Heteroaryl derivatives as DDR inhibitors

Abstract

The present invention relates to compounds of formula (I) that inhibit discoidin domain receptors (DDR inhibitors), to methods for preparing such compounds, to intermediate compounds useful in such preparations, to pharmaceutical compositions containing them, and to their therapeutic uses. The compounds of the present invention may be useful, for example, in the treatment of a number of disorders associated with DDR mechanisms. JPEG2025525570000235.jpg45105

Description

[Technical Field]

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

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

[0003] 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 stable dimers in a non-covalently bound, ligand-dependent manner (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 found to be involved in a range of diseases, including pulmonary fibrosis, and in particular idiopathic pulmonary fibrosis (IDF). The first evidence for a protective role of DDR1 deficiency 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, these animals exhibited significantly reduced myofibroblast proliferation and apoptosis compared with wild-type mice. Bronchoalveolar lavage cell counts and cytokine ELISA confirmed that the knockout mice lacked inflammation. These results indicated that DDR1 expression is required for the development of pulmonary inflammation and fibrosis.

[0007] DDR2 deficiency or downregulation reduces bleomycin-induced pulmonary fibrosis (Zhao H, Bian H, Bu X, Zhang S, Zhang P, Yu J, et al. Mol Ther 2016;24:1734-1744). Zhao et al. demonstrated that DDR2 plays an important role in inducing pulmonary fibrosis and angiogenesis, particularly by synergizing with transforming growth factor (TGF)-β to induce myofibroblast differentiation. Furthermore, they demonstrated that treating injured mice with specific siRNA against DDR2 demonstrated therapeutic efficacy against pulmonary fibrosis. In a second publication, Jia et al. demonstrated that DDR2-deficient mice were protected from bleomycin-induced pulmonary fibrosis (Jia S, Am J Respir Cell Mol Biol 2018;59:295-305). Furthermore, DDR2-null fibroblasts were significantly more prone to apoptosis than wild-type fibroblasts, supporting the case that apoptosis-resistant fibroblasts are important for the progression of fibrosis.

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

[0009] In particular, antagonism of DDR receptors may be useful in treating fibrosis and diseases, disorders, and conditions resulting from fibrosis. Furthermore, antagonism of both DDR1 and DDR2 receptors may be particularly effective in treating the above diseases, disorders, and conditions.

[0010] Several efforts have been made in the past few years 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. However, there is potential to develop selective inhibitors of both the DDR1 and DDR2 receptors, which are administered via the inhalation route and feature a favorable inhalation profile corresponding to good activity in the lungs, good lung retention, and low metabolic stability, which are useful for the treatment of diseases, disorders, or conditions associated with DDR receptor dysregulation in the respiratory field, particularly idiopathic pulmonary fibrosis (IPF), in order to minimize systemic exposure and associated safety issues.

[0011] To this end, it has been surprisingly found that a novel series of compounds of general formula (I) shown below solves the problem of providing DDR1 and DDR2 receptor inhibitors for inhaled administration that act as selective inhibitors of the DDR1 and DDR2 receptors with respect to other human protein kinases. Such compounds exhibit high efficacy, a good inhalation profile, low metabolic stability, low systemic exposure, improved safety and tolerability. Summary of the Invention

[0012] In a first aspect, the present invention provides a compound of formula (I): [ka] [During the ceremony, A is: [ka] wherein [ka] indicates a direct bond to NH; W1 and W2 are substituents of ring A selected from the group consisting of hydrogen, halogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, R1R2N-(C1-C4) alkyl and (C3-C6) cycloalkyl, preferably selected from H, CH3, OCH3, OCF3, CF3, C(CH3)3, CH2CH3, C(CH3)2CF3, OCF2H, CHF2, CH2CF3, CH2N(CH3)2 and cyclopropyl; Z is selected from the group consisting of (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, hydroxy, and (C3-C6) cycloalkyl, preferably selected from CH3, CF2H, OCH3, CH2OH, and cyclopropyl; L is [ka] (In the formula, [ka] indicates a direct bond to the phenyl, [ka] indicates a direct bond to B) selected from the group consisting of: B is a monocyclic or bicyclic heteroaryl ring, preferably selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyrazolo[1,5-a]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyridinyl, thieno[3,2-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl and pyrazolyl; Y1 and Y2 are hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)alkoxy-(C1-C4)alkoxy, hydroxy-(C1-C4)alkoxy, hydroxy-(C1-C4)alkyl, (C1-C4)alkyl-heterocycloalkyl-(C0-C4)alkoxy, (C1-C4)haloalkoxy, halogen, cyano, cyano-(C1-C4)alkyl, cyano-(C1-C4)alkyl-heterocycloalkyl, CONR1R2, NHCOR1, NR1R2, R1R2N-(C1-C4)alkyl, heterocycloalkyl, (C1-C4)alkyl-heterocycloalkyl substituents on Ring B independently selected from the group consisting of cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, (C1-C4)alkyl-heterocycloalkyl-carbonyl, (C0-C4)alkyl-heterocycloalkyl-carbonyl, (C1-C4)alkyl-phenyl, and monocyclic (C1-C4)alkyl-heteroaryl, where Y1 is preferably selected from CONH2, CF2H, OCH3, cyano, Br, NHCOCH3, NH2, 4-methylpiperazine-1-carbonyl, 4-methylpiperazin-1-yl, and 1-methyl-1H-pyrazol-4-yl, and Y2 is preferably hydrogen; R1 and R2 are independently selected from the group consisting of hydrogen, (C1-C4) alkyl, (C1-C4) hydroxyalkyl, (C1-C4) alkoxy(C1-C4) alkyl, (C1-C4) alkylamino-(C1-C4) alkyl, di-(C1-C4) alkylamino-(C1-C4) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted heterocycloalkyl-(C1-C4) alkoxy, wherein any substituent is one or more and is selected from the group consisting of (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, hydroxy, and (C1-C4) haloalkoxy; wherein R1 and R2 are preferably selected from the group consisting of CH2CH2N(CH3)2, CH2CHOCH3, CH3, CH2CH2OH, oxetan-3-yl, and 3-hydroxycyclobutyl; R4 is selected from hydroxy and hydroxymethyl. or stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

[0013] In a second aspect, the present invention refers to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in admixture with at least one or more pharmaceutically acceptable carriers and / or excipients.

[0014] In a third aspect, the invention refers to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0015] In a further aspect, the present invention refers to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising 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 DDR dysregulation.

[0016] In another aspect, the present invention refers to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of fibrosis and / or a disease, disorder or condition in which fibrosis is involved.

[0017] In yet another aspect, the present invention refers to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of idiopathic pulmonary fibrosis (IPF).

[0018] In a further aspect, the present invention refers to methods for preparing compounds of formula (I) and intermediate compounds useful in preparing compounds of formula (I).

[0019] Detailed Description of the Invention definition Unless otherwise specified, the compounds of formula (I) of the present invention are intended to include stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

[0020] Unless otherwise specified, the compounds of formula (I) of the present invention are intended to include compounds of formula (Ia), (Ia'), (Ia''), (Ib) and (Ib1).

[0021] 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 any free acidic or basic group, if any, into any base or acid corresponding addition salt thereof that is conventionally considered to be pharmaceutically acceptable. Suitable examples of such salts 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 carboxyl groups.

[0022] Cations of inorganic bases which may be suitably used to prepare salts include ions of alkali metals or alkaline earth metals such as potassium, sodium, calcium or magnesium.

[0023] Salts obtained by reacting a compound with an inorganic or organic acid, with the primary compound acting as a base, include, for example, hydrochlorides, hydrobromides, sulfates, phosphates, methanesulfonates, camphorsulfonates, acetates, oxalates, maleates, fumarates, succinates, and citrates.

[0024] 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.

[0025] The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are not superimposable.

[0026] The terms "racemate" or "racemic mixture" refer to a composition of equimolar amounts of two enantiomeric species, lacking optical activity.

[0027] As used herein, the term "halogen" or "halogen atom" or "halo" includes fluorine, chlorine, bromine, and iodine atoms.

[0028] The term "(C x -C y "(C1-C4)alkyl" refers to a straight or branched chain alkyl group having from x to y carbon atoms. Thus, when x is 1 and y is 4, for example, the term "(C1-C4)alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Such groups are also designated herein by their atom arrangement, i.e., CH3, CH2CH3, etc.

[0029] The term "(C x -C y ")Haloalkyl" refers to a straight or branched chain alkyl group containing at least one halogen substituent having x to y carbon atoms. Examples include CF3, C(CH3)2CF3, and OCF2H.

[0030] The term "(C x -C y "(C1-C4)alkoxy" refers to a straight or branched chain alkyl group having x to y carbon atoms containing at least one oxygen atom, particularly, but not limited to, an oxygen atom directly bonded to Ring A or Ring B or a phenyl ring, i.e., when W, Y, or Z is, respectively, (C1-C4)alkoxy. Examples include OCH3 and OCH2CH3.

[0031] The term "(C x -C y )haloalkoxy" refers to an alkoxy group containing at least one halogen substituent (C x -C y)alkoxy. Examples include OCF3 and OCF2H.

[0032] The term "(C x -C y )hydroxyalkyl" refers to a group containing at least one hydroxy substituent (C x -C y ) alkyl. Examples include CH2OH, CH(OH)CH3, and CH2CH2OH.

[0033] The term “(C x -C y ")Cycloalkyl" refers to a saturated hydrocarbon containing x to y ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0034] The term "monocyclic or bicyclic heteroaryl ring" refers to a monocyclic or bicyclic aromatic group containing 1 to 3 heteroatoms independently selected from N, S, and O, and includes groups having two such monocyclic rings or one such monocyclic ring and one monocyclic aryl ring, e.g., a phenyl ring, which are fused together by a common bond or linked by a single bond.Monocyclic or bicyclic heteroaryl rings include pyrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyridazinyl, imidazolyl, benzofuranyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, benzothiophenyl, benzo[c]thiophenyl, quinazolinyl, pteridinyl, 1H-pyrazolo[5,1-c][1,2,4]triazolyl, pyrrolidinyl, indolizinyl, benzothiazolyl, pyrazolo[5,1-b]thiazolyl, 1H-imidazo[1,2-b] Pyrazolyl, 1H-pyrazolo[3,4-b]pyridinyl, 1,6-dihydropyrrolo[2,3-b]pyrrolyl, 1,4-dihydropyrrolo[3,2-b]pyrrolyl, 4H-thieno[3,2-b]pyrrolyl, isobenzofuranyl, 1,2,4-triazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, tetrazolyl, 6H-furo[2,3-b]pyrrolyl, 6H-thieno[2,3-b]pyrrolyl, 4H-furo[3,2-b]pyrrolyl, benzo[d ]isothiazolyl, thiazolo[4,5-b]pyridinyl, 1,3,5-triazinyl, 1,2,3,4-thiatriazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,4-tetrazinyl, 1,2,4,5-tetrazinyl, 1,2,3,5-tetrazinyl, 1H-imidazo[4,5-b]pyridinyl, 7H-purinyl, 1H-pyrrolyl, 1-methyl-1H-pyrrolyl, 1-methyl-1H-1,2,4-triazolyl, 1-methyl-1H-tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, These include midazo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, thieno[3,2-d]pyrimidinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazinyl, furo[3,2-d]pyrimidin-4-yl and pyrazolo[1,5-a]pyrimidinyl.

[0035] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, or spirocyclic ring system of 3 to 12 atoms containing one or more heteroatoms independently selected from N, S, and O. Examples of heterocycloalkyl include piperazinyl, pyrrolidinyl, azetidinyl, morpholinyl, and piperidinyl.

[0036] The term "spirocyclic ring system" refers to a saturated or partially unsaturated bicyclic ring system of 5 to 12 atoms containing one or more heteroatoms independently selected from N, S, and O, in which the two rings have only one atom in common.

[0037] Any compound term, such as "(C-C) alkyl-heterocycloalkyl-carbonyl," is intended to be understood conventionally with the moieties from which it is derived, e.g., (C-C) alkyl, heterocycloalkyl, and carbonyl groups, joined together in the order shown, with the carbon atom of the carbonyl group being the point of attachment to the remainder of the compound of formula (I).

[0038] When referring to a substituent, a dash (“-”) that is not between two letters, words or symbols is meant to represent a point of attachment to such substituent.

[0039] Carbonyl groups are preferably represented herein as CO or other common designations such as -C(O)-, -CO-, -(CO)- or -C(=O)-.

[0040] Whenever a basic amino group is present in the compound of formula (I), a physiologically acceptable anion will be present and may be selected from chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate, and naphthalenedisulfonate. Similarly, when an acidic group is present, the corresponding physiological cation may also be present, and these include, for example, alkali metal ions or alkaline earth metal ions.

[0041] The term "Ki" refers to the dissociation constant for the enzyme-inhibitor complex, which is expressed in molar units. It is an indicator of the binding affinity of the inhibitor to the DDR1 or DDR2 receptor.

[0042] As mentioned above, the present invention refers to a series of compounds represented by general formula (I) as detailed herein below, which have inhibitory activity against receptors DDR1 and DDR2. Antagonism against receptors DDR1 and DDR2 can be particularly effective in treating diseases in which DDR receptors play a role, such as fibrosis and any other diseases, disorders and conditions in which fibrosis is associated.

[0043] In fact, as described in the experimental section below, the compound of formula (I) of the present invention can act as an inhibitor of both DDR1 and DDR2 receptors in a substantial and effective manner.In particular, the following Table 3 shows that the inhibitory activity (expressed as Ki) of representative compounds of the present invention against DDR1 and DDR2 receptors in binding assays is less than 100nM.This indicates that the two isoforms of DDR receptors that are mainly involved in fibrosis and diseases resulting from fibrosis can be inhibited.Therefore, the compound of formula (I) can be used to treat fibrosis, particularly pulmonary fibrosis, when DDR1 and DDR2 are involved.

[0044] As shown in the Comparative Examples section of the Experimental Section, and in particular in Table 4, in contrast to Comparative Example compound C1, which is characterized by having a -CH2- linker between L and heteroaryl ring B, the presence of a direct bond between L and heteroaryl ring B in the compounds of the present invention unexpectedly and significantly determines an associated increase in inhibitory activity against DDR1 and DDR2 receptors.

[0045] Furthermore, as shown in the same part section, in contrast to Comparative Example C2, which is characterized by the replacement of heteroaryl ring B with an alkyl group, the presence of such heteroaryl ring B in the compounds of the present invention unexpectedly and significantly determines an associated increase in inhibitory activity against DDR1 and DDR2 receptors.

[0046] Advantageously, the compounds of the present invention have extremely high efficacy and can be administered to humans at lower doses relative to compounds described in the prior art, thereby reducing the adverse events typically associated with the administration of higher doses of drugs.

[0047] In addition to their remarkable potency in terms of inhibitory activity on both the DDR1 and DDR2 receptors, the compounds of the present invention are also characterized as selective inhibitors of the DDR1 and DDR2 receptors for other human protein kinases, with a favorable inhalation profile that allows them to act efficiently in the pulmonary compartment while minimizing drawbacks related to systemic exposure, such as safety and tolerability issues.

[0048] The compounds of the present invention are therefore useful in the treatment of fibrosis, in particular idiopathic pulmonary fibrosis, and may be particularly appreciated when focusing on suitable and effective compounds 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, minimizing systemic exposure and associated safety issues.

[0049] Thus, the present invention provides a compound of formula (I): [ka] [During the ceremony, A is: [ka] wherein [ka] indicates a direct bond to NH; W1 and W2 are substituents of Ring A selected from the group consisting of hydrogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, R1R2N-(C1-C4) alkyl, and (C3-C6) cycloalkyl; Z is selected from the group consisting of (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, hydroxy, and (C3-C6) cycloalkyl; L is [ka] (In the formula, [ka] indicates a direct bond to the phenyl, [ka] indicates a direct bond to B) selected from the group consisting of: B is a monocyclic or bicyclic heteroaryl ring; Y1 and Y2 are independently hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)alkoxy-(C1-C4)alkoxy, hydroxy-(C1-C4)alkoxy, hydroxy-(C1-C4)alkyl, (C1-C4)alkyl-heterocycloalkyl-(C0-C4)alkoxy, (C1-C4)haloalkoxy, halogen, cyano, cyano-(C1-C4)alkyl, cyano-(C1-C4)alkyl-heterocycloalkyl alkyl, CONR1R2, NHCOR1, NR1R2, R1R2N—(C1-C4)alkyl, heterocycloalkyl, (C1-C4)alkyl-heterocycloalkyl, heterocycloalkyl-(C1-C4)alkyl, (C1-C4)alkyl-heterocycloalkyl-carbonyl, (C0-C4)alkyl-heterocycloalkyl-carbonyl(C1-C4)alkyl-phenyl, and monocyclic (C1-C4)alkyl-heteroaryl; R1 and R2 are independently selected from the group consisting of hydrogen, (C1-C4) alkyl, (C1-C4) hydroxyalkyl, (C1-C4) alkoxy(C1-C4) alkyl, (C1-C4) alkylamino-(C1-C4) alkyl, di-(C1-C4) alkylamino-(C1-C4) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted heterocycloalkyl-(C1-C4) alkoxy, wherein any substituent is one or more and is selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, and (C1-C4) haloalkoxy; R4 is selected from hydroxy and hydroxymethyl. or stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

[0050] All of the recited meanings of each of the variables A, B, L, Z, W1, W2, Y1, Y2, R1, R2 and R4 of the compounds of formula (I) of the present invention are intended to be alternatives and can be combined with each other in embodiments within the scope of the present invention.

[0051] Preferred halogens in the (C1-C4)haloalkyl and (C1-C4)haloalkoxy substituents are fluorine and chlorine, with fluorine being more preferred.

[0052] W1 and W2 are substituents of ring A that may be attached to A at any available position. W1 and W2 are preferably selected from the group consisting of H, F, CH3, OCH3, OCF3, CF3, C(CH3)3, CH2CH3, C(CH3)2CF3, OCF2H, CHF2, CH2CF3, CH2N(CH3)2 and cyclopropyl.

[0053] Z is preferably selected from the group consisting of CH3, CF2H, OCH3, CH2OH and cyclopropyl.

[0054] L is [ka] is selected from the group consisting of:

[0055] In a preferred embodiment, L is [ka] is selected from the group consisting of:

[0056] B is a monocyclic or bicyclic heteroaryl ring, preferably selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyrazolo[1,5-a]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyridinyl, thieno[3,2-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, and pyrazolyl. Particularly preferred B rings are pyridin-3-yl, pyrimidin-5-yl, pyrazinyl, pyrazolo[1,5-a]pyridin-3-yl, pyrazolo[1,5-a]pyrazin-3-yl, pyrazolo[1,5-a]pyrimidin-3-yl, imidazo[1,2-a]pyrazin-3-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl and imidazo[1,2-b]pyridazin-3-yl.

[0057] Y1 is a substituent of ring B that can be attached to B at any available position.

[0058] Y1 is preferably hydrogen, (C1-C4)haloalkyl, (C1-C4)alkoxy, cyano, CONR1R2, NHCOR1, NR1R2, (C1-C4)alkyl-heterocycloalkyl-carbonyl, and monocyclic (C1-C4)alkyl-heteroaryl, where preferred monocyclic heteroaryl is selected from the group consisting of pyrazolyl. Y1 is more preferably selected from the group consisting of CONH2, CF2H, OCH3, cyano, NHCOCH3, NH2, 4-methylpiperazine-1-carbonyl, 4-methylpiperazin-1-yl, and 1-methyl-1H-pyrazol-4-yl.

[0059] Y2 is a substituent of ring B which may be bonded to B at any available position. In preferred embodiments, Y2 independently has the same preferred meaning as Y1, where more preferably Y2 is hydrogen.

[0060] R1 and R2 are independently preferably selected from the group consisting of CH2CH2N(CH3)2, CH2CH2OCH3, CH3, CH2CH2OH, oxetan-3-yl and 3-hydroxycyclobutyl.

[0061] The optional substituents on R1 and / or R2 are one or more, preferably 1 to 3, selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl and (C1-C4) haloalkoxy, preferably selected from the group consisting of CH3, OCH3, OCF3, CF3, CF2H, C(CH3)3, C(CH3)2CF3 and OCF2H.

[0062] Thus, in a preferred embodiment, the present invention comprises: A: [ka] is a ring selected from the group consisting of: W1 and W2 are independently selected from the group consisting of H, CH3, OCH3, OCF3, CF3, C(CH3)3, CH2CH3, C(CH3)2CF3, OCF2H, CHF2, CH2CF3, CH2N(CH3)2 and cyclopropyl; Z is selected from the group consisting of CH3, CF2H, OCH3, CH2OH, and cyclopropyl; L [ka] or [ka] selected from the group consisting of: B is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyrazolo[1,5-a]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyridinyl, thieno[3,2-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, and pyrazolyl; Y1 is selected from the group consisting of hydrogen, (C1-C4)haloalkyl, (C1-C4)alkoxy, cyano, CONR1R2, NHCOR1, NR1R2, (C1-C4)alkyl-heterocycloalkyl-carbonyl, and monocyclic (C1-C4)alkyl-heteroaryl; more preferably selected from the group consisting of CONH2, CF2H, OCH3, cyano, NHCOCH3, NH2, 4-methylpiperazine-1-carbonyl, and 4-methylpiperazin-1-yl; and Y2 is hydrogen; R1 and R2 are independently selected from the group consisting of CH2CH2N(CH3)2, CH2CH2OCH3, CH3, CH2CH2OH, oxetan-3-yl, and 3-hydroxycyclobutyl; R4 is hydroxy or hydroxymethyl; Compounds of formula (I) and stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.

[0063] In another preferred embodiment, the present invention provides a compound in which L is C [ka] Formula (Ia) [ka] (wherein W1, W2, A, Z, B, Y1 and Y2 are as defined above.) The present invention relates to compounds of formula (I) represented by:

[0064] The compounds of formula (Ia) contain a stereogenic center which is the carbon atom of the pyrrolidine ring attached to the phenyl moiety. In a preferred embodiment of the compounds of formula (Ia), the stereogenic center has the S configuration, and therefore the preferred C moiety is C*: [ka] wherein W1, W2, A, Z, Y1, and Y2 are as defined above. is.

[0065] In yet another preferred embodiment, the present invention relates to compounds of formula (I), designated compounds of formula (Ib), wherein L is [ka] wherein W1, W2, A, Z, B, Y1, and Y2 are as defined above. is selected from.

[0066] Particularly preferred embodiments of the present invention are the compounds of formula (Ia) and pharmaceutically acceptable salts thereof, as listed below in Table 1. These compounds are particularly active against the receptors DDR1 and DDR2, as further shown below in Table 3.

[0067] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14]

[0068] In a particularly preferred embodiment, the present invention relates to compounds of formula (Ib1) wherein L is E: [ka] is.

[0069] Further particularly preferred embodiments of the present invention are the compounds of formula (Ib1) and pharmaceutically acceptable salts thereof listed in Table 2 below. These compounds are particularly active against the receptors DDR1 and DDR2, as further shown in Table 3 below.

[0070] [Table 2]

[0071] The compounds of the present invention, including all of the compounds listed above, can be prepared from readily available starting materials using the following general methods and procedures, or by using slightly modified methods readily available to those of ordinary skill in the art. While specific embodiments of the present invention are shown or described below, those of ordinary skill in the art will understand that all embodiments or aspects of the present invention can be obtained using the methods described herein, or by using other methods, reagents, and starting materials. Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used, unless otherwise specified. Where optimal reaction conditions can vary with the particular reactants or solvents used, such conditions can be readily determined by one of ordinary skill in the art by routine optimization procedures. Therefore, the processes described below should not be construed as limiting the scope of synthetic methods available for preparing the compounds of the present invention.

[0072] 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 the general rules of chemistry (Protective groups in organic syntheses, 3rd ed. T.W. Greene, P.G.M. Wuts).

[0073] In Schemes 1-7, compounds of Formula (I) can be prepared as described below, and at least one non-limiting synthetic route is provided for preparing the exemplified compounds (i.e., example compounds).

[0074] Compounds of formula (Ia) above can generally be prepared by the methods outlined in Schemes 1 to 16 below. Scheme 1 [ka]

[0075] Compounds of formula (Ia) can be obtained, for example, starting from commercially available compound (II) as described in Scheme 1, where Z is as defined above except for hydroxy, and R is (C-C) alkyl, preferably ethyl. Compounds of formula (III) can be prepared from compounds of formula (II) by palladium-catalyzed cross-coupling. The reaction can be carried out by reacting compounds of formula (II) with potassium alkyltrifluoroborate in a suitable organic solvent, such as dioxane, in the presence of an inorganic base, such as cesium carbonate, using a suitable palladium catalyst system, such as Pd(dppf)Cl, at elevated temperature (about 100°C) for several hours, following the standard Suzuki protocol. The 1,3-dipolar cycloaddition can be carried out by reaction of the α,β-unsaturated compound of formula (III) with a suitable precursor such as a 1,3-dipole or azomethine ylide, for example, N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine, in a solvent such as dioxane, under acid catalysis, for example, with TFA, as shown in Scheme 1. The compound of formula (IV) can be converted to the debenzylated compound of formula (V) by reduction under a hydrogen atmosphere, typically at 4 bar pressure, in the presence of a suitable catalyst, such as Pd / C, in a suitable solvent, such as, but not limited to, EtOH, at temperatures ranging from rt to 60° C. for several hours.

[0076] The Boc-protected compound of formula (VI) can be prepared by reacting the compound of formula (V) with di-tert-butyl-dicarbonate under basic conditions using an organic base such as TEA in a suitable solvent such as dichloromethane. Compounds of formula (IV), (V), and (VI) contain a stereogenic center, which is the carbon atom of the pyrrolidine ring attached to the phenyl moiety. These compounds are obtained as racemic mixtures. Separation of the racemic mixture of compounds of formula (VI) can be achieved by chiral resolution methods such as chiral purification. Both enantiomers of the compound of formula (Ia) are within the scope of the present invention.

[0077] Accordingly, the present invention provides a process for preparing a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, comprising: a) Formula (III) [ka] and N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine [ka] is reacted in the presence of a solvent under an acid catalyst to obtain a compound of formula (IV) [ka] wherein R and Z are as defined above. to obtain the intermediate compound The process includes:

[0078] In a preferred embodiment, the method further comprises: b) cleaving the benzyl group of the intermediate compound of formula (IV) by reduction under a hydrogen atmosphere in the presence of a Pd catalyst to give a compound of formula (V): [ka] to obtain an intermediate compound of c) Boc-protection of the free nitrogen of the compound of formula (V) by reaction with di-tert-butyl-dicarbonate to give the compound of formula (VI) [ka] A step of obtaining an intermediate compound of include.

[0079] The process of the present invention further comprises converting the intermediate compound of formula (VI) to a compound of formula (Ia).

[0080] Thus, the present invention provides a compound of formula (IV) [ka] wherein R is (C1-C4) alkyl, preferably ethyl, and Z is selected from the group consisting of (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, and (C3-C6) cycloalkyl. The present invention provides an intermediate compound of the formula:

[0081] The present invention further provides the use of an intermediate compound of formula (IV) as defined above in the preparation of a compound of formula (Ia).

[0082] The present invention also relates to compounds of formula (VI) in racemic or enantiomeric form, i.e., (R) or (S) form. [ka] wherein R is (C1-C4) alkyl, preferably ethyl, and Z is selected from the group consisting of (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, and (C3-C6) cycloalkyl. The present invention provides an intermediate compound of the formula:

[0083] The present invention further provides the use of an intermediate compound of formula (VI) as defined above in the preparation of a compound of formula (Ia).

[0084] Thus, the present invention provides the use of an intermediate compound of formula (IV) and / or an intermediate compound of formula (VI) as defined above in the preparation of a compound of formula (Ia).

[0085] Scheme 2 [ka] Stereochemically defined compounds of formula (Ia) can be prepared starting from compounds of formula (VI) (where R is (C-C) alkyl, preferably ethyl) with the appropriate configuration (R) or (S) at the stereocenter, as described in Scheme 2. Compounds of formula (VII) can be obtained from compounds of formula (VI) by removal of the Boc protecting group under acidic conditions, for example using an organic acid such as TFA. Compounds of formula (VII) can be converted to compounds of formula (VIII) by a cross-coupling reaction, such as a Buchwald coupling, with an appropriate heteroaryl halide in the presence of a palladium catalyst such as Pd(dppf)Cl or other palladium source / phosphine-based ligand at elevated temperature (about 100°C) for several hours in an organic solvent such as dimethylacetamide, using a suitable base such as CsCO. Compounds of formula (Ia) can be prepared by reacting compounds of formula (VIII) with heteroarylamines in the presence of a strong base such as BuLi, LiHMDS or LDA in a suitable solvent such as THF by means of a transamination reaction.

[0086] Scheme 3 [ka] In a different approach, for example, compounds of formula (Ia) having S configuration at the stereocenter can be obtained by, as a first step, transamination of a heteroarylamine with a compound of formula (VI) (wherein R is (C1-C4) alkyl, preferably ethyl) in the presence of a strong base such as BuLi, LiHMDS or LDA in a suitable solvent such as THF, followed by removal of the protecting group of w under acidic conditions using TFA or HCl in 4-dioxane to give compounds of formula (X), as depicted in Scheme 3. Compounds of formula (X) can be converted to compounds of formula (Ia) by means of a Buchwald coupling reaction using a suitable palladium catalyst such as Pd(dppf)Cl, for example a Buchwald third generation catalyst such as BPC-304 or BPC-305 or Pd 175 (all Johnson Matthey, UK), or any other palladium source / phosphine based ligand, in the presence of a base such as CsCO, NaOtBu or LiHMDS at elevated temperature (about 100°C) for several hours, in a suitable solvent such as 4-dioxane or DMA.

[0087] Scheme 4 [ka] In a different approach, stereochemically defined compounds of formula (Ia) (where Y is CONH and Y is hydrogen) can be prepared from compounds of formula (VII) (where R is (C-C) alkyl, preferably ethyl) with the appropriate configuration of stereocenters, as depicted in Scheme 4. Such compounds of formula (VII) can be subjected to a Buchwald coupling reaction with an appropriate cyano-heteroaryl bromide in the presence of an inorganic base such as DMA and CsCO, in the presence of a suitable palladium source / phosphine-based ligand at elevated temperature to give compounds of formula (XI). Compounds of formula (XII) can be obtained by converting the cyano group (CN) to a primary amide group in the presence of a peroxide such as hydrogen peroxide, an inorganic base such as KCO and a suitable solvent such as DMSO; subsequent transamination reaction with a heteroarylamine in the presence of a strong base such as BuLi, LiHMDS or LDA in a suitable solvent such as THF gives compounds of formula (Ia) (where Y is CONH and Y is hydrogen).

[0088] Scheme 5 [ka] Alternatively, compounds of formula (Ia) with defined stereochemistry, where Y1 is CONH2 and Y2 is hydrogen, can be obtained from compounds of formula (XII), where R is (C1-C4) alkyl, preferably ethyl, by basic hydrolysis of the ester in the presence of LiOH in a HO / THF mixture, followed by amidation using a common coupling agent, such as HATU, in the presence of an organic base, such as DIPEA, in a suitable solvent, such as DMF, to obtain compounds of formula (Ia), where Y1 is CONH2 and Y2 is hydrogen, as depicted in Scheme 5.

[0089] Scheme 6 [ka] Alternatively, stereochemically defined compounds of formula (Ia) (where Y is CONH and Y is hydrogen) can be obtained by starting with compounds of formula (VII) (where R is (C-C) alkyl, preferably ethyl) and reacting an appropriate cyano-heteroaryl bromide in the presence of DMA and an inorganic base such as CsCO at elevated temperature in the presence of a suitable palladium source / phosphine-based ligand via a Buchwald coupling to give compounds of formula (XI), as depicted in Scheme 6. Compounds of formula (XI) can be converted to compounds of formula (XIII) by transamination with an appropriate amine, followed by conversion of the cyano group to a primary amide group by oxidation using a peroxide such as HO, an inorganic base such as KCO, and a suitable solvent such as DMSO.

[0090] Scheme 7 [ka] In another approach, stereochemically defined compounds of formula (Ia) (where Y is CONR1R2 and Y is hydrogen) can be prepared starting from compounds of formula (X) by performing a Buchwald coupling using a suitable commercially available bromo-heteroaryl ester, as depicted in Scheme 7. After basic hydrolysis of the ester, for example using LiOH in a HO / THF mixture, compounds of formula (Ia) can be prepared by amidation with an amine NHR1R2 under suitable amide coupling reaction conditions, in the presence of an activating agent such as HATU or TBTU, with an organic base such as DIPEA or TEA, in a suitable organic solvent such as DCM or DMF, typically at temperatures around RT for a period ranging from several hours to overnight. Alternatively, such compounds of formula (Ia) can be prepared by nucleophilic aromatic substitution (S) using a suitable commercially available fluoro-heteroaryl ester in the presence of a suitable base such as DIPEA in a suitable solvent such as DMSO. N Compounds of formula (X) can be converted to compounds of formula (XIV) via a methyl group, Ar, followed by basic ester hydrolysis and amidation to give compounds of formula (Ia).

[0091] Scheme 8 [ka] In a different approach, compounds of formula (Ia) with defined stereochemistry (where Y is NH and Y is hydrogen) can be obtained from compounds of formula (X) by reaction with an appropriate commercially available NO-heteroaryl fluoride under nucleophilic aromatic substitution conditions using a suitable inorganic base such as cesium carbonate, followed by reduction of the nitro group to an amine group under a hydrogen atmosphere and in the presence of a suitable catalyst such as Pd / C in a suitable solvent such as EtOH or EtOAc, as depicted in Scheme 8.

[0092] Scheme 9 [ka] Alternatively, compounds of formula (Ia) can be obtained starting from compounds of formula (X) by reaction with an SEM-protected heteroaryl bromide under Buchwald coupling conditions using a suitable palladium source / phosphine-based ligand in the presence of a suitable base such as NaOtBu in a suitable solvent such as dioxane at elevated temperature, as described in Scheme 9. Compounds of formula (Ia) can be obtained after removal of the SEM under acidic conditions in the presence of HCl in dioxane.

[0093] Accordingly, the present invention provides intermediate compounds of formula (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), and (XVI) as defined above and their use in the preparation of compounds of formula (Ia).

[0094] Scheme 10 [ka] L [ka] Compounds of formula (Ib1), which are compounds of formula (Ib), can be prepared by reacting a compound of formula (XVII) with a suitable commercially available nitro-heteroaryl fluoride under nucleophilic aromatic substitution conditions using a suitable inorganic base, such as cesium carbonate, and a suitable solvent, such as DMSO, followed by removal of the protecting group under acidic conditions, for example, using HCl in 4-dioxane, to give compounds of formula (XIX), as depicted in Scheme 10. Such compounds of formula (XIX) can be subjected to a Buchwald coupling reaction with compounds of formula (XXI), obtained after transamination between a compound of formula (II) as defined above (wherein R is (C-C) alkyl, preferably methyl), and a suitable heteroarylamine, in the presence of a suitable palladium source / phosphine-based ligand at elevated temperature in the presence of DMA and an inorganic base, such as CsCO, to give compounds of formula (XXII). Compounds of formula (Ib1), where Y is NH, were obtained from compounds of formula (XXII) by reduction of the nitro group to an amine group under a hydrogen atmosphere and in the presence of a suitable catalyst, such as Pd / C, in a suitable solvent, such as EtOH or EtOAc.

[0095] Scheme 11 [ka] In a different approach, compounds of formula (Ib1) (where Y1 is NHCOR1) can be obtained by starting from compounds of formula (XXII) and reducing the nitro group to an amine group in a suitable solvent such as EtOH or EtOAc under a hydrogen atmosphere and in the presence of a suitable catalyst such as Pd / C to give compounds of formula (XXIII), as described in Scheme 11. Compounds of formula (Ib1) can be prepared by acetylation of compounds of formula (XXIII) with a suitable commercially available acyl chloride, i.e., R1COCl, or anhydride, in the presence of a suitable solvent such as pyridine or TEA.

[0096] Accordingly, the present invention provides intermediate compounds of formula (XVII), (XIX), (XXI), (XXII) and (XXIII) as defined above and their use in the preparation of compounds of (Ib) or (Ib1).

[0097] Scheme 12 [ka] Compounds of formula (Ia) with defined stereochemistry can be prepared starting from compounds of formula (II) as defined above, as depicted in Scheme 12. The reaction can be carried out by reacting compounds of formula (II) with tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate according to the standard Suzuki protocol, in the presence of an inorganic base such as cesium carbonate, in the presence of a suitable palladium catalyst system such as Pd(dppf)Cl, in a suitable organic solvent such as dioxane, at elevated temperature (approximately 100°C) for several hours. Compounds of formula (XXV) can be converted to compounds of formula (XXVI) by reduction, typically under a hydrogen atmosphere at 5 bar pressure, in the presence of a suitable catalyst such as Pd / C, in a suitable solvent such as, but not limited to, EtOH, at temperatures ranging from rt to 60°C for several hours.

[0098] Compounds of formula (XXVIII) can be prepared by transamination of compounds of formula (XXVI) with heteroarylamines in a suitable solvent such as THF in the presence of a strong base such as BuLi, LiHMDS or LDA, followed by removal of the Boc protecting group under acidic conditions, for example using an organic acid such as TFA.

[0099] Compounds of formula (Ia) can be obtained by a cross-coupling reaction such as Buchwald coupling in the presence of a suitable heteroaryl halide in the presence of a palladium catalyst such as Pd-170 or other palladium source / phosphine-based ligand at elevated temperature (about 120°C) for several hours in an organic solvent such as dimethylacetamide in the presence of a suitable base such as CsCO.

[0100] Accordingly, the present invention relates to intermediate compounds of formula (XXV), (XXVI), (XXVII) and (XXVIII) as defined above and their use in the preparation of compounds of formula (Ia).

[0101] Compounds of formula (Ia) containing a stereocenter in the pyrrolidine ring are obtained as racemic mixtures unless otherwise specified. Separation of the racemic mixture can be achieved by chiral resolution methods, such as chiral chromatographic purification. Both enantiomers of compounds of formula (Ia) are within the scope of the present invention. If the absolute configuration of the stereocenter has not been determined, the stereoisomers, or enantiomers, are identified as "first-eluting" and "second-eluting" in chiral chromatographic purification, depending on the method used.

[0102] Scheme 13 [ka] As depicted in Scheme 13, intermediate compounds of formula (L) can be prepared by a palladium-catalyzed Heck-type cross-coupling reaction between compounds of formula (II) and compounds (XLV), as defined above. The reaction can be carried out by reacting a compound of formula (II) and a common enone, such as propenoic acid (XLV), in the presence of a base, such as TEA, a ligand, such as triphenylphosphine, a palladium source, such as palladium acetate, in a suitable organic solvent, such as DMF, at elevated temperatures, about 110° C., for several hours.

[0103] 1,3-Dipolar cycloaddition can be carried out by reaction of an α,β-unsaturated compound of formula (XLVI) with a 1,3-dipole such as an azomethine ylide or a suitable precursor, such as N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine, under acid catalysis, for example, with TFA, in a solvent such as dioxane, to give a compound of formula (XLVII), as shown in Scheme 13. Such a compound can be converted to a compound of formula (XLVIII) via acyl chloride formation using a suitable reagent, such as oxalyl chloride, in a suitable solvent, such as THF, at rt, followed by reduction with a reducing agent, such as lithium borohydride. Compounds of formula (XLIX) can then be prepared by hydrogenation using Pd / C at acidic pH in a suitable solvent, such as EtOH, at rt for removal of the benzyl (Bn) protecting group. Compounds of formula (L) may be doubly protected using di-tert-butyl dicarbonate in the presence of an acid such as TEA and 4-dimethylaminopyridine in a suitable solvent such as DCM at rt, followed by the addition of tert-butyldimethylchlorosilane in the presence of TEA at rt.

[0104] Scheme 14 [ka] L [ka] Compounds of formula (Ia′), which are compounds of formula (I), wherein R 4 is hydroxymethyl, can be prepared starting from the corresponding compound of formula (L) as described in Scheme 14.

[0105] Compounds of formula (LII) can be prepared by reacting a compound of formula (L) (wherein Z is as defined above and R is (C1-C4) alkyl, preferably ethyl) with a heteroarylamine by transamination in the presence of a strong base such as BuLi, LiHMDS or LDA in a suitable solvent such as THF, followed by removal of the Boc protecting group using TFA under acidic conditions in a solvent such as DCM at rt. Compounds of formula (LIII) can be obtained by reacting a compound of formula (LII) with tert-butyldimethylchlorosilane in the presence of a base such as TEA in a suitable solvent such as DCM at rt. Compounds of formula (Ia') can then be obtained by means of a Buchwald coupling reaction using a suitable palladium catalyst such as Pd2(dppf)Cl2, Buchwald third generation catalyst or any other palladium source / phosphine based ligand in the presence of a base such as Cs2CO3, NaOtBu or LiHMDS at elevated temperature (about 100°C) for several hours, in a suitable solvent such as 4-dioxane or DMA, followed by removal of the TBDMS protecting group under acidic conditions using 37% HCl in a solvent such as water and ethanol at rt.

[0106] Accordingly, the present invention provides intermediate compounds of formula (XLVI), (XLVII), (XLVIII), (XLIX), (L), (LI), (LII), (LIII) and (LIV) as defined above and their use in the preparation of compounds of formula (Ia').

[0107] Scheme 15 [ka] As depicted in Scheme 15, intermediate compounds of formula (LXII) can be prepared by reacting compounds of formula (II), as defined above, with compound (LV) via a Heck-type palladium-catalyzed cross-coupling. The reaction can be carried out by reacting a compound of formula (II) with a common enone, such as but-3-en-2-one, in the presence of a base, such as TEA, in the presence of a ligand, such as triphenylphosphine, in the presence of a palladium source, such as palladium acetate, in a suitable organic solvent, such as DMF, at elevated temperatures, about 110° C., for several hours.

[0108] A 1,3-dipolar cycloaddition can then be carried out by reacting the α,β-unsaturated compound of formula (LVI) with a 1,3-dipole or a suitable precursor such as an azomethine ylide, for example, N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine, in a solvent such as dioxane under acid catalysis, for example with TFA. Compounds of formula (LVIII) can be prepared by hydrogenation using Pd / C at acidic pH in a suitable solvent such as EtOH at rt. Compounds of formula (LIX) can be prepared using di-tert-butyl dicarbonate in the presence of TEA and a base such as 4-dimethylaminopyridine in a suitable solvent such as DCM at rt.

[0109] Compounds of formula (LX) can be prepared via a Baeyer-Villiger reaction in the presence of a peroxy acid as an oxidizing agent, for example trifluoroperacetic acid formed in situ by combining urea-hydrogen peroxide (1:1) complex and trifluoroacetic anhydride at rt in a suitable solvent stream such as DCM, and finally in the presence of a suitable base such as potassium carbonate or a buffer such as disodium phosphate.

[0110] Compounds of formula (LXII) can be obtained by deprotection in the presence of a base such as potassium carbonate in a suitable solvent such as EtOH at 40° C., followed by removal of the protecting group under acidic conditions, for example using HCl in 1,4-dioxane at rt.

[0111] Scheme 16 [ka] L [ka] Compounds of formula (Ia″), which are compounds of formula (I), wherein R4 is hydroxy, can be prepared starting from the corresponding compound of formula (LXII), as described in Scheme 16.

[0112] Compounds of formula (LXIII) can be obtained by means of a Buchwald coupling reaction using a suitable palladium catalyst such as Pd(dppf)Cl, a Buchwald third generation catalyst or any other palladium source / phosphine-based ligand at elevated temperature (about 100°C) for several hours in the presence of a base such as CsCO, NaOtBu or LiHMDS in a suitable solvent such as 4-dioxane or DMA. Compounds of formula (Ia'') can be prepared by reacting compounds of formula (LXIII) with heteroarylamines by means of a transamination reaction in the presence of a strong base such as BuLi, LiHMDS or LDA in a suitable solvent such as THF.

[0113] Accordingly, the present invention provides intermediate compounds of formula (LVI), (LVII), (LVIII), (LIX), (LX), (LXI), (XLII) and (LXIII) as defined above and their use in the preparation of compounds of formula (Ia″).

[0114] The compounds of formula (I) of the present invention have surprisingly been found to 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, disorders or conditions in which the DDR receptors are involved.

[0115] In this regard, the compounds of formula (I) of the present invention have been found to have extremely high antagonistic drug effects against DDR1 and DDR2. Table 2 in the experimental section of this specification shows such potency as the inhibition constant Ki of representative compounds of formula (I) of the present invention. In particular, the compounds exhibit potency with a Ki of less than 100 nM. Preferred compounds of the present invention have a Ki of 25 to 5 nM against DDR1 and DDR2. Even more preferred compounds of the present invention have a Ki of 5 nM against DDR1 and DDR2.

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

[0117] In a preferred embodiment, the present invention refers to compounds of formula (I) and pharmaceutically acceptable salts thereof for use in the treatment of diseases, disorders or conditions associated with DDR dysregulation.

[0118] In another aspect, the present invention refers to the use of compounds of formula (I) as defined above and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of a disorder associated with DDR dysregulation.

[0119] In another preferred embodiment, the present invention refers to compounds of formula (I) and pharmaceutically acceptable salts thereof for use in the prevention and / or treatment of diseases, disorders or conditions associated with DDR receptor mechanisms. In a more preferred embodiment, the present invention refers to compounds of formula (I) for use in the prevention and / or treatment of fibrosis and / or diseases, disorders or conditions involving fibrosis.

[0120] As used herein, the term "fibrosis" or "fibrotic disorder" refers to a 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.

[0121] Preferably, the compounds of formula (I) as defined 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.

[0122] More preferably, the compounds of formula (I) as defined above are useful in the treatment of idiopathic pulmonary fibrosis (IPF).

[0123] In one embodiment, the present invention also refers to a method for preventing and / or treating disorders associated with DDR receptor mechanisms, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) above.

[0124] In a further aspect, the present invention refers to the use of compounds of formula (I) above for the treatment of disorders associated with DDR receptor mechanisms.

[0125] In another embodiment, the present invention refers to the use of a compound of formula (I) above in the manufacture of a medicament for the treatment of a disorder associated with DDR receptor mechanisms.

[0126] In a further aspect, the present invention refers 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) above.

[0127] In a further aspect, the present invention refers to compounds of formula (I) as defined above for the treatment of diseases, disorders or conditions associated with dysregulation of DDR receptors 1 and 2.

[0128] As used herein, a "safe and effective amount" of a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically active agent means an amount of the compound that is sufficient to treat the patient's condition, yet low enough to avoid serious side effects, which may nevertheless be routinely determined by one of ordinary skill in the art.

[0129] The compound of formula (I) may be administered once or according to a dosing regimen of multiple doses at different time intervals over a period of time. The typical daily dose may vary depending on the route of administration selected.

[0130] The present invention also refers to pharmaceutical compositions comprising at least a compound of formula (I) according to any of the embodiments in admixture with one or more pharmaceutically acceptable carriers and / or excipients.

[0131] In certain embodiments, the present invention refers to a pharmaceutical composition, a pharmaceutical composition, which is a mixture of a compound of Formula (I) and at least one or more pharmaceutically acceptable carriers and / or excipients, e.g., as described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA.

[0132] 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.

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

[0134] In certain preferred embodiments, the pharmaceutical compositions comprising the compounds of formula (I) are solid oral dosage forms such as tablets, gel capsules, capsules, caplets, granules, lozenges and bulk powders.

[0135] In certain embodiments, the pharmaceutical composition comprising a compound of Formula (I) is a tablet.

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

[0137] 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 known inert diluents such as water, and suitable known excipients such as preservatives, wetting agents, sweeteners, flavoring agents, and agents for emulsifying and / or suspending the compounds of the present invention.

[0138] 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 aerosol or a propellant-free inhalable formulation.

[0139] For administration as a dry powder, single or multi-dose inhalers known in the art can be used, in which case the powder can be filled into gelatin, plastic or other capsules, cartridges or blister packs or reservoirs.

[0140] 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 inhalation fraction, may be added to powders of the compound of the present invention.

[0141] Inhalation aerosols containing a propellant gas such as a hydrofluoroalkane contain the compounds of the invention in solution or dispersion form. Propellant-driven formulations may also contain other ingredients as cosolvents, stabilizers and possibly other excipients.

[0142] Propellant-free formulations containing the compounds of the invention may be in the form of solutions or suspensions in aqueous, alcoholic or hydroalcoholic vehicles, which may be delivered by jet or ultrasonic nebulizers, or by soft mist nebulizers, as known in the art.

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

[0144] 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.

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

[0146] All preferred groups or embodiments described above for compounds of formula (I) may be combined with one another and apply mutatis mutandis.

[0147] Various aspects of the invention described herein are illustrated in the following examples, which are not meant to limit the invention in any way.

[0148] Preparation of Intermediates and Example Compounds Chemical names of compounds were generated using the Structure-To-Name tool in the PerkinElmer ChemDraw Professional application (v. 20.0.0.41.) All reagents whose synthesis is not described in the experimental section are either commercially available, known compounds, or can be prepared by known methods by one skilled in the art.

[0149] In the following methods, some starting materials are identified by an "Intermediate" or "Example" number as well as by a step number, which is provided solely as an aid to those skilled in the art.

[0150] When reference is made to the use of "similar" or "analogous" methods, such methods may include minor variations, such as variations in reaction temperature, reagent / solvent amounts, reaction time, work-up conditions, or chromatographic purification conditions, as would be understood by one of ordinary skill in the art. Unless otherwise noted, all compounds were obtained as the free base.

[0151] Abbreviation AcOH = acetic acid; acetone-d6 = deuterated acetone; ACN = acetonitrile; ACN-d3 = deuterated acetonitrile; CDCl3 = deuterated chloroform; CV = column volume; DCM = dichloromethane; DIPEA = N,N-diisopropylethylamine; DMF = dimethylformamide; DMSO = dimethyl sulfoxide; DMSO-d6 = deuterated dimethyl sulfoxide; ee = enantiomeric excess; Et2O = diethyl ether; EtOAc = ethyl acetate; eq.= equivalents; FCC = flash column chromatography; h = hours / s; HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HCOOH = formic acid; HPLC = high-pressure liquid chromatography; LC-MS = liquid chromatography / mass spectrometry; LDA = lithium diisopropylamide; Na / LiHMDS = sodium / lithium bis(trimethylsilyl)amide; MeOH = methyl alcohol; min = minutes; TBAF = tetrabutylammonium Fluoride; 2-MeTHF = 2-methyltetrahydrofuran; NaBH3CN = sodium cyanoborohydride; NMR = nuclear magnetic resonance; MeOH-d4 = deuterated methanol; Pd(dba)2 = bis(dibenzylideneacetone)palladium(0); Pd(dppf)Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); RT / rt = room temperature; RuPhos = 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; SCX = strong cation exchange; SFC = supercritical fluid chromatography; STAB = sodium triacetoxyborohydride; SM = starting material; tBu = tert-butyl; tBuBrettPhos Pd G3 = [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate 3rd generation; tBuOK = potassium tert-butoxide; TBDMS = tert-butyldimethylsilyl; TBTU = 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate; TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin layer chromatography; t. R = retention time; UPLC = ultra-performance liquid chromatography; VCD = vibrational circular dichroism; XantPhos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; IPA = isopropanol; WE = working electrode; CE = counter electrode.

[0152] General Experimental Details NMR characterization: 1 H-NMR spectra were measured on a Varian MR-400 spectrometer equipped with a 5 mm 1H / nX broadband probehead, a self-shielded Z-gradient coil for inverse detection, a deuterium digital lock channel unit, and a quadrature digital detection unit with transmitter offset frequency shift, operating at 400 MHz (proton frequency). Chemical shifts are reported as δ values in ppm relative to trimethylsilane (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, brs = broad singlet, and nd = not determined.

[0153] In some cases, the signal NH from the amide or amine bond (exchangeable proton) is not visible. In a few cases, some signals may be hidden under the signal of water or the signal of DMSO or residual solvent.

[0154] LC / UV / MS analysis method LC / MS retention times are expected to be subject to experimental error of ±0.5 minutes. Method 1: Acquity CSH C18 column, 50 mm x 2.1 mm, 1.7 μm, maintained at 40 °C; Mobile phase: Eluent B (ACN / water 95:5 + 0.05% HCOOH) in Eluent A (water / ACN 95:5 + 0.05% HCOOH), 1% to 99.9% in 1.5 min. Flow rate: 1 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters PDA + Waters QDA.

[0155] Method 2: Waters Sunfire C18 column, 4.6 x 50 mm, 3.5 μm, maintained at 40 °C. Mobile phase: ACN in water + 10 mM ammonium bicarbonate, 95% in 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.

[0156] Method 3: Acquity CSH C18 column, 50 mm x 2.1 mm, 1.7 μm, maintained at 40 °C; Mobile phase: Eluent B (ACN / water 95:5 + 0.05% HCOOH) in Eluent A (water / ACN 95:5 + 0.05% HCOOH), 1% to 99.9% in 3.5 min. Flow rate: 1 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters PDA + Waters QDA.

[0157] Method 4: Waters Acquity QSM, Kinetex C8 column, 100 mm x 2.1 mm, 1.7 μm, maintained at 55°C; mobile phase: eluent A (0.025 M HCOOH, pH 3), eluent B (ACN + 0.1% FA). Gradient mode: Eluent B increased from 1% to 30% from 0 to 3 min, increased from 30% to 50% from 3 to 6.50 min, increased from 50% to 80% from 6.50 to 7.50 min, held at 80% from 7.50 to 8 min, decreased from 80% to 1% from 8 to 8.10 min, and held at 1% until the end of 10 min at 8.10 min. Flow rate: 0.5 mL / min. Wavelength: 210-400 nm PAD. UPLC + Waters PDA + Xevo TQS MS instrument.

[0158] Method 5: Acquity UPLC HSS C18 column, 100 x 2.1 mm, 1.8 μm (Plus guard cartridge), maintained at 40 °C. Mobile phase: ACN (0.1% formic acid) in water (0.1% formic acid), 5% to 95% in 5.6 min. Flow rate: 0.4 ml / min. Wavelength: 210-400 nm DAD. UPLC + Waters DAD + Waters SQD2, single quadrupole UPLC-MS.

[0159] Method 6: Agilent Zorbax column, 4.6 x 50 mm, 3.5 μm, maintained at 40°C. Mobile phase: ACN (0.1% formic acid) in water (0.1% formic acid), 5% to 95% in 2 min. Flow rate: 3.0 mL / min. Wavelength: 210-400 nm DAD. Waters 2795 / 2695 separation module + Waters DAD + Micromass ZQ, single quadrupole LC-MS.

[0160] Method 7: Acquity BEH C18 (2.1 mm x 50 mm, 1.7 μm) maintained at 60°C; flow rate 1.0 mL / min; detection wavelength 220-300 nm; injection volume 1.0 μL; mobile phase: ACN (eluent B); eluent A: water (0.1% v / v TFA), 2% to 98% in 2 min. Flow rate: 1 mL / min. Wavelength: 220-300 nm.

[0161] Method 8: Acquity UPLC BEH Shield RP18 column, 100 x 2.1 mm, 1.72 μm (Plus Guard cartridge), maintained at 40°C. Mobile phase: ACN in water + 10 nM ammonium bicarbonate, 5% to 95% in 5.6 min. Flow rate: 0.4 ml / min. Wavelength: 210-400 nm DAD. UPLC + Waters DAD + Waters SQD2, single quadrupole UPLC-MS.

[0162] Method 9: Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm maintained at 25°C. Mobile phase: Water (0.1% formic acid) in MeCN (0.1% formic acid), 80% to 5% over 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 equipped with a DAD detector / Thermo Scientific ISQ EC mass spectrometer.

[0163] Method 10: Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm maintained at 25°C. Mobile phase: Water (0.1% formic acid) in MeCN (0.1% formic acid), 90% to 5% in 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 equipped with a DAD detector / Thermo Scientific ISQ EC mass spectrometer.

[0164] Method 11: Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm maintained at 25°C. Mobile phase: Water (0.1% formic acid) in MeCN (0.1% formic acid), 60% to 5% in 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 equipped with a DAD detector / Thermo Scientific ISQ EC mass spectrometer.

[0165] Method 12: Kinetex® XB-C18 column, 4.6 x 50 mm, 2.6 μm, maintained at 25°C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid), 60% to 5% in 3.90 min; flow rate: 1.0 ml / min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC mass spectrometer.

[0166] Method 13: Acquity CSH C18 column, 50 mm x 2.1 mm, 1.7 μm, maintained at 40°C; Mobile phase: Eluent B (ACN) in Eluent A (water + 0.1% HCOOH), 1% to 99.9% in 1.5 min. Flow rate: 1 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters PDA + Waters QDA.

[0167] Method 14: Acquity CSH C18 column, 50 mm x 2.1 mm, 1.7 μm, maintained at 40°C; Mobile phase: Eluent B (ACN) in Eluent A (water + 0.1% HCOOH), 1% to 99.9% in 3.5 min. Flow rate: 1 mL / min. Wavelength: 210-400 nm DAD. UPLC + Waters PDA + Waters QDA.

[0168] Method 15: 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% in 2 min. Flow rate: 3.0 mL / min. Wavelength: 210-400 nm DAD. Waters 2795 / 2695 Separation Module + Waters DAD + Micromass ZQ, single quadrupole LCMS.

[0169] Method 16: Acquity UPLC BEH-Waters, 1.7 μm C18 (2.1 × 100 mm), 130 Å, maintained at 25 °C. Mobile phase: Water (0.1% formic acid) in MeCN (0.1% formic acid), 80% to 5% in 2.70 min; flow rate: 0.5 ml / min; wavelength: 254 nm. Shimadzu LCMS-2020 single quadrupole liquid chromatograph mass spectrometer.

[0170] Chiral Supercritical Fluid Chromatography (SFC) Separation Protocol Diastereomeric separation of the compounds was achieved by supercritical fluid chromatography (SFC) using an LC system. Analysis of the two enantiomers was performed from the final reconstituted sample.

[0171] Alternatively, diastereomeric separation of compounds was achieved by supercritical fluid chromatography (SFC) using a Waters Thar Prep100 preparative SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV / VIS detector, 2767 liquid handler equipped with a stacked injection module). The Waters 2767 liquid handler was used as the autosampler and fraction collector. Appropriate isocratic methods were selected based on methanol, ethanol, or isopropanol solvents under unmodified or basic conditions. The SFC method used was modifier CO2 at 100 mL / min, 120 bar backpressure, and 40 °C column temperature. The modifier used under basic conditions was diethylamine (0.1% v / v). The modifier used under acidic conditions was formic acid (0.1% v / v) or trifluoroacetic acid (0.1% v / v). SFC purification was controlled by Waters Fractionlynx software, monitored from 210 to 400 nm with a typical collection start at 260 nm. Collected fractions were analyzed by SFC (Waters / Thar SFC system equipped with a Waters SQD). Fractions containing the desired product were concentrated by vacuum centrifugation.

[0172] Analytical conditions for supercritical fluid chromatography-mass spectrometry Method 1: SFC-MS was performed on a Gilson Preparative LC system (Gilson Pump-333; Gilson 151; Gilson Valvemate 6 position) using a Chiralcel OD-H (30 mm x 250 mm, 5 μm) column with an isocratic run (10:90 MeOH:CO2), a flow rate of 180 mL / min, BPR 120 BarG, a detector wavelength of 237 nm, an injection volume of 1500 μL (135 mg), and a column temperature of 40 °C.

[0173] Method 2: SFC-MS was performed on a Gilson Preparative LC system using a Lux C1 (4.6 mm x 250 mm, 5 μm) column with an isocratic run (20:80 MeOH:CO (0.2% v / v NH) at 210-400 nm wavelength, injection volume 1.0 μL, BPR 125 Barg, 4 mL / min, and 40 °C column temperature.

[0174] Method 3: SFC-MS was performed on a Gilson Preparative LC system using an AMS (4.6 mm x 250 mm, 5 μm) column with an isocratic run (20:80 MeOH:CO (0.2% v / v NH), detector wavelength 210-400 nm, injection volume 1.0 μL, BPR 125 Barg, 4 mL / min, and 40 °C column temperature.

[0175] Method 4: SFC-MS was performed using a Waters LUX Cellulose-1 (20 × 250 mm, 5 μm) column. TM Waters with SQD TM The analysis was carried out on a / Thar SFC system, isocratic (30% MeOH (NH4OH 0.1%):CO2), flow rate 100 mL / min, 120 bar, 40°C column temperature, DAD wavelength 265 nm.

[0176] Method 5: SFC-MS was performed using a Waters LUX Cellulose-1 (20 × 250 mm, 5 μm) column. TM Waters with SQD TM The run was performed on a / Thar SFC system using an isocratic run (50% IPA (NH4OH 0.1%):CO2), a flow rate of 100 mL / min, 120 bar, a column temperature of 40°C, and a DAD wavelength of 265 nm.

[0177] Method 6: SFC-MS was performed using a LUX Cellulose-iC5 (20 × 250 mm, 5 μm) column with a Waters TM Waters with SQD TMThe run was performed on a / Thar SFC system using an isocratic run (50% EtOH (NH4OH 0.1%):CO2), a flow rate of 100 mL / min, 120 bar, a column temperature of 40°C, and a DAD wavelength of 265 nm.

[0178] Method 7: SFC-MS was performed using a LUX Cellulose-iC5 (20 × 250 mm, 5 μm) column with a Waters TM Waters with SQD TM The run was performed on a / Thar SFC system using an isocratic run (30% IPA (NH4OH 0.1%):CO2), a flow rate of 100 mL / min, 120 bar, a column temperature of 40°C, and a DAD wavelength of 265 nm.

[0179] Method 8: SFC-MS was performed using a LUX Cellulose-iC5 (20 × 250 mm, 5 μm) column with a Waters TM Waters with SQD TM The run was performed on a / Thar SFC system with an isocratic run (40% MeOH (NH4OH 0.1%):CO2), a flow rate of 100 mL / min, 120 bar, a column temperature of 40°C, and a DAD wavelength of 265 nm.

[0180] IR and VCD spectroscopy The stereochemistry of the two enantiomers of tert-butyl 3-(2-methyl-5-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)pyrrolidine-1-carboxylate was determined using vibrational circular dichroism (VCD) spectroscopy. By comparison of experimental and computer-simulated VCD spectra, the absolute configurations of the two enantiomeric pairs can be confidently assigned without prior knowledge of the relative stereochemistry. IR spectra are used to aid in the assignment of relative stereochemistry. IR and VCD difference spectra further confirm the assignment of the two enantiomers.

[0181] IR and VCD were recorded at BioTools, Inc. on a chiral IR equipped with a dual PEM spectrometer at rt. PEM was recorded at 1400 cm. -1Optimized for 4cm across -1 A resolution of 100 uL was used. For all experiments, a 7.1 mg concentration solution in 100 uL of CDCl3 was probed using a 100 μm pathlength cell equipped with BaF2 windows. Solution spectra were recorded for 24 hours per enantiomer. Because both enantiomers were available, baseline correction was introduced using the virtually racemic mixture.

[0182] All solvents were purchased from commercial sources and used without further purification. Unless otherwise noted, flash chromatography (FCC) was performed on a Biotage Isolera followed by SCX(NH) to give the free base of the product.

[0183] For reversed-phase FCC the following gradient / eluent was used: gradient A:B 100:0 to 0:10 in 12 CV, eluent A: H2O / ACN / HCOOH 95:5:0.1 eluent B: H2O / ACN / HCOOH 5:95:0.1.

[0184] General synthesis method Intermediate 1: 5-Bromo-N-(2-(dimethylamino)ethyl)nicotinamide [ka] In a 20 mL vial, 5-bromonicotinic acid (200 mg, 0.990 mmol), N1,N1-dimethylethane-1,2-diamine (131 mg, 1.485 mmol), and TBTU (477 mg, 1.485 mmol) were dissolved in DCM (2 mL), and then DIPEA (0.345 mL, 1.980 mmol) was added in one portion. The solution was stirred at rt overnight. The crude material was washed with saturated NH4Cl solution (1 × 10 mL), saturated NaHCO3 solution (1 × 10 mL), and brine (1 × 15 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by reverse-phase chromatography: gradient A:B 100:0 to 0:100 in 10 CV; eluent A: water / ACN / HCOOH 95:5:0.1; eluent B = water / ACN / HCOOH 5:95:0.1. The appropriate fractions were combined, loaded onto an Isolute SCX-2 cartridge, washed with MeOH, and the product was eluted with 2N methanolic ammonia. The residue was concentrated in vacuo to give the title compound (60 mg, 0.220 mmol, 22.27% yield). LC-MS (ESI, m / z): Method 1, t R =0.2 min, m / z(M+1)=271.83 / 273.78

[0185] Similarly, the following intermediates were prepared by reaction of the bromo derivative with the appropriate amine.

[0186] Intermediate 2: 5-Bromo-N-(2-methoxyethyl)nicotinamide [ka] SM: 5-bromonicotinic acid: 0.5 mg (1 equivalent) 2-Methoxyethan-1-amine: 1.5 g (1.5 equivalents) Amount / yield (275 mg, 1.061 mmol, 43%) LC-MS (ESI, m / z): Method 1, t R =0.56 min, m / z(M+1)=258.8 / 260.7

[0187] Intermediate 3: 5-Bromo-N-(2-hydroxyethyl)nicotinamide [ka] SM: 5-bromonicotinic acid 2.5 g (1 equivalent); 2-aminoethan-1-ol: 1.134 g (1.5 equivalents) Amount / Yield: 660mg / 22% LC-MS (ESI, m / z): Method 1, t R =0.44 min, m / z(M+1)=245.0 / 247.0 m / z(M+1)=297.85

[0188] Intermediate 35: (4-chlorothieno[3,2-d]pyrimidin-6-yl)(morpholino)methanone [ka] SM: 4-chlorothieno[3,2-d]pyrimidine-6-carboxylic acid 100 mg (1 equivalent) Morpholine: 41 mg (1 equivalent); HATU: 213 mg (1.2 equivalents) Amount / Yield: 132mg / 100% LC-MS (ESI, m / z): Method 17, t R =1.09 min, m / z(M+1)=284.07

[0189] Intermediate 4: N-(5-bromopyridin-3-yl)acetamide [ka] To a solution of 5-bromopyridin-3-amine (1 g, 5.78 mmol) in DCM (30 mL) was added acetic anhydride (1.745 mL, 18.50 mmol), followed by DIPEA (2.73 mL, 15.61 mmol). The solution was stirred at room temperature. The next day, UPLC-MS analysis showed complete conversion of SM. The solution was diluted with saturated NaHCO3 solution (20 mL) and extracted with DCM (20 mL × 2), followed by EtOAc (20 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by FCC on a silica gel column eluting with a gradient of 0 to 80% EtOAc in n-heptane to give the title compound (1.1 g, 5.17 mmol, 88% yield). LC-MS (ESI, m / z): Method 1, t R =0.56 min, m / z(M+1)=214.8 / 216.8

[0190] Intermediate 5: 2-[(5-bromopyrazolo[3,4-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane [ka] To a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (1000 mg, 5.05 mmol, 1.00 equiv.) and tBuOK (850 mg, 7.57 mmol, 1.50 equiv.) in DMF (15.00 mL) at 0 °C, 2-(trimethylsilyl)ethoxymethyl chloride (1.1 mL, 6.06 mmol, 1.20 equiv.) was slowly added, and the mixture was warmed to rt and stirred overnight. The reaction mixture was quenched with NH4Cl (saturated aqueous, 20 mL) and extracted with EtOAc (50 mL). The organic phase was washed with HO (50 mL), brine (saturated aqueous, 50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by FCC on silica gel eluting with a gradient of 0-60% EtOAc in cyclohexane to give the title compound (1.2 g, 3.65 mmol, 72%). LC-MS (ESI, m / z): (Method 2), t R =1.95 min, m / z(M+1)=328.0 / 330.0 1H NMR (400MHz, DMSO-d6)δ 8.80(d, J=2.3Hz, 1H), 8.71(d, J=2.1Hz, 1H), 8.36(s, 1H), 5.88(s, 2H), 3.70(t, J=8.0Hz, 2H), 0.92(t, J=8.0Hz, 2H), 0.01(s, 9H).

[0191] Intermediate 6: 5-(tert-butyl)-1-methyl-1H-pyrazol-3-amine [ka] To a solution of 3-chloro-4,4-dimethylpent-2-enenitrile (5.00 g, 34.8 mmol, 1.00 equiv.) and KCO (4812 mg, 34.8 mmol, 1.00 equiv.) in EtOH (25 mL), methylhydrazine (2.0 mL, 38.3 mmol, 1.10 equiv.) was added, and the reaction mixture was heated at 80 °C for 4 h. The reaction mixture was cooled to room temperature, and the filtrate was filtered under vacuum through a Celite pad. The residue was purified by column silica gel chromatography, eluting with 0-100% EtOAc in cyclohexane, followed by 0-100% MeOH in EtOAc, to give a 5:1 mixture of the desired product (its regioisomers). The mixture was washed with cyclohexane and filtered. The resulting residue was separated by achiral SFC (YMC Cellulose-SC 20 × 250 mm, 5 μm 10 / 90 IPA (0.1% DEA) / CO2, 100 ml / min, 120 bar, 40 °C, DAD 230 nm) and dried under vacuum at 40 °C to give the title compound (2.75 g, 17.2 mmol, 49%). LC-MS (ESI, m / z): (Method 6), t R =2.09 min, m / z(M+1)=154.2 1H NMR (400MHz, CDCl3) δ 5.40 (s, 1H), 3.76 (s, 3H), 3.32-3.31 (m, 2H), 1.32 (s, 9H).

[0192] Intermediate 7: 5-(trifluoromethoxy)pyridin-3-amine hydrochloride [ka] Step 1 - tert-Butyl N-[5-(trifluoromethoxy)-3-pyridyl]carbamate (Intermediate 8) [ka] A solution of a mixture of tert-butyl carbamate (102 mg, 0.868 mmol, 1.20 eq), Xantphos (63 mg, 0.108 mmol, 0.150 eq), tris(dibenzylideneacetone)dipalladium(0) adduct (37 mg, 0.0362 mmol, 0.0500 eq), and CsCO (283 mg, 0.868 mmol, 1.20 eq) in 1,4-dioxane (5 mL) was degassed with nitrogen and treated with 3-bromo-5-(trifluoromethoxy)pyridine (175 mg, 0.723 mmol, 1.00 eq). The reaction was stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature and filtered through a Celite pad, which was then washed with dioxane, and the combined organic phase was concentrated in vacuo. The residue was purified by column silica gel chromatography eluting with 0-100% EtOAc in cyclohexane and dried under vacuum overnight to give the title compound (115 mg, 0.413 mmol, 57%). LC-MS (ESI, m / z): (Method 2), t R =1.24 min, m / z(M+1)=279.1 1 H NMR (400MHz, CDCl3) δ 8.33(d, J=2.3Hz, 1H), 8.23-8.21(m, 1H), 8.07(s, 1H), 7.04(s, 1H), 1.54(s, 9H).

[0193] Step 2 - 5-(trifluoromethoxy)pyridin-3-amine hydrochloride (Intermediate 7) HCl 4N dioxane solution (3.0 mL, 0.413 mmol, 1.00 eq) was added to a solution of intermediate 8 (115 mg, 0.413 mmol, 1.00 eq) in 1,4-dioxane (3 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether (20 mL), filtered, and the resulting white solid was washed with ether and dried under vacuum to give the title compound (60 mg, 0.280 mmol, 68%). LC-MS (method 2):t R =0.88 min; m / z(M+1)=179.0. 1 H NMR (400MHz, DMSO-d6) δ 8.07 (d, J=2.0Hz, 1H), 8.03 (d, J=1.5Hz, 1H), 7.30 (d, J=1.0Hz, 1H).

[0194] Intermediate 36: 2-[4-(3-bromoimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl]acetonitrile [ka] To a solution of 3-bromo-6-piperazin-1-yl-imidazo[1,2-a]pyridine (362 mg, 1.29 mmol) and formaldehyde solution (37% aqueous, 0.12 mL, 1.67 mmol) in MeOH (6.00 mL) was added NaBHCN (105 mg, 1.67 mmol), and the mixture was stirred at rt for 5 h. The reaction mixture was diluted with EtOAc and washed with NaHCO, water, and brine. The organic phase was dried over MgSO, filtered, and concentrated in vacuo. The residue was loaded onto an Isolute SCX-II cartridge, washed with MeOH / water (50 mL), and released with 1N NH in MeOH (25 mL). The ammonia eluent was concentrated in vacuo to give the crude material which was purified by FCC (cyclohexane:10% 0.7N NH3 in DCM in MeOH, 3:1) to give the title compound (54 mg, 0.169 mmol, 13%). LC-MS(ESI): Method 2, t R =1.32 min;m / z(M+1)=320.0;322.0

[0195] Intermediate 37 - 5-Bromo-N-(oxetan-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide [ka] 5-Bromo-N-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (0.75 g, 2.53 mmol) was dissolved in anhydrous THF (5.3 ml) and the temperature was raised to 0 °C. NaH (60% in mineral oil) (0.203 g, 5.07 mmol) was then slowly added, and the solution was stirred at the same temperature for 30 min. (2-(chloromethoxy)ethyl)trimethylsilane (0.897 ml, 5.07 mmol) was added, and the reaction mixture was stirred at RT overnight. The mixture was diluted with water and extracted with AcOEt. The organic layer was dried over Na2SO4. The crude material was purified by FCC (cyclohexane -> 100% AcOEt) to give the desired product (400 mg, 940 mmol, 37%). LC-MS(ESI): Method 16, t R =2.55 minutes; m / z(M+1)=427.85

[0196] Intermediate 38 - 1-(5-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylmethanamine [ka] The intermediate was prepared according to the method for Intermediate 37. SM: 1-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylmethanamine 374 mg (1 equivalent); (2-(chloromethoxy)ethyl)trimethylsilane 367 mg (1.5 equivalents) Amount / Yield: 516mg / 78% LC-MS(ESI): Method 16, t R =1.83 min; m / z(M+1)=387.05

[0197] Intermediate 39 - 4-[(3-Bromoimidazo[1,2-a]pyridin-6-yl)methyl]morpholine [ka] Intermediate 39 was prepared in the same manner as described for the synthesis of Example C1, using DCM as the solvent and NaBH(OAc) 3 as the reducing agent. SM: 3-bromoimidazo[1,2-a]pyridine-6-carbaldehyde: 500 mg (1 equiv.); morpholine (0.24 mL, 1.25 equiv.) Amount / Yield: 320mg / 57% LC-MS(ESI): Method 2, t R =1.26 min;m / z(M+1)=296.0;298.0

[0198] Intermediate 40 - 3-Bromo-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine [ka] A suspension of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (500 mg, 2.15 mmol), 1-methylpiperazine (0.72 mL, 6.45 mmol), and DIPEA (0.37 mL, 2.15 mmol) in DME (1.5 mL) was heated to 100 °C. The reaction mixture was diluted with EtOAc and washed with NaHCO, and the organic phase was dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by FCC (0–100% EtOAc in cyclohexane, followed by 10% 0.7 N NH in DCM in MeOH) to give the title compound (610 mg, 2.06 mmol, 96%). LC-MS(ESI): Method 2, t R =1.32 min;m / z(M+1)=296.0;298.1

[0199] The following intermediates were prepared using the methods described for the synthesis of intermediate 40. [Table 3]

[0200] Intermediate 43: N-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)acetamide [ka] 3-Bromo-5-chloropyrazolo[1,5-a]pyrimidine (500 mg, 2.151 mmol) in THF (10 mL) was placed in one chamber of a COware gas reactor, followed by the addition of TEA (0.300 mL, 2.15 mmol). The other chamber was charged with aqueous NH3 (5 mL, 73.4 mmol). The tube was closed with a sealant cap, and the system was purged with nitrogen and placed under vacuum. The tube was heated at 80 °C and stirred until complete conversion. The volatiles were removed in vacuo, and then the residue was dissolved in pyridine (10 mL) and acetyl chloride (253 mg, 3.2 mmol) was added in one portion. The reaction mixture was diluted with DCM, and the crude was washed with NaHCO3, NH4Cl, and brine. The organic layer was dried over Na2SO4 and evaporated in vacuo. The title compound (336 mg, 1.32 mmol, 61% yield) was obtained and used directly in the next step. LC-MS(ESI): Method 14 t R =0.97min;m / z(M+1)=254.9.0-226.8

[0201] Intermediate 44: 5-Bromo-N,N-bis(4-methoxybenzyl)pyrimidin-2-amine [ka] Reference: “Modification of a dihydropyrrolopyrimidine phosphoinositide 3-kinase (PI3K) inhibitor to improve oral bioavailability” Kawada, Hatsuo; et al, Bioorganic & Medicinal Chemistry (2015), 23(24), 7650-7660

[0202] Example 1 - (S)-5-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)nicotinamide [ka] Step 1 - Ethyl 4-methyl-3-vinylbenzoate (Intermediate 10) [ka] Ethyl 3-bromo-4-methylbenzoate (100 g, 411 mmol), potassium trifluoro(vinyl)borate (83 g, 617 mmol), and K2CO3 (114 g, 823 mmol) were placed in an oven-dried 2 L reaction vessel, and dioxane (1000 mL) was added under an argon atmosphere. The solution was flushed with argon (10 min), and then Pd(dppf)Cl2 (30.1 g, 41.1 mL) was added. The solution was stirred at reflux for 6 h. The reaction mixture was filtered through a Celite® pad and dried under reduced pressure. The residue was purified by FCC on silica gel eluting with 0–20% AcOEt in n-heptane. The appropriate fractions were collected and dried to give the title compound (61.5 g, 323 mmol, 79% yield). LC-MS(ESI):(Method 3) t R =2.23 minutes; m / z(M+1)=190.9 1 H NMR(CDCl3, 400MHz)δ 8.15(s, 1H), 7.84(dd, 1H, J=1.5, 7.9Hz), 7.22(d, 1H, J=7.9Hz), 6.94(dd, 1H, J=11.0, 17.5Hz), 5.7 -5.8(m, 1H), 5.38(dd, 1H, J=0.9, 11.0Hz), 4.39(q, 2H, J=7.0Hz), 2.40(s, 3H), 1.41(t, 3H, J=7.1Hz)

[0203] Step 2 - Ethyl 3-(1-benzylpyrrolidin-3-yl)-4-methylbenzoate (Intermediate 11) [ka] A mixture of Intermediate 10 (78.4 g, 412 mmol), N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (73.4 g, 309 mmol), and 0.01% TFA in dioxane (1 L) (0.317 ml, 4.12 mmol) was placed in a round-bottom vessel and heated to reflux for 2 hours. The reaction was cooled to RT, and an additional equivalent of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (73.4 g, 309 mmol) was added, and the solution was then stirred at reflux. This process was repeated twice, and the mixture was then maintained under stirring at reflux until completion. The solvent was removed under reduced pressure, and the crude material was used in the next step without further purification. LC-MS(ESI):(Method 3) t R =1.07 min; m / z(M+1)=324.0

[0204] Step 3 - Ethyl 4-methyl-3-(pyrrolidin-3-yl)benzoate (Intermediate 12) [ka] A 1 L reaction vessel was purged with nitrogen and charged with palladium / C 10 (50% wet) (21.88 g, 10.28 mmol). The system was purged with nitrogen once more and placed under vacuum. A solution of intermediate 11 (133 g, 411 mmol) in ethanol (500 ml) was then charged and the system was purged with nitrogen once more. The solution was then placed under a hydrogen atmosphere (4 bar), warmed to 60° C., and stirred for 8 hours. The reaction vessel was evacuated and rinsed with 200 mL EtOH. The reaction mixture was filtered through a Celite® pad and concentrated; the crude material was then dissolved in EtO (400 mL) and extracted with HCl 1N (3×150 mL). LC-MS(ESI):(Method 3) t R =0.69 min; m / z(M+1)=233.9 1H NMR(CDCl3, 400MHz)δ 7.91(s, 1H), 7.79(dd, 1H, J=1.5, 7.9Hz), 7.22(d, 1H, J=7.6Hz), 4.37(q, 2H, J=7.0Hz), 3.4-3.5(m, 1H), 3.4-3.4(m, 1H), 3.31(ddd, 2H, J=4.6, 8.6, 11.0Hz), 3.17(td, 1H, J=7.6, 11.0Hz), 2.93(dd, 1H, J=8.1, 10.7Hz), 2.42(s, 3H), 2.2-2.3(m, 1H), 1.9-2.0(m, 1H), 1.40(t, 3H, J=7.1Hz)

[0205] Step 4 - tert-Butyl 3-(5-(ethoxycarbonyl)-2-methylphenyl)pyrrolidine-1-carboxylate (Intermediate 13) [ka] Intermediate 12 (20.35 g, 87 mmol) and di-tert-butyl dicarbonate were placed in a 500 mL flask and dissolved in DCM (300 mL). TEA (18.24 mL, 131 mmol) was then added in one portion and the reaction was stirred at rt. The crude material was washed with NH4Cl solution (2 x 100 mL) and brine (1 x 100 mL). The crude material was purified on FCC silica gel eluting with a gradient of 0 to 20% EtOAc in n-heptane. Collection of appropriate fractions afforded the title compound (24.5 g, 73.5 mmol, 84% yield). LC-MS(ESI):(Method 1) t R = 1.35 min; m / z (M+1-tBu): 277.9

[0206] Intermediate 9: 3-Bromo-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] In a 400 mL reaction vessel, 5-(trifluoromethyl)pyridin-3-amine (10.40 g, 64.2 mmol) was dissolved in THF (100 mL) under nitrogen. The mixture was stirred at −5° C., and a 1 M solution of NaHMDS in THF (92 mL, 92 mmol) was added dropwise. The reaction was stirred for 30 minutes at −5° C. Methyl 3-bromo-4-methylbenzoate (4.76 mL, 30.6 mmol) was added, and the temperature was raised to 25° C. for 1 hour. The reaction was quenched with water (13.7 mL, 760 mmol), and then the solution was transferred to a 1 L round-bottom flask and the solvent was evaporated under reduced pressure. The crude material was dissolved in DCM (200 mL) and washed with HCl 1N (2 × 200 mL) and brine (1 × 100 mL). The organic layer was dried under reduced pressure and used in the next step without further purification. 1 H NMR (acetone-d6, 400 MHz) δ 10.07 (br s, 1H), 9.18 (d, 1H, J = 1.3 Hz), 8.74 (s, 1H), 8.68 (s, 1H), 8.22 (d, 1H, J = 1.1 Hz), 7.9-8.0 (m, 1H), 7.52 (d, 1H, J = 7.9 Hz), 2.47 (s, 3H)

[0207] Step 5 - tert-butyl (R)-3-(5-(ethoxycarbonyl)-2-methylphenyl)pyrrolidine-1-carboxylate (Intermediate 14a) and tert-butyl (S)-3-(5-(ethoxycarbonyl)-2-methylphenyl)pyrrolidine-1-carboxylate (Intermediate 14b) Intermediate 13 (20.097 g, 0.060 mol) as a racemic mixture was dissolved in MeOH to 90 mg / mL and then purified by SFC according to Method 1. The combined fractions of each of the first-eluting (Intermediate 14a) and second-eluting (Intermediate 14b) peaks were then evaporated to near dryness using a rotary evaporator. The resulting solid was then transferred to a final container with DCM, which was stripped with a compressed air stream at 35°C and then stored in a vacuum oven at 35°C and 5 mbar until constant weight.

[0208] First-eluting enantiomer (intermediate 14a) [ka] Amount: 9.6g Chiral analysis (SFC method 2): R 1.238 min, ee 100% LC-MS(ESI): Method 7 t R = 1.723 min; m / z (M+1-tBu) = 278.2

[0209] Second eluting enantiomer (intermediate 14b) [ka] Amount: 9.2g Chiral analysis (SFC method 2): R 1.562 min, ee 100% LC-MS(ESI): Method 7 t R = 1.722 min; m / z (M+1-tBu) = 278.2

[0210] The absolute configurations of intermediates 14a and 14b were determined by IR and VCD spectroscopy.

[0211] The following intermediates 15a and 15b were synthesized from intermediates 14a (first eluting) and 14b (second eluting), respectively, under non-racemizing conditions. The absolute configurations of intermediates 14a and 14b were determined by IR and VCD spectroscopy.

[0212] Intermediate 15a: tert-butyl (R)-3-(2-methyl-5-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)pyrrolidine-1-carboxylate [ka] 3-(Trifluoromethyl)aniline (0.373 ml, 3.00 mmol) was dissolved in dry THF (25 ml) under N. The mixture was stirred at -78 °C for 15 min, then 2.5 M butyllithium in hexane (1.140 ml, 2.85 mmol) was added dropwise over 5 min, and the reaction was stirred for 1 h at -78 °C. A THF solution of Intermediate 14a (10 ml) was added dropwise over 10 min, the temperature was raised to RT, and the reaction was stirred for 1 h. The reaction was quenched by the addition of 10 mL of HO, and the solvent was evaporated under reduced pressure. The solid was dissolved in DCM (50 mL), and the organic layer was washed with HO (2 × 20 mL). Purification was carried out by FCC on silica gel, eluting with a gradient of 0-30% EtOAc in n-heptane. The appropriate fractions were combined and dried to give the title compound (554 mg, 1.235 mmol, 82% yield). Chiral analysis (SFC method 3): R 1.16 min, ee 100% LC-MS(ESI): Method 7 t R = 1.79 min; m / z (M+1-tBu) = 393.3 IR and VCD spectroscopy: Configuration R was assigned.

[0213] Intermediate 15b: tert-butyl (S)-3-(2-methyl-5-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)pyrrolidine-1-carboxylate [ka] Similarly, intermediate 15b was prepared by reaction of intermediate 13b with the appropriate amine. SM: Intermediate 14b: 4g (1 equivalent) 3-(trifluoromethyl)aniline: 3.87g (2 equivalents) Amount / Yield: 4.23g / 79% Chiral analysis (SFC method 2): R =2.46 min, ee 99.8% LC-MS(ESI): Method 7 t R =1.79 min;m / z(M+1- t-But)=393.3 IR and VCD spectroscopy: Configuration S was assigned.

[0214] Step 6 - Ethyl (S)-4-methyl-3-(pyrrolidin-3-yl)benzoate (Intermediate 16) [ka] A 20 mL vial was charged with intermediate 14b (4.800 g, 14.40 mmol), and then TFA (8.32 mL, 108 mmol) was added dropwise. The solution was stirred for 10 min at rt. The solution was then diluted with DCM (10 mL), and the organic phase was extracted with saturated NaHCO solution at 0 °C. The organic phase was evaporated in vacuo to give intermediate 15 (3.40 g, 14.57 mmol, 101% yield). LC-MS(ESI):(Method 1) t R =0.50 min; m / z(M+1)=234.0 1 H NMR (400MHz, DMSO-d6) δ ppm 7.86(d, J=1.32Hz, 1H), 7.69(dd, J=7.78, 1.64Hz, 1H), 7.30(d, J=7.89Hz, 1H), 4.30(q, J=7.0 9Hz, 1H), 4.24-4.34(m, 1H), 3.40(quin, J=8.06Hz, 1H), 3.27(dd, J=10.52, 7.67Hz, 1H), 2.93 -3.10(m, 2H), 2.69(dd, J=10.52, 7.89Hz, 1H), 2.11-2.22(m, 1H), 1.69(dq, J=12.30, 8.10Hz, 1H), 1.31(t, J=7.13Hz, 3H)

[0215] Step 7 - Ethyl (S)-3-(1-(5-cyanopyridin-3-yl)pyrrolidin-3-yl)-4-methylbenzoate (Intermediate 17) [ka] A 100 ml reaction vessel was charged with a mixture of 5-bromonicotinonitrile (4.00 g, 21.86 mmol), Intermediate 16, RuPhos (1.360 g, 2.91 mmol), Pd(dppf)Cl (1.066 g, 1.457 mmol), and CsCO (14.24 g, 43.7 mmol). The reactor was evacuated and backfilled with Ar, then DMA (35 ml) was added. The solution was heated to 120 °C and stirred for 2 h. The solution was diluted with EtOAc and washed twice with saturated NaHCO solution, and the organic layer was evaporated in vacuo. Purification by FCC on silica gel eluting with 40% EtOAc in n-heptane gave the title compound (3.3 g, 9.84 mmol, 67.5% yield). LC-MS(ESI):(Method 1) t R =1.20 min; m / z(M+1)=336.0

[0216] The following intermediates were prepared using the methods described for the synthesis of intermediate 17: [Table 4]

[0217] Step 8 - Ethyl (S)-3-(1-(5-carbamoylpyridin-3-yl)pyrrolidin-3-yl)-4-methylbenzoate (Intermediate 18) [ka] In a 100 mL flask, intermediate 17 (2 g, 5.96 mmol) was dissolved in DMSO (20 mL), followed by the addition of K2CO3 (1.5 g, 10.85 mmol, 1.8 equiv). The suspension was stirred for 5 min at room temperature. A 30% (w / w) solution of HO2 in HO (1.827 mL, 17.89 mmol, 3 equiv) was added dropwise at 0 °C, and the mixture was stirred for 2 h at room temperature. The reaction was quenched with 5 mL of HO, and the desired product began to precipitate as a white solid. The solid was filtered, washed with water, and dried overnight to give intermediate 18 in quantitative yield. LC-MS(ESI):(Method 1) t R =0.70 min; m / z(M+1)=354.3 1 H NMR (400MHz, DMSO-d6) δ ppm 8.32(d, J=1.53Hz, 1H), 8.10(d, J=2.85Hz, 1H), 8.03(br s, 1H), 7.81(d, J=1.53Hz, 1H), 7.73(dd, J=7.89, 1.75Hz, 1H), 7.45(br s, 1H) 7.37(s, 1H), 7.33-7.35(m, 1H), 4.24(q, J=7.09Hz, 2H), 3.73-3.82(m, 2H), 3.41-3.55(m, 2H), 3.34(br d, J=2.41Hz, 1H), 2.36-2.44(m, 1H), 2.46(s, 3H), 2.04-2.17(m, 1H), 1.23(t, J=7.13Hz, 3H).

[0218] The following example compounds and intermediates were prepared starting from the appropriate intermediate using the method described for the synthesis of Intermediate 18. [Table 5-1] [Table 5-2]

[0219] Step 9 - (S)-5-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)nicotinamide (Example 1) 5-(Trifluoromethyl)pyridin-3-amine (68.8 mg, 0.424 mmol) was dissolved in dry THF (5 mL) under nitrogen, and the mixture was stirred at −78° C. for 15 minutes. Then, 2.5 M butyllithium in hexane (0.191 mL, 0.478 mmol) was added dropwise over 5 minutes, and the reaction was stirred for 1 hour at −78° C. A solution of Intermediate 18 (50 mg, 0.141 mmol) in THF (5 mL) was added dropwise over 10 minutes, the temperature was raised to room temperature, and the reaction was stirred for 1 hour. The reaction was quenched by the addition of 10 mL of HO, and the solvent was evaporated under reduced pressure. The solid was dissolved in EtOAc and washed with saturated NH4Cl solution. The organic phase was evaporated in vacuo. Purification by FCC on amino silica gel eluting with DCM / EtOH 9:1 gave the title compound (16.8 mg, 0.036 mmol, 25.3% yield). LC-MS(ESI):(Method 3) t R =1.23 min; m / z(M+1)=470.2 1 H NMR (DMSO-d6, 400MHz) δ 10.60(s, 1H), 9.1-9.2(m, 1H), 8.66(s, 1H), 8.56(s, 1H), 8.28(d, 1H, J=1.5Hz), 8.08(d, 1H, J=2.9Hz), 7.99(br s, 1H), 7.9-8.0(m, 1H), 7.79(dd, 1H, J=1.8, 7.9Hz), 7.3-7.4(m, 2H), 7.31(t, 1H, J=2.2Hz), 3.7-3.9(m, 2H), 3.5-3.6(m, 1H), 3.45(br d, 1H, J=7.5Hz), 3.3-3.4(m, 1H), 2.45(s, 3H), 2.3-2.4(m, 1H), 2.22(br d, 1H, J=8.6Hz)

[0220] The following example compounds and intermediates were prepared by reacting the appropriate intermediate with the appropriate amine using the reference method described in the synthesis of Example 1, Step 9. In some cases, 2.5 M n-butyllithium in hexanes was replaced with 1 M LiHMDS in THF. [Table 6-1] [Table 6-2]

[0221] Example 2 - (R)-5-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)nicotinamide [ka] Step 1 - Ethyl (S)-4-methyl-3-(pyrrolidin-3-yl)benzoate (Intermediate 16b) [ka] Intermediate 16b was prepared following the same method as described for the synthesis of intermediate 16. SM: Intermediate 14a: 580 mg (1 equivalent) Amount / Yield: 366mg / 90% LC-MS(ESI):(Method 1) t R =0.50 min; m / z(M+1)=234.0

[0222] Step 2 - Ethyl (S)-3-(1-(5-cyanopyridin-3-yl)pyrrolidin-3-yl)-4-methylbenzoate (Intermediate 17b) [ka] Intermediate 17b was prepared following the same method as described for the synthesis of intermediate 17. SM: Intermediate 16b: 350 mg (1 equivalent) Amount / Yield: 318mg / 63% LC-MS(ESI):(Method 1) t R =1.2 minutes; m / z(M+1)=336.0

[0223] Step 3 - Ethyl (R)-3-(1-(5-carbamoylpyridin-3-yl)pyrrolidin-3-yl)-4-methylbenzoate (Intermediate 18b) [ka] Intermediate 18b was prepared following the same method as described for the synthesis of intermediate 18. SM: Intermediate 17b: 184 mg (1 equivalent) Amount / Yield: 116mg / 60% LC-MS(ESI):(Method 1) t R =0.68 min; m / z(M+1)=354.3

[0224] Step 4 - (R)-5-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)nicotinamide (Example 2) The compound of Example 2 was prepared by the same method as described in step 9 for the synthesis of the compound of Example 1. SM: Intermediate 18b: 50 mg (1 equivalent) 5-(trifluoromethyl)pyridin-3-amine: 69 mg (3 equivalents) Amount / Yield: 15mg / 22.58% LC-MS(ESI):(Method 1) t R =0.71 min; m / z(M+1)=470.0 1 H NMR (DMSO-d6, 400MHz)δ 10.60(s, 1H), 9.15(d, 1H, J=2.2Hz), 8.66(s, 1H), 8.56(s, 1H), 8.29(d, 1H, J=1.5Hz), 8 .08(d, 1H, J=2.9Hz), 8.01(s, 1H), 7.9-8.0(m, 1H), 7.79(dd, 1H, J=1.5, 7.9Hz), 7.44(br s, 1H), 7.3-7.4(m, 2H), 3.7-3.8(m, 2H), 3.5-3.6(m, 1H), 3.3-3.5(m, 2H), 2.50(s, 3H), 2.3-2.4(m, 1H), 2.1-2.3(m, 1H)

[0225] The following example compounds were prepared by reacting intermediate 18 with the appropriate amine following the reference method described for the synthesis of Example 1, Step 9. 2.5 M butyllithium in hexane was replaced with 1 M LiHMDS in THF. Such methods may involve minor variations recognized by those skilled in the art, such as reaction temperature, amounts of reagents / solvents, reaction times, work-up conditions, or chromatographic purification conditions. [Table 7]

[0226] Example 5 - (S)-5-(3-(5-((3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)carbamoyl)-2-methylphenyl)pyrrolidin-1-yl)nicotinamide [ka] Step 1 - (S)-3-(1-(5-carbamoylpyridin-3-yl)pyrrolidin-3-yl)-4-methylbenzoic acid (Intermediate 19) [ka] Intermediate 18 (500 mg, 1.415 mmol) was dissolved in THF (1 mL) and HO (1.5 mL). LiOH (67.8 mg, 2.83 mmol) was then added. The mixture was stirred overnight at rt. The solvent was evaporated in vacuo. Purification by FCC on reverse phase (gradient A:B 100:0 to 75:25 in 10 CV, eluent A: HO:ACN:HCOOH 95:5:0.1, eluent B: HO:ACN:HCOOH 5:95:0.1) gave the title compound (148 mg, 0.455 mmol, 32.2% yield). LC-MS(ESI):(Method 1) t R =0.51 min; m / z(M-1)=324.2

[0227] The following intermediates were prepared using the method described for the synthesis of intermediate 19. [Table 8]

[0228] Step 2 - (S)-5-(3-(5-((3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)carbamoyl)-2-methylphenyl)pyrrolidin-1-yl)nicotinamide (Example 5) Intermediate 19 (60 mg, 0.184 mmol), HATU (140 mg, 0.369 mmol), DIPEA (0.097 ml, 0.553 mmol), and 3-(tert-butyl)-1-methyl-1H-pyrazol-5-amine (56.5 mg, 0.369 mmol) were dissolved in DMF (1.5 ml). The solution was stirred for 24 hours at 50° C. The solution was then diluted with EtOAc (5 mL) and washed with 2 M NaOH (2 mL). The organic layer was evaporated in vacuo. Purification was carried out by FCC on amino silica gel with the elution system DCM / MeOH. The title compound was eluted with 3% MeOH. The appropriate fractions were collected and evaporated in vacuo to give the title compound (30 mg, 0.065 mmol, 35.3% yield). LC-MS(ESI):(Method 3) t R =1.20 min; m / z(M+1)=461.3 1 H NMR (acetone-d6, 400MHz) δ 9.34(br s, 1H), 8.39(s, 1H), 8.11(d, 1H, J=2.6Hz), 8.01(s, 1H), 7.79(br d, 1H, J=7.9Hz), 7.51(br s, 1H), 7.3-7.4(m, 2H), 6.67(br s, 1H), 6.05(s, 1H), 3.8-3.9(m, 2H), 3.4-3.7(m, 6H), 2.51(s, 3H), 2.5-2.5(m, 1H), 2.2-2.4(m, 1H), 1.22(s, 9H)

[0229] The following examples and intermediates were prepared using the methods described for the synthesis of the compound of Example 5, starting from the appropriate intermediates. [Table 9]

[0230] Example 6 - (S)-5-(3-(5-((3-(tert-butyl)isoxazol-5-yl)carbamoyl)-2-methylphenyl)pyrrolidin-1-yl)nicotinamide [ka] Step 1 - (S)-N-(3-(tert-butyl)isoxazol-5-yl)-3-(1-(5-cyanopyridin-3-yl)pyrrolidin-3-yl)-4-methylbenzamide (Example 7) [ka] A 2-5 mL vial was charged with 3-tert-butyl-1,2-oxazol-5-amine (125 mg, 0.894 mmol) and dissolved in 2 mL of THF. The vial was purged with argon and backfilled. A 2 M solution of LDA in THF (1.118 mL, 1.118 mmol) was then added and stirred at room temperature for 6 hours. Intermediate 17 was then dissolved in 2 mL of THF and added to the solution. The resulting solution was stirred overnight at room temperature. LC-MS analysis showed complete conversion. The solvent was evaporated. The resulting solid was dissolved in EtOAc (5 mL) and washed with saturated NaHCO3 solution (5 mL). Purification by FCC on silica gel eluting with a gradient of 40% acetone in n-heptane was performed. The appropriate fractions were combined and evaporated in vacuo to give the title compound (95 mg, 0.221 mmol, 49.5%). LC-MS(ESI):(Method 3) t R =2.28 min; m / z(M+1)=430.2 1H NMR (ACN-d3, 400MHz) δ 9.73(br s, 1H), 8.21(d, 1H, J=2.9Hz), 8.13(s, 1H), 7.83(s, 1H), 7.74(d, 1H, J=7.9Hz), 7.38(d, 1H, J=7.9Hz), 7.21(br s, 1H), 6.40(s, 1H), 3.7-3.9(m, 2H), 3.59(dt, 1H, J=3.3, 8.9Hz), 3.4-3.5(m, 2H), 2.48(s, 3H), 2.4-2.5(m, 1H), 2.2-2.3(m, 1H), 1.31(s, 9H)

[0231] Similarly, the following examples were prepared by reacting intermediate 17 with the appropriate amine and varying the strong base. Example 48: (S)-3-(1-(5-cyanopyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(4-(trifluoromethoxy)pyridin-2-yl)benzamide [ka] SM: Intermediate 17: 75 mg (1 equivalent) 4-(trifluoromethoxy)pyridin-2-amine: 59.7 mg (1.5 equivalents) Base: LiHMDS Amount / yield: 130mg / quantitative LC-MS (ESI, m / z): Method 1, t R =1.27 min, m / z(M+1)=468.2

[0232] Example 49: (S)-3-(1-(5-cyanopyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethoxy)pyridin-2-yl)benzamide [ka] SM: Intermediate 17: 150 mg, (1 equivalent) 5-(trifluoromethoxy)pyridin-2-amine: mg (2 equivalents) Base: LiHMDS Amount / yield: 78mg / 37% LC-MS (ESI, m / z): Method 1, t R =1.27 min, m / z(M+1)=468.08

[0233] Example 50: (S)—N-(5-(tert-butyl)isoxazol-3-yl)-3-(1-(5-cyanopyridin-3-yl)pyrrolidin-3-yl)-4-methylbenzamide [ka] SM: Intermediate 17: 150 mg (1 equivalent) 5-tert-butyl-1,2-oxazol-3-amine: 125 mg (2 equivalents) Base: LiHMDS Amount / Yield: 157mg / 82% LC-MS (ESI, m / z): Method 1, t R =1.24 min, m / z(M+1)=430.3

[0234] Example 120: 4-(difluoromethyl)-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] SM: Intermediate 102: 50 mg (1 equivalent); 5-(trifluoromethyl)pyridin-3-amine: 58 mg (2.5 equivalents) Base: LiHMDS Amount / Yield: 18 mg (27%) LC-MS (ESI, m / z): Method 4, t R =5.91 min, m / z(M+1)=464.2 1H NMR (acetone-d6, 400MHz) δ 10.26(br s, 1H), 9.13(br d, 1H, J=2.2Hz), 8.68(br d, 2H, J=17.8Hz), 8.45(s, 1H), 8.31(s, 1H), 8.14(s, 2H), 8.07(br d, 1H, J=8.1Hz), 7.80(br d, 1H, J=8.1Hz), 7.35(br t, 1H, J=54.7Hz), 4.0-4.1(m, 1H), 3.8-3.9(m, 1H), 3.71(dt, 1H, J=2.8, 8.9Hz), 3.4-3.6(m, 2H), 2.5-2.6(m, 1H), 2.3-2.5(m, 1H)

[0235] The following example compounds were prepared using the methods described for the compound of Example 120 and the appropriate intermediates. [Table 10]

[0236] Example 8 - (S)-3-(1-(5-cyanopyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(6-(trifluoromethyl)pyrimidin-4-yl)benzamide [ka] Similarly, the compound of Example 8 was prepared by reaction of intermediate 17 with the appropriate amine. SM: Intermediate 17: 150 mg (1 equivalent) 6-(trifluoromethyl)pyrimidin-4-amine: 146 mg (2 equivalents) Base: LDA Amount / Yield: 107mg / 53% LC-MS (ESI, m / z): Method 3, t R =2.23 min, m / z(M+1)=453.1 1H NMR(ACN-d3, 400MHz)δ 9.57(br s, 1H), 9.02(s, 1H), 8.62(s, 1H), 8.21(d, 1H, J=2.8Hz), 8.13(s, 1H), 7.86(s, 1H), 7.78(dd, 1H, J=1.5, 7.9Hz), 7.40(d, 1H, J=8.1Hz), 7.21(br s, 1H), 3.7-3.9(m, 2H), 3.4-3.6(m, 3H), 2.50(s, 3H), 2.4-2.5(m, 1H), 2.2-2.3(m, 1H)

[0237] Step 2 - (S)-5-(3-(5-((3-(tert-butyl)isoxazol-5-yl)carbamoyl)-2-methylphenyl)pyrrolidin-1-yl)nicotinamide (Example 6) The compound of Example 6 was prepared using the same method as described for the synthesis of Intermediate 18. SM: Example 7: 90 mg (1 equivalent) Amount / Yield: 41.5mg / 44% LC-MS(ESI):(Method 3) t R =1.38 min; m / z(M+1)=448.1 1 H NMR(ACN-d3, 400MHz)δ 9.90(br s, 1H), 8.2-8.3(m, 1H), 8.12(d, 1H, J=2.8Hz), 7.86(s, 1H), 7.74(d, 1H, J=7.6Hz), 7.37(d, 1H, J=8.1Hz), 7.2-7.3(m, 1H), 6.83(br s, 1H), 6.40(s, 1H), 6.04(br s, 1H), 3.7-3.9(m, 2H), 3.4-3.6(m, 3H), 2.3-2.5(m, 4H), 2.1-2.3(m, 1H), 1.31(s, 9H)

[0238] The following example compounds were prepared using the compound of Example 6 and the methods described for the appropriate intermediates / examples. [Table 11-1] [Table 11-2]

[0239] Example 12 - (S)-4-methyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(4-(trifluoro-methoxy)pyridin-2-yl)benzamide [ka] Step 1 - Ethyl (S)-4-methyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)benzoate (Intermediate 20) [ka] Intermediate 20 was prepared by reacting intermediate 16 with the appropriate bromo derivative following the method described for the synthesis of intermediate 17. SM: Intermediate 16: 3.4g (1 equivalent) 5-Bromopyrimidine: 3.48g (1.5 equivalents) Amount / Yield: 3.4g / 42% LC-MS (ESI, m / z): Method 1, t R =1.03 min, m / z(M+1)=312.2

[0240] Step 2 - (S)-4-Methyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(4-(trifluoromethoxy)pyridin-2-yl)benzamide (Example 12) The compound of Example 12 was prepared by reacting Intermediate 20 with the appropriate amine using the method described for Example 7, Step 1, substituting LiHDMS for LDA. SM: Intermediate 20: 50 mg (1 equivalent) 4-(trifluoromethoxy)pyridin-2-amine: (3.5 equivalents) Amount / Yield: 52mg / 73% LC-MS (ESI, m / z): Method 3, t R =2.06 min, m / z(M+1)=444.1 1H NMR (acetone-d6, 400MHz) δ 9.92 (br s, 1H), 8.43(s, 1H), 8.40(d, 1H, J=5.7Hz), 8.35(s, 1H), 8.1-8.2(m, 3H), 7.91(dd, 1H, J=1.8, 7.9Hz), 7.40(d, 1H, J=7.9Hz), 7.0-7.1(m, 1H), 3.8-4.0(m, 2H), 3.66(dt, 1H, J=3.2, 8.8Hz), 3.4-3.6(m, 2H), 2.53(s, 3H), 2.5-2.5(m, 1H), 2.3-2.4(m, 1H)

[0241] The following example compounds were prepared using the method described for Example 12, Step 2 and the appropriate amine. [Table 12-1] [Table 12-2] [Table 12-3]

[0242] Example 22 - (S)-3-(1-(5-(difluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] Step 1 - tert-Butyl (S)-3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidine-1-carboxylate (Intermediate 21) [ka] Intermediate 21 was prepared following the same method as described for the synthesis of intermediates 15a and 15b. SM: Intermediate 14b: 9.50g (1 equivalent) 5-(trifluoromethyl)pyridin-3-amine: 9.70 (2.1 equivalents) Amount / Yield: 8.23g / 64% LC-MS (ESI, m / z): Method 3, t R =2.40 min, m / z(M+1)=450.2 1 H NMR (ACN-d3, 400MHz)δ 9.08(br s, 1H), 9.05(d, 1H, J=2.0Hz), 8.63(s, 1H), 8.58(s, 1H), 7.82(d, 1H, J=1.3Hz), 7.72 (dd, 1H, J=1.8, 7.9Hz), 7.34(d, 1H, J=7.9Hz), 3.75(dd, 1H, J=7.7, 10.3Hz), 3.64(br d, 1H, J=4.2Hz), 3.54(ddd, 1H, J=3.2, 8.0, 10.7Hz), 3.3-3.4(m, 2H), 2.43(s, 3H), 2.22(br d, 1H, J=2.4Hz), 2.0-2.1(m, 1H), 1.44(br s, 9H)

[0243] Step 2 - (S)-4-Methyl-3-(pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide Hydrochloride (Intermediate 22) [ka] Intermediate 21 (8.2 g, 18.24 mmol) was dissolved in 22 mL of 4 M HCl in dioxane (22.80 mL, 91 mmol) and stirred at rt for 6 h. Since the reaction was not complete, TFA (2 mL, 30.4 mmol) was added and the solution was stirred at rt for 1 h. The solvent was evaporated in vacuo to give the title compound in quantitative yield, which was used in the next step without further purification. LC-MS (ESI, m / z): Method 1, t R =0.55 min, m / z(M+1)=350.1

[0244] The following intermediate was prepared using the method described in Intermediate 22. [Table 13]

[0245] Step 3 - (S)-3-(1-(5-(difluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 22) The compound of Example 22 was prepared by reacting Intermediate 22 with the appropriate bromo derivative following the procedure described for the synthesis of Intermediate 17. SM: Intermediate 22: 80 mg (1 equivalent, 0.229 mmol) 3-Bromo-5-(difluoromethyl)pyridine: 71.4 mg (1.5 equivalents) Amount / yield (31 mg, 28%) LC-MS (ESI, m / z): Method 4, t R =7.79 min, m / z(M+1)=477.2 1 H NMR(MeOH-d4, 400MHz)δ 9.06(s, 1H), 8.58-8.60(m, 2H), 8.0-8.1(m, 1H), 7.94(d, 2H, J=9.9Hz), 7.77(d, 1H, J=7.4Hz), 7.37(d, 1H, J=7.9Hz), 7.14(br s, 1H), 6.80(t, 1H, J=55.7Hz), 3.8-3.9(m, 2H), 3.63(dt, 1H, J=3.3, 8.8Hz), 3.4-3.6(m, 2H), 2.50(s, 3H), 2.4-2.5(m, 1H), 2.2-2.4(m, 1H)

[0246] The following example compounds were prepared using the appropriate bromo derivatives following the procedure described for Example 22, Step 3. [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4] [Table 14-5] [Table 14-6] [Table 14-7] [Table 14-8] [Table 14-9] [Table 14-10] [Table 14-11] [Table 14-12] [Table 14-13]

[0247] Similarly, the following intermediates were synthesized according to the methods described: [Table 15-1] [Table 15-2] [Table 15-3]

[0248] Example 38 - (S)-5-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)-N-(oxetan-3-yl)nicotinamide [ka] Step 1 - Methyl (S)-5-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)nicotinate (Intermediate 23) [ka] Intermediate 23 was prepared following the same method as described for the synthesis of intermediate 17. SM: Intermediate 22: 746 mg (1 equivalent) Methyl 5-bromonicotinate: 692 mg (1.5 equivalents) Amount / Yield: 389mg / 38% LC-MS (ESI, m / z): Method 6, t R =1.74 min, m / z(M+1)=485.5 1 H NMR (400MHz, DMSO-d6)δ 10.66(s, 1H), 9.20(d, J=2.1Hz, 1H), 8.71(s, 1H), 8.60(t, J=2.3Hz, 1H), 8.39(d, J=1.8 Hz, 1H), 8.25(d, J=2.9Hz, 1H), 7.96(d, J=1.6Hz, 1H), 7.83(dd, J=1.8, 7.9Hz, 1H), 7.43( d, J=8.0Hz, 1H), 7.38-7.36(m, 1H), 3.88(s, 3H), 3.86-3.80(m, 2H), 3.66-3.60(m, 1H), 3 .57-3.48(m, 1H), 3.47-3.41(m, 1H), 2.50(s, 3H), 2.42-2.41(m, 1H), 2.31-2.21(m, 1H).

[0249] Step 2 - Lithium (S)-5-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)nicotinate (Intermediate 24) [ka] To a solution of Intermediate 23 (273 mg, 0.564 mmol, 1.00 equiv) in THF (5.00 mL) was added a solution of LiOH HO (24 mg, 0.564 mmol, 1.00 equiv) in HO (2.00 mL), and the reaction mixture was stirred at 65 °C for 4 h. The reaction mixture was concentrated in vacuo to give the title compound (228 mg, 0.479 mmol, 85%). LC-MS (ESI, m / z): Method 6, t R =1.45 min, m / z(M+1)=471.5 1 H NMR (400MHz, DMSO-d6) δ 12.4 (s, 1H). 9.36(d, J=1.4Hz, 1H), 8.79(s, 1H), 8.64(s, 1H), 8.41(s, 1H), 8.29(s, 1H), 7.80(dd, J=1.4, 7.9Hz, 1H), 7.54(d, J=2.1Hz, 1H), 7 .35(d, J=8.0Hz, 1H), 7.20(s, 1H), 3.67-3.53(m, 2H), 3.09(t, J=9.1Hz, 1H), 2.43(s, 3H), 2.41-2.34(m, 1H), 2.24-2.22(m, 1H).

[0250] Step 3 - (S)-5-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)-N-(oxetan-3-yl)nicotinamide (Example 38) To a solution of intermediate 24 (lithium salt, 88 mg, 0.185 mmol, 1.00 equiv.), HATU (105 mg, 0.277 mmol, 1.50 equiv.), and DIPEA (80 μL, 0.462 mmol, 2.50 equiv.) in DMF (2.50 mL) was added 3-aminooxetane (13 μL, 0.185 mmol, 1.00 equiv.), and the mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc (25 mL), washed successively with water (25 mL), HO:brine (1:1) (25 mL), and brine (25 mL), dried over MgSO, filtered, and concentrated in vacuo. The material was purified by preparative HPLC to give the title compound (45 mg, 0.0844 mmol, 46%). LC-MS (ESI, m / z): Method 5, t R=3.54 min, m / z(M+1)=526.2 1 H NMR (400MHz, DMSO-d6)δ 10.64(s, 1H), 9.19-9.12(m, 2H), 8.69-8.68(m, 1H), 8.59(t, J=2.1Hz, 1H), 8.32(d, J=1.8Hz, 1 H), 8.13(d, J=3.0Hz, 1H), 7.96(d, J=1.5Hz, 1H), 7.82(dd, J=1.8, 7.8Hz, 1H), 7.41(d, J=8.1Hz , 1H), 7.34(t, J=2.3Hz, 1H), 5.05-4.98(m, 1H), 4.77(t, J=6.9Hz, 2H), 4.59(t, J=6.4Hz, 2H), 3 .85-3.79(m, 2H), 3.64-3.59(m, 1H), 3.53-3.36(m, 2H), 2.45-2.41(m, 1H), 2.28-2.21(m, 1H).

[0251] The following example compounds were prepared using the method described for Example 38, Step 3, using the appropriate amine. [Table 16]

[0252] Example 41 - (S)-3-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)-N-(oxetan-3-yl)isonicotinamide [ka] Step 1 - Methyl (S)-3-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)isonicotinate (Intermediate 25) [ka] A suspension of intermediate 22 (190 mg, 0.544 mmol, 1.00 equiv), methyl 3-fluoroisonicotinate (253 mg, 1.63 mmol, 3.00 equiv), and DIPEA (0.28 mL, 1.63 mmol, 3.00 equiv) in DMSO (10.00 mL) was stirred at rt for 1 day. The reaction mixture was heated to 50 °C and stirred for 3 days. The reaction mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (2 × 30 mL) and brine (saturated aqueous, 50 mL). The organic phase was dried over MgSO and concentrated in vacuo. The residue was purified by FCC on silica gel eluting with 0 to 100% 10% 7N NH in MeOH in cyclohexane to give the title compound (150 mg, 0.310 mmol, 57%). LC-MS (ESI, m / z): Method 6, t R =1.68 min, m / z(M+1)=485.5 1 H NMR (400MHz, CDCl3)δ 9.12(s, 1H), 8.91(d, J=2.3Hz, 1H), 8.62-8.51(m, 2H), 8.37(s, 1H), 8.08(d, J=5.0Hz, 1H), 7.88-7.80(m, 2H), 7.42(d, J=4.9Hz, 1H), 7.33( d, J=8.2Hz, 1H), 3.94(s, 3H), 3.87-3.80(m, 2H), 3.63-3.47(m, 2H), 3.03-2.96(m, 1H), 2.47(s, 3H), 2.43-2.31(m, 1H), 1.97-1.88(m, 1H).

[0253] The following example compounds and intermediates were prepared using the method described for Intermediate 25, starting from the appropriate fluoro or chloro derivative and ACN as solvent at various temperatures between rt and 80°C. [Table 17-1] [Table 17-2]

[0254] Step 2 - Lithium (S)-3-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)isonicotinate (Intermediate 26) [ka] Intermediate 26 was prepared following the same method as described for Intermediate 24. SM: Intermediate 25: 150 mg, 1.00 equivalent. Amount / Yield: 148mg / 73.3% LC-MS (ESI, m / z): Method 6, t R =1.33 min, m / z(M+1)=471.5

[0255] Step 3 - S)-3-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)-N-(oxetan-3-yl)isonicotinamide (Example 41) The compound of Example 41 was prepared with various corresponding amines following the same method as described in Step 3 of Example 38. SM: Intermediate 26: 74 mg, 1.00 equivalent Oxetan-3-amine: 16.4 μL, 2 equivalents. Amount / yield: 5.1mg / 8.2% LC-MS (ESI, m / z): Method 6, t R =3.39 min, m / z(M+1)=526.2 1H NMR (400MHz, DMSO-d6)δ 10.63(s, 1H), 9.22(d, J=6.0Hz) 9.17(d, J=2.0), 8.69(s, 1H), 8.59(s, 1H), 8.17(s, 1H), 7.93-7.89(m, 2H), 7.81(dd, J=1.8, 7.8Hz, 1H), 7.40(d, J=7.8Hz, 1H), 7.14(d, J=4.8Hz, 1H), 4.92-4.86(m, 1H), 4.74-4.68(m, 2H), 4.54-4.44(m, 2H), 3.74-3.66(m, 2H) 3.51-3.54(m, 2H), 2.44(s, 3H), 2.36-2.29(m, 1H), 2.18-2.12(m, 1H).

[0256] Example 128 - (S)-3-(1-(imidazo[1,5-a]pyrazin-8-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] To a solution of intermediate 22 (50 mg, 0.143 mmol) in DMF (1 mL) was added sodium hydride (17.17 mg, 0.429 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 h, then 8-chloroimidazo[1,5-a]pyrazine (26.4 mg, 0.172 mmol) was added at 0° C., and the mixture was stirred overnight at rt. The mixture was quenched with water and extracted with DCM. The organic layers were combined and concentrated in vacuo. After purification by FCC (NH silica, 50% acetone in n-heptane), the appropriate fractions were combined and evaporated in vacuo to give the title compound (18 mg, 0.04 mmol, 27% yield). LC-MS (ESI, m / z): Method 4, t R =4.43 min, m / z(M+1)=467.3 1H NMR (400MHz, acetone-d6) δ ppm 10.01(1H, br s) 9.11(1H, s) 8.70(1H, s) 8.63(1H, s) 8.22(1H, s) 8.11(1H, s) 7.86(1H, dd, J=7.89, 1.75Hz) 7.77(1H, s) 7.55(1H, d, J=4.82Hz) 7.42(1H, d, J=7.89Hz) 7.04(1H, d, J=4.82Hz) 4.33(1H, br dd, J=10.19, 7.78Hz) 4.17(1H, br t, J=8.33Hz) 3.88-4.02(2H, m) 3.75-3.86(1H, m) 2.55(3H, s) 2.48(1H, dtd, J=12.25, 6.43, 6.43, 2.52Hz) 2.24-2.35(1H, m)

[0257] Example 42 - (S)-4-methyl-3-(1-(2-nitropyridin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] Step 1 - (S)-4-Methyl-3-(1-(2-nitropyridin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Intermediate 27) [ka] To a solution of 3-fluoro-2-nitropyridine (50.0 mg, 0.352 mmol, 1.00 equiv) and Intermediate 22 (129 mg, 0.369 mmol, 1.05 equiv) in ACN (3.50 mL) was added KCO (anhydrous, 146 mg, 1.06 mmol, 3.00 equiv) in one portion, and the resulting mixture was stirred at 50 °C overnight. The cooled reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic phase was washed with brine (100 mL), dried over MgSO, filtered, and concentrated in vacuo to give the title compound (157 mg, 0.333 mmol, 95%). LC-MS (ESI, m / z): Method 6, t R=1.55 min, m / z(M+1)=472.3 1 H NMR (400MHz, DMSO-d6)δ 10.71(s, 1H), 9.24(d, J=1.8Hz, 1H), 8.75(s, 1H), 8.65(s, 1H), 7.99(d, J=1.0Hz, 1H), 7.88(d, J=5.6Hz, 2H), 7.71-7.68(m, 1 H), 7.62(dd, J=4.0, 8.6Hz, 1H), 7.46(d, J=7.8Hz, 1H), 3.86-3.78(m, 1H), 3.61-3.48(m, 2H), 2.50(s, 3H), 2.39-2.26(m, 3H).

[0258] Step 2 - (S)-3-(1-(2-aminopyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 42) A suspension of intermediate 27 (150 mg, 0.318 mmol, 1.00 equiv) and Pd / C (10% dry, 5.1 mg, 4.77 μmol, 0.0150 equiv) in EtOH (3.0 mL) and EtOAc (0.5 mL) was stirred under a hydrogen atmosphere at rt for 5 h. Additional Pd / C (10% dry, 29 mg, 0.0270 mmol, 0.0850 equiv) was added, and the solution was stirred under a hydrogen atmosphere at rt overnight. The reaction mixture was filtered through Celite®, washed with EtOAc (50 mL), and then concentrated in vacuo. The material was purified twice by preparative HPLC to give the title compound (16 mg, 0.0363 mmol, 11%). LC-MS (ESI, m / z): Method 5, t R =3.61 min, m / z(M+1)=442.3 1H NMR (400MHz, DMSO-d6)δ 10.68(s, 1H), 9.21(d, J=2.3Hz, 1H), 8.71(s, 1H), 8.64(t, J=2.0Hz, 1H), 8.04(d, J=1.8Hz, 1H), 7.80(dd, J=1.9, 8.0Hz, 1H), 7.62(dd, J=1.4, 4.9Hz, 1H), 7.39(d, J=8.1Hz, 1H), 7.17(dd, J=1.5 , 7.6Hz, 1H), 6.55(dd, J=4.8, 7.6Hz, 1H), 5.48(s, 2H), 3.79-3.72(m, 1H), 3.50-3.44(m, 1H), 3. 28-3.22(m, 1H), 3.15(dd, J=7.8, 8.8Hz, 1H), 2.46(s, 3H), 2.44-2.41(m, 1H), 2.10-2.09(m, 1H).

[0259] Example 43 - 4-Methyl-3-[(3S)-1-(1H-pyrazolo[3,4-b]pyridin-5-yl)pyrrolidin-3-yl]-N-[5-(trifluoromethyl)-3-pyridyl]benzamide [ka] Step 1 - 4-Methyl-N-[5-(trifluoromethyl)-3-pyridyl]-3-[(3S)-1-[1-(2-trimethyl-silylethoxymethyl)pyrazolo[3,4-b]pyridin-5-yl]pyrrolidin-3-yl]benzamide (Intermediate 28) [ka] To a degassed solution of Intermediate 5 (94 mg, 0.286 mmol, 1.00 equiv), Intermediate 22 (100 mg, 0.286 mmol, 1.00 equiv), and NaOtBu (96 mg, 0.858 mmol, 3.00 equiv) in dioxane (3 mL) was added tBuBrettPhos Pd G3 (49 mg, 0.057 mol, 0.20 equiv), and the mixture was degassed for 5 min, heated at 80 °C, and stirred overnight. The solution was cooled to rt, diluted with EtOAc, washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. LC-MS (ESI, m / z): Method 6, t R=1.99 min, m / z(M+1)=597.7

[0260] Step 3 - 4-Methyl-3-[(3S)-1-(1H-pyrazolo[3,4-b]pyridin-5-yl)pyrrolidin-3-yl]-N-[5-(trifluoromethyl)-3-pyridyl]benzamide (Example 43) To a solution of intermediate 28 in 1,4-dioxane (1 mL) was added HCl (4 M in 1,4-dioxane, 1.0 mL, 4.00 mmol, 62.8 equiv.), and the mixture was stirred at rt for 5 h and then concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (4.0 mg, 8.60 μmol, 13%). LC-MS (ESI, m / z): Method 5, t R =4.67 min, m / z(M+1)=467.3 1 H NMR (400 MHz, DMSO-d) δ 13.20(s, 1H), 10.64(s, 1H), 9.18(d, J=2.3Hz, 1H), 8.68-8.67(m, 1H), 8.58 (t, J=2.1Hz, 1H), 8.19(d, J=2.5Hz, 1H), 7.98(d, J=1.5Hz, 1H), 7.90(s, 1H) , 7.81(dd, J=1.9, 8.0Hz, 1H), 7.41(d, J=8.1Hz, 1H), 7.22(d, J=2.3Hz, 1H), 3.86-3.75(m, 2H), 3.63-3.36(m, 3H), 2.46-2.41(m, 1H), 2.27-2.18(m, 1H).

[0261] The following example compounds were prepared using the methods described in Example 43, using the appropriate intermediates. [Table 18]

[0262] Example 130 - (S)-3-(1-(2-acetamidopyrimidin-5-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] Intermediate 73 (100 mg, 0.226 mmol) was dissolved in DCM (3 ml) and DIPEA (0.118 ml, 0.68 mmol) was added, followed by acetyl chloride (0.016 ml, 0.23 mmol) in one portion. The reaction mixture was stirred at rt for 1 h. The solution was quenched with saturated NaHCO3 solution and extracted with DCM. Purification was carried out by FCC (silica NH eluting with 10% MeOH in DCM). The appropriate fractions were combined and evaporated in vacuo to give the title compound (23 mg, 0.047 mmol, 21.00% yield). LC-MS (ESI, m / z): Method 5, t R =5.7 minutes, m / z(M+1)=485.31 1 H NMR (400MHz, DMSO-d6)δ ppm 10.64(1H, s) 10.10(1H, s) 9.19(1H, d, J=2.41Hz) 8.70(1H, s) 8.60(1H, s) 8.09(2H, s) 7.95(1H, d, J=1.75Hz) 7.79-7.84(1H, m) 7.41(1H, d, J=8.11Hz) 3.72-3.84(2H, m) 3.58(1H, td, J=8.71, 2.96Hz) 3.40-3.48(1H, m) 3.35(1H, br s) 2.47-2.48(3H, m) 2.40(1H, br dd, J=6.14, 2.85Hz) 2.15-2.27(1H, m) 2.06(3H, s)

[0263] Example 100 - (S)-3-(1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] To a solution of intermediate 62 (100 mg, 0.187 mmol, 1.00 equiv) in DCM (1 mL) was added TFA (3.0 mL, 39.2 mmol, 210 equiv), and the mixture was stirred at 80 °C for 3 h. The reaction mixture was concentrated in vacuo, and 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 (34 mg, 0.0817 mmol, 44%). LC-MS (ESI, m / z): Method 5, t R =4.0 min, m / z(M+1)=416.5 1 H NMR (400 MHz, DMSO-d) δ 12.22(s, 1H), 10.64(s, 1H), 9.18(d, J=2.3Hz, 1H), 8.69-8.67(m, 1H), 8. 60(t, J=2.1Hz, 1H), 7.95(d, J=1.5Hz, 1H), 7.78(dd, J=1.8, 7.8Hz, 1H), 7 .37(d, J=7.8Hz, 1H), 7.14(s, 2H), 3.76-3.70(m, 1H), 3.41(t, J=8.3Hz, 1 H), 3.20-3.07(m, 2H), 2.44(s, 3H), 2.41-2.31(m, 1H), 2.10-2.00(m, 1H).

[0264] The following example compounds were prepared using the method described in Example 100 at various temperatures from rt to 80°C. [Table 19]

[0265] Example 104 - 3-((3R,4S)-3-(4-(hydroxymethyl)-1-(pyrimidin-5-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide and 3-((3S,4R)-3-(4-(hydroxymethyl)-1-(pyrimidin-5-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] Step 1 - (E)-3-(5-(ethoxycarbonyl)-2-methylphenyl)acrylic acid (Intermediate 74) [ka] To a solution of ethyl 3-bromo-4-methylbenzoate (6.53 ml, 37.0 mmol) in DMF (45 mL) was added TEA (25.8 ml, 185 mmol), triphenylphosphine (1.942 g, 7.40 mmol), palladium acetate (0.416 g, 1.851 mmol), and prop-2-enoic acid (3.81 ml, 55.5 mmol). The reaction was stirred at 110 °C. The mixture was concentrated and then basified with saturated NaHCO solution. The product was extracted with DCM after oxidation of the aqueous phase. The organic layer was dried on a phase separator, and the remaining solvent was removed under reduced pressure. The crude material was purified by FCC (100% heptane to 100% ethyl acetate) to give the title compound (5.18 g, 22.11 mmol, 60%). LC-MS(ESI): Method 1, t R =0.94 min; m / z(M+1)=235.23

[0266] Step 2 - (3S,4R)-1-benzyl-4-(5-(ethoxycarbonyl)-2-methylphenyl)pyrrolidine-3-carboxylic acid and (3R,4S)-1-benzyl-4-(5-(ethoxycarbonyl)-2-methylphenyl)pyrrolidine-3-carboxylic acid (Intermediate 75) [ka] A solution of intermediate 74 (2.36 g, 10.07 mmol) in neat N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (10.31 ml, 40.3 mmol) was stirred at 80° C. for 1 h. The crude mixture was concentrated and then diluted with a 1:1 mixture of MTBE / heptane to precipitate the desired product, which was filtered to give the title compound (3.63 g, 9.87 mmol, 98%). LC-MS(ESI): Method 1, t R =0.66 minutes.

[0267] Step 3 - Ethyl 3-((3R,4S)-1-benzyl-4-(hydroxymethyl)pyrrolidin-3-yl)-4-methylbenzoate and Ethyl 3-((3S,4R)-1-benzyl-4-(hydroxymethyl)pyrrolidin-3-yl)-4-methylbenzoate (Intermediate 76) [ka] To a suspension of intermediate 75 (3.17 g, 8.63 mmol) in THF (45 mL), oxalyl chloride (2.265 mL, 25.9 mmol) was added, and the mixture was stirred until the formation of the acyl chloride intermediate. Lithium borohydride (0.570 g, 26.2 mmol) was added, and the mixture was stirred at rt overnight. The reaction crude was purified by FCC (100% heptane to 100% ethyl acetate) to give the title compound (1.87 g, 5.29 mmol, 61%).

[0268] Step 4 - Ethyl 3-((3R,4S)-4-(hydroxymethyl)pyrrolidin-3-yl)-4-methylbenzoate and Ethyl 3-((3S,4R)-4-(hydroxymethyl)pyrrolidin-3-yl)-4-methylbenzoate (Intermediate 77) [ka] To a solution of intermediate 76 (1.87 g, 5.29 mmol) in EtOH (25 mL) was added palladium on carbon (1.5 g, 14.10 mmol) and 0.2 M HCl to an acid pH. The reaction flask was placed under vacuum and then under a stream of H2. The reaction crude was stirred overnight. The mixture was filtered and the residual solvent was removed under reduced pressure. The crude was used directly in the next step. LC-MS(ESI): Method 1, t R =0.45 min; m / z(M+1)=264.22

[0269] Step 5 - tert-butyl (3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(5-(ethoxycarbonyl)-2-methylphenyl)pyrrolidine-1-carboxylate and tert-butyl (3R,4S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(5-(ethoxycarbonyl)-2-methylphenyl)pyrrolidine-1-carboxylate (Intermediate 78) [ka] To a solution of intermediate 77 (1.39 g, 5.3 mmol) in DCM (30 mL) was added TEA (2.72 ml, 19.6 mmol), 4-dimethylaminopyridine (0.065 g, 0.53 mmol), and di-tert-butyl dicarbonate (1.732 g, 7.9 mmol). After Boc protection was complete, tert-butyldimethylchlorosilane (2.291 ml, 13.2 mmol) and TEA were added. The reaction was stirred at rt for 30 min. The product was extracted with DCM after washing the crude with 2N HCl. The organic layer was dried on a phase separator cartridge, and residual solvent was removed under pressure. The crude was first purified by FCC (gradient: 100% heptane to 100% AcOEt) to give the title compound (230 g, 0.48 mmol, 9.1%). LC-MS (ESI): Method 14, t R = 3.60 min; m / z (M+1) = not ionized

[0270] Step 6 - tert-butyl (3S,4R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidine-1-carboxylate and tert-butyl (3R,4S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidine-1-carboxylate (Intermediate 79) [ka] The intermediate was prepared according to the method of Example 1, Step 9. SM: Intermediate 78: 230 mg (1 equivalent); 5-(trifluoromethyl)pyridin-3-amine: 195 mg (2.5 equivalents) Amount / Yield: 130mg / 46% LC-MS (ESI): Method 14, t R = 1.06 min; m / z (M+1) = not ionized

[0271] Step 7 - 3-((3R,4S)-4-(hydroxymethyl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide and 3-((3S,4R)-4-(hydroxymethyl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Intermediate 80) [ka] Intermediate 80 was prepared following the procedure described for Intermediate 16. SM: Intermediate 79: 133mg Amount / Yield: 85mg / 100% LC-MS(ESI): Method 13, t R =0.53 min; m / z(M+1)=380.17

[0272] Step 8 - 3-((3R,4S)-4-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide and 3-((3S,4R)-4-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Intermediate 81) [ka] Intermediate 80 (85 mg, 0.224 mmol) was dissolved in DCM (2 mL) and TEA (0.120 ml, 0.861 mmol) was added. Then, tert-butyldimethylchlorosilane (0.092 ml, 0.53 mmol) was added. The solution was quenched with NaHCO3 solution and extracted with DCM. The organic phase was evaporated in vacuo to give the title compound (110 mg, 0.223 mmol, 99%). LC-MS(ESI): Method 1, t R =0.84 min; m / z(M+1)=494.26

[0273] Step 9 - 3-((3R,4S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-(pyrimidin-5-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide and 3-((3S,4R)-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-(pyrimidin-5-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Intermediate 82) [ka] Intermediate 82 was prepared according to the method of Intermediate 17 using RuPhos / Pd(dppf)Cl 2 as catalyst. SM: Intermediate 81: 110 mg (1 equivalent); 5-Bromopyrimidine: 53 mg (1.5 equivalents) Amount / Yield: 29mg / 25% LC-MS(ESI): Method 1, t R =1.47min;m / z(M+1- t-But)=572.35

[0274] Step 10 - 3-((3R,4S)-3-(4-(hydroxymethyl)-1-(pyrimidin-5-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide and 3-((3S,4R)-3-(4-(hydroxymethyl)-1-(pyrimidin-5-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 104) Intermediate 82 (29 mg, 0.05 mmol) was dissolved in water (0.5 mL) and ethanol (1.5 mL), and 37% HCl (4.17 μl, 0.051 mmol) was added. The solution was stirred at rt overnight. The solvent was concentrated in vacuo, and 1 mL of saturated NaHCO solution was added and diluted with DCM. The organic phase was washed with HO, then evaporated and purified by SCX eluting with NH37 MeOH to give the title compound (10 mg, 0.022 mmol, 43%). LC-MS (ESI, m / z): Method 4, t R=5.32 min, m / z(M+1)=458.3 1 H NMR (400MHz, acetone-d6) δ ppm 10.03(1H, br s) 9.11(1H, d, J=1.75Hz) 8.69(1H, s) 8.63(1H, s) 8.45(1H, s) 8.13(2H, s) 8.11(1H, s) 7.85(1H, dd, J=7.89, 1.75Hz) 7.40(1H, d, J=7.89Hz) 3.88-3.94(1H, m) 3.83(1H, d, J=8.77Hz) 3.78(1H, dd, J=9.43, 8.11Hz) 3.71(1H, br d, J=4.38Hz) 3.54-3.64(2H, m) 3.40-3.49(2H, m) 2.53(3H, s)

[0275] Example 105 - 3-((3S,4R)-3-(4-hydroxy-1-(pyrimidin-5-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide and 3-((3R,4S)-4-hydroxy-1-(pyrimidin-5-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] Step 1 - Ethyl (E)-4-methyl-3-(3-oxobut-1-en-1-yl)benzoate (Intermediate 83) [ka] Intermediate 83 was prepared according to the method of Example 104, Step 1. SM: Ethyl 3-bromo-4-methylbenzoate: 6 g (1 eq.); but-3-en-2-one: 5.19 g (3 eq.) Amount / Yield: 5g / 87% LC-MS(ESI): Method 13, t R =1.09 min; m / z(M+1)=233.22

[0276] Step 2 - Ethyl 3-((3R,4S)-4-acetyl-1-benzylpyrrolidin-3-yl)-4-methylbenzoate and Ethyl 3-(4-acetyl-1-benzylpyrrolidin-3-yl)-4-methylbenzoate and Ethyl 3-((3S,4R)-4-acetyl-1-benzylpyrrolidin-3-yl)-4-methylbenzoate (Intermediate 84) [ka] Intermediate 84 was prepared according to the method of Example 104, Step 2. SM: Intermediate 83: 5 g (1 eq.); N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine: 7.67 g (1.5 eq.) Amount / Yield: 7.7g / 98% LC-MS(ESI): Method 13, t R =0.67 min; m / z(M+1)=366.29

[0277] Step 3 - Ethyl 3-((3R,4S)-4-acetylpyrrolidin-3-yl)-4-methylbenzoate and Ethyl 3-((3S,4R)-4-acetylpyrrolidin-3-yl)-4-methylbenzoate (Intermediate 85) [ka] Intermediate 85 was prepared following the method of Example 104, Step 4 in quantitative yield. SM: Intermediate 84: 7.7g (1 equivalent); LC-MS(ESI): Method 13, t R =0.51 min; m / z(M+1)=276.26

[0278] Step 4 - tert-butyl (3S,4R)-3-acetyl-4-(5-(ethoxycarbonyl)-2-methylphenyl)pyrrolidine-1-carboxylate and tert-butyl (3R,4S)-3-acetyl-4-(5-(ethoxycarbonyl)-2-methylphenyl)pyrrolidine-1-carboxylate (Intermediate 86) [ka] Intermediate 86 was prepared following the method of Example 104, Step 3 in quantitative yield. SM: Intermediate 85: 2.8g (1 equivalent); Amount / Yield: 1.5g / 40% LC-MS(ESI): Method 13, t R = 1.27 min; m / z (M+1-BOC) = 276.26

[0279] Step 5 - tert-butyl (3R,4S)-3-acetoxy-4-(5-(ethoxycarbonyl)-2-methylphenyl)pyrrolidine-1-carboxylate and tert-butyl (3S,4R)-3-acetoxy-4-(5-(ethoxycarbonyl)-2-methylphenyl)pyrrolidine-1-carboxylate (Intermediate 87) [ka] To a solution of intermediate 86 (1.56 g, 4.15 mmol) in DCM (15 mL) was added trifluoroacetic anhydride (3465 mL, 24.93 mmol), urea compound and hydrogen peroxide (1:1) (2.345 g, 24.9 mmol), and disodium phosphate (1.769 g, 12.46 mmol). The crude material was diluted with DCM and washed with NaHCO solution, and the organic layer was then dried on a phase separator cartridge. The remaining solvent was evaporated in vacuo, and the crude material was used directly in the next step. (810 mg, 2.069 mmol, 50%) LC-MS(ESI): Method 13, t R = 1.32 min; m / z (M+1- t-butyl) = 292.13

[0280] Step 6 - tert-butyl (3R,4S)-3-(5-(ethoxycarbonyl)-2-methylphenyl)-4-hydroxypyrrolidine-1-carboxylate and tert-butyl (3S,4R)-3-(5-(ethoxycarbonyl)-2-methylphenyl)-4-hydroxypyrrolidine-1-carboxylate (Intermediate 88) [ka] To a solution of intermediate 87 (0.70 g, 1.79 mmol) in EtOH (20 mL) was added potassium carbonate (0.741 g, 5.36 mmol) and the reaction was stirred at 40 °C overnight. The mixture was concentrated, then diluted with DCM and washed with NaHCO solution. The organic layer was dried over a phase separator cartridge and purified by FCC (1 / 1 heptane / AcOEt) to give the title compound (480 mg, 1.39 mmol, 78%). LC-MS (ESI): Method 14, t R = 1.12 min; m / z (M+1- t-butyl) = 250.22

[0281] Step 7 - Ethyl 3-((3R,4S)-4-hydroxypyrrolidin-3-yl)-4-methylbenzoate and Ethyl 3-((3S,4R)-4-hydroxypyrrolidin-3-yl)-4-methylbenzoate m (Intermediate 89) [ka] Intermediate 89 was prepared according to the method of Example 43, Step 3. SM: Intermediate 88: 213 mg (1 equivalent); Amount / Yield: 152mg / 100% LC-MS(ESI): Method 13, t R =0.44 min; m / z(M+1)=250.27

[0282] Step 8 - Ethyl 3-((3R,4S)-4-hydroxy-1-(pyrimidin-5-yl)pyrrolidin-3-yl)-4-methylbenzoate and Ethyl 3-((3S,4R)-4-hydroxy-1-(pyrimidin-5-yl)pyrrolidin-3-yl)-4-methylbenzoate (Intermediate 90) [ka] The intermediate was prepared according to the method of Intermediate 17 using RuPhos / Pd(dppf)Cl2 as catalyst. SM: Intermediate 89: 152 mg (1 equivalent); 5-Bromopyrimidine: 116 mg (1.2 equivalents) Amount / Yield: 76mg / 38% LC-MS (ESI, m / z): Method 13, t R =0.80 min, m / z(M+1)=328

[0283] Step 9 - 3-((3S,4R)-3-(4-hydroxy-1-(pyrimidin-5-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide and 3-((3R,4S)-4-hydroxy-1-(pyrimidin-5-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 105) The compound of Example 105 was prepared according to the method of Example 104, Step 6. SM: Intermediate 90: 75 mg (1 equivalent); 5-(trifluoromethyl)pyridin-3-amine: 130 mg (3.5 equivalents) Amount / yield: 30mg / 30% LC-MS(ESI): Method 4, t R =4.44 min; m / z(M+1)=444.2 1 H NMR(DMSO-d6, 400MHz)δ 10.59(br s, 1H), 9.12(d, 1H, J=2.4Hz), 8.65(s, 1H), 8.53(t, 1H, J=1.9Hz), 8.16(s, 2H), 7.8-7.8(m, 2H), 7.38(d, 1H, J=8.6Hz), 6.8-7.0(m, 1H), 5. 45(d, 1H, J=5.3Hz), 4.44(quin, 1H, J=5.5Hz), 3.8-3.9(m, 1H), 3.6-3.7(m, 2H), 3.45(dd, 1H, J=6.7, 9.8Hz), 3.2-3.3(m, 1H), 2.47(s, 3H)

[0284] Example 106 - (S)-4-methyl-3-(1-(thieno[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] Intermediate 71 (200 mg, 0.36 mmol), XPhos Pd G2 (28.0 mg, 0.04 mmol), molybdenum hexacarbonyl (94 mg, 0.36 mmol), and DIPEA (0.095 mL, 0.53 mmol) were dissolved in a 2.0 N solution of methanamine in THF (2.0 mL, 4.0 mmol). The mixture was heated at 150 °C for 10 min. The solvent was evaporated in vacuo, and the crude material was subjected to reverse-phase FCC. Appropriate fractions were combined to give the title compound (20 mg, 0.04 mmol, 11.6% yield). LC-MS (ESI, m / z): Method 4, t R =7.08 min, m / z(M+1)=484.21 1 H NMR (DMSO-d6, 400MHz)δ 10.62(s, 1H), 9.15(d, 1H, J=2.2Hz), 8.66(s, 1H), 8.55(s, 1H), 8.33(s, 1H), 7.97(s, 1H), 7.79(dd, 1H, J=1.8, 7.9Hz), 7.66(d, 1H, J=6. 1Hz), 7.50(d, 1H, J=6.1Hz), 7.39(d, 1H, J=7.9Hz), 4.3-4.3(m, 1H), 4.1-4.1(m, 1H), 3.7-4.0(m, 3H), 2.3-2.4(m, 1H), 2.2-2.3(m, 1H).

[0285] The following example compounds were prepared starting from the appropriate intermediates using the methods described for the compound of Example 106. [Table 20]

[0286] Example 109 and Example 110 - 4-Methoxy-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] Step 1 - tert-Butyl 3-(5-(ethoxycarbonyl)-2-methoxyphenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (Intermediate 91) [ka] Ethyl 3-bromo-4-methoxybenzoate (5.0 g, 19.30 mmol), (tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (6.27 g, 21.23 mmol), and Pd(dppf)Cl (0.706 g, 0.965 mmol) were dissolved in 1,4-dioxane (50 mL), and the mixture was then degassed with Ar for 5 min. Cesium carbonate (18.86 g, 57.9 mmol) was dissolved in 20 mL of water, and this solution was added to the reaction mixture, which was stirred at 90 °C for 3 h. The reaction mixture was filtered through a pad of Celite, and then the solvent was evaporated; the residue was purified by FCC (eluent A: n-heptane, eluent B: ethyl acetate, gradient A:B 100:0 to 60:40). The appropriate fractions were collected and evaporated to dryness to give the desired product (8.06 g, 23.20 mmol, 100% yield). 1 H NMR (acetone-d6, 400MHz)δ 7.96(d, 1H, J=8.6Hz), 7.86(dd, 1H, J=2.0, 16.0Hz), 7.18(d, 1H, J=8.8Hz), 6.5-6.6(m, 1H), 4.5-4.6(m , 2H), 4.33(q, 2H, J=7.0Hz), 4.2-4.3(m, 2H), 4.01(s, 3H), 1.49(d, 9H, J=5.7Hz), 1.35(t, 3H, J=7.1Hz)

[0287] The following intermediates were prepared using the method described in Intermediate 91 using the appropriate bromo intermediate. [Table 21]

[0288] Step 2 - tert-Butyl 3-(5-(ethoxycarbonyl)-2-methoxyphenyl)pyrrolidine-1-carboxylate (Intermediate 94) [ka] Intermediate 91 (8 g, 23.03 mmol) was dissolved in EtOH (25 ml) and ethyl acetate (25 ml), then Pd / C 10R424 (Johnson Matthey, 50% wet) (2.4 g, 1.15 mmol) was added in one portion. The vessel was closed and three cycles of vacuum-H2 were performed, setting the reaction to run at 40 °C under 5 bar of hydrogen and stirring until completion. The mixture was filtered through a pad of Celite, and the solvent was then removed under reduced pressure to give the desired product (8 g, 22.89 mmol, 99%). 1 H NMR (acetone-d6, 400MHz)δ 7.93(dd, 1H, J=2.0, 8.6Hz), 7.88(s, 1H), 7.1-7.1(m, 1H), 4.3-4.4(m, 2H), 3.9-4.0(m, 3H), 3.6-3.8(m, 2H), 3. 5-3.5(m, 1H), 3.3-3.4(m, 1H), 3.2-3.3(m, 1H), 2.1-2.3(m, 1H), 2.06-2.04(m, 1H), 1.46(s, 9H), 1.3-1.4(m, 3H)

[0289] The following intermediates were prepared according to the method described for Intermediate 94 using the corresponding intermediates. [Table 22]

[0290] Step 3 - tert-Butyl 3-(2-methoxy-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidine-1-carboxylate (Intermediate 97) [ka] Intermediate 97 was prepared according to the method of Example 1, Step 9, substituting LiHDMS for LDA. SM: Intermediate 94: 2.0 g, 5.7 mmol (1 eq.) 4-(trifluoromethoxy)pyridin-2-amine: 1.9 (2 eq.) Amount / Yield: 2.47g / 93 LC-MS (ESI, m / z): Method 14, t R =2.41 min, m / z(M+1)= 1 H NMR (acetone-d6, 400MHz) δ 9.94 (br s, 1H), 9.13(d, 1H, J=1.5Hz), 8.71(s, 1H), 8.63(s, 1H), 7.9-8.0(m, 2H), 7.16(d, 1H, J=8.6Hz), 3.97(s, 3H), 3.7-3.8(m, 1H), 3.70(br dd, 1H, J=7.5, 14.5Hz), 3.5-3.6(m, 1H), 3.37(br dd, 1H, J=7.3, 17.0Hz), 3.1-3.3(m, 1H), 2.2-2.3(m, 1H), 2.1-2.2(m, 1H), 1.46(s, 9H)

[0291] The following examples / intermediates were prepared using the method described for Intermediate 97 using the corresponding intermediates. [Table 23]

[0292] Step 4 - 4-Methoxy-3-(pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Intermediate 99) [ka] Intermediate 99 was prepared following the same method as described for the synthesis of intermediate 22. SM intermediate 97: 2.5g (1.00 equivalent); Amount / Yield: 1.9g / 100% LC-MS (ESI, m / z): Method 13, t R =0.57 min, m / z(M+1)=366.2

[0293] The following intermediates were prepared using the method described for Intermediate 99 using the corresponding intermediates: [Table 24]

[0294] Step 5 - 4-Methoxy-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 111) [ka] Example 111 was prepared following the same method as described for the synthesis of intermediate 31. SM intermediate 99: 0.18g (1.00 equivalent); 5-Bromopyrimidine: 0.12 g (1.5 equivalents); Pd-170: 33 mg (0.1 equivalents) Amount / yield: 53mg / 24% LC-MS (ESI, m / z): Method 4, t R =6.58 min, m / z(M+1)=444.31 1 H NMR(ACN-d3, 400MHz)δ 9.0-9.1(m, 2H), 8.63(s, 1H), 8.57(s, 1H), 8.45(s, 1H), 8.12(s, 2H), 7.92(dd, 1H, J=2.2, 8.6Hz), 7.86(d, 1H, J=2.2Hz) , 7.13(d, 1H, J=8.6Hz), 3.95(s, 3H), 3.8-3.9(m, 2H), 3.5-3.6(m, 1H), 3.3-3.5(m, 2H), 2.4-2.5(m, 1H), 2.2-2.3(m, 1H)

[0295] The following example compounds were prepared using the methods described for the compound of Example 111 using the corresponding intermediates. [Table 25]

[0296] Step 6 - 4-Methoxy-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide and 4-Methoxy-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 109 and Example 110) [ka] The racemic mixture of Example 111 (43 mg, 0.098 mmol) was separated by chiral SFC (LUX Cellulose-110 × 250 mm, 5 μm 35 / 65 MeOH (0.1% NHOH) / CO, 15 mL / min, 120 bar, 40 °C, DAD 260 nm) to give the desired product. First eluting enantiomer (12 mg, 0.0271 mmol, 28%). Chiral analysis (SFC method 4): R 2.41 min, ee 99.93% LC-MS(ESI): Method 5, t R =4.45 min, m / z(M+1)=444.6 Second eluting enantiomer (7 mg, 16%): Chiral analysis (SFC method 4): R 3.65 minutes, ee 99.88% LC-MS(ESI): Method 5, t R =4.44 min, m / z(M+1)=444.5 of the first and second eluting isomers 1 The H NMR spectrum of the racemic mixture 1 The H NMR spectrum could be overlaid.

[0297] The following example compounds as single enantiomers were prepared by suitable chiral SFC methods identified in the separation screening conditions using the methods described in Example 109 and Example 110. [Table 26-1] [Table 26-2]

[0298] Example 123 - (S)-(3-(1-(6-(hydroxymethyl)imidazo[1,2-a]pyridin-3-yl)pyrrolidin-3-yl)-4-methylphenyl)(5-(trifluoromethyl)pyridin-3-yl)methanone [ka] To a solution of intermediate 57 (105 mg, 0.172 mmol) in THF (1.0 mL) was added 1 M TBAF in THF (0.52 mL, 0.52 mmol), and the mixture was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc and NaHCO and washed with water and brine. The organic phase was dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by achiral SFC (GREENSEP 2-EP 20 × 250 mm, 5 μm 10–20% MeOH (0.1% NHOH) / CO, 100 mL / min, 120 bar, 40 °C, DAD 240 nm) to give the title compound (32 mg, 0.0646 mmol, 38%). LC-MS(ESI): Method 5, t R =3.53 min, m / z(M+1)=496.5 1 H NMR (400MHz, DMSO-d6)δ 10.68(s, 1H), 9.21(d, J=2.3Hz, 1H), 8.71-8.70(m, 1H), 8.63(t, J=2.4Hz, 1H), 8.13(s, 1H) ), 8.09(d, J=1.5Hz, 1H), 7.81(dd, J=1.8, 8.1Hz, 1H), 7.45-7.38(m, 2H), 7.29(s, 1H), 7.1 1(dd, J=1.5, 9.3Hz, 1H), 5.25(t, J=5.8Hz, 1H), 4.51(d, J=5.8Hz, 2H), 3.87-3.80(m, 1H), 3.64-3.58(m, 1H), 3.48-3.41(m, 2H), 3.39-3.33(m, 2H), 2.47(s, 3H), 2.19-2.09(m, 1H).

[0299] Example 44 - 3-(3-((6-aminopyridin-3-yl)oxy)azetidin-1-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] Step 1 - tert-Butyl 3-((6-nitropyridin-3-yl)oxy)azetidine-1-carboxylate (Intermediate 29) [ka] In a 20 mL vessel, 5-fluoro-2-nitropyridine (0.902 g, 6.35 mmol) and tert-butyl 3-hydroxyazetidine-1-carboxylate (1.00 g, 5.77 mmol) were dissolved in DMSO (10 mL), and then CsCO (3.76 g, 11.55 mmol) was added in one portion. The reaction was stirred overnight at rt. The crude was quenched with HO, and the product was extracted with DCM (2 × 50 mL). The organic layer was washed with brine (1 × 50 mL) and dried under reduced pressure to give intermediate 29 (2.01 g, 6.81 mmol, quantitative yield). The compound was used in the next step without further purification. LC-MS (ESI, m / z): Method 1, t R =0.95 min, m / z(M+1)=239.9

[0300] Step 2 - 5-(Azetidin-3-yloxy)-2-nitropyridine Hydrochloride (Intermediate 30) [ka] Intermediate 29 (1.20 g, 4.06 mmol) was dissolved in dioxane (10 mL), and then a 3.7 M solution of HCl in dioxane (10.000 mL, 37.0 mmol) was added in one portion. The reaction was stirred overnight at rt and monitored by UPLC-MS. The solvent was evaporated under reduced pressure to give the title compound in quantitative yield (0.941 g, 4.06 mmol), which was used in the next step without further purification. LC-MS (ESI, m / z): Method 1, tR =0.14 min, m / z(M+1)=237.0

[0301] Step 3 - 4-Methyl-3-(3-((6-nitropyridin-3-yl)oxy)azetidin-1-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Intermediate 31) [ka] In a 20 mL microwave vial, Intermediate 8 (300 mg, 0.835 mmol), Intermediate 30 (290 mg, 1.253 mmol), cesium carbonate (816 mg, 2.506 mmol), and Pd-170 (56.3 mg, 0.084 mmol) were dissolved in DMA (4 mL), the vial was closed with a sealing cap, refilled with Ar, and the reaction was stirred at 120 °C until conversion was complete. The reaction was quenched with HO (5 mL), the product extracted with DCM (2 × 20 mL), the organic layers combined, washed with brine (1 × 20 mL), and the solvent evaporated to dryness. The crude product was purified by FCC on silica NH gel eluting with a gradient of 40% acetone in n-heptane. The appropriate fractions were combined and evaporated to dryness to give the title compound (330 mg, 0.697 mmol, 83% yield). LC-MS (ESI, m / z): Method 3, t R =2.10 min, m / z(M+1)=474.2 1 H NMR (acetone-d6, 400MHz) δ 9.88 (br s, 1H), 9.1-9.2(m, 1H), 8.71(s, 1H), 8.63(s, 1H), 8.3-8.3(m, 2H), 7.69(dd, 1H, J=2.9, 9.0Hz), 7.43(dd, 1H) , J=1.4, 7.8Hz), 7.2-7.2(m, 2H), 5.4-5.5(m, 1H), 4.6-4.6(m, 2H), 4.08(dd, 2H, J=4.3, 8.9Hz), 2.30(s, 3H)

[0302] Step 4 - 3-(3-((6-aminopyridin-3-yl)oxy)azetidin-1-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 44) The compound of Example 44 was prepared according to the method described for the synthesis of Example 42, Step 2. SM: Intermediate 31: 230 mg, 1.00 equivalent Amount / Yield: 135mg / 63% LC-MS (ESI, m / z): Method 3, t R =1.18 min, m / z(M+1)=444.2 1 H NMR (acetone-d6, 400MHz) δ 9.88 (br s, 1H), 9.13(d, 1H, J=2.0Hz), 8.71(s, 1H), 8.62(s, 1H), 7.65(d, 1H, J=3.1Hz), 7.40(dd, 1H, J=1.4, 7.8Hz), 7.16-7.18(m, 2H) , 7.10(dd, 1H, J=3.1, 8.8Hz), 6.53(d, 1H, J=9.0Hz), 5.0-5.1(m, 3H), 4.4-4.5(m, 2H), 3.91(dd, 2H, J=4.7, 8.4Hz), 2.28(s, 3H)

[0303] Example 45 - 3-(3-((6-acetamidopyridin-3-yl)oxy)azetidin-1-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] Step 1 - 3-(3-((6-acetamidopyridin-3-yl)oxy)azetidin-1-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 45) The compound from Example 44 (60 mg, 0.135 mmol) and TEA (0.057 mL, 0.406 mmol) were dissolved in DCM (1 mL). Acetic anhydride (0.038 mL, 0.406 mmol) was then added in one portion, and the reaction was stirred at room temperature until complete. The solvent was evaporated, and the crude material was purified by FCC (12 CV gradient A:B 100:0 to 0:10, eluent A: HO / ACN / HCOOH 95:5:0.1, eluent B: HO / ACN / HCOOH 5:95:0.1). Appropriate fractions were collected, and the organic solvent was evaporated under reduced pressure. The aqueous phase was then basified to pH 7-8 with saturated NaHCO3 solution and extracted with Me-THF. The organic layer was dried to give the title compound (52 mg, 0.107, 79% yield). LC-MS (ESI, m / z): Method 3, t R =1.81 min, m / z(M+1)=486.2 1 H NMR (acetone-d6, 400 MHz) δ 9.90 (br s, 1H), 9.34 (br s, 1H), 9.15(s, 1H), 8.73(s, 1H), 8.65(s, 1H), 8.17(d, 1H, J=9.0Hz), 7.95(d, 1H, J=3.1Hz), 7.43(dd, 1H, J=1.5, 7.7Hz), 7.37(dd, 1H) , J=3.1, 9.0Hz), 7.20(dd, 2H, J=3.1, 4.6Hz), 5.2-5.2(m, 1H), 4.5-4.6(m, 2H), 3.99(dd, 2H, J=4.6, 8.8Hz), 2.31(s, 3H), 2.16(s, 3H)

[0304] Example 46 - 3-(3-((6-(2-methoxyacetamido)pyridin-3-yl)oxy)azetidin-1-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] Step 1 - 3-(3-((6-(2-methoxyacetamido)pyridin-3-yl)oxy)azetidin-1-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide The compound from Example 44 (60 mg, 0.135 mmol) was dissolved in pyridine (1.0 mL, 12.36 mmol), then methoxyacetyl chloride (22.03 mg, 0.203 mmol) was added in one portion, and the solution was stirred at room temperature until complete. The crude material was purified by FCC (12 CV gradient A:B 100:0 to 0:10, eluent A: HO / ACN / HCOOH 95:5:0.1, eluent B: HO / ACN / HCOOH 5:95:0.1). Appropriate fractions were collected, and the organic solvent was evaporated under reduced pressure. The remaining aqueous phase was basified with NaHCO to pH 7-8 and extracted with DCM. The organic layer was dried to give the title compound (57.3 mg, 0.111 mmol, 82% yield). LC-MS (ESI, m / z): Method 4, t R =6.79 min, m / z(M+1)=516.2 1 H NMR (acetone-d6, 400MHz) δ 9.88 (br s, 1H), 9.13 (s, 1H), 8.81 (br s, 1H), 8.71(s, 1H), 8.63(s, 1H), 8.16(d, 1H, J=9.0Hz), 7.98(d, 1H, J=2.9Hz), 7.4-7.4(m, 2H), 7.18(dd, 2H, J=3.1, 4. 6Hz), 5.2-5.2(m, 1H), 4.52(dd, 2H, J=6.9, 8.0Hz), 4.02(s, 2H), 3.98(dd, 2H, J=4.5, 8.7Hz), 3.49(s, 3H), 2.29(s, 3H)

[0305] Example 47 - 3-(3-((5-aminopyridin-3-yl)oxy)azetidin-1-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide [ka] Step 1 - tert-Butyl 3-((5-nitropyridin-3-yl)oxy)azetidine-1-carboxylate (Intermediate 32) [ka] Intermediate 32 was prepared according to the same method as described for the synthesis of intermediate 29 with various corresponding fluorine derivatives. SM: tert-butyl 3-hydroxyazetidine-1-carboxylate, 1.00 g (1.00 equivalents) 3-Fluoro-5-nitropyridine: 0.902 g (1.1 equivalents) Amount / Yield: 1.2g / 70% LC-MS (ESI, m / z): Method 1, t R =0.99 min, m / z(M+1)=240.0

[0306] Step 2: 3-(Azetidin-3-yloxy)-5-nitropyridine hydrochloride (Intermediate 33) [ka] Intermediate 33 was prepared following the same method as described for the synthesis of intermediate 30. SM: Intermediate 32g, 1.20 (1.00 equivalent) Amount / Yield: 0.94g / 100% LC-MS (ESI, m / z): Method 1, t R =0.14 min, m / z(M+1)=237.0

[0307] Step 3: 4-methyl-3-(3-((5-nitropyridin-3-yl)oxy)azetidin-1-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Intermediate 34) [ka] Intermediate 34 was prepared following the same method as described for the synthesis of intermediate 31. SM: Intermediate 8, 300 mg (1.00 equivalent) Intermediate 33, 290 mg (1.5 equivalents) Amount / Yield: 230mg / 58% LC-MS (ESI, m / z): Method 3, t R =2.16 min, m / z(M+1)=474.2

[0308] Step 4 - 3-(3-((5-aminopyridin-3-yl)oxy)azetidin-1-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 47) The compound of Example 47 was prepared following the same method as described for the synthesis of Example 42, Step 2. SM: Intermediate 34, 230 mg (1.00 equivalent) Amount / yield: 82mg / 38% LC-MS (ESI, m / z): Method 3, t R =1.13 min, m / z(M+1)=444.1 1 H NMR (acetone-d6, 400MHz) δ 9.89 (br s, 1H), 9.13(d, 1H, J=2.0Hz), 8.7-8.7(m, 1H), 8.63(s, 1H), 7.72(d, 1H, J=2.2Hz), 7.52(d, 1H, J=2. 4Hz), 7.41(dd, 1H, J=1.6, 7.8Hz), 7.2-7.2(m, 2H), 6.57(t, 1H, J=2.3Hz), 5.1-5.1(m, 1H), 4.90(br s, 2H), 4.4-4.5(m, 2H), 3.93(dd, 2H, J=4.6, 8.6Hz), 2.29(s, 3H)

[0309] The following example compounds and intermediates were prepared starting from the appropriate intermediates using the methods described for the synthesis of Intermediate 18. [Table 27]

[0310] The following example compounds and intermediates were prepared starting from the appropriate intermediates using the methods described for the synthesis of Example 130 compound (acetyl chloride). [Table 28]

[0311] The following compounds of formula (I) were prepared by application of the above experimental conditions: (S)-3-(1-(4-((dimethylamino)methyl)pyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; (S)-4-methyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)benzamide; (S)-4-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)pyrimidine-2-carboxamide; (S)—N-methyl-3-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)isonicotinamide; (S)-4-methyl-3-(1-(3-(methylamino)pyrazin-2-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; (S)-3-(1-(8-aminoimidazo[1,2-a]pyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; (S)-3-(1-(6-cyanopyrimidin-4-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; (S)-4-methyl-3-(1-(1-methyl-1H-imidazol-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; (S)-3-(1-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; (S)-3-(1-(4-cyanopyrimidin-5-yl)pyrrolidin-3-yl)-N-(4-(difluoromethoxy)pyridin-2-yl)-4-methylbenzamide; (S)-5-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)nicotinamide; (S)-3-(1-(6-bromo-5H-pyrrolo[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; 3-((1-(imidazo[1,5-a]pyrazin-8-yl)azetidin-3-yl)oxy)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; (S)-4-methyl-3-(1-(pyrimidin-4-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; (S)—N-methyl-4-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)thieno[3,2-d]pyrimidine-7-carboxamide; (S)—N-methyl-4-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide; (S)-4-methyl-3-(1-(2-(methylamino)thieno[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; (S)—N-methyl-4-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide; (S)—N-methyl-4-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)thieno[2,3-d]pyrimidine-6-carboxamide; 4-hydroxy-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; 3-(1-(2-cyanopyridin-4-yl)pyrrolidin-3-yl)-4-methoxy-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; 4-(hydroxymethyl)-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; 4-cyclopropyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; 4-Cyclopropyl-3-(1-(pyrazolo[1,5-a]pyrimidin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide; 4-hydroxy-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide, eluting first; 4-hydroxy-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide, eluting second; 3-(4-hydroxy-1-(pyrimidin-5-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide, eluting first; 4-cyclopropyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide, eluting first; 4-cyclopropyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide, eluting second; 4-cyclopropyl-3-(1-(pyrazolo[1,5-a]pyrimidin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide, eluting first; and 4-Cyclopropyl-3-(1-(pyrazolo[1,5-a]pyrimidin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide, eluting second.

[0312] Newly synthesized comparative compounds characterized by having a -CH2- linker between L and the heteroaryl ring B (C1) or by the replacement of the heteroaryl ring B with an alkyl group (C2) were prepared as follows: Example C1 (S)-3-(1-(imidazo[1,2-a]pyridin-3-ylmethyl)pyrrolidin-3-yl)-4-methyl-N-(5(trifluoromethyl)pyridin-3-yl)benzamide [ka] Step 1 - (S)-3-(1-(imidazo[1,2-a]pyridin-3-ylmethyl)pyrrolidin-3-yl)-4-methyl-N-(5(trifluoromethyl)pyridin-3-yl)benzamide (Example C1) Intermediate 22 (100 mg, 0.286 mmol, 1.00 equiv) was added to a solution of imidazo[1,2-a]pyridine-3-carbaldehyde (42 mg, 0.286 mmol, 1.00 equiv) and titanium(IV) isopropoxide (0.25 mL, 0.859 mmol, 3.00 equiv) in MeOH (3.00 mL), and the reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was then cooled to rt, NaBHCN (45 mg, 0.716 mmol, 2.50 equiv) was added, and the resulting mixture was stirred at rt overnight. It was then diluted with EtOAc (20 mL), quenched with NH Cl (aqueous saturated, 20 mL), the precipitate was filtered off, and the layers were separated. The organic phase was washed with water (20 mL), HO:brine (1:1) (20 mL), and brine (saturated aqueous, 20 mL), then dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (67 mg, 0.129 mmol, 45%). LC-MS (ESI, m / z): Method 5, t R = min, m / z(M+1) = 480.2 1 H NMR (400MHz, DMSO-d6)δ 10.63(s, 1H), 9.20(d, J=2.3Hz, 1H), 8.72-8.71(m, 1H), 8.63(t, J=2.0Hz, 1H), 8.53(d, J=6 .8Hz, 1H), 7.96(d, J=1.8Hz, 1H), 7.72(dd, J=1.8, 7.8Hz, 1H), 7.52(d, J=7.3Hz, 2H), 7.30( d, J=8.1Hz, 1H), 7.17-7.12(m, 1H), 6.84-6.80(m, 1H), 4.08-3.96(m, 2H), 3.62-3.54(m, 1H) ), 2.89-2.76(m, 2H), 2.71-2.57(m, 2H), 2.35(s, 3H), 2.33-2.29(m, 1H), 1.78-1.69(m, 1H).

[0313] Example C2 (S)-3-(1-(2-amino-2-oxoethyl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example C2) [ka] To a suspension of intermediate 22 (50 mg, 0.143 mmol, 1.00 equiv) and K2CO3 (30 mg, 0.215 mmol, 1.50 equiv) in ACN (2.00 mL) was added 2-bromoacetamide (20 mg, 0.143 mmol, 1.00 equiv), and the reaction mixture was stirred at rt for 3 days. The reaction mixture was diluted with EtOAc (15 mL) and washed with water (2 × 10 mL) and brine (saturated aqueous, 15 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (31 mg, 0.0763 mmol, 53%). LC-MS (ESI, m / z): Method 8, t R =3.98 min, m / z(M+1)=407.4 1H NMR (400MHz, DMSO-d6)δ 10.67(s, 1H), 9.22(d, J=2.3Hz, 1H), 8.71(s, 1H), 8.66(t, J=2.3Hz, 1H), 8.03( d, J=1.8Hz, 1H), 7.77(dd, J=1.8, 7.8Hz, 1H), 7.35(d, J=8.0Hz, 1H), 7.28-7.23 (m, 1H), 7.18-7.14(m, 1H), 3.65-3.57(m, 1H), 3.17-3.05(m, 2H), 2.98(t, J=8. 4Hz, 1H), 2.90-2.69(m, 3H), 2.41(s, 3H), 2.37-2.28(m, 1H), 1.87-1.77(m, 1H).

[0314] Pharmacological activity of the compounds of the present invention In vitro assays Binding assay Life Technologies LanthaScreen TM DDR1 and DDR2 binding assays were performed using a europium kinase binding assay. Compounds were incubated with 5 nM DDR1 (Carna Biosciences) or 5 nM DDR2 (Life Technologies) in white 384-well OptiPlates (PerkinElmer) containing 20 nM or 10 nM Kinase Tracer 178, respectively, and 2 nM europium anti-GST antibody (Life Technologies) in assay buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, and 0.01% BRIJ35) for 1 hour at room temperature. Fluorescence emission 665 nm / 615 nm ratios after excitation at 340 nm were obtained using a Tecan Spark 20M plate reader. IC 50 Values were determined with GraphPad Prism 7.0 software using a four-parameter model: log(inhibitor) vs. response. The Cheng-Prusoff equation (Ki = IC 50 / (1+[Tracer] / Kd) to calculate IC 50 Values were converted to Ki.

[0315] The results for individual compounds are shown in Table 3 below, with the compounds classified in terms of binding potency (nM) for DDR1 and DDR2 inhibitory activity. [Table 29-1] [Table 29-2] [Table 29-3] +:Ki 25~100nM ++: Ki 5nM~25nM +++: Ki less than 5nM -:Ki >100nM

[0316] As can be seen, the compounds in Table 3, i.e., the compounds of the present invention, show good activity as antagonists of DDR1 and DDR2. Therefore, the compounds of the present invention can be effectively used for the treatment of diseases, disorders or conditions associated with DDR receptors, such as fibrosis, for example, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

[0317] Comparative Example The compounds of Examples C1 and C2 were tested in the same binding assay as above. [Table 30]

[0318] The compounds of the present invention have binding affinities for the DDR1 and DDR2 receptors, expressed as K, of less than 100 nM, with many of the compounds being less than 25 nM or less than 5 nM, as shown in Table 3. In contrast, Comparative Example C1 has a binding affinity for the DDR1 receptor of greater than 140 nM and for the DDR2 receptor of 588 nM; and Example C2 has a binding affinity for the DDR1 receptor of greater than 480 nM and for the DDR2 receptor of 588 nM.

[0319] Thus, both the presence of a direct bond between L and heteroaryl ring B and the presence of said heteroaryl ring B in the compounds of the present invention determine an unexpected and remarkable increase in inhibitory activity against DDR1 and DDR2 receptors.

Claims

1. Formula (I) 【Chemical 1】 [During the ceremony, A is: 【Chemistry 2】 wherein 【Chemistry 3】 indicates a direct bond to NH; W1 and W2 are hydrogen, halogen, (C １ -C ４ ) alkyl, (C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkoxy, (C １ -C ４ ) haloalkoxy, R1R2N-(C １ -C ４ ) alkyl and (C ３ -C ６ ) a substituent on Ring A selected from the group consisting of cycloalkyl; Z is (C １ -C ４ ) alkyl, (C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkoxy, (C １ -C ４ ) haloalkoxy, (C １ -C ４ ) hydroxyalkyl, hydroxy and (C ３ -C ６ ) cycloalkyl; L is 【Chemistry 4】 (In the formula, 【Chemistry 5】 indicates a direct bond to the phenyl, 【Chemistry 6】 indicates a direct bond to B) selected from the group consisting of: B is a monocyclic or bicyclic heteroaryl ring; Y1 and Y2 are independently hydrogen, (C １ -C ４ ) alkyl, (C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkoxy, (C １ -C ４ ) alkoxy-(C １ -C ４ ) alkoxy, hydroxy-(C １ -C ４ ) alkoxy, hydroxy-(C １ -C ４ ) alkyl, (C １ -C ４ ) alkyl-heterocycloalkyl-(C ０ -C ４ ) alkoxy, (C １ -C ４ ) haloalkoxy, halogen, cyano, cyano-(C １ -C ４ ) alkyl, cyano-(C １ -C ４ ) alkyl-heterocycloalkyl, CONR1R2, NHCOR1, NR1R2, R1R2N-(C １ -C ４ ) alkyl, heterocycloalkyl, (C １ -C ４ ) alkyl-heterocycloalkyl, heterocycloalkyl-(C １ -C ４ ) alkyl, (C １ -C ４ ) alkyl-heterocycloalkyl-carbonyl, (C ０ -C ４ ) alkyl-heterocycloalkyl-carbonyl (C １ -C ４ ) alkyl-phenyl and monocyclic (C １ -C ４ ) alkyl-heteroaryl; R1 and R2 are independently hydrogen, (C １ -C ４ ) alkyl, (C １ -C ４ ) hydroxyalkyl, (C １ -C ４ )Alkoxy(C １ -C ４ ) alkyl, (C １ -C ４ ) alkylamino-(C １ -C ４ ) alkyl, di-(C １ -C ４ ) alkylamino-(C １ -C ４ ) alkyl, optionally substituted (C ３ -C ６ )cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heterocycloalkyl-(C １ -C ４ )alkoxy, wherein the optional substituents are one or more; (C １ -C ４ ) alkyl, (C １ -C ４ ) alkoxy, (C １ -C ４ ) haloalkyl, hydroxy and (C １ -C ４ ) haloalkoxy; R4 is selected from hydroxy and hydroxymethyl. or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof.

2. L 【Chemistry 7】 2. The compound of formula (I) of claim 1 selected from the group consisting of: or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof.

3. A: 【Chemistry 8】 is a ring selected from the group consisting of: W1 and W2 are independently H, F, or CH ３ , OCH ３ , OCF ３ , C.F. ３ , C(CH ３ ) ３ , C.H. ２ CH ３ , C(CH ３ ) ２ CF ３ , OCF ２ H, CHF ２ , C.H. ２ CF ３ , C.H. ２ N(CH ３ ) ２ and cyclopropyl; Z is CH ３ , C.F. ２ H, OCH ３ , C.H. ２ selected from the group consisting of OH and cyclopropyl; B is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyrazolo[1,5-a]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyridinyl, thieno[3,2-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, and pyrazolyl; Y1 is hydrogen, (C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkoxy, cyano, CONR1R2, NHCOR1, NR1R2, (C １ -C ４ ) alkyl-heterocycloalkyl-carbonyl and monocyclic (C １ -C ４ ) alkyl-heteroaryl; and Y2 is hydrogen; R1 and R2 are independently CH ２ CH ２ N(CH ３ ) ２ , C.H. ２ CH ２ OCH ３ , C.H. ３ , C.H. ２ CH ２ OH, oxetan-3-yl, and 3-hydroxycyclobutyl; 3. A compound of formula (I) according to claim 1 or 2, or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof.

4. Y1 is CONH ２ , C.F. ２ H, OCH ３ , cyano, NHCOCH ３ , N.H. ２ , 4-methylpiperazine-1-carbonyl, 4-methylpiperazin-1-yl, and 1-methyl-1H-pyrazol-4-yl; and Y2 is hydrogen.

4. A compound of formula (I) according to claim 3 or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof.

5. L is C 【Chemistry 9】 and formula (Ia) 【Chemistry 10】 5. The compound according to any one of claims 1 to 4, represented by: or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof.

6. L or C is C* 【Chemistry 11】 6. The compound according to any one of claims 1 to 5, wherein:

7. L 【Chemistry 12】 5. The compound of any one of claims 1 to 4, wherein:

8. A compound of formula (Ia) according to claim 5 selected from the group consisting of: (S)-5-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)nicotinamide (Example 1); (R)-5-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)nicotinamide (Example 2); (S)-5-(3-(5-((5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)carbamoyl)-2-methylphenyl)pyrrolidin-1-yl)nicotinamide (Example 3); (S)-5-(3-(2-methyl-5-((5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)nicotinamide (Example 4); (S)-5-(3-(5-((3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)carbamoyl)-2-methylphenyl)pyrrolidin-1-yl)nicotinamide (Example 5); (S)-5-(3-(5-((3-(tert-butyl)isoxazol-5-yl)carbamoyl)-2-methylphenyl)pyrrolidin-1-yl)nicotinamide (Example 6); (S)—N-(3-(tert-butyl)isoxazol-5-yl)-3-(1-(5-cyanopyridin-3-yl)pyrrolidin-3-yl)-4-methylbenzamide (Example 7); (S)-3-(1-(5-cyanopyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(6-(trifluoromethyl)pyrimidin-4-yl)benzamide (Example 8); (S)-5-(3-(2-methyl-5-((4-(trifluoromethoxy)pyridin-2-yl)carbamoyl)phenyl)pyrrolidin-1-yl)nicotinamide (Example 9); (S)-5-(3-(2-methyl-5-((5-(trifluoromethoxy)pyridin-2-yl)carbamoyl)phenyl)pyrrolidin-1-yl)nicotinamide (Example 10); (S)-5-(3-(5-((5-(tert-butyl)isoxazol-3-yl)carbamoyl)-2-methylphenyl)pyrrolidin-1-yl)nicotinamide (Example 11); (S)-4-methyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(4-(trifluoromethoxy)pyridin-2-yl)benzamide (Example 12); (S)—N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-4-methyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)benzamide (Example 13); (S)-4-methyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)benzamide (Example 14); (S)-4-methyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (Example 15); (S)—N-(5-(tert-butyl)isoxazol-3-yl)-4-methyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)benzamide (Example 16); (S)—N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-4-methyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)benzamide (Example 17); (S)-4-methyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethoxy)pyridin-3-yl)benzamide (Example 18); (S)—N-(3-(tert-butyl)isoxazol-5-yl)-4-methyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)benzamide (Example 19); (S)-4-methyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethoxy)pyridin-2-yl)benzamide (Example 20); (S)—N-(4-(difluoromethoxy)pyridin-2-yl)-4-methyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)benzamide (Example 21); (S)-3-(1-(5-(difluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 22); (S)—N-(2-(dimethylamino)ethyl)-5-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)nicotinamide (Example 23); (S)—N-(2-methoxyethyl)-5-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)nicotinamide (Example 24); (S)-3-(1-(2-methoxypyrimidin-5-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 25); (S)-4-methyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 26); (S)-3-(1-(5-cyanopyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 27); (S)-3-(1-(5-acetamidopyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 28); (S)—N-methyl-5-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)nicotinamide (Example 29); (S)—N-(2-hydroxyethyl)-5-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)nicotinamide (Example 30); (S)-3-(1-(3-aminopyrazin-2-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 31); (S)-4-methyl-3-(1-(pyrazolo[1,5-a]pyrazin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 32); (S)-4-methyl-3-(1-(pyrazin-2-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 33); (S)-4-methyl-3-(1-(pyrazolo[1,5-a]pyridin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 34); (S)-4-methyl-3-(1-(pyrazolo[1,5-a]pyrimidin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 35); (S)-3-(1-(imidazo[1,2-b]pyridazin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 36); (S)-3-(1-(imidazo[1,2-a]pyrazin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 37); (S)-5-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)-N-(oxetan-3-yl)nicotinamide (Example 38); N-((1s,3R)-3-hydroxycyclobutyl)-5-((S)-3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)nicotinamide (Example 39); (S)-4-methyl-3-(1-(5-(4-methylpiperazine-1-carbonyl)pyridin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 40); (S)-3-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)-N-(oxetan-3-yl)isonicotinamide (Example 41); (S)-3-(1-(2-aminopyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 42); and (S)-3-(1-(1H-pyrazolo[3,4-b]pyridin-5-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 43); (S)-6-(3-(5-((4-(difluoromethoxy)pyridin-2-yl)carbamoyl)-2-methylphenyl)pyrrolidin-1-yl)pyrazine-2-carboxamide (Example 51); (S)-4-(3-(5-((5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)carbamoyl)-2-methylphenyl)pyrrolidin-1-yl)picolinamide (Example 52); (S)-4-(3-(5-((2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-yl)carbamoyl)-2-methylphenyl)pyrrolidin-1-yl)picolinamide (Example 53); (S)-6-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)pyrimidine-4-carboxamide (Example 54); (S)-3-(1-(4-cyanopyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)benzamide (Example 55); (S)-3-(1-(4-cyanopyridin-3-yl)pyrrolidin-3-yl)-N-(5-ethylisoxazol-3-yl)-4-methylbenzamide (Example 56); (S)-4-(3-(2-methyl-5-((4-(trifluoromethoxy)pyridin-2-yl)carbamoyl)phenyl)pyrrolidin-1-yl)picolinamide (Example 57); (S)-4-methyl-3-(1-(pyrazin-2-yl)pyrrolidin-3-yl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)benzamide (Example 58); (S)—N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-4-methyl-3-(1-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)benzamide (Example 59); (R)-4-methyl-3-(1-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)benzamide (Example 60); (S)-4-methyl-3-(1-(6-(morpholine-4-carbonyl)thieno[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 61); (S)-4-methyl-3-(1-(pyrazolo[1,5-a]pyrimidin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethoxy)pyridin-3-yl)benzamide (Example 62); (S)-4-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)picolinamide (Example 63); 4-(3-(2-methoxy-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)picolinamide (Example 64); (S)-1-methyl-4-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)-1H-pyrazole-5-carboxamide (Example 65); (S)-3-(1-(3-carbamoylphenyl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 66); (S)—N-(4-(difluoromethyl)pyridin-2-yl)-4-methyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)benzamide (Example 67); (S)-4-methyl-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)benzamide (Example 68); (S)—N-(5-ethylisoxazol-3-yl)-4-methyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)benzamide (Example 69); (S)—N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-4-methyl-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)benzamide (Example 70); (S)-3-(1-(imidazo[1,2-a]pyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 71); (S)-4-methyl-3-(1-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 72); (S)-3-(1-(6-(4-(cyanomethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 73); (S)-4-methyl-3-(1-(5-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 74); (S)-3-(1-(4-cyanopyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 75); (S)-3-(1-(4-methoxypyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 76); (S)-4-methyl-3-(1-(6-(morpholinomethyl)imidazo[1,2-a]pyridin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 77); (S)-3-(1-(6-cyanoimidazo[1,2-a]pyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 78); (S)-3-(1-(5-(2-methoxyethoxy)pyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 79); (S)-4-methyl-3-(1-(6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 80); (S)-4-methyl-3-(1-(5-((1-methylpiperidin-4-yl)oxy)pyridin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 81); (S)-4-methyl-3-(1-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyrazin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 82); (S)-4-methyl-3-(1-(5-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 83); (S)-4-methyl-3-(1-(6-morpholinoimidazo[1,2-b]pyridazin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 84); (S)-3-(1-(2-acetamidopyridin-4-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 85); (S)-4-methyl-3-(1-(5-methylpyrazolo[1,5-a]pyrimidin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 86); (S)—N-methyl-4-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)picolinamide (Example 87); (S)-4-methyl-3-(1-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 88); (S)-4-methyl-3-(1-(5-(morpholine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 89); 4-methyl-3-[(3R)-1-pyrazolo[1,5-a]pyrimidin-3-ylpyrrolidin-3-yl]-N-[5-(trifluoromethyl)-3-pyridyl]benzamide (Example 90); N-[4-(difluoromethoxy)-2-pyridyl]-4-methyl-3-[(3S)-1-pyrazolo[1,5-a]pyrimidin-3-ylpyrrolidin-3-yl]benzamide (Example 91); N-[4-(difluoromethoxy)-2-pyridyl]-4-methyl-3-[(3S)-1-pyrazin-2-ylpyrrolidin-3-yl]benzamide (Example 92); 3-[(3S)-1-(4-cyano-3-pyridyl)pyrrolidin-3-yl]-N-[4-(difluoromethoxy)-2-pyridyl]-4-methyl-benzamide (Example 93); (S)-3-(1-(6-cyanopyrazin-2-yl)pyrrolidin-3-yl)-N-(4-(difluoromethoxy) Pyridin-2-yl)-4-methyl-benzamide (Example 94); (S)—N-(5-ethylisoxazol-3-yl)-4-methyl-3-(1-(pyrazolo[1,5-a]pyrimidin-3-yl)pyrrolidin-3-yl)benzamide (Example 95); (S)—N-(5-ethylisoxazol-3-yl)-4-methyl-3-(1-(pyrazolo[1,5-a]pyrazin-3-yl)pyrrolidin-3-yl)benzamide (Example 96); (S)-3-(1-(6-methoxypyrazolo[1,5-a]pyrimidin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 97); (S)-4-methyl-3-(1-(pyrazolo[1,5-a]pyrazin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethoxy)pyridin-3-yl)benzamide (Example 98); (S)-4-methyl-3-(1-(2-(methylamino)pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 99); (S)-3-(1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 100); (S)-3-(1-(3-((dimethylamino)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 101); (S)-5-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)-N-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (Example 102); (S)-3-(1-(5-(2-hydroxyethoxy)pyridin-3-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 103); 3-(4-(hydroxymethyl)-1-(pyrimidin-5-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 104); 3-(4-hydroxy-1-(pyrimidin-5-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 105); (S)-4-methyl-3-(1-(thieno[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 106); (S)-4-methyl-3-(1-(thieno[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 107); (S)—N-methyl-4-(3-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)thieno[3,2-d]pyrimidine-6-carboxamide (Example 108); 4-Methoxy-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide, first-eluting enantiomer (Example 109); 4-Methoxy-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide, second-eluting enantiomer (Example 110); 4-Methoxy-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide, racemic mixture (Example 111); 4-Methoxy-3-(1-(pyrazolo[1,5-a]pyrimidin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 112); 4-(difluoromethoxy)-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 113); 4-Methoxy-3-(1-(pyrazolo[1,5-a]pyrimidin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide, first-eluting enantiomer (Example 114); 4-Methoxy-3-(1-(pyrazolo[1,5-a]pyrimidin-3-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide, second-eluting enantiomer (Example 115); 4-(difluoromethoxy)-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide, first-eluting enantiomer (Example 116); 4-(difluoromethoxy)-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide, second-eluting enantiomer (Example 117); 4-(3-(2-(difluoromethoxy)-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)picolinamide, first-eluting enantiomer (Example 118); 4-(3-(2-(difluoromethoxy)-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)picolinamide, second-eluting enantiomer (Example 119); 4-(difluoromethyl)-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide, (Example 120); (1-(pyrimidin-5-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide, second-eluting enantiomer (Example 121); 3-(4-hydroxy-1-(pyrimidin-5-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide, second-eluting enantiomer (Example 122); (S)-(3-(1-(6-(hydroxymethyl)imidazo[1,2-a]pyridin-3-yl)pyrrolidin-3-yl)-4-methylphenyl)(5-(trifluoromethyl)pyridin-3-yl)methanone (Example 123); N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-4-(difluoromethyl)-3-(1-(pyrimidin-5-yl)pyrrolidin-3-yl)benzamide (Example 124); (S)-3-(1-(6-bromothieno[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 125); (S)-4-methyl-3-(1-(6-(4-methylpiperazine-1-carbonyl)thieno[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide, (Example 126); 4-(3-(2-methoxy-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)pyrrolidin-1-yl)-N-methylpicolinamide, (Example 127); (S)-3-(1-(imidazo[1,5-a]pyrazin-8-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 128); (S)-3-(1-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 129); (S)-3-(1-(2-acetamidopyrimidin-5-yl)pyrrolidin-3-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 130); and (S)—N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-4-methyl-3-(1-(thieno[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl)benzamide (Example 131).

9. A compound of formula (Ib) according to claim 6, selected from the group consisting of: 3-(3-((6-aminopyridin-3-yl)oxy)azetidin-1-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 44); 3-(3-((6-acetamidopyridin-3-yl)oxy)azetidin-1-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 45); 3-(3-((6-(2-methoxyacetamido)pyridin-3-yl)oxy)azetidin-1-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 46); 3-(3-((5-aminopyridin-3-yl)oxy)azetidin-1-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 47); 5-((1-(2-methyl-5-((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenyl)azetidin-3-yl)oxy)nicotinamide (Example 132); and 3-(3-((5-acetamidopyridin-3-yl)oxy)azetidin-1-yl)-4-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)benzamide (Example 133).

10. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 9 in admixture with at least one or more pharmaceutically acceptable carriers and / or excipients.

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

12. A compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 or 11 for use as a medicament.

13. 13. A compound of formula (I) or a pharmaceutical composition for use according to claim 12 in the prevention and / or treatment of diseases, disorders or conditions associated with DDR dysregulation.

14. 14. A compound of formula (I) or a pharmaceutical composition for use according to claim 12 or 13 in the prevention and / or treatment of fibrosis and / or in the prevention and / or treatment of diseases, disorders or conditions in which fibrosis is involved.

15. 15. A compound of formula (I) or a pharmaceutical composition for use according to claim 14 in the prevention and / or treatment of fibrosis, including pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.

16. 16. A compound of formula (I) or a pharmaceutical composition for use according to claim 15 in the prevention and / or treatment of idiopathic pulmonary fibrosis (IPF).

17. Formula (IV) 【Chemistry 13】 and compounds of formula (VI) 【Chemistry 14】 Compounds of [Wherein R is (C １ -C ４ ) alkyl, and Z is (C １ -C ４ ) alkyl, (C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkoxy, (C １ -C ４ ) haloalkoxy, (C １ -C ４ ) hydroxyalkyl and (C ３ -C ６ ) cycloalkyl, wherein the compound of formula (VI) is in its racemic or enantiomeric form, (R) or (S). An intermediate compound selected from:

18. Use of an intermediate compound of formula (IV) and / or an intermediate compound of formula (VI) as defined in claim 17 in the preparation of a compound of formula (Ia) as defined in claim 5.

19. A method for preparing a compound of formula (Ia) as defined in claim 5 or a pharmaceutically acceptable salt thereof, comprising: a) Formula (III) 【Chemistry 15】 and N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine 【Chemistry 16】 is reacted in the presence of a solvent under an acid catalyst to obtain a compound of formula (IV) 【Chemistry 17】 Intermediate compound of wherein R and Z are defined in claim 17. The method includes the step of obtaining

20. moreover: b) Cleavage of the benzyl group of the intermediate compound of formula (IV) by reduction under a hydrogen atmosphere in the presence of a Pd catalyst to give the intermediate compound of formula (V): 【Chemistry 18】 to obtain an intermediate compound of c) Boc-protection of the free nitrogen of the intermediate compound of formula (V) by reaction with di-tert-butyl-dicarbonate to give the intermediate compound of formula (VI) 【Chemistry 19】 to obtain the intermediate compound 20. The method of claim 18, comprising the steps of:

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