ml) and quenched with 5% citric acid (10 ml). The phases were separated and the organic layer was washed with saturated NaHCO 3(水性) and brine, dried over Na2SO4 and evaporated. The crude was purified by preparative HPLC (mobile phase: ACN+0.1% FA, H2O+0.1% FA) to give the title compound (40 mg, 0.073 mmol, 40.2% yield). 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: t R = 2.19 minutes; m / z (M+1) = 550.9

[0309] Example 75 Preparation of 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Sodium 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 58) [ka] 6-(tert-Butyl)-3-ethyl 4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (15 g, 48.2 mmol) was dissolved in MeOH (482 mL), and then 1 M NaOH (72.3 mL, 72.3 mmol) was added, and the RM was stirred at RT overnight. The reaction mixture was dried under reduced pressure to give 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)

[0310] Step 2: tert-Butyl 3-((3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 59) [ka] 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 minutes, 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 showed complete SM consumption. Further addition of HATU and DIPEA and an increase in reaction temperature were necessary to achieve complete conversion. The reaction was quenched by the addition of water and then extracted with DCM (×3). The organic layers were combined and washed with a 1:1 NaCl (sat):HO solution, followed by brine. The combined organic layers were then concentrated under reduced pressure and the crude was purified by FCC (AcOEt / DCM 0% to 100%) to give 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)

[0311] Step 3: N-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (Intermediate 60) [ka] 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 h. The crude was concentrated under reduced pressure and triturated with EtO to give the title compound (1.834 g, 4.26 mmol, 93% yield). 1 H 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)

[0312] Step 4: 6-((1H-Pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(tert-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 (×3). MeOH (1.160 mL) followed by acetic acid (0.040 mL, 0.696 mmol) were added to the reaction mixture, the tube was sealed, and the mixture was stirred at 50 °C for 1 h. The reaction was then cooled to rt, and STAB (80 mg, 1.275 mmol) was added. The reaction was stirred at 50 °C until complete consumption of SM was confirmed by LC-MS. Further addition of STAB was required to observe complete consumption. The reaction mixture was quenched with saturated NaHCO3, transferred to a separatory funnel, and the desired product was extracted with DCM (×3). The combined organic layers were washed once with brine and concentrated under reduced pressure, and the crude mixture was purified by HPLC. The pure fractions were concentrated to give the desired product containing the formic acid. The compound was triturated with 0.1 M NaHCO3 solution to give the title compound (46 mg, 0.088 mmol, 37.7% yield). 1 H 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: t R = 1.96 min; m / z (M+1) = 526.2

[0313] The compounds listed in the table below were prepared via reductive amination as described in Example 75, steps 1-4, using the corresponding commercially available aldehyde in step 4. [Table 76]

[0314] Example 77 Preparation of 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-butyl 3-((3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 61) [ka] Intermediate 58 (1 g, 3.28 mmol) and HATU (2.491 g, 6.55 mmol) were weighed into a reaction tube backfilled with argon (×3). 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 then 3-(tert-butyl)-1-methyl-1H-pyrazol-5-amine (0.502 g, 3.28 mmol) was added, and the reaction mixture was stirred at rt until complete consumption of SM was confirmed by LC-MS. Further addition of HATU was required to achieve complete conversion. The reaction mixture was then extracted with DCM / HO (x3), and the combined organic layers were washed with 1:1 NaCl (saturated):HO solution, followed by brine. The combined organic layers were then concentrated under reduced pressure, and the crude material was purified by flash column chromatography using a Puriflash apparatus (0-50% AcOEt / hexane; product eluted with 50% AcOEt) to give 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-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (Intermediate 62) [ka] 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 RT for 16 h. The reaction mixture was then concentrated and the residue was triturated with EtO to give the title compound in quantitative yield. 1 H 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-(tert-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 (×3). MeOH (1409 μl) followed by glacial AcOH (48.6 μl, 0.845 mmol) were added to the reaction mixture, the tube was sealed, and the mixture was stirred at 50 °C for 1 h. The reaction was then cooled to rt, and STAB (80 mg, 1.268 mmol) was added. The reaction was stirred at 50 °C until LC-MS confirmed complete consumption of SM. Further addition of STAB was required to observe complete consumption. The reaction mixture was quenched with saturated NaHCO 、 Transferred to a separatory funnel and the desired product extracted with DCM (x3). The combined organic layers were washed once with brine and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (0–10% MeOH / DCM) on a Puriflash apparatus and the pure fractions were concentrated to give the title compound (39 mg, 0.087 mmol, 30.8% yield). 1 H 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: t R = 1.90 min; m / z (M+1) = 450.0

[0317] The compounds listed in the table below were prepared via reductive amination as described in Example 77, steps 1-4, using the corresponding commercially available aldehyde in step 4. [Table 77]

[0318] Example 79: Preparation of N-(5-tert-butyl-2-methyl-pyrazol-3-yl)-6-(7-methylimidazo[1,2-a]pyridine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: N-(5-tert-butyl-2-methyl-pyrazol-3-yl)-6-(7-methylimidazo[1,2-a]pyridine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 79) 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 19 × 150 mm, 10 μm 5–60% ACN / HO (0.1% FA), 20 ml / min, RT) gave the title compound (23 mg, 43%). 1 H 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: t R = 3.33 minutes; m / z (M+1) = 477.4

[0319] The compounds listed in the table below were prepared as described in Example 79, Step 1, using the corresponding commercially available carboxylic acid in Step 1. [Table 78] [Table 79]

[0320] Example 84: Preparation of 6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-butyl 3-((3-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 63) [ka] 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 RT until complete consumption of SM was confirmed by LC-MS. To achieve complete conversion, the reaction temperature was raised to 40 °C, and further addition of HATU and 3-(trifluoromethyl)aniline was necessary. The reaction mixture was diluted with DCM, and water was added. The mixture was stirred for 15 min, the phases were separated, and the organic phase was washed with water, 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 in DCM) to yield 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-carboxamide hydrochloride (Intermediate 64) [ka] Intermediate 63 (2.82 g, 6.61 mmol) was dissolved in a minimum amount of DCM (6.01 ml), then EtO (60.1 ml) was added, followed by 4 N HCl in dioxane (16.53 ml, 66.1 mmol), and the RM was stirred at RT overnight. EtO was added to the RM until no more precipitation was observed, then the solid was filtered and the remaining solvent was evaporated under reduced pressure to give the title compound (2.3353 g, 6.44 mmol, 97% yield). 1 H 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]pyrazin-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide Intermediate 64 (0.10 g, 0.276 mmol), imidazo[1,2-a]pyrazine-3-carbaldehyde (0.041 g, 0.276 mmol), and magnesium sulfate (0.033 g, 0.276 mmol) were placed in a round-bottom flask under argon. Anhydrous DCM (1.378 ml) was added, followed by TEA (0.038 ml, 0.276 mmol). The reaction mixture was stirred for 30 min at room temperature. STAB (0.117 g, 0.551 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM and washed with a 1:1 mixture of K2CO3 (saturated) and water. The aqueous phase was extracted twice with DCM, and the combined organic phases were dried over Na2SO4 and evaporated under reduced pressure. The crude material was purified by FCC using DCM / MeOH (DCM to 5% MeOH in DCM) to give the title compound (32 mg, 0.070 mmol, 25.4% yield). 1 H 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: t R = 1.85 min; m / z (M+1) = 458.0

[0323] The compounds listed in the table below were prepared via reductive amination as described in Example 84, steps 1-3, using the corresponding commercially available aldehyde in step 3. [Table 80] [Table 81]

[0324] Example 90: Preparation of 6-(imidazo[1,2-a]pyrazine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Imidazo[1,2-a]pyrazine-3-carboxylic acid (0.049 g, 0.303 mmol) was dissolved in DMF (0.689 mL) and DCM (2.067 mL), followed by the addition of DIPEA (0.289 mL, 1.654 mmol) and HATU (0.231 g, 0.606 mmol). The mixture was stirred for 15 min, and Intermediate 64 (0.1 g, 0.276 mmol) was added. The reaction mixture was stirred at RT overnight, diluted with DCM, and water was added. The mixture was stirred for 15 min, the phases were separated, and the organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by FCC (DCM to 10% MeOH in DCM) to give the title compound (71.64 mg, 0.152 mmol, 55% yield). 1 H 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: t R = 2.77 minutes; m / z (M+1) = 471.9

[0325] The compounds listed in the table below were prepared via the amide coupling described in Example 90, using the corresponding commercially available carboxylic acid in Step 1. General procedural or reactant variations are indicated in the table. [Table 82] [Table 83] [Table 84] [Table 85] [Table 86]

[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 [ka] Step 1: N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 65) [ka] To a solution of 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (1590 mg, 5.61 mmol, 1.00 equiv.) and HATU (2560 mg, 6.73 mmol, 1.20 equiv.) in N,N-dimethylformamide (22.50 mL), N,N-diisopropylethylamine (2.9 mL, 16.8 mmol, 3.00 equiv.) was added, the reaction mixture was stirred at room temperature for 15 minutes, and 3-fluoro-5-(trifluoromethyl)aniline (1055 mg, 5.89 mmol, 1.05 equiv.) was added. The reaction mixture was stirred at room temperature for an additional 16 hours. The reaction mixture was purified with (ethyl acetate / cyclohexane 0% to 100%) to give tert-butyl 3-((3-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (1.35 g, 3.04 mmol, 1.00 equiv), which was dissolved in DCM (35 mL) and trifluoroacetic acid (5.0 mL, 65.9 mmol, 21.7 equiv) was added. The reaction mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The reaction mixture was partitioned between saturated aqueous 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 (ethyl acetate / cyclohexane 0% to 100%, followed by 3:1 ethyl acetate:ethanol / ethyl acetate 0% to 100%) to give the title compound (500 mg, 2.69 mmol, 48% yield). 1 H 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 a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (25 mg, 0.153 mmol, 1.16 equiv.) in N,N-dimethylformamide (1.50 mL), HATU (61 mg, 0.160 mmol, 1.22 equiv.) and N,N-diisopropylethylamine (0.069 mL, 0.394 mmol, 3.00 equiv.) were added, and the reaction mixture was stirred at room temperature for 30 min. Intermediate 65 (50 mg, 0.131 mmol, 1.00 equiv.) was added, and the reaction mixture was heated at 40 °C overnight and then diluted with DMSO. Purification by reverse-phase preparative HPLC (Sunfire C18 19 × 150 mm, 10 μm column, 20–80% ACN / HO (0.1% FA), 20 mL / min, RT) afforded the title compound (29.2 mg, 45%). 1 H 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: t R = 4.75 minutes; 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 [ka] Step 1: 6-(tert-butyl) 3-ethyl 2-amino-7-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (Intermediate 66a), 6-(tert-butyl) 3-ethyl 2-amino-5-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (Intermediate 66b) [ka] To a mixture 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) was added ethyl 2-cyanoacetate (5.3 g, 46.9 mmol) and TEA (6.78 mL, 67 mmol) and refluxed for 4 h. The reaction mixture was cooled and the solvent was evaporated. The crude product was purified by FCC (hexane:AcOEt 5%-15%) to give 13.4 g as a mixture of two regioisomers (1:1 by LCMS and NMR).

[0329] Step 2: 6-(tert-butyl) 3-ethyl 7-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (Intermediate 67a), 6-(tert-butyl) 3-ethyl 5-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (Intermediate 67b) [ka] To the regioisomeric mixture obtained in Step 1, intermediate 66a and intermediate 66b (13.9 g, 40.8 mmol) were added dropwise to a solution of THF (204 mL) at 0 °C. Isoamyl nitrite (8.25 mL, 61.2 mmol) was added dropwise, and the reaction mixture was heated to RT and stirred for 30 minutes. The reaction mixture was then heated at reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by FCC (hexane / AcOEt 95:5 to 90:10) to give the title compound as a 1:1 mixture of regioisomeric intermediates 67a and 67b (2.98 g).

[0330] Step 3: Ethyl 7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate hydrochloride (Intermediate 68a) and Ethyl 5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate hydrochloride (Intermediate 68b) [ka] A mixture of the two regioisomeric intermediates 67a and 67b (2.05 g, 6.30 mmol) was dissolved in EtO (31.5 mL), and then 4 N HCl in dioxane (15.75 mL, 63.0 mmol) was added. The reaction mixture was stirred at RT overnight. The solid was filtered, and the residual solvent was evaporated under reduced pressure to give the title compound as a mixture of regioisomers 68a and 68b (1.4 g).

[0331] Step 4: Ethyl 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 69a), Ethyl 6-(imidazo[1,2-a]pyridine-3-carbonyl)-5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 69b) [ka] A mixture of intermediate 68a and intermediate 68b (1 g, 3.82 mmol) was dissolved in DCM (19.10 mL), DIPEA (4.00 mL, 22.92 mmol) was added, followed by T3P (4.55 mL, 7.64 mmol), and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with DCM, water was added, and the mixture was stirred for 10 min. The phases were then separated, the aqueous phase was washed with DCM (3 × 50 mL), and the combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by FCC (DCM:MeOH 0% to 10%) to give 0.77 g of the mixture of title compounds.

[0332] Step 5: Lithium 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 70a) and Lithium 6-(imidazo[1,2-a]pyridine-3-carbonyl)-5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 70b) [ka] 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 1 M LiOH (1.489 mL, 1.489 mmol) was added and the reaction was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure to give 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) A mixture of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (0.250 g, 1.037 mmol), Intermediate 70a, and 70b (0.3 g, 0.864 mmol) was dissolved in DMF (2.159 ml) and DCM (6.48 ml), followed by the addition of DIPEA (0.905 ml, 5.18 mmol) and HATU (0.657 g, 1.728 mmol). The reaction mixture was stirred at 45 °C until complete conversion of the starting material. The reaction mixture was diluted with DCM, and water was added. The mixture was stirred for 15 min, the phases were separated, and the organic phase was washed with 5% citric acid, water, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The regioisomeric mixture was purified by preparative HPLC to give the title compound (35 mg, 0.062 mmol, 7.18% yield) as a pure compound. The exact positional isomerism of the compound of Example 97 is as follows: 1 The assignment was made by H-NMR spectrum. 1 H 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: t R = 3.94 minutes; m / z (M+1) = 565.1

[0334] The compounds listed in the table below were prepared by amide coupling as described in Example 98, steps 1-6, using the corresponding commercially available arylamine in step 6. 1 The assignment was made by H-NMR spectrum. [Table 87]

[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 [ka] Step 1: 6-(tert-butyl) 3-ethyl (R)-2-amino-7-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (Intermediate 71a) and 6-(tert-butyl) 3-ethyl (R)-2-amino-5-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (Intermediate 71b) [ka] To a mixture of tert-butyl (R)-2-methyl-4-oxopiperidine-1-carboxylate (4 g, 18.75 mmol) and sulfur (0.6 g, 18.75 mmol) in ethanol (37.5 ml), ethyl 2-cyanoacetate (2.12 g, 18.75 mmol) and triethanolamine (2.71 g, 26.8 mmol) were added and refluxed for 4 h. The reaction mixture was cooled and the solvent was evaporated. The crude product was purified by FCC (hexane:AcOEt; 5%-15%) to give 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: 6-(tert-butyl) 3-ethyl (R)-7-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (Intermediate 72a) and 6-(tert-butyl) 3-ethyl (R)-5-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (Intermediate 72b) [ka] To a solution of the regioisomeric mixture of intermediates 71a and 71b (4.90 g, 28.8 mmol) in THF (72 mL) at 0 °C, isoamyl nitrite (2.53 g, 21.6 mmol) was added dropwise, and the reaction mixture was heated to RT and stirred for 30 min. The reaction mixture was then heated at reflux for 6 h. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by FCC (hexane:AcOEt 95:5 to 90:10) to give the title compound as a 1:1 mixture of regioisomers (1.06 g).

[0337] Step 3: Ethyl (R)-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate hydrochloride (Intermediate 73a) and Ethyl (R)-5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate hydrochloride (Intermediate 73b) [ka] A mixture of the two regioisomeric intermediates 72a and 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 stirred at RT overnight. It was then diluted with DCM, and a 1:1 mixture of HO and NaHCO (saturated) was added, and the mixture was stirred for 10 min. The phases were then separated, and the organic phase was washed with water and brine, then dried over NaSO, filtered, and concentrated under reduced pressure. The crude mixture of regioisomers was separated by FCC (DCM: 5M NH / MEOH 98 / 2) to give the pure regioisomers as follows: Intermediate 73a (quantitative yield) 1 H 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: Ethyl (R)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 74) [ka] Intermediate 73a (0.48 g, 2.130 mmol) and imidazo[1,2-a]pyridine-3-carboxylic acid (0.415 g, 2.56 mmol) were dissolved in DMF (5.33 mL) and DCM (15.98 mL), followed by the addition of DIPEA (1.488 mL, 8.52 mmol) and HATU (2.025 g, 5.33 mmol). The reaction mixture was stirred overnight at RT, diluted with DCM, water was added, and the mixture was stirred for 10 min. The phases were then separated, the aqueous phase was washed with DCM (3 × 50 mL), and the combined organic phases were washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified by FCC using DCM:MeOH (0% to 10% MeOH) to give 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: Lithium (R)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 75) [ka] To a solution of Intermediate 74 (0.66 g, 1.786 mmol) in MeOH (8.93 ml) was added 1 M LiOH (3.57 ml, 3.57 mmol), and the reaction mixture was stirred at RT overnight. The solution was concentrated under reduced pressure to give 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-carboxamide (Example 100) Intermediate 75 (0.10 g, 0.288 mmol) and 3-(trifluoromethyl)aniline (0.072 mL, 0.576 mmol) were dissolved in DMF (0.720 mL) and DCM (2.159 mL), followed by the addition of DIPEA (0.302 mL, 1.728 mmol) and HATU (0.274 g, 0.720 mmol). The reaction mixture was stirred overnight at RT, diluted with DCM, and water was added. The mixture was stirred for 15 min, the phases were separated, and the organic phase was washed with water, a 5% wt solution of citric acid, 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 give the title compound (54.03 mg, 0.112 mmol, 38.7% yield). Non-racemic chemical reactions of reagents of known absolute configuration were carried out and determined by assumption. 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: t R = 2.14 minutes; m / z (M+1) = 485.1

[0341] The compounds listed in the table below were prepared by amide coupling as described in Example 100, steps 1-6, using the corresponding commercially available arylamine in step 6. [Table 88]

[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 [ka] Step 1: 6-(tert-butyl) 3-ethyl 2-amino-7,7-dimethyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (Intermediate 76a) and 6-(tert-butyl) 3-ethyl 2-amino-5,5-dimethyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (Intermediate 76b) [ka] To a mixture of tert-butyl 2,2-dimethyl-4-oxopiperidine-1-carboxylate (5 g, 22.00 mmol) and sulfur (0.705 g, 22.00 mmol) in ethanol (44.0 ml), ethyl 2-cyanoacetate (2.341 ml, 22.00 mmol) and TEA (4.38 ml, 31.5 mmol) were added and refluxed for 6 h. The solvent was evaporated and the crude material was purified by FCC (hexane:AcOEt 95:5 to 85:15) to give the pure regioisomers as follows: Intermediate 76a (0.67 g, 1.890 mmol, 8.59% yield). 1 H 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). 1 H 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 1 The assignment was made by H-NMR spectrum.

[0343] Step 2: 6-(tert-butyl) 3-ethyl 7,7-dimethyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (Intermediate 77) [ka] 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 heated to RT and stirred for 30 min. The reaction mixture was heated at reflux for 6 h, concentrated under reduced pressure, and the crude product was purified by FCC using hexane:AcOEt (95:5 to 90:10) to give the title compound (160 mg, 0.471 mmol, 24.94% yield). 1 H 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) [ka] To a solution of intermediate 77 (0.16 g, 0.471 mmol) in DCM (3.93 mL) was added 4 N HCl in dioxane (1.768 mL, 7.07 mmol), and the reaction mixture was stirred at RT overnight. The solid was filtered, and the remaining solvent was evaporated under reduced pressure to give the title compound (0.10 g, 0.363 mmol, 77% yield). 1 H 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: Ethyl 6-(imidazo[1,2-a]pyridine-3-carbonyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 79) [ka] Intermediate 78 (0.10 g, 0.363 mmol) and imidazo[1,2-a]pyridine-3-carboxylic acid (0.071 g, 0.435 mmol) were dissolved in DMF (0.906 ml) and DCM (2.72 ml), followed by the addition of DIPEA (0.317 ml, 1.813 mmol) and HATU (0.345 g, 0.906 mmol). The reaction mixture was stirred at RT overnight. To achieve complete conversion, the temperature was further increased to 80 °C, and further addition of HATU and imidazo[1,2-a]pyridine-3-carboxylic acid was necessary. The reaction mixture was cooled, diluted with DCM, water was added, and the mixture was stirred for 15 min. 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). 1 H 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) [ka] To a solution of intermediate 79 (74 mg, 0.193 mmol) in MeOH (965 μL) was added 1 M LiOH (772 μL, 0.772 mmol), and the reaction mixture was stirred at RT overnight. The crude was then concentrated under reduced pressure to give the title compound (68 mg, 0.188 mmol, 98% yield). 1 H 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 min, followed by the addition of 3-(trifluoromethyl)aniline (0.058 g, 0.360 mmol), and stirred at RT overnight. Further addition of amine and HATU was required for complete conversion. The reaction mixture was cooled, diluted with DCM, water was added, stirred for 15 min, 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 give 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: t R = 2.93 minutes; m / z (M+1) = 499.1

[0348] Example 103: 6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Example 104: 6-(Imidazo[1,2-a]pyrazin-3-ylmethyl)-5-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide - eluted first [ka] Example 105: 6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-5-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide - eluted second [ka] Step 1: Lithium 6-(tert-butoxycarbonyl)-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 81a), Lithium 6-(tert-butoxycarbonyl)-5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 81b) [ka] Intermediate 67a (0.430 g, 1.32 mmol) was dissolved in MeOH (26.4 ml), and then 1 M LiOH (5.29 ml, 5.29 mmol) was added. The reaction mixture was stirred overnight at 40° C. The crude was concentrated under reduced pressure to give a mixture of the title compounds.

[0349] Step 2: tert-butyl 7-methyl-3-((3-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 82a) and tert-butyl 5-methyl-3-((3-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 82b) [ka] 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 the addition of 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, the phases were separated, and the organic phase was washed with water, a 5% wt solution of citric acid, 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-carboxamide hydrochloride (Intermediate 83a) and 5-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (Intermediate 83b) [ka] A mixture of intermediate 82a and intermediate 82b (750 mg, 1.70 mmol) was dissolved in DCM (20 mL) and MeOH (4 mL). 4N HCl in dioxane (4.26 mL, 17.03 mmol) was then added, and the mixture was stirred at RT overnight. EtO was added until no more precipitate was observed. The solid was then filtered, and the remaining solvent was evaporated under reduced pressure to give 650 mg of a mixture of the 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]pyrazin-3-ylmethyl)-5-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 104), 6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-5-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 105) A mixture of intermediates 83a and 83b (0.140 g, 0.372 mmol), imidazo[1,2-a]pyrazine-3-carbaldehyde (0.066 g, 0.446 mmol), and magnesium sulfate (0.045 g, 0.372 mmol) was placed in a round-bottom flask under argon. Anhydrous DCM (3.72 ml) was added, followed by TEA (0.052 ml, 0.372 mmol), and the reaction mixture was stirred for 30 minutes at room temperature. STAB (0.236 g, 1.115 mmol) was then added, and the reaction mixture was stirred until LC-MS showed complete consumption of the starting material. The reaction mixture was then diluted with DCM and diluted with NaCO. 3(飽和) The mixture was washed with a 1:1 mixture of HCl 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 purified by preFCC (DCM / MeOH 0% to 5% MeOH) to give 60 mg of the regioisomeric mixture. The mixture was dissolved in MeOH to 11 mg / mL and then purified by preparative HPLC (Method Prep 1) to give Example 105 (3.3 mg, 0.007 mmol, 2% yield) and a mixture of Examples 103 and 104, which was further separated by SFC (Method Prep 2) to give Example 103 (12.9 mg, 0.027 mmol, 7% yield) and Example 104 (2.8 mg, 0.006 mmol, 1% yield).

[0352] 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: t R = 4.23 points; m / z (M+1) = 472.2; ee 99.3%

[0353] Example 103: 1 H 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: t R = 4.99 points; m / z (M+1) = 472.2; ee 100%

[0354] 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: t R = 3.57 min; m / z (M+1) = 472.2; ee 98.3%

[0355] 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 [ka] Example 107: 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide—second eluting enantiomer [ka] Step 1: 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide—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) A mixture of 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) was placed in a round-bottom flask under argon. Anhydrous DCM (5.31 ml) was added, followed by TEA (0.074 ml, 0.531 mmol). The reaction mixture was stirred for 30 min at RT. STAB (0.337 g, 1.592 mmol) was added, and the reaction mixture was stirred at RT. Further addition of STAB and aldehyde was required to achieve complete conversion of SM. The reaction mixture was diluted with DCM and NaHCO 3(飽和) was added and the mixture was stirred for 15 min. The phases were separated, the aqueous phase was extracted twice with DCM, the organic phases were combined, washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The crude was purified by FCC (DCM / MeOH 0%-5%) to give 190 mg of a mixture of enantiomers, which was then purified by chiral SFC (Method Prep 3) to give:

[0356] Example 106 (39 mg, 0.082 mmol, 31% 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: t R = 6.92 points; m / z (M+1) = 471.2;

[0357] Example 107: (36 mg, 0.077 mmol, 29% yield) 1 H 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 minutes; m / z (M+1) = 471.2

[0358] 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 [ka] Step 1: tert-Butyl 3-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 89) [ka] To a suspension of 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (250 mg, 0.882 mmol) in anhydrous acetonitrile (4.4 mL), 5-(trifluoromethyl)pyridin-3-amine (157 mg, 0.971 mmol) and 1-methylimidazole (0.25 mL, 3.09 mmol) were added until complete dissolution was achieved. TCFH (371 mg, 1.32 mmol) was then added, and the reaction mixture was stirred at room temperature under an argon atmosphere for 22 hours. The reaction mixture was then diluted with saturated NaHCO 3 3(水性) The mixture was partitioned between 100 ml of ethyl acetate and 100 ml of ethyl acetate, and the aqueous phase was extracted with EtOAc. The combined organic phases were passed through a hydrophobic frit and concentrated under reduced pressure. Purification by column chromatography on silica gel (0-25% EtOAc in cyclohexane with 0.1% NEt) gave 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)

[0359] Step 2: N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 90) [ka] To a stirred solution of Intermediate 89 (290 mg, 0.678 mmol) in anhydrous DCM (6.78 mL) cooled in an ice / water bath under an argon atmosphere was added TFA (0.52 mL, 6.78 mmol) dropwise over 5 minutes. The reaction mixture was stirred for 3 hours. Further TFA (0.17 mL, 2.26 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 1:1 DCM:MeOH and loaded onto a pre-conditioned 5 g Isolute SCX-II cartridge, washed with MeOH, and then released with 2M NH3 / MeOH. The 2M NH3 / MeOH eluent was concentrated under reduced pressure to give the desired product (193 mg, 0.59 mmol, 87%). 1 H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.12 (d, J = 2.3 Hz, 1H), 8.67 (d, J = 1.0 Hz, 1H), 8.59 - 8.57 (m, 1H), 8.12 (s, 1H), 3.88 (s, 2H), 3.17 (d, J = 5.0 Hz, 1H), 2.90 (t, J = 5.7 Hz, 2H), 2.78 - 2.73 (m, 2H)

[0360] 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) Prepared from intermediate 90 (40 mg, 0.122 mmol) and pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (17 mg, 0.104 mmol) according to general procedure G. Purification by reverse-phase preparative HPLC (Sunfire C18 19 × 150 mm, 10 μm 20–80% acetonitrile / water-10 mM NH4HCO3), 20 mL / min) gave the title compound (6 mg, 0.013 mmol, 12%). LCMS(ESI): Method 6t R = 3.79 min, m / z [M+1]+ = 473.3 1 H 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)

[0361] The compounds listed in the table below were prepared by amide coupling as described in Example 109, steps 1-3, using the corresponding commercially available or independently synthesized carboxylic acid in step 3. Modifications of coupling agents, salt freebasing, or chromatographic purification conditions (e.g., preparative HPLC or flash chromatography) are noted in the table. [Table 89] [Table 90] [Table 91] [Table 92]

[0362] Example 112: Preparation of compound N-(3-(tert-butyl)isoxazol-5-yl)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Ethyl 6-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylate (Intermediate 91) [ka] To a suspension of Intermediate 38 (125 mg, 0.505 mmol), 6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazine-3-carboxylic acid hydrochloride (124 mg, 0.605 mmol), and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (232 mg, 0.722 mmol) in anhydrous 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 under a nitrogen atmosphere at room temperature for 2 hours and then allowed to stand for 16 hours. The reaction mixture was diluted, and the organic phase was washed with saturated NaHCO 3 . 3(水性) , then saturated NaCl (水性) The residue was purified by FCC eluting with DCM-methanolic ammonia (2M; 20:1) / 0-100% to give the desired product (196 mg, 0.477 mmol, 95%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.33 (s, 1H), 4.94 (s, 2H), 4.88 (s, 2H), 4.32 (q, J = 7.2 Hz, 2H), 4.28 (t, J = 5.4 Hz, 2H), 4.05 (t, J = 5.2 Hz, 2H), 4.01 (t, J = 5.5 Hz, 2H), 3.17 - 3.12 (m, 2H), 1.37 (t, J = 7.1 Hz, 3H)

[0363] Step 2: 6-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (Intermediate 92) [ka] Sodium hydroxide (68 mg, 1.71 mmol) was added to a solution of intermediate 91 (191 mg, 0.528 mmol) in methyl alcohol (10) and water (0.50), and the mixture was stirred at 50° C. for 3 days. The mixture was cooled in an ice bath and 1 M hydrogen chloride (1.7 mL, 1.71 mmol) was added dropwise. The solution was concentrated under reduced pressure to precipitate a colorless solid, which was filtered and washed with acetone (2) to give the desired product (76 mg, 0.228 mmol, 43%), which was used directly in the next step.

[0364] Step 3: N-(3-(tert-butyl)isoxazol-5-yl)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 112) Thionyl chloride (0.13 mL, 1.80 mmol) was added to Intermediate 92 (30 mg, 0.0900 mmol), and the mixture was stirred at room temperature overnight. The mixture was evaporated to dryness under reduced pressure, and the residue was suspended in dry pyridine (1.0 mL). 3-tert-butylisoxazol-5-amine (19 mg, 0.135 mmol) was added, and the mixture was stirred for 1 h. The mixture was evaporated to dryness under reduced pressure, and the residue was dissolved in 9:1 DMSO:water (1.0 mL). The mixture was purified on a Sunfire C18 19 x 150 mm, 10 μm column using 5-60% ACN / HO (0.1% FA) at 20 mL / min to give the desired product (17 mg, 0.0381 mmol, 42%). LCMS (ESI): Method 15t R = 3.48 minutes, [M+H] + = 456.2 1 H NMR (400 MHz, DMSO-d6) d 11.77 (s, 1H), 8.34 (s, 1H), 7.40 (s, 1H), 6.37 (s, 1H), 4.95 - 4.89 (s, 2H), 4.80 - 4.79 (m, 2H), 4.14 (t, J = 5.1 Hz, 2H), 4.00 (t, J = 5.1 Hz, 2H), 3.91 (t, J = 5.4 Hz, 2H), 3.02 (s, 2H), 1.29 (s, 9H)

[0365] Example 113: Preparation of compound N-(3-(tert-butyl)isoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Ethyl 6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 93) [ka] To a suspension of Intermediate 38 (125 mg, 0.505 mmol), pyrazolo[1,5-a]pyrazine-3-carboxylic acid (99 mg, 0.605 mmol), and TBTU (232 mg, 0.722 mmol) in DCM (2 mL) and DMF (2 mL) was added N,N-diisopropylethylamine (0.35 mL, 2.02 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted and the organic phase was washed with saturated NaHCO 3 3(水性) , then saturated NaCl (水性) The residue was purified by silica chromatography eluting with DCM-methanolic ammonia (2M; 20:1) / 0-100% to give the title compound (149 mg, 82%). 1 H NMR (400 MHz, CDCl3) δ 9.48 (d, J = 1.5 Hz, 1H), 8.43 (dd, J = 1.5, 4.8 Hz, 1H), 8.20 (s, 1H), 8.05 (d, J = 4.8 Hz, 1H), 8.04 (s, 1H), 4.98 (s, 2H), 4.32 (q, J = 7.0 Hz, 2H), 4.02 (t, J = 5.9 Hz, 2H), 3.23 - 3.18 (m, 2H), 1.38 (t, J = 7.0 Hz, 3H)

[0366] Step 2: 6-(Pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (Intermediate 94) [ka] Sodium hydroxide (49 mg, 1.23 mmol) was added to a solution of Intermediate 93 (142 mg, 0.398 mmol) in methyl alcohol (10 ml) and water (0.5 ml), and the mixture was stirred at 50° C. for 64 hours. The mixture was cooled in an ice bath, and 1 M aqueous hydrogen chloride (1.2 ml, 1.23 mmol) was added dropwise. The solution was concentrated under reduced pressure to precipitate a colorless solid, which was filtered and washed with acetone (2 mL) to give the title compound (86 mg, 66%). LCMS(ESI): Method 15tR = 0.47 min; m / z [M+H] + =329.2

[0367] Step 3: N-(3-tert-butyl)isoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 113) Prepared from the previous intermediate 94 (30 mg, 0.0914 mmol) and 3-tert-butylisoxazol-5-amine (19 mg, 0.137 mmol) according to general procedure I. Purification by reverse-phase preparative HPLC (Sunfire C18 19 × 150 mm, 10 μm 20–80% ACN / HO (0.1% FA), 20 ml / min, RT) gave the title compound (4 mg, 9%). LCMS (ESI): Method 7t R = 3.92 minutes; m / z [M+H] + = 451.2 1 H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 9.36 (d, J = 1.5 Hz, 1H), 8.93 (dd, J = 1.4, 4.7 Hz, 1H), 8.55 (s, 1H), 8.34 (s, 1H), 8.11 (d, J = 4.6 Hz, 1H), 6.37 (s, 1H), 4.99 (s, 2H), 3.95 (t, J = 5.8 Hz, 2H), 3.07 (t, J = 6.0 Hz, 2H), 1.29 (s, 9H)

[0368] Example 116: Preparation of compound N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-Butyl 3-((5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 95) [ka] To a solution of 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (142 mg, 0.500 mmol) and DMF (0.0019 mL, 0.0250 mmol) in CPME (1 mL) was added dropwise at 20 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was azeotroped with CPME. The residue was suspended in ACN (1 mL) and cooled to 0 °C in an ice bath. To the mixture was added a solution of 5-tert-butyl-2-methyl-pyrazol-3-amine (77 mg, 0.500 mmol) and pyridine (0.081 mL, 1.00 mmol) in ACN (1 mL). The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water and DCM. The combined organic phase was filtered through a hydrophobic frit and the solvent was concentrated under reduced pressure. The residue was purified by FCC on silica gel (0-50% EtOAc in cyclohexane) to give the desired product (186 mg, 0.444 mmol, 89%). 1 H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 6.08 (s, 1H), 4.57 (s, 2H), 3.65 (s, 3H), 3.62 (m, 2H), 2.95 (t, J = 5.4 Hz, 2H), 1.47 (s, 9H), 1.26 (s, 9H)

[0369] Step 2: N-(5-tert-butyl-1-methyl-pyrazol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 96) [ka] To a solution of intermediate 95 (186 mg, 0.444 mmol) in 1,4-dioxane (3 mL) was added 4N HCl in dioxane (3 mL). The reaction mixture was stirred at room temperature for 3 hours, then diluted with ether and filtered to give a white solid, which was washed with ether and dried overnight under reduced pressure to give the desired product as a dihydrochloride salt (144 mg, 0.368 mmol, 83%). 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.73 - 9.69 (m, 2H), 8.44 (s, 1H), 6.16 (s, 1H), 4.42 (s, 2H), 3.70 (s, 3H), 3.40 - 3.40 (m, 2H), 3.13 (t, J = 5.6 Hz, 2H), 1.29 (s, 9H)

[0370] Step 3: N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 116) Prepared from pyrazolo[1,5-a]pyrazine-3-carboxylic acid (10 mg, 0.068 mmol) and intermediate 96 (20 mg, 0.068 mmol) by general procedure I. Purification by reverse-phase preparative HPLC (Xbridge Phenyl 19 × 150 mm, 10 μm 40–100% MeOH / HO (10 mM NHCO), 20 mL / min) gave the title compound (7 mg, 0.015 mmol, 26%). LCMS (ESI): Method 7t R = 3.91 min, m / z [M+H]+ = 464.2 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 9.40 (d, J = 1.3 Hz, 1H), 8.97 (dd, J = 1.4, 4.7 Hz, 1H), 8.59 (s, 1H), 8.24 (s, 1H), 8.14 (d, J = 4.5 Hz, 1H), 6.47 (s, 1H), 5.04 - 4.97 (m, 2H), 3.97 (t, J = 5.8 Hz, 2H), 3.88 (s, 3H), 3.12 - 3.09 (m, 2H), 1.40 (s, 9H)

[0371] The compounds listed in the table below were prepared by amide coupling as described in Example 116, steps 1-3, using the corresponding commercially available or independently synthesized aldehyde in step 3. Such procedures may involve minor variations. Modifications to the coupling agent are indicated in the table below. [Table 93]

[0372] Example 119: Preparation of compound 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(tert-pentyl)isoxazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-Butyl 3-((3-(tert-pentyl)isoxazol-5-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 97) [ka] To a solution of 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (150 mg, 0.529 mmol) and DMF (2 μL, 0.0265 mmol) in CPME (1 mL) was added oxalyl chloride (55 μL, 0.635 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was azeotroped with CPME. The residue was suspended in ACN (2 mL) and cooled to 0°C in an ice bath. To the mixture was added 3-(1,1-dimethylpropyl)isoxazol-5-amine (82 mg, 0.529 mmol) and pyridine (86 μL, 1.06 mmol). The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between DCM and water. The combined organic phase was filtered through a hydrophobic frit and the solvent was concentrated under reduced pressure. The residue was purified by reverse phase chromatography to give the desired product (14 mg, 0.033 mmol; 6%). 1 H NMR (400 MHz, CDCl3) δ 8.61 - 8.61 (m, 1H), 7.67 (s, 1H), 6.23 (s, 1H), 4.51 (s, 2H), 3.55 (t, J = 5.6 Hz, 2H), 2.88 (t, J = 5.6 Hz, 2H), 1.52 (q, J = 7.5 Hz, 2H) 1.36 (s, 9H), 1.17 (s, 6H), 0.69 (t, J = 7.5 Hz, 3H)

[0373] Step 2: N-(3-(tert-pentyl)isoxazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (Intermediate 98) [ka] To a solution of intermediate 97 (14 mg, 0.0334 mmol) in 1,4-dioxane (1 ml) was added 4N hydrogen chloride in dioxane (1.0 ml, 0.033 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ether and filtered to give a white solid, which was washed with ether and dried under reduced pressure to give the title compound as a hydrochloride salt in quantitative yield. LCMS(ESI): Method 16t R = 1.04 min; m / z [M+H] + =320.1

[0374] Step 3: 6-(Imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(tert-pentyl)isoxazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 119) Prepared from imidazo[1,2-a]pyridine-3-carboxylic acid (7 mg, 0.04 mmol) and intermediate 98 (estimated 0.0334 mmol) by general procedure N. Quenched with water, filtered, washed with water, and dried under vacuum overnight to give the title compound (17 mg, 0.027 mmol; 81%). LCMS (ESI): Method 7t R = 4.52 minutes; m / z [M+H] + = 464.8 1 H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 9.01 (d, J = 7.1 Hz, 1H), 8.39 (s, 1H), 8.18 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.17 - 7.12 (m, 1H), 6.37 (s, 1H), 5.07 (s, 2H), 4.03 (t, J = 5.6 Hz, 2H), 3.12 (t, J = 5.9 Hz, 2H), 1.66 (q, J = 7.4 Hz, 2H), 1.29 (s, 6H), 0.81 (t, J = 7.5 Hz, 3H)

[0375] Example 121: Preparation of compound N-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-Butyl 3-[[6-methoxy-5-(trifluoromethyl)-3-pyridyl]carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylate (Intermediate 99) [ka] Intermediate 99 was prepared from 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (167 mg, 0.589 mmol) according to the procedure described in Example 109, Step 1. The reaction mixture was concentrated under reduced pressure, quenched with water, and filtered to give a solid which was washed with water and dried under reduced pressure to give the title compound (220 mg, 0.481 mmol, 82%). 1 H NMR (400 MHz, CDCl3) δ 8.46 (m, 1H), 8.29 (m, 1H), 7.71 - 7.64 (m, 1H), 4.60 (s, 2H), 4.03 (s, 3H), 3.67 (t, J = 5.4 Hz, 2H), 2.99 (t, J = 5.7 Hz, 2H), 2.80 (s, 2H), 1.50 (s, 9H)

[0376] Step 2: N-[6-Methoxy-5-(trifluoromethyl)-3-pyridyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 100) [ka] To a solution of Intermediate 99 (220 mg, 0.481 mmol) in 1,4-dioxane (5 ml) was added 4N hydrogen chloride in dioxane (5.0 ml, 0.481 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ether, filtered, and the resulting solid was washed with ether and dried under reduced pressure to give the title compound as a dihydrochloride salt (240 mg, 0.558 mmol, 116%). 1 H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.68 (s, 2H), 8.81 (d, J = 2.1 Hz, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.48 (s, 1H), 4.38 (m, 2H), 3.99 (s, 3H), 3.35 (m, 2H), 3.13 (t, J = 5.7 Hz, 2H)

[0377] Step 3: N-[6-Methoxy-5-(trifluoromethyl)-3-pyridyl]-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 121) To a solution of Intermediate 100 (50 mg, 0.116 mmol), pyrazolo[1,5-a]pyrazine-3-carboxylic acid (19 mg, 0.116 mmol), and 1-methylimidazole (0.074 mL, 0.930 mmol) in ACN (5.00 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (49 mg, 0.174 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with water and extracted with DCM. The combined organic phase was filtered through a hydrophobic frit, and the solvent was concentrated under reduced pressure. The residue was purified by preparative HPLC (Sunfire C18 19 × 150 mm, 10 μm column, 5–60% ACN / H2O (10 mM NH4CO3), 20 mL / min) to give the title compound (4.02 mg, 97%). LCMS (ESI): Method 7t R = 4.36 minutes; m / z [M+H]+ = 503.2 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.37 (d, J = 1.5 Hz, 1H), 8.94 (dd, J = 1.4, 4.7 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.56 (s, 1H), 8.48 (d, J = 2.5 Hz, 1H), 8.19 (s, 1H), 8.11 (d, J = 4.6 Hz, 1H), 5.00 - 5.00 (m, 2H), 3.99 (s, 3H), 3.95 (t, J = 5.8 Hz, 2H), 3.07 - 3.07 (m, 2H)

[0378] Example 122: Preparation of compound N-(5-(1,1-difluoroethyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-Butyl 3-[[5-(1,1-difluoroethyl)-3-pyridyl]carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylate (Intermediate 101) [ka] Intermediate 101 was prepared from 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (167 mg, 0.589 mmol) according to the procedure described in Example 109, Step 1. The resulting residue was triturated with water and allowed to stand overnight. The solid was filtered, washed with water, and dried under reduced pressure to give the title compound (182 mg, 0.430 mmol, 73%). 1H NMR (400 MHz, CDCl3) δ 8.74 (m, 1H), 8.53 (s, 1H), 8.40 (s, 1H), 7.71 (s, 1H), 4.61 (s, 2H), 3.71 - 3.65 (m, 2H), 3.00 (t J = 5.4 Hz, 2H), 1.97 (t, J = 18.2 Hz, 3H), 1.50 (s, 9H)

[0379] Step 2: N-[5-(1,1-difluoroethyl)-3-pyridyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 102) [ka] Intermediate 102 was prepared starting from Intermediate 101 (182 mg, 0.430 mmol) according to the procedure described in Example 121, Step 2. The title compound was obtained as the dihydrochloride salt (151 mg, 0.381 mmol, 89%). 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.65 (s, 2H), 9.15 (d, J = 1.9 Hz, 1H), 8.61 (s, 1H), 8.56 (s, 2H), 4.40 (t, J = 4.9 Hz, 2H), 3.48 - 3.34 (m, 2H), 3.17 - 3.10 (m, 2H), 2.06 (t, J = 19.1 Hz, 3H)

[0380] Step 3: N-(5-(1,1-difluoroethyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 122) To a solution of Intermediate 102 (50 mg, 0.126 mmol), pyrazolo[1,5-a]pyrazine-3-carboxylic acid (21 mg, 0.126 mmol), and 1-methylimidazole (0.080 mL, 1.01 mmol) in ACN (5 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (53 mg, 0.189 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then allowed to stand overnight. The reaction was quenched with water, washed with DCM, and the combined organic phase was filtered through a hydrophobic frit and the solvent was concentrated under reduced pressure. The residue was purified by preparative HPLC (Xbridge Phenyl 19 x 150 mm, 10 μm 20-80% MeOH / H2O (10 mM NH4CO3), 20 ml / min, RT) to give the title compound (7.5 mg, 0.0160 mmol, 13%). LCMS (ESI): Method 7t R = 3.94 min; m / z [M+H]+ = 516.5 1 H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.36 (d, J = 1.4 Hz, 1H), 8.93 (dd, J = 1.4, 4.7 Hz, 1H), 8.56 (s, 1H), 8.20 (s, 1H), 8.11 (d, J = 4.6 Hz, 1H), 6.31 (s, 1H), 4.99 - 4.99 (m, 2H), 3.95 (dd, J = 5.8, 5.8 Hz, 2H), 3.67 (s, 3H), 3.08 - 3.03 (m, 2H), 1.33 - 1.21 (m, 4H)

[0381] Example 123: Preparation of compound N-(5-(tert-butyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-Butyl 3-[(5-tert-butyl-3-pyridyl)carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylate (Intermediate 103) [ka] Intermediate 103 was prepared starting from 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (83 mg, 0.293 mmol) according to the procedure described in Example 109, Step 1. The title compound (56 mg, 0.135 mmol, 46%) was obtained. 1 H NMR (400 MHz, CDCl3) δ 9.07-8.64 (m, 1H), 8.54 (s, 1H), 8.33 (d, J = 1.5 Hz, 1H), 8.24 (t, J = 2.0 Hz, 1H), 7.72 (s, 1H), 4.58 (s, 2H), 3.66 (t, J = 5.6 Hz, 2H), 3.00 (t, J = 5.4 Hz, 2H), 1.49 (s, 9H), 1.33 (s, 9H)

[0382] Step 2: N-(5-tert-butyl-3-pyridyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 104) [ka] Intermediate 104 was prepared starting from Intermediate 103 (56 mg, 0.135 mmol) according to the procedure described in Example 121, Step 2. The desired product was obtained as the dihydrochloride salt (41 mg, 0.106 mmol, 78%). 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.58 - 9.58 (m, 2H), 9.21 (d, J = 1.8 Hz, 1H), 8.78 (s, 1H), 8.67 (s, 1H), 8.65 (d, J = 1.8 Hz, 1H), 4.41 (t, J = 4.8 Hz, 2H), 3.4 (m, 2H) (Under water peak), 3.14 (t, J = 5.7 Hz, 2H), 1.38 (s, 9H)

[0383] Step 3 - N-(5-tert-butyl-3-pyridyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 123) To a solution of Intermediate 104 (41 mg, 0.106 mmol), pyrazolo[1,5-a]pyrazine-3-carboxylic acid (17 mg, 0.106 mmol), and 1-methylimidazole (0.067 mL, 0.845 mmol, 8.00 equiv) in ACN (4.1 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (44 mg, 0.158 mmol). The reaction mixture was stirred at room temperature for 30 minutes and allowed to stand overnight. The reaction was quenched with water and washed with DCM. The combined organic phase was filtered through a hydrophobic frit and the solvent was concentrated under reduced pressure to give a light brown gum. The residue was purified by preparative HPLC (Xbridge Phenyl 19 x 150 mm, 10 μm 20-80% MeOH / H2O (10 mM NH4CO3), 20 ml / min) to give the title compound (48 mg, 0.0677 mmol, 64%). LCMS (ESI): Method 7t R = 3.94 min; m / z [M+H]+ = 516.5 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.36 (d, J = 1.4 Hz, 1H), 8.93 (dd, J = 1.4, 4.7 Hz, 1H), 8.56 (s, 1H), 8.20 (s, 1H), 8.11 (d, J = 4.6 Hz, 1H), 6.31 (s, 1H), 4.99 - 4.99 (m, 2H), 3.95 (dd, J = 5.8, 5.8 Hz, 2H), 3.67 (s, 3H), 3.08 - 3.03 (m, 2H), 1.33 - 1.21 (m, 4H)

[0384] Example 125: Preparation of compound N-(5-(difluoromethoxy)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-Butyl 3-[[5-(difluoromethoxy)-3-pyridyl]carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylate (Intermediate 105) [ka] Intermediate 105 was prepared starting from 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (167 mg, 0.589 mmol) according to the procedure described in Example 109, Step 1. The desired product (179 mg, 0.421 mmol, 71%) was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.50 - 8.49 (m, 1H), 8.24 (m, 3H), 7.69 (s, 1H), 6.79 - 6.39 (t, J = 73.6 Hz, 1H), 4.61 (s, 2H), 3.72 - 3.65 (m, 2H), 2.99 (t, J = 5.6 Hz, 2H), 1.50 (s, 9H)

[0385] Step 2: N-[5-(difluoromethoxy)-3-pyridyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; dihydrochloride (Intermediate 106) [ka] Intermediate 106 was prepared starting from Intermediate 105 (179 mg, 0.421 mmol) according to the procedure described in Example 121, Step 2. The desired product was obtained as the dihydrochloride salt (146 mg, 0.367 mmol, 87%). 1 H NMR (400 MHz, DMSO-d6) d 10.90 (s, 1H), 9.70 (s, 2H), 8.93 (s, 1H), 8.56 (s, 1H), 8.31 (s, 1H), 8.27 (t, J = 26.8Hz, 1H), 7.36 (s, 1H), 4.38 (s, 2H), 3.43 - 3.36 (m, 2H), 3.16 - 3.08 (m, 2H)

[0386] Step 3: N-(5-(difluoromethoxy)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 125) To a solution of Intermediate 106 (50 mg, 0.126 mmol), pyrazolo[1,5-a]pyrazine-3-carboxylic acid (20 mg, 0.126 mmol), and 1-methylimidazole (0.080 mL, 1.00 mmol) in ACN (5 mL) was added TCFH (53 mg, 0.188 mmol). The reaction mixture was stirred at room temperature for 30 minutes and allowed to stand overnight. The reaction was quenched with water and washed with DCM. The combined organic layers were filtered through a hydrophobic frit, and the solvent was concentrated under reduced pressure. The residue was purified by preparative HPLC (Xbridge Phenyl 19 × 150 mm, 10 μm 20–80% MeOH / H2O (10 mM NH4CO3), 20 mL / min) to give the title compound (59 mg, 0.0238 mmol, 19%). LCMS (ESI): Method 7t R = 3.94 min; m / z [M+H]+ = 516.5 1 H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.36 (d, J = 1.4 Hz, 1H), 8.93 (dd, J = 1.4, 4.7 Hz, 1H), 8.56 (s, 1H), 8.20 (s, 1H), 8.11 (d, J = 4.6 Hz, 1H), 6.31 (s, 1H), 4.99 - 4.99 (m, 2H), 3.95 (dd, J = 5.8, 5.8 Hz, 2H), 3.67 (s, 3H), 3.08 - 3.03 (m, 2H), 1.33 - 1.21 (m, 4H)

[0387] Example 126: Preparation of compound 6-(pyrazolo[1,5-a]pyrazine-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 [ka] Step 1: tert-Butyl 3-((5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 107) [ka] To a solution of 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (250 mg, 0.882 mmol) and DMF (0.0034 mL, 0.0441 mmol) in CPME (2 mL) was added dropwise oxalyl chloride (0.088 mL, 1.06 mmol) at 20 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was azeotropically distilled with CPME, and the residue was suspended in ACN (1 mL) and cooled to 0 °C in an ice bath. To the mixture was added a solution of 5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)isoxazol-3-amine (171 mg, 0.882 mmol) and pyridine (0.14 mL, 1.76 mmol) in ACN (1 mL). The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between DCM and water. The combined organic phase was filtered through a hydrophobic frit, and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% EtOAc in cyclohexane) to give the title compound (255 mg, 0.555 mmol, 63%). 1 H NMR (400 MHz, CDCl3) δ 9.65 (s, 1H), 7.91 (s, 1H), 7.13 (s, 1H), 4.64 (s, 2H), 3.68 (t, J = 5.4 Hz, 2H), 3.01 (t, J = 5.8 Hz, 2H), 1.60 (s, 6H), 1.49 (s, 9H)

[0388] Step 2: N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 108) [ka] To a solution of intermediate 107 (255 mg, 0.555 mmol) in 1,4-dioxane (3 ml) was added 4 N HCl in dioxane (3.0 m, 0.555 mmol) at 0° C. The reaction mixture was allowed to warm to RT and stirred at room temperature over the weekend. The reaction mixture was then diluted with diethyl ether, filtered, and the resulting solid was washed with ether and dried under reduced pressure to give the title compound as the HCl salt (190 mg, 0.480 mmol, 86%). 1 H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 9.64 - 9.55 (m, 2H), 8.52 (s, 1H), 7.11 (s, 1H), 4.42 (s, 2H), 3.15 (t, J = 5.6 Hz, 2H), 1.63 (s, 6H)

[0389] Step 3: 6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-N-[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)isoxazol-3-yl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 126) To a solution of Intermediate 108 (50 mg, 0.126 mmol), pyrazolo[1,5-a]pyrazine-3-carboxylic acid (21 mg, 0.126 mmol), and 1-methylimidazole (0.081 mL, 1.01 mmol) in ACN (2 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (53 mg, 0.189 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was then quenched with aqueous NH4Cl and filtered to give a solid that was washed with water, dried under reduced pressure, washed with ether, filtered, dried under reduced pressure and purified by preparative HPLC (Xbridge Phenyl 19 × 150 mm, 10 μm 40–100% MeOH / HO (10 mM NH4CO3), 20 ml / min, RT) to give the title compound (14 mg, 0.0282 mmol, 22%). LCMS (ESI): Method 7t R = 4.42 min, m / z [M+H]+ = 505.4 1H NMR (400 MHz, DMSO-d6) δ 11.40 - 11.36 (s, 1H), 9.40 (s, 1H), 8.96 (d, J = 3.8 Hz, 1H), 8.59 (s, 1H), 8.41 (s, 1H), 8.14 (d, J = 4.5 Hz, 1H), 7.12 (s, 1H), 5.03 - 4.98 (s, 2H), 3.98 (t, J = 4.9 Hz, 2H), 3.10 (s, 2H), 1.63 (s, 6H)

[0390] Example 127: Preparation of compound 6-(imidazo[1,2-a]pyrazine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-Butyl 3-[[5-(trifluoromethyl)-3-pyridyl]carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylate (Intermediate 109) [ka] To a solution of 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (1500 mg, 5.29 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (3713 mg, 13.2 mmol), and 1-methylimidazole (1.3 mL, 15.9 mmol) in ACN (150 mL) was added 5-(trifluoromethyl)pyridin-3-amine (858 mg, 5.29 mmol), and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and water, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by FCC (80 g, 0-100% EtOAc in c-Hex, 10 CV) to give the title compound (1866 mg, 4.37 mmol, 82%). 1H NMR (400 MHz, CDCl3) δ 8.92 (m, 1H), 8.65 (s, 1H), 8.60 (s, 1H), 7.67 - 7.63 (m, 1H), 4.62 - 4.57 (m, 2H), 3.69 (t, J = 5.4 Hz, 2H), 3.02 (t, J = 5.4 Hz, 2H), 1.52 (s, 9H)

[0391] Step 2: N-[5-(trifluoromethyl)-3-pyridyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; Hydrochloride (Intermediate 110) [ka] To a solution of Intermediate 109 (2612 mg, 6.11 mmol) in 1,4-dioxane (16.80 mL) was added 4 M HCl (38 mL, 0.153 mol), and the mixture was stirred at room temperature overnight. The mixture was concentrated and then diluted with MeOH. The resulting solid was filtered and dried to give the title compound as a hydrochloride salt (1819 mg; 5.00 mmol, 82%). 1 H NMR (400 MHz, DMSO-d6) d 10.85 (s, 1H), 9.38 (s, 2H), 9.22 (d, J = 2.3 Hz, 1H), 8.76 (d, J = 1.3 Hz, 1H), 8.66 (t, J = 1.9 Hz, 1H), 8.49 (s, 1H), 4.45 (s, 2H), 3.45 - 3.41 (m, 2H), 3.17 (t, J = 6.1 Hz, 2H)

[0392] Step 3: 6-(Imidazo[1,2-a]pyrazine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 127) A solution of imidazo[1,2-a]pyrazine-3-carboxylic acid (100 mg, 0.613 mmol, 1.00 equiv) in thionyl chloride (0.89 mL, 12.3 mmol, 20.0 equiv) was heated at reflux overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in toluene and reconcentrated to give the intermediate acyl chloride. Imidazo[1,2-a]pyrazine-3-carbonyl chloride (111 mg, 0.611 mmol) and Intermediate 110 (222 mg, 0.611 mmol) were dissolved in THF (10 mL), followed by the addition of DIPEA (0.23 mL, 1.34 mmol) and 4-(dimethylamino)pyridine (3.7 mg, 0.0306 mmol). The reaction was stirred at room temperature for 2 h, then concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Sunfire C18 19 × 150 mm, 10 μm column, 20–80% ACN / HO (0.1% FA), 20 mL / min, RT) to give the title compound (3.03 mg, 1.04%). LCMS (ESI): Method 6t R = 3.79 minutes; m / z [M+H]+ = 473.2 1 H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.25 (d, J = 1.6 Hz, 1H), 9.15 (d, J = 2.0 Hz, 1H), 8.89 (dd, J = 1.4, 4.8 Hz, 1H), 8.71 (d, J = 0.9 Hz, 1H), 8.61 (t, J = 1.8 Hz, 1H), 8.35 (s, 1H), 8.28 (s, 1H), 8.10 (d, J = 4.6 Hz, 1H)

[0393] Example 128: Preparation of compound 6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-N-(5-(trifluoromethoxy)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: 6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-N-(5-(trifluoromethoxy)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 128) [ka] A mixture of Intermediate 93 (40 mg, 0.117 mmol) and Intermediate 86 (30 mg, 0.140 mmol) in THF (2 ml) was cooled to −30° C., then n-butyllithium solution (1.7 M in pentane, 0.247 mL, 0.420 mmol) was added and the reaction stirred while warming to room temperature. The reaction was quenched with NH4Cl (sat. aq.) and the organic phase extracted with DCM. The combined organic phase was filtered through a hydrophobic frit and the solvent concentrated under reduced pressure. The resulting crude residue was purified by washing with DCM to give the title compound (5.1 mg, 0.010 mmol, 8.9%). LCMS (ESI): Method 7t R = 4.04 min; m / z [M+H]+ = 489.3 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 9.41 (d, J = 1.3 Hz, 1H), 8.99 - 8.94 (m, 2H), 8.60 (s, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.38 (s, 1H), 8.29 (s, 1H), 8.15 (d, J = 4.8 Hz, 1H), 5.04 (s, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.11 (s, 2H)

[0394] Example 146: Preparation of N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-6-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Ethyl 6-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 133) [ka] According to general procedure C, starting from 3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (450 mg, 2.79 mmol) and intermediate 38 (692 mg, 2.79 mmol), the resulting crude product was purified by column chromatography on silica gel (0-100% EtOAc in cyclohexane) to afford the title compound (529 mg, 1.48 mmol, 53%). 1 H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.46 (d, J = 1.7 Hz, 1H), 8.13 - 8.10 (m, 2H), 4.22 (q, J = 7.1 Hz, 2H), 3.80 (s, 2H), 3.63 (s, 2H), 2.89 - 2.85 (m, 2H), 2.78 - 2.74 (m, 2H), 2.49 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H)

[0395] Step 2: 6-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (Intermediate 134) [ka] To a suspension of Intermediate 133 (529 mg, 1.48 mmol) in MeOH (12 mL) was added 5 M NaOH (水性) (0.89 mL, 4.45 mmol) was added. The reaction mixture was stirred under nitrogen atmosphere at 60° C. for 2.5 h and then at RT for 16 h. The reaction mixture was diluted with 1 M HCl (水性)The mixture was acidified to pH 5-6 by dropwise addition and concentrated under reduced pressure. The residue was suspended in water and filtered, and the solid was washed with water and dried under reduced pressure to give the title compound (416 mg, 85%). 1 H NMR (400 MHz, DMSO-d6) δ 13.15 (brs, 1H), 12.52 (brs, 1H), 8.46 (d, J = 1.7 Hz, 1H), 8.12 (d, J = 1.5 Hz, 1H), 8.07 (s, 1H), 3.81 (s, 2H), 3.62 (s, 2H), 2.89 - 2.85 (m, 2H), 2.79 - 2.74 (m, 2H), 2.49 (s, 3H)

[0396] Step 3: N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-6-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 146) Prepared from 5-cyclopropyl-2-methyl-pyrazol-3-amine (14 mg, 0.100 mmol) and intermediate 134 (22 mg, 0.0670 mmol) according to general procedure I, but without the addition of DMAP or DIPEA. The crude product was purified by preparative HPLC (Sunfire C18 19 × 150 mm, 10 μm 20–80% acetonitrile / water (10 mM NH4HCO3), 20 ml / min) followed by lyophilization to give the title compound (9.5 mg, 32%). LC-MS (ESI) Method 7: t R = 2.58 min; m / z [M+H]+ = 448.3 1H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 9.98 (s, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 8.09 (s, 1H), 5.91 (s, 1H), 3.83 (s, 2H), 3.65 (s, 2H), 3.58 (s, 3H), 2.85 (d, J = 5.1 Hz, 2H), 2.79 - 2.68 (m, 2H), 2.52 (s, 3H), 1.84 - 1.77 (m, 1H), 0.85 - 0.80 (m, 2H), 0.64 - 0.59 (m, 2H)

[0397] The compounds listed in the table below were prepared by amide coupling as described in Example 146, steps 1-3, using the corresponding commercially available amine in step 3. [Table 94]

[0398] Example 149: Preparation of 6-((3-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: 6-[[3-(4-methylpiperazin-1-yl)-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-5-yl]methyl]-N-[5-(trifluoromethyl)-3-pyridyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Intermediate 135) [ka] Prepared from intermediate 126 (35 mg, 0.09 mmol) and intermediate 90 (30 mg, 0.09 mmol) according to general procedure K. The residue was purified by FCC (0–50% [75:15:10 EtOAc:EtOH:7M NH / MeOH] in cyclohexane) to give the title compound. LC-MS (ESI) Method 16 t R = 1.86 min; m / z [M−H] - = 685

[0399] Step 2: 6-[[3-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-N-[5-(trifluoromethyl)-3-pyridyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 149) To DCM (2 mL) was added a mixture of intermediate 135 (59 mg, 0.0859 mmol) in TFA (0.020 mL, 0.258 mmol). The mixture was stirred overnight at RT. Further TFA (0.020 mL, 0.258 mmol, 3.00 equiv) was added and the mixture was stirred for an additional 2 h. The mixture was then diluted with water, basified with saturated Na2CO3, and extracted with 2x EtOAc. The combined organic phases were dried over MgSO4, filtered, and concentrated. Purification by preparative HPLC (Xbridge Phenyl 19 x 150 mm, 10 μm 40-100% MeOH / H2O (10 mM NH4CO3), 20 ml / min) gave the title compound (3 mg, 6%). LC-MS (ESI) Method 7: t R = 2.36 min; m / z [M + H] + = 557.4 1H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 10.59 (s, 1H), 9.12 (d, J = 2.1 Hz, 1H), 8.68 (s, 1H), 8.59 (t, J = 2.1 Hz, 1H), 8.42 (d, J = 1.9 Hz, 1H), 8.20 (d, J = 1.8 Hz, 1H), 8.16 (s, 1H), 3.80 (s, 2H), 3.65 (s, 2H), 2.90 (t, J = 5.5 Hz, 2H), 2.77 (t, J = 5.6 Hz, 2H), 2.25 (s, 3H)

[0400] The compounds listed in the table below were prepared via reductive amination as in Example 149, Step 1, using the corresponding commercially available or independently synthesized aldehydes. [Table 95] [Table 96]

[0401] Example 156: Preparation of compound N-(3-(tert-butyl)isoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrimidin-6-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Ethyl 6-(pyrazolo[1,5-a]pyrimidin-6-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 136) [ka] Prepared from pyrazolo[1,5-a]pyrimidine-6-carbaldehyde (82 mg, 0.555 mmol) and intermediate 38 (125 mg, 0.505 mmol) by general procedure L. Purification by FCC (0-100% DCM / 2M methanolic ammonia in DCM 20:1) gave the desired product (123 mg, 71%). 1 H NMR (400 MHz, CDCl3) δ 8.66 - 8.65 (m, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 2.5 Hz, 1H), 7.96 (s, 1H), 6.71 (dd, J = 0.9, 2.3 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.78 - 3.73 (m, 4H), 3.06 - 3.01 (m, 2H), 2.88 (t, J = 5.8 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H)

[0402] Step 2: 6-(pyrazolo[1,5-a]pyrimidin-6-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (Intermediate 137) [ka] Following the procedure of Intermediate 94 and starting from Intermediate 136 (120 mg, 0.350 mmol), the desired product (102 mg, 93%) was obtained. LCMS (ESI) Method 15: t R = 0.71 min; m / z [M+H]+ = 315.2

[0403] Step 3: N-(3-tert-butyl)isoxazol-5-yl)6-(pyrazolo[1,5-a]pyrimidin-6-yl)methyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 156) Prepared from intermediate 137 (30 mg, 0.095 mmol) and 3-tert-butylisoxazol-5-amine (20 mg, 0.143 mmol) according to general procedure I. Purification by preparative HPLC (Sunfire C18 19 × 150 mm, 10 μm 20–80% ACN / HO (10 mM NHCO), 20 ml / min) gave the title compound (4 mg, 10%). LCMS (ESI): Method 7t R = 3.15 min, m / z [M+H] + = 437.2 1 H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 9.08 (d, J = 1.1 Hz, 1H), 8.59 (d, J = 2.1 Hz, 1H), 8.24 (s, 1H), 8.22 (d, J = 2.3 Hz, 1H), 6.73 (dd, J = 0.8, 2.3 Hz, 1H), 6.35 (s, 1H), 3.79 (s, 2H), 3.72 (s, 2H), 2.92 (t, J = 6.3 Hz, 2H), 2.81 (t, J = 5.8 Hz, 2H), 1.28 (s, 9H)

[0404] Example 157: Preparation of compound (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]pyridine-3-carboxamide [ka] Step 1: tert-Butyl (R)-3-((3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 138) [ka] Prepared according to the preparation of Example 47, Step 1, starting from 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (350 mg, 1.24 mmol) and Intermediate 14 (355 mg, 1.24 mmol). Purification by FCC (0-10% 2M NH / MeOH in DCM) afforded the title compound (580 mg, 84%). 1 H NMR (300 MHz, CDCl3) δ 8.29 - 8.22 (m, 2H), 7.86 (s, 1H), 7.67 (s, 1H), 7.19 (s, 1H), 4.61 (s, 2H), 3.70 - 3.55 (m, 5H), 3.05 - 2.96 (m, 4H), 2.82 (s, 6H), 2.57 (dd, J = 6.4, 11.5 Hz, 1H), 2.46 - 2.23 (m, 2H), 2.07 - 1.99 (m, 1H), 1.48 (s, 9H)

[0405] Step 2: (R)—N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 139) [ka] To a solution of Intermediate 138 (576 mg, 1.04 mmol) in anhydrous DCM (10.4 mL) was added TFA (1.6 mL, 20.8 mmol) dropwise over 5 minutes while stirring on an ice / water bath under an argon atmosphere. The reaction mixture was stirred for 1.5 hours, concentrated under reduced pressure, and the residue was dissolved in MeOH and loaded onto a 20 g Isolute SCX-II cartridge pre-conditioned with MeOH, washed with MeOH, and then eluted with 2M NH3 / MeOH. The 2M NH3 / MeOH eluent was concentrated under reduced pressure to give the title compound (356 mg, 75%). 1H NMR (300 MHz, CDCl3) δ 8.00 - 7.92 (m, 2H), 7.69 (d, J = 5.3 Hz, 2H), 7.34 (s, 1H), 4.06 (s, 2H), 3.71 (d, J = 13.5 Hz, 1H), 3.59 (d, J = 13.3 Hz, 1H), 3.17 - 3.11 (m, 2H), 2.99 - 2.92 (m, 2H), 2.87 - 2.54 (m, 5H), 2.45 (dd, J = 6.3, 8.5 Hz, 1H), 2.24 (s, 6H), 2.09 - 1.95 (m, 1H), 1.84 - 1.72 (m, 1H)

[0406] Step 3: (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]pyridine-3-carboxamide (Example 157) Prepared from intermediate 139 (59 mg, 0.130 mmol) and 3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (20 mg, 0.124 mmol) according to general procedure J. Purification by preparative HPLC (Xbridge Phenyl 19 × 150 mm, 10 μm 40–100%, methanol / water (10 mM NH4HCO3), 20 mL / min, RT) gave the title compound (34 mg, 45%). LCMS (ESI): Method 7t R = 2.18 min; m / z [M+H]+ = 598.4 1H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 10.32 (s, 1H), 8.49 (d, J = 2.0 Hz, 1H), 8.15 - 8.10 (m, 3H), 7.94 (s, 1H), 7.33 (s, 1H), 3.84 (s, 2H), 3.70 (d, J = 13.6 Hz, 1H), 3.66 (s, 2H), 3.57 (d, J = 13.7 Hz, 1H), 2.93 - 2.87 (m, 2H), 2.81 - 2.65 (m, 4H), 2.63 - 2.55 (m, 1H), 2.49 - 2.43 (m, 1H), 2.31 (dd, J = 5.7, 7.8 Hz, 1H), 2.09 (s, 6H), 1.93 - 1.82 (m, 1H), 1.68 - 1.59 (m, 1H)

[0407] The compounds listed in the table below were prepared by reductive amination as described in Example 157, steps 1-3, using the corresponding commercially available or independently synthesized aldehyde in step 3. [Table 97] [Table 98]

[0408] Example 162: Preparation of (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-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: (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-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 162) Prepared from intermediate 139 (40 mg, 0.0884 mmol) and lithium 5-methylimidazo[1,2-a]pyridine-3-carboxylate (16 mg, 0.0884 mmol) according to general procedure H. Purification by reverse-phase preparative HPLC (Xbridge Phenyl 19 × 150 mm, 10 μm 40–100%, MeOH / water (10 mM NH4HCO3), 20 mL / min, RT) afforded the title compound (22 mg, 39%). LC-MS (ESI) Method 7: R = 2.55 minutes; m / z [M+H] + = 611.3 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.-7 - 8.21 (m, 1H), 8.12 (s, 1H), 7.-6 - 7.93 (m, 2H), 7.-4 - 7.60 (m, 1H), 7.39 (dd, J = 6.9, 8.9 Hz, 1H), 7.35 (s, 1H), 6.91 (s, 1H), 4.98 (s, 2H), 3.89 (s, 2H), 3.71 (d, J = 13.6 Hz, 1H), 3.58 (d, J = 13.6 Hz, 1H), 3.04 (s, 2H), 2.-4 - 2.69 (m, 2H), 2.-5 - 2.58 (m, 1H), 2.-9 - 2.43 (m, 1H), 2.32 (dd, J = 5.6, 7.5 Hz, 1H), 2.09 (s, 6H), 1.-0 - 1.83 (m, 1H), 1.-8 - 1.59 (m, 1H)

[0409] Example 163: Preparation of compound 6-[(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl]-N-[3-(2-pyrrolidin-1-ylethoxy)-5-(trifluoromethyl)phenyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-Butyl 3-[[3-(2-pyrrolidin-1-ylethoxy)-5-(trifluoromethyl)phenyl]carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylate (Intermediate 140) [ka] This was prepared from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (190 mg, 0.671 mmol) and Intermediate 18 (193 mg, 0.704 mmol) according to general procedure M. The residue was purified by FCC (0-100% EtOAc in cyclohexane, followed by 0-20% 7N NH in EtOAc). The residue was dissolved in MeOH and loaded onto an SCX cartridge, which was washed with MeOH. The compound was eluted using 7N NH in MeOH. The solution was concentrated under reduced pressure. 1 H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.58 (s, 1H), 7.37 (s, 1H), 6.93 (s, 1H), 4.62 (s, 2H), 4.16 (dd, J = 5.8, 5.8 Hz, 2H), 3.71 - 3.64 (m, 2H), 3.02 - 2.96 (m, 2H), 2.95 - 2.88 (m, 2H), 2.80 (s, 9H), 2.66 - 2.61 (m, 4H), 1.84 - 1.78 (m, 4H)

[0410] Step 2: N-[3-(2-pyrrolidin-1-ylethoxy)-5-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 141) [ka] Following the procedure of Intermediate 139 and starting from Intermediate 140 (60 mg, 0.111 mmol), the desired product (44 mg, 90% yield) was obtained. 1 H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.63 (s, 1H), 7.55 (s, 1H), 7.34 (s, 1H), 6.93 (s, 1H), 4.16 (t, J = 5.8 Hz, 2H), 4.06 (s, 2H), 3.13 (t, J = 5.9 Hz, 2H), 2.94 - 2.90 (m, 4H), 2.66 - 2.61 (m, 4H), 1.84 - 1.80 (m, 4H)

[0411] Step 3: 6-[(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl]-N-[3-(2-pyrrolidin-1-ylethoxy)-5-(trifluoromethyl)phenyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 163) Prepared from intermediate 141 (40 mg, 0.0910 mmol) and 3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (15 mg, 0.0910 mmol) according to general procedure J. Purified by reverse-phase preparative HPLC (Xbridge Phenyl 19 × 150 mm, 10 μm column) using 40-100% MeOH / HO ( 10 Purification by HPLC (mM NH4CO3), 20 ml / min, RT) gave the title compound (15 mg, 28%). LCMS (ESI): Method 7t R = 2.64 min, m / z [M+H] + = 585.2 1H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 10.28 (s, 1H), 8.49 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 1.9 Hz, 1H), 8.10 (s, 1H), 7.76 (s, 1H), 7.65 (s, 1H), 6.98 (s, 1H), 4.14 (t, J = 5.8 Hz, 2H), 3.84 (s, 2H), 3.66 (s, 2H), 2.91 - 2.87 (2H, m), 2.84 - 2.77 (4H, m) 1.72 - 1.68 (m, 4H)

[0412] The compounds listed in the table below were prepared via reductive amination as described in Example 163, steps 1-3, using the corresponding commercially available or independently synthesized aldehyde in step 3. [Table 99]

[0413] Example 165: Preparation of 6-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Ethyl 6-[6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylate (Intermediate 142) [ka] Prepared from intermediate 38 (405 mg, 1.6 mmol) and intermediate 113 (851 mg, 1.6 mmol) according to general procedure M. The residue was purified by FCC (0-100% EtOAc in cyclohexane, followed by 0-100% MeOH in EtOAc) to give the desired product (330 mg, 45%). 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 1.8 Hz, 1H), 8.03 (s, 1H), 7.89 (s, 1H), 7.57 (d, J = 9.6 Hz, 1H), 7.25 (m, 1H), 5.01 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 4.09 (m, 2H), 3.24 - 3.14 (m, 6H), 2.61 (t, J = 4.7 Hz, 4H), 2.37 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H).

[0414] Step 2: 6-[6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (Intermediate 143) [ka] Following the procedure of Example 140, Step 2, starting from Intermediate 142 (330 mg, 0.728 mmol), the crude obtained was washed with MeOH and the combined organic phases were evaporated to give the title compound (310 mg, 100%). 1 H NMR (400 MHz, MeOH-d4)δ 8.46 (d, J = 1.8 Hz, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.60 (d, J = 9.6 Hz, 1H), 7.52 (dd, J = 2.3, 9.6 Hz, 1H), 5.03 (s, 2H), 4.07 (t, J = 5.7 Hz, 2H), 3.19 (t, 5.4 Hz, 2H), 3.07 (t, J = 4.7 Hz, 4H), 2.68 (s, 3H).-

[0415] Step 3: 6-[6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl]-N-[5-(trifluoromethyl)-3-pyridyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 165) Prepared from 5-(trifluoromethyl)pyridin-3-amine (19 mg, 0.118 mmol) and intermediate 143 (assumed 50% purity, 100 mg, 0.118 mmol) according to general procedure N. The residue was purified by preparative HPLC (Xbridge Phenyl 19 × 150 mm, 10 μm 40–100% MeOH / HO (10 mM NHCO), 20 ml / min, RT) to give the title compound (13 mg, 19% yield). LC-MS (ESI) Method 7: t R = 2.70 min; m / z [M + H] + = 570.4 1 H NMR (400 MHz, DMSO) δ 10.66 (s, 1H), 9.15 (d, J = 2.1 Hz, 1H), 8.70 (s, 1H), 8.61 (t, J = 2.1 Hz, 1H), 8.41 (d, J = 1.9 Hz, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.61 (d, J = 9.8 Hz, 1H), 7.49 (dd, J = 2.3, 9.8 Hz, 1H), 5.03 (s, 2H), 3.99 (t, J = 5.7 Hz, 2H), 3.08 (m, 6H), 2.51 (m, 4H-under DMSO peak), 2.24 (s, 3H)

[0416] Example 166: Preparation of 6-(6-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: 6-[(2-aminopyrimidin-5-yl)methyl]-N-(5-isobutyl-2-methyl-pyrazol-3-yl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Intermediate 144) [ka] Prepared according to general procedure H from 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (406 mg, 1.68 mmol) and Intermediate 64 (550 mg, 0.40 mmol). The reaction was diluted with aqueous NH4Cl and filtered to give a solid that was dried under reduced pressure. The solid was washed with MeOH to give the title compound (533 mg, 57%). 1 H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.17 (s, 1H), 8.27 (s, 2H), 8.22 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 9.6 Hz, 1H), 7.68 - 7.61 (m, 2H), 7.49 (d, J = 7.8 Hz, 1H), 5.09 (s, 2H), 4.06 - 3.99 (m, 2H), 3.16 - 3.10 (m, 2H)

[0417] Step 2: 6-(6-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 166) Intermediate 144 (35 mg, 0.0637 mmol) and Pd-PEPPSI™-IPent catalyst (5.1 mg, 6.37 μmol) were placed in a nitrogen-flushed microwave vial. THF (2.0 mL) was added, and while the solution was degassed, 2 M sodium tert-butoxide (0.37 mL, 0.733 mmol) and 2-methyl-2,6-diazaspiro[3.3]heptane dihydrochloride (117 mg, 0.63 mmol) were added. The reaction was then heated in a microwave at 120 °C for 2 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (Luna Phenyl-Hexyl 21.2 × 150 mm, 10 μm column, 20–80% MeOH / HO (0.1% FA), 20 mL / min). The isolated material was dissolved in EtOAc and washed with saturated aqueous NaHCO3, and the organic layer was concentrated and lyophilized to give the title compound (2.3 mg, 6%). LC-MS (ESI) Method 7: t R = 3.12 min; m / z [M + H] + = 581.2 1 H NMR (300 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.22 (s, 2H), 8.07 (d, J = 1.8 Hz, 1H), 8.01 - 7.98 (m, 2H), 7.63 - 7.58 (m, 2H), 7.46 (d, J = 7.4 Hz, 1H), 6.98 (dd, J = 2.3, 9.5 Hz, 1H), 5.01 (s, 2H), 3.98 (dd, J = 5.5, 5.5 Hz, 2H), 3.89 (s, 4H), 3.28 (s, 4H), 3.08 - 3.06 (m, 2H), 2.20 (s, 3H)

[0418] Example 167: Preparation of 6-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: 6-[6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)imidazo[1,2-a]pyridine-3-carbonyl]-N-[3-(trifluoromethyl)phenyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 167) To a solution of intermediate 144 (150 mg, 0.273 mmol) in DMF (1.5 mL) and water (0.5 mL) was added 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (79 mg, 0.355 mmol), K2CO3 (45 mg, 0.328 mmol), and Pd(dppf)Cl2·DCM (3.4 mg, 4.10 μmol). The reaction was heated at 100 °C under a stream of nitrogen for 4 h. Water was added to the mixture, followed by extraction with DCM. The organic phase was separated, passed through a hydrophobic frit, and concentrated under reduced pressure. The residue was purified by FCC (0–20% MeOH in DCM) to give the title compound (75 mg, 49%). LC-MS (ESI) Method 7: t R = 3.29 min; m / z [M + H] + = 566.3 1 H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.91 (s, 1H), 8.22 (s, 2H), 8.12 (s, 1H), 8.00 (d, J = 8.9 Hz, 1H), 7.72 - 7.70 (m, 2H), 7.60 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 6.34 (t, J = 3.6 Hz, 1H), 5.05 (s, 2H), 4.00 (t, J = 5.6 Hz, 2H), 3.10 - 3.04 (m, 4H), 2.60 (t, J = 5.6 Hz, 2H), 2.30 (s, 3H)

[0419] Example 168: N-(3-(tert-butyl)isoxazol-5-yl)-6-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-Butyl 3-[(5-tert-butylisoxazol-3-yl)carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylate (Intermediate 145) [ka] Following the procedure of Intermediate 95, starting from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (142 mg, 0.500 mmol) and 3-amino-5-tert-butylisoxazole (70 mg, 0.500 mmol), the title compound (164 mg, 0.404 mmol, 81%) was obtained. 1 H NMR (400 MHz, CDCl3) d 10.84 (s, 1H), 8.10 (s, 1H), 6.88 (s, 1H), 4.67 - 4.62 (m, 2H), 3.68 (t, J = 4.9 Hz, 2H), 3.03 (t, J = 5.8 Hz, 2H), 1.42 (s, 9H), 1.37 (s, 9H)

[0420] Step 2: N-(3-tert-butylisoxazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (Intermediate 146) [ka] Following the procedure of Intermediate 86 and starting from Intermediate 145 (100 mg, 0.247 mmol), the title compound (56 mg, 0.162 mmol, 66%) was obtained. 1H NMR (400 MHz, DMSO-d6) d 11.93 (s, 1H), 9.65 - 9.60 (m, 2H), 8.52 (s, 1H), 6.41 (s, 1H), 4.47 - 4.38 (m, 2H), 3.40 (m, 2H), 3.20 - 3.12 (m, 2H), 1.33 (s, 9H)

[0421] Step 3: N-(3-(tert-butyl)isoxazol-5-yl)-6-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide Example 168 Prepared from Intermediate 113 (107 mg, 0.161 mmol) and Intermediate 146 (55 mg, 0.161 mmol) according to the procedure in Example 122, Step 3. The residue was purified by preparative HPLC (Sunfire C18 19 × 150 mm, 10 μm 5–60% ACN / HO (0.1% FA), 20 ml / min, RT) and SCX cartridge eluting with 1N NH in methanol to give the title compound (9 mg, 10%). LC-MS (ESI) Method 7: t R = 2.88 min; m / z [M + H] + = 548.5 1 H NMR (400 MHz, DMSO-d6) d 11.78 (s, 1H), 8.41 (d, J = 1.8 Hz, 1H), 8.36 (s, 1H), 8.03 (s, 1H), 7.62 (d, J = 9.8 Hz, 1H), 7.49 (dd, J = 2.3, 9.8 Hz, 1H), 6.39 (s, 1H), 5.02 (s, 2H), 3.98 (t, J = 5.6 Hz, 2H), 3.09 - 3.08 (m, 6H), 2.57 - 2.55 (m, 2H), 2.29 (s, 3H), 1.30 (s, 9H)

[0422] Example 169: Preparation of 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 169) Following the procedure of Example 1, Step 3, starting from 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-amine (145 mg, 0.879 mmol) and Intermediate 54 (100 mg, 0.293 mmol), the desired product (44 mg, 0.095 mmol, 11%) was obtained. LC-MS (ESI) Method 1: t R = 0.88 min; m / z [M + H] + = 461.1 1 H NMR (ACN-d3, 400 MHz) δ 9.60 (br s, 1H), 8.97 (br s, 1H), 8.23 ​​(s, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.36 (br s, 1H), 7.09 (s, 1H), 6.46 (br s, 1H), 3.88 (s, 3H), 3.80 (s, 2H), 3.66 (s, 2H), 2.91 (br t, 2H, J = 5.6 Hz), 2.79 (t, 2H, J = 5.8 Hz)

[0423] Example 170: Preparation of 6-(6-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: 6-(6-hydroxyimidazo[1,2-a]pyridine-3-carbonyl)-N-[3-(trifluoromethyl)phenyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Intermediate 147) [ka] Following the procedure of Example 90, 6-hydroxyimidazo[1,2-a]pyridine-3-carboxylic acid (110 mg, 0.617 mmol) and Intermediate 64 (202 mg, 0.617 mmol) gave the title compound (169 mg, 0.347 mmol, 56%). 1 H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.79 (s, 1H), 8.59 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 4.4 Hz, 2H), 8.00 - 7.96 (m, 2H), 7.63 - 7.58 (m, 2H), 7.45 (d, J = 7.9 Hz, 1H), 7.17 (dd, J = 2.4, 9.5 Hz, 1H), 5.02 (s, 2H), 4.01 - 3.96 (m, 2H), 3.09 - 3.06 (m, 2H)

[0424] Step 2: 6-(6-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 170) To a solution of intermediate 147 (109 mg, 0.224 mmol) in DMF (2.0 mL) was added K2CO3 (77 mg, 0.560 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (46 mg, 0.246 mmol), and the mixture was heated to 85 °C and stirred for 6 h. The reaction mixture was diluted with EtOAc, washed with water, water:brine 1:1, brine, dried over MgSO4, filtered, and concentrated. The residue was purified by preparative HPLC (Xbridge Phenyl 19 × 150 mm, 10 μm 40–100% MeOH / H2O (10 mM NH4CO3), 20 mL / min) to give the title compound (20 mg, 14%). LC-MS (ESI) Method 7: t R = 3.22 min; m / z [M + H] + = 600.5 1 H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.22 (s, 2H), 8.09 (s, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 9.7 Hz, 1H), 7.60 (dd, J = 8.0, 8.0 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.30 (dd, J = 2.4, 9.7 Hz, 1H), 5.04 (s, 2H), 4.12 (t, J = 5.6 Hz, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.59 (t, J = 4.6 Hz, 3H), 3.08 (s, 2H), 2.74 (t, J = 5.6 Hz, 2H).

[0425] Example 171: Preparation of N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-Butyl 3-[[4-[(dimethylamino)methyl]-3-(trifluoromethyl)phenyl]carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylate (Intermediate 148) [ka] Prepared from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (96 mg, 0.339 mmol) and intermediate 27 (74 mg, 0.339 mmol) according to general procedure N. The crude residue was purified by FCC (0-6% 2M NH / MeOH in DCM) to give the title compound (121 mg, 0.250 mmol 73%). 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.15 - 8.13 (m, 2H), 7.97 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 4.59 (s, 2H), 3.60 - 3.55 (m, 2H), 3.50 (s, 2H), 2.88 - 2.82 (m, 2H), 2.19 (s, 6H), 1.43 (s, 9H)

[0426] Step 2: N-[4-[(dimethylamino)methyl]-3-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 149) [ka] Following the procedure of Intermediate 139 and starting from Intermediate 148 (121 mg, 0.250 mmol) gave the title compound (78 mg, 81%). 1H NMR (400 MHz, DMSO) δ 10.28 (s, 1H), 8.14 (d, J = 2.1 Hz, 1H), 8.04 (s, 1H), 7.97 (dd, J = 1.8, 8.5 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 3.87 (s, 2H), 3.48 (s, 2H), 2.92 - 2.87 (m, 2H), 2.77 - 2.71 (m, 2H), 2.17 (s, 6H)

[0427] Step 3: N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 171) Following the procedure of Example 125, Step 3, pyrazolo[1,5-a]pyrazine-3-carboxylic acid (12 mg, 0.0756 mmol) and Intermediate 149 (29 mg, 0.0756 mmol) gave the title compound (11 mg, 27%). LC-MS (ESI) Method 7: t R = 4.41 min; m / z [M + H] + = 529.2 1 H NMR (400 MHz, DMSO-d6) d 10.38 - 10.36 (m, 1H), 9.37 (d, J = 1.5 Hz, 1H), 8.93 (dd, J = 1.4, 4.7 Hz, 1H), 8.56 (s, 1H), 8.20 - 8.10 (m, 3H), 7.99 (dd, J = 1.9, 8.5 Hz, 1H), 7.72 - 7.68 (m, 1H), 4.99 (s, 2H), 3.95 (t, J = 5.7 Hz, 2H), 3.06 (s, 2H), 2.19 (s, 6H)

[0428] Example 172: Preparation of N-(3-(morpholinomethyl)-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-Butyl 3-[[3-(morpholinomethyl)-5-(trifluoromethyl)phenyl]carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylate (Intermediate 150) [ka] Following the procedure of Intermediate 89, starting from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (327 mg, 1.15 mmol) and Intermediate 12 (300 mg, 1.15 mmol), the desired product (370 mg, 58%) was obtained. 1 H NMR (400 MHz, CDCl3) d 7.85 (s, 1H), 7.79 (s, 1H), 7.65 (s, 1H), 7.37 (s, 1H), 5.30 (s, 2H), 4.61 (s, 2H), 3.74 - 3.64 (m, 6H), 3.53 (s, 2H), 3.00 (t, J = 5.7 Hz, 2H), 2.46 (t, J = 4.4 Hz, 4H), 1.51 (s, 9H)

[0429] Step 2: N-[3-(morpholinomethyl)-5-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide dihydrochloride (Intermediate 151) [ka] Following the procedure of Intermediate 90 and starting from Intermediate 150 (350 mg, 0.666 mmol), the title compound (314 mg, 94.6%) was obtained. 1H NMR (400 MHz, DMSO-d6) d 11.51 (s, 1H), 10.87 (s, 1H), 9.81 - 9.73 (m, 2H), 8.57 (s, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 7.92 (s, 1H), 4.52 - 4.40 (m, 4H), 4.00 (d, J = 11.9 Hz, 2H), 3.86 (t, J = 11.6 Hz, 2H), 3.45 - 3.37 (m, 2H), 3.31 (d, J = 12.1 Hz, 2H), 3.18 (t, J = 5.4 Hz, 4H)

[0430] Step 3: N-[3-(morpholinomethyl)-5-(trifluoromethyl)phenyl]-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxamide (Example 172) Prepared from pyrazolo[1,5-a]pyrazine-3-carboxylic acid (49 mg, 0.301 mmol) and Intermediate 151 (150 mg, 0.301 mmol) according to Procedure M. The title compound was obtained by trituration with EtO (90 mg, 49%). LC-MS (ESI) Method 7: t R = 3.05 min; m / z [M + H] + = 571.2 1 H NMR (400 MHz, DMSO-d6) d 10.44 (s, 1H), 9.41 (d, J = 1.5 Hz, 1H), 8.97 (dd, J = 1.4, 4.7 Hz, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 8.19 (s, 1H), 8.15 (d, J = 4.8 Hz, 1H), 8.01 (s, 1H), 7.41 (s, 1H), 5.04 - 5.01 (m, 2H), 3.99 (dd, J = 5.7, 5.7 Hz, 2H), 3.62 (d, J = 20.2 Hz, 6H), 3.11 (s, 2H), 2.46 (s, 4H)

[0431] Example 173: Preparation of 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridazin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: 6-(Imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridazin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 173) To a stirred suspension of 5-(trifluoromethyl)pyridazin-3-amine (33 mg, 0.202 mmol) in THF (0.5 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1 M solution in THF, 0.32 mL, 0.318 mmol) dropwise over 2 minutes. The reaction mixture was stirred for 1.5 hours, followed by the dropwise addition of a suspension of 6-(imidazo[1,2-a]pyridine-3-carbonyl)-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carbonyl chloride (50 mg, 0.145 mmol) obtained according to Procedure H, starting from Intermediate 40 (acid form), in DCM (1.2 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated NH4Cl. (水性) The mixture was quenched with HCl and the aqueous phase was extracted with DCM. The organic phase was passed through a hydrophobic frit and concentrated under reduced pressure. Purification by preparative HPLC (Luna Phenyl-Hexyl 21.2 x 150 mm, 10 μm 40-100% MeOH / water (0.1% FA) 20 mL / min, RT) gave the title compound (6 mg, 8%). LC-MS (ESI) Method 7: t R = 3.37 min; m / z [M + H] + = 473.2 1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 9.39 (d, J = 1.6 Hz, 1H), 8.89 (td, J = 1.1, 7.0 Hz, 1H), 8.62 (dd, J = 0.8, 2.0 Hz, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.66 (td, J = 1.1, 9.0 Hz, 1H), 7.40 (ddd, J = 1.3, 6.8, 9.0 Hz, 1H), 7.03 (dt, J = 1.2, 6.9 Hz, 1H), 4.97 (s, 2H), 3.94 - 3.89 (m, 2H), 3.07 - 3.02 (m, 2H)

[0432] Example 174: Preparation of 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-Butyl 3-((3-fluoro-5-(trifluoromethoxy)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 152) [ka] Following the procedure of Example 1, Step 4, starting with 6-(tert-butyl) 3-ethyl 4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (271 mg, 0.871 mmol) and N-3-fluoro-5-(trifluoromethoxy)aniline (600 mg, 2.61 mmol), the title compound (153 mg, 0.332 mmol, 38%) was obtained.

[0433] Step 2: N-(3-fluoro-5-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 153) [ka] Following the procedure of Intermediate 139 and starting from Intermediate 152 (303 mg, 0.658 mmol), the title compound (80 mg, 0.222 mmol, 34%) was obtained.

[0434] Step 3: 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 174) Following procedure K, starting from 1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (36 mg, 0.244 mmol) and intermediate 153 (80 mg, 0.222 mmol), the title compound (15 mg, 0.031 mmol, 14%) was obtained. LC-MS (ESI) Method 7: t R = 5.16 minutes; m / z (M+1) = 492.3 1 H NMR (ACN-d3, 400 MHz) δ 11.47 (bs, 1H), 8.79 (br s, 1H), 8.54 (d, 1H, J = 2.0 Hz), 8.12 (d, 1H, J = 2.0 Hz), 8.04 (s, 1H), 7.86 (s, 1H), 7.5-7.6 (m, 2H), 6.84 (br d, 1H, J = 8.6 Hz), 3.84 (s, 2H), 3.69 (s, 2H), 2.93 (br t, 2H, J = 5.8 Hz), 2.81 (t, 2H, J = 5.8 Hz)

[0435] Example 175: Preparation of N-(5-(tert-butyl)isoxazol-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-Butyl 3-((5-(tert-butyl)isoxazol-3-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 154) [ka] Following the procedure of Intermediate 95, starting from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (142 mg, 0.500 mmol) and 3-amino-5-tert-butylisoxazole (70 mg, 0.500 mmol), the title compound (164 mg, 0.404 mmol, 81%) was obtained. 1 H NMR (400 MHz, CDCl3) d 10.84 (s, 1H), 8.10 (s, 1H), 6.88 (s, 1H), 4.67 - 4.62 (m, 2H), 3.68 (t, J = 4.9 Hz, 2H), 3.03 (t, J = 5.8 Hz, 2H), 1.42 (s, 9H), 1.37 (s, 9H)

[0436] Step 2: N-(5-tert-butylisoxazol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (Intermediate 155) [ka] Following the procedure of Intermediate 86, starting from Intermediate 154 (164 mg, 0.404 mmol, 1.00 equiv) gave the title product. 1 H NMR (400 MHz, DMSO-d6) d 11.32 (s, 1H), 9.65 - 9.56 (m, 2H), 8.49 (s, 1H), 6.74 (s, 1H), 4.42 (s, 2H), 3.39 (m, 2H-under water peak), 3.15 (t, J = 5.8Hz, 2H), 1.37 (s, 9H)

[0437] Step 3: N-(5-(tert-butyl)isoxazol-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 175) Prepared from intermediate 155 (52 mg, 0.152 mmol) and pyrazolo[1,5-a]pyrazine-3-carboxylic acid (25 mg, 0.152 mmol) according to procedure N. Purification was achieved by washing with DMSO, followed by water, drying, and then washing with DCM to give the title compound (28.39 mg, 40.26%). LC-MS (ESI) Method 6: t R = 4.20 min; m / z [M + H] + = 451.4 1 H NMR (400 MHz, DMSO-d6) δ 11.22 - 11.19 (s, 1H), 9.41 - 9.39 (d, J = 1.46Hz, 1H), 8.97 (dd, J = 1.4, 4.7 Hz, 1H), 8.59 (s, 1H), 8.38 (s, 1H), 8.14 (d, J = 4.5 Hz, 1H), 6.75 (s, 1H), 5.02 - 5.00 (s, 2H), 4.01 - 3.95 (t, J = 5.7Hz, 2H), 3.10 (s, 2H), 1.37 (s, 9H)

[0438] Example 176: Preparation of compound N-(4-chloro-3-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-butyl 3-((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 156) [ka] Following the procedure of Example 47, Step 1, starting with 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (200 mg, 0.706 mmol) and 4-chloro-3-(trifluoromethyl)aniline (138 mg, 0.706 mmol), the crude residue obtained was purified by FCC (0-50% EtOAc in cyclohexane) to afford the title compound (231 mg, 0.501 mmol, 71%). 1 H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.18 (s, 1H), 8.04 (dd, J = 2.3, 8.8 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 4.60 (s, 2H), 3.59 (t, J = 5.6 Hz, 2H), 2.86 (t, J = 5.6 Hz, 2H), 1.44 (s, 9H)

[0439] Step 2: N-[4-chloro-3-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 157) [ka] Following the procedure of Intermediate 96 and starting from Intermediate 156 (230 mg, 0.499 mmol), the title compound (180 mg, 0.454 mmol, 91%) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.33 (d, J = 2.5 Hz, 1H), 8.13 (s, 1H), 8.05 (dd, J = 2.4, 8.8 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 4.11 (s, 1H), 3.97 (s, 2H), 2.98 (t, J = 5.8 Hz, 2H), 2.81 (t, J = 5.6 Hz, 2H)

[0440] Step 3: N-(4-chloro-3-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 176) Following the procedure of Example 121, Step 3, pyrazolo[1,5-a]pyrazine-3-carboxylic acid (81 mg, 0.499 mmol) and Intermediate 157 (180 mg, 0.499 mmol) gave the title compound (4.39 mg, 1.64%). LC-MS (ESI) Method 6: t R = 4.78 min; m / z [M + H] + = 506.2 1 H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 9.37 (d, J = 1.5 Hz, 1H), 8.94 (dd, J = 1.4, 4.7 Hz, 1H), 8.56 (s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 8.22 (s, 1H), 8.11 (d, J = 4.8 Hz, 1H), 8.05 (dd, J = 2.5, 8.8 Hz, 1H), 7.72 (d, J = 8.9 Hz, 1H), 5.00 (s, 2H), 3.95 (t, J = 5.6 Hz, 2H), 3.06 (s, 2H)

[0441] Example 177: Preparation of 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-Butyl 3-[[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylate (Intermediate 158) [ka] Following the procedure of Example 109, Step 1, 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (300 mg, 1.06 mmol) and 3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)aniline (275 mg, 1.06 mmol) gave the title compound (516 mg, 0.984 mmol, 93%). 1 H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.14 (s, 1H), 7.61 - 7.56 (m, 2H), 6.94 (s, 1H), 4.60 (s, 2H), 3.66 - 3.57 (t, 2H), 3.21 (t, J = 4.9 Hz, 4H), 2.86 (t, J = 5.7 Hz, 2H), 2.47 (t, J = 5.0 Hz, 4H), 2.24 (s, 3H), 1.44 (s, 9H)

[0442] Step 2: N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 159) [ka] Following the procedure for Intermediate 86 and starting from Intermediate 158 (515 mg, 0.982 mmol), the resulting residue was diluted with MeOH, passed through an SCX cartridge (5 g, eluted with 1N NH3 / MeOH), and concentrated to give the title compound (430 mg, 1.01 mmol, 103%). 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 6.94 (s, 1H), 4.14 (s, 3H), 3.22 (t, J = 5.71 Hz, 4H), 3.15 (t, J = 6.43 Hz, 2H), 2.93 (t, J = 5.3 Hz, 2H), 2.25 (s, 3H)

[0443] Step 3: 6-(Imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 177) According to general procedure M, starting from imidazo[1,2-a]pyridine-3-carboxylic acid (79 mg, 0.490 mmol) and intermediate 159 (208 mg, 0.490 mmol), the resulting crude was purified by preparative HPLC (Sunfire C18 19 × 150 mm, 10 μm 20–80% ACN / HO (10 mM NHCO), 20 ml / min, RT) to give the title compound (49 mg, 17.59%). LC-MS (ESI) Method 7: t R = 2.84 min; m / z [M + H] + = 569.2 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.98 (d, J = 7.0 Hz, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.75 (d, J = 8.9 Hz, 1H), 7.62 (s, 1H), 7.59 (s, 1H), 7.51 - 7.45 (m, 1H), 7.13 - 7.09 (m, 1H), 6.95 (s, 1H), 5.06 - 5.02 (m, 2H), 4.00 (t, J = 5.6 Hz, 2H), 3.22 (t, J = 4.9 Hz, 4H), 3.09 (t, J = 6.5 Hz, 2H), 2.50 - 2.45 (m, 4H), 2.25 (s, 3H)

[0444] The compounds listed in the table below were prepared by amide coupling as described in Example 177, steps 1-3, using the corresponding commercially available carboxylic acid in step 3. [Table 100]

[0445] Example 179: Preparation of N-(3-(tert-pentyl)isoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-butyl 3-((3-(tert-pentyl)isoxazol-5-yl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 160) [ka] Following the procedure of Intermediate 95, 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (150 mg, 0.529 mmol) and 3-(1,1-dimethylpropyl)isoxazol-5-amine (82 mg, 0.529 mmol) gave the title compound (14 mg, 6%). 1 H NMR (400 MHz, CDCl3) δ 8.61 - 8.61 (m, 1H), 7.67 (s, 1H), 6.23 (s, 1H), 4.51 (s, 2H), 3.55 (t, J = 5.6 Hz, 2H), 2.88 (t, J = 5.6 Hz, 2H), 1.52 (q, J = 7.5 Hz, 2H) 1.36 (s, 9H), 1.17 (s, 6H), 0.69 (t, J = 7.5 Hz, 3H)

[0446] Step 2: N-(3-(tert-pentyl)isoxazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide hydrochloride (Intermediate 161) [ka] Following the procedure of Intermediate 86, Intermediate 160 (14 mg, 0.0334 mmol) gave the title compound by precipitation from Et2O (17 mg, estimated quantitative). LC-MS (ESI) Method 16: t R = 1.04 min; m / z [M + H] + = 320.1

[0447] Step 3: N-(3-(tert-pentyl)isoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 179) Following the procedure of Example 121, Step 3, intermediate 161 (52 mg, 0.146 mmol) and pyrazolo[1,5-a]pyrazine-3-carboxylic acid (24 mg, 0.146 mmol) gave a crude product which was purified by SFC (TORUS-2PIC 20 × 250 mm, 5 μm 5-15% MeOH (0.1% DEA) / CO2, 100 ml / min, 120 bar, 40°C, DAD 260 nm) to give the title compound (15 mg, 23%). LC-MS (ESI) Method 7: t R = 4.45 min; m / z [M + H] + = 465.6 1 H NMR (400 MHz, DMSO-d6) δ 11.76 - 11.76 (s, 1H), 9.36 (d, J = 1.4 Hz, 1H), 8.93 (dd, J = 1.4, 4.7 Hz, 1H), 8.55 (s, 1H), 8.34 (s, 1H), 8.11 (d, J = 4.8 Hz, 1H), 6.32 (s, 1H), 4.99 - 4.99 (s, 2H), 3.95 (t, J = 5.8 Hz, 2H), 3.07 - 3.07 (m, 2H), 1.62 (q, J = 7.4 Hz, 2H), 1.25 (s, 6H), 0.77 (t, J = 7.5 Hz, 3H)

[0448] Example 180: Preparation of compound N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: Methyl 6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 162) [ka] Pyrazolo[1,5-a]pyrazine-3-carboxylic acid (0.083 g, 0.507 mmol) was placed in a flask, followed by the addition of DMF (1.491 ml). DIPEA (0.195 ml, 1.115 mmol) was then added. After 5 min, HATU (0.212 g, 0.558 mmol) was added, and the solution was stirred at RT for 30 min. Intermediate 36 (0.1 g, 0.507 mmol) was then added, and the reaction mixture was stirred at RT for 1 h. The RM was poured onto ice, and the solid was filtered through a Schoot funnel to give the title compound (0.153 g, 0.447 mmol, 88%). 1 H NMR (300 MHz, DMSO-d6) δ 9.33 (d, J = 1.4 Hz, 1H), 8.91 (dd, J = 4.7, 1.5 Hz, 1H), 8.54 (s, 1H), 8.25 (s, 1H), 8.08 (d, J = 4.7 Hz, 1H), 4.95 (s, 2H), 3.93 (t, J = 5.8 Hz, 2H), 3.78 (s, 3H), 3.03 (s, 2H)

[0449] Step 180: N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide Following the procedure of Example 128, Step 1, the crude product obtained from Intermediate 162 (50 mg, 0.146 mmol) and Intermediate 112 (33 mg, 0.175 mmol) was purified by SFC (YMC Amylose-C MeOH TORUS-2PIC 20 × 250 mm, 5 μm 15-25% MeOH (0.1% DEA) / CO, 100 ml / min, 120 bar, 40°C, DAD 260 nm) to give the title compound (15 mg, 21%). LC-MS (ESI) Method 7: t R = 3.74 min; m / z [M + H] + = 502.5 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 9.37 (d, J = 1.5 Hz, 1H), 8.94 (dd, J = 1.4, 4.7 Hz, 1H), 8.56 (s, 1H), 8.20 (s, 1H), 8.16 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 4.6 Hz, 1H), 8.01 (dd, J = 1.7, 8.6 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 5.00 - 5.00 (m, 2H), 4.65 (s, 2H), 3.95 (dd, J = 5.8, 5.8 Hz, 2H), 3.07 - 3.05 (m, 2H), 2.58 - 2.55 (m, 1H)

[0450] Example 181: Preparation of compound 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-morpholino-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-Butyl 3-[[3-morpholino-5-(trifluoromethyl)phenyl]carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylate (Intermediate 163) [ka] Following the procedure of Intermediate 89, starting from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (300 mg, 1.06 mmol) and 3-morpholino-5-(trifluoromethyl)aniline (261 mg, 1.06 mmol), the title compound (489 mg, 0.956 mmol, 90%) was obtained. 1H NMR (400 MHz, DMSO-d6) d 10.21 (s, 1H), 8.14 (s, 1H), 7.63 (s, 1H), 7.59 (s, 1H), 6.96 (s, 1H), 4.60 (s, 2H), 3.77 (t, J = 4.8 Hz, 4H), 3.59 (t, J = 5.8 Hz, 2H), 3.19 (t, J = 4.8 Hz, 4H), 2.85 (t, J = 5.6 Hz, 2H), 1.44 (s, 9H)

[0451] Step 2: N-[3-morpholino-5-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 164) [ka] Following the procedure of Intermediate 86 and starting from Intermediate 163 (489 mg, 0.956 mmol), the title compound (404 mg, 0.982 mmol, quantitative yield) was obtained. 1 H NMR (400 MHz, DMSO-d6) d 10.16 (s, 1H), 8.05 (s, 1H), 7.64 (s, 1H), 7.59 (s, 1H), 6.95 (s, 1H), 3.90 (s, 2H), 3.77 (t, J = 4.8 Hz, 4H), 3.20 - 3.16 (m, 4H), 2.92 (t, J = 5.6 Hz, 2H), 2.76 (t, J = 5.5 Hz, 2H)

[0452] Step 3: 6-(Imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-morpholino-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 181) Following general procedure M, from intermediate 164 (196 mg, 0.476 mmol) and imidazo[1,2-a]pyridine-3-carboxylic acid (77 mg, 0.476 mmol), the crude product was purified by FCC (25 g, 0–50% 3:1 EtOAc:EtOH in cyclohexane) to give the title compound (162 mg, 60%). LC-MS (ESI) Method 7: t R = 3.97 min; m / z [M + H] + = 556.2 1 H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.97 (d, J = 6.9 Hz, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.64 (s, 1H), 7.60 (s, 1H), 7.51 - 7.45 (m, 1H), 7.13 - 7.10 (m, 1H), 6.97 (s, 1H), 5.04 (s, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.77 (t, J = 4.8 Hz, 4H), 3.22 - 3.16 (m, 4H), 3.09 (t, J = 5.8 Hz, 3H)

[0453] The compounds listed in the table below were prepared by amide coupling as described in Example 181, steps 1-3, using the corresponding commercially available or independently synthesized carboxylic acid in step 3. [Table 101]

[0454] Example 183: Preparation of compound N-(3-isobutylisoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-Butyl 3-[(3-isobutylisoxazol-5-yl)carbamoyl]-5,7-dihydro-4H-thieno[2,3-c]pyridine-6-carboxylate (Intermediate 165) [ka] Following the procedure of Intermediate 95, 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (250 mg, 0.882 mmol) and 3-isobutylisoxazol-5-amine gave the title compound (226 mg, 0.557 mmol, 63%). 1 H NMR (400 MHz, CDCl3) δ 8.63 - 8.62 (s, 1H), 7.76 (s, 1H), 6.31 (s, 1H), 4.64 (s, 2H), 3.68 (t, J = 5.6 Hz, 2H), 3.01 (t, J = 5.4 Hz, 2H), 2.51 (d, J = 7.1 Hz, 2H), 2.05 - 1.96 (m, 1H), 1.61 (s, 4H), 1.49 (s, 9H), 0.99 - 0.96 (d, J = 6.7 Hz, 6H)

[0455] Step 2: N-(3-isobutylisoxazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 166) [ka] Following the procedure of Intermediate 96 and starting from Intermediate 165 (226 mg, 0.557 mmol) gave the title compound (143 mg, 0.418 mmol, 75%). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 6.31 (s, 1H), 4.41 (s, 2H), 3.15 (t, J = 5.2 Hz, 2H), 2.51 (d, J = 7.0 Hz, 2H), 2.05 - 1.96 (m, 1H), 0.97 (d, J = 6.6 Hz, 6H)

[0456] Step 3: N-(3-isobutylisoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 183) Following the procedure of Example 121, Step 3, starting from Intermediate 166 (52 mg, 0.152 mmol) and pyrazolo[1,5-a]pyrazine-3-carboxylic acid (25 mg, 0.152 mmol), the resulting residue was purified by preparative HPLC (Sunfire C18 3 × 50 mm, 3 μm 5–95% ACN / HO (10 mM NHCO), 1.7 ml / min, RT) to give the title compound (13.16 mg, 19.21%). LC-MS (ESI) Method 17: t R = 4.26 min; m / z [M + H] + = 451.4 1 H NMR (400 MHz, DMSO-d6) δ 11.77 - 11.77 (m, 1H), 9.36 (d, J = 1.4 Hz, 1H), 8.93 (dd, J = 1.4, 4.7 Hz, 1H), 8.56 (s, 1H), 8.34 (s, 1H), 8.11 (d, J = 4.8 Hz, 1H), 6.27 (s, 1H), 4.99 - 4.99 (m, 2H), 3.94 (t, J = 5.8 Hz, 2H), 3.10 - 3.05 (m, 2H), 2.47 (d, J = 7.2 Hz, 2H), 2.01 - 1.93 (m, 1H), 0.94 (d, J = 6.5 Hz, 6H)

[0457] Example 184: Preparation of compound N-(3-cyano-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: tert-Butyl 3-((3-cyano-5-(trifluoromethyl)phenyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Intermediate 167) [ka] Following the procedure of Example 47, Step 1, starting from 6-tert-butoxycarbonyl-5,7-dihydro-4H-thieno[2,3-c]pyridine-3-carboxylic acid (500 mg, 1.76 mmol) and 3-amino-5-(trifluoromethyl)benzonitrile (345 mg, 1.85 mmol), the title compound was precipitated in water to give (704 mg, 1.56 mmol, 88%). 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.33 - 8.32 (s, 1H), 8.17 - 8.15 (s, 1H), 7.64 (s, 2H), 4.58 - 4.56 (m, 2H), 3.69 (t, J = 5.6 Hz, 2H), 3.01 (t, J = 5.4 Hz, 3H), 1.57 (s, 9H)

[0458] Step 2: N-(3-cyano-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Intermediate 168) [ka] Following the procedure of Intermediate 86, starting from Intermediate 167 (704 mg, 1.56 mmol), the title product was precipitated with Et2O to give the HCl salt (596 mg, 1.54 mmol, 99%). 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.60 - 9.52 (m, 2H), 8.55 (d, J = 9.1 Hz, 3H), 8.10 (s, 1H), 4.44 (s, 2H), 3.43 (t, J = 5.8 Hz, 2H), (t, J = 5.8 Hz, 2H)

[0459] Step 3: N-(3-cyano-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 184) Following the procedure of Example 121, Step 3, starting from Intermediate 168 (75 mg, 0.213 mmol) and pyrazolo[1,5-a]pyrazine-3-carboxylic acid (35 mg, 0.213 mmol), the title compound was obtained by precipitation from water (63 mg, 0.126 mmol, 59%). LC-MS (ESI) Method 6: t R = 4.44 min; m / z [M + H] + = 497.5 1 H NMR (400 MHz, DMSO-d6) d 10.72 (s, 1H), 9.41 (s, 1H), 8.97 (d, J = 3.5 Hz, 1H), 8.61 (s, 1H), 8.52 - 8.47 (m, 2H), 8.30 (s, 1H), 8.15 (d, J = 4.0 Hz, 1H), 8.09 (s, 1H), 5.04 - 5.00 (m, 2H), 4.00 (s, 2H), 3.11 (s, 2H)

[0460] Example 185: Preparation of 6-(imidazo[1,2-a]pyridine-3-carbonyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide [ka] Step 1: 6-(tert-butyl) 3-ethyl 2-amino-4-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (Intermediate 169) [ka] To a solution of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (5000 mg, 23.4 mmol) in EtOH (50 mL) was added ethyl cyanoacetate (2.5 mL, 23.4 mmol), sulfur (750 mg, 23.4 mmol), and TEA (4.7 mL, 33.5 mmol). The reaction mixture was heated at reflux for 90 min. After cooling to RT and filtration, the residue was purified by FCC (0-50% EtOAc in cyclohexane) and triturated with cyclohexane to give the title compound (2540 mg, 7.46 mmol, 32%). 1 H NMR (400 MHz, CDCl3) δ 6.08 - 6.01 (s, 2H), 4.89-4.59 (m, 1H), 4.36 - 4.22 (m, 2H), 4.14 - 3.91 (m, 2H), 3.34-2.96 (m, 2H), 1.49 (s, 9H), 1.36 (t, J = 7.1 Hz, 3H), 1.17 (d, J = 6.8 Hz, 3H)

[0461] Step 2: 6-(tert-butyl) 3-ethyl 4-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (Intermediate 170) [ka] To a suspension of intermediate 169 (200 mg, 0.587 mmol) in 1,4-dioxane (2 mL) at −5 °C was added concentrated HCl (0.50 mL, 0.587 mmol), followed by the dropwise addition of 0.2 mL of aqueous sodium nitrite (45 mg, 0.646 mmol). The reaction mixture was stirred at −5 °C for 1 h and then added to 50% phosphoric acid solution (1.0 mL, 17.2 mmol) and EtO (1 mL). The reaction mixture was warmed to RT and stirred for 45 min. The reaction mixture was poured onto ice and extracted with DCM. The organic phase was filtered through a hydrophobic frit, the solvent was concentrated under reduced pressure, and the residue was purified by FCC (0–50% EtOAc in cyclohexane) to give the title compound (90 mg, 0.277 mmol, 47%). 1 H NMR (400 MHz, CDCl3) d 7.99 (s, 1H), 5.13-4.86 (m, 1H), 4.35 - 4.27 (m, 2H), 4.23 - 4.02 (m, 2H), 3.53 - 3.47 (m, 1H), 3.18 - 3.06 (m, 1H), 1.42 (s, 9H), 1.36 (t, J = 7.1 Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H)

[0462] Step 3: Ethyl 4-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 171) [ka] Following the procedure of Intermediate 86 and starting from Intermediate 170 (90 mg, 0.277 mmol), the title compound (60 mg, 0.229 mmol, 83%) was obtained. 1 H NMR (400 MHz, DMSO-d6) d 9.45 - 9.45 (m, 2H), 8.37 (s, 1H), 4.44 (d, J = 15.9 Hz, 1H), 4.37 - 4.28 (m, 3H), 3.61 - 3.54 (m, 1H), 1.35 (dd, J = 7.1, 7.1 Hz, 6H)

[0463] Step 4: Ethyl 6-(imidazo[1,2-a]pyridine-3-carbonyl)-4-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Intermediate 172) [ka] Following the procedure of Example 121, Step 3, starting from Intermediate 171 (60 mg, 0.229 mmol) and imidazo[1,2-a]pyridine-3-carboxylic acid (37 mg, 0.229 mmol), the title compound (73 mg, 0.178 mmol, 78%) was obtained. 1 H NMR (400 MHz, CDCl3) d 8.94 (d, J = 6.8 Hz, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.61 (d, J = 9.1 Hz, 1H), 7.31-7.25 (t, J = 7.2 Hz, 1H), 5.36 (d, J = 16.4 Hz, 1H), 4.63 - 4.48 (m, 2H), 4.28 - 4.21 (m, 2H), 3.55 (d, J = 3.5 Hz, 1H), 3.42 (d, J = 11.1 Hz, 1H), 1.32 - 1.26 (d, J = 7.1 Hz, 1H), 1.26-1.21 (d, J = 6.7 Hz, 3H)

[0464] Step 4: 6-(Imidazo[1,2-a]pyridine-3-carbonyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 185) To a solution of intermediate 172 (73 mg, 0.198 mmol) and 3-(trifluoromethyl)aniline (0.030 mL, 0.237 mmol) in THF (3 mL) at −40°C, 1.7 M tert-butyllithium solution in pentane (0.35 mL, 3.77 mmol) was added dropwise. The reaction mixture was warmed to RT and stirred overnight. The reaction was carefully quenched with aqueous NH₄Cl and extracted with DCM. The organic phase was filtered through a hydrophobic frit, and the solvent was concentrated under reduced pressure. The residue was purified by preparative HPLC (Sunfire C18 19 × 150 mm, 10 μm 20–80% ACN / H₂O (10 mM NH₄CO₃), 20 mL / min, RT) to give the title compound (19 mg, 0.0386 mmol, 20%). LC-MS (ESI) Method 6: t R = 4.79 min; m / z [M + H] + = 485.5 1 H NMR (400 MHz, DMSO-d6) d 10.48 (s, 1H), 8.96 (d, J = 7.0 Hz, 1H), 8.21 (s, 1H), 8.16 (d, J = 9.3 Hz, 2H), 8.00 (d, J = 8.2 Hz, 1H), 7.75 (m, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.51 - 7.45 (m, 2H), 7.13 - 7.09 (m, 1H), 5.32 (d, J = 16.7 Hz, 1H), 4.33 (d, J = 12.3 Hz, 1H), 3.58 - 3.56 (m, 3H), 1.18 (d, J = 6.8 Hz, 3H)

[0465] Example 186: Preparation of...

Claims

1. Formula (I) 【Chemical 1】 [During the ceremony, Rx, Ry and Rz are independently H or -(C １ -C ４ ) alkyl; L is -C(O)- and -CH ２ - selected from the group consisting of; Hy may be -(C １ -C ４ ) alkyl, halogen atom, cyano, —O—(C １ -C ４ ) alkyl, —O—(C １ -C ４ ) alkylene-OH, —O—(C １ -C ４ ) alkylene-O-(C １ -C ４ ) alkyl, —O—(C １ -C ４ ) alkylene-heterocycloalkyl, -(C １ -C ４ ) alkylene-NR ４ R ５ , -(C １ -C ６ ) haloalkyl and optionally one or more —(C １ -C ４ ) a bicyclic heteroaryl substituted with at least one substituent selected from the group consisting of heterocycloalkyl substituted with alkyl, or Hy is a bicyclic semi-saturated heteroaryl; R １ teeth: - Het may be - (C １ -C ４ ) alkyl, -(C １ -C ４ ) haloalkyl, optionally one or more -(C １ -C ６ ) cycloalkyl substituted with haloalkyl, —O—(C １ -C ４ ) haloalkyl, —O—(C １ -C ４ ) alkyl, -(C １ -C ４ ) alkylene-OH, -(C １ -C ４ ) alkylene-NR ４ R ５ , heterocycloalkyl, -(C １ -C ４ ) alkylene-aryl and heteroaryl substituted with one or more substituents selected from the group consisting of aryl and aryl, wherein the aryl is (C １ -C ４ ) substituted with one or more groups selected from alkyl and halogen atoms; -X 【Chemistry 2】 wherein: R ２ is H or —O(C １ -C ４ ) haloalkyl, halogen atom, —O-cycloalkyl and —(C １ -C ４ ) haloalkyl; R ３ is H or a halogen atom, cyano, optionally one or more -(C １ -C ４ ) alkyl-substituted heterocycloalkyl, -(C １ -C ４ ) alkylene-heterocycloalkyl, -(C １ -C ４ ) alkylene-heterocycloalkyl-(CH ２ ) ｎ -NR ４ R ５ , -(C １ -C ４ ) alkylene-NR ４ R ５ , -(C １ -C ４ ) alkylene-NR ４ R ６ , -O(C １ -C ４ ) alkyl, —O(C １ -C ４ ) haloalkyl, —O—(C １ -C ４ ) alkylene-OH, optionally -(C １ -C ４ ) alkyl-substituted heteroaryl, —O—(C １ -C ４ ) alkylene-NR ４ R ５ , -O-(C １ -C ４ ) alkylene-O-(C １ -C ４ ) alkyl, —O—(C １ -C ４ )alkylene-heterocycloalkyl and —O-heterocycloalkyl, wherein each of said heterocycloalkyls is optionally selected from the group consisting of —(C １ -C ４ ) alkyl, oxo, halogen atom, —C(O)—(C １ -C ４ ) substituted with one or more groups selected from alkyl and heterocycloalkyl; n is 0, 1 or 2; R ４ is H or -(C １ -C ４ ) alkyl; R ５ is H or -(C １ -C ４ ) alkyl; R ６ is -heterocycloalkyl, -(C １ -C ４ ) alkylene-O-(C １ -C ４ ) alkyl and -(C １ -C ４ ) alkylene-OH. or a pharmaceutically acceptable salt thereof.

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

3. L is -CH ２ -, wherein the formula (Iaa) 【Chemistry 5】 3. The compound of formula (Ia) of claim 2, represented by: or a pharmaceutically acceptable salt thereof.

4. 4. A compound of formula (Iaa) of claim 3, selected from the following: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 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; 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; 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; 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; 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide 6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-((1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-b]pyridazin-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyrazolo[1,5-a]pyrimidin-6-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-7-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-5-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-5-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 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; 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; (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]pyridine-3-carboxamide; (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]pyridine-3-carboxamide; (R)-6-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)—N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (R)—N-(3-((3-(dimethylamino)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; 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; 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; and 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.

5. L is —C(O)—, 【Chemistry 6】 3. The compound of formula (Ia) of claim 2, represented by: or a pharmaceutically acceptable salt thereof.

6. 6. A compound of formula (Iab) of claim 5, selected from the following: 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethoxy)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-fluoro-5-(trifluoromethoxy)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-((dimethylamino)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(morpholinomethyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 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; (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; (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; 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; 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; N-(3-((6-oxa-1-azaspiro[3.3]heptan-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-((2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-((3-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; 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; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((methyl(oxetan-3-yl)amino)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-(oxetan-3-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-((3-((dimethylamino)methyl)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; 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; 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; N-(3-((4-acetylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methyl-3-oxopiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(piperidin-1-ylmethyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(((2-methoxyethyl)(methyl)amino)methyl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(2-(4-methylpiperazin-1-yl)ethoxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((1-methylpyrrolidin-3-yl)oxy)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyrazine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-b]pyridazine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 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; 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; (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; (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; 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; (R)—N-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-cyano-5-(trifluoromethyl)phenyl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(6-((dimethylamino)methyl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(6-(2-hydroxyethoxy)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; (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-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(6-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(6-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(morpholinomethyl)-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-morpholino-5-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-morpholino-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-cyano-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; and N-(3-(hydroxymethyl)-5-(trifluoromethyl)phenyl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide.

7. R １ is Het, 【Chemistry 7】 2. The compound of formula (I) of claim 1, represented by: or a pharmaceutically acceptable salt thereof.

8. L is —C(O)—, 【Chemistry 8】 8. The compound of formula (Ib) of claim 7, represented by: or a pharmaceutically acceptable salt thereof.

9. 9. A compound of formula (Ibb) of claim 8 selected from the following: or a pharmaceutically acceptable salt thereof: N-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 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; 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; 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; 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; 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; N-(5-(tert-butyl)isoxazol-3-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)isoxazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-cyclobutyl-1-methyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(2-(tert-butyl)pyridin-4-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-isopropyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(1-methyl-3-propyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(1-benzyl-3-(tert-butyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-ethyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-isobutyl-1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(4-(tert-butyl)oxazol-2-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-(2-hydroxyethyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(7-methylimidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(6-methylimidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-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; N-(3-(tert-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; N-(3-(tert-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; N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 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; 6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 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; N-(3-(tert-butyl)isoxazol-5-yl)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)isoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(1-methyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(5-(1,1-difluoroethyl)pyridin-3-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(5-(tert-butyl)pyridin-3-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 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; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(tert-pentyl)isoxazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 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; N-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(5-(1,1-difluoroethyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(5-(tert-butyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 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; N-(5-(difluoromethoxy)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyrazolo[1,5-a]pyrazine-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; 6-(imidazo[1,2-a]pyrazine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-N-(5-(trifluoromethoxy)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 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; 6-(5-methoxypyrazolo[1,5-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyrazolo[5,1-b]thiazole-7-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 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; 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; 6-(7-fluoroimidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-6-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)isoxazol-5-yl)-6-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridazin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(5-(tert-butyl)isoxazol-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-pentyl)isoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-isobutylisoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; and 6-(Imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethoxy)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide.

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

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

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

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

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

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

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

17. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising: a) Intermediate IIb 【Chemistry 9】 to give intermediate VIIb by amide coupling 【Chemistry 10】 Obtaining; b) deprotecting the BOC group from intermediate VIIb to give intermediate VIIIb 【Chemistry 11】 Obtaining; c) amide coupling of intermediate VIIIb with an appropriate acid to give a compound of formula (I); The process includes the steps of: wherein the compound of formula (I) 【Chemistry 12】 where: Rx, Ry and Rz are independently H; L is selected from the group consisting of —C(O)— and —CH 2 —; Hy is a bicyclic heteroaryl optionally substituted with at least one substituent selected from the group consisting of -(C1-C4)alkyl, halogen, 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 heterocycloalkyl optionally substituted with one or more -(C1-C4)alkyl, or Hy is a bicyclic semi-saturated heteroaryl; R 1 is: Het is optionally substituted by —(C 1 -C 4 )alkyl, —(C 1 -C 4 )haloalkyl, cycloalkyl optionally substituted by one or more —(C 1 -C 6 )haloalkyl, —O—(C 1 -C 4 )haloalkyl, —O—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylene-OH, —(C 1 -C 4 )alkylene-NR 4 R 5 , heterocycloalkyl, —(C 1 -C 4 )alkylene-aryl, and aryl, wherein the aryl is optionally substituted by one or more groups selected from —(C 1 -C 4 )alkyl and halogen atoms; and -X 【Chemistry 13】 wherein: R 2 is H or selected from the group consisting of —O(C 1 -C 4 )haloalkyl, a halogen atom, —O-cycloalkyl, and —(C 1 -C 4 )haloalkyl; R 3 is H or a halogen atom, cyano, heterocycloalkyl optionally substituted with one or more —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylene-heterocycloalkyl, —(C 1 -C 4 )alkylene-heterocycloalkyl-(CH 2 ) n —NR 4 R 5 , —(C 1 -C 4 )alkylene-NR 4 R 5 , —(C 1 -C 4 )alkylene-NR 4 R 6 , —O(C 1 -C 4 )alkyl, —O(C 1 -C 4 )haloalkyl, —O—(C 1 -C 4 )alkylene-OH, heteroaryl optionally substituted with —(C 1 -C 4 )alkyl, —O—(C 1 -C 4 )alkylene-NR 4 R 5 is selected from the group consisting of —O—(C 1 -C 4 )alkylene-O—(C 1 -C 4 )alkyl, —O—(C 1 -C 4 )alkylene-heterocycloalkyl, and —O-heterocycloalkyl, wherein each of said heterocycloalkyls is optionally substituted with one or more groups selected from —(C 1 -C 4 )alkyl, oxo, halogen atoms, —C(O)—(C 1 -C 4 )alkyl, and heterocycloalkyl; n is 0, 1 or 2; R 4 is H or —(C 1 -C 4 )alkyl; R 5 is H or —(C 1 -C 4 )alkyl; R 6 is selected from the group consisting of -heterocycloalkyl, -(C 1 -C 4 )alkylene-O-(C 1 -C 4 )alkyl, and -(C 1 -C 4 )alkylene-OH; method.

18. Step a) is the following reaction 【Chemistry 14】 wherein Het, R 1 , R 2 , R 3 are as defined in claim 17; The reaction is carried out in the presence of chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) and 1-methylimidazole to give a transiently activated acylimidazolinium intermediate, which is reacted with the appropriate amine XIIb or XIIIb in a solvent such as N,N-dimethylformamide (DMF) at room temperature.

18. The method of claim 17.

19. The method of claim 17 or 18, wherein the amide coupling in step c) is carried out in the presence of 1.20 to 2.00 equivalents of (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate (HATU).

20. The method of any of claims 17 to 19, wherein the amide coupling in step c) is carried out in N,N-dimethylformamide / dichloromethane (DMF / DCM) as a solvent at a concentration of 0.1 M.

21. The amide coupling of step c) is carried out by adding 3.00 to 8.00 equivalents of N,N-diisopropylethylamine (DIPEA) followed by addition of amine XIIIb with stirring at room temperature; wherein amine XIIIb is Het-NH 2 ; Het is as defined in claim 17; The method of any one of claims 17 to 20.

22. A method for producing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 17 to 21, wherein in the compound of formula (I), Formula (Ib) wherein R 1 is Het 【Chemistry 15】 The method is represented by:

23. A method for producing a compound of formula (Ib) according to claim 22, wherein L is -C(O)- and the compound of formula (Ibb) 【Chemistry 16】 The method is represented by:

24. A method for preparing a compound of formula (Ibb) of claim 23, wherein the compound of formula (Ibb) is selected from the following: N-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 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; 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; 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; 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; 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; N-(5-(tert-butyl)isoxazol-3-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)isoxazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-cyclobutyl-1-methyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(2-(tert-butyl)pyridin-4-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-isopropyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(1-methyl-3-propyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(1-benzyl-3-(tert-butyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-ethyl-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-isobutyl-1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(4-(tert-butyl)oxazol-2-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-(2-hydroxyethyl)-1H-pyrazol-5-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(7-methylimidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(6-methylimidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-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; N-(3-(tert-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; N-(3-(tert-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; 6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 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; 6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 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; N-(3-(tert-butyl)isoxazol-5-yl)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)isoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(1-methyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(5-(1,1-difluoroethyl)pyridin-3-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(5-(tert-butyl)pyridin-3-yl)-6-(imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 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; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(tert-pentyl)isoxazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 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; N-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(5-(1,1-difluoroethyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(5-(tert-butyl)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 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; N-(5-(difluoromethoxy)pyridin-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyrazolo[1,5-a]pyrazine-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; 6-(imidazo[1,2-a]pyrazine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-N-(5-(trifluoromethoxy)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 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; 6-(5-methoxypyrazolo[1,5-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(pyrazolo[5,1-b]thiazole-7-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 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; 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; 6-(7-fluoroimidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-6-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-butyl)isoxazol-5-yl)-6-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; 6-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethyl)pyridazin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(5-(tert-butyl)isoxazol-3-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-(tert-pentyl)isoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; N-(3-isobutylisoxazol-5-yl)-6-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide; and 6-(Imidazo[1,2-a]pyridine-3-carbonyl)-N-(5-(trifluoromethoxy)pyridin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide.

25. Intermediate compound VIIb: 【Chemistry 17】 wherein R 1 is as defined in claim 17.

26. Intermediate compound VIIIb 【Chemistry 18】 wherein R 1 is as defined in claim 17.

27. ​​Formula (I) 【Chemistry 19】 [In the formula, Rx, Ry, Rz, L, Hy, and R 1 are as defined in claim 17.] 26. Use of intermediate compound VIIb of claim 25 for the preparation of a compound of formula:

28. Formula (I) 【Chemistry 20】 [In the formula, Rx, Ry, Rz, L, Hy, and R 1 are as defined in claim 17.] 27. Use of intermediate compound VIIIb of claim 26 for the preparation of a compound of formula:

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