4-(7H-Pyrrolo[2,3-D]pyrimidin-4-yl)-3,6-dihydropyridine-1-(2H)-carboxamide derivatives as LIMK and / or ROCK kinase inhibitors for use in the treatment of cancer

Abstract

The present invention relates to compounds of formula (I), particularly LIMK and / or ROCK kinase inhibitors. The present invention also relates to these novel inhibitors for use in the treatment of conditions selected from the group consisting of cancer, virion infection, ocular hypertension and glaucoma formation, neurofibromatosis types 1 and 2, psoriasis lesions, inflammatory diseases and hyperalgesia, central sensitization and chronic pain, reproductive erectile dysfunction, and neurological disorders. This specification discloses the synthesis and characterization of exemplary compounds and their pharmacological data (e.g., pages 37-163; Examples 1-169; Compounds; Biological Studies; Tables; Figures 1 / 6-6 / 6). An exemplary compound is, for example, 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-phenyl-3,6-dihydropyridine-1(2H)-carboxamide (Example 1, Compound 5).

Description

[Technical Field]

[0001] The present invention relates to novel inhibitors of LIMK and / or ROCK kinases and their therapeutic uses. The present invention also relates to these novel inhibitors as anti-cancer agents. [Background technology]

[0002] LIM kinases (LIMKs) are serine / threonine and tyrosine kinases involved in regulating cytoskeletal dynamics. LIM kinases phosphorylate cofilin, leading to its inhibition (Scott, RW and Olson, MF (2007) LIM kinases: function, regulation and association with human disease. Journal of molecular medicine (Berlin, Germany). 85, 555-568). Cofilin, a member of the actin depolymerizing factor (ADF) family, regulates actin polymerization dynamics by promoting rapid turnover of actin filaments (Bamburg, JR and Bernstein, BW (2010) Roles of ADF / cofilin in actin polymerization and beyond. F1000 biology reports. 2, 62; Mizuno, K. (2013) Signaling mechanisms and functional roles of cofilin phosphorylation and dephosphorylation. Cellular signaling. 25, 457-469; Pollard, TD and Borisy, GG (2003) Cellular motility driven by assembly and disassembly of actin filaments. Cell. 112, 453-465). LIMK also regulates microtubule dynamics independently of regulating actin remodeling. The molecular mechanism by which LIMK regulates microtubule dynamics remains unknown (Prunier, C., Prudent, R., Kapur, R., Sadoul, K., and Lafanechere, L. (2017) LIM kinases: cofilin and beyond. Oncotarget. 8, pp. 41749-41763).Thus, LIMK plays an important role in cytoskeletal remodeling, contributing to many cellular functions such as cell motility, morphogenesis, division, differentiation, apoptosis, neuronal morphology, neuritogenesis, and tumorigenesis.

[0003] The LIMK family consists of only two members, LIMK1 and LIMK2. Recently, LIMK has been implicated in many diseases, including cancers, viral infections, ocular hypertension, and glaucoma formation, and has therefore emerged as a novel therapeutic target. It also plays a role in neurofibromatosis types 1 and 2 (NF1 and NF2). LIMK is also involved in psoriatic lesions, inflammatory responses, the development of inflammatory hyperalgesia, central sensitization and chronic pain, oocyte maturation, and age-related erectile dysfunction. More recently, LIMK has been shown to play an important role in neuronal development and plasticity, implicating it in several neurological disorders, including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Williams-Beuren syndrome, schizophrenia, and intellectual disability.

[0004] Rho-associated coiled-coil-containing kinase (ROCK) is a serine / threonine kinase that is a member of the AGC kinase family (Hartmann, S.; Ridley, AJ; Lutz, S. The Function of Rho-Associated Kinases ROCK1 and ROCK2 in the Pathogenesis of Cardiovascular Disease. Front. Pharmacol. 2015, 6, 276). ROCK phosphorylates several targets: 1) myosin light chain (MLC) in conjunction with myosin light chain phosphatase (MLCP), which subsequently inactivates MLCP and sustains MLC phosphorylation (Amano, M.; Nakayama, M.; Kaibuchi, K. Rho-kinase / ROCK: A key regulator of the cytoskeleton and cell polarity. Cytoskeleton 2010, 67, 545-554). This results in stimulation of actomyosin contractility and cell contraction. 2 / phosphorylates LIMK2, which is activated and phosphorylates cofilin, resulting in the inactivation of cofilin and the stabilization of actin filaments (Maekawa, M.; Ishizaki, T.; Boku, S.; Watanabe, N.; Fujita, A.; Iwamatsu, A.; Obinata, T.; Ohashi, K.; Mizuno, K.; Narumiya, S. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 1999, 285, 895-898).3 / It phosphorylates ezrin, radixin, and moesin (ERM), which are involved in actin / plasma membrane interactions (Matsui, T.; Maeda, M.; Doi, Y.; Yonemura, S.; Amano, M.; Kaibuchi, K.; Tsukita, S.; Tsukita, S. Rho-kinase phosphorylates COOH-terminal threonines of ezrin / radixin / moesin (ERM) proteins and regulates their head-to-tail association. J. Cell Biol. 1998, 140, 647-657). 4 / It phosphorylates collapsin response mediator protein-2 (CRMP-2), thereby inhibiting its ability to stimulate microtubule assembly and axonal growth (Arimura, N.; Menager, C.; Fukata, Y.; Kaibuchi, K. Role of CRMP-2 in neuronal polarity. J. Neurobiol. 2004, 58, 34-47). 5 / It phosphorylates the tumor suppressor PTEN (phosphatase and tensin homolog), thereby preventing PTEN from inhibiting cell proliferation and survival (Li, Z.; Dong, X.; Wang, Z.; Liu, W.; Deng, N.; Ding, Y.; Tang, L.; Hla, T.; Zeng, R.; Li, L. et al. Regulation of PTEN by Rho small GTPases. Nat. Cell Biol. 2005, 7, 399-404).

[0005] Collectively, these actions play a role in actin cytoskeleton remodeling, cell contractility, and cell death. Thus, ROCK regulates a variety of cellular functions, including growth, apoptosis, migration, and metabolism.

[0006] ROCK is involved in a variety of pathologies, namely cardiac diseases, e.g., cardiac fibrosis, cardiac hypertrophy, systemic blood pressure disorders, pulmonary hypertension, renal pathologies, e.g., hypertensive nephropathy, Bartter and Gitelman syndrome, diabetic nephropathy, asthma, chronic obstructive pulmonary disease, traumatic brain injury, Alzheimer's and Parkinson's diseases, obesity, diabetes mellitus, cancer, autoimmune diseases (lupus erythematosus, rheumatoid arthritis). [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2015158283, 2015, 172 pages [Patent Document 2] International Publication No. 2008016534, 2008, p. 133 [Non-patent literature]

[0008] [Non-Patent Document 1] Scott, RW and Olson, MF (2007) LIM kinases: function, regulation and association with human disease. Journal of molecular medicine (Berlin, Germany). 85, pp. 555-568 [Non-patent document 2] Bamburg, JR and Bernstein, BW (2010) Roles of ADF / cofilin in actin polymerization and beyond. F1000 biology reports. 2, 62 [Non-patent document 3] Mizuno, K. (2013) Signaling mechanisms and functional roles of cofilin phosphorylation and dephosphorylation. Cellular signaling. 25, pp. 457-469

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[0009] An object of the present invention is to provide novel small molecules with inhibitory activity against LIMK and / or ROCK kinases.

[0010] An object of the present invention is to provide novel inhibitors of LIMK and / or ROCK kinases.

[0011] Another object of the present invention is to provide novel inhibitors of LIMK and ROCK kinases.

[0012] Another object of the present invention is to provide novel and potent inhibitors that target both LIMK and ROCK or that are specific for LIMK according to the target disease.

[0013] Another object of the present invention is to provide new small molecules as inhibitors of LIMK and / or ROCK kinases, which have a wide range of cytotoxicity, from low to high, depending on their potential applications. [Means for solving the problem]

[0014] Accordingly, the present invention provides compounds having the following formula (I):

[0015] [ka]

[0016] [In the formula, - "a" is a single bond and "b" is a double bond, or "a" is a double bond and "b" is a single bond; R1 is selected from the group consisting of H, (C1-C6) alkyl groups, halogen, and (C3-C7) cycloalkyl groups; R2 is selected from the group consisting of H and (C1-C6) alkyl groups; or R1 and R2 together with the carbon atoms carrying them can form a (C5-C7)cycloalkyl group or a (C5-C7)heterocycloalkyl group, said heterocycloalkyl group being optionally substituted with a (C1-C6)alkyl group; - n is 0, 1, or 2; - Each R i are the same or different and are selected from (C1-C6) alkyl groups; - R is selected from the group consisting of a (C3-C7)cycloalkyl group optionally fused with an aryl group, an aryl group, a heteroaryl group, a heterocycloalkyl group fused with an aryl group, and an aryl group fused with a heterocycloalkyl group, wherein the aryl group and the heteroaryl group are optionally substituted with at least one substituent R3 selected from the group consisting of: H, (C1-C6) alkyl, wherein said alkyl is optionally interrupted by at least one heteroatom; heterocycloalkyl, Aryl, wherein said aryl is optionally substituted with at least one substituent such as: (C1-C6)alkoxy, NR a R b , where R a and R b are each independently H or a (C1-C6) alkyl group: -XR c where X is a bond, a (C1-C6) alkylene group, preferably —CH2—, or —C(═O)—; R c is a heterocycloalkyl group optionally substituted with at least one (C1-C6) alkyl group, SO2CH3, or (C1-C6) alkylamino group; halogens, -C(=O)-NR a R b , where R a and R b are each independently H or a (C1-C6) alkyl group; -C(=O)-N(R d )-X1-NR a R b , where R d , R a and R b are each independently H or a (C1-C6) alkyl group, and X1 is a (C1-C6) alkylene group, preferably CH2, or -O-X2-NR e R f, where X2 is a (C1-C6) alkylene group, and R e and R f are each independently H or a (C1-C6) alkyl group, or R e and R f at least one of is an amino protecting group such as a carbamate (Boc) or contains one fluorophore such as a difluoroborane derivative, or Heteroaryl, wherein said heteroaryl is optionally substituted with at least one substituent such as: (C1-C6)alkoxy, NR a R b , where R a and R b are each independently H or a (C1-C6) alkyl group; -C(=O)-NR a R b , where R a and R b are each independently H or a (C1-C6) alkyl group, or -NH-C(=O)-R a , where R a is H or a (C1-C6) alkyl group; halogens, Halo(C1-C6)alkyl, Aryloxy, wherein said aryloxy is optionally substituted with at least one substituent such as: (C1-C6)alkoxy, NR a R b , where R a and R b are each independently H or a (C1-C6) alkyl group; -XR c where X is a bond, a (C1-C6) alkylene group, preferably —CH2— or —C(═O)—, and R cis a heterocycloalkyl group optionally substituted with at least one (C1-C6) alkyl group, SO2CH3, or (C1-C6) alkylamino group; halogens, -C(=O)-NR a R b , where R a and R b are each independently H or a (C1-C6) alkyl group, or -C(=O)-N(R d )-X1-NR a R b , where R d , R a and R b are each independently H or a (C1-C6) alkyl group, and X1 is a (C1-C6) alkylene group, preferably CH2; -O-halo(C1-C6)alkyl, Cyano, (C1-C6)alkoxy, and -X-NR a R b wherein X is selected from the group consisting of a (C1-C6) alkylene group, —OC(═O)—, —C(═O)—, and —NH—C(═O)—; R a and R b are each independently H or a (C1-C6) alkyl group. or a pharmaceutically acceptable salt, racemate, diastereomer or enantiomer thereof.

[0017] The present invention provides compounds having the following formula (I):

[0018] [ka]

[0019] [In the formula, - "a" is a single bond and "b" is a double bond, or "a" is a double bond and "b" is a single bond; R1 is selected from the group consisting of H, (C1-C6) alkyl groups, halogen, and (C3-C7) cycloalkyl groups; R2 is selected from the group consisting of H and (C1-C6) alkyl groups; or R1 and R2 together with the carbon atoms carrying them can form a (C5-C7)cycloalkyl group or a (C5-C7)heterocycloalkyl group, said heterocycloalkyl group being optionally substituted with a (C1-C6)alkyl group; - n is 0, 1, or 2; - Each R i are the same or different and are selected from (C1-C6) alkyl groups; - R is selected from the group consisting of a (C3-C7)cycloalkyl group optionally fused with an aryl group, an aryl group, a heteroaryl group, a heterocycloalkyl group fused with an aryl group, and an aryl group fused with a heterocycloalkyl group, wherein the aryl group and the heteroaryl group are optionally substituted with at least one substituent R3 selected from the group consisting of: H, (C1-C6) alkyl, wherein said alkyl is optionally interrupted by at least one heteroatom; heterocycloalkyl, Aryl, wherein said aryl is optionally substituted with at least one substituent such as: (C1-C6)alkoxy, NR a R b , where R a and R b are each independently H or a (C1-C6) alkyl group: -XR c where X is a bond, a (C1-C6) alkylene group, preferably —CH2—, or —C(═O)—; R c is a heterocycloalkyl group optionally substituted with at least one (C1-C6) alkyl group, SO2CH3, or (C1-C6) alkylamino group; halogens, -C(=O)-NR a R b , where R a and R b are each independently H or a (C1-C6) alkyl group; -C(=O)-N(R d )-X1-NR a R b , where R d , R a and R b are each independently H or a (C1-C6) alkyl group, and X1 is a (C1-C6) alkylene group, preferably CH2, or -O-X2-NR e R f , where X2 is a (C1-C6) alkylene group, and R e and R f are each independently H or a (C1-C6) alkyl group, or R e and R f at least one of is an amino protecting group such as carbamate (Boc), or contains one fluorophore, or is SO2CH3, or Heteroaryl, wherein said heteroaryl is optionally substituted with at least one substituent such as: (C1-C6)alkoxy, NR a R b , where R a and R b are each independently H or a (C1-C6) alkyl group; -C(=O)-NR a R b , where R a and R b are each independently H or a (C1-C6) alkyl group, or -NH-C(=O)-R a , where R a is H or a (C1-C6) alkyl group; halogens, Halo(C1-C6)alkyl, Aryloxy, wherein said aryloxy is optionally substituted with at least one substituent such as: (C1-C6)alkoxy, · OH, NR a R b , where R a and R b are each independently H or a (C1-C6) alkyl group; -XR c where X is a bond, a (C1-C6) alkylene group, preferably —CH2— or —C(═O)—, and R c is a heterocycloalkyl group optionally substituted with at least one (C1-C6) alkyl group, SO2CH3, or (C1-C6) alkylamino group; halogens, -O-benzyl, -OC(=O)-NR a R b , where R a and R are each independently H or a (C1-C6) alkyl group; -NH-C(=O)-R a , where R a is H or a (C1-C6) alkyl group; -C(=O)-NR a R b , where R a and R b are each independently H or a (C1-C6) alkyl group; -C(=O)-N(R d )-X1-NR a R b , where R d , R a and R b are each independently H or a (C1-C6) alkyl group, and X1 is a (C1-C6) alkylene group, preferably CH2; heteroaryloxy, wherein said heteroaryloxy is optionally substituted with at least one substituent such as: -C(=O)-NRa R b , where R a and R b are each independently H or a (C1-C6) alkyl group; -O-halo(C1-C6)alkyl, Cyano, (C1-C6)alkoxy, -X-NR a R b wherein X is selected from the group consisting of a (C1-C6) alkylene group, —OC(═O)—, —C(═O)—, and —NH—C(═O)—; R a and R b are each independently H or a (C1-C6) alkyl group; -X'-R c where X' is -C(=O)- or -O-(C1-C6) alkylene group, R c is a cycloalkyl group optionally substituted with at least one halogen, or R c is SO2CH3 or a heterocycloalkyl group optionally substituted with at least one (C1-C6) alkyl group, and -O-X2-NR e R f , where X2 is a (C1-C6) alkylene group, and R e and R f are each independently H or a (C1-C6) alkyl group, or R e and R f at least one of which is an amino-protecting group such as carbamate (Boc)] or a pharmaceutically acceptable salt, racemate, diastereomer or enantiomer thereof.

[0020] According to one embodiment, in formula (I), R is a (C3-C7) cycloalkyl group, preferably an unsubstituted cyclohexyl group.

[0021] According to another embodiment, in formula (I), R is an aryl group optionally substituted with at least one substituent R as defined above, preferably an optionally substituted phenyl group as defined above.

[0022] According to one embodiment, when R is an aryl group substituted with at least one substituted aryl group, preferably a substituted phenyl group, the following R groups can be mentioned:

[0023] [ka] [ka] [ka]

[0024] According to one embodiment, in formula (I), R is -O-X-NR as defined above. e R f and at least one aryl group substituted with a group, preferably an aryl group substituted with a phenyl group, preferably a phenyl group.

[0025] Preferably, in this embodiment, -O-X2-NR e R f The groups may be any of the following: -O-X2-NHBoc, preferably -O-(CH2)3-NHBoc, -O-X2-NH-C(=O)alkyl, preferably -O-(CH2)3-NH-C(=O)Me, -O-X2-NH-SO2-alkyl, preferably -O-(CH2)3-NH-SO2-Me, -O-X2-NR e R f is selected from the group e and R f is an alkyl group, preferably methyl, and a group having the formula

[0026] [ka]

[0027] is.

[0028] According to one embodiment, R e and R f At least one of the groups is an amino-protecting group, such as carbamate (Boc), or contains a fluorophore, such as a difluoroborane derivative, including the fluorophore 5,5-difluoro-1,3-dimethyl-5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine.

[0029] Thus, according to this embodiment, the following compounds may be mentioned:

[0030] [ka]

[0031] According to one embodiment, when R is an aryl group, preferably a phenyl group, substituted with at least one substituted heteroaryl group, the following R groups may be mentioned:

[0032] [ka]

[0033] The following definitions are set forth herein to illustrate and define the meaning and scope of the various terms used to describe the invention.

[0034] "C t ~C z " means a carbon-based chain which may have t to z carbon atoms, for example C1-C3 means a carbon-based chain which may have 1 to 3 carbon atoms.

[0035] The term "alkyl group," unless otherwise specified, refers to a straight-chain or branched, saturated hydrocarbon-based aliphatic group containing 1 to 12 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, or pentyl groups.

[0036] The term "aryl group" means a cyclic aromatic group containing 6 to 10 carbon atoms. Examples of the aryl group include a phenyl group and a naphthyl group.

[0037] The term "heteroaryl group" means a 5- to 10-membered aromatic monocyclic or bicyclic group containing 1 to 4 heteroatoms selected from O, S, or N. Examples include imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, pyrazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, indazolyl, benzothiazolyl, isobenzothiazolyl, benzotriazolyl, quinolinyl, and isoquinolinyl groups.

[0038] Examples of heteroaryl having 5 to 6 atoms and including 1 to 4 nitrogen atoms include the following representative groups: pyrrolyl group, pyrazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group, and 1,2,3-triazinyl group.

[0039] Examples of heteroaryl include thiophenyl, oxazolyl, furazanyl, 1,2,4-thiadiazolyl, naphthyridinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, cinnolinyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothiophenyl, thienopyridyl, thienopyrimidinyl, pyrrolopyridyl, imidazopyridyl, benzazaindole, 1,2,4-triazinyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, purinyl, quinazolinyl, quinolinyl, isoquinolyl, 1,3,4-thiadiazolyl, thiazolyl, isothiazolyl, carbazolyl, and the corresponding groups resulting from their fusion, or fusion, with a phenyl nucleus.

[0040] The term "heterocycloalkyl group" means a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic group containing 1 to 3 heteroatoms selected from O, S, or N. The heterocycloalkyl group may be attached to the remainder of the molecule via a carbon atom or a heteroatom. The term bicyclic heterocycloalkyl includes fused bicyclic and spirocyclic rings.

[0041] Examples of saturated heterocycloalkyl containing 5 to 6 atoms include oxetanyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, azepinyl, oxazepinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, dithiolanyl, thiazolidinyl, tetrahydropyranyl, tetrahydropyridinyl, dioxanyl, morpholinyl, piperidinyl, piperazinyl, tetrahydrothiopyranyl, dithianyl, thiomorpholinyl, and isoxazolidinyl.

[0042] Among heterocycloalkyls, mention may also be made, by way of example, of bicyclic groups such as (8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, octahydroindozilinyl, diazepanyl, dihydroimidazopyrazinyl and diazabicycloheptanyl, or diazaspirocycles such as 1,7-diazaspiro[4.4]non-7-yl or 1-ethyl-1,7-diazaspiro[4.4]non-7-yl.

[0043] If a heterocycloalkyl is substituted, the substitutions may be on one (or several) carbon atoms and / or on a heteroatom. If a heterocycloalkyl comprises several substituents, they may be carried by the same atom or by different atoms.

[0044] The term "cycloalkyl group," unless otherwise specified, refers to a cyclic carbon-based group containing from 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like groups.

[0045] When an alkyl group is substituted with an aryl group, the term "arylalkyl" or "aralkyl" group is used. An "arylalkyl" or "aralkyl" group is an aryl-alkyl-group, in which the aryl and alkyl groups are as defined above. Among the arylalkyl groups, particular mention may be made of benzyl or phenethyl groups.

[0046] The term "halogen" means fluorine, chlorine, bromine or iodine.

[0047] The term "alkoxy group" refers to an -O-alkyl group, wherein alkyl is as defined above. Examples include an -O-(C1-C4) alkyl group, in particular an -O-methyl group, an -O-ethyl group, an -O-propyl group, an -O-isopropyl group as an -O-C3 alkyl group, and an -O-butyl group, an -O-isobutyl group, or an -O-tert-butyl group as an -O-C4 alkyl group.

[0048] The above "alkyl", "cycloalkyl", "aryl", "heteroaryl" and "heterocycloalkyl" groups can be substituted with one or more substituents, including the following groups: amino, hydroxyl, thiol, oxo, halogen, alkyl, alkoxy, alkylthio, alkylamino, aryloxy, arylalkoxy, cyano, trifluoromethyl, carboxy, and carboxyalkyl groups.

[0049] The term "alkylthio" means an -S-alkyl group, wherein alkyl is as defined above.

[0050] The term "alkylamino" means an --NH-alkyl group, wherein the alkyl group is as defined above.

[0051] The term "aryloxy" refers to the group --O-aryl, wherein the aryl group is as defined above.

[0052] The term "arylalkoxy" means an aryl-alkoxy- group in which the aryl and alkoxy groups are as previously defined.

[0053] The term "carboxyalkyl" refers to a HOOC-alkyl- group, in which the alkyl group is as defined above. Examples of carboxyalkyl groups include carboxymethyl or carboxyethyl in particular.

[0054] The term "haloalkyl group" refers to an alkyl group as defined above in which one or more hydrogen atoms have been replaced by a halogen atom. Examples include fluoroalkyl, in particular CF3 or CHF2.

[0055] The term "carboxyl" refers to a COOH group. The term "oxo" means "=O".

[0056] In some embodiments of the present invention, the compounds of the present invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, and individual diastereomeric mixtures, and all such isomeric forms of these compounds are included in the present invention unless expressly stated otherwise.

[0057] In some embodiments, compounds of the present invention may contain one or more double bonds and therefore may exist as individual Z and / or E isomers or mixtures thereof. All such isomeric forms of these compounds are included in the present invention, unless expressly specified otherwise.

[0058] In embodiments where the compounds of the invention can contain multiple tautomeric forms, the invention also includes all tautomeric forms of said compounds, unless expressly stated otherwise.

[0059] A preferred family of compounds according to the present invention are compounds having the formula (II):

[0060] [ka]

[0061] (In the formula, - a, b, n, R i , R1, and R2 are as defined above in formula (I), - m is 1 or 2 and each R3 is the same or different and is as defined above in formula (I).

[0062] Compounds of formula (II) are compounds of formula (I) where R is a phenyl group substituted with at least one R3 group.

[0063] A preferred family of compounds according to the present invention are compounds having the formula (III):

[0064] [ka]

[0065] (In the formula, - a, b, n, R i , R1, and R2 are as defined above in formula (I), - R4 is H, halogen or aryloxy.

[0066] A preferred family of compounds according to the present invention are compounds having the formula (IV):

[0067] [ka]

[0068] (In the formula, R1 is H or a (C1-C6) alkyl group; - R3 H, (C1-C6) alkyl, aryl, preferably phenyl, said aryl optionally substituted with at least one substituent such as (C1-C6)alkoxy, in particular OMe, or halogen, such as F; heteroaryl, such as pyridinyl, imidazolyl, pyrrolyl, or triazolyl; halogens such as F, Cl, or Br, Halo(C1-C6)alkyl such as CF3, aryloxy, in particular phenyloxy, wherein said aryloxy is optionally substituted with at least one substituent such as (C1-C6)alkoxy, preferably OMe; -O-halo(C1-C6)alkyl, for example OCF3, Cyano, (C1-C6)alkoxy, such as OMe, and -OC(=O)-NR a R b , where R a and R bare each independently H or a (C1-C6) alkyl group; is selected from the group consisting of R4 is H, halogen or aryloxy, such as phenyloxy; or R3 and R4 together with the carbon atoms that carry them form a phenyl or heterocycloalkyl group, preferably containing two oxygen atoms and three carbon atoms).

[0069] Preferably, in formula (IV), R1 is methyl.

[0070] Preferred compounds of formula (IV) are:

[0071] [ka] [ka] [ka] [ka]

[0072] A preferred family of compounds according to the present invention are compounds having the formula (V):

[0073] [ka]

[0074] (In the formula, - "a" is a single bond and "b" is a double bond, or "a" is a double bond and "b" is a single bond; R1 is a (C1-C6) alkyl group, preferably methyl; R5 is a (C1-C6) alkyl group, preferably methyl; R6 is H or a (C1-C6) alkyl group, preferably methyl; - R3 halogens such as F, Cl, or Br, and Aryloxy, especially phenyloxy (selected from the group consisting of:

[0075] Preferably, in formula (V), R1 is methyl.

[0076] Preferred compounds of formula (V) are

[0077] [ka]

[0078] A preferred family of compounds according to the present invention are compounds having the formula (VI):

[0079] [ka]

[0080] where R3 is a halogen.

[0081] Preferred compounds of formula (VI) are:

[0082] [ka]

[0083] A preferred family of compounds according to the present invention is the compound having formula (VII):

[0084] [ka]

[0085] (In the formula, R1 is halogen, preferably Cl; - R3 is -OC(=O)-NR aR b where R a and R b are each independently H or a (C1-C6) alkyl group).

[0086] Preferred compounds of formula (VII) are:

[0087] [ka]

[0088] A preferred family of compounds according to the present invention are compounds having the formula (VIII):

[0089] [ka]

[0090] (In the formula, R1 is a (C3-C7)cycloalkyl group, preferably cyclopropyl; - R3 aryl, preferably phenyl, wherein said aryl is optionally substituted with at least one substituent such as (C1-C6)alkoxy, in particular OMe; heteroaryls such as pyrrolyl; halogens such as F, Cl, or Br, aryloxy, in particular phenyloxy, wherein said aryloxy is optionally substituted with at least one substituent such as (C1-C6)alkoxy, preferably OMe; -OC(=O)-NR a R b , where R a and R b are each independently H or a (C1-C6) alkyl group; (selected from the group consisting of:

[0091] Preferably, in formula (VIII), R1 is cyclopropyl.

[0092] Preferred compounds of formula (VIII) are:

[0093] [ka]

[0094] A preferred family of compounds according to the present invention is the compound having the formula (IX):

[0095] [ka]

[0096] (In the formula, R1 is a (C1-C6) alkyl group, preferably methyl; R2 is a (C1-C6) alkyl group, preferably methyl; - R3 H, aryl, preferably phenyl, wherein said aryl is optionally substituted with at least one substituent such as (C1-C6)alkoxy, in particular OMe; halogens, such as F, Cl, or Br, (C1-C6)alkoxy such as OMe, -OC(=O)-NR a R b , where R a and R b are each independently H or a (C1-C6) alkyl group; (selected from the group consisting of:

[0097] Preferably, in formula (IX), R1 and R2 are the same, and more preferably, they are methyl.

[0098] Preferred compounds of formula (IX) are:

[0099] [ka]

[0100] A preferred family of compounds according to the present invention are compounds having the formula (X):

[0101] [ka]

[0102] (In the formula, - p is 0, 1, or 2; - R3 H, (C1-C6) alkyl, wherein said alkyl is optionally interrupted by at least one heteroatom; heterocycloalkyl, such as morpholinyl; aryl, preferably phenyl, wherein said aryl is optionally substituted with at least one substituent such as (C1-C6)alkoxy; heteroaryls such as pyridinyl; halogens, aryloxy, Halo(C1-C6)alkyl, Cyano, (C1-C6)alkoxy, and -X-NR a R b wherein X is selected from the group consisting of a (C1-C6) alkylene group, —OC(═O)—, —C(═O)—, and —NH—C(═O)—; R a and R b are each independently H or a (C1-C6) alkyl group; (selected from the group consisting of:

[0103] Preferred compounds of formula (X) are:

[0104] [ka] [ka]

[0105] A preferred family of compounds according to the present invention are compounds having the following formula (XI):

[0106] [ka]

[0107] (In the formula, X1 is -O-, -S-, or -N((C1-C6)alkyl)-, such as -N(Me)-; - R3 is a halogen).

[0108] Preferred compounds of formula (XI) are:

[0109] [ka]

[0110] A preferred family of compounds according to the present invention are compounds having the following formula (XII):

[0111] [ka]

[0112] wherein R1 and R2 are as defined above in formula (I).

[0113] Preferably, in formula (XII), R1 is a (C1-C6) alkyl group such as methyl or ethyl, or a (C3-C7) cycloalkyl group such as cyclopropyl.

[0114] Preferably, in formula (XII), R2 is H or a (C1-C6) alkyl group such as ethyl.

[0115] Preferred compounds of formula (XII) are:

[0116] [ka]

[0117] A preferred family of compounds according to the present invention are compounds having the following formula (XIII):

[0118] [ka]

[0119] wherein R1 and R2 are as defined above in formula (I).

[0120] Preferably, in formula (XIII), R1 is a (C1-C6) alkyl group such as methyl or ethyl, or a (C3-C7) cycloalkyl group such as cyclopropyl.

[0121] Preferably, in formula (XIII), R2 is H or a (C1-C6) alkyl group such as ethyl.

[0122] Preferred compounds of formula (XIII) are:

[0123] [ka]

[0124] The present invention also relates to a medicament comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

[0125] The present invention also relates to a medicament comprising a compound of formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII) or a pharmaceutically acceptable salt thereof.

[0126] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0127] The present invention also relates to a pharmaceutical composition comprising a compound of Formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), or (XIII) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0128] Said excipients are selected according to the pharmaceutical form and the desired mode of administration from the usual excipients known to those skilled in the art.

[0129] The present invention relates to a compound of formula (I) as defined above, or an addition salt of this compound with a pharmaceutically acceptable acid, for use as a medicament.

[0130] The present invention relates to a compound of formula (I) as defined above, or a pharmaceutically acceptable salt of this compound, for use as a medicament.

[0131] The present invention also relates to a compound of formula (I) as defined above, or of formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII) as defined above, for use in the treatment of a condition selected from the group consisting of cancers such as breast cancer, lung cancer, pancreatic cancer, prostate cancer, colorectal cancer, leukemia, glioma, melanoma and osteosarcoma, virion infections (such as HIV, Ebola and herpes viruses), ocular hypertension and glaucoma formation, neurofibromatosis types 1 and 2 (NF1 and NF2), psoriatic lesions, inflammatory diseases and hyperalgesia, central sensitization and chronic pain, reproductive (oocyte maturation) erectile dysfunction, and neurological diseases such as amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease, Williams-Beuren syndrome, schizophrenia, intellectual disability, etc.

[0132] Thus, the present invention also relates to a compound as defined above for use in a method for the treatment of a condition as defined above.

[0133] The present invention also relates to a compound of formula (I) as defined above, or of formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII) as defined above, for use in the treatment of cancer.

[0134] The present invention also relates to a method for treating the above-mentioned pathological conditions, which comprises administering to a patient an effective dose of a compound according to the invention or a pharmaceutically acceptable salt thereof.

[0135] Thus, the compounds of the present invention can be used to treat several pathologies involving the regulation of cytoskeletal dynamics, cytoskeletal remodeling, cell motility, morphogenesis, division, differentiation, apoptosis, neuronal morphology, neuritogenesis, and tumorigenesis.

[0136] This includes cancers such as breast cancer, lung cancer, pancreatic cancer, prostate cancer, colorectal cancer, leukemia, glioma, melanoma and osteosarcoma, virion infections (such as HIV, Ebola and herpes viruses), ocular hypertension and glaucoma formation, neurofibromatosis types 1 and 2 (NF1 and NF2), psoriatic lesions, inflammatory diseases and hyperalgesia, central sensitization and chronic pain, reproductive (oocyte maturation) erectile dysfunction, and neurological diseases such as amyotrophic lateral sclerosis, Parkinson's and Alzheimer's disease, Williams-Beuren syndrome, schizophrenia, intellectual disability.

[0137] In the pharmaceutical composition of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, local, topical, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above or a salt thereof is administered in unit dosage form in a mixture with conventional pharmaceutical excipients to animals and humans for the treatment of the above disorders and diseases.

[0138] Suitable unit dosage forms include oral forms such as tablets, soft or hard gel capsules, powders, granules, and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal dosage forms, inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous dosage forms, rectal dosage forms, and dosage forms by implant. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions.

[0139] According to usual practice, the dosage appropriate for each patient is determined by the physician according to the mode of administration and the weight and response of said patient. [Brief explanation of the drawings]

[0140] [Figure 1] Figure 1 shows an example of a Western blot after treatment of HeLa cells with multiple inhibitors. [Figure 2] Figure 2 shows confocal imaging of the actin cytoskeleton. [Figure 3] FIG. 3 shows the migration properties measured by wound healing assay. [Figure 4] Figure 4 shows microtubule dynamics by visualization of the mitotic spindle. [Figure 5] FIG. 5 shows the results of an in vivo assay in an ALS (amyotrophic lateral sclerosis) mouse model. [Figure 6] FIG. 6 shows the results of an in vivo assay in an ALS (amyotrophic lateral sclerosis) mouse model. DETAILED DESCRIPTION OF THE INVENTION [Example]

[0141] chemical synthesis General Procedure A: Hydrazone Formation To a suspension of 4-hydroxy-6-hydrazinylpyrimidine (1.0 equiv.) in EtOH (0.5 M) was added the corresponding ketone (1.5 equiv.). The reaction was refluxed for 3 h and then cooled to 0° C. The solid was collected by filtration, washed with EtO, and dried under high vacuum to give the desired product.

[0142] General Procedure B: Fischer Synthesis A suspension of the hydrazone (1.0 equiv.) in tetralin (0.25 M) was heated to 260° C. in a sealed tube for 3 h. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed several times with petroleum ether and EtO, and dried under high vacuum to give the desired product.

[0143] General Procedure C: Chlorination A solution of the tricyclic compound (1.0 equiv.) in POCl3 (0.15 M) was heated at 100 °C for 1 h. Excess POCl3 was removed in vacuo, and the resulting dark slurry was suspended in CHCl2 and poured into an ice bath. The mixture was stirred for 1 h and extracted with CHCl2. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired product.

[0144] General Procedure D: Suzuki-Miyaura Cross Coupling To a solution of the chlorinated heterocycle (1.0 equiv.) in THF (0.25 M) was added a boronic ester (1.1 equiv.), followed by a 2 M aqueous solution of Na2CO3 (3.0 equiv.). The solution was degassed with argon for 20 minutes, and Pd(PPh3)4 (0.1 equiv.) was added. The mixture was then heated at 120 °C under microwave irradiation for 1.5 hours, cooled, and extracted with CHCl2. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired product.

[0145] General Procedure E: Hydrogenation Pd / C (10% by weight, 0.05 equivalents) was added to a solution of the N-protected compound (1.0 equivalents) in MeOH (0.06 M). The reaction was stirred under H pressure until completion. The mixture was filtered through a pad of Celite, which was rinsed several times with MeOH. MeOH was evaporated under reduced pressure, and the crude reaction mixture was used in the next step without further purification.

[0146] General Procedure F1: Boc Deprotection, Free Amine To a solution of the N-Boc protected compound (1.0 equiv.) in CHCl (0.04 M) was added TFA (35.0 equiv.) (CHCl / TFA 10 / 1) slowly at 0° C. The mixture was allowed to warm to room temperature and stirred until completion (TLC monitoring). The solvent was then removed under reduced pressure. The residue was taken up in CHCl and a 2 M aqueous solution of NaOH was added. The mixture was stirred for 30 min and extracted with CHCl. The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo to give the desired product.

[0147] General Procedure F2: Boc Deprotection (Amine TFA Salt) To a solution of the N-Boc-protected compound (1.0 equiv.) in CHCl (0.04 M) was added TFA (35.0 equiv.) slowly at 0° C. The mixture was allowed to warm to room temperature and stirred until complete (TLC monitoring). The solvent was then removed under reduced pressure, and the residue was co-evaporated three times with EtO. The resulting solid was taken up in EtO, filtered, washed with EtO and pentane, and dried under vacuum at 60° C. to give the desired amine as a TFA salt.

[0148] General Procedure G: Urea Synthesis Using Isocyanates To a solution of the desired amine (1.0 equiv.) in anhydrous CHCl (0.07 M) under argon, DIPEA (3.0 equiv.) was added. The solution was cooled to 0° C., and the corresponding isocyanate (1.1 equiv.) was added. The mixture was stirred at this temperature until completion (TLC monitoring). The solvent was then removed under reduced pressure, and the residue was purified by silica gel column chromatography to give the desired product.

[0149] General Procedure H: Urea Synthesis Using 4-Nitrophenyl Chloroformate To a solution of the desired aniline (1.0 equiv.) in THF (0.07 M) was added DIPEA (1.1-2.1 equiv.) and 4-nitrophenyl chloroformate (1.2 equiv.) at 0°C. The mixture was stirred at 0°C until the starting material completely disappeared (TLC monitoring). Then, the second amine (as the free or salt derivative) (1.2 equiv.) and DIPEA (2.1 equiv.) were added, and the reaction mixture was stirred at 50°C until completion (TLC monitoring). The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give the desired product.

[0150] General procedure I: Urea synthesis using the Curtius rearrangement To a solution of the acid (1.0 equiv.), EtN (1.2 equiv.) in THF (0.05 M) was added at 0 °C. Ethyl chloroformate (1.5 equiv.) was added, and the reaction was stirred at 0 °C for 1 h (TLC monitoring). A solution of NaN (1.5 equiv.) in HO was then added at 0 °C and stirred for 1.5 h (TLC monitoring). The reaction was quenched with ice, quickly extracted with EtOAc, dried over MgSO, filtered, and the solvent removed under reduced pressure without heating. The acyl azide was dissolved in toluene (0.05 M) and stirred at reflux for 1 h. The toluene was removed under reduced pressure. To this freshly prepared isocyanate, a solution of the amine (1.0 equiv.) and DIPEA (2.2 equiv.) in anhydrous CHCl was added at 0 °C. The mixture was stirred at this temperature until complete (TLC monitoring). The solvent was then removed under reduced pressure and the residue was purified by silica gel column chromatography to give the desired product.

[0151] General Procedure J: Boc Deprotection (Amine HCl Salt) Hydrochloric acid (4 M HCl solution in dioxane, 18 equiv.) was slowly added to a solution of the N-Boc-protected compound (1.0 equiv.) in dioxane (0.11 M) at 0° C. The mixture was allowed to warm to room temperature and stirred until completion (TLC monitoring). Diethyl ether was added to precipitate the amine salt, which was filtered, washed with EtO, and then dried under vacuum at 60° C. to give the desired amine as the HCl salt.

[0152] General Procedure K: Modified Fischer Synthesis A suspension of the hydrazone (1.0 equiv.) in diphenyl ether (0.22 M) was degassed with Ar for 20 min and then heated to reflux for 3 h. After cooling to room temperature, the solid was filtered, washed several times with EtO, and then dried under vacuum at 60 °C to give the desired product.

[0153] General Procedure L: Mitsunobu Reaction To a solution of 3-nitrophenol (1.0 equiv.) in dry THF (0.28 M) under argon, primary alcohol (2.0 equiv.) and triphenylphosphine (1.7 equiv.) were added. The mixture was stirred at room temperature for 10 minutes until triphenylphosphine was completely dissolved. Diisopropyl azodicarboxylate (DIAD) (1.7 equiv.) was then added dropwise over 5–10 minutes at room temperature. The reaction mixture was stirred at room temperature for 24 hours, then diluted with HO and extracted twice with EtO. The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography to give the desired product.

[0154] General Procedure M: Williamson Reaction To a solution of 3-nitrophenol (1.0 equiv.) in dry MeCN (0.80 M) under argon, K2CO3 (1.6 equiv.) and the corresponding alkyl halide (8.0 equiv.) were added. The resulting suspension was stirred under reflux until complete conversion (TLC monitoring) and then concentrated under reduced pressure. The residue was partitioned between DCM and HO. The aqueous layer was separated and extracted twice with DCM, and then the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography to give the desired product.

[0155] General Procedure N: Reduction of the nitro group A 50 mL round-bottom flask was charged with the aromatic nitro compound (1.0 equiv.), followed by the addition of a suspension of 10 wt. % Pd / C (0.1 equiv.) in MeOH (0.18 M). The flask was flushed with hydrogen and stirred at room temperature under hydrogen gas until complete conversion of the starting material. The reaction mixture was then filtered through Celite, washed with methanol, and concentrated under reduced pressure to give the desired amine.

[0156] General Procedure O: N-Alkylation To a solution of alkyl halide (1.0 equiv.) in dry THF (0.18 M) under an argon atmosphere was added amine (3.1 equiv.). The reaction mixture was stirred at reflux until complete conversion, then cooled to room temperature and concentrated under reduced pressure. The residue was stirred in 1 M aqueous HCl for 15 min, washed twice with Et2O, and then treated with 10% aqueous NaOH to a pH of approximately 10-13. The aqueous layer was extracted with Et2O (3 times), and the combined organic layers were then dried over MgSO4, filtered, and concentrated under reduced pressure to give the desired product.

[0157] General Procedure P: Ullmann Coupling with Ar-I An oven-dried microwave reaction vial was charged with a magnetic stir bar, 3-aminophenol (1.2 equiv.), copper(I) iodide (5 mol%), 2-picolinic acid (10 mol%), aryl iodide (1.0 equiv.), and K3PO4 (2.0 equiv.). The tube was then evacuated and backfilled with argon. The evacuation / backfill procedure was repeated two more times. Under argon, the remaining liquid reagents were added, followed by dry DMSO (0.5 M). The vial was sealed and placed on a hotplate preheated to 80 °C, and the reaction mixture was vigorously stirred for 18–36 h. The reaction mixture was cooled to room temperature. EtOAc and HO were added, and the aqueous layer was separated and extracted with EtOAc (2×). The combined organic layers were washed with brine (3×), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to give the desired aniline.

[0158] Family 1. 3-Methylpyrrolopyrimidine derivatives [ka]

[0159] 5-Methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol (1) To a solution of LiOH (3.5 g, 147.7 mmol, 1.5 equiv.) in anhydrous MeOH (120 mL) was added cyanoacetamide (12.4 g, 147.7 mmol, 1.5 equiv.) under argon. The solution was stirred for 20 minutes, and a solution of phthalimidoacetone in anhydrous THF (140 mL) was added over 30 minutes. The reaction mixture was then stirred at room temperature for 2 hours and at 55°C for 1 hour. Sodium methoxide (NaOMe) solution (25% in methanol, 31.6 mL, 147.7 mmol, 1.5 equiv.) was added dropwise at 55°C, and the mixture was stirred for 3 hours. Ethyl formate (HCOOEt, 39.7 mL, 492.2 mmol, 5.0 equiv.) was then added, followed by NaOMe solution (25% in methanol, 63.2 mL, 295.3 mmol, 3.0 equiv.), and the reaction mixture was stirred at 55°C overnight. After cooling, the reaction mixture was diluted with water (500 mL), heated at 60° C. for 1 hour, and concentrated under reduced pressure to a small volume (approximately 500 mL). The resulting solution was gradually acidified with 6N aqueous HCl to pH=7, cooled to approximately 5° C., and stirred at this temperature for 30 minutes. The solid was filtered, washed with water (100 mL), and dried under vacuum at 50° C. overnight to give compound 1 (8.65 g, 59%) as a light brown solid. 1 H NMR (250 MHz, DMSO-d6) δ 11.50 (br s, 2H, 2 x NH), 7.73 (s, 1H, CH), 6.75 - 6.72 (m, 1H, CH), 2.26 (d, J = 1.1 Hz, 3H, CH3). Org. Process Res. Dev. 2007, 11(1), pp. 86-89.

[0160] 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine(2) Hydroxy compound 1 (2.0 g, 13.4 mmol) was dissolved in POCl3 (50 mL) and stirred at reflux for 1.5 h. After cooling, the mixture was slowly poured into a vigorously stirred ice-water bath and stirred for 30 min. The mixture was carefully neutralized to pH 7 with solid NaOH. The mixture was then extracted with CHCl2 (3 × 150 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography using a 100 / 0 to 70 / 30 PE / EtOAc gradient solvent system. Finally, the product was precipitated into a mixture of acetone / PE to give 2 (3.6 g, 81%) as a beige solid. 1 H NMR (250 MHz, CDCl3) δ 9.49 (br s, 1H, NH), 8.60 (s, 1H, CH), 7.11 (dd, J = 2.3 Hz, J = 1.2 Hz, 1H, CH), 2.50 (d, J = 1.2 Hz, 3H, CH3). West, RAJ Org. Chem. 1961, 26, pp. 4959-4961.

[0161] tert-Butyl 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3) The reaction was carried out as described in General Procedure D using chlorinated bicyclic compound 2 (0.50 g, 2.99 mmol), N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1.02 g, 3.29 mmol, 1.1 equiv.), Pd(PPh3)4 (0.35 g, 0.30 mmol, 0.1 equiv.), and a 2 M solution of Na2CO3 (4.5 mL, 8.98 mmol, 3.0 equiv.) in THF (12 mL). The crude reaction mixture was purified by silica gel column chromatography using a 90 / 10 to 60 / 40 CHCl2 / acetone gradient solvent system to give compound 3 (0.63 g, 67%) as a beige solid. f (CH2Cl2 / acetone 60 / 40) 0.33, Mp: 190-192°C. 1H NMR (250 MHz, CDCl3) δ 10.40 (br s, 1H, NH), 8.81 (s, 1H, CH), 7.12 (s, 1H, CH), 6.06 - 5.87 (m, 1H, CH), 4.24 - 4.09 (m, 2H, CH2), 3.72 (t, J = 5.6 Hz, 2H, CH2), 2.77 - 2.65 (m, 2H, CH2), 2.29 (d, J = 1.1 Hz, 3H, CH3), 1.51 (s, 9H, 3 x CH3). HRMS (EI-MS) m / z C 17 H 23 N4O2[M+H] + Calculated value: 315.1816, Measured value: 315.1814.

[0162] 5-Methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (4) To a solution of N-Boc-protected compound 3 (1.68 g, 5.35 mmol) in 1,4-dioxane (5 mL) at 0 °C was added 4 M HCl solution in 1,4-dioxane (20 mL, 80.0 mmol, 15.0 equiv.). The reaction mixture was stirred at room temperature for 1 h. After completion, EtO (200 mL) was added and the resulting precipitate was filtered and washed with EtO (3 × 30 mL) to give compound 4 (1.47 g, 96%) as a beige solid. Mp: >260 °C. 1 H NMR (400 MHz, DMSO-d6) δ 13.23 (br s, 1H, NH), 9.94 (br s, 2H, NH + H + ), 8.98 (s, 1H, CH), 7.73 (s, 1H, CH), 6.39 - 6.28 (m, 1H, CH), 4.48 - 4.11 (m, 1H, H + ), 3.91 - 3.81 (m, 2H, CH2), 3.41 - 3.30 (m, 2H, CH2), 2.98 - 2.88 (m, 2H, CH2), 2.31 (d, J = 1.2 Hz, 3H, CH3). HRMS (EI-MS) m / z C12 H 15 N4[M+H] + Calculated value: 215.1291, Measured value: 215.1295.

[0163] Subfamily 1.1. 3-Methylpyrrolopyrimidine derivatives with unsubstituted hydropyridine

[0164] [ka]

[0165] [Table 1A]

[0166] [Table 1B]

[0167] [Table 1C]

[0168] [Table 1D]

[0169] Example 1: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-phenyl-3,6-dihydropyridine-1(2H)-carboxamide (5) The reaction was carried out as described in general procedure G using amine 4 (70 mg, 0.24 mmol) in anhydrous CHCl (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 40 / 60 to give compound 5 (64 mg, 80%) as an off-white solid. f (CH2Cl2 / acetone 30 / 70) 0.35. Mp: 245-247°C. 1H NMR (250 MHz, MeOD-d4) δ 8.63 (s, 1H, CH), 7.45 - 7.36 (m, 2H, 2 x CH), 7.33 - 7.24 (m, 2H, 2 x CH), 7.23 (d, J = 1.3 Hz, 1H, CH), 7.09 - 6.98 (m, 1H, CH), 6.08 - 6.00 (m, 1H, CH), 4.29 (q, J = 2.8 Hz, 2H, CH2), 3.84 (t, J = 5.6 Hz, 2H, CH2), 2.80 - 2.68 (m, 2H, CH2), 2.30 (d, J = 1.2 Hz, 3H, CH3). HRMS (EI-MS) m / z C 19 H 20 N5O [M+H] + Calculated value: 334.1662, Measured value: 334.1661.

[0170] Example 2: N-(3-fluorophenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (6) The reaction was carried out as described in general procedure G using amine 4 (70 mg, 0.24 mmol) in anhydrous CHCl (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone 90 / 10 to 60 / 40 to give compound 65 (51 mg, 60%) as an off-white solid. f (CH2Cl2 / acetone 70 / 30) 0.28. Mp: 241-243°C. 1H NMR (400 MHz, DMSO-d6) δ 11.83 (br s, 1H, NH), 8.79 (br s, 1H, NH), 8.65 (s, 1H, CH), 7.49 (d, J = 12.4 Hz, 1H, CH), 7.38 - 7.23 (m, 3H, 3 x CH), 6.86 - 6.66 (m, 1H, CH), 6.05 (s, 1H, CH), 4.34 - 4.10 (m, 2H, CH2), 3.81 - 3.69 (m, 2H, CH2), 2.74 - 2.64 (m, 2H, CH2), 2.23 (s, 3H, CH3). 19 F NMR (376 MHz, DMSO-d6) δ -112.7 - -113.0 (m). HRMS (EI-MS) m / z C 19 H 19 FN5O [M+H] + Calculated value: 352.1568, Measured value: 352.1570.

[0171] Example 3: N-(3-chlorophenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (7) The reaction was carried out as described in general procedure G using amine 4 (70 mg, 0.24 mmol) in anhydrous CHCl (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 60 / 40 to give compound 7 (42 mg, 47%) as an off-white solid. f (CH2Cl2 / acetone 70 / 30) 0.29. Mp: 232-234°C. 1H NMR (400 MHz, DMSO-d6) δ 11.84 (br s, 1H, NH), 8.77 (br s, 1H, NH), 8.65 (s, 1H, CH), 7.70 (t, J = 2.1 Hz, 1H, CH), 7.45 (dd, J = 8.2 Hz, J = 2.0 Hz, 1H, CH), 7.32 (s, 1H, CH), 7.27 (t, J = 8.1 Hz, 1H, CH), 6.99 (dd, J = 8.0 Hz, J = 2.1 Hz, 1H, CH), 6.09 - 6.01 (m, 1H, CH), 4.26 - 4.19 (m, 2H, CH2), 3.74 (t, J = 5.6 Hz, 2H, CH2), 2.73 - 2.61 (m, 2H, CH2), 2.24 (s, 3H, CH3). HRMS (EI-MS) m / z C 19 H 19 ClNO [M+H] + Calculated value: 368.1273, Measured value: 368.1275.

[0172] Example 4: N-(3-bromophenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (8) The reaction was carried out as described in general procedure G using amine 4 (70 mg, 0.24 mmol) in anhydrous CHCl (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 60 / 40 to give compound 8 (69 mg, 70%) as a white solid. f (CH2Cl2 / acetone 70 / 30) 0.28. Mp: 223-225°C. 1H NMR (400 MHz, DMSO-d6) δ 11.82 (br s, 1H, NH), 8.75 (br s, 1H, NH), 8.65 (s, 1H, CH), 7.83 (s, 1H, CH), 7.50 (d, J = 8.3 Hz, 1H, CH), 7.31 (s, 1H, CH), 7.21 (t, J = 8.0 Hz, 1H, CH), 7.12 (d, J = 8.0 Hz, 1H, CH), 6.05 (s, 1H, 4.30 - 4.13 (m, 2H, CH2), 3.73 (t, J = 5.6 Hz, 2H, CH2), 2.75 - 2.62 (m, 2H, CH2), 2.23 (s, 3H, CH3). HRMS (EI-MS) m / z C 19 H 19 BrNO [M+H] + Calculated value: 412.0767, Measured value: 412.0766.

[0173] Example 5: N-(3-Methoxyphenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (9) The reaction was carried out as described in general procedure G using amine 4 (70 mg, 0.24 mmol) in anhydrous CHCl (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 60 / 40 to give compound 9 (40 mg, 46%) as a white solid. f (CH2Cl2 / acetone 70 / 30) 0.30. Mp: 212-214°C. 1H NMR (400 MHz, DMSO-d6) δ 11.82 (br s, 1H, NH), 8.65 (s, 1H, CH), 8.56 (br s, 1H, NH), 7.38 - 7.06 (m, 4H, 4 x CH), 6.67 - 6.37 (m, 1H, CH), 6.15 - 5.95 (m, 1H, CH), 4.22 (s, 2H, CH2), 3.72 (m, 5H, CH2+ OCH3), 2.74 - 2.59 (m, 2H, CH2), 2.24 (s, 3H, CH3). HRMS (EI-MS) m / z C 20 H 22 NO2[M+H] + Calculated value: 364.1768, Measured value: 364.1770.

[0174] Example 6: N-(3-cyanophenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (10) The reaction was carried out as described in general procedure G using amine 4 (70 mg, 0.24 mmol) in anhydrous CHCl (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 40 / 60 to give compound 10 (65 mg, 76%) as an off-white solid. f (CH2Cl2 / acetone 50 / 50) 0.19. Mp: 207-209°C. 1H NMR (250 MHz, DMSO-d6) δ 8.63 (s, 1H, CH), 7.89 - 7.86 (m, 1H, CH), 7.71 (ddd, J = 8.2 Hz, J = 2.3 Hz, J = 1.2 Hz, 1H, CH), 7.44 (td, J = 7.6 Hz, J = 2.4 Hz, 1H, CH), 7.35 (dt, J = 7.7 Hz, J = 1.4 Hz, 1H, CH), 7.24 (d, J = 1.2 Hz, 1H, CH), 6.13 - 5.98 (m, 1H, CH), 4.37 - 4.23 (m, 2H, CH2), 3.86 (t, J = 5.6 Hz, 2H, CH2), 2.80 - 2.67 (m, 2H, CH2), 2.31 (d, J = 1.2 Hz, 3H, CH3). 1 HRMS (EI-MS) m / z C 20 H 19 NO [M+H] + Calculated value: 359.1615, Measured value: 359.1616.

[0175] Example 7: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-(trifluoromethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxamide (11) The reaction was carried out as described in general procedure G using amine 4 (70 mg, 0.24 mmol) in anhydrous CHCl (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 30 / 70 to give compound 11 (69 mg, 72%) as an off-white solid. f (CH2Cl2 / acetone 50 / 50) 0.33. Mp: decomposition 231°C. 1H NMR (400 MHz, DMSO-d6) δ 11.83 (br s, 1H, NH), 8.93 (br s, 1H, NH), 8.65 (s, 1H, CH), 7.97 (s, 1H, CH), 7.80 (d, J = 8.3 Hz, 1H, CH), 7.48 (t, J = 8.0 Hz, 1H, CH), 7.32 (s, 1H, CH), 7.28 (d, J = 7.8 Hz, 1H, CH), 6.11 - 5.96 (m, 1H, CH), 4.30 - 4.11 (m, 2H, CH2), 3.76 (t, J = 5.6 Hz, 2H, CH2), 2.73 - 2.61 (m, 2H, CH2), 2.24 (s, 3H, CH3). 19 F NMR (376 MHz, DMSO-d6) δ -61.2 (s). HRMS (EI-MS) m / z C 20 H 19 F3N5O [M+H] + Calculated value: 402.1536, Measured value: 402.1536.

[0176] Example 8: N-(4-chloro-3-(trifluoromethyl)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (12) The reaction was carried out as described in general procedure G using amine 4 (70 mg, 0.24 mmol) in anhydrous CHCl (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl and acetone 80 / 20 to 40 / 60 to give compound 12 (49 mg, 47%) as an off-white solid. f (CH2Cl2 / acetone 60 / 40) 0.22. Mp: 228-230°C. 1H NMR (400 MHz, DMSO-d6) δ 11.83 (br s, 1H, NH), 9.03 (br s, 1H, NH), 8.65 (s, 1H, CH), 8.10 (d, J = 2.6 Hz, 1H, CH), 7.85 (dd, J = 8.8 Hz, J =2.6 Hz, 1H, CH), 7.59 (d, J = 8.8 Hz, 1H, CH), 7.31 (s, 1H, CH), 6.10 - 6.02 (m, 1H, CH), 4.29 - 4.18 (m, 2H, CH2), 3.75 (t, J = 5.6 Hz, 2H, CH2), 2.73 - 2.64 (m, 2H, CH2), 2.23 (s, 3H, CH3). 19 F NMR (376 MHz, DMSO-d6) δ -61.4 (s). HRMS (EI-MS) m / z C 20 H 18 ClF3N5O [M+H] + Calculated value: 436.1146, Measured value: 436.1145.

[0177] Example 9: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(naphthalen-2-yl)-3,6-dihydropyridine-1(2H)-carboxamide (13) The reaction was carried out as described in general procedure G using amine 4 (70 mg, 0.24 mmol) in anhydrous CHCl (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 30 / 70 to give compound 13 (55 mg, 60%) as an off-white solid. f (CH2Cl2 / acetone 50 / 50) 0.31. Mp: 233-235°C. 1H NMR (250 MHz, MeOD-d4) δ 8.64 (s, 1H, CH), 7.91 (d, J = 2.1 Hz, 1H, CH), 7.84 - 7.69 (m, 3H, 3xCH), 7.56 (dd, J = 8.8 Hz, J = 2.2 Hz, 1H, CH), 7.47 - 7.30 (m, 2H, 2 x CH), 7.24 (d, J = 1.2 Hz, 1H, CH), 6.13 - 5.99 (m, 1H, CH), 4.39 - 4.31 (m, 2H, CH2), 3.90 (t, J = 5.6 Hz, 2H, CH2), 2.83 - 2.69 (m, 2H, CH2), 2.33 (d, J = 1.2 Hz, 3H, CH3). HRMS (EI-MS) m / z C 23 H 22 N5O [M+H] + Calculated value: 384.1819, Measured value: 384.1815.

[0178] Example 10: N-(benzo[d][1,3]dioxol-5-yl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (14) The reaction was carried out as described in general procedure G using amine 4 (70 mg, 0.24 mmol) in anhydrous CHCl (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 40 / 60 to give compound 14 (32 mg, 35%) as an off-white solid. f (CH2Cl2 / acetone 60 / 40) 0.13. Mp: 235-237°C. 1H NMR (400 MHz, DMSO-d6) δ 11.85 (br s, 1H, NH), 8.64 (s, 1H, CH), 8.47 (br s, 1H, NH), 7.38 - 7.24 (m, 1H, CH), 7.22 - 7.11 (m, 1H, CH), 6.93 - 6.69 (m, 2H, 2 x CH), 6.09 - 5.81 (m, 3H, CH + HRMS (EI-MS) m / z C 20 H 20 N5O3[M+H] + Calculated value: 378.1561, Measured value: 378.1560.

[0179] Example 11: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-phenoxy-phenyl)-3,6-dihydropyridine-1(2H)-carboxamide (15) The reaction was carried out as described in general procedure G using amine 4 (70 mg, 0.24 mmol) in anhydrous CHCl (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 70 / 30 to give compound 15 (50 mg, 49%) as a white solid. f (CH2Cl2 / acetone 60 / 40) 0.21. Mp: 196-198°C. 1H NMR (400 MHz, MeOD-d4) δ 8.62 (s, 1H, CH), 7.41 - 6.93 (m, 9H, 9xCH), 6.69 - 6.61 (m, 1H, CH), 6.13 - 5.96 (m, 1H, CH), 4.30 - 4.22 (m, 2H, HRMS (EI-MS) m / z C 25 H 24 NO2[M+H] + Calculated value: 426.1925, Measured value: 426.1923.

[0180] Example 12: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(4-phenoxy-phenyl)-3,6-dihydropyridine-1(2H)-carboxamide (16) The reaction was carried out as described in general procedure G using amine 4 (70 mg, 0.24 mmol) in anhydrous CHCl (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 30 / 70 to give compound 16 (87 mg, 85%) as a white solid. f (CH2Cl2 / acetone 60 / 40) 0.18. Mp: 224-226°C. 1H NMR (400 MHz, DMSO-d6) δ 11.83 (br s, 1H, NH), 8.65 (s, 1H, CH), 8.61 (br s, 1H, NH), 7.52 (d, J = 8.9 Hz, 2H, 2 x CH), 7.35 (t, J = 7.8 Hz, 2H, 2 x CH), 7.32 (s, 1H, CH), 7.08 (t, J = 7.4 Hz, 1H, CH), 6.95 (d, J = 8.3 Hz, 4H, 4xCH), 6.05 (s, 1H, CH), 4.28 - 4.17 (m, 2H, CH2), 3.74 (t, J = 5.6 Hz, 2H, CH2), 2.75 - 2.62 (m, 2H, CH2), 2.24 (s, 3H, CH3). HRMS (EI-MS) m / z C 25 H 24 NO2[M+H] + Calculated value: 426.1925, Measured value: 426.1927.

[0181] Example 13: N-([1,1'-biphenyl]-3-yl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (17) The reaction was carried out as described in General Procedure I using biphenyl-3-carboxylic acid (61 mg, 0.31 mmol) and amine 4 (89 mg, 0.31 mmol). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 60 / 40 to give compound 17 (43 mg, 34%) as a white solid. f (CH2Cl2 / acetone 70 / 30) 0.31. Mp: 235-237°C. 1H NMR (400 MHz, DMSO-d6) δ 11.83 (br s, 1H, NH), 8.68 (br s, 1H, NH), 8.65 (s, 1H, CH), 7.83 (s, 1H, CH), 7.71 - 7.18 (m, 9H, 9xCH), 6.17 - 5.97 (m, 1H, CH), 4.33 - 4.15 (m, 2H, CH2), 3.83 - 3.67 (m, 2H, CH2), 2.78 - 2.62 (m, 2H, CH2), 2.25 (s, 3H, CH3). HRMS (EI-MS) m / z C 25 H 24 N5O [M+H] + Calculated value: 410.1975, Measured value: 410.1983.

[0182] Example 14: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-(pyridin-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxamide (18) The reaction was carried out as described in General Procedure I using 3-(pyridin-4-yl)benzoic acid (62 mg, 0.31 mmol) and amine 4 (89 mg, 0.31 mmol). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 50 / 50 to give compound 18 (19 mg, 15%) as a beige solid. f (CH2Cl2 / acetone 50 / 50) 0.24. Mp: 208-210°C. 1H NMR (400 MHz, DMSO-d6) δ 11.83 (br s, 1H, NH), 8.77 (br s, 1H, NH), 8.71 - 8.59 (m, 3H, 3 x CH), 8.01 - 7.90 (m, 1H, CH), 7.73 - 7.56 (m, 2H, 2 x CH), 7.45 - 7.36 (m, 3H, 3xCH), 7.32 (s, 1H, CH), 6.07 (s, 1H, CH), 4.26 (s, 2H, CH2), 3.77 (s, 2H, CH2), 2.70 (s, 2H, CH2), 2.25 (s, 3H, CH3). HRMS (EI-MS) m / z C 24 H 24 NO [M+H] + Calculated value: 411.1928, Measured value: 411.1933.

[0183] Example 15: N-(3-(1H-pyrrol-1-yl)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (19) The reaction was carried out as described in General Procedure I using 3-(1H-pyrrol-1-yl)benzoic acid (58 mg, 0.31 mmol) and amine 4 (89 mg, 0.31 mmol, 1.0 equiv.). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 50 / 50 to give compound 19 (61 mg, 49%) as an off-white solid. f (CH2Cl2 / acetone 50 / 50) 0.28. Mp: 215-217°C. 1H NMR (400 MHz, DMSO-d6) δ 11.85 (br s, 1H, NH), 8.75 (br s, 1H, NH), 8.66 (s, 1H, CH), 7.76 (s, 1H, CH), 7.52 - 7.06 (m, 6H, 6 x CH), 6.26 HRMS (EI-MS) m / z C 23 H 23 NO [M+H] + Calculated value: 399.1928, Measured value: 399.1928.

[0184] Example 16: N-(3-ethylphenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (20) The reaction was carried out as described in general procedure H using 3-ethylaniline (31 μL, 0.25 mmol) and amine 4 (85 mg, 0.30 mmol) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 30 / 70 to give compound 20 (52 mg, 58%) as a white solid. f (CH2Cl2 / acetone 60 / 40) 0.20. Mp: 210-212°C. 1H NMR (400 MHz, DMSO-d6) δ 11.82 (br s, 1H, NH), 8.65 (s, 1H, CH), 8.51 (br s, 1H, NH), 7.40 - 7.28 (m, 3H, 3 x CH), 7.14 (t, J = 7.7 Hz, 1H, CH), 6.80 (d, J = 7.6 Hz, 1H, CH), 6.04 (s, 1H, CH), 4.30 - 4.14 (m, 2H, CH2), 3.73 (t, J = 5.6 Hz, 2H, CH2), 2.73 - 2.64 (m, 2H, CH2), 2.55 (q, J = 7.7 Hz, 2H, CH2), 2.24 (s, 3H, CH3), 1.17 (t, J = 7.6 Hz, 3H, CH3). HRMS (EI-MS) m / z C 21 H 24 N5O [M+H] + Calculated value: 362.1975, Measured value: 362.1975.

[0185] Example 17: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-(trifluoromethoxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxamide (21) The reaction was carried out as described in general procedure H using 3-(trifluoromethoxy)aniline (33 μL, 0.25 mmol) and amine 4 (85 mg, 0.30 mmol, 1.2 equiv.) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 20 / 80 to give compound 21 (73 mg, 70%) as a white solid. f (CH2Cl2 / acetone 60 / 40) 0.18. Mp: 227-229°C. 1H NMR (400 MHz, DMSO-d6) δ 11.83 (br s, 1H, NH), 8.87 (br s, 1H, NH), 8.65 (s, 1H, CH), 7.67 (s, 1H, CH), 7.52 (d, J = 8.3 Hz, 1H, CH), 7.36 (t, J = 8.3 Hz, 1H, CH), 7.32 (s, 1H, CH), 6.91 (d, J = 8.2 Hz, 1H, CH), 6.05 (s, 1H, CH), 4.33 - 4.13 (m, 2H, CH2), 3.75 (t, J = 5.7 Hz, 2H, CH2), 2.76 - 2.61 (m, 2H, CH2), 2.23 (s, 3H, CH3). 19 F NMR (376 MHz, DMSO-d6) δ -56.6 (s). HRMS (EI-MS) m / z C 20 H 19 F3N5O2[M+H] + Calculated value: 418.1485, Measured value: 418.1484.

[0186] Example 18: 3-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,2,3,6-tetra-hydropyridine-1-carboxamido)phenyl dimethylcarbamate (22) The reaction was carried out as described in general procedure H using 3-aminophenyldimethylcarbamate (45 mg, 0.25 mmol) and amine 4 (85 mg, 0.30 mmol, 1.2 equiv.) in THF (4 mL). The crude mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 20 / 80 to give compound 22 (60 mg, 57%) as a white solid. f (CH2Cl2 / acetone 60 / 40) 0.21. Mp: 214-216°C. 1H NMR (400 MHz, DMSO-d6) δ 11.81 (br s, 1H, NH), 8.89 - 8.45 (m, 2H, NH + CH), 7.60 - 7.10 (m, 4H, 4 x CH), 6.87 - 6.49 (m, 1H, CH), 6.07 - 5.92 (m, 1H, CH), 4.29 - 4.09 (m, 2H, CH2), 3.71 (t, J = 5.7 Hz, 2H, CH2), 3.03 (s, 3H, NCH3), 2.91 (s, 3H, NCH3), 2.75 - 2.60 (m, 2H, CH2), 2.23 (s, 3H, CH3). HRMS (EI-MS) m / z C 22 H 25 N6O3[M+H] + Calculated value: 421.1983, Measured value: 421.1978.

[0187] 3-(1H-imidazol-1-yl)aniline (23) An oven-dried microwave vial was charged with a magnetic stir bar, CuI (28 mg, 0.15 mmol, 0.05 equiv.), KPO (1.31 g, 6.17 mmol, 2.1 equiv.), imidazole (0.20 g, 2.94 mmol, 1.0 equiv.), and 1,10-phenanthroline (52 mg, 0.29 mmol, 0.1 equiv.). The tube was then evacuated and backfilled with argon. The evacuation / backfill procedure was repeated two more times. Under a counterflow of argon, 3-iodoaniline (0.42 mL, 3.53 mmol, 1.2 equiv.) and degassed 1,4-dioxane (1.5 mL) were added via syringe. The tube was placed in a preheated oil bath at 110 °C, and the solution was vigorously stirred for 24 h. The reaction mixture was cooled to room temperature, diluted with 2-3 mL of EtOAc, and filtered through a Celite plug, rinsing with EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using a gradient solvent system of PE / EtOAc (90 / 10 to 80 / 20) to give compound 23 (0.38 g, 82%) as a beige solid. 1H NMR (250 MHz, DMSO-d₆) δ 7.82 (s, 1H, CH), 7.28–7.16 (m, 3H, 3 x CH), 6.79–6.73 (m, 1H, CH), 6.70–6.63 (m, 2H, 2 x CH), 3.75 (br s, 2H, NH₂). All spectral data correspond to literature values found in Suresh, P.; Pitchumani, K.J. Org. Chem. 2008, 73, 9121–9124.

[0188] Example 19: N-(3-(1H-imidazol-1-yl)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (24) The reaction was carried out as described in general procedure H using aniline 23 (40 mg, 0.25 mmol) and amine 4 (85 mg, 0.30 mmol, 1.2 equiv.) in THF (4 mL). The crude mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 40 / 60 to give compound 24 (45 mg, 45%) as an off-white solid. f (CH2Cl2 / acetone 50 / 50) 0.23. Mp: 245-247°C. 1H NMR (400 MHz, DMSO-d6) δ 11.84 (br s, 1H, NH), 8.83 (br s, 1H, NH), 8.65 (s, 1H, CH), 8.13 (s, 1H, H), 7.80 (t, J = 2.2 Hz, 1H, CH), 7.62 (s, 1H, CH), 7.52 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H, CH), 7.39 (t, J = 8.1 Hz, 1H, CH), 7.32 (s, 1H, CH), 7.20 (dd, J = 7.9 Hz, J = 2.2 Hz, 1H, CH), 7.11 (s, 1H, CH), 6.11 - 6.02 (m, 1H, CH), 4.32 - 4.16 (m, 2H, CH2), 3.76 (t, J = 5.5 Hz, 2H, CH2), 2.70 (s, 2H, CH2), 2.24 (s, 3H, CH3). HRMS (EI-MS) m / z C 22 H 22 N7O [M+H] + Calculated value: 400.1880, Measured value: 400.1880.

[0189] 3-(1H-1,2,4-triazol-1-yl)aniline (84) 25 GB 156 An oven-dried microwave vial was charged with a magnetic stir bar, CuI (28 mg, 0.15 mmol, 0.05 equiv.), KPO (1.31 g, 6.17 mmol, 2.1 equiv.), 1,2,4-triazole (0.20 g, 2.94 mmol, 1.0 equiv.), and 1,10-phenanthroline (52 mg, 0.29 mmol, 0.1 equiv.). The tube was then evacuated and backfilled with argon. The evacuation / backfill procedure was repeated two more times. Under a counterflow of argon, 3-iodoaniline (0.42 mL, 3.53 mmol, 1.2 equiv.) and degassed 1,4-dioxane (1.5 mL) were added via syringe. The tube was placed in a preheated oil bath at 110 °C, and the solution was vigorously stirred for 24 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (2-3 mL), and filtered through a Celite plug, rinsing with EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using a gradient solvent system of PE / EtOAc 90 / 10 to 70 / 30 to afford compound 25 (0.41 g, 87%) as a brown solid. f (CH2Cl2 / acetone 60 / 40) 0.49. Mp: 114-116°C. 1 H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H, CH), 8.17 (s, 1H, CH), 7.15 (t, J = 8.0 Hz, 1H, CH), 7.04 (t, J = 2.1 Hz, 1H, CH), 6.94 (ddd, J = 7.9 Hz, J = HRMS (EI-MS) m / z C8H9N4[M+H] + Calculated value: 161.0822, Measured value: 161.0820.

[0190] Example 20: N-(3-(1H-1,2,4-triazol-1-yl)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (26) The reaction was carried out as described in general procedure H using aniline 25 (40 mg, 0.25 mmol) and amine 4 (85 mg, 0.30 mmol, 1.2 equiv.) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 40 / 60 to give compound 26 (63 mg, 63%) as a white solid. f (CH2Cl2 / acetone 50 / 50) 0.21. Mp: 228-230°C. 1 H NMR (400 MHz, DMSO-d6) δ 11.83 (br s, 1H, NH), 9.22 (s, 1H, CH), 8.90 (br s, 1H, NH), 8.65 (s, 1H, CH), 8.22 (s, 1H, CH), 8.13 - 8.06 (m, 1H, CH), 7.63 - 7.53 (m, 1H, CH), 7.45 - 7.39 (m, 2H, 2 x CH), 7.32 (s, 1H, CH), 6.18 - 5.99 (m, 1H, CH), 4.34 - 4.21 (m, 2H, CH2), 3.77 (t, J = 5.6 Hz, 2H, CH2), 2.77 - 2.64 (m, 2H, CH2), 2.28 - 2.18 (m, 3H, CH3). HRMS (EI-MS) m / z C 21 H 21 N8O [M+H] + Calculated value: 401.1833, Measured value: 401.1832.

[0191] 3-(3-methoxyphenoxy)aniline (27) An oven-dried microwave vial was charged with a magnetic stir bar, CuI (29 mg, 0.15 mmol, 0.05 equiv), 2-picolinic acid (123 mg, 0.30 mmol, 0.10 equiv), 3-aminophenol (0.39 g, 3.60 mmol, 1.2 equiv), and KPO (1.27 g, 3.60 mmol, 2.0 equiv). The tube was then evacuated and backfilled with argon. The evacuation / backfill procedure was repeated two more times. Under a counterflow of argon, 3-iodoanisole (0.36 mL, 3.00 mmol, 1.0 equiv) and DMSO (6 mL) were added via syringe. The tube was placed in an oil bath preheated to 80 °C, and the reaction mixture was vigorously stirred for 24 h. The reaction mixture was cooled to room temperature. EtOAc (30 mL) and HO (5 mL) were added, and the mixture was stirred. The organic layer was separated, and the aqueous layer was extracted twice with EtOAc (30 mL). The combined organic layers were dried over MgSO and filtered through a pad of silica gel. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography using a gradient solvent system of cyclohexane / EtOAc (100 / 0 to 90 / 10) to give compound 27 (87 mg, 85%) as a brown oil. 1 H NMR (250 MHz, CDCl3) δ 7.23 (t, J = 8.2 Hz, 1H, CH), 7.11 (t, J = 8.0 Hz, 1H, CH), 6.70–6.60 (m, 3H, 3 x CH), 6.47–6.43 (m, 1H, CH), 6.41 (m, 1H, CH), 6.35 (m, 1H, CH), 3.78 (s, 3H, OCH3), 3.69 (br s, 2H, NH2). All spectral data correspond to literature values found in Maiti, D.; Buchwald, SLJ Am. Chem. Soc. 2009, 131, pp. 17423–17429.

[0192] Example 21: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(4-phenoxy-phenyl)-3,6-dihydropyridine-1(2H)-carboxamide (28) The reaction was carried out as described in general procedure H using aniline 27 (54 mg, 0.25 mmol) and amine 4 (85 mg, 0.30 mmol, 1.2 equiv.) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 20 / 80 to give compound 28 (63 mg, 55%) as a beige solid. f (CH2Cl2 / acetone 50 / 50) 0.21. Mp: decomposition 132°C. 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (br s, 1H, NH), 8.68 (br s, 1H, NH), 8.66 (s, 1H, CH), 7.36 - 7.21 (m, 5H, 5 x CH), 6.71 (dd, J = 8.3 Hz, J = 2.4 Hz, 1H, CH), 6.65 - 6.52 (m, 3H, 3xCH), 6.09 - 6.02 (m, 1H, CH), 4.24 - 4.16 (m, 2H, CH2), 3.74 (s, 3H, OCH3), 3.71 (t, J = 5.5 Hz, 2H, CH2), 2.69 - 2.61 (m, 2H, CH2), 2.22 (s, 3H, CH3). HRMS (EI-MS) m / z C 26 H 26 N5O3[M+H] + Calculated value: 456.2030, Measured value: 456.2031.

[0193] Example 22: N-[3-(2-methoxyphenyl)phenyl]-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxamide (29) The reaction was carried out as described in general procedure H using 2'-methoxy-[1,1'-biphenyl]-3-amine (26 mg, 0.13 mmol) and amine 4 (47 mg, 0.16 mmol, 1.2 equiv.) in THF (4 mL). The crude mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 40 / 60 to give 29 (43 mg, 72%) as a white solid. f (CH2Cl2 / acetone 50 / 50) 0.18. Mp: decomposition 205°C. 1 H NMR (250 MHz, DMSO-d6) δ 11.83 (s, 1H, NH), 8.65 (s, 1H, CH), 8.62 (s, 1H, NH), 7.60 (s 1H, CH), 7.49 (d, J = 8.0 Hz, 1H, CH), 7.40 - 7.20 (m, 4H, 4 x CH), 7.18 - 6.95 (m, 3H, 3 x CH), 6.05 (s, 1H, CH), 4.27 - 4.19 (m, 2H, CH2), 3.86 - 3.63 (m, 5H, OCH3+ CH2), 2.68 (s, 2H, CH2), 2.24 (s, 3H, CH3). HRMS (EI-MS) m / z CH6H 26 NO2[M+H] + Calculated value: 440.2081, Measured value: 440.2080.

[0194] Example 23: N-[3-(3-methoxyphenyl)phenyl]-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxamide (30) The reaction was carried out as described in general procedure H using 3'-methoxy-[1,1'-biphenyl]-3-amine (26 mg, 0.13 mmol) and amine 4 (47 mg, 0.16 mmol, 1.2 equiv.) in THF (4 mL). The crude mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 40 / 60 to give 30 (47 mg, 78%) as a white solid. f(CH2Cl2 / acetone 50 / 50) 0.19. Mp: decomposition 224°C. 1 H NMR (250 MHz, DMSO-d6) δ 11.83 (s, 1H, NH), 8.68 (s, 1H, CH), 8.65 (s, 1H, NH), 7.81 (s, 1H, CH), 7.56 (d, J = 7.9 Hz, 1H, CH), 7.47 - 7.04 (m, 6H, 6 x CH), 6.94 (d, J = 8.1 Hz, 1H, CH), 6.07 (s, 1H, CH), 4.26 (s, 2H, CH2), 3.82 (s, 3H, CH3), 3.76 (t, J = 4.6 Hz, 2H, CH2), 2.70 (s, 2H, CH2), 2.25 (s, 3H, CH3). HRMS (EI-MS) m / z C 26 H 26 NO2[M+H] + Calculated value: 440.2081, Measured value: 440.2083.

[0195] Example 24: N-[3-(4-methoxyphenyl)phenyl]-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxamide (31) The reaction was carried out as described in general procedure H using 4'-methoxy-[1,1'-biphenyl]-3-amine (26 mg, 0.13 mmol) and amine 4 (47 mg, 0.16 mmol, 1.2 equiv.) in THF (4 mL). The crude mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 40 / 60 to give 31 (43 mg, 72%) as a white solid. f (CH2Cl2 / acetone 50 / 50) 0.25. Mp: decomposition 252°C. 1H NMR (250 MHz, DMSO-d6) δ 11.83 (s, 1H, NH), 8.65 (s, 2H, CH + NH), 7.77 (s, 1H, CH), 7.60 - 7.45 (m, 3H, 3xCH), 7.37 - 7.15 (m, 3H, 3xCH), 7.03 (d, J = 8.8 Hz, 2H, CH), 6.06 (s, 1H, CH), 4.25 (s, 2H, CH2), 3.85 - 3.71 (m, 5H, OCH3+ CH2), 2.69 (s, 2H, CH2), 2.25 (s, 3H, CH3). HRMS (EI-MS) m / z C 26 H 26 NO2[M+H] + Calculated value: 440.2081, Measured value: 440.2082.

[0196] Example 25: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxamide (32) The reaction was carried out as described in general procedure H using 3-aminopyridine (75 mg, 0.80 mmol) and amine 4 (240 mg, 0.96 mmol, 1.2 equiv.) in THF (12 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / MeOH 100 / 0 to 95 / 5 to give compound 32 (162 mg, 60%) as a beige solid. f (CH2Cl2 / MeOH 90 / 10)0.24. Mp:170℃. 1H NMR (400 MHz, MeOD-d4) δ 8.72 (brs, 1H, CH), 8.66 (s, 1H, CH), 8.22 (brs, 1H, CH), 8.07 - 8.00 (m, 1H, CH), 7.44 (dd, J = 8.4, 4.9 Hz, 1H, CH), 7.28 (brs, 1H, CH), 6.09 (s, 1H, CH), 4.36 - 4.31 (m, 2H, CH2), 3.87 (t, J = 5.6 Hz, 2H, CH2), 2.78 - 2.71 (m, 2H, CH2), 2.32 (s, 3H, CH3). HRMS (EI-MS): m / z C 18 H 19 NO [M+H] + Calculated value: 335.1615; Measured value: 335.1617.

[0197] Example 26: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(2-thienyl)-3,6-dihydro-2H-pyridine-1-carboxamide (33) The reaction was carried out as described in general procedure G using amine 4 (550 mg, 2.19 mmol) in anhydrous CHCl (30 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 50 / 50 to give compound 33 (278 mg, 54%) as a beige solid. f (CH2Cl2 / acetone 50 / 50) 0.57. Mp: 241-143°C. 1H NMR (400 MHz, MeOD-d4) δ 8.62 (s, 1H, CH), 7.28 (dd, J = 5.1, 3.2 Hz, 1H, CH), 7.25 - 7.21 (m, 2H, CH), 7.13 (dd, J = 5.1, 1.4 Hz, 1H, CH), 6.07 - 6.01 (m, 1H, CH), 4.27 (q, J = 2.9 Hz, 2H, CH2), 3.83 (t, J = 5.6 Hz, 2H, CH2), 2.76 - 2.68 (m, 2H, CH2), 2.30 (d, J = 1.2 Hz, 3H, CH3). HRMS (EI-MS): m / z C 17 H 18 N5OS [M+H] + Calculated value: 340.1227; Measured value: 340.1227.

[0198] Example 27: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-tetralin-1-yl-3,6-dihydro-2H-pyridine-1-carboxamide (34-rac and 35-R) The reaction was carried out with 1,2,3,4-tetrahydro-1-naphthylamine as a racemic mixture or with the pure (R) enantiomer (73 mg, 0.50 mmol) and amine 4 (150 mg, 0.60 mmol, 1.2 equiv.) in THF (7 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / MeOH 100 / 0 to 95 / 5 to give compound 34-rac (122 mg, 63%) or 35-R (116 mg, 60%) as a beige solid in each case. Traces of DIPEA were removed by washing the solid with water. f (CH2Cl2 / MeOH 95 / 5)0.34. Mp:170℃. 1H NMR (400 MHz, MeOD-d4) δ 8.61 (s, 1H, CH), 7.31 - 7.26 (m, 1H), 7.23 (d, J = 1.2 Hz, 1H), 7.16 - 7.03 (m, 3H), 6.00 (dt, J = 3.3, 1.7 Hz, 1H, CH), 5.06 (t, J = 6.4 Hz, 1H, CH), 4.19 (q, J = 3.0 Hz, 2H, CH2), 3.81 - 3.69 (m, 2H, CH2), 2.91 - 2.72 (m, 2H, CH2), 2.70 - 2.62 (m, 2H, CH2), 2.31 (d, J = 1.2 Hz, 3H, CH3), 2.12 - 1.93 (m, 2H, CH2), 1.91 - 1.76 (m, 2H, CH2). HRMS (EI-MS): m / z C 23 H 26 NO [M+H] + Calculated value: 388.2132; Measured value: 388.2131.

[0199] (4-Methylsulfonylpiperazin-1-yl)-(3-nitrophenyl)methanone (170) 1-Methylsulfonyl-piperazine (350 μL, 4.04 mmol, 1.5 equiv) and EtN (670 μL, 4.84 mmol, 1.8 equiv) were suspended in DCM (15 mL). The solution was cooled to 0° C., and 3-nitrobenzoyl chloride (500 mg, 2.69 mmol, 1.0 equiv) in 7.0 mL of DCM was added dropwise. The reaction was stirred at room temperature for 3 hours and then washed with saturated NaHCO solution (30 mL) and 1 M HCl solution (30 mL). The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure to give compound 170 (684 mg, 81%) as a brown amorphous solid, which was used in the next step without further purification. f (EP / AcOEt 20 / 80) 0.41 1H NMR (400 MHz, CDCl3) δ (ppm) 8.35 - 8.31 (m, 1H, CH), 8.30 - 8.27 (m, 1H, CH), 7.79 - 7.74 (m, 1H, CH), 7.66 (t, J = 7.9 Hz, 1H, CH), 4.09-3.44 (m, 4H, 2 x CH2), 3.30 (brs, 4H, 2 x CH2), 2.83 (s, 3H, CH3). HRMS (EI-MS) m / z C 12 H 16 N3O5S [M+H] + Calculated value: 314.0803, Measured value: 314.0805.

[0200] (3-Aminophenyl)-(4-methylsulfonylpiperazin-1-yl)methanone (171) To a solution of compound 170 in ethanol (15 mL) was added tin chloride (1.51 g, 7.95 mmol, 5.0 equiv.). The reaction was heated to 80° C. for 6 hours. The solvent was then concentrated under reduced pressure, water was added, and the pH was adjusted to approximately 12 with a solution of 2 M NaOH. The resulting solid was filtered through diatomaceous earth, and the collected filtrate was extracted with EtOAc (3×30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give compound 171 (303 mg, 67%) as a brown oil, which was used in the next step without further purification. f (CH2Cl2 / acetone 50 / 50) 0.27. 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.18 (t, J = 7.7 Hz, 1H, CH), 6.76 - 6.68 (m, 3H, 3 x CH), 3.94 - 3.49 (m, 6H, NH2+ 2 x CH2), 3.23 (brs, 4H, 2 x CH2), 2.80 (s, 3H, CH3). HRMS (EI-MS) m / z C 12 H 18 N3O5S [M+H] + Calculated value: 284.1066, Measured value: 284.1063.

[0201] (Example 27-1) 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-[3-(4-methylsulfonylpiperazine-1-carbonyl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxamide (172) The reaction was carried out as described in general procedure H using aniline 171 (150 mg, 0.53 mmol), 4-nitrophenyl chloroformate (128 mg, 0.64 mmol, 1.2 equiv), DIPEA (190 μL, 1.11 mmol, 2.1 equiv), and amine 4 (159 mg, 0.64 mmol, 1.2 equiv) in dry THF (7.6 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / acetone from 100 / 0 to 20 / 80 to give compound 172 (143 mg, 52%) as a beige solid. f (CH2Cl2 / acetone 30 / 70) 0.29. Mp: 140-142°C. 1 H NMR (400 MHz, MeOD-d4) 8.63 (s, 1H, CH), 7.59 (t, J = 1.9 Hz, 1H, CH), 7.51 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H, CH), 7.40 (t, J = 7.9 Hz, 1H, CH), 7.24 (d, J = 1.3 Hz, 1H, CH), 7.11 (dt, J = 7.5, 1.3 Hz, 1H, CH), 6.08 - 6.03 (m, 1H, CH), 4.31 (q, J = 2.8 Hz, 2H, CH2), 3.86 (t, J = 5.6 Hz, 2H, CH2), 3.95 - 3.54 (m, HRMS (EI-MS) m / z C 25 H 30 N7O4S [M+H] + Calculated value: 524.2068, Measured value: 524.2075.

[0202] [ka]

[0203] tert-Butyl N-[3-(3-bromophenoxy)propyl]carbamate (36) tert-Butyl N-(3-hydroxypropyl)carbamate (912 mg, 5.20 mmol, 1.5 equiv.) and triphenylphosphine (1.0 g, 3.81 mmol, 1.1 equiv.) were added to a solution of 3-bromophenol (600 mg, 3.47 mmol) in THF (12 mL) in a microwave tube. A solution of DIAD (768 mg, 3.81 mmol, 1.1 equiv.) in THF (5 mL) was added dropwise, the tube was sealed, and the mixture was heated in a microwave at 120° C. for 1 h. After cooling, additional amounts of triphenylphosphine and DIAD (1 equiv.) were added, and the tube was heated at 120° C. for 30 min. The mixture was concentrated, and the residue was taken up in EtOAc, washed with saturated NaCl solution (30 mL), dried over MgSO4, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of EP / Et2O from 100 / 0 to 50 / 50 to give compound 36 (874 mg, 77%) as a white solid. f (EP / Et2O 50 / 50)0.51. Mp:77~79℃. 1 H NMR (400 MHz, CDCl3) δ 7.18 - 7.01 (m, 3H, 3 x CH), 6.85 - 6.79 (m, 1H, CH), 4.72 (s, 1H, NH), 4.00 (t, J = 6.2 Hz, 2H, CH2), 3.31 (q, J = 6.3 HRMS (EI-MS) m / z C 14 H 21 BrNO3[M+H] + Calculated value: 330.0699, Measured value: 330.0695.

[0204] tert-Butyl N-[3-[3-(3-nitrophenyl)phenoxy]propyl]carbamate (37) Compound 36 (300 mg, 0.91 mmol), 3-phenylboronic acid (304 mg, 1.82 mmol, 2.0 equiv.), and KCO (377 mg, 2.73 mmol, 3.0 equiv.) were suspended in a mixture of DME / EtOH / HO (1.8 mL, 1.2 mL, and 0.6 mL). The solution was degassed under Ar for 20 min, and Pd(PPh) (53 mg, 0.045 mmol, 0.05 equiv.) was added. The reaction was heated in a microwave at 160 °C for 15 min. After cooling, the mixture was extracted with CHCl (3 × 10 mL). The combined organic layers were dried (MgSO), filtered, and evaporated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of EP / Et2O from 100 / 0 to 70 / 30 to give compound 37 (267 mg, 79%) as a yellow solid. f (EP / Et2O 50 / 50)0.26, Mp:93~95℃. 1 H NMR (400 MHz, MeOD-d4) δ 8.41 (t, J = 1.9 Hz, 1H, CH), 8.20 (ddd, J = 8.2, 2.2, 0.8 Hz, 1H, CH), 8.03 - 7.98 (m, 1H, CH), 7.67 (t, J = 8.0 Hz, 1H, CH), 7.39 (t, J = 7.9 Hz, 1H, CH), 7.24 (d, J = 7.7 Hz, 1H, CH), 7.22 - 7.19 (m, 1H, CH), 6.99 (dd, J = 8.2, 1.8 Hz, 1H, CH), 4.09 (t, J = 6.2 Hz, 2H, CH2), 3.26 (t, J = HRMS (EI-MS) m / z C 20 H 24 NaN2O5[M+Na] + Calculated value: 395.1577, Measured value: 395.1575.

[0205] N-[3-[3-(3-nitrophenyl)phenoxy]propyl]acetamide (38) A 4 N solution of HCl in dioxane (1.10 mL, 4.3 mmol, 8.0 equiv) was added to the Boc-protected amine 37 (200 mg, 0.54 mmol) in CHCl (2 mL) under argon at 0 °C. The reaction was stirred at room temperature for 2 h or until complete (TLC). The solvent was then evaporated, the residue was taken up in CHCl (5 mL), and a saturated solution of KCO was added until pH 8-9. The mixture was stirred for 30 min and extracted with CHCl (2 × 5 mL). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure to give the desired product, which was used in the next step without further purification.

[0206] The free amine was then placed in a round-bottom flask under Ar, diluted with anhydrous CHCl (2 mL), and cooled to 0 °C. Triethylamine (38 μL, 0.28 mmol, 1.5 equiv.) was added, followed by acetic anhydride (0.26 mL, 2.69 mmol, 5 equiv.), and the mixture was heated at 40 °C for 2 h. The reaction was then quenched with NaCO, and the aqueous layer was extracted with AcOEt (3 × 10 mL). The combined organic layers were washed with brine, dried over MgSO, and the solvent was removed under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / MeOH 100 / 0 to 95 / 5 to give compound 38 (139 mg, 82%) as a yellow oil. f (CH2Cl2 / MeOH 95 / 5) 0.48. 1H NMR (400 MHz, MeOD-d4) δ 8.37 (t, J = 2.0 Hz, 1H, CH), 8.21 - 8.13 (m, 1H, CH), 8.00 - 7.94 (m, 1H, CH), 7.64 (t, J = 8.0 Hz, 1H, CH), 7.37 (t, J = 7.9 Hz, 1H, CH), 7.24 - 7.15 (m, 1H, CH), 7.17 (t, J = 2.1 Hz, 1H, CH), 6.97 (dd, J = 8.3, 2.4 Hz, 1H, CH), 4.08 (t, J = 6.1 Hz, 2H, CH2), 3.37 (t, J = 6.9 Hz, 2H, CH2), 1.99 (p, J = 6.6 Hz, 2H, CH2), 1.94 (s, 3H, CH3). HRMS (EI-MS): m / z C 17 H 19 N2O4[M+H] + Calculated value: 315.1339; Measured value: 315.1334.

[0207] N-(3-((3'-amino-[1,1'-biphenyl]-3-yl)oxy)propyl)acetamide (39) Pd / C (10% by weight) (5 mg, 0.04 mmol, 0.1 equiv.) was added to a solution of nitro compound 38 (133 mg, 0.42 mmol) in AcOEt (12 mL) in a small hydrogenation reactor. The reaction was stirred under 15 bar H pressure until completion. The mixture was then filtered through a pad of Celite, which was rinsed several times with MeOH. The solvent was evaporated under reduced pressure to give the desired amine 39 (101 mg, 84%) as a yellow oil, which was used in the next step without further purification. f (CH2Cl2 / MeOH 90 / 10) 0.19. 1H NMR (400 MHz, MeOD-d4) δ 7.27 (t, J = 7.9 Hz, 1H, CH), 7.18 - 7.07 (m, 3H, CH), 6.96 (t, J = 2.0 Hz, 1H, CH), 6.93 - 6.88 (m, 1H, CH), 6.88 - 6.83 (m, 1H, CH), 6.72 - 6.67 (m, 1H, CH), 4.03 (t, J = 6.1 Hz, 2H, CH2-4), 3.35 (t, J = 6.9 Hz, 2H, CH2-2), 2.00 - 1.94 (m, 2H, CH2-3), 1.93 (s, 3H CH3). HRMS (EI-MS): m / z C 17 H 21 N2O2[M+H] + Calculated value: 285.1598; Measured value: 285.1595.

[0208] N-[3-[3-(3-nitrophenyl)phenoxy]propyl]methanesulfonamide (173) A 4N solution of HCl in dioxane (1.10 mL, 4.3 mmol, 8.0 equiv) was added to the Boc-protected amine 37 (200 mg, 0.54 mmol) in CHCl (2 mL) under argon at 0 °C. The reaction was stirred at room temperature for 2 h or until complete (TLC). The solvent was then evaporated, and the residue was taken up in CHCl (5 mL), and a saturated solution of KCO was added until the pH reached 8–9. The mixture was stirred for 30 min and extracted with CHCl (2 × 5 mL). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure to give the desired product, which was used in the next step without further purification.

[0209] The free amine was then placed in a round-bottom flask under Ar and diluted with anhydrous CHCl (2 mL). Triethylamine (38 μL, 0.28 mmol, 1.5 equiv.) was added, followed by methanesulfonyl chloride (47 μL, 0.61 mmol, 1.1 equiv.), and the reaction was stirred at room temperature overnight. The reaction was then quenched with 0.1 M HCl (15 mL), and the aqueous layer was extracted with AcOEt (3 × 10 mL). The combined organic layers were washed with brine, dried over MgSO, and the solvent was removed under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / MeOH 100 / 0 to 98 / 2 to afford compound 173 (132 mg, 69%) as a yellow oil. f (CH2Cl2 / MeOH 90 / 10) 0.75. 1 H NMR (400 MHz, MeOD-d4) δ 8.30 (t, J = 2.0 Hz, 1H, CH), 8.11 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H, CH), 7.91 (ddd, J = 7.8, 1.7, 0.9 Hz, 1H, CH), 7.59 (t, J = 8.0 Hz, 1H, CH), 7.33 (t, J = 7.9 Hz, 1H, CH), 7.17 - 7.10 (m, 2H, 2 x CH), 6.98 - 6.91 (m, 1H, CH), 4.10 (t, J = 6.1 Hz, 2H, CH2), 3.28 (t, J = 6.8 Hz, 2H, CH2), 2.94 (s, 3H, CH3), 2.02 (p, J = 6.5 Hz, 2H, CH2). HRMS (EI-MS) m / z C 16 H 19 N2O5S [M+H] + Calculated value: 351.1009, Measured value: 351.1007.

[0210] N-[3-[3-(3-aminophenyl)phenoxy]propyl]methanesulfonamide (174) Hydrazine monohydrate (14 μL, 0.29 mmol, 0.2 equiv) and Fe(acac) (1.3 mg, 0.25% mol) were added to a solution of compound 173 (512 mg, 1.46 mmol) in methanol (1.5 mL) in a sealed tube. The reaction was then heated to 130° C. for 15 min. After cooling, the crude product was filtered through diatomaceous earth, and the filtrate was evaporated under reduced pressure to give amine 174 (289 mg, 62%) as a brown oil, which was used in the next step without further purification. f (CH2Cl2 / MeOH 80 / 20) 0.49. 1 H NMR (400 MHz, MeOD-d4) δ (ppm) 7.29 (t, J = 7.9 Hz, 1H, CH), 7.19 - 7.09 (m, 3H, CH), 6.99 - 6.96 (m, 1H, CH), 6.94 - 6.86 (m, 2H, CH), 6.74 - 6.69 (m, 1H, CH), 4.12 (t, J = 6.0 Hz, 2H, CH2), 3.28 (t, J = 6.8 Hz, 2H, CH2), 2.93 (s, 3H, CH3), 2.03 (p, J = 6.5 Hz, 2H, CH2). HRMS (EI-MS) m / z C 16 H 21 N2O5S [M+H] + Calculated value: 321.1269, Measured value: 321.1267.

[0211] Example 28: N-(3'-(3-acetamidopropoxy)-[1,1'-biphenyl]-3-yl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxamide (40) The reaction was carried out as described in general procedure H using aniline 39 (97 mg, 0.34 mmol) and amine 4 (94 mg, 0.38 mmol, 1.1 equiv.) in THF (5 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / MeOH 100 / 0 to 90 / 10 to give compound 40 (74 mg, 40%) as a beige solid.f (CH2Cl2 / MeOH 90 / 10) 0.18. 1 H NMR (400 MHz, MeOD-d4) 8.64 (s, 1H, CH), 7.71 (brs, 1H, CH), 7.46 - 7.23 (m, 5H, 5 x CH), 7.22 - 7.14 (m, 2H, 2 x CH), 6.93 - 6.86 (m, 1H, CH), 6.07 (brs, 1H, CH), 4.32 (d, J = 2.0 Hz, 2H, CH2), 4.08 (t, J = 6.2 Hz, 2H, CH2), 3.86 (t, J = 5.6 Hz, 2H, CH2), 3.37 (t, J = 6.9 Hz, 2H, CH2), 2.74 (brs, 2H, CH2), 2.31 (s, 3H, CH3), 2.03 - 1.96 (m, 2H, CH2), 1.94 (s, 3H, CH3). HRMS (EI-MS): m / z C 30 H 33 N6O3[M+H] + Calculated value: 525.2609; Measured value: 525.2611.

[0212] (Example 28-1) N-[3-[3-[3-(methanesulfonamido)propoxy]phenyl]phenyl]-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxamide (175) The reaction was carried out as described in general procedure H using aniline 174 (273 mg, 0.85 mmol), 4-nitrophenyl chloroformate (205 mg, 1.02 mmol, 1.2 equiv), DIPEA (310 μL, 1.79 mmol, 2.1 equiv), and amine 4 (255 mg, 1.02 mmol, 1.2 equiv) in dry THF (12.0 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / acetone from 100 / 0 to 20 / 80 to give compound 174 (283 mg, 59%) as a beige solid. f (CH2Cl2 / acetone 50 / 50) 0.24. Mp: 114-116°C. 1H NMR (400 MHz, MeOD-d4) δ (ppm) 8.63 (s, 1H, CH), 7.89 (s, 0.65H, NH), 7.71 (s, 1H, CH), 7.46 - 7.15 (m, 7H, 7 x CH), 6.97 - 6.88 (m, 1H, CH), 6.05 (brs, 1H, CH), 4.35 - 4.29 (m, 2H, CH2), 4.14 (t, J = 6.1 Hz, 2H, CH2), 3.87 (t, J = 5.6 Hz, 2H, CH2), 3.28 (t, J = 6.9 Hz, 2H, CH2), 2.93 (s, 3H, CH3), 2.77 - 2.72 (m, 2H, CH2), 2.31 (s, 3H, CH3), 2.04 (p, J = 6.5 Hz, 2H, CH2). HRMS (EI-MS) m / z C 29 H 33 N6O4S [M+H] + Calculated value: 561.2286, Measured value: 561.2279.

[0213] 3-[4-(ジメチルアミノ)フェノキシ]アニリン(41) An oven-dried screw-cap test tube was charged with a magnetic stir bar, copper(I) iodide (28 mg, 0.15 mmol, 0.1 equiv.), 2-picolinic acid (36 mg, 0.30 mmol, 0.2 equiv.), 4-bromo-N,N-dimethylaniline (300 mg, 1.5 mmol), 3-aminophenol (196 mg, 1.80 mmol, 1.2 equiv.), and KPO (636 mg, 3.00 mmol, 2 equiv.). The tube was then evacuated and backfilled with argon. The evacuation / backfill procedure was repeated two more times. Under a counterflow of argon, dimethyl sulfoxide (5 mL) was added via syringe. The tube was placed on a plate preheated to 90 °C, and the reaction mixture was vigorously stirred for 24 h. The reaction mixture was then cooled to room temperature. Ethyl acetate and water were added, and the mixture was stirred. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 25 mL). The combined organic layers were dried over MgSO4, filtered, and the mixture was concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of EP / AcOEt (100 / 0 to 80 / 20). The product was then precipitated with pentane to give aniline 41 (0.181 g, 53%) as an amorphous beige solid. 1 H NMR (250 MHz, CDCl3) δ 7.07 (t, J= 8.0 Hz, 1H, CH), 7.02-6.95 (m, 2H, 2 x CH), 6.80-6.72 (m, 2H, 2 x CH), 6.36 (dd, J= 8.1, 2.3 Hz, 2H, 2 x HRMS (EI-MS): m / z C 14 H 17 NO [M+H] + Calculated value: 229.1335; Measured value: 229.1338.

[0214] Example 29: N-[3-[4-(dimethylamino)phenoxy]phenyl]-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxamide (42) The reaction was carried out as described in General Procedure H using the prepared aniline derivative 41 (66 mg, 0.29 mmol) and amine 4 (100 mg, 0.35 mmol, 1.2 equiv.) in THF (4 mL). The crude mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 50 / 50. The product was then precipitated with pentane to give 42 (57 mg, 42%) as an amorphous beige solid. 1 H NMR (250 MHz, DMSO) δ 11.82 (s, 1H, NH), 8.64 (s, 1H, CH), 8.60 (s, 1H, NH), 7.31 (s, 1H, CH), 7.26 - 7.08 (m, 3H, 3 x CH), 7.00 - 6.85 (m, 2H, 2 x CH), 6.82 - 6.69 (m, 2H, 2 x CH), 6.57 - 6.44 (m, 1H, CH), 6.02 (s, 1H, CH), 4.18 (s, 2H, CH2), 3.69 (s, 2H, CH2), 2.87 (s, 6H, 2 x CH3), 2.65 (s, 2H, CH2), 2.22 (s, 3H, CH3). HRMS (EI-MS): m / z C 27 H 28 N6O2[M+H] + Calculated value: 469.2347; Measured value: 469.2341.

[0215] 3-(3-aminophenoxy)-N,N-dimethylaniline (176) An oven-dried microwave reaction vial was charged with 3-aminophenol (196 mg, 1.80 mmol, 1.2 equiv), CuI (29 mg, 0.15 mmol, 10 mol%), 2-picolinic acid (37 mg, 0.30 mmol, 20 mol%), and KPO (637 mg, 3.00 mmol, 2.0 equiv). It was then evacuated and backfilled with argon three times, and then 3-bromo-N,N-dimethylaniline (300 mg, 1.50 mmol, 1.0 equiv) and dry DMSO (3.0 mL) were added under argon, and the reaction mixture was stirred on a preheated plate at 90 °C for 24 h. The reaction mixture was diluted with HO (25 mL) and EtOAc (25 mL), the aqueous layer was separated and extracted with EtOAc (3 × 20 mL), and the combined organic layers were then washed with brine (3 × 15 mL), dried over MgSO, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE / EtOAc 100 to 80 / 20 to afford compound 176 (166 mg, 49%) as a brown oil. f (PE / EtOAc 90 / 10) 0.19. 1 H NMR (250 MHz, CDCl3) δ 7.17 (t, J = 8.1 Hz, 1H, CH), 7.08 (t, J = 8.0 Hz, 1H, CH) 6.48 (ddd, J = 8.2, 2.5, 0.8 Hz, 1H, CH), 6.45 - 6.30 (m, 5H, HRMS (EI-MS) m / z C 14 H 17 NO [M+H] + Calculated value: 229.1335, Measured value: 229.1338.

[0216] Example 94: N-(3-(3-(dimethylamino)phenoxy)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (177) The reaction was carried out as described in general procedure H using aniline 176 (78 mg, 0.34 mmol, 1.0 equiv), 4-nitrophenyl chloroformate (83 mg, 0.41 mmol, 1.2 equiv), DIPEA (143 μL, 0.82 mmol, 2.4 equiv), and amine 4 (103 mg, 0.41 mmol, 1.2 equiv) in dry THF (5 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / MeOH 100 to 95 / 5 to give compound 177 (124 mg, 78%) as a brown solid. f (DCM / MeOH 95 / 5)0.38. Mp: 114~116℃. 1 H NMR (250 MHz, DMSO-d6) δ 11.82 (s, 1H, NH7), 8.64 (s, 2H, NH + CH-2), 7.35 - 7.10 (m, 5H, CH-6 + 4 x CH), 6.58 (ddd, J = 7.6, 2.4, 1.4 Hz, 1H, CH), 6.49 (ddd, J = 8.5, 2.5, 0.8 Hz, 1H, CH), 6.37 (t, J = 2.3 Hz, 1H, CH), 6.24 (ddd, J = 8.0, 2.2, 0.8 Hz, 1H, CH), 6.03 (br s, 1H, CH), 4.19 (d, J = 3.0 Hz, 2H, HRMS (EI-MS) m / z C 27 H 29 N6O2[M+H] + Calculated value: 469.2347, Measured value: 469.2348.

[0217] [ka]

[0218] 1-(2-Bromoethoxy)-3-nitrobenzene (178) The reaction was carried out as described in General Procedure M using 3-nitrophenol (500 mg, 3.59 mmol, 1.0 equiv), 1,2-dibromoethane (2.47 mL, 28.70 mmol, 8.0 equiv), and K2CO3 (794 mg, 5.74 mmol, 1.6 equiv) in dry MeCN (4.5 mL) over 9 h. The crude residue was purified by silica gel column chromatography using a gradient solvent system of PE / EtOAc 100 to 95 / 5 to give compound 178 (698 mg, 79%) as a yellow solid. f (PE / EtO Ac 90 / 10) 0.50. 1 H NMR (250 MHz, DMSO-d₆) δ 7.84 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H, CH), 7.74 (t, J = 2.3 Hz, 1H, CH), 7.60 (t, J = 8.2 Hz, 1H, CH), 7.45 (ddd, J = 8.3, 2.5, 1.0 Hz, 1H, CH), 4.58–4.37 (m, 2H, CH₂), 3.92–3.77 (m, 2H, CH₂). All spectral data correspond to literature values found in Kawamoto M. et al., Chem. Commun., 2010, 46, pp. 8344–8346.

[0219] 1-Methyl-4-(2-(3-nitrophenoxy)ethyl)piperazine (180) The reaction was carried out as described in general procedure O using alkyl halide 178 (406 mg, 1.65 mmol, 1.0 equiv) and 1-methylpiperazine (568 μL, 5.12 mmol, 3.1 equiv) in dry THF (9 mL) for 24 h to afford compound 180 (362 mg, 83%) as a beige solid. 1H NMR (250 MHz, CDCl3) δ 7.81 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H, CH), 7.74 (t, J = 2.3 Hz, 1H, CH), 7.41 (t, J = 8.2 Hz, 1H, CH), 7.22 (ddd, J = 8.3, 2.5, 1.0 Hz, 1H, CH), 4.17 (t, J = 5.7 Hz, 2H, CH2), 2.84 (t, J = 5.7 Hz, 2H, CH2), 2.62 (brs, 4H, 2 x CH2), 2.47 (brs, 4H, 2 x CH2), 2.29 (s, 3H, CH3). All spectral data are from Lee S. et al., J. Med. This corresponded to the literature values listed in Chem., 2020, 63, pp. 3908-3914.

[0220] 3-(2-(4-methylpiperazin-1-yl)ethoxy)aniline (182) The reaction was carried out as described in General Procedure N using nitro 180 (315 mg, 1.19 mmol, 1.0 equiv) and Pd / C 10 wt% (128 mg, 0.12 mmol, 0.1 equiv) in MeOH (7 mL) over 2 h to afford compound 182 (261 mg, 93%) as a yellow oil, which was used in the next step without further purification. 1 H NMR (250 MHz, DMSO-d6) δ 6.87 (t, J = 8.3 Hz, 1H, CH), 6.28 - 6.00 (m, 3H, 3 x CH), 5.00 (brs, 2H, NH2), 3.94 (t, J = 5.9 Hz, 2H, CH2), 2.63 (t, J = 5.9 Hz, 2H, CH2), 2.46 (brs, 4H, 2 x CH2), 2.31 (brs, 4H, 2 x CH2), 2.14 (s, 3H, CH3). HRMS (EI-MS) m / z C 13 H 22 NO [M+H] + Calculated value: 236.1757, Measured value: 236.1760.

[0221] Example 95: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxamide (184) The reaction was carried out as described in general procedure H using aniline 182 (81 mg, 0.34 mmol, 1.0 equiv), 4-nitrophenyl chloroformate (83 mg, 0.41 mmol, 1.2 equiv), DIPEA (144 μL, 0.83 mmol, 2.4 equiv), and amine 4 (104 mg, 0.41 mmol, 1.2 equiv) in dry THF (5 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / MeOH / NH4OH from 100 to 80 / 20 / 1, followed by preparative TLC using a solvent system of DCM / MeOH / NH4OH 80 / 20 / 1 to give compound 184 (24 mg, 15%) as a pale orange solid. R f (DCM / MeOH / NH4OH 90 / 10 / 1)0.34. Mp: decomposition 111℃. 1 H NMR (250 MHz, DMSO-d6) δ 11.83 (s, 1H, NH), 8.64 (s, 1H, NH), 8.54 (s, 1H, CH), 7.33 - 7.30 (m, 1H, CH), 7.25 - 7.01 (m, 3H, 3 x CH), 6.52 (dt, J = 7.4, 2.3 Hz, 1H, CH), 6.08 - 6.02 (m, 1H, CH), 4.21 (d, J = 2.8 Hz, 2H, CH2), 4.02 (t, J = 5.8 Hz, 2H, CH2), 3.72 (t, J = 5.6 Hz, 2H, CH2), 2.68 (t, J = 5.6 Hz, HRMS (EI-MS) m / z C 26 H 34 N7O2[M+H]+ Calculated value: 476.2768, Measured value: 476.2768.

[0222] 1-(3-Bromopropoxy)-3-nitrobenzene (179) The reaction was carried out as described in general procedure M using 3-nitrophenol (500 mg, 3.59 mmol, 1.0 equiv), 1,3-dibromopropane (2.91 mL, 28.70 mmol, 8.0 equiv), and K2CO3 (794 mg, 5.74 mmol, 1.6 equiv) in dry MeCN (4.5 mL) for 56 h. The crude reaction mixture was purified by silica gel column chromatography using PE / DCM 70 / 30 to give compound 179 (634 mg, 68%) as a yellow oil. f (PE / EtO Ac 90 / 10) 0.45. 1 H NMR (250 MHz, CDCl3) δ 7.84 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H, CH), 7.74 (t, J = 2.3 Hz, 1H, CH), 7.44 (t, J = 8.2 Hz, 1H, CH), 7.23 (ddd, J = 8.3, HRMS (EI-MS) m / z C9H 11 BrNO3[M+H] + Calculated value: 259.9917, Measured value: 259.9915.

[0223] 1-Methyl-4-(3-(3-nitrophenoxy)propyl)piperazine (181) The reaction was carried out as described in General Procedure O using alkyl halide 179 (400 mg, 1.54 mmol, 1.0 equiv), 1-methylpiperazine (530 μL, 4.77 mmol, 3.1 equiv) in dry THF (9 mL) for 56 h to afford compound 181 (369 mg, 86%) as a yellow oil. 1H NMR (250 MHz, CDCl3) δ 7.80 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H, CH), 7.72 (t, J = 2.3 Hz, 1H, CH), 7.40 (t, J = 8.2 Hz, 1H, CH), 7.21 (ddd, J = 8.3, HRMS (EI-MS) m / z C 14 H 22 N3O3[M+H] + Calculated value: 280.1656, Measured value: 280.1655.

[0224] 3-(3-(4-methylpiperazin-1-yl)propoxy)aniline (183) The reaction was carried out as described in General Procedure N using nitro compound 181 (276 mg, 0.99 mmol, 1.0 equiv.) and Pd / C 10 wt.% (105 mg, 0.01 mmol, 0.1 equiv.) in MeOH (5.5 mL) for 2 h to give compound 183 (208 mg, 85%) as a beige solid. Mp: 54-56 °C. 1 H NMR (400 MHz, CDCl3) δ 7.04 (t, J = 8.0 Hz, 1H, CH), 6.29 (ddd, J = 15.3, 8.0, 2.2 Hz, 2H, 2 x CH), 6.24 (t, J = 2.3 Hz, 1H, CH), 3.96 (t, J = 6.4 HRMS (EI-MS) m / z C 14 H 24 NO [M+H] + Calculated value: 250.1914, Measured value: 250.1916.

[0225] Example 96: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxamide (185) The reaction was carried out as described in general procedure H using aniline 183 (178 mg, 0.71 mmol, 1.0 equiv), 4-nitrophenyl chloroformate (173 mg, 0.86 mmol, 1.2 equiv), DIPEA (448 μL, 2.57 mmol, 2.4 equiv), and amine 4 (246 mg, 0.86 mmol, 1.2 equiv) in dry THF (10 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / MeOH / NH4OH 100-90 / 10 / 1 to give compound 185 (77 mg, 22%) as a beige powder. f (DCM / MeOH / NH4OH 90 / 10 / 1)0.46. Mp:102~104℃. 1 H NMR (250 MHz, DMSO-d6) δ 11.83 (s, 1H, NH), 8.64 (s, 1H, CH), 8.54 (s, 1H, NH), 7.36 - 7.27 (m, 1H, 1H, CH), 7.20 (t, J = 2.1 Hz, 1H, CH), 7.17 - 7.03 (m, 2H, 2 x CH), 6.50 (dt, J = 7.5, 2.0 Hz, 1H, CH), 6.09 - 6.00 (m, 1H, CH), 4.27 - 4.16 (m, 2H, CH2), 3.94 (t, J = 6.4 Hz, 2H, CH2), 3.72 (t, J = 5.6 Hz, 2H, CH2), 2.72 - 2.63 (m, 2H, CH2), 2.49 - 2.27 (m, 10H, 5 x CH2), 2.24 (d, J = 1.1 Hz, 3H, CH3), 2.17 (s, 3H, CH3), 1.85 (p, J = 6.7 Hz, 2H, CH2). HRMS (EI-MS) m / z C 27 H 36 N7O2[M+H] +Calculated value: 490.2925, Measured value: 490.2922.

[0226] [ka]

[0227] tert-Butyl (3-(3-nitrophenoxy)propyl)carbamate (186) The reaction was carried out as described in General Procedure L using 3-nitrophenol (200 mg, 1.44 mmol, 1.0 equiv.), 3-(Boc-amino)-1-propanol (492 μL, 2.88 mmol, 2.0 equiv.), PPh3 (642 mg, 2.45 mmol, 1.7 equiv.), and DIAD (0.482 mL, 2.45 mmol, 1.7 equiv.) in dry THF (5 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE / EtOAc from 95 / 5 to 80 / 20 to afford compound 186 (412 mg, 96%) as a yellow oil. f (PE / EtOAc 80 / 20) 0.33. 1 H NMR (250 MHz, CDCl3) δ 7.82 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H, CH), 7.72 (t, J = 2.3 Hz, 1H, CH), 7.43 (t, J = 8.2 Hz, 1H, CH), 7.22 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H, CH), 4.69 (s, 1H, NH), 4.10 (t, J = 6.0 Hz, 2H, CH2), 3.34 (q, J = 6.6 Hz, 2H, CH2), 2.02 (p, J = 6.4 Hz, 2H, CH2), 1.44 (s, 9H, 3 x CH3). HRMS (EI-MS) m / z C 14 H 21 N2O5[M+H] + Calculated value: 297.1445, Measured value: 297.1440.

[0228] tert-Butyl (3-(3-aminophenoxy)propyl)carbamate (187) The reaction was carried out as described in General Procedure N using nitro compound 186 (239 mg, 0.81 mmol, 1.0 equiv) and Pd / C 10 wt% (86 mg, 0.081 mmol, 0.1 equiv) in MeOH (4.5 mL) for 3 h to give compound 187 (196 mg, 91%) as a yellow solid. Mp: 68-70 °C. 1 H NMR (250 MHz, CDCl3) δ 7.05 (t, J = 8.0 Hz, 1H, CH), 6.37 - 6.27 (m, 2H, 2 x CH), 6.24 (t, J = 2.3 Hz, 1H, CH), 4.75 (brs, 1H, NH), 3.98 (t, J = HRMS (EI-MS) m / z C 14 H 23 N2O3[M+H] + Calculated value: 267.1703, Measured value: 267.1702.

[0229] (Example 97) tert-Butyl (3-(3-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridine-1-carboxamido)phenoxy)propyl)carbamate (188) The reaction was carried out as described in general procedure H using aniline 187 (78 mg, 0.29 mmol, 1.0 equiv), 4-nitrophenyl chloroformate (71 mg, 0.35 mmol, 1.2 equiv), DIPEA (122 μL, 0.70 mmol, 2.4 equiv), and amine 4 (88 mg, 0.35 mmol, 1.2 equiv) in dry THF (4.0 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / MeOH 98 / 2 to 95 / 5 to give compound 188 (85 mg, 57%) as a white powder. f(DCM / MeOH 95 / 5)0.42. Mp: Decomposition 103℃. 1 H NMR (250 MHz, DMSO-d6) δ 11.81 (s, 1H, NH), 8.64 (s, 1H, CH), 8.54 (s, 1H, NH), 7.35 - 7.27 (m, 1H, CH), 7.24 - 7.16 (m, 1H, CH), 7.17 - 7.02 (m, 2H, 2 x CH), 6.88 (t, J = 5.1 Hz, 1H, NH), 6.50 (dt, J = 7.6, 2.0 Hz, 1H, CH), 6.12 - 5.99 (m, 1H, CH), 4.21 (d, J = 2.6 Hz, 2H, CH2), 3.92 (t, J = 6.2 Hz, 2H, CH2), 3.73 (t, J = 5.6 Hz, 2H, CH2), 3.07 (q, J = 6.6 Hz, 2H, CH2), 2.68 (brs, 2H, CH2), 2.24 (s, 3H, CH3), 1.82 (p, J = 6.6 Hz, 2H, CH2), 1.37 (s, 9H, 3 x CH3). HRMS (EI-MS) m / z C 27 H 35 N6O4[M+H] + Calculated value: 507.2714, Measured value: 507.2709.

[0230] 1-((4,4-difluorocyclohexyl)methoxy)-3-nitrobenzene (189) The reaction was carried out as described in General Procedure L using 3-nitrophenol (300 mg, 2.16 mmol, 1.0 equiv.), (4,4-difluorocyclohexyl)methanol (562 μL, 4.32 mmol, 2.0 equiv.), PPh3 (963 mg, 3.67 mmol, 1.7 equiv.), and DIAD (0.723 mL, 3.67 mmol, 1.7 equiv.) in dry THF (8 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE / DCM 100 to 75 / 25 to give compound 189 (524 mg, 89%) as a yellow solid. f(PE / DCM 80 / 20)0.28. Mp:75~77℃. 1 H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 8.1, 2.0 Hz, 1H, CH), 7.71 (t, J = 2.3 Hz, 1H, CH), 7.43 (t, J = 8.2 Hz, 1H, CH), 7.21 (dd, J = 8.3, 2.5 Hz, 1H, CH), 3.89 (d, J = 6.0 Hz, 2H, CH2), 2.25-2.10 (m, 2H, CH2), 2.03 - 1.89 (m, 3H, CH + CH2), 1.89 - 1.66 (m, 2H, CH2), 1.53 - 1.39 (m, 2H, CH2). 19 F NMR (376 MHz, CDCl3) δ -91.6 (d, J = 236.5 Hz, 1F), -102.2 (dtt, J = 236.1, 33.5, 10.5 Hz, 1F). HRMS (EI-MS) No MH+ or MH- ionization was detected.

[0231] 3-((4,4-difluorocyclohexyl)methoxy)aniline (190) The reaction was carried out as described in General Procedure N using nitro 189 (308 mg, 1.14 mmol, 1.0 equiv) and Pd / C 10% by weight (121 mg, 0.114 mmol, 0.1 equiv) in MeOH (6 mL) for 3 h to give compound 190 (239 mg, 87%) as a colorless oil, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.05 (t, J = 8.0 Hz, 1H, CH), 6.34 - 6.27 (m, 2H, 2 x CH), 6.23 (t, J = 2.3 Hz, 1H, CH), 3.77 (d, J = 6.3 Hz, 2H, CH2), 3.65 (s, 2H, NH2), 2.19 - 2.06 (m, 2H, CH2), 1.99 - 1.90 (m, 2H, CH2), 1.85 - 1.65 (m, 3H, CH + CH2), 1.49 - 1.34 (m, 2H, CH2). 19 F NMR (376 MHz, CDCl3) δ -91.4 (d, J = 235.7 Hz, 1F), -102.0 (dtt, J = 236.2, 33.2, 9.5 Hz, 1F). HRMS (EI-MS) m / z C 13 H 18 F2NO [M+H] + Calculated value: 242.1351, Measured value: 242.1350.

[0232] Example 98: N-(3-((4,4-difluorocyclohexyl)methoxy)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (191) The reaction was carried out as described in general procedure H using aniline 190 (101 mg, 0.42 mmol, 1.0 equiv), 4-nitrophenyl chloroformate (101 mg, 0.50 mmol, 1.2 equiv), DIPEA (175 μL, 1.01 mmol, 2.4 equiv), and amine 4 (126 mg, 0.50 mmol, 1.2 equiv) in dry THF (6.0 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / MeOH 98 / 2 to 95 / 5 to give compound 191 (119 mg, 59%) as a white powder. f (DCM / MeOH 95 / 5)0.31. Mp: Decomposition 223℃. 1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H, NH), 8.65 (s, 1H, CH), 8.54 (s, 1H, NH), 7.31 (s, 1H, CH), 7.21 (s, 1H, CH), 7.17 - 7.05 (m, 2H, 2 x CH), 6.52 (d, J = 7.6 Hz, 1H, CH), 6.04 (brs, 1H, CH), 4.21 (d, J = 3.0 Hz, 2H,CH2), 3.80 (d, J = 5.8 Hz, 2H, CH2), 3.72 (t, J = 5.6 Hz, 2H, CH2), 2.67 (brs, 2H, CH2), 2.23 (s, 3H, CH3), 2.11 - 1.97 (m, 2H, CH2), 2.0 - 1.7 (m, 5H, 2 x CH2+ CH), 1.39 - 1.20 (m, 2H, CH2). 19 F NMR (376 MHz, DMSO) δ -89.2 (d, J = 232.1 Hz, 1F), -99.6 (dt, J = 231.0, 35.9 Hz, 1F). HRMS (EI-MS) m / z C 26 H 30 F2N5O2[M+H] + Calculated value: 482.2362, Measured value: 482.2363.

[0233] 4-((3-ニトロフェノキシ)メチル)ピペリジン(192) The reaction was carried out as described in General Procedure L using 3-nitrophenol (700 mg, 5.03 mmol, 1.0 equiv.), 1-Boc-4-piperidinemethanol (2.17 g, 10.10 mmol, 2.0 equiv.), PPh3 (2.24 g, 8.55 mmol, 1.7 equiv.), and DIAD (1.68 mL, 8.55 mmol, 1.7 equiv.) in dry THF (28 mL). The reaction mixture was filtered through silica gel. The crude intermediate product was then dissolved in dry DCM (30 mL). The reaction mixture was cooled to 0 °C, and then 4 N HCl in 1,4-dioxane (6.0 mL, 24.10 mmol, 8.0 equiv.) was added. The solution was stirred at room temperature for 3 h and concentrated under reduced pressure. The white residue was partitioned between Et2O (20 mL) and HO (20 mL), and the organic layer was removed. The aqueous layer was then washed with EtO (15 mL), treated with a saturated aqueous solution of NaHCO to pH 8-9, and extracted with DCM (3 x 40 mL). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure to give compound 192 (326 mg, 27%) as a sticky orange solid, which was used in the next step without further purification. 1 H NMR (250 MHz, DMSO-d6) δ 7.80 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H, CH), 7.68 (t, J = 2.3 Hz, 1H, CH), 7.56 (t, J = 8.2 Hz, 1H, CH), 7.40 (ddd, J = 8.3, 2.5, 1.0 Hz, 1H, CH), 3.93 (d, J = 6.3 Hz, 2H, CH2), 2.99 (d, J = 12.2 Hz, 2H, CH2), 2.59 - 2.46 (m, 2H, CH2), 1.97 - 1.78 (m, 1H, CH), 1.72 (d, J = 12.8 Hz, 2H, CH2), 1.22 (qd, J = 12.1, 4.1 Hz, 2H, CH2). HRMS (EI-MS) m / z C 12 H 17 N2O3[M+H] + Calculated value: 237.1234, Measured value: 237.1235.

[0234] 1-Methyl-4-((3-nitrophenoxy)methyl)piperidine (193) To a microwave reaction vial containing compound 192 (216 mg, 0.91 mmol, 1.0 equiv.) was added formic acid (0.8 mL) and formaldehyde solution (37% by weight in HO, 0.48 mL, 6.40 mmol, 7.0 equiv.). The tube was sealed and subjected to two 10-minute cycles of microwave irradiation at 90 °C. The reaction mixture was then diluted with HO (10 mL) and DCM (35 mL), and a saturated aqueous solution of NaHCO was added to bring the pH to approximately 9. The aqueous layer was extracted with DCM (3 × 20 mL), and the combined organic layers were then dried over MgSO, filtered, and concentrated under reduced pressure to give compound 193 (207 mg, 90%) as a yellow solid. The product was used in the next step without further purification. Mp: 68-70 °C. 1 H NMR (250 MHz, DMSO-d6) δ 7.80 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H, CH), 7.69 (t, J = 2.3 Hz, 1H, CH), 7.56 (t, J = 8.2 Hz, 1H, CH), 7.41 (ddd, J = 8.3, 2.5, 1.0 Hz, 1H, CH), 3.95 (d, J = 5.9 Hz, 2H, CH2), 2.88 - 2.70 (m, 2H, CH2), 2.15 (s, 3H, CH3), 1.92 - 1.79 (m, 2H, CH2), 1.78 - 1.61 (m, 3H, CH + CH2), 1.42 - 1.15 (m, 2H, CH2). HRMS (EI-MS) m / z C 13 H 19 N2O3[M+H] + Calculated value: 251.1390, Measured value: 251.1387.

[0235] 3-((1-methylpiperidin-4-yl)methoxy)aniline (194) The reaction was carried out as described in General Procedure N using nitro 193 (171 mg, 0.72 mmol, 1.0 equiv) and Pd / C 10% by weight (77 mg, 0.07 mmol, 0.1 equiv) in MeOH (4 mL) for 2 h to give compound 194 (131 mg, 82%) as a beige solid, which was used in the next step without further purification. 1 H NMR (250 MHz, DMSO-d6) δ 6.86 (t, J = 8.3 Hz, 1H, CH), 6.16 - 6.09 (m, 2H, 2 x CH), 6.05 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H, CH), 4.99 (s, 2H, NH2), 3.69 (d, J = 5.9 Hz, 2H, CH2), 2.81 - 2.70 (m, 2H, CH2), 2.14 (s, 3H, CH3), 1.83 (td, J = 11.6, 2.4 Hz, 2H, CH2), 1.77 - 1.54 (m, 3H, CH + CH2), 1.37 - 1.15 (m, 2H, CH2). HRMS (EI-MS) m / z C 13 H 21 NO [M+H] + Calculated value: 221.1648, Measured value: 221.1645.

[0236] Example 99: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-((1-methylpiperidin-4-yl)methoxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxamide (195) The reaction was carried out as described in general procedure H using aniline 194 (113 mg, 0.51 mmol, 1.0 equiv), 4-nitrophenyl chloroformate (124 mg, 0.62 mmol, 1.2 equiv), DIPEA (322 μL, 3.60 mmol, 3.6 equiv), and amine 4 (177 mg, 0.62 mmol, 1.2 equiv) in dry THF (7.3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / MeOH / NHOH 98 / 2 / 1 to 94 / 6 / 1 to give compound 195 (80 mg, 34%) as a white powder. f (DCM / MeOH / NH4OH 95 / 5 / 1)0.27. Mp: Decomposition 135℃. 1 H NMR (250 MHz, DMSO-d6) δ 11.83 (s, 1H, NH), 8.64 (s, 1H, CH), 8.54 (s, 1H, NH), 7.32 (brs, 1H, CH), 7.20 (brs, 1H, CH), 7.16 - 7.02 (m, 2H, 2 x CH), 6.51 (d, J = 7.4 Hz, 1H, CH), 6.04 (s, 1H, CH), 4.21 (brs, 2H, CH2), 3.87 - 3.66 (m, 4H, 2 x CH2), 2.83 (d, J = 11.0 Hz, 2H, CH2), 2.67 (brs, 2H, CH2), 2.23 (s, HRMS (EI-MS) m / z C 26 H 33 N6O2[M+H] + Calculated value: 461.2660, Measured value: 461.2663.

[0237] Example 100: N-methyl-4-(4-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridine-1-carboxamide))phenoxy)picolinamide (196) The reaction was carried out as described in general procedure H using 4-(4-aminophenoxy)-N-methylpicolinamide (100 mg, 0.41 mmol, 1.0 equiv.), 4-nitrophenyl chloroformate (99 mg, 0.49 mmol, 1.2 equiv.), DIPEA (258 μL, 1.48 mmol, 3.6 equiv.), and amine 4 (142 mg, 0.49 mmol, 1.2 equiv.) in dry THF (6 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / MeOH / NHOH 98 / 2 / 0.1 to 93 / 7 / 0.1 to give compound 196 (175 mg, 88%) as a beige powder. f (DCM / MeOH / NH4OH 95 / 5 / 0.1)0.44. Mp: Decomposition 149℃. 1 H NMR (250 MHz, CDCl3) δ 11.83 (s, 1H, NH), 8.80 - 8.71 (m, 2H, 2 x NH), 8.65 (s, 1H, CH), 8.52 - 8.48 (m, 1H, CH), 7.70 - 7.60 (m, 2H, 2 x CH), 7.38 (d, J = 2.8 Hz, 1H, CH), 7.35 - 7.29 (m, 1H, CH), 7.17 - 7.08 (m, 3H, 3 x CH), 6.06 (brs, 1H, CH), 4.30 - 4.21 (m, 2H, CH2), 3.76 (t, J = 5.5 Hz, 2H, CH2), 2.79 (d, J = 4.8 Hz, 3H, CH3), 2.70 (brs, 2H, CH2), 2.29 - 2.22 (m, 3H, CH3). HRMS (EI-MS) m / z C 26 H 26 N7O3[M+H] + Calculated value: 484.2092, Measured value: 484.2086.

[0238] 4-(3-aminophenoxy)-N-methyl-2-pyridinecarboxamide (197) To a solution of 3-aminophenol (336 mg, 3.08 mmol, 1.05 equiv) in dry DMSO (2 mL) under argon was added t-BuOK (361 mg, 3.22 mmol, 1.1 equiv). The solution was stirred at room temperature for 30 minutes, and then 4-chloro-N-methylpicolinamide (500 mg, 2.93 mmol, 1.0 equiv) was added. The reaction mixture was stirred at 80 °C for 3 hours, cooled to room temperature, and then diluted with HO (40 mL) and EtOAc (50 mL). The aqueous layer was separated and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / MeOH 100 to 98 / 2 to give compound 197 (516 mg, 72%) as a colorless oil. f (DCM / MeOH 98 / 2) 0.59. 1 H NMR (250 MHz, DMSO-d6) δ 8.75 (q, J = 4.8 Hz, 1H, NH), 8.49 (dd, J = 5.6, 0.5 Hz, 1H, CH), 7.41 (d, J = 2.6 Hz, 1H, CH), 7.20 - 7.02 (m, 2H, 2 x CH), 6.51 (ddd, J = 8.1, 2.1, 0.9 Hz, 1H, CH), 6.32 (t, J = 2.2 Hz, 1H, CH), 6.27 (ddd, J = 7.9, 2.4, 0.9 Hz, 1H, CH), 5.39 (s, 2H, NH2), 2.79 (d, J = 4.9 Hz, 3H, CH3). HRMS (EI-MS) m / z C 13 H 14 N3O2[M+H] + Calculated value: 244.1081, Measured value: 244.1080.

[0239] Example 101: N-methyl-4-(3-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridine-1-carboxamide))phenoxy)picolinamide (198) The reaction was carried out as described in general procedure H using aniline 197 (110 mg, 0.45 mmol, 1.0 equiv), 4-nitrophenyl chloroformate (109 mg, 0.54 mmol, 1.2 equiv), DIPEA (284 μL, 1.63 mmol, 3.6 equiv), and amine 4 (156 mg, 0.54 mmol, 1.2 equiv) in dry THF (7 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / MeOH 98 / 2 to 95 / 5 to give compound 198 (160 mg, 73%) as a beige powder. f (DCM / MeOH 95 / 5)0.54. Mp:211~213℃. 1 H NMR (250 MHz, DMSO-d6) δ 11.82 (s, 1H, NH), 8.85 - 8.71 (m, 2H, 2 x NH), 8.64 (s, 1H, CH), 8.52 (d, J = 5.6 Hz, 1H, CH), 7.52 - 7.33 (m, 4H, 4 x CH), 7.30 (brs, 1H, CH), 7.18 (dd, J = 5.6, 2.6 Hz, 1H, CH), 6.80 (ddd, J = 7.8, 2.3, 1.3 Hz, 1H, CH), 6.03 (brs, 1H, CH), 4.21 (d, J = 3.1 Hz, 2H, CH2), 3.73 (t, J = HRMS (EI-MS) m / z C 26 H 26 N7O3[M+H] + Calculated value: 484.2092, Measured value: 484.2088.

[0240] 3-(3-fluorophenoxy)aniline (199) The reaction was carried out as described in General Procedure P using 3-fluoroiodobenzene (235 μL, 2.00 mmol, 1.0 equiv.), 3-aminophenol (262 mg, 2.40 mmol, 1.2 equiv.), copper(I) iodide (19 mg, 0.10 mmol, 5 mol%), 2-picolinic acid (25 mg, 0.20 mmol, 10 mol%), and KPO (849 mg, 4.00 mmol, 2.0 equiv.) in dry DMSO (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE / EtOAc from 90 / 10 to 80 / 20 to give compound 199 (406 mg, quantitative) as an orange liquid. f (PE / EtOAc 80 / 20) 0.35. 1 H NMR (400 MHz, CDCl3) δ 7.33 - 7.22 (m, 1H, CH), 7.14 (t, J = 8.0 Hz, 1H, CH), 6.85 - 6.70 (m, 3H, 3 x CH), 6.46 (ddd, J = 19.6, 8.1, 2.2 Hz, 2H, 2 x CH), 6.38 (t, J = 2.3 Hz, 1H, CH), 3.74 (brs, 2H, NH2). 19 F NMR (376 MHz, CDCl3) δ -111.2. HRMS (EI-MS) m / z C 12 H 11 FNO [M+H] + Calculated value: 204.0819, Measured value: 204.0824.

[0241] Example 102: N-(3-(3-fluorophenoxy)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (200) The reaction was carried out as described in general procedure H using aniline 199 (77 mg, 0.38 mmol, 1.0 equiv), 4-nitrophenyl chloroformate (91 mg, 0.45 mmol, 1.2 equiv), DIPEA (237 μL, 1.36 mmol, 2.4 equiv), and amine 4 (130 mg, 0.45 mmol, 1.2 equiv) in dry THF (5.4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / MeOH 98 / 2 to 97 / 3 to give compound 200 (129 mg, 76%) as a brown solid. f (DCM / MeOH 95 / 5)0.33. Mp: Decomposition 150℃. 1 H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H, NH), 8.70 (s, 1H, NH), 8.64 (s, 1H, CH), 7.47 - 7.38 (m, 1H, CH), 7.38 - 7.23 (m, 4H, 4 x CH), 6.96 (td, J = 8.5, 2.5 Hz, 1H, CH), 6.90 - 6.80 (m, 2H, 2 x CH), 6.67 (d, J = 8.0 Hz, 1H, CH), 6.03 (brs, 1H, CH), 4.20 (d, J = 3.0 Hz, 2H, CH2), 3.71 (t, J = 5.5 Hz, 2H, CH2), 2.66 (brs, 2H, CH2), 2.22 (s, 3H, CH3). 19 F NMR (376 MHz, DMSO-d6) δ -111.0 (s, 1F). HRMS (EI-MS) m / z C 25 H 23 FN5O2[M+H] + Calculated value: 444.1830, Measured value: 444.1835.

[0242] 3-(4-fluorophenoxy)aniline (201) The reaction was carried out as described in General Procedure P using 4-fluoroiodobenzene (231 μL, 2.00 mmol, 1.0 equiv.), 3-aminophenol (262 mg, 2.40 mmol, 1.2 equiv.), copper(I) iodide (19 mg, 0.10 mmol, 5 mol%), 2-picolinic acid (25 mg, 0.20 mmol, 10 mol%), and KPO (849 mg, 4.00 mmol, 2.0 equiv.) in dry DMSO (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE / EtOAc (100 to 90 / 10) to afford compound 201 (332 mg, 82%) as an orange oil. f (PE / EtO Ac 90 / 10) 0.32. 1 H NMR (250 MHz, CDCl3) δ 7.12 - 6.94 (m, 5H, 5 x CH), 6.41 (ddd, J = 8.0, 2.2, 0.9 Hz, 1H, CH), 6.34 (ddd, J = 8.1, 2.3, 0.9 Hz, 1H, CH), 6.28 (td, J = 2.3, 0.4 Hz, 1H, CH), 3.69 (brs, 2H, NH2). HRMS (EI-MS) m / z C 12 H 11 FNO [M+H] + Calculated value: 204.0819, Measured value: 204.0823.

[0243] All spectral data corresponded to literature values found in Maiti D., Buchwald SL, J. Am. Chem. Soc. 2009, 131, 17423-17429.

[0244] Example 103: N-(3-(4-fluorophenoxy)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (202) The reaction was carried out as described in general procedure H using aniline 201 (79 mg, 0.39 mmol, 1.0 equiv), 4-nitrophenyl chloroformate (94 mg, 0.47 mmol, 1.2 equiv), DIPEA (244 μL, 1.40 mmol, 2.4 equiv), and amine 4 (134 mg, 0.47 mmol, 1.2 equiv) in dry THF (5.6 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / MeOH 98 / 2 to 97 / 3 to give compound 202 (129 mg, 74%) as a white powder. f (DCM / MeOH 95 / 5)0.25. Mp:213~215℃. 1 H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H, NH), 8.65 (s, 1H, NH), 8.64 (s, 1H, CH), 7.34 - 7.28 (m, 2H, 2 x CH), 7.27 - 7.19 (m, 4H, 4 x CH), 7.12 - 7.00 (m, 2H, 2 x CH), 6.59 (dd, J = 7.6, 2.3 Hz, 1H, CH), 6.03 (brs, 1H, CH), 4.26 - 4.15 (m, 2H, CH2), 3.71 (t, J = 5.6 Hz, 2H, CH2), 2.66 (brs, 2H, CH2), 2.22 (s, 3H, CH3). 19 F NMR (376 MHz, DMSO-d6) δ -119.99 - -120.08 (m, 1F). HRMS (EI-MS) m / z C 25 H 23 FN5O2[M+H] + Calculated value: 444.1830, Measured value: 444.1836.

[0245] 3-(3-chlorophenoxy)aniline (203) The reaction was carried out as described in General Procedure P using 3-chloroiodobenzene (248 μL, 2.00 mmol, 1.0 equiv.), 3-aminophenol (262 mg, 2.40 mmol, 1.2 equiv.), copper(I) iodide (19 mg, 0.10 mmol, 5 mol%), 2-picolinic acid (25 mg, 0.20 mmol, 10 mol%), and KPO (849 mg, 4.00 mmol, 2.0 equiv.) in dry DMSO (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE / EtOAc from 95 / 5 to 80 / 20 to give compound 203 (427 mg, 97%) as an orange liquid. f (PE / Et0Ac 80 / 20) 0.39. 1 H NMR (250 MHz, CDCl3) δ 7.23 (t, J = 8.1 Hz, 1H, CH), 7.12 (t, J = 8.0 Hz, 1H, CH), 7.05 (ddd, J = 7.9, 2.0, 1.0 Hz, 1H, CH), 6.99 (t, J = 2.1 Hz, 1H, CH), 6.90 (ddd, J = 8.2, 2.4, 1.0 Hz, 1H, CH), 6.46 (ddd, J = 8.0, 2.2, 0.9 Hz, 1H, CH), 6.40 (ddd, J = 8.0, 2.3, 0.9 Hz, 1H, CH), 6.34 (t, J = 2.2 Hz, 1H, CH), 3.72 (brs, 2H, NH2). HRMS (EI-MS) m / z C 12 H 11 ClNO [M+H] + Calculated value: 220.0524, Measured value: 220.0525.

[0246] Example 104: N-(3-(3-chlorophenoxy)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (204) The reaction was carried out as described in general procedure H using aniline 203 (90 mg, 0.41 mmol, 1.0 equiv), 4-nitrophenyl chloroformate (99 mg, 0.49 mmol, 1.2 equiv), DIPEA (258 μL, 1.48 mmol, 2.4 equiv), and amine 4 (141 mg, 0.49 mmol, 1.2 equiv) in dry THF (5.9 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / MeOH 98 / 2 to 95 / 5 to give compound 204 (161 mg, 85%) as a white solid. f (DCM / MeOH 95 / 5)0.39. Mp: decomposition 124℃. 1 H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H, NH), 8.70 (s, 1H, NH), 8.64 (s, 1H, CH), 7.45 - 7.25 (m, 5H, 5 x CH), 7.22 - 7.16 (m, 1H, CH), 7.08 - 7.05 (m, 1H, CH), 6.98 (dd, J = 8.3, 2.4 Hz, 1H, CH), 6.66 (d, J = 8.0 Hz, 1H, CH), 6.09 - 5.99 (m, 1H, CH), 4.20 (d, J = 3.1 Hz, 2H, CH2), 3.72 (t, J = 5.6 Hz, 2H, CH2), 2.67 (brs, 2H, CH2), 2.22 (s, 3H, CH3). HRMS (EI-MS) m / z C 25 H 23 ClNO2[M+H] + Calculated value: 460.1535, Measured value: 460.1539.

[0247] 3-(4-Bromo-2-chlorophenoxy)aniline (205) To a solution of 3-aminophenol (274 mg, 2.51 mmol, 1.05 equiv) in dry DMSO (2 mL) under argon was added t-BuOK (295 mg, 2.63 mmol, 1.1 equiv). The solution was stirred at room temperature for 30 minutes, and then 4-bromo-2-chloro-1-fluorobenzene (290 μL, 2.39 mmol, 1.0 equiv) was added. The reaction mixture was stirred at 80° C. for 18 hours, then cooled to room temperature and diluted with HO (25 mL) and EtOAc (50 mL). The aqueous layer was separated and extracted with EtOAc (2×50 mL), and the combined organic layers were washed with brine (3×20 mL), dried over MgSO, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE / EtOAc 100 to 90 / 10 to give compound 205 (612 mg, 86%) as an orange oil. f (PE / EtO Ac 90 / 10) 0.21. 1 H NMR (250 MHz, CDCl3) δ 7.59 (d, J = 2.4 Hz, 1H, CH), 7.31 (dd, J = 8.7, 2.4 Hz, 1H, CH), 7.10 (t, J = 8.0 Hz, 1H, CH), 6.87 (d, J = 8.7 Hz, 1H, CH), 6.44 (ddd, J = 8.0, 2.2, 0.9 Hz, 1H, CH), 6.33 (ddd, J = 8.0, 2.4, 0.9 Hz, 1H, CH), 6.28 (t, J = 2.2 Hz, 1H, CH), 3.72 (brs, 2H, NH2). HRMS (EI-MS) m / z C 12 H 10 BrClNO [M+H] + Calculated value: 299.9607, Measured value: 299.9606.

[0248] Example 105: N-(3-(4-bromo-2-chlorophenoxy)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (206) The reaction was carried out as described in general procedure H using aniline 205 (65 mg, 0.22 mmol, 1.0 equiv), 4-nitrophenyl chloroformate (53 mg, 0.26 mmol, 1.2 equiv), DIPEA (137 μL, 0.79 mmol, 2.4 equiv), and amine 4 (75 mg, 0.26 mmol, 1.2 equiv) in dry THF (3.1 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / MeOH 98 / 2 to 96 / 4 to give compound 206 (87 mg, 73%) as a white solid. f (DCM / MeOH 95 / 5)0.30. Mp: decomposition 148℃. 1 H NMR (250 MHz, DMSO-d6) δ 11.85 (s, 1H, NH), 8.70 (s, 1H, NH), 8.64 (s, 1H, CH), 7.89 (d, J = 2.4 Hz, 1H, CH), 7.57 (dd, J = 8.7, 2.4 Hz, 1H, CH), 7.40 - 7.19 (m, 4H, 4 x CH), 7.06 (d, J = 8.8 Hz, 1H, CH), 6.61 (ddd, J = 7.8, 2.5, 1.2 Hz, 1H, CH), 6.03 (brs, 1H, CH), 4.19 (d, J = 3.1 Hz, 2H, CH2), 3.70 (t, J = 5.6 Hz, 2H, CH2), 2.66 (brs, 2H, CH2), 2.22 (d, J = 1.1 Hz, 3H, CH3). HRMS (EI-MS) m / z C 25 H 22 BrClNO2[M+H] + Calculated value: 540.0620, Measured value: 540.0621.

[0249] 3-(Pyridin-3-yloxy)aniline (207) The reaction was carried out as described in General Procedure P using 3-iodopyridine (410 mg, 2.00 mmol, 1.0 equiv.), 3-aminophenol (262 mg, 2.40 mmol, 1.2 equiv.), copper(I) iodide (19 mg, 0.10 mmol, 5 mol%), 2-picolinic acid (25 mg, 0.20 mmol, 10 mol%), and KPO (849 mg, 4.00 mmol, 2.0 equiv.) in dry DMSO (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE / EtOAc from 80 / 20 to 50 / 50 to afford compound 207 (247 mg, 55%) as a brown oil. f (PE / EtOAc 50 / 50) 0.30. 1 H NMR (250 MHz, CDCl3) δ 8.41 (dd, J = 2.8, 0.8 Hz, 1H, CH), 8.35 (dd, J = 4.5, 1.6 Hz, 1H, CH), 7.34 - 7.21 (m, 2H, 2 x CH), 7.12 (t, J = 8.0 Hz, 1H, CH), 6.46 (ddd, J = 8.0, 2.2, 0.9 Hz, 1H, CH), 6.39 (ddd, J = 8.0, 2.3, 0.9 Hz, 1H, CH), 6.34 (t, J = 2.2 Hz, 1H, CH), 3.73 (brs, 2H, NH2). HRMS (EI-MS) m / z C 11 H 11 NO [M+H] + Calculated value: 187.0866, Measured value: 187.0871.

[0250] All spectral data corresponded to literature values found in Maiti D., Buchwald SL, J. Am. Chem. Soc. 2009, 131, 17423-17429.

[0251] Example 106: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-(pyridin-3-yloxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxamide (208) The reaction was carried out as described in general procedure H using aniline 207 (70 mg, 0.38 mmol, 1.0 equiv), 4-nitrophenyl chloroformate (91 mg, 0.45 mmol, 1.2 equiv), DIPEA (236 μL, 1.35 mmol, 2.4 equiv), and amine 4 (130 mg, 0.45 mmol, 1.2 equiv) in dry THF (5.4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / MeOH 98 / 2 to 95 / 5 to give compound 208 (112 mg, 68%) as a white powder. f (DCM / MeOH 95 / 5)0.24. Mp: decomposition 132℃. 1 H NMR (250 MHz, DMSO-d6) δ 11.83 (s, 1H, NH), 8.71 (s, 1H, NH), 8.64 (s, 1H, CH), 8.43 - 8.32 (m, 2H, 2 x CH), 7.49 - 7.40 (m, 2H, 2 x CH), 7.38 - 7.24 (m, 4H, 4 x CH), 6.72 - 6.61 (m, 1H, CH), 6.03 (brs, 1H, CH), 4.19 (d, J = 2.4 Hz, 2H, CH2), 3.71 (t, J = 5.5 Hz, 2H, CH2), 2.66 (brs, 2H, CH2), 2.22 (s, 3H, CH3). HRMS (EI-MS) m / z C 24 H 23 N6O2[M+H] + Calculated value: 427.1877, Measured value: 427.1885.

[0252] 1-(benzyloxy)-3-iodobenzene (209) To a solution of 3-iodophenol (500 mg, 2.27 mmol, 1.0 equiv) in acetone (3 mL) was added K2CO3 (471 mg, 3.41 mmol, 1.5 equiv) and benzyl bromide (406 μL, 3.41 mmol, 1.5 equiv). The resulting suspension was stirred at room temperature for 18 h, diluted with a saturated solution of NH4Cl (15 mL), and then the aqueous layer was separated and extracted with Et2O (2 × 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was precipitated in PE at 0 °C. After filtering the solid, the filtrate was evaporated and precipitated again to give compound 209 (366 mg, 52%) as a white powder. 1 H NMR (250 MHz, CDCl3) δ 7.48 - 7.27 (m, 7H, 7 x CH), 7.05 - 6.89 (m, 2H, CH), 5.03 (s, 2H, CH2).

[0253] All spectral data corresponded to literature values as described in Kutz SK et al., Synthesis, 2017, 49, 275-292.

[0254] 3-(3-(benzyloxy)phenoxy)aniline (210) The reaction was carried out as described in General Procedure P using iodoaryl 209 (310 mg, 1.00 mmol, 1.0 equiv.), 3-aminophenol (131 mg, 1.20 mmol, 1.2 equiv.), copper(I) iodide (10 mg, 0.05 mmol, 5 mol%), 2-picolinic acid (12 mg, 0.10 mmol, 10 mol%), and KPO (425 mg, 2.00 mmol, 2.0 equiv.) in dry DMSO (2 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE / EtOAc from 90 / 10 to 80 / 20 to afford compound 210 (221 mg, 76%) as a brown oil. f (PE / EtOAc 80 / 20) 0.38. 1H NMR (250 MHz, CDCl3) δ 7.46 - 7.30 (m, 5H, 5 x CH), 7.22 (t, J = 8.1 Hz, 1H, CH), 7.09 (t, J = 8.0 Hz, 1H, CH), 6.72 (dd, J = 8.2, 2.4 Hz, 1H, CH), 6.68 - 6.58 (m, 2H, 2 x CH), 6.48 - 6.37 (m, 2H, 2 x CH), 6.33 (t, J = 2.2 Hz, 1H, CH), 5.02 (s, 2H, CH2), 3.68 (s, 2H, NH2). HRMS (EI-MS) m / z C 19 H 18 NO2[M+H] + Calculated value: 292.1332, Measured value: 292.1336.

[0255] Example 107: N-(3-(3-(benzyloxy)phenoxy)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (211) The reaction was carried out as described in general procedure H using aniline 210 (54 mg, 0.19 mmol, 1.0 equiv), 4-nitrophenyl chloroformate (45 mg, 0.22 mmol, 1.2 equiv), DIPEA (116 μL, 0.67 mmol, 2.4 equiv), and amine 4 (64 mg, 0.22 mmol, 1.2 equiv) in dry THF (2.6 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / MeOH 100 to 97 / 3 to give compound 211 (79 mg, 79%) as a white powder. f (DCM / MeOH 95 / 5)0.29. Mp: decomposition 110℃. 1H NMR (250 MHz, DMSO-d6) δ 11.82 (s, 1H, NH), 8.67 (brs, 1H, NH), 8.64 (s, 1H, CH), 7.48 - 7.19 (m, 10H, 10 x CH), 6.78 (ddd, J = 8.3, 2.5, 0.9 Hz, 1H, CH), 6.66 (t, J = 2.3 Hz, 1H, CH), 6.64 - 6.53 (m, 2H, 2 x CH), 6.05 - 5.99 (m, 1H, CH), 5.08 (s, 2H, CH2), 4.26 - 4.14 (m, 2H, CH2), 3.71 (t, J = 5.5 Hz, 2H, CH2), 2.66 (brs, 2H, CH2), 2.22 (d, J = 1.0 Hz, 3H, CH3). HRMS (EI-MS) m / z C 32 H 30 N5O3[M+H] + Calculated value: 532.2343, Measured value: 532.2351.

[0256] 3-(3-aminophenoxy)phenol (212) The reaction was carried out as described in General Procedure N using compound 210 (139 mg, 0.48 mmol, 1.0 equiv.) and Pd / C 10 wt% (51 mg, 0.05 mmol, 0.1 equiv.) in MeOH (2.7 mL) for 3 h to afford compound 212 (90 mg, 94%) as a beige amorphous solid. 1H NMR (250 MHz, DMSO-d6) δ 9.51 (s, 1H, OH), 7.12 (t, J = 8.1 Hz, 1H, CH), 6.98 (t, J = 8.0 Hz, 1H, CH), 6.48 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H, CH), 6.39 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H, CH), 6.35 - 6.27 (m, 2H, 2 x CH), 6.17 (t, J = 2.2 Hz, 1H, CH), 6.12 (ddd, J = 7.9, 2.4, 1.0 Hz, 1H, CH), 5.20 (brs, 2H, NH2). HRMS (EI-MS) m / z C 12 H 12 NO2[M+H] + Calculated value: 202.0863, Measured value: 202.0867.

[0257] Example 108: N-(3-(3-hydroxyphenoxy)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (213) The reaction was carried out as described in general procedure H using aniline 212 (79 mg, 0.39 mmol, 1.0 equiv), 4-nitrophenyl chloroformate (95 mg, 0.47 mmol, 1.2 equiv), DIPEA (246 μL, 1.41 mmol, 2.4 equiv), and amine 4 (136 mg, 0.47 mmol, 1.2 equiv) in dry THF (5.6 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / MeOH 98 / 2 to 96 / 4 to give compound 213 (80 mg, 46%) as a white powder. f (DCM / MeOH 95 / 5)0.22. Mp: decomposition 144℃. 1H NMR (250 MHz, DMSO-d6) δ 11.81 (s, 1H, NH), 9.55 (s, 1H, OH), 8.65 (s, 1H, NH), 8.64 (s, 1H, CH), 7.37 - 7.20 (m, 4H, 4 x CH), 7.15 (t, J = 8.1 Hz, 1H, CH), 6.61 (ddd, J = 7.7, 2.4, 1.3 Hz, 1H, CH), 6.52 (ddd, J = 8.1, 2.3, 0.9 Hz, 1H, CH), 6.43 (ddd, J = 8.1, 2.4, 0.9 Hz, 1H, CH), 6.38 (t, J = 2.3 Hz, 1H, CH), 6.08 - 5.98 (m, 1H, CH), 4.20 (d, J = 3.1 Hz, 2H, CH2), 3.71 (t, J = 5.5 Hz, 2H, CH2), 2.66 (brs, 2H, CH2), 2.22 (d, J = 1.1 Hz, 3H, CH3). HRMS (EI-MS) m / z C 25 H 24 N5O3[M+H] + Calculated value: 442.1874, Measured value: 442.1883.

[0258] 3-Iodophenyl dimethylcarbamate (214) Under an argon atmosphere, to a solution of 3-iodophenol (600 mg, 2.73 mmol, 1.0 equiv) in dry MeCN (14 mL) were added KCO (567 mg, 4.10 mmol, 1.5 equiv) and dimethylcarbamyl chloride (377 μL, 4.10 mmol, 1.5 equiv). The reaction mixture was stirred under reflux for 18 h, then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and HO (20 mL), and the aqueous layer was separated and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with KOH 1M (15 mL), dried over MgSO, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE / EtOAc 100 to 90 / 10 to give compound 214 (730 mg, 92%) as a colorless oil.f (PE / EtO Ac 90 / 10) 0.40. 1 H NMR (250 MHz, CDCl3) δ 7.57 - 7.47 (m, 2H, 2 x CH), 7.14 - 7.01 (m, 2H, 2 x CH), 3.04 (d, J = 18.5 Hz, 6H, 2 x CH3). HRMS (EI-MS) m / z C9H 11 INO2[M+H] + Calculated value: 291.9829, Measured value: 291.9834.

[0259] 3-(3-aminophenoxy)phenyl dimethylcarbamate (215) The reaction was carried out as described in General Procedure P using iodoaryl 214 (582 mg, 2.00 mmol, 1.0 equiv.), 3-aminophenol (262 mg, 2.40 mmol, 1.2 equiv.), copper(I) iodide (19 mg, 0.10 mmol, 5 mol%), 2-picolinic acid (25 mg, 0.20 mmol, 10 mol%), and KPO (849 mg, 4.00 mmol, 2.0 equiv.) in dry DMSO (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE / EtOAc from 80 / 20 to 70 / 30 to give compound 215 (166 mg, 30%) as a brown oil. f (PE / EtOAc 70 / 30) 0.18. 1 H NMR (250 MHz, CDCl3) δ 7.28 (t, J = 8.2 Hz, 1H, CH), 7.10 (t, J = 8.0 Hz, 1H, CH), 6.85 (dd, J = 8.2, 2.3 Hz, 2H, 2 x CH), 6.76 (t, J = 2.3 Hz, 1H, HRMS (EI-MS) m / z C 15 H 17N2O3[M+H] + Calculated value: 273.1234, Measured value: 273.1235.

[0260] Example 109: 3-(3-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridine-1-carboxamido)phenoxy)phenyl dimethylcarbamate (216) The reaction was carried out as described in general procedure H using aniline 215 (69 mg, 0.25 mmol, 1.0 equiv), 4-nitrophenyl chloroformate (61 mg, 0.30 mmol, 1.2 equiv), DIPEA (157 μL, 0.91 mmol, 2.4 equiv), and amine 4 (87 mg, 0.30 mmol, 1.2 equiv) in dry THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / MeOH 98 / 2 to 95 / 5 to give compound 216 (81 mg, 64%) as a white powder after co-evaporation with ethanol. f (DCM / MeOH 95 / 5)0.27. Mp: decomposition 132℃. 1 H NMR (250 MHz, DMSO-d6) δ 11.84 (s, 1H, NH), 8.72 (s, 1H, NH), 8.64 (s, 1H, CH), 7.45 - 7.19 (m, 5H, 5 x CH), 6.94 - 6.81 (m, 2H, 2 x CH), 6.74 (t, J = 2.3 Hz, 1H, CH), 6.64 (ddd, J = 7.8, 2.4, 1.2 Hz, 1H, CH), 6.12 - 5.97 (m, 1H, CH), 4.28 - 4.13 (m, 2H, CH2), 3.72 (t, J = 5.6 Hz, 2H, CH2), 3.00 (s, 3H, HRMS (EI-MS) m / z C 28 H 29 N6O4[M+H] + Calculated value: 513.2245, Measured value: 513.2235.

[0261] N-(3-iodophenyl)acetamide (217) A solution of 3-iodoaniline (329 μL, 2.74 mmol, 1.0 equiv) in acetic anhydride (5.5 mL) was stirred at room temperature for 4 hours. The reaction mixture was poured into cold water, neutralized with KOH 1M, and extracted with DCM (4 × 50 mL). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure to give compound 217 (714 mg, quantitative) as a brown solid. The resulting product was used in the next step without further purification. 1 H NMR (250 MHz, CDCl3) δ 7.90 (s, 1H, CH), 7.45 (t, J = 8.9 Hz, 2H, 2 x CH), 7.27 (brs, 1H, NH), 7.03 (t, J = 8.0 Hz, 1H, CH), 2.17 (s, 3H, CH3).

[0262] All spectral data corresponded to literature values found in Linstad EJ et al., Org. Biomol. Chem., 2017, 15, 2246-2252.

[0263] N-(3-(3-aminophenoxy)phenyl)acetamide (218) The reaction was carried out as described in General Procedure P using iodoaryl 217 (522 mg, 2.00 mmol, 1.0 equiv.), 3-aminophenol (262 mg, 2.40 mmol, 1.2 equiv.), copper(I) iodide (19 mg, 0.10 mmol, 5 mol%), 2-picolinic acid (25 mg, 0.20 mmol, 10 mol%), and KPO (849 mg, 4.00 mmol, 2.0 equiv.) in dry DMSO (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE / EtOAc from 80 / 20 to 50 / 50 to give compound 218 (320 mg, 66%) as a brown oil. f (PE / EtOAc 50 / 50) 0.16. 1H NMR (250 MHz, DMSO-d6) δ 9.98 (s, 1H, NH), 7.36 - 7.19 (m, 3H, 3 x CH), 6.99 (t, J = 8.0 Hz, 1H, CH), 6.65 (ddd, J = 7.4, 2.3, 1.6 Hz, 1H, HRMS (EI-MS) m / z C 14 H 15 N2O2[M+H] + Calculated value: 243.1128, Measured value: 243.1134.

[0264] Example 110: N-(3-(3-acetamidophenoxy)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (219) The reaction was carried out as described in general procedure H using aniline 218 (100 mg, 0.41 mmol, 1.0 equiv), 4-nitrophenyl chloroformate (100 mg, 0.50 mmol, 1.2 equiv), DIPEA (260 μL, 1.49 mmol, 2.4 equiv), and amine 4 (143 mg, 0.50 mmol, 1.2 equiv) in dry THF (6.0 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / MeOH 98 / 2 to 94 / 6 to give compound 219 (46 mg, 24%) as a white powder after co-evaporation with ethanol. f (DCM / MeOH 95 / 5)0.30. Mp: Decomposition 156℃. 1H NMR (250 MHz, DMSO-d6) δ 11.84 (s, 1H, NH), 10.00 (s, 1H, NH), 8.68 (s, 1H, NH), 8.64 (s, 1H, CH), 7.50 - 7.17 (m, 7H, 7 x CH), 6.77 - 6.56 (m, 2H, 2 x CH), 6.03 (brs, 1H, CH), 4.20 (s, 2H, CH2), 3.71 (t, J = 5.6 Hz, 2H, CH2), 2.66 (brs, 2H, CH2), 2.22 (s, 3H, CH3), 2.01 (s, 3H, CH3). HRMS (EI-MS) m / z C 27 H 27 N6O3[M+H] + Calculated value: 483.2139, Measured value: 483.2135.

[0265] 3-Iodo-N-methylbenzamide (220) Under an argon atmosphere, 3-iodobenzoic acid (400 mg, 1.61 mmol, 1.0 equiv.), DMAP (236 mg, 1.93 mmol, 1.2 equiv.), and HATU (734 mg, 1.93 mmol, 1.2 equiv.) were suspended in dry THF (16 mL), followed by the addition of DIPEA (336 μL, 1.93 mmol, 1.2 equiv.). The resulting suspension was stirred at room temperature for 20 min, and then methylamine hydrochloride (130 mg, 1.93 mmol, 1.2 equiv.) was added. The reaction mixture was stirred at room temperature for 30 min and concentrated to dryness. The residue was dissolved in DCM (50 mL), and the organic layer was washed with 1 M HCl (15 mL), HO (15 mL), a saturated solution of NaHCO (15 mL), HO (4 × 30 mL), and brine (30 mL). The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure to give compound 220 (328 mg, 78%) as a white solid, which was used in the next step without further purification. 1H NMR (250 MHz, DMSO-d₆) δ 8.52 (brs, 1H, NH), 8.17 (t, J = 1.6 Hz, 1H, CH), 7.85 (dddd, J = 10.8, 7.8, 1.7, 1.1 Hz, 2H, 2 x CH), 7.27 (td, J = 7.8, 0.4 Hz, 1H, CH), 2.77 (d, J = 4.6 Hz, 3H, CH₆). All spectral data are consistent with literature values found in Sun X. et al., Chem. Commun., 2020, 56, pp. 1298-1301.

[0266] 3-(3-aminophenoxy)-N-methylbenzamide (221) The reaction was carried out as described in General Procedure P using iodoaryl 220 (274 mg, 1.05 mmol, 1.0 equiv.), 3-aminophenol (138 mg, 1.26 mmol, 1.2 equiv.), copper(I) iodide (10 mg, 0.05 mmol, 5 mol%), 2-picolinic acid (14 mg, 0.11 mmol, 10 mol%), and KPO (446 mg, 2.10 mmol, 2.0 equiv.) in dry DMSO (2.1 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / MeOH 100 to 98 / 2 to afford compound 221 (184 mg, 72%) as an orange oil. f (DCM / MeOH 95 / 5) 0.29. 1H NMR (250 MHz, CDCl3) δ 7.44 (dt, J = 7.7, 1.4 Hz, 1H, CH), 7.38 - 7.35 (m, 1H, CH), 7.30 (t, J = 7.9 Hz, 1H, CH), 7.12 - 7.01 (m, 2H, 2 x CH), 6.57 (brs, 1H, NH), 6.40 (ddd, J = 8.0, 2.2, 0.9 Hz, 1H, CH), 6.34 (ddd, J = 8.0, 2.3, 0.9 Hz, 1H, CH), 6.26 (t, J = 2.2 Hz, 1H, CH), 3.73 (brs, 2H, NH2), 2.91 (d, J = 4.8 Hz, 3H, CH3). HRMS (EI-MS) m / z C 14 H 15 N2O2[M+H] + Calculated value: 243.1128, Measured value: 243.1132.

[0267] Example 111: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-(3-(methylcarbamoyl)phenoxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxamide (222) The reaction was carried out as described in general procedure H using aniline 221 (76 mg, 0.29 mmol, 1.0 equiv), 4-nitrophenyl chloroformate (70 mg, 0.35 mmol, 1.2 equiv), DIPEA (182 μL, 1.05 mmol, 2.4 equiv), and amine 4 (100 mg, 0.35 mmol, 1.2 equiv) in dry THF (4.0 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM / MeOH 98 / 2 to 95 / 5 to give compound 222 (57 mg, 41%) as a white powder. f (DCM / MeOH 95 / 5)0.3. Mp: Decomposition 190℃. 1H NMR (250 MHz, DMSO-d6) δ 11.84 (s, 1H, NH), 8.70 (brs, 1H, NH), 8.64 (s, 1H, CH), 8.47 (d, J = 4.7 Hz, 1H, NH), 7.60 (dt, J = 7.8, 1.3 Hz, 1H, CH), 7.54 - 7.42 (m, 2H, 2 x CH), 7.37 - 7.22 (m, 5H, 4 x CH), 7.17 (ddd, J = 8.0, 2.6, 1.1 Hz, 1H, CH), 6.67 - 6.61 (m, 1H, CH), 6.07- 5.99 (m, 1H, CH), 4.20 (d, HRMS (EI-MS) m / z C 27 H 27 N6O3[M+H] + Calculated value: 483.2139, Measured value: 483.2148.

[0268] Subfamily 1.2 3-Methylpyrrolopyrimidine derivatives with substituted hydropyridines

[0269] [ka]

[0270] [Table 2]

[0271] tert-Butyl 6-methyl-4-(1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylate (43a) and tert-butyl 2-methyl-4-(1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylate (43b) DBU (1.96 mL, 13.1 mmol, 1.4 equiv.) and perfluoro-1-butanesulfonyl fluoride (1.68 mL, 9.4 mmol) were added dropwise to a solution of N-Boc-2-methyl-piperidone (2.0 g, 9.4 mmol) in anhydrous THF (60 mL) at 0 °C under an argon atmosphere. The mixture was allowed to warm to room temperature and stirred overnight. The next day, TLC monitoring was performed to ensure complete conversion (if not, additional DBU (0.25 equiv.) and perfluoro-1-butanesulfonyl fluoride (0.5 equiv.) could be added every 1.5 h). The reaction mixture was then treated with a saturated aqueous solution of NaHCO (50 mL) and extracted with EtO (2 × 100 mL). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography using a gradient solvent system of PE / EtOAc 100 / 0 to 95 / 5 to give compounds 43a-43b (4.03 g, 87%) as a colorless oil containing a mixture of diastereoisomers (7 / 3). f (PE / EtOAc 70 / 30)0.37. Product 43a (main product) 1 H NMR (250 MHz, CDCl3) δ 5.72 (m, 1H, CH), 4.78 - 4.57 (m, 1H, CH), 4.32 - 4.15 (m, 1H, CH), 3.08 - 2.89 (m, 1H, CH), 2.67 - 2.48 (m, 1H, CH), 2.26 - 2.13 (m, 1H, CH), 1.47 (s, 9H, 3 xC H3), 1.23 (d, J = 6.8 Hz, 3H, CH3).Product 43b 1H NMR (250 MHz, CDCl3) δ 5.76 (m, 1H, CH), 4.78 - 4.57 (m, 1H, CH), 4.51 - 4.34 (m, 1H, CH), 3.63 (ddt, J = 18.8 Hz, J = 4.7 Hz, J = 2.5 Hz, 1H, CH), 2.87 - 2.72 (m, 1H, CH), 2.11 - 2.00 (m, 1H, CH), 1.46 (s, 9H, 3 x CH3), 1.17 (d, J = 6.9 Hz, 3H, CH3). HRMS (EI-MS) m / z C 15 H 19 F9NO5S [M+H] + Calculated value: 496.0835, Measured value: 496.0835.

[0272] tert-Butyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (44a) and tert-butyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (44b) To a solution of 43a-43b (5.0 g, 10.0 mmol) in 1,4-dioxane (50 mL) was added bis(pinacolato)diboron (2.9 g, 11.5 mmol, 1.15 equiv), potassium acetate (3.5 g, 35.2 mmol, 3.5 equiv), and dppf (170 mg, 0.3 mmol, 0.03 equiv). The solution was degassed for 15 min, and Pd(dppf)Cl·DCM (245 mg, 0.3 mmol, 0.03 equiv) was added. The mixture was then heated at 80 °C overnight, cooled, and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using a 95 / 5 solvent system of PE / EtOAc to give compounds 44a-44b (3.77 g, 83%) as a colorless oil containing a mixture of diastereoisomers (7 / 3). f(PE / EtOAc 90 / 10)0.19. Product 44a (main) 1 H NMR (250 MHz, CDCl3) δ 6.41 - 6.33 (m, 1H, CH), 4.53 - 4.34 (m, 1H, CH), 4.12 - 3.94 (m, 1H, CH), 2.82 - 2.63 (m, 1H, CH), 2.26 - 2.09 (m, 2H, 2 x CH), 1.44 (s, 9H, 3 x CH3), 1.25 (s, 12H, 4 x CH3), 1.17 (d, J = 6.9 Hz, 3H, CH3).Product 44b 1 H NMR (250 MHz, CDCl3) δ 6.48 - 6.42 (m, 1H, CH), 4.53 - 4.34 (m, 1H, CH), 4.20 (dt, J = 20.2 Hz, J = 3.8 Hz, 1H, CH), 3.66 - 3.51 (m, 1H, CH), 2.50 - 2.34 (m, 1H, CH), 2.09 - 1.98 (m, 1H, CH), 1.44 (s, 9H, 3 x CH3), 1.25 (s, 12H, 4 x CH3), 1.04 (d, J = 6.8 Hz, 3H, CH3). HRMS (EI-MS) m / z C 17 H 31 BNO4[M+H] + Calculated value: 324.2341, Measured value: 324.2342.

[0273] tert-Butyl 6-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (45a) and tert-butyl 2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (45b) The reaction was carried out as described in General Procedure D using chlorinated bicyclic compound 2 (0.4 g, 2.4 mmol) and boronic esters 44a-44b (850 mg, 2.6 mmol, 1.1 equiv.) in THF (12 mL). The crude mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 70 / 30 to give compounds 45a-45b (1.25 g, 80%) as a white solid containing a mixture of diastereoisomers (7 / 3). f (PE / EtOAc 70 / 30)0.18. Mp:161~163℃. Product 45a (main) 1 H NMR (250 MHz, MeOD-d4) δ 8.59 (s, 1H, CH), 7.18 (d, J = 1.0 Hz, 1H, CH), 5.90 - 5.86 (m, 1H, CH), 4.76 - 4.57 (m, 1H, CH), 4.22 (dd, J = 13.3 Hz, J = 4.8 Hz, 1H, CH), 3.21 - 3.00 (m, 1H, CH), 2.70 - 2.52 (m, 1H, CH), 2.51 - 2.37 (m, 1H, CH), 2.24 (d, J = 1.1 Hz, 3H, CH3), 1.49 (s, 9H, 3 x CH3), 1.31 (d, J = 6.8 Hz, 3H, CH3).Product 45b 1 H NMR (250 MHz, MeOD-d4) δ 8.59 (s, 1H, CH), 7.18 (d, J = 1.0 Hz, 1H, CH), 5.95 - 5.90 (m, 1H, CH), 4.76 - 4.57 (m, 1H, CH), 4.42 (dt, J = 19.5 Hz, J = 3.3 Hz, 1H, CH), 3.87 - 3.69 (m, 1H, CH), 2.94 - 2.77 (m, 1H, CH), 2.51 - 2.37 (m, 1H, CH), 2.24 (d, J = 1.1 Hz, 3H, CH3), 1.49 (s, 9H, 3xCH3), 1.25 (d, J = 6.8 Hz, 1H, CH3). HRMS (EI-MS) m / z C 18 H25 N4O2[M+H] + Calculated value: 329.1972, Measured value: 329.1972.

[0274] 5-Methyl-4-(6-methyl-1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate (46a) and 5-methyl-4-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate (46b) The reaction was carried out as described in General Procedure F2 using N-Boc protected compounds 45a-45b (0.6 g, 1.8 mmol) and TFA (4.9 mL, 63.9 mmol, 35.0 equiv.) in CHCl (50 mL). The reaction was complete after 1 h. Workup afforded compounds 46a-46b (0.44 g, 72%) as off-white solids containing a mixture of diastereoisomers (7 / 3). Mp: 199-201 °C. Product 46a (major) 1 H NMR (250 MHz, MeOD-d4) δ 8.60 (s, 1H, CH), 7.21 (d, J = 1.2 Hz, 1H, CH), 5.92 - 5.85 (m, 1H, CH), 3.70 - 3.58 (m, 1H, CH), 3.34 - 3.21 (m, 1H, CH), 3.10 - 2.95 (m, 1H, CH), 2.61 - 2.50 (m, 2H, 2 x CH), 2.32 (d, J = 1.2 Hz, 3H, CH3), 1.31 (d, J = 7.0 Hz, 3H, CH3). 19 F NMR (235 MHz, MeOD-d4) δ -76.9 (s).Product 46b 1H NMR (250 MHz, MeOD-d4) δ 8.60 (s, 1H, CH), 7.21 (d, J = 1.2 Hz, 1H, CH), 6.03 - 5.95 (m, 1H, CH), 3.70 - 3.58 (m, 1H, CH), 3.33 - 3.29 (m, 1H, CH), 3.10 - 2.95 (m, 1H, CH), 2.71 - 2.59 (m, 1H, CH), 2.30 (d, J = 1.2 Hz, 3H, CH3), 2.28 - 2.14 (m, 1H, CH), 1.26 (d, J = 7.0 Hz, 3H, CH3). 19 F NMR (235 MHz, MeOD-d4) δ -76.9 (s). HRMS (EI-MS) m / z C 13 H 18 N4[M+H] + Calculated value: 229.1448, Measured value: 229.1447.

[0275] Example 30: N-(3-fluorophenyl)-6-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (47a) and N-(3-fluorophenyl)-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (47b) The reaction was carried out as described in General Procedure G using amines 46a-46b (70 mg, 0.20 mmol) in anhydrous CHCl (5 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 70 / 30 to afford compounds 47a-47b (61 mg, 84%) as a white solid containing a mixture of diastereoisomers (7 / 3). f (CH2Cl2 / acetone 50 / 50) 0.28. Mp: 154-156°C. Product 47a (major) 11H NMR (400 MHz, MeOD-d4) δ 8.62 (s, 1H, CH), 7.32 (dt, J = 11.6 Hz, J = 2.2 Hz, 1H, CH), 7.29 - 7.22 (m, 2H, 2 x CH), 7.19 (ddd, J = 8.2 Hz, J = 2.1 Hz, J = 1.1 Hz, 1H, CH), 6.73 (tdd, J = 8.4 Hz, J = 2.5 Hz, J = 1.1 Hz, 1H, CH), 6.03 - 5.99 (m, 1H, CH), 4.96 - 4.88 (m, 1H, CH), 4.32 (dd, J = 13.7 Hz, J = 5.4 Hz, 1H, CH), 3.38 - 3.27 (m, 1H, CH), 2.83 - 2.69 (m, 1H, CH), 2.63 - 2.56 (m, 1H, CH), 2.32 (d, J = 1.2 Hz, 3H, CH3), 1.42 (d, J = 6.8 Hz, 3H, CH3). 19 19F NMR (376 MHz, MeOD-dz) δ -115.0 (s). Product 47b 1 1H NMR (400 MHz, MeOD-d4) δ 8.63 (s, 1H, CH), 7.32 (dt, J = 11.6 Hz, J = 2.2 Hz, 1H, CH), 7.29 - 7.22 (m, 2H, 2 x CH), 7.19 (ddd, J = 8.2 Hz, J = 2.1 Hz, J = 1.1 Hz, 1H, CH), 6.73 (tdd, J = 8.4 Hz, J = 2.5 Hz, J = 1.1 Hz, 1H, CH), 6.07 - 6.04 (m, 1H, CH), 4.87 - 4.79 (m, 1H, CH), 4.54 (dt, J = 19.0 Hz, J = 3.7 Hz, 1H, CH), 4.07 - 3.89 (m, 1H, CH), 3.07 - 2.92 (m, 1H, CH), 2.58 - 2.51 (m, 1H, CH), 2.32 (d, J = 1.2 Hz, 3H, CH3), 1.36 (d, J = 6.8 Hz, 3H, CH3). 19 It should be noted that in the original text, "MeOD-d4" is a deuterated solvent used in NMR experiments, and "MeOD-dz" in the translation of item seems to be a typo and should be "MeOD-d4". Also, the chemical shift values and coupling constants in NMR data are crucial for chemical structure determination and are accurately presented in the translation.F NMR (376 MHz, MeOD-d4) δ -76.9 (s). HRMS (EI-MS) m / z C 20 H 21 FN5O [M+H] + Calculated value: 366.1725, Measured value: 366.1723.

[0276] Example 31: N-(3-chlorophenyl)-6-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (48a) and N-(3-chlorophenyl)-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (48b) The reaction was carried out as described in general procedure G using amines 46a-46b (70 mg, 0.20 mmol) in anhydrous CHCl (5 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 70 / 30 to afford compounds 48a-48b (43 mg, 56%) as a white solid containing a diastereoisomeric mixture (7 / 3). f (CH2Cl2 / acetone 50 / 50) 0.31. Mp: 159-161°C. Product 48a (major) 11H NMR (400 MHz, MeOD-d4) δ 8.62 (s, 1H, CH), 7.56 (t, J = 2.0 Hz, 1H, CH), 7.36 - 7.30 (m, 1H, CH), 7.27 - 7.19 (m, 2H, 2 x CH), 7.04 - 6.93 (m, 1H, CH), 6.02 - 5.97 (m, 1H, CH), 4.97 - 4.86 (m, 1H, CH), 4.31 (dd, J = 13.7 Hz, J = 5.3 Hz, 1H, CH), 3.38 - 3.26 (d, J = 3.8 Hz, 1H, CH), 2.83 - 2.69 (m, 1H, CH), 2.63 - 2.57 (m, 1H, CH), 2.34 - 2.29 (m, 3H, CH3), 1.42 (d, J = 6.7 Hz, 3H, CH3). Product 48b 1 1H NMR (400 MHz, MeOD-d4) δ 8.63 (s, 1H, CH), 7.56 (t, J = 2.0 Hz, 1H, CH), 7.36 - 7.30 (m, 1H, CH), 7.27 - 7.19 (m, 2H, 2 x CH), 7.04 - 6.93 (m, 1H, CH), 6.08 - 6.03 (m, 1H, CH), 4.85 - 4.77 (m, 1H, CH), 4.54 (dt, J = 18.9 Hz, J = 3.6 Hz, 1H, CH), 4.03 - 3.91 (m, 1H, CH), 3.05 - 2.94 (m, 1H, CH), 2.57 - 2.50 (m, 1H, CH), 2.34 - 2.29 (m, 3H, CH3), 1.36 (d, J = 6.7 Hz, 3H, CH3). HRMS (EI-MS) m / z C 20 H 21 ClN5O [M+H] + Calculated value: 382.1429, Measured value: 382.1426.

[0277] Example 32: N-(3-bromophenyl)-6-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (49a) and N-(3-bromophenyl)-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (49b) The reaction was carried out as described in general procedure G using amines 46a-46b (70 mg, 0.20 mmol) in anhydrous CHCl (5 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 70 / 30 to afford compounds 49a-49b (61 mg, 71%) as a white solid containing a mixture of diastereoisomers (7 / 3). f (CH2Cl2 / acetone 50 / 50) 0.31. Mp: 159-161°C. Product 49a (major) 1 H NMR (400 MHz, MeOD-d4) δ 8.62 (s, 1H, CH), 7.72 - 7.70 (m, 1H, CH), 7.37 (dt, J = 7.3 Hz, J = 2.1 Hz, 1H, CH), 7.25 - 7.22 (m, 1H, CH), 7.21 - 7.13 (m, 2H, 2 x CH), 6.03 - 5.99 (m, 1H, CH), 4.96 - 4.88 (m, 1H, CH), 4.31 (dd, J = 13.7 Hz, J = 5.3 Hz, 1H, CH), 3.38 - 3.26 (m, 1H, CH), 2.82 - 2.69 (m, 1H, CH), 2.64 - 2.51 (m, 1H, CH), 2.32 (d, J = 1.3 Hz, 3H, CH3), 1.42 (d, J = 6.7 Hz, 3H, CH3).Product 49b 1H NMR (400 MHz, MeOD-d4) δ 8.63 (s, 1H, CH), 7.72 - 7.70 (m, 1H, CH), 7.37 (dt, J = 7.3 Hz, J = 2.1 Hz, 1H, CH), 7.25 - 7.22 (m, 1H, CH), 7.21 - 7.13 (m, 2H, 2 x CH), 6.08 - 6.03 (m, 1H, CH), 4.87 - 4.74 (m, 1H, CH), 4.54 (dt, J = 18.9 Hz, J = 3.6 Hz, 1H, CH), 4.04 - 3.92 (m, 1H, CH), 3.06 - 2.93 (m, 1H, CH), 2.64 - 2.51 (m, 1H, CH), 2.32 (m, 3H, CH3), 1.36 (d, J = 6.8 Hz, 3H, CH3). HRMS (EI-MS) m / z C 20 H 21 BrNO [M+H] + Calculated value: 426.0924, Measured value: 426.0921.

[0278] Dimethyl 2,6-dimethyl-4-oxopiperidine-3,5-dicarboxylate (50) Ammonia gas was bubbled through a mixture of dimethyl-1,3-acetonedicarboxylate (19.0 g, 109 mmol) and acetaldehyde (12.5 mL, 284 mmol, 2.6 equiv.) at -30 °C until the liquid was saturated. The solution was stored in a freezer (4 °C) for 20 h. After evaporation of the solvent under reduced pressure, the yellow residue was purified by silica gel column chromatography using a gradient solvent system of PE / EtOAc (100 / 0 to 70 / 30) to give compound 50 (14.0 g, 53%) as an orange oil. 1 H NMR (250 MHz, CDCl3) δ 3.74 - 3.65 (m, 8H, 2 x CH + 2 x OCH3), 2.97 - 2.91 (m, 2H, 2 x CH), 1.26 - 1.23 (d, J = 6.6 Hz, 3H, CH3), 1.15 - 1.09 (d, J = 6.6 Hz, 3H, CH3) (See International Publication 2015158283, 2015, p. 172).

[0279] 2,6-Dimethylpiperidin-4-one hydrochloride (51) A solution of 50 (14.0 g, 65 mmol) in 10% aqueous HCl (100 mL) was heated to 110° C. for 24 h. The solution was cooled and the solvent was removed under reduced pressure to give compound 51 (8.5 g, 80%) as an orange solid, which was used in the next step without further purification. 1 H NMR (250 MHz, DMSO-d6) δ 10.11 - 9.79 (m, 2H, NH + H + ), 3.91 - 3.74 (m, 1H, CH), 3.61 - 3.43 (m, 1H, CH), 2.77 - 2.60 (m, 2H, CH2), 2.48 - 2.35 (m, 2H, CH2), 1.35 (d, J = 6.4 Hz, 3H, CH3), 1.30 (d, J = 6.7 Hz, 3H, CH3). International Publication 2015158283, 2015, 172 pages.

[0280] tert-Butyl 2,6-dimethyl-4-oxopiperidine-1-carboxylate (52) Na2CO3 (11.0 g, 104 mmol, 2.0 equiv.) was added portionwise to a solution of 51 (8.5 g, 52 mmol) in 1,4-dioxane (70 mL) and HO (70 mL). Then, Boc2O (22.7 g, 104 mmol, 2.0 equiv.) was added, and the resulting reaction mixture was stirred at room temperature for 24 h. The solvent was removed under reduced pressure, and the resulting aqueous solution was extracted with Et2O (3 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude mixture was purified by silica gel column chromatography using a gradient solvent system of PE / EtOAc 97 / 3 to 80 / 20 to give compound 122 52 (2.5 g, 21%) as an off-white solid containing a mixture of diastereoisomers (trans / cis, 9 / 1). The major isomer (trans) 52: 1 H NMR (250 MHz, CDCl3) δ 4.44 - 4.23 (m, 2H, 2 x CH), 2.83 (dd, J = 17.8 Hz, J = 6.4 Hz, 2H, 2 x CH), 2.35 (dd, J = 17.8 Hz, J = 1.9 Hz, 2H, 2 x CH), 1.48 (s, 9H, 3 x CH3), 1.23 (dd, J = 6.8 Hz, J = 0.7 Hz, 6H, 2 x CH3). International Publication 2015158283, 2015, 172 pages.

[0281] tert-Butyl 2,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-pyridine-1(2H)-carboxylate (53) A 1 M solution of NaHMDS in THF (5.7 mL, 5.72 mmol, 1.3 equiv) was added dropwise to a solution of 52 (1.0 g, 4.40 mmol) in anhydrous THF (25 mL) at −78 °C under argon. The solution was stirred at this temperature for 1 h, and then a solution of N-phenyl-bis(trifluoromethanesulfonimide) (1.89 g, 5.28 mmol, 1.2 equiv) in THF (12 mL) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 2.5 h. The solvent was removed under reduced pressure, and the residue was taken up in EtO (40 mL) and washed with cold water (2 × 10 mL). The ether layer was dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a solvent system of PE / EtOAc 99 / 1 to give compound 53 (0.98 g, 62%) as an off-white solid containing the trans product as a mixture of enantiomers. 1 H NMR (250 MHz, CDCl3) δ 5.82 - 5.77 (m, 1H, CH), 4.42 - 4.27 (m, 2H, 2 x CH), 2.91 - 2.77 (m, 1H, CH), 2.17 (dd, J = 16.5 Hz, J = 2.8 Hz, 1H, CH), 1.48 (s, 9H, 3 x CH3), 1.36 (d, J = 6.3 Hz, 3H, CH3), 1.25 - 1.21 (d, J = 6.3 Hz, 3H, CH3). Heterocycles, 1996, 43, 10, pp. 2131-2138.

[0282] tert-Butyl 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (54) To a solution of 53 (1.0 g, 2.78 mmol) in 1,4-dioxane (20 mL) was added bis(pinacolato)diboron (0.78 g, 3.06 mmol, 1.1 equiv), potassium acetate (0.82 g, 8.34 mmol, 3.0 equiv), and dppf (46 mg, 0.08 mmol, 0.03 equiv). The solution was degassed for 15 min, and Pd(dppf)Cl·CHCl (68 mg, 0.08 mmol, 0.03 equiv) was added. The mixture was then heated to 80 °C for 12 h, cooled, and extracted with EtOAc (2 × 100 mL). The organic layer was washed with brine (100 mL), dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient solvent system of PE / EtOAc 95 / 5 to 70 / 30 to give compound 54 (0.72 g, 77%) as a white solid containing the trans product as a mixture of enantiomers. 1 H NMR (250 MHz, CDCl3) δ 6.55 (dd, J = 5.0 Hz, J = 2.9 Hz, 1H CH), 4.25 - 4.03 (m, 2H, 2 x CH), 2.41 - 2.27 (m, 1H, CH), 2.14 (ddd, J = 16.0 Hz, J = 2.4 Hz, J = 0.9 Hz, 1H, CH), 1.44 (s, 9H, 3 x CH3), 1.26 - 1.21 (m, 15H, 5xCH3), 1.02 (dd, J = 6.5 Hz, J = 0.6 Hz, 3H, CH3).International Publication 2008016534, 2008, 133 pages.

[0283] tert-Butyl 2,6-dimethyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (55) The reaction was carried out as described in general procedure D using chlorinated bicyclic compound 2 (0.30 g, 1.80 mmol) and boronic acid pinacol ester 54 (0.67 g, 1.98 mmol, 1.1 equiv.) in THF (9 mL). The crude mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 70 / 30 to give compound 55 (0.43 g, 70%) as a beige solid containing the trans product as a mixture of enantiomers. f (CH2Cl2 / acetone 80 / 20) 0.26. Mp: decomposition 119°C. 1 H NMR (400 MHz, CDCl3) δ 9.81 (br s, 1H, NH), 8.81 (s, 1H, CH), 7.19 - 6.97 (m, 1H, CH), 6.17 (dd, J = 5.2 Hz, J = 2.8 Hz, 1H, CH), 4.51 - 4.40 (m, 2H, 2 x CH), 3.06 - 2.95 (m, 1H, CH), 2.67 (dd, J = 15.9 Hz, J = 2.4 Hz, 1H, CH), 2.35 (d, J = 1.2 Hz, 3H, CH3), 1.52 (s, 9H, 3xCH3), 1.43 (d, J = 6.4 Hz, 3H, CH3), 1.28 (d, J = 6.2 Hz, 3H, CH3). HRMS (EI-MS) m / z C 19 H 27 N4O2[M+H] + Calculated value: 343.2129, Measured value: 343.2128.

[0284] 4-(2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-methyl-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate (56) The reaction was carried out as described in General Procedure F1 using N-Boc protected compound 55 (0.4 g, 1.17 mmol) in CHCl (32 mL). The reaction was complete after 1 h. Workup afforded compound 56 (0.31 g, 74%) as a pale yellow solid containing the trans product as a mixture of enantiomers. Mp: decomposition 136 °C. 1 H NMR (400 MHz, DMSO-d6) δ 11.80 (br s, 1H, NH), 8.60 (s, 1H, CH), 7.29 (s, 1H, CH), 5.93 (s, 1H, CH), 3.74 (s, 1H, CH), 3.63 (s, 2H, NH + H + ), 3.22 (s, 1H, CH), 2.60 - 2.53 (m, 1H, CH), 2.29 - 2.19 (m, 4H, CH + CH3), 1.23 (d, J = 6.9 Hz, 3H, CH3), 1.16 (d, J = 5.6 Hz, 3H, CH3). 19 F NMR (376 MHz, DMSO-d6) δ -73.5 (s). HRMS (EI-MS) m / z C 14 H 19 N4[M+H] + Calculated value: 243.1604, Measured value: 243.1603.

[0285] Example 33: N-(3-fluorophenyl)-2,6-dimethyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (57) The reaction was carried out as described in general procedure G using amine 56 (60 mg, 0.25 mmol) in anhydrous CHCl (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 30 / 70 to give compound 57 (51 mg, 54%) as a white solid containing the trans product as a mixture of enantiomers. f(CH2Cl2 / acetone 80 / 20) 0.11. Mp: 210-212°C. 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (br s, 1H, NH), 8.87 (br s, 1H, NH), 8.67 (s, 1H, CH), 7.48 (d, J = 12.0 Hz, 1H, CH), 7.34 (s, 1H, CH), 7.32 - 7.24 (m, 2H, 2 x CH), 6.75 (t, J = 8.1 Hz, 1H, CH), 6.24 - 6.12 (m, 1H, CH), 4.60 - 4.55 (m, 1H, CH), 4.55 - 4.48 (m, 1H, CH), 2.95 (d, J = 14.8 Hz, 1H, CH), 2.72 (d, J = 16.0 Hz, 1H, CH), 2.29 (s, 3H, CH3), 1.37 (d, J = 6.3 Hz, 3H, CH3), 1.19 (d, J = 6.3 Hz, 3H, CH3). 19 F NMR (376 MHz, DMSO-d6) δ -112.9 (s). HRMS (EI-MS) m / z C 21 H 23 FN5O [M+H] + Calculated value: 380.1881, Measured value: 380.1880.

[0286] Example 34: N-(3-chlorophenyl)-2,6-dimethyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (58) The reaction was carried out as described in general procedure G using amine 56 (60 mg, 0.25 mmol) in anhydrous CHCl (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 30 / 70 to give compound 58 (72 mg, 73%) as a white solid containing the trans product as a mixture of enantiomers. f (CH2Cl2 / acetone 80 / 20) 0.10. Mp: 240-242°C.1 H NMR (400 MHz, DMSO-d6) δ 11.84 (br s, 1H, NH), 8.84 (br s, 1H, NH), 8.67 (s, 1H, CH), 7.70 (s, 1H, CH), 7.44 (d, J = 8.3 Hz, 1H, CH), 7.34 (s, 1H, CH), 7.27 (t, J = 8.1 Hz, 1H, CH), 6.99 (d, J = 7.9 Hz, 1H, CH), 6.23 - 6.10 (m, 1H, CH), 4.61 - 4.55 (m, 1H, CH), 4.55 - 4.49 (m, 1H, CH), 2.95 (d, J = 17.5 Hz, HRMS (EI-MS) m / z C 21 H 23 ClNO [M+H] + Calculated value: 396.1586, Measured value: 396.1585.

[0287] Example 35: N-(3-bromophenyl)-2,6-dimethyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (59) The reaction was carried out as described in general procedure G using amine 56 (60 mg, 0.25 mmol) in anhydrous CHCl (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 30 / 70 to give compound 59 (77 mg, 71%) as a white solid containing the trans product as a mixture of enantiomers. f (CH2Cl2 / acetone 80 / 20) 0.11. Mp: 238-240°C. 1H NMR (400 MHz, DMSO-d6) δ 11.84 (br s, 1H, NH), 8.83 (br s, 1H, NH), 8.67 (s, 1H, CH), 7.84 (t, J = 2.0 Hz, 1H, CH), 7.49 (d, J = 8.2 Hz, 1H, CH), 7.33 (s, 1H, CH), 7.21 (t, J = 8.0 Hz, 1H, CH), 7.12 (d, J = 8.0 Hz, 1H, CH), 6.22 - 6.11 (m, 1H, CH), 4.64 - 4.47 (m, 2H, 2 x CH), 3.00 - 2.88 (m, 1H, CH), 2.72 (d, J HRMS (EI-MS) m / z C 21 H 23 BrNO [M+H] + Calculated value: 440.1080, Measured value: 440.1081.

[0288] Example 36: 2,6-dimethyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-phenoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxamide (60) The reaction was carried out as described in general procedure G using amine 56 (60 mg, 0.25 mmol) in anhydrous CHCl (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 30 / 70 to give compound 60 (56 mg, 49%) as a white solid containing the trans product as a mixture of enantiomers. f (CH2Cl2 / acetone 80 / 20) 0.15. Mp: 212-214°C. 1H NMR (400 MHz, DMSO-d6) δ 11.84 (br s, 1H, NH), 8.76 (br s, 1H, NH), 8.66 (s, 1H, CH), 7.47 - 7.22 (m, 6H, 6xCH), 7.13 (t, J = 7.2 Hz, 1H, CH), 7.02 (d, J = 7.9 Hz, 2H, 2 x CH), 6.60 (d, J = 8.0 Hz, 1H, CH), 6.15 (s, 1H, CH), 4.62 - 4.52 (m, 1H, CH), 4.52 - 4.44 (m, 1H, CH), 2.92 (d, J = 15.9 Hz, 1H, CH), 2.69 (d, J = 16.1 Hz, 1H, CH), 2.28 (s, 3H, CH3), 1.34 (d, J = 6.2 Hz, 3H, CH3), 1.17 (d, J = 6.3 Hz, 3H, CH3). HRMS (EI-MS) m / z C 27 H 28 NO2[M+H] + Calculated value: 454.2238, Measured value: 454.2238.

[0289] Family 2. Unsubstituted pyrrolopyrimidine derivatives with hydropyridine

[0290] [ka]

[0291] [Table 3]

[0292] tert-Butyl 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (61) The reaction was carried out as described in General Procedure D using 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.60 g, 3.91 mmol) and N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1.3 g, 4.30 mmol, 1.1 equiv.) in THF (10 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 50 / 50. To remove the final impurity, the product was precipitated in a mixture of acetone / pentane to give compound 61 (0.85 g, 72%) as a pale yellow solid. f (CH2Cl2 / acetone 70 / 30) 0.43. Mp: 159-161°C. 1 H NMR (400 MHz, MeOD-d4) δ 8.64 (s, 1H, CH), 7.42 (d, J = 3.7 Hz, 1H, CH), 6.77 - 6.73 (m, 1H, CH), 6.72 (d, J = 3.6 Hz, 1H, CH), 4.21 - 4.15 (m, HRMS (EI-MS) m / z C 16 H 21 N4O2[M+H] + Calculated value: 301.1659, Measured value: 301.1659.

[0293] 4-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (62) The reaction was carried out as described in General Procedure J using N-Boc-protected compound 61 (100 mg, 0.28 mmol). The reaction mixture was stirred at room temperature for 1 h. After completion, EtO (20 mL) was added, and the resulting precipitate was filtered and washed with EtO (3 × 10 mL) to give compound 62 (87 mg, 96%) as a light brown solid, MP: decomposition >260 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.91 (br s, 1H, NH), 9.63 (br s, 2H, NH + H + ), 8.98 - 8.82 (m, 1H, CH), 7.93 - 7.76 (s, 1H, CH), 7.07 - 6.91 (m, 2H, 2 x CH), 4.57 - 4.08 (m, 1H, H + ), 3.96 - 3.86 (s, 2H, CH2), 3.44 - 3.26 (s, 2H, CH2), 3.12 - 2.87 (s, 2H, CH2). HRMS (EI-MS) m / z C 11 H 13 N4[M+H] + Calculated value: 201.1135, Measured value: 201.1135.

[0294] Example 37: N-(3-chlorophenyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydro-pyridine-1(2H)-carboxamide (63) The reaction was carried out as described in general procedure G using amine 62 (70 mg, 0.26 mmol). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 50 / 50 to give compound 63 (64 mg, 71%) as a white solid. f (CH2Cl2 / acetone 50 / 50) 0.29. Mp: decomposition 122°C. 1H NMR (250 MHz, MeOD-d4) δ 8.68 (s, 1H, CH), 7.57 (t, J = 2.0 Hz, 1H, CH), 7.48 (d, J = 3.6 Hz, 1H, CH), 7.33 (ddd, J = 8.2 Hz, J = 2.0 Hz, J = 1.2 Hz, 1H, CH), 7.24 (t, J = 8.0 Hz, 1H, CH), 7.01 (ddd, J = 7.7 Hz, J = 2.1 Hz, J = 1.2 Hz, 1H, CH), 6.90 - 6.83 (m, 1H, CH), 6.82 (d, J = 3.6 Hz, 1H, CH), 4.41 - 4.28 (m, 2H, HRMS (EI-MS) m / z C 18 H 17 ClNO [M+H] + Calculated value: 354.1116, Measured value: 354.1114.

[0295] Family 3. 3-Chloropyrropyrimidine derivatives with hydropyridine

[0296] [ka]

[0297] [Table 4]

[0298] tert-Butyl 4-(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (64) To a solution of 61 (500 mg, 1.66 mmol) in anhydrous DMF (0.047 M) was added N-chlorosuccinimide (222 mg, 1.66 mmol, 1.0 equiv). The reaction mixture was heated to 70 °C and stirred for 4 h until completion (TLC monitoring). After cooling, it was poured into water and the aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (4 × 200 mL) and saturated sodium thiosulfate solution, dried over MgSO, filtered, and concentrated. The residue was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 60 / 40 to give compound 64 (340 mg, 61%) as a white solid. f (CH2Cl2 / acetone 70 / 30) 0.41. Mp: decomposition 189°C. 1 H NMR (250 MHz, MeOD-d4) δ 8.69 (s, 1H, CH), 7.51 (s, 1H, CH), 6.11 (s, 1H, CH), 4.17 (q, J = 2.8 Hz, 2H, CH2), 3.71 (t, J = 5.6 Hz, 2H, CH2), 2.66 (m, 2H, CH2), 1.50 (s, 9H, CH3). HRMS (EI-MS) m / z C 16 H 20 ClN4O2[M+H] + Calculated value: 335.1269, Measured value: 335.1272.

[0299] 5-Chloro-4-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (65) The reaction was carried out as described in general procedure J using 64 (250 mg, 0.75 mmol). The desired product 65 (195 mg, 85%) was obtained as a white solid. f (CH2Cl2 / MeOH 80 / 20)0.03. Mp: Decomposition>266℃. 1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H, NH), 9.70 (s, 2H, NH2(sel)), 8.88 (s, 1H, CH), 7.95 (s, 1H, CH), 6.27 (s, 1H, CH), 3.86 (s, 2H, CH2), 3.42 - 3.21 (s, 2H, CH2), 2.88 (s, 2H, CH2). HRMS (EI-MS) m / z C 11 H 12 ClN4[M+H] + Calculated value: 235.0745, Measured value: 235.0743.

[0300] Example 38: [3-[[4-(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carbonyl]amino]phenyl]N,N-dimethylcarbamate (66) The reaction was carried out as described in general procedure H using 3-aminophenyldimethylcarbamate (24 mg, 0.14 mmol) and 65 (50 mg, 0.16 mmol, 1.2 equiv.). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 10 / 0 to 60 / 40 to give compound 66 (42 mg, 70%) as a white solid. f (CH2Cl2 / acetone 50 / 50) 0.25. Mp: decomposition 132°C. 1H NMR (250 MHz, DMSO-d6) δ 12.53 (s, 1H, NH), 8.77 (s, 1H, CH), 8.69 (s, 1H, NH), 7.79 (t, J = 2.1 Hz, 1H, CH), 7.42 - 7.28 (m, 2H, 2 x CH), 7.22 (t, J = 8.0 Hz, 1H, CH), 6.69 (d, J = 8.3 Hz, 1H, CH), 6.22 (s, 1H, CH), 4.25 (s, 2H, CH2), 3.73 (t, J = 5.5 Hz, 2H, CH2), 3.03 (s, 3H, NCH3), 2.90 (s, 3H, NCH3), 2.71 (s, 2H, CH2). HRMS (EI-MS) m / z C 21 H 22 ClN6O3[M+H] + Calculated value: 441.1436, Measured value: 441.1436.

[0301] Family 4. 3-Cyclopropylpyrrolopyrimidine derivatives with unsubstituted hydropyridines.

[0302] [ka]

[0303] [Table 5]

[0304] tert-Butyl 4-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (67) Under an argon atmosphere, NIS (1.10 g, 4.89 mmol, 1.05 equiv.) was added to a solution of 1461 (1.40 g, 4.66 mmol) in anhydrous DMF (25 mL) at 0 °C. The mixture was stirred at this temperature for 20 minutes and allowed to warm to room temperature. The solution was poured onto ice (50 g) and the aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with a saturated solution of NaCl (4 × 50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was dissolved in a minimum amount of acetone, precipitated with pentane, and filtered to give compound 67 (1.79 g, 90%) as a light brown solid. R f (CH2Cl2 / acetone 70 / 30) 0.16. Mp: 151-153°C. 1 H NMR (400 MHz, MeOD-d4) δ 8.67 (s, 1H, CH), 7.61 (s, 1H, CH), 6.02 - 5.92 (m, 1H, CH), 4.25 - 4.14 (m, 2H, CH2), 3.73 (t, J = 5.6 Hz, 2H, CH2), 2.62 - 2.52 (m, 2H, CH2), 1.49 (s, 9H, 3 x CH3). HRMS (EI-MS) m / z C 16 H 20 IN4O2[M+H] + Calculated value: 427.0625, Measured value: 427.0626.

[0305] tert-Butyl 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,6-dihydro-pyridine-1(2H)-carboxylate (68) NaH (60% dispersion in mineral oil, 0.18 g, 4.50 mmol, 1.2 equiv.) was added to a solution of the iodide derivative 67 (1.60 g, 3.75 mmol) in anhydrous THF (35 mL) at room temperature under an argon atmosphere. After stirring the solution for 30 min, p-toluenesulfonyl chloride (0.79 g, 4.13 mmol, 1.1 equiv.) was added. Stirring was continued overnight. Upon completion, the reaction was quenched with HO (20 mL), and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with a saturated solution of NaCl (100 mL), dried over MgSO, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE / EtOAc 100 / 0 to 50 / 50 to give compound 68 (1.78 g, 82%) as a white solid. f (CH2Cl2 / acetone 70 / 30) 0.91. Mp: 183-185°C. 1 H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H, CH), 8.21 (s, 1H, CH), 8.07 (d, J = 8.4 Hz, 2H, 2 x CH), 7.47 (d, J = 8.2 Hz, 2H, 2 x CH), 6.11 - 5.96 (m, HRMS (EI-MS) m / z C 23 H 26 IN4O4S [M+H] + Calculated value: 581.0714, Measured value: 581.0712.

[0306] tert-Butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (69) A microwave vial was charged with a magnetic stir bar, compound 68 (0.70 g, 1.21 mmol), cyclopropylboronic acid (0.26 g, 3.05 mmol, 2.5 equiv), KPO (0.90 g, 4.24 mmol, 3.5 equiv), P(Cy) (68 mg, 0.24 mmol, 0.2 equiv), toluene (15 mL), and HO (1.5 mL). The solution was degassed with argon for 15 minutes while stirring. Pd(OAc) (27 mg, 0.12 mmol, 0.1 equiv) was added to the solution, the tube was sealed, and the reaction mixture was heated at 140 °C under microwave irradiation for 1 hour. After cooling, cyclopropylboronic acid (0.10 g, 1.21 mmol, 1.0 equiv) was added, and the reaction mixture was stirred at 140 °C under microwave irradiation for 30 minutes. After completion, HO (30 mL) was added and the aqueous phase was extracted with CHCl (2×100 mL). The combined organic layers were washed with a saturated solution of NaCl (50 mL), dried over MgSO, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 60 / 40 to afford compound 69 (0.36 g, 60%) as a beige solid. f (CH2Cl2 / acetone 70 / 30) 0.90. Mp: decomposition 90°C. 1 H NMR (400 MHz, MeOD-d4) δ 8.77 (s, 1H, CH), 8.03 (d, J = 8.4 Hz, 2H, 2 x CH), 7.55 (d, J = 1.3 Hz, 1H, CH), 7.37 (d, J = 8.1 Hz, 2H, 2 x CH), 6.20 - 6.05 (m, 1H, CH), 4.18 - 4.06 (m, 2H, CH2), 3.68 (t, J = 5.6 Hz, 2H, CH2), 2.65 - 2.57 (m, 2H, CH2), 2.37 (s, 3H, CH3), 1.85 - 1.75 (m, 1H, CH), 1.48 (s, 9H, 3 x CH3), 0.99 - 0.83 (m, 2H, CH2), 0.72 - 0.61 (m, 2H, CH2). HRMS (EI-MS) m / z C 26 H 31 N4O4S [M+H] + Calculated value: 495.2061, Measured value: 495.2058.

[0307] 5-Cyclopropyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (70) To a solution of 69 (0.30 g, 0.61 mmol) in THF / HO (12 mL, 5:1) was added KOH (0.31 g, 5.46 mmol, 9.0 equiv). The reaction mixture was heated to reflux for 24 h. After cooling, the solution was extracted with CHCl (2 × 50 mL), and the combined organic layers were washed with a saturated solution of NaCl (30 mL), dried over MgSO, filtered, and concentrated under reduced pressure. The residue was taken up in CHCl (20 mL), the solution was cooled to 0 °C, and TFA (1.6 mL, 21.35 mmol, 35.0 equiv) was added. The mixture was stirred at room temperature for 2 h. Excess TFA was removed under reduced pressure. The residue was taken up in CHCl (10 mL), and 2 M aqueous NaOH (3 mL) was added. The mixture was stirred for 30 min and extracted with CHCl (30 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give 70 (125 mg, 85%) as a white solid. Mp: 184-186 °C. 1 H NMR (400 MHz, MeOD-d4) δ 8.60 (s, 1H, CH), 7.13 (d, J = 1.1 Hz, 1H, CH), 6.25 - 6.15 (m, 1H, CH), 3.58 - 3.51 (m, 2H, CH2), 3.14 (t, J = 5.7 Hz, HRMS (EI-MS) m / z C 14 H 17 N4[M+H] + Calculated value: 241.1448, Measured value: 241.1447.

[0308] Example 39: 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-fluoro-phenyl)-5,6-dihydropyridine-1(2H)-carboxamide (71) The reaction was carried out as described in general procedure G using amine 70 (50 mg, 0.21 mmol) and 3-fluorophenyl isocyanate (26 μL, 0.23 mmol, 1.1 equiv.) in anhydrous CHCl (5 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 30 / 70 to give compound 71 (44 mg, 56%) as a white solid. f (CH2Cl2 / acetone 50 / 50) 0.28. Mp: 149-151°C. 1 H NMR (250 MHz, MeOD-d4) δ 8.63 (s, 1H, CH), 7.41 - 7.12 (m, 4H, 4 x CH), 6.81 - 6.67 (m, 1H, CH), 6.29 - 6.17 (m, 1H, CH), 4.36 - 4.21 (m, 2H, CH2), 3.85 (t, J = 5.6 Hz, 2H, CH2), 2.86 - 2.70 (m, 2H, CH2), 1.95 - 1.77 (m, 1H, CH2), 0.99 - 0.77 (m, 2H, CH2), 0.67 - 0.51 (m, 2H, CH2). 19 F NMR (235 MHz, MeOD-d4) δ -114.87 - -115.04 (m). HRMS (EI-MS) m / z C 21 H 21 FN5O [M+H] + Calculated value: 378.1725, Measured value: 378.1724.

[0309] Example 40: N-(3-chlorophenyl)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxamide (72) The reaction was carried out as described in general procedure G using amine 70 (50 mg, 0.21 mmol) and 3-chlorophenyl isocyanate (28 μL, 0.23 mmol, 1.1 equiv.) in anhydrous CHCl (5 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 30 / 70 to give compound 72 (55 mg, 67%) as a white solid. f (CH2Cl2 / acetone 50 / 50) 0.28. Mp: 174-176°C. 1 H NMR (400 MHz, MeOD-d4) δ 8.63 (s, 1H, CH), 7.55 (t, J = 2.1 Hz, 1H, CH), 7.31 (d, J = 8.2 Hz, 1H, CH), 7.24 (t, J = 8.0 Hz, 1H, CH), 7.16 (s, 1H, CH), 7.01 (d, J = 7.2 Hz, 1H, CH), 6.25 - 6.19 (m, 1H, CH), 4.36 - 4.23 (m, 2H, CH2), 3.85 (t, J = 5.6 Hz, 2H, CH2), 2.84 - 2.71 (m, 2H, CH2), 1.93 - 1.77 (m, 1H, CH), 0.90 - 0.83 (m, 2H, CH2), 0.64 - 0.57 (m, 2H, CH2). HRMS (EI-MS) m / z C 21 H 21 ClNO [M+H] + Calculated value: 394.1429, Measured value: 394.1426.

[0310] Example 41: N-(3-bromophenyl)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxamide (73) The reaction was carried out as described in general procedure G using amine 70 (50 mg, 0.21 mmol) and 3-bromophenyl isocyanate (29 μL, 0.23 mmol, 1.1 equiv.) in anhydrous CHCl (5 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 30 / 70 to give compound 73 (46 mg, 50%) as a white solid. f (CH2Cl2 / acetone 50 / 50) 0.28. Mp: 179-181°C. 1 H NMR (250 MHz, MeOD-d4) δ 8.63 (s, 1H, CH), 7.74 - 7.66 (m, 1H, CH), 7.40 - 7.32 (m, 1H, CH), 7.23 - 7.11 (m, 3H, CH + 2 x CH), 6.25 - 6.19 (m, 1H, CH), 4.34 - 4.23 (m, 2H, CH2), 3.85 (t, J = 5.6 Hz, 2H, CH2), 2.85 - 2.70 (m, 2H, CH2), 1.95 - 1.78 (m, 1H, CH), 0.94 - 0.78 (m, 2H, CH2), 0.67 - 0.54 (m, 2H, CH2). HRMS (EI-MS) m / z C 21 H 21 BrNO [M+H] + Calculated value: 438.0924, Measured value: 438.0922.

[0311] Example 42: 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-phenylphenyl)-3,6-dihydropyridine-1(2H)-carboxamide (74) The reaction was carried out as described in general procedure H using 1,1'-biphenyl]-3-amine (31 μL, 0.25 mmol) and amine 70.HCl (37 mg, 0.12 mmol, 1.2 equiv.) in anhydrous THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 40 / 60 to give the desired compound 74 (25 mg, 48%) as a yellow solid. f (CH2Cl2 / acetone 40 / 60) 0.3. Mp: decomposition 145°C. 1 H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H, NH), 8.73 - 8.57 (m, 2H, NH + CH), 7.82 (s, 1H, CH), 7.62 (d, J = 7.6 Hz, 2H, 2 x CH), 7.54 (d, J = 8.0 Hz, 1H, CH), 7.47 (t, J = 7.5 Hz, 2H, 2 x CH), 7.35 (q, J = 7.8 Hz, 2H, 2 x CH), 7.27 - 7.22 (m, 2H, 2 x CH), 6.29 (s, 1H, CH), 4.25 (s, 2H, CH2), 3.77 (t, J = 5.5 Hz, 2H, HRMS (EI-MS) m / z C 27 H 26 NO[M+H] + Calculated value: 436.2132, Measured value: 436.2130.

[0312] Example 43: [3-[[4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carbonyl]amino]phenyl]N,N-dimethylcarbamate (75) The reaction was carried out as described in general procedure H using 3-aminophenyldimethylcarbamate (18 mg, 0.10 mmol) and amine 70.HCl (38 mg, 0.12 mmol, 1.2 equiv.) in anhydrous THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone 100 / 0 to 25 / 75 to give the desired compound 75 (35 mg, 64%) as a white solid. f (CH2Cl2 / acetone 20 / 80) 0.28. Mp: decomposition 132°C. 1 H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H, NH), 8.67 (s, 1H, CH), 8.64 (s, 1H, NH), 7.35 (t, J = 2.1 Hz, 1H, CH), 7.31 (d, J = 2.1, Hz, 1H, CH), 7.28 - 7.19 (m, 2H, 2 x CH), 6.71 - 6.66 (m, 1H, CH), 6.27 (s, 1H, CH), 4.24 - 4.19 (m, 2H, CH2), 3.74 (t, J = 5.6 Hz, 2H, CH2), 3.03 (s, 3H, NCH3), 2.90 (s, 3H, NCH3), 2.73 - 2.64 (m, 2H, CH2), 1.88 - 1.77 (m, 1H, CH), 0.84 - 0.76 (m, 2H, CH2), 0.63 - 0.52 (m, 2H, CH2). HRMS (EI-MS) m / z C 24 H 27 N6O3[M+H] + Calculated value: 447.2139, Measured value: 447.2137.

[0313] Example 44: 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-[3-(2-methoxyphenyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxamide (76) The reaction was carried out as described in general procedure H using 2'-methoxy-[1,1'-biphenyl]-3-amine (25 mg, 0.12 mmol) and amine 70.HCl (48 mg, 0.15 mmol, 1.2 equiv.) in anhydrous THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 30 / 70 to give the desired compound 76 (35 mg, 58%) as a white solid. f (CH2Cl2 / acetone 30 / 70) 0.43. Mp: decomposition 140°C. 1 H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H, NH), 8.68 (s, 1H, CH), 8.61 (s, 1H, NH), 7.59 (s, 1H, CH), 7.48 (d, J = 8.2 Hz, 1H, CH), 7.33 (t, J = 8.2 Hz, 1H, CH), 7.31 - 7.21 (m, 3H, 3xCH), 7.10 (d, J = 8.3 Hz, 1H, CH), 7.08 - 6.98 (m, 2H, 2 x CH), 6.30 (s, 1H, CH), 4.24 (s, 2H, CH2), 3.76 (s, 5H, OCH3+ CH2), 2.71 (s, 2H, CH2), 1.84 (m, 1H, CH), 0.85 - 0.78 (m, 2H, CH2), 0.64 - 0.57 (m, 2H, CH2). HRMS (EI-MS) m / z C 28 H 28 NO2[M+H] + Calculated value: 466.2238, Measured value: 466.2234.

[0314] Example 45: 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-[3-(3-methoxyphenyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxamide (77) The reaction was carried out as described in general procedure H using 3'-methoxy-[1,1'-biphenyl]-3-amine (25 mg, 0.12 mmol) and amine 70.HCl (48 mg, 0.15 mmol, 1.2 equiv.) in anhydrous THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 40 / 60 to give the desired compound 77 (40 mg, 67%) as a white solid. f (CH2Cl2 / acetone 30 / 70) 0.67. Mp: decomposition 199°C. 1 H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H, NH), 8.66 (s, 2H, NH + CH), 7.80 (s, 1H, CH), 7.55 (d, J = 8.1 Hz, 1H, CH), 7.38 (t, J = 7.9 Hz, 1H, CH), 7.33 (t, J = 7.9 Hz, 1H, CH), 7.29 - 7.22 (m, 2H, 2 x CH), 7.18 (d, J = 7.7 Hz, 1H, CH), 7.16 - 7.11 (m, 1H, CH), 6.94 (dd, J = 8.2, 2.6 Hz, 1H, CH), 6.29 (s, 1H, CH), 4.30 - 4.20 (m, 2H, CH2), 3.82 (s, 3H, OCH3), 3.77 (t, J = 5.7 Hz, 2H, CH2), 2.72 (s, 2H, CH2), 1.91 - 1.78 (m, 1H, CH), 0.86 - 0.76 (m, 2H, CH2), 0.65 - 0.52 (m, 2H, CH2). HRMS (EI-MS) m / z C 28 H 28 NO2[M+H] + Calculated value: 466.2238, Measured value: 466.2235.

[0315] Example 46: 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-[3-(4-methoxyphenyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxamide (78) The reaction was carried out as described in general procedure H using 4'-methoxy-[1,1'-biphenyl]-3-amine (25 mg, 0.12 mmol) and amine 70.HCl (48 mg, 0.15 mmol, 1.2 equiv.) in anhydrous THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 40 / 60 to give the desired compound 78 (40 mg, 67%) as a pale beige solid. f (CH2Cl2 / acetone 30 / 70) 0.4. Mp: decomposition 149°C. 1 H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H, NH), 8.67 (s, 1H, CH), 8.64 (s, 1H, NH), 7.77 (s, 1H, CH), 7.55 (d, J = 8.6 Hz, 2H, 2 x CH), 7.48 (d, J = 8.1 Hz, 1H, CH), 7.33 - 7.24 (m, 2H, 2 x CH), 7.19 (d, J = 7.6 Hz, 1H, CH), 7.03 (d, J = 8.5 Hz, 2H, 2 x CH), 6.30 (s, 1H, CH), 4.31 - 4.19 (m, 2H, CH2), 3.84 - 3.71 HRMS (EI-MS) m / z C 28 H 28 NO2[M+H] + Calculated value: 466.2238, Measured value: 466.2234.

[0316] Example 47: 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-phenoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxamide (79) The reaction was carried out as described in general procedure G using amine 70.HCl (48 mg, 0.15 mmol) in CHCl (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 70 / 30 to give the desired compound 79 (35 mg, 58%) as a white solid. f (CH2Cl2 / acetone 30 / 70) 0.52. Mp: decomposition 124°C. 1 H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H, NH), 8.66 (s, 2H, CH + NH), 7.39 (t, J = 8.0 Hz, 2H, 2 x CH), 7.33 - 7.20 (m, 4H, 4xCH), 7.13 (t, J = 7.4 Hz, 1H, CH), 7.01 (d, J = 7.7 Hz, 2H, 2 x CH), 6.64 - 6.57 (m, 1H, CH), 6.26 (s, 1H, CH), 4.22 - 4.17 (m, 2H, CH2), 3.72 (t, J = 5.5 Hz, 2H, CH2), 2.68 (m, 2H, CH2), 1.87 - 1.74 (m, 1H, CH), 0.85 - 0.72 (m, 2H, CH2), 0.64 - 0.53 (m, 2H, CH2). HRMS (EI-MS) m / z C 27 H 26 NO2[M+H] + Calculated value: 452.2081, Measured value: 452.2076.

[0317] 3-(1H-pyrrol-1-yl)aniline (80) An oven-dried microwave vial was charged with a magnetic stir bar, CuI (29 mg, 0.15 mmol, 0.05 equiv.), KPO (1.33 g, 6.26 mmol, 2.1 equiv.), and 1,10-phenanthroline (107 mg, 0.60 mmol, 0.2 equiv.). The tube was then evacuated and backfilled with argon. The evacuation / backfill procedure was repeated two more times. Under a counterflow of argon, 3-iodoaniline (0.43 mL, 3.58 mmol, 1.2 equiv.), pyrrole (0.21 mL, 2.98 mmol), and degassed 1,4-dioxane (1.5 mL) were added via syringe. The tube was placed in a preheated oil bath at 11 °C, and the solution was vigorously stirred for 24 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (2-3 mL), and filtered through a plug of Celite eluting with EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using a gradient solvent system of PE / EtOAc 90 / 10 to 80 / 20 to give compound 80 (0.41 g, 87%) as a brown solid. 1 H NMR (250 MHz, CDCl3) δ 7.22 (t, J = 8.0 Hz, 1H, H), 7.11 (t, J = 2.2 Hz, 2H, 2 x CH), 6.83 (ddd, J = 8.0 Hz, J = 2.1 Hz, J = 0.9 Hz, 1H, CH), 6.71 (t, J = 2.2 Hz, 1H, CH), 6.57 (ddd, J = 8.0 Hz, J = 2.3 Hz, J =0.9 Hz, 1H, CH), 6.40 (t, J = 2.2 Hz, 2H, 2 x CH), 3.76 (br s, 2H, NH2). Tetrahedron 2011, 67, pp. 898-903.

[0318] Example 48: 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-pyrrol-1-ylphenyl)-3,6-dihydropyridine-1(2H)-carboxamide (81) The reaction was carried out as described in general procedure H using 3-(1H-pyrrol-1-yl)aniline 80 (22 mg, 0.14 mmol) and amine 70.HCl (53 mg, 0.16 mmol, 1.2 equiv.) in anhydrous THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 50 / 50 to give the desired compound 81 (42 mg, 70%) as a white solid. f (CH2Cl2 / acetone 70 / 30) 0.25. Mp: decomposition 140°C. 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H, NH), 8.72 (s, 1H, NH), 8.65 (s, 1H, CH), 7.74 (s, 1H, CH), 7.41 (d, J = 7.9 Hz, 1H, CH), 7.32 (t, J = 8.0 Hz, 1H, CH), 7.27 - 7.21 (m, 3H, 3 x CH), 7.13 (d, J = 7.7 Hz, 1H, CH), 6.43 - 6.07 (m, 3H, 3 x CH), 4.31 - 4.16 (m, 2H, CH2), 3.77 (t, J = 5.4 Hz, 2H, CH2), 2.77 - 2.68 (m, 2H, CH2), 1.91 - 1.77 (m, 1H, CH), 0.86 - 0.75 (m, 2H, CH2), 0.66 - 0.53 (m, 2H, CH2). HRMS (EI-MS) m / z C 25 H 24 NO[M+H] + Calculated value: 425.2084, Measured value: 425.2084.

[0319] Example 49: 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-[3-(3-methoxyphenoxy)phenyl]-3,6-dihydropyridine-1(2H)-carboxamide (82) The reaction was carried out as described in general procedure H using 3-(3-methoxyphenoxy)aniline (22 mg, 0.11 mmol) and amine 70.HCl (47 mg, 0.15 mmol, 1.2 equiv.) in anhydrous THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 40 / 60 to give the desired compound 82 (32 mg, 53%) as a white solid. f (CH2Cl2 / acetone 40 / 60) 0.35. Mp: decomposition 186°C. 1 H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H, NH), 8.69 - 8.61 (m, 2H, NH + CH), 7.39 - 7.07 (m, 5H, 5xCH), 6.71 (dd, J = 8.2, J = 2.4 Hz, 1H, CH), 6.62 (d, J = 7.9 Hz, 1H, CH), 6.58 (t, J = 2.3 Hz, 1H, CH), 6.57 - 6.53 (m, 1H, CH), 6.25 (s, 1H, CH), 4.22 - 4.17 (m, 2H, CH2), 3.80 - 3.64 (m, 5H, OCH3+ C 28 H 28 N5O3[M+H] + Calculated value: 482.2187, Measured value: 482.2186. Example 50: N-cyclohexyl-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (83) The reaction was carried out as described in general procedure H using cyclohexylamine (13 mg, 0.11 mmol) and amine 70.HCl (51 mg, 0.16 mmol, 1.2 equiv.) in anhydrous THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 40 / 60 to give the desired compound 83 (35 mg, 60%) as a white solid. f (CH2Cl2 / acetone 30 / 70) 0.27. Mp: 201°C. 1 H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H, NH), 8.62 (s, 1H, CH), 7.23 (s, 1H, CH), 6.20 (m, 2H, NH + CH), 4.03 (s, 2H, CH2), 3.57 (t, J = 5.5 Hz, 2H, CH2), 3.51 - 3.41 (m, 1H, CH), 2.59 (s, 2H, CH2), 1.84 - 1.63 (m, 5H, CH + CH2), 1.57 (d, J = 11.9 Hz, 1H, CH2), 1.33 - 0.99 (m, 5H, 2 x CH2, CH), 0.85 - 0.74 (m, 2H, CH2), 0.63 - 0.53 (m, 2H, CH2). HRMS (EI-MS) m / z C 21 H 28 NO[M+H] + Calculated value: 366.2290, Measured value: 366.2288.

[0320] Family 5. 2,3-Dimethylpyrrolopyrimidine derivatives with unsubstituted hydropyridine.

[0321] [ka]

[0322] [Table 6]

[0323] 6-[(2E)-2-(1-methylpropylidene)hydrazino]pyrimidin-4-ol (84) The reaction was carried out as described in General Procedure A using 4-hydroxy-6-hydrazinylpyrimidine (2.0 g, 15.9 mmol). The desired product 84 (2.7 g, 95%) was obtained as a white solid. f (Acetone) 0.31. Mp: Decomposition 225°C. 1 H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H, NH), 9.40 (s, 1H, OH), 7.90 (s, 1H, CH), 5.55 (s, 1H, CH), 2.25 (q, J = 7.4 Hz, 2H, CH2), 1.88 (s, 3H, CH3), 1.04 (t, J = 7.4 Hz, 3H, CH3). HRMS (EI-MS) m / z C8H 13 NO[M+H] + Calculated value: 181.1084, Measured value: 181.1083.

[0324] 5,6-Dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol (85) The reaction was carried out as described in general procedure K using 84 (400 mg, 2.21 mmol). The desired product 85 (300 mg, 92%) was obtained as a light brown solid. f (CH2Cl2 / acetone 20 / 80) 0.35. Mp: decomposition > 266°C. 1 H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H, OH), 11.38 (s, 1H, NH), 7.67 (s, 1H, CH), 2.18 (s, 3H, CH3), 2.15 (s, 3H, CH3). HRMS (EI-MS) m / z C8H 10 NO[M+H] + Calculated value: 164.0818, Measured value: 164.0814.

[0325] 4-Chloro-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (86) The reaction was carried out as described in General Procedure C using 85 (400 mg, 2.45 mmol). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 70 / 30 to give compound 86 (267 mg, 60%) as a white solid. f (CH2Cl2 / acetone 70 / 30) 0.49. Mp: decomposition 232°C. 1 H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H, NH), 8.40 (s, 1H, CH), 2.32 (s, 3H, CH3), 2.30 (s, 3H, CH3). HRMS (EI-MS) m / z C8H9ClN3[M+H] + Calculated value: 182.0480, Measured value: 182.0475.

[0326] tert-Butyl 4-(5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (87) The reaction was carried out as described in general procedure D using 86 (109 mg, 0.6 mmol). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 50 / 50 to give compound 87 (58 mg, 30%) as a white solid. f (CH2Cl2 / acetone 60 / 40) 0.26. Mp: decomposition 162°C. 1 H NMR (250 MHz, CDCl3) δ 11.07 (s, 1H, NH), 8.72 (s, 1H, CH), 5.92 (s, 1H, CH), 4.15 (s, 2H, CH2), 3.71 (t, J = 5.6 Hz, 2H, CH2), 2.76 - 2.65 (m, 2H, CH2), 2.44 (s, 3H, CH3), 2.18 (s, 3H, CH3), 1.50 (s, 9H, CH3). HRMS (EI-MS) m / z C 18 H 25 N4O2[M+H] +Calculated value: 329.1972, Measured value: 329.1973.

[0327] 5,6-Dimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (88) The reaction was carried out using 87 (350 mg, 1.07 mmol) as described in general procedure J. The desired product 88 (345 mg, quantitative) was obtained as a yellow solid (HCl salt). Mp: decomposition >266°C. 1 H NMR (400 MHz, DMSO-d6) δ 13.27 (s, 1H, NH), 9.95 (s, 2H, NH2(salt)), 8.92 (s, 1H, CH), 6.28 (s, 1H, CH), 3.86 (s, 2H, CH2), 3.35 (s, 2H, HRMS (EI-MS) m / z C 13 H 17 N4[M+H] + Calculated value: 229.1448, Measured value: 229.1446.

[0328] Example 51: N-(3-bromophenyl)-4-(5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxamide (89) The reaction was carried out as described in General Procedure G using 88 (42 mg, 0.14 mmol). The crude mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 50 / 50 to give compound 89 (45 mg, 75%) as a white solid. f (CH2Cl2 / acetone 50 / 50): 0.25. Mp: decomposition > 266°C. 1H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H, NH), 8.75 (s, 1H, NH), 8.55 (s, 1H, CH), 7.83 (s, 1H, CH), 7.50 (d, J = 8.6 Hz, 1H, CH), 7.21 (t, J = 8.1 Hz, 1H, CH), 7.12 (d, J = 8.0 Hz, 1H, CH), 5.97 (s, 1H, CH), 4.21 (s, 2H, CH2), 3.73 (t, J = 5.6 Hz, 2H, CH2), 2.66 (s, 2H, CH2), 2.33 (s, 3H, CH3), 2.13 (s, 3H, CH3). HRMS (EI-MS) m / z C 20 H 21 BrNO[M+H] + Calculated value: 426.0924, Measured value: 426.0919.

[0329] Example 52: 4-(5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-phenyl-3,6-dihydro-2H-pyridine-1-carboxamide (90) The reaction was carried out as described in General Procedure G using 88 (52 mg, 0.17 mmol). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 50 / 50 to give compound 90 (43 mg, 72%) as a white solid. f (CH2Cl2 / acetone 70 / 30) 0.48. Mp: decomposition > 266°C. 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H, NH), 8.59 - 8.53 (m, 2H, NH + CH), 7.50 (d, J = 8.0 Hz, 2H, CH), 7.24 (t, J = 7.7 Hz, 2H, CH), 6.94 (t, J = 7.3 Hz, 1H, CH), 5.98 (s, 1H, CH), 4.21 (s, 2H, CH2), 3.73 (t, J = 5.5 Hz, 2H, CH2), 2.66 (s, 2H, CH2), 2.33 (s, 3H, CH3), 2.14 (s, 3H, CH3). HRMS (EI-MS) m / z C 20 H 22 NO[M+H] + Calculated value: 348.1819, Measured value: 348.1821.

[0330] Example 53: 4-(5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-methoxyphenyl)-3,6-dihydro-2H-pyridine-1-carboxamide (91) The reaction was carried out as described in General Procedure G using 88 (48 mg, 0.16 mmol). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 40 / 60 to give compound 91 (33 mg, 55%) as a white solid. f (CH2Cl2 / acetone 30 / 70) 0.36. Mp: decomposition > 266°C. 1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H, NH), 8.60 - 8.53 (m, 2H, NH + CH), 7.20 (s, 1H, CH), 7.17 - 7.06 (m, 2H, CH), 6.52 (d, J = 7.5 Hz, 1H, HRMS (EI-MS) m / z C 21 H 24 NO2[M+H] + Calculated value: 378.1925, Measured value: 378.1922.

[0331] Example 54: 4-(5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-phenyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxamide (92) The reaction was carried out as described in general procedure H using 1,1'-biphenyl]-3-amine (16 mg, 0.14 mmol) and 88 (51 mg, 0.17 mmol, 1.2 equiv.) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a 70 / 30 solvent system of CHCl / acetone to give compound 92 (29 mg, 48%) as a white solid. f (CH2Cl2 / acetone 50 / 50) 0.35. Mp: decomposition 144°C. 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H, NH), 8.68 (s, 1H, NH), 8.57 (s, 1H, CH), 7.83 (s, 1H, CH), 7.62 (d, J = 7.6 Hz, 2H, CH), 7.55 (d, J = 8.0 Hz, 1H, CH), 7.47 (t, J = 7.6 Hz, 2H, CH), 7.35 (q, J = 7.8 Hz, 2H, CH), 7.24 (d, J = 7.7 Hz, 1H, CH), 5.99 (s, 1H, CH), 4.24 (s, 2H, CH2), 3.76 (t, J = 4.9 Hz, 2H, CH2), 2.68 (s, 2H, CH2), 2.33 (s, 3H, CH3), 2.14 (s, 3H, CH3). HRMS (EI-MS) m / z C 26 H 26 N5O [M+H] + Calculated value: 424.2132, Measured value: 424.2128.

[0332] Example 55: 4-(5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-[3-(4-methoxyphenyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxamide (93) The reaction was carried out as described in general procedure H using 4'-methoxy-[1,1'-biphenyl]-3-amine (26 mg, 0.13 mmol) and amine salt 88 (48 mg, 0.16 mmol, 1.2 equiv.) in THF (4 mL). The crude mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 40 / 60 to give 93 (30 mg, 50%) as a white solid. f (CH2Cl2 / acetone 30 / 70) 0.53. Mp: decomposition 248°C. 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H, NH), 8.64 (s, 1H, NH), 8.56 (s, 1H, CH), 7.77 (s, 1H, CH), 7.55 (d, J = 8.4 Hz, 2H, CH), 7.49 (d, J = 7.9 Hz, 1H, CH), 7.30 (t, J = 7.8 Hz, 1H, CH), 7.19 (d, J = 7.7 Hz, 1H, CH), 7.03 (d, J = 8.3 Hz, 2H, CH), 5.99 (s, 1H, CH), 4.23 (s, 2H, CH2), 3.80 (s, 3H, CH3), 3.79 - 3.71 (m, 2H, CH2), 2.67 (s, 2H, CH2), 2.33 (s, 3H, CH3), 2.14 (s, 3H, CH3). HRMS (EI-MS) m / z C 27 H 28 NO2[M+H] + Calculated value: 454.2238, Measured value: 454.2238.

[0333] Example 56: [3-[[4-(5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carbonyl]amino]phenyl]N,N-dimethylcarbamate (94) The reaction was carried out as described in general procedure H using 3-aminophenyldimethyl carbamate (45 mg, 0.25 mmol) and amine salt 88 (50 mg, 0.17 mmol, 1.2 equiv.) in THF (4 mL). The crude mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 50 / 50 to give 94 (35 mg, 58%) as a pale yellow solid. f (CH2Cl2 / acetone 30 / 70): 0.41. Mp: decomposition 142°C. 1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H, NH), 8.69 (s, 1H, NH), 8.57 (s, 1H, CH), 7.38 (s, 1H, CH), 7.32 (d, J = 8.2 Hz, 1H, CH), 7.22 (t, J = 8.1 Hz, 1H, CH), 6.69 (d, J = 7.4 Hz, 1H, CH), 5.99 (s, 1H, CH), 4.21 (s, 2H, CH2), 3.73 (t, J = 5.4 Hz, 2H, CH2), 3.04 (s, 3H, CH3), 2.91 (s, 3H, CH3), 2.65 (s, 2H, CH2), 2.33 (s, 3H, CH3), 2.13 (s, 3H, CH3). HRMS (EI-MS) m / z C 23 H 27 N6O3[M+H] + Calculated value: 435.2136, Measured value: 435.2139.

[0334] Family 6. Tricyclic derivatives of pyrrolopyrimidine and unsubstituted hydropyridine with alkyl rings at the 2- and 3-positions.

[0335] [ka]

[0336] [Table 7A]

[0337] [Table 7B]

[0338] 6-(2-Cyclopentylidenehydrazinyl)pyrimidin-4-ol (95) The reaction was carried out as described in General Procedure A using 4-hydroxy-6-hydrazinylpyrimidine (1.0 g, 7.93 mmol) and cyclopentanone (1.05 mL, 11.89 mmol, 1.5 equiv) in EtOH (16 mL). The precipitate was filtered and washed with EtO (2 x 20 mL) to give compound 95 (1.18 g, 77%) as a white solid. f (CH2Cl2 / acetone 50 / 50) 0.10. Mp:>260℃. 1 H NMR (250 MHz, MeOD-d4) δ 7.91 (s, 1H, CH), 5.84 (s, 1H, CH), 2.52 - 2.27 (m, 4H, CH2+ CH2), 1.97 - 1.65 (m, 4H, CH2+ CH2). HRMS (EI-MS) m / z C9H 13 N4O [M+H] + Calculated value: 193.1084, Measured value: 193.1085.

[0339] 6-(2-Cyclohexylidenehydrazinyl)pyrimidin-4-ol (96) The reaction was carried out as described in general procedure A using 4-hydroxy-6-hydrazinylpyrimidine (1.0 g, 7.93 mmol) and cyclohexanone (1.16 mL, 11.89 mmol, 1.5 equiv) in EtOH (16 mL). The precipitate was filtered and washed with EtO (2 × 20 mL) to give 96 (1.17 g, 72%) as a white solid. f (CH2Cl2 / acetone 50 / 50) 0.11. Mp:>260°C. 1 H NMR (250 MHz, MeOD-d4) δ 7.90 (d, J = 0.8 Hz, 1H, CH), 5.86 (d, J = 0.8 Hz, 1H, CH), 2.49 - 2.39 (m, 2H, CH2), 2.39 - 2.31 (m, 2H, CH2), 1.80 - 1.59 (m, 6H, 3 x CH2). HRMS (EI-MS) m / z C 10 H 15 N4O [M+H] +Calculated value: 207.1240, Measured value: 207.1239.

[0340] 6-(2-Cycloheptylidenehydrazinyl)pyrimidin-4-ol (97) The reaction was carried out as described in general procedure A using 4-hydroxy-6-hydrazinylpyrimidine (1.0 g, 7.93 mmol) and cycloheptanone (1.4 mL, 11.89 mmol, 1.5 equiv.) in EtOH (16 mL). The precipitate was filtered and washed with EtO (2 x 20 mL) to give compound 97 (1.3 g, 76%) as a beige solid. f (CH2Cl2 / acetone 50 / 50) 0.11. Mp:>260°C. 1 H NMR (400 MHz, DMSO-d6) δ 11.65 (br s, 1H, OH), 9.22 (s, 1H, NH), 7.89 (s, 1H, CH), 5.55 (s, 1H, CH), 2.48 - 2.44 (m, 2H, CH2), 2.44 - 2.40 (m, 2H, CH2), 1.68 - 1.60 (m, 2H, CH2), 1.59 - 1.45 (m, 6H, 3 x CH2). HRMS (EI-MS) m / z C 11 H 17 N4O [M+H] + Calculated value: 221.1397, Measured value: 221.1396.

[0341] 5,6,7,8-Tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-ol (98) The reaction was carried out as described in general procedure B using hydrazone 95 (0.5 g, 2.60 mmol) in tetralin (10 mL). The precipitate was filtered and washed several times with PE (3 × 10 mL) and EtO (10 mL) to give compound 98 (0.39 g, 85%) as a gray solid. f (CH2Cl2 / MeOH / NH4OH 90 / 9 / 1)0.33. Mp:>260℃. 1H NMR (250 MHz, DMSO-d6) δ 11.66 (br s, 1H, OH), 11.59 (s, 1H, NH), 7.69 (s, 1H, CH), 2.79 - 2.64 (m, 4H, 2 x CH2), 2.42 - 2.26 (m, 2H, CH2). HRMS (EI-MS) m / z C9H 10 N3O [M+H] + Calculated value: 176.0818, Measured value: 176.0821.

[0342] 6,7,8,9-Tetrahydro-5H-pyrimido[4,5-b]indol-4-ol (99) The reaction was carried out as described in general procedure B using hydrazone 96 (0.5 g, 2.42 mmol) in tetralin (10 mL). The precipitate was filtered and washed several times with PE (3 × 10 mL) and EtO (10 mL) to give compound 99 (0.41 g, 89%) as a beige solid. f (CH2Cl2 / MeOH / NH4OH 90 / 9 / 1)0.35. Mp:>260℃. 1 H NMR (400 MHz, DMSO-d6) δ 11.56 (br s, 1H, OH), 11.37 (s, 1H, NH), 7.68 (s, 1H, CH), 2.66 (t, J = 5.9 Hz, 2H, CH2), 2.55 (t, J = 6.0 Hz, 2H, CH2), 1.79 - 1.65 (m, 4H, 2 x CH2). HRMS (EI-MS) m / z C 10 H 12 N3O [M+H] + Calculated value: 190.0975, Measured value: 190.0975.

[0343] 5,6,7,8,9,10-Hexahydrocyclohepta[4,5]pyrrolo[2,3-d]pyrimidin-4-ol (100) The reaction was carried out as described in general procedure B using hydrazone 97 (0.5 g, 2.27 mmol) in tetralin (10 mL). The precipitate was filtered and washed several times with PE (3 × 10 mL) and EtO (10 mL) to give compound 100 (0.41 g, 88%) as a beige solid. f (CH2Cl2 / MeOH / NH4OH 90 / 9 / 1)0.34. Mp:>260℃. 1 H NMR (250 MHz, DMSO-d6) δ 11.53 (br s, 1H, OH), 11.40 (s, 1H, NH), 7.66 (s, 1H, CH), 3.01 - 2.83 (m, 2H, CH2), 2.74 - 2.61 (m, 2H, CH2), 1.83 - 1.72 (m, 2H, CH2), 1.66 - 1.52 (m, 4H, 2 x CH2). HRMS (EI-MS) m / z C 11 H 14 N3O [M+H] + Calculated value: 204.1131, Measured value: 204.1132.

[0344] 4-Chloro-5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidine (101) The reaction was carried out as described in General Procedure C using tricyclic compound 98 (1.0 g, 5.71 mmol) in POCl (40 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 70 / 30 to give 101 (0.83 g, 75%) as a white solid. f (CH2Cl2 / acetone 80 / 20) 0.31. Mp: decomposition 239°C. 1 H NMR (250 MHz, DMSO-d6) δ 12.31 (br s, 1H, NH), 8.42 (s, 1H, CH), 2.95 - 2.81 (m, 4H, 2 x CH2), 2.48 - 2.38 (m, 2H, CH2). HRMS (EI-MS) m / z C9H9ClN3[M+H] +Calculated value: 194.0480, Measured value: 194.0480.

[0345] 4-Chloro-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indole (102) The reaction was carried out as described in General Procedure C using tricyclic compound 99 (1.0 g, 5.28 mmol) in POCl (40 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 70 / 30 to give compound 102 (0.86 g, 78%) as a white solid. f (CH2Cl2 / acetone 80 / 20) 0.34. Mp: decomposition 240°C. 1 H NMR (250 MHz, DMSO-d6) δ 12.13 (s, 1H, NH), 8.41 (s, 1H, CH), 2.84 - 2.76 (m, 2H, CH2), 2.76 - 2.67 (m, 2H, CH2), 1.87 - 1.73 (m, 4H, 2 x CH2). HRMS (EI-MS) m / z C 10 H 11 ClN3[M+H] + Calculated value: 208.0636, Measured value: 208.0637.

[0346] 4-Chloro-5,6,7,8,9,10-hexahydrocyclohepta[4,5]pyrrolo[2,3-d]pyrimidine (103) The reaction was carried out as described in General Procedure C using tricyclic compound 100 (1.0 g, 4.92 mmol) in POCl (35 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 70 / 30 to give compound 103 (0.81 g, 74%) as an off-white solid. f (CH2Cl2 / acetone 80 / 20) 0.36. Mp: 249-251°C. 1H NMR (250 MHz, DMSO-d6) δ 12.19 (s, 1H, NH), 8.39 (s, 1H, CH), 3.12 - 2.94 (m, 2H, CH2), 2.89 - 2.77 (m, 2H, CH2), 1.90 - 1.74 (m, 2H, CH2), 1.74 - 1.59 (m, 4H, 2 x CH2). HRMS (EI-MS) m / z C 11 H 13 ClN3[M+H] + Calculated value: 222.0793, Measured value: 222.0792.

[0347] tert-Butyl 4-(5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (104) The reaction was carried out as described in General Procedure D using chlorinated tricyclic compound 101 (0.35 g, 1.81 mmol) and N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.62 g, 1.99 mmol, 1.1 equiv.) in THF (9 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 50 / 50 to give compound 104 (0.54 g, 88%) as a white solid. f (CH2Cl2 / acetone 70 / 30) 0.23. Mp: 213-215°C. 1 H NMR (250 MHz, DMSO-d6) δ 11.95 (s, 1H, NH), 8.55 (s, 1H, CH), 6.56 - 6.46 (m, 1H, CH), 4.15 - 4.04 (m, 2H, CH2), 3.56 (t, J = 5.7 Hz, 2H, HRMS (EI-MS) m / z C 19 H 25N4O2[M+H] + Calculated value: 341.1972, Measured value: 341.1970.

[0348] tert-Butyl 4-(6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (105) The reaction was carried out as described in general procedure D using chlorinated tricyclic compound 102 (0.45 g, 2.17 mmol) and N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.74 g, 2.38 mmol, 1.1 equiv.) in THF (9 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 50 / 50 to give compound 105 (0.67 g, 87%) as a white solid. f (CH2Cl2 / acetone 70 / 30) 0.26. Mp: 214-216°C. 1 H NMR (250 MHz, DMSO-d6) δ 11.73 (s, 1H, NH), 8.54 (s, 1H, CH), 6.07 - 5.95 (m, 1H, CH), 4.13 - 3.97 (m, 2H, CH2), 3.64 - 3.49 (m, 2H, CH2), 2.78 - 2.64 (m, 2H, CH2), 2.65 - 2.53 (m, 4H, 2 x CH2), 1.90 - 1.67 (m, 4H, 2 x CH2), 1.43 (s, 9H, 3 x CH3). HRMS (EI-MS) m / z C 20 H 27 N4O2[M+H] + Calculated value: 355.2129, Measured value: 355.2129.

[0349] tert-Butyl 4-(5,6,7,8,9,10-hexahydrocyclohepta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (106) The reaction was carried out as described in general procedure D using chlorinated tricyclic compound 103 (0.45 g, 2.03 mmol) and N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.69 g, 2.23 mmol, 1.1 equiv.) in THF (9 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 50 / 50 to give compound 106 (0.50 g, 67%) as a white solid. f (CH2Cl2 / acetone 70 / 30) 0.27. Mp: 180-182°C. 1 H NMR (250 MHz, DMSO-d6) δ 11.78 (s, 1H, NH), 8.53 (s, 1H, CH), 5.86 (s, 1H, CH), 4.11 - 3.98 (m, 2H, CH2), 3.65 - 3.51 (m, 2H, CH2), 2.89 - 2.79 (m, 2H, CH2), 2.79 - 2.69 (m, 2H, CH2), 2.63 - 2.53 (m, 2H, CH2), 1.89 - 1.75 (m, 2H, CH2), 1.76 - 1.55 (m, 4H, 2 x CH2), 1.44 (s, 9H, 3 x CH3). HRMS (EI-MS) m / z C 21 H 29 N4O2[M+H] + Calculated value: 369.2285, Measured value: 369.2286.

[0350] 4-(1,2,3,6-tetrahydropyridin-4-yl)-5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidine (107) The reaction was carried out as described in general procedure F1 using N-Boc protected compound 104 (1.0 g, 2.94 mmol) in CHCl (80 mL). The reaction was complete after 1 h. Workup afforded compound 107 (0.65 g, 92%) as a beige solid. Mp: >260°C. 1H NMR (250 MHz, DMSO-d6) δ 11.91 (br s, 1H, NH), 8.53 (s, 1H, CH), 6.53 (s, 1H, CH), 3.50 - 3.38 (m, 2H, CH2), 2.98 - 2.75 (m, 6H, 3 x CH2), 2.59 - 2.45 (m, 2H, CH2), 2.45 - 2.30 (m, 2H, CH2). HRMS (EI-MS) m / z C 14 H 17 N4[M+H] + Calculated value: 241.1448, Measured value: 241.1446.

[0351] 4-(1,2,3,6-tetrahydropyridin-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indole (108) The reaction was carried out as described in General Procedure F1 using N-Boc protected compound 105 (1.0 g, 2.82 mmol) in CHCl (80 mL). The reaction was complete after 1 h. Workup afforded compound 108 (0.68 g, 95%) as a pale yellow solid. Mp: 187-189 °C. 1 H NMR (250 MHz, MeOD-d4) δ 8.51 (s, 1H, CH), 6.03 (tt, J = 3.3, 1.7 Hz, 1H, CH), 3.54 (dt, J = 2.9 Hz, J = 2.9 Hz, 2H, CH2), 3.10 (t, J = 5.7 Hz, HRMS (EI-MS) m / z C 15 H 19 N4[M+H] + Calculated value: 255.1604, Measured value: 255.1603.

[0352] 4-(1,2,3,6-tetrahydropyridin-4-yl)-5,6,7,8,9,10-hexahydrocyclohepta[4,5]pyrrolo[2,3-d]pyrimidine ditrifluoroacetate (109) The reaction was carried out as described in general procedure F2 using N-Boc protected compound 106 (1.0 g, 2.71 mmol) in CH2Cl2 (80 mL). The reaction was complete after 1 h. Workup afforded compound 109 (1.17 g, 87%) as a yellow solid. Mp: decomposition 176 °C. 1 H NMR (250 MHz, DMSO-d6) δ 12.32 (br s, 1H, NH), 9.21 (s, 2H, NH + H + ), 8.70 (s, 1H, CH), 6.08 - 5.95 (m, 1H, CH), 3.92 - 3.79 (m, 2H, CH2), 3.47 - 3.30 (m, 2H, CH2), 2.94 - 2.85 (m, 2H, CH2), 2.82 - 2.71 (m, 4H, 2 x CH2), 1.89 - 1.77 (m, 2H, CH2), 1.76 - 1.58 (m, 4H, 2 x CH2). 19 F NMR (235 MHz, DMSO-d6) δ -74.2 (s). HRMS (EI-MS) m / z C 16 H 21 N4[M+H] + Calculated value: 269.1761, Measured value: 269.1760.

[0353] Example 57: N-(3-fluorophenyl)-4-(5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (110) The reaction was carried out as described in general procedure G using amine 107 (60 mg, 0.25 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 30 / 70 to give compound 110 (57 mg, 60%) as a pale yellow solid.f (CH2Cl2 / acetone 70 / 30) 0.27. Mp: decomposition 217°C. 1 H NMR (400 MHz, DMSO-d6) δ 11.96 (br s, 1H, NH), 8.77 (br s, 1H, NH), 8.57 (s, 1H, CH), 7.52 - 7.43 (m, 1H, CH), 7.33 - 7.20 (m, 2H, CH), 6.79 - 6.71 (m, 1H, CH), 6.61 - 6.53 (m, 1H, CH), 4.29 - 4.20 (m, 2H, CH2), 3.71 (t, J = 5.6 Hz, 2H, CH2), 2.92 - 2.82 (m, 4H, 2 x CH2), 2.78 - 2.71 (m, 2H, CH2), 2.46 - 2.37 (m, 2H, CH2). 19 F NMR (376 MHz, DMSO-d6) δ -112.9 (s). HRMS (EI-MS) m / z C 21 H 21 FN5O [M+H] + Calculated value: 378.1725, Measured value: 378.1724.

[0354] Example 58: N-(3-chlorophenyl)-4-(5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (111) The reaction was carried out as described in general procedure G using amine 107 (60 mg, 0.25 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 30 / 70 to give compound 111 (82 mg, 83%) as a white solid. f (CH2Cl2 / acetone 70 / 30) 0.26. Mp: decomposition 208°C. 1H NMR (400 MHz, DMSO-d6) δ 11.96 (br s, 1H, NH), 8.75 (br s, 1H, NH), 8.57 (s, 1H, CH), 7.69 (s, 1H, CH), 7.45 (d, J = 8.3 Hz, 1H, CH), 7.26 (t, J = 8.1 Hz, 1H, CH), 6.98 (d, J = 8.0 Hz, 1H, CH), 6.60 - 6.53 (m, 1H, CH), 4.30 - 4.21 (m, 2H, CH2), 3.71 (t, J = 5.7 Hz, 2H, CH2), 2.91 - 2.81 (m, 4H, 2 x CH2), 2.77 - 2.69 (m, 2H, CH2), 2.46 - 2.37 (m, 2H, CH2). HRMS (EI-MS) m / z C 21 H 21 ClNO [M+H] + Calculated value: 394.1429, Measured value: 394.1430.

[0355] Example 59: N-(3-bromophenyl)-4-(5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (112) The reaction was carried out as described in general procedure G using amine 107 (60 mg, 0.25 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 30 / 70 to give compound 112 (46 mg, 42%) as a beige solid. f (CH2Cl2 / acetone 70 / 30) 0.25. Mp: decomposition 216°C. 1H NMR (400 MHz, DMSO-d6) δ 11.96 (br s, 1H, NH), 8.73 (br s, 1H, NH), 8.57 (s, 1H, CH), 7.83 (s, 1H, CH), 7.50 (d, J = 8.3 Hz, 1H, CH), 7.20 (t, J = 8.0 Hz, 1H, CH), 7.11 (d, J = 8.0 Hz, 1H, CH), 6.57 (s, 1H, CH), 4.26 - 4.21 (m, 2H, CH2), 3.70 (t, J = 5.5 Hz, 2H, CH2), 2.93 - 2.81 (m, 4H, 2 x CH2), 2.78 - 2.69 (m, 2H, CH2), 2.45 - 2.37 (m, 2H, CH2). HRMS (EI-MS) m / z C 21 H 21 BrNO [M+H] + Calculated value: 438.0924, Measured value: 438.0925.

[0356] Example 60: N-(3-fluorophenyl)-4-(6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indol-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (113) The reaction was carried out as described in general procedure G using amine 108 (60 mg, 0.24 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 20 / 80 to give compound 113 (86 mg, 91%) as a pale yellow solid. f (CH2Cl2 / acetone 20 / 80) 0.27. Mp: decomposition 246°C. 1H NMR (400 MHz, DMSO-d6) δ 11.75 (br s, 1H, NH), 8.77 (br s, 1H, NH), 8.56 (s, 1H, CH), 7.49 (dt, J = 12.6 Hz, J = 2.1 Hz, 1H, CH), 7.34 - 7.21 (m, 2H, 2 x CH), 6.80 - 6.70 (m, 1H, CH), 6.12 - 6.03 (m, 1H, CH), 4.26 - 4.16 (m, 2H, CH2), 3.72 (t, J = 5.6 Hz, 2H, CH2), 2.75 - 2.65 (m, 4H, 2 x CH2), 2.58 (t, J = 5.8 Hz, 2H, CH2), 1.87 - 1.78 (m, 2H, CH2), 1.77 - 1.69 (m, 2H, CH2). 19 F NMR (376 MHz, DMSO-d6) δ -112.9 (s). HRMS (EI-MS) m / z C 22 H 23 FN5O [M+H] + Calculated value: 392.1881, Measured value: 392.1880.

[0357] Example 61: N-(3-chlorophenyl)-4-(6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indol-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (114) The reaction was carried out as described in general procedure G using amine 108 (60 mg, 0.24 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 20 / 80 to give compound 114 (84 mg, 86%) as a beige solid. f (CH2Cl2 / acetone 20 / 80) 0.28. Mp: decomposition 177°C. 1H NMR (400 MHz, DMSO-d6) δ 11.77 (br s, 1H, NH), 8.76 (br s, 1H, NH), 8.57 (s, 1H, CH), 7.70 (s, 1H, CH), 7.45 (d, J = 8.4 Hz, 1H, CH), 7.26 (t, J = 8.1 Hz, 1H, CH), 6.99 (d, J = 8.8 Hz, 1H, CH), 6.08 (s, 1H, CH), 4.26 - 4.18 (m, 2H, CH2), 3.72 (t, J = 5.6 Hz, 2H, CH2), 2.76 - 2.64 (m, 4H, 2 x CH2), 2.61 - 2.55 (m, 2H, CH2), 1.87 - 1.78 (m, 2H, CH2), 1.78 - 1.68 (m, 2H, CH2). HRMS (EI-MS) m / z C 22 H 23 ClNO [M+H] + Calculated value: 408.1586, Measured value: 408.1584.

[0358] Example 62: N-(3-bromophenyl)-4-(6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indol-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (115) The reaction was carried out as described in general procedure G using amine 108 (60 mg, 0.24 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 20 / 80 to give compound 115 (95 mg, 87%) as a beige solid. f (CH2Cl2 / acetone 20 / 80) 0.28. Mp: decomposition 19°C. 1H NMR (400 MHz, DMSO-d6) δ 11.75 (brs, 1H, NH), 8.74 (brs, 1H, NH), 8.56 (s, 1H, CH), 7.86 - 7.80 (m, 1H, CH), 7.50 (d, J = 8.1 Hz, 1H, CH), 7.21 (t, J = 8.0 Hz, 1H, CH), 7.12 (d, J = 8.7 Hz, 1H, CH), 6.07 (s, 1H, CH), 4.26 - 4.16 (m, 2H, CH2), 3.71 (t, J = 5.6 Hz, 2H, CH2), 2.73 (t, J = 5.9 Hz, 2H, CH2), 2.69 - 2.66 (m, 2H, CH2), 2.57 (t, J = 5.7 Hz, 2H, CH2), 1.88 - 1.79 (m, 2H, CH2), 1.78 - 1.68 (m, 2H, CH2). HRMS (EI-MS) m / z C 22 H 23 BrNO [M+H] + Calculated value: 452.1080, Measured value: 452.1079.

[0359] Example 63: N-(3-fluorophenyl)-4-(5,6,7,8,9,10-hexahydrocyclohepta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (116) The reaction was carried out as described in general procedure G using amine 109 (60 mg, 0.16 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 30 / 70 to give compound 116 (54 mg, 84%) as a beige solid. f (CH2Cl2 / acetone 60 / 40) 0.27. Mp: decomposition 151°C. 1H NMR (400 MHz, DMSO-d6) δ 11.80 (br s, 1H, NH), 8.79 (br s, 1H, NH), 8.55 (s, 1H, H2CH), 7.49 (dt, J = 12.3 Hz, J = 2.2 Hz, 1H, CH), 7.33 - 7.22 (m, 2H, 2 x CH), 6.81 - 6.69 (m, 1H, CH), 5.97 - 5.85 (m, 1H, CH), 4.23 - 4.15 (m, 2H, CH2), 3.73 (t, J = 5.6 Hz, 2H, CH2), 2.88 - 2.80 (m, 2H, CH2), 2.80 - 2.73 (m, 2H, CH2), 2.70 - 2.64 (m, 2H, CH2), 1.85 - 1.77 (m, 2H, CH2), 1.73 - 1.66 (m, 2H, CH2), 1.65 (s, 2H, CH2). 19 F NMR (376 MHz, DMSO-d6) δ -112.9 (s). HRMS (EI-MS) m / z C 23 H 25 FN5O [M+H] + Calculated value: 406.2038, Measured value: 406.2035.

[0360] Example 64: N-(3-chlorophenyl)-4-(5,6,7,8,9,10-hexahydrocyclohepta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (117) The reaction was carried out as described in general procedure G using amine 109 (60 mg, 0.16 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 30 / 70 to give compound 117 (63 mg, 94%) as a beige solid. f (CH2Cl2 / acetone 60 / 40) 0.27. Mp: decomposition 163°C. 1H NMR (400 MHz, DMSO-d6) δ 11.80 (br s, 1H, NH), 8.77 (br s, 1H, NH), 8.55 (s, 1H, CH), 7.70 (s, 1H, CH), 7.45 (d, J = 8.4 Hz, 1H, CH), 7.27 (t, J = 8.1 Hz, 1H, CH), 6.99 (d, J = 8.2 Hz, 1H, CH), 5.96 - 5.87 (m, 1H, CH), 4.27 - 4.10 (m, 2H, CH2), 3.73 (t, J = 5.6 Hz, 2H, CH2), 2.88 - 2.81 (m, 2H, CH2), 2.80 - HRMS (EI-MS) m / z C 23 H 25 ClNO [M+H] + Calculated value: 422.1742, Measured value: 422.1740.

[0361] Example 65: N-(3-bromophenyl)-4-(5,6,7,8,9,10-hexahydrocyclohepta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (118) The reaction was carried out as described in general procedure G using amine 109 (60 mg, 0.16 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 30 / 70 to give compound 118 (61 mg, 82%) as a beige solid. f (CH2Cl2 / acetone 60 / 40) 0.28. Mp: decomposition 178°C. 1H NMR (400 MHz, DMSO-d6) δ 11.80 (br s, 1H, NH), 8.75 (br s, 1H, NH), 8.55 (s, 1H, CH), 7.83 (s, 1H, CH), 7.50 (d, J = 8.2 Hz, 1H, CH), 7.21 (t, J = 7.9 Hz, 1H, CH), 7.12 (d, J = 8.0 Hz, 1H, CH), 5.98 - 5.86 (m, 1H, CH), 4.26 - 4.13 (m, 2H, CH2), 3.72 (t, J = 5.5 Hz, 2H, CH2), 2.88 - 2.80 (m, 2H, CH2), 2.80 - HRMS (EI-MS) m / z C 23 H 25 BrNO [M+H] + Calculated value: 466.1237, Measured value: 466.1234.

[0362] Example 66: N-phenyl-4-(5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (119) The reaction was carried out as described in general procedure G using amine 107 (60 mg, 0.25 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 40 / 60 to give compound 119 (47 mg, 75%) as a pale yellow solid. f (CH2Cl2 / acetone 50 / 50) 0.24. Mp: decomposition 215°C. 1H NMR (250 MHz, MeOD-d4) δ 8.54 (s, 1H, CH), 7.47 - 7.35 (m, 2H, 2 x CH), 7.35 - 7.21 (m, 2H, 2 x CH), 7.09 - 6.97 (m, 1H, CH), 6.57 - 6.43 (m, 1H, CH), 4.36 - 4.27 (m, 2H, CH2), 3.81 (t, J = 5.6 Hz, 2H, CH2), 3.03 - 2.86 (m, 4H, 2 x CH2), 2.86 - 2.73 (m, 2H, CH2), 2.61 - 2.40 (m, 2H, CH2). HRMS (EI-MS) m / z C 21 H 22 N5O [M+H] + Calculated value: 360.1819, Measured value: 360.1819.

[0363] Example 67: N-phenyl-4-(6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indol-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (120) The reaction was carried out as described in general procedure G using amine 108 (60 mg, 0.25 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 80 / 20 to give compound 207, 120 (69 mg, 78%) as a white solid. f (CH2Cl2 / acetone 20 / 80) 0.20. Mp: 255-257°C. 1H NMR (400 MHz, DMSO-d6) δ 11.74 (br s, 1H, NH), 8.56 (s, 2H, NH + CH), 7.50 (d, J = 8.0 Hz, 2H, 2 x CH), 7.24 (t, J = 7.7 Hz, 2H, 2 x CH), 6.94 (t, J = 7.3 Hz, 1H, CH), 6.07 (s, 1H, CH), 4.27 - 4.12 (m, 2H, CH2), 3.71 (t, J = 5.6 Hz, 2H, CH2), 2.78 - 2.63 (m, 4H, 2 x CH2), 2.63 - 2.54 (m, 2H, CH2), 1.87 - 1.77 (m, 2H, CH2), 1.77 - 1.69 (m, 2H, CH2). HRMS (EI-MS) m / z C 22 H 24 N5O [M+H] + Calculated value: 374.1975, Measured value: 374.1972.

[0364] Example 68: N-(3-Methoxyphenyl)-4-(5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (121) The reaction was carried out as described in general procedure G using amine 107 (60 mg, 0.25 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 40 / 60 to give compound 121 (55 mg, 89%) as a white solid. f (CH2Cl2 / acetone 50 / 50) 0.21. Mp: decomposition 206°C. 1H NMR (250 MHz, MeOD-d4) δ 8.54 (s, 1H, CH), 7.16 (t, J = 8.1 Hz, 1H, CH), 7.09 (t, J = 2.2 Hz, 1H, CH), 6.97 (ddd, J = 8.1 Hz, J = 2.0 Hz, J = 1.0 Hz, 1H, CH), 6.60 (ddd, J = 8.2 Hz, J = 2.5 Hz, J = 1.0 Hz, 1H, CH), 6.48 (m, 1H, CH), 4.34 - 4.25 (m, 2H, CH2), 3.80 (t, J = 5.6 Hz, 2H, CH2), 3.78 (s, 3H, OCH3), 3.05 - 2.85 (m, 4H, 2 x CH2), 2.85 - 2.73 (m, 2H, CH2), 2.62 - 2.42 (m, 2H, CH2). HRMS (EI-MS) m / z C 22 H 24 NO2[M+H] + Calculated value: 390.1925, Measured value: 390.1923.

[0365] Example 69: 3-(4-(5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridine-1-carboxamido)phenyl dimethylcarbamate (122) The reaction was carried out as described in general procedure H using 3-aminophenyldimethylcarbamate (45 mg, 0.25 mmol) and amine 107 (72 mg, 0.30 mmol, 1.2 equiv.) in THF (4 ml). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 10 / 90 to give compound 122 (99 mg, 89%) as a pale yellow solid. f (CH2Cl2 / acetone 20 / 80) 0.24. Mp: 227-229°C. 1H NMR (250 MHz, DMSO-d6) δ 11.96 (s, 1H, NH), 8.68 (br s, 1H, NH), 8.58 (s, 1H, H2), 7.38 (d, J = 2.2 Hz, 1H, CH), 7.32 (d, J = 8.1 Hz, 1H, CH), 7.22 (t, J = 8.0 Hz, 1H, CH), 6.69 (d, J = 7.9 Hz, 1H, CH), 6.62 - 6.53 (m, 1H, CH), 4.36 - 4.18 (m, 2H, CH2), 3.70 (t, J = 5.3 Hz, 2H, CH2), 3.03 (s, 3H, NCH3), 2.97 - 2.81 (m, 7H, 2 x CH2+ 2.80 - 2.69 (m, 2H, CH2), 2.46 - 2.35 (m, 2H, CH2). HRMS (EI-MS) m / z C 24 H 27 N6O3[M+H] + Calculated value: 447.2139, Measured value: 447.2141.

[0366] Example 70: N-([1,1'-biphenyl]-3-yl)-4-(5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (123) The reaction was carried out as described in general procedure H using 3-aminobiphenyl (42 mg, 0.25 mmol) and amine 107 (72 mg, 0.30 mmol, 1.2 equiv.) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 10 / 90 to give compound 123 (63 mg, 58%) as a white solid. f (CH2Cl2 / acetone 50 / 50) 0.26. Mp: 245-247°C. 1H NMR (250 MHz, DMSO-d6) δ 11.96 (br s, 1H, NH), 8.66 (br s, 1H, NH), 8.58 (s, 1H, CH), 7.87 - 7.78 (m, 1H, CH), 7.66 - 7.58 (m, 2H, 2 x CH), 7.57 - 7.41 (m, 3H, 3 x CH), 7.40 - 7.28 (m, 2H, 2 x CH), 7.28 - 7.17 (m, 1H, CH), 6.66 - 6.52 (m, 1H, CH), 4.32 - 4.23 (m, 2H, CH2), 3.73 (t, J = 5.5 Hz, 2H, CH2), 2.94 - 2.81 (m, 4H, 2 x CH2), 2.79 - 2.70 (m, 2H, CH2), 2.48 - 2.35 (m, 2H, CH2). HRMS (EI-MS) m / z C 27 H 26 N5O [M+H] + Calculated value: 436.2132, Measured value: 436.2131.

[0367] Example 71: N-(3-(pyridin-4-yl)phenyl)-4-(5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (124) The reaction was carried out as described in general procedure H using 3-(pyridin-4-yl)aniline (43 mg, 0.25 mmol) and amine 107 (72 mg, 0.30 mmol, 1.2 equiv.) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 60 / 40 to 0 / 100 to give compound 124 (84 mg, 77%) as an off-white solid. f (acetone) 0.16, Mp:>260℃. 1H NMR (400 MHz, DMSO-d6) δ 11.97 (br s, 1H, NH), 8.74 (br s, 1H, NH), 8.64 (d, J = 5.7 Hz, 2H, 2 x CH), 8.58 (s, 1H, CH), 7.98 - 7.93 (m, 1H, CH), 7.66 - 7.61 (m, 3H, 3 x CH), 7.44 - 7.34 (m, 2H, 2 x CH), 6.64 - 6.56 (m, 1H, CH), 4.32 - 4.24 (m, 2H, CH2), 3.74 (t, J = 5.6 Hz, 2H, CH2), 2.92 - 2.82 (m, 4H, 2 x 2.80 - 2.72 (m, 2H, CH2), 2.46 - 2.37 (m, 2H, CH2). HRMS (EI-MS) m / z C 26 H 25 NO [M+H] + Calculated value: 437.2084, Measured value: 437.2080.

[0368] Example 72: N-(3-phenoxyphenyl)-4-(5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (125) The reaction was carried out as described in general procedure G using amine 107 (60 mg, 0.25 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 30 / 70 to give compound 125 (67 mg, 59%) as a yellow solid. f (CH2Cl2 / acetone 50 / 50) 0.26. p: decomposition 154°C. 1H NMR (400 MHz, DMSO-d6) δ 11.96 (br s, 1H, NH), 8.64 (br s, 1H, NH), 8.57 (s, 1H, CH), 7.39 (t, J = 7.8 Hz, 2H, 2 x CH), 7.33 - 7.20 (m, 3H, 3 x CH), 7.13 (t, J = 7.4 Hz, 1H, CH), 7.01 (d, J = 8.0 Hz, 2H, 2 x CH), 6.61 (d, J = 8.0 Hz, 1H, CH), 6.58 - 6.53 (m, 1H, CH), 4.25 - 4.16 (m, 2H, CH2), 3.68 (t, J = 5.6 HRMS (EI-MS) m / z C 27 H 26 NO2[M+H] + Calculated value: 452.2081, Measured value: 452.2079.

[0369] Example 73: N-(3-phenoxyphenyl)-4-(6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indol-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (126) The reaction was carried out as described in general procedure G using amine 108 (60 mg, 0.24 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 20 / 80 to give compound 126 (87 mg, 81%) as an off-white solid. f (CH2Cl2 / acetone 20 / 80) 0.31. Mp: decomposition 171°C. 1H NMR (400 MHz, DMSO-d6) δ 11.74 (br s, 1H, NH), 8.65 (br s, 1H, NH), 8.56 (s, 1H, CH), 7.39 (t, J = 7.8 Hz, 2H, 2 x CH), 7.34 - 7.20 (m, 3H, 3 x CH), 7.13 (t, J = 7.4 Hz, 1H, CH), 7.01 (d, J = 8.0 Hz, 2H, 2 x CH), 6.61 (d, J = 8.0 Hz, 1H, CH), 6.08 - 6.01 (m, 1H, CH), 4.23 - 4.11 (m, 2H, CH2), 3.69 (t, J = 5.6 Hz, 2H, CH2), 2.75 - 2.69 (m, 2H, CH2), 2.69 - 2.63 (m, 2H, CH2), 2.60 - 2.54 (m, 2H, CH2), 1.86 - 1.78 (m, 2H, CH2), 1.78 - 1.68 (m, 2H, CH2). HRMS (EI-MS) m / z C 28 H 28 NO2[M+H] + Calculated value: 466.2238, Measured value: 466.2236.

[0370] Example 74: N-(3-cyanophenyl)-4-(7,9,11-triazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraen-12-yl)-3,6-dihydropyridine-1(2H)-carboxamide (127) The reaction was carried out as described in General Procedure G using 107.HCl (50 mg, 0.16 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 40 / 60 to give compound 127 (42 mg, 69%) as a white solid. f (CH2Cl2 / acetone 50 / 50) 0.4. Mp: decomposition > 266°C. 1H NMR (250 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.92 (s, 1H), 8.58 (s, 1H), 7.98 (s, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.57 - 7.30 (m, 2H), HRMS (EI-MS) m / z C 22 H 21 NO[M+H] + Calculated value: 385.1771, Measured value: 385.1768.

[0371] Example 75: 4-(7,9,11-triazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraen-12-yl)-N[3(trifluoromethyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxamide (128) The reaction was carried out as described in General Procedure G using 107.HCl (50 mg, 0.15 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 50 / 50 to give compound 128 (55 mg, 80%) as a white solid. f (CH2Cl2 / acetone 50 / 50) 0.22. Mp: decomposition 220°C. 1H NMR (250 MHz, DMSO-d6) δ 11.90 (s, 1H, NH), 8.86 (s, 1H, NH), 8.57 (s, 1H, CH), 7.96 (s, 1H, CH), 7.80 (d, J = 8.4 Hz, 1H, CH), 7.48 (t, J = 8.0 Hz, 1H, CH), 7.27 (d, J = 8.2 Hz, 1H, CH), 6.73 - 6.46 (m, 1H, CH), 4.31 - 4.23 (m, 2H, CH2), 3.73 (t, J = 5.6 Hz, 2H, CH2), 2.95 - 2.81 (m, 4H, CH2), 2.75 (brs, 2H, CH2), 2.47 - 2.32 (m, 2H, CH2). 19 F NMR (235 MHz, DMSO-d6) δ -61.26 (CF3). HRMS (EI-MS) m / z C 22 H 21 F3N5O[M+H] + Calculated value: 428.1693, Measured value: 428.1690.

[0372] Example 76: N-(3-ethylphenyl)-4-(7,9,11-triazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraen-12-yl)-3,6-dihydropyridine-1(2H)-carboxamide (129) The reaction was carried out as described in general procedure H using the amine salt 107.HCl (58 mg, 0.19 mmol) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 60 / 40 to give compound 129 (45 mg, 75%) as a pale yellow solid. f (CH2Cl2 / acetone 70 / 30) 0.24. Mp: decomposition 192°C. 1H NMR (250 MHz, MeOD-d4) δ 8.54 (s, 1H, CH), 7.35 - 7.10 (m, 3H, CH), 6.97 - 6.81 (m, 1H, CH), 6.48 (s, 1H, CH), 4.36 - 4.20 (m, 2H, CH2), 3.79 (t, J = 5.6 Hz, 2H, CH2), 2.99 - 2.84 (m, 4H, CH2), 2.80 (s, 2H, CH2), 2.69 - 2.41 (m, 4H, CH2), 1.23 (t, J = 7.6 Hz, 3H, CH3). HRMS (EI-MS) m / z C 23 H 26 NO[M+H] + Calculated value: 388.2132, Measured value: 388.2130.

[0373] Example 77: N-(3-morpholinophenyl)-4-(7,9,11-triazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraen-12-yl)-3,6-dihydropyridine-1(2H)-carboxamide (130) The reaction was carried out as described in general procedure H using the amine salt 107.HCl (51 mg, 0.16 mmol) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 40 / 60 to afford 130 (40 mg, 67%) as a pale yellow solid. f (CH2Cl2 / acetone 30 / 70) 0.32. Mp: decomposition 250°C. 1H NMR (250 MHz, DMSO-d6) δ 11.96 (s, 1H, NH), 8.57 (s, 1H, CH), 8.42 (s, 1H, NH), 7.30 - 6.90 (m, 3H, CH), 6.57 (brs, 2H, CH + CH), 4.24 (s, 2H, CH2), 3.86 - 3.58 (m, 6H, CH2), 3.05 (brs, 4H, CH2), 2.87 (brs, 4H, CH2), 2.73 (s, 2H, CH2), 2.45 - 2.29 (m, 2H, CH2). HRMS (EI-MS) m / z C 25 H 29 N6O2[M+H] + Calculated value: 445.2347, Measured value: 445.2347.

[0374] Example 78: N-[3-(dimethylcarbamoylamino)phenyl]-4-(7,9,11-triazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraen-12-yl)-3,6-dihydropyridine-1(2H)-carboxamide (131) The reaction was carried out as described in General Procedure H using the amine salt 107.HCl (51 mg, 0.16 mmol) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone / MeOH from 100 / 0 / 0 to 0 / 95 / 5 to give compound 131 (37 mg, 62%) as a white solid. f (Acetone) 0.42. Mp: Decomposition 208°C. 1H NMR (250 MHz, DMSO-d6) δ 11.99 (s, 1H, NH), 8.58 (s, 1H, CH), 8.52 (s, 1H, NH), 8.20 (s, 1H, NH), 7.66 (s, 1H, CH), 7.06 (s, 3H, CH), 6.57 (s, 1H, CH), 4.24 (s, 2H, CH2), 3.69 (t, J = 5.4 Hz, 2H, CH2), 2.98 - 2.80 (m, 10H, 2x CH3+ 2x CH2), 2.73 (s, 2H, CH2), 2.46 - 2.30 (m, 2H, CH2). HRMS (EI-MS) m / z C 24 H 28 N7O2[M+H] + Calculated value: 446.2299, Measured value: 446.2300.

[0375] Example 79: N-[3-[(dimethylamino)methyl]phenyl]-4-(7,9,11-triazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraen-12-yl)-3,6-dihydropyridine-1(2H)-carboxamide (132) The reaction was carried out as described in general procedure H using the amine salt 107.HCl (54 mg, 0.17 mmol) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone 100 / 0 to 86 / 14 (0.1% NH in water) to give compound 132 (25 mg, 42%) as a pale yellow solid. f (CH2Cl2 / MeOH / NH3( 水溶液 )91 / 9 / 0.1)0.21. Mp: Decomposition 180℃. 1 H NMR (250 MHz, DMSO-d6) δ 11.97 (s, 1H, NH), 8.70 - 8.43 (m, 2H, NH + CH ar), 7.50 (s, 1H, CH), 7.44 (d, J = 8.3 Hz, 1H, CH), 7.21 (t, J = 7.8 Hz, 1H, CH), 6.91 (d, J = 7.5 Hz, 1H, CH), 6.57 (s, 1H, CH), 4.25 (s, 2H, CH2), 3.70 (t, J = 4.4 Hz, 2H, CH2), 3.50 (s, 2H, CH2), 3.08 - 2.80 (m, 4H, CH2), 2.73 (s, 2H, CH2), 2.45 - 2.32 (m, 2H, CH2), 2.25 (s, 6H, CH3). HRMS (EI-MS) m / z C 24 H 29 NO[M+H] + Calculated value: 417.2397, Measured value: 417.2397.

[0376] Example 80: N-[3-(methylcarbamoyl)phenyl]-4-(7,9,11-triazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraen-12-yl)-3,6-dihydropyridine-1(2H)-carboxamide (133) The reaction was carried out as described in general procedure H using the amine salt 107.HCl (53 mg, 0.17 mmol) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 10 / 90 to give compound 133 (55 mg, 94%) as a white solid. f (CH2Cl2 / acetone 10 / 90) 0.27. Mp: decomposition 228°C. 1H NMR (250 MHz, DMSO-d6) δ 11.96 (s, 1H, NH), 8.74 (s, 1H, NH), 8.58 (s, 1H, CH), 8.39 - 8.28 (m, 1H, CH), 7.95 (s, 1H, CH), 7.68 (d, J = 8.1 Hz, 1H, CH), 7.47 - 7.22 (m, 2H, CH), 6.58 (s, 1H, CH), 4.27 (s, 2H, CH2), 3.72 (t, J = 5.5 Hz, 2H, CH2), 2.94 - 2.81 (m, 4H, 2 x CH2), 2.81 - 2.67 (m, 5H, CH2, CH3), 2.46 - 2.37 (m, 2H, CH2). HRMS (EI-MS) m / z C 23 H 25 N6O2[M+H] + Calculated value: 417.2033, Measured value: 417.2034.

[0377] Example 81: N-[3-(dimethylcarbamoyl)phenyl]-4-(7,9,11-triazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraen-12-yl)-3,6-dihydropyridine-1(2H)-carboxamide (134) The reaction was carried out as described in general procedure H using the amine salt 107.HCl (52 mg, 0.17 mmol) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone 100 / 0 to 05 / 95 to give compound 134 (50 mg, 83%) as a white solid. f (Acetone) 0.21. Mp: Decomposition 245°C. 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H, NH), 8.70 (s, 1H, NH), 8.57 (s, 1H, CH), 7.59 - 7.53 (m, 2H, CH), 7.30 (t, J = 7.8 Hz, 1H, CH), 6.95 (d, J = 7.6, Hz, 1H, CH), 6.62 - 6.52 (m, 1H, CH), 4.28 - 4.24 (m, 2H, CH2), 3.71 (t, J = 5.5 Hz, 2H, CH2), 3.03 - 2.81 (m, 10H, CH3+ CH2), 2.74 (m, 2H, CH2), 2.48 - 2.34 (m, 2H, CH2). HRMS (EI-MS) m / z C 24 H 26 N6O2[M+H] + Calculated value: 431.2190, Measured value: 431.2189.

[0378] Example 82: N-[3-(methoxymethoxymethyl)phenyl]-4-(7,9,11-triazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraen-12-yl)-3,6-dihydropyridine-1(2H)-carboxamide (135) The reaction was carried out as described in general procedure H using the amine salt 107.HCl (113 mg, 0.36 mmol) in THF (8 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 30 / 70 to give compound 135 (120 mg, 92%) as a white solid. f (CH2Cl2 / acetone 30 / 70) 0.35. Mp: decomposition 196°C. 1H NMR (250 MHz, DMSO-d6) δ 11.95 (s, 1H, NH), 8.67 - 8.49 (m, 2H, NH + CH), 7.58 - 7.35 (m, 2H, CH), 7.21 (t, J = 7.7 Hz, 1H, CH), 6.90 (d, J = 7.4 Hz, 1H, CH), 6.65 - 6.43 (m, 1H, CH), 4.64 (s, 2H, CH2), 4.47 (s, 2H, CH2), 4.2 (s, 2H, CH2), 3.70 (t, J = 5.3 Hz, 2H, CH2), 3.30 (s, 3H, CH3), 2.99 - 2.80 (m, 4H, CH2), 2.73 (s, 2H, CH2), 2.47 - 2.33 (m, 2H, CH2). HRMS (EI-MS) m / z C 24 H 28 N5O3[M+H] + Calculated value: 434.2187, Measured value: 434.2186.

[0379] Example 83: N-[3-(4-methoxyphenyl)phenyl]-4-(7,9,11-triazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraen-12-yl)-3,6-dihydropyridine-1(2H)-carboxamide (136) The reaction was carried out as described in General Procedure H using 107.HCl (48 mg, 0.15 mmol) in THF (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 10 / 90 to give compound 136 (45 mg, 75%) as a pale yellow solid. f (CH2Cl2 / acetone 20 / 80) 0.56. Mp: decomposition 240°C. 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H, NH), 8.63 (s, 1H, NH), 8.58 (s, 1H, CH), 7.77 (s, 1H, CH), 7.55 (d, J = 8.3 Hz, 2H, CH), 7.48 (d, J = 8.1 Hz, 1H, CH), 7.30 (t, J = 7.9 Hz, 1H, CH), 7.19 (d, J = 7.7 Hz, 1H, CH), 7.02 (d, J = 8.3 Hz, 2H, CH), 6.59 (s, 1H, CH), 4.27 (s, 2H, CH2), 3.79 (s, 3H, CH3), 3.73 (t, J = 4.8 Hz, 2H, CH2), 2.88 (s, 4H, CH2), 2.75 (s, 2H, CH2), 2.47 - 2.36 (m, 2H, CH2). HRMS (EI-MS) m / z C 28 H 28 NO2[M+H] + Calculated value: 466.2238, Measured value: 466.2240.

[0380] Example 84: N-[3-(3-methoxyphenyl)phenyl]-4-(7,9,11-triazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraen-12-yl)-3,6-dihydropyridine-1(2H)-carboxamide (137) The reaction was carried out as described in general procedure H using the amine salt 107.HCl (48 mg, 0.15 mmol) in THF (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 40 / 60 to give compound 137 (34 mg, 57%) as a white solid. f (CH2Cl2 / acetone 40 / 60) 0.53. Mp: decomposition 208°C. 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H, NH), 8.65 (s, 1H, NH), 8.58 (s, 1H, CH), 7.80 (s, 1H, CH), 7.55 (d, J = 8.0 Hz, 1H, CH), 7.38 (t, J = 8.0 Hz, 1H, CH), 7.33 (t, J = 7.9 Hz, 1H, CH), 7.24 (d, J = 8.3 Hz, 1H, CH), 7.18 (d, J = 7.7 Hz, 1H, CH), 7.13 (s, 1H, CH), 6.94 (dd, J = 8.2, 2.5 Hz, 1H, CH), 6.59 (s, 1H, CH), 4.31 - 4.23 (m, 2H, CH2), 3.82 (s, 3H, CH3), 3.73 (t, J = 5.6 Hz, 2H, CH2), 2.97 - 2.84 (m, 4H, CH2), 2.76 (s, 2H, CH2), 2.47 - 2.37 (m, 2H, CH2). HRMS (EI-MS) m / z C 28 H 28 NO2[M+H] + Calculated value: 466.2238, Measured value: 466.2232.

[0381] Family 7. Tricyclic derivatives of pyrrolopyridine and unsubstituted hydropyridine with heteroalkyl rings at the 2- and 3-positions.

[0382] [ka]

[0383] [Table 8]

[0384] 6-(2-(tetrahydro-4H-thiopyran-4-ylidene)hydrazinyl)pyrimidin-4-ol (138) The reaction was carried out as described in General Procedure A using 4-hydroxy-6-hydrazinylpyrimidine (1.0 g, 7.93 mmol) and tetrahydro-4H-thiopyran-4-one (1.38 mL, 11.89 mmol, 1.5 equiv.) in EtOH (16 mL). The precipitate was filtered and washed with EtO (2×20 mL) to give compound 138 (1.51 g, 85%) as a white solid. f (CH2Cl2 / acetone 50 / 50) 0.14. Mp:>260°C. 1 H NMR (250 MHz, DMSO-d6) δ 11.67 (br s, 1H, OH), 9.77 (s, 1H, NH), 7.90 (d, J = 0.8 Hz, 1H, CH), 5.56 (d, J = 0.8 Hz, 1H, CH), 2.81 - 2.67 (m, 6H, 3 x CH2), 2.61 - 2.53 (m, 2H, CH2). HRMS (EI-MS) m / z C9H 13 N4OS [M+H] + Calculated value: 225.0805, Measured value: 225.0804.

[0385] 6-(2-(tetrahydro-4H-pyran-4-ylidene)hydrazinyl)pyrimidin-4-ol (139) The reaction was carried out as described in General Procedure A using 4-hydroxy-6-hydrazinylpyrimidine (1.0 g, 7.93 mmol) and tetrahydro-4H-pyran-4-one (1.11 mL, 11.89 mmol, 1.5 equiv.) in EtOH (16 mL). The precipitate was filtered and washed with EtO (2×20 mL) to give compound 139 (1.28 g, 77%) as a beige solid. f (CH2Cl2 / acetone 50 / 50) 0.06. Mp:>260℃. 1H NMR (250 MHz, DMSO-d6) δ 11.65 (br s, 1H, OH), 9.74 (s, 1H, NH), 7.89 (d, J = 0.8 Hz, 1H, CH), 5.56 (d, J = 0.8 Hz, 1H, CH), 3.73 (t, J = 5.7 Hz, 2H, CH2), 3.65 (t, J = 5.8 Hz, 2H, CH2), 2.55 (t, J = 5.8 Hz, 2H, CH2), 2.36 (t, J = 5.6 Hz, 2H, CH2HRMS (EI-MS) m / z C9H 13 N4O2[M+H] + Calculated value: 209.1033, Measured value: 209.1032.

[0386] Benzyl 4-(2-(6-hydroxypyrimidin-4-yl)hydrazono)piperidine-1-carboxylate (140) The reaction was carried out as described in General Procedure A using 4-hydroxy-6-hydrazinylpyrimidine (1.0 g, 7.93 mmol) and 1-Cbz-4-piperidone (2.77 g, 11.89 mmol, 1.5 equiv.) in EtOH (16 mL). The precipitate was filtered and washed with EtO (2 x 20 mL) to give compound 140 (2.41 g, 89%) as a white solid. f (CH2Cl2 / acetone 50 / 50) 0.11. Mp: 242-244°C. 1 H NMR (250 MHz, DMSO-d6) δ 11.67 (br s, 1H, OH), 9.72 (s, 1H, NH), 7.90 (d, J = 0.9 Hz, 1H, CH), 7.50 - 7.19 (m, 5H, 5 x CH), 5.56 (d, J = 0.8 HRMS (EI-MS) m / z C 17 H 20 N5O3[M+H]+ Calculated value: 342.1561, Measured value: 342.1560.

[0387] 5,7,8,9-Tetrahydrothiopyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-ol (141) The reaction was carried out as described in general procedure B using hydrazone 138 (0.5 g, 2.23 mmol) in tetralin (10 mL). The precipitate was filtered and washed several times with PE (3 × 10 mL) and EtO (10 mL) to give compound 141 (0.40 g, 86%) as a brown solid. f (CH2Cl2 / MeOH / NH4OH 90 / 9 / 1)0.39. Mp:>260℃. 1 H NMR (250 MHz, DMSO-d6) δ 11.70 (br s, 1H, OH), 11.60 (s, 1H, NH), 7.73 (s, 1H, CH), 3.85 - 3.76 (m, 2H, CH2), 2.96 - 2.75 (m, 4H, 2 x CH2). HRMS (EI-MS) m / z C9H 10 N3OS [M+H] + Calculated value: 208.0539, Measured value: 208.0538.

[0388] 5,7,8,9-Tetrahydropyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-ol (142) The reaction was carried out as described in general procedure B using hydrazone 139 (0.5 g, 2.40 mmol) in tetralin (10 mL). The precipitate was filtered and washed several times with PE (3 × 10 mL) and EtO (10 mL) to give compound 142 (0.44 g, 95%) as a brown solid. f (CH2Cl2 / MeOH / NH4OH 90 / 9 / 1)0.26. Mp:>260℃. 1H NMR (250 MHz, DMSO-d6) δ 11.73 (br s, 1H, OH), 11.67 (s, 1H, NH), 7.74 (s, 1H, CH), 4.79 - 4.65 (m, 2H, CH2), 3.87 (t, J = 5.5 Hz, 2H, CH2), 2.66 (t, J = 5.5 Hz, 2H, CH2). HRMS (EI-MS) m / z C9H 10 N3O2[M+H] + Calculated value: 192.0768, Measured value: 192.0769.

[0389] Benzyl 4-hydroxy-5,7,8,9-tetrahydro-6H-pyrido[3',4':4,5]pyrrolo[2,3-d]pyrimidine-6-carboxylate (143) The reaction was carried out as described in general procedure B using hydrazone 140 (0.5 g, 1.46 mmol) in tetralin (10 mL). The precipitate was filtered and washed several times with PE (3 × 10 mL) and EtO (10 mL) to give compound 143 (0.45 g, 94%) as a beige solid. f (CH2Cl2 / MeOH / NH4OH 90 / 9 / 1)0.42. Mp:>260℃. 1 H NMR (250 MHz, DMSO-d6) δ 11.76 (br s, 1H, OH), 11.70 (s, 1H, NH), 7.75 (s, 1H, H2), 7.45 - 7.26 (m, 5H, 5xH), 5.12 (s, 2H, OCH2), 4.61 (s, 2H, CH 2(5) ), 3.73 (t, J = 5.8 Hz, 2H, CH 2(7) ), 2.68 (t, J = 5.7 Hz, 2H, CH 2(8) ). HRMS (EI-MS) m / z C 17 H 17 N4O3[M+H] + Calculated value: 325.1295, Measured value: 325.1294.

[0390] 4-Chloro-5,7,8,9-tetrahydrothiopyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidine (144) The reaction was carried out as described in General Procedure C using tricyclic compound 141 (1.0 g, 4.83 mmol) in POCl (35 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 100 / 0 to 70 / 30 to give compound 144 (0.74 g, 68%) as a beige solid. f (CH2Cl2 / acetone 60 / 40) 0.28. Mp:>260℃. 1 H NMR (250 MHz, DMSO-d6) δ 12.34 (br s, 1H, NH), 8.46 (s, 1H, CH), 3.95 (s, 2H, CH2), 3.03 - 2.92 (m, 4H, 2 x CH2). HRMS (EI-MS) m / z C9H9ClN3S [M+H] + Calculated value: 226.0200, Measured value: 226.0200.

[0391] 4-Chloro-5,7,8,9-tetrahydropyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidine (145) In a round-bottom flask, 142 (0.2 g, 1.05 mmol) was suspended in CHCl3 (4 mL) and treated with 2 drops of N,N-dimethylformamide and oxalyl chloride (0.4 mL, 4.73 mmol, 4.5 equiv.). The reaction mixture was heated to reflux for 5 h. The solvent was removed under reduced pressure, and the residue was dissolved in CHCl2 (100 mL) and shaken with saturated aqueous NaCO3 (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl2 / acetone from 100 / 0 to 50 / 50 to give compound 145 (65 mg, 30%) as a beige solid. R f (CH2Cl2 / acetone 70 / 30) 0.34. Mp:>260℃. 1H NMR (250 MHz, DMSO-d6) δ 12.43 (s, 1H, NH), 8.79 - 8.13 (m, 1H, CH), 5.07 - 4.76 (m, 2H, CH2), 3.96 (t, J = 5.4 Hz, 2H, CH2), 2.90 - 2.75 (m, 2H, CH2). HRMS (EI-MS) m / z C9H9ClN3O [M+H] + Calculated value: 210.0429, Measured value: 210.0428.

[0392] Benzyl 4-chloro-5,7,8,9-tetrahydro-6H-pyrido[3',4':4,5]pyrrolo[2,3-d]pyrimidine-6-carboxylate hydrochloride (146) The reaction was carried out as described in General Procedure C using tricyclic compound 143 (1.0 g, 3.08 mmol) in POCl (25 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 20 / 80 to give compound 146 (0.62 g, 53%) as a white solid. f (CH2Cl2 / acetone 60 / 40) 0.31. Mp: 180-182°C. 1 H NMR (250 MHz, DMSO-d6) δ 12.45 (s, 1H, NH), 8.48 (s, 1H, CH), 7.52 - 7.22 (m, 5H, 5 x CH), 5.14 (s, 2H, OCH2), 5.00 (br s, 1H, H + ), 4.87 - 4.64 (m, 2H, CH2), 3.93 - 3.69 (m, 2H, CH2), 2.91 - 2.78 (m, 2H, CH2). HRMS (EI-MS) m / z C 17 H 17 ClN4O2[M+H] + Calculated value: 343.0956, Measured value: 343.0954.

[0393] 4-Chloro-6-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-d]pyrimidine (147) In a round-bottom flask, 146 (2.3 g, 6.71 mmol) was dissolved in anhydrous THF (90 mL) under argon, and the solution was cooled to 0 °C for 10 min. LiAlH (1.27 g, 33.55 mmol, 5.0 equiv.) was then added slowly, and the mixture was stirred at 0 °C for another 10 min and at room temperature for 2 h. Water (2 mL), 2 M aqueous NaOH (2 mL), and HO (2 mL) were added dropwise to the mixture successively. The precipitate was filtered through a Celite pad and washed with MeOH (50 mL). The solvent was removed under reduced pressure, and the crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / MeOH from 95 / 5 to 85 / 15 to give compound 147 (1.18 g, 79%) as a white solid. f (CH2Cl2 / MeOH 90 / 10)0.17. Mp:250~252℃. 1 H NMR (250 MHz, MeOD-d4) δ 8.42 (s, 1H, CH), 3.86 - 3.82 (m, 2H, CH2), 2.99 - 2.85 (m, 4H, 2 x CH2), 2.57 (s, 3H, NCH3). HRMS (EI-MS) m / z C 10 H 12 ClN4[M+H] + Calculated value: 223.0745, Measured value: 223.0745.

[0394] tert-Butyl 4-(5,7,8,9-tetrahydrothiopyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (148) The reaction was carried out as described in general procedure D using chlorinated tricyclic compound 144 (0.35 g, 1.55 mmol) and N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.52 g, 1.71 mmol, 1.1 equiv.) in THF (9 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 40 / 60 to give compound 148 (0.49 g, 85%) as a white solid. f (CH2Cl2 / acetone 80 / 20) 0.21. Mp: 211-213°C. 1 H NMR (250 MHz, MeOD-d4) δ 8.57 (s, 1H, CH), 6.06 - 5.95 (m, 1H, CH), 4.21 - 4.10 (m, 2H, CH2), 3.76 - 3.66 (m, 4H, 2 x CH2), 3.10 - 2.93 (m, 2.69 - 2.56 (m, 2H, CH2), 1.51 (s, 9H, 3 x CH3). HRMS (EI-MS) m / z C 19 H 25 N4O2S [M+H] + Calculated value: 373.1693, Measured value: 373.1693.

[0395] tert-Butyl 4-(5,7,8,9-tetrahydropyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (149) The reaction was carried out as described in General Procedure D using chlorinated tricyclic compound 145 (0.35 g, 1.67 mmol) and N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.57 g, 1.84 mmol, 1.1 equiv.) in THF (9 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 60 / 40 to give compound 149 (0.53 g, 89%) as a white solid. f(CH2Cl2 / acetone 80 / 20) 0.27. Mp: 236-238°C. 1 H NMR (250 MHz, DMSO-d6) δ 12.02 (s, 1H, NH), 8.61 (s, 1H, CH), 6.11 - 5.94 (m, 1H, CH), 4.67 (s, 2H, CH2), 4.11 - 4.00 (m, 2H, CH2), 4.01 - 3.90 (m, 2H, CH2), 3.63 - 3.50 (m, 2H, CH2), 2.89 - 2.79 (m, 2H, CH2), 2.64 - 2.56 (m, 2H, CH2), 1.45 (s, 9H, 3 x CH3). HRMS (EI-MS) m / z C 19 H 25 N4O3[M+H] + Calculated value: 357.1921, Measured value: 357.1921.

[0396] tert-Butyl 4-(6-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (150) The reaction was carried out as described in General Procedure D using chlorinated tricyclic compound 147 (0.35 g, 1.58 mmol) and N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.54 g, 1.73 mmol, 1.1 equiv.) in THF (9 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone / NHOH from 70 / 28 / 2 to 0 / 98 / 2. After evaporation, the product was dissolved in CHCl (20 mL) and the pH was adjusted to 7 by adding 1 M aqueous HCl. The organic layer was separated, dried over MgSO, filtered, and concentrated in vacuo to give compound 150 (0.46 g, 79%) as a pink solid. f (CH2Cl2 / acetone / NH4OH 70 / 28 / 2) 0.18. Mp: 210-212°C. 1H NMR (250 MHz, DMSO-d6) δ 11.90 (s, 1H, NH), 8.57 (s, 1H, CH), 6.09 - 5.96 (m, 1H, CH), 4.05 (s, 2H, CH2), 3.57 (t, J = 5.4 Hz, 2H, CH2), 3.40 (s, 2H, CH2), 2.86 - 2.77 (m, 2H, CH2), 2.75 - 2.65 (m, 2H, CH2), 2.63 - 2.54 (m, 2H, CH2), 2.39 (s, 3H, NCH3), 1.44 (s, 9H, 3 x CH3). HRMS (EI-MS) m / z C 20 H 28 NO2[M+H] + Calculated value: 370.2238, Measured value: 370.2236.

[0397] 4-(1,2,3,6-tetrahydropyridin-4-yl)-5,7,8,9-tetrahydrothiopyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidine (151) The reaction was carried out as described in General Procedure F1 using N-Boc protected compound 148 (1.0 g, 2.68 mmol) in CHCl (80 mL). The reaction was complete after 1 h. Workup afforded compound 151 (0.56 g, 98%) as a beige solid. Mp: 241-243 °C. 1 H NMR (250 MHz, MeOD-d4) δ 8.56 (s, 1H, CH), 6.01 (tt, J = 3.2, 1.8 Hz, 1H, CH), 3.83 - 3.74 (m, 2H, CH2), 3.53 (dt, J = 2.9 Hz, J = 2.9 Hz, 2H, HRMS (EI-MS) m / z C 14 H 17 N4S [M+H] + Calculated value: 273.1168, Measured value: 273.1168.

[0398] 4-(1,2,3,6-tetrahydropyridin-4-yl)-5,7,8,9-tetrahydropyrano[3',4':4,5]pyrrolo[2,3 d]pyrimidine (152) The reaction was carried out as described in General Procedure F1 using N-Boc protected compound 149 (1.0 g, 2.81 mmol) in CHCl (80 mL). The reaction was complete after 1 h. Workup afforded compound 152 (0.60 g, 83%) as an off-white solid. Mp: 231-233 °C. 1 H NMR (250 MHz, DMSO-d6) δ 12.01 (br s, 1H, NH), 8.59 (s, 1H, CH), 6.07 - 5.97 (m, 1H, CH), 4.72 - 4.62 (m, 2H, CH2), 3.95 (t, J = 5.6 Hz, 2H, HRMS (EI-MS) m / z C 14 H 17 N4O [M+H] + Calculated value: 257.1397, Measured value: 257.1396.

[0399] 6-Methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-d]pyrimidine (153) The reaction was carried out as described in General Procedure F1 using N-Boc protected compound 150 (1.0 g, 2.71 mmol) in CH2Cl2 (80 mL). The reaction was complete after 1 h. Workup afforded compound 153 (0.61 g, 84%) as a beige solid. Mp: decomposition 226 °C. 1H NMR (250 MHz, MeOD-d4) δ 8.58 (s, 1H, CH), 6.11 - 6.04 (m, 1H, CH), 3.69 - 3.57 (m, 4H, 2 x CH2), 3.21 (t, J = 5.8 Hz, 2H, CH2), 3.04 - 2.86 (m, 4H, 2 x CH2), 2.72 - 2.63 (m, 2H, CH2), 2.54 (s, 3H, NCH3). HRMS (EI-MS) m / z C 15 H 20 N5[M+H] + Calculated value: 270.1713, Measured value: 270.1713.

[0400] Example 85: N-(3-fluorophenyl)-4-(5,7,8,9-tetrahydrothiopyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (154) The reaction was carried out as described in general procedure G using amine 151 (70 mg, 0.26 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 20 / 80 to give compound 154 (86 mg, 83%) as a beige solid. f (CH2Cl2 / acetone 40 / 60) 0.27. Mp: decomposition 200°C. 1 H NMR (400 MHz, DMSO-d6) δ 11.96 (br s, 1H, NH), 8.77 (br s, 1H, NH), 8.61 (s, 1H, CH), 7.48 (d, J = 12.3 Hz, 1H, CH), 7.35 - 7.22 (m, 2H, 2 x CH), 6.75 (t, J = 8.3 Hz, 1H, CH), 6.13 - 5.99 (m, 1H, CH), 4.27 - 4.17 (m, 2H, CH2), 3.84 - 3.65 (m, 4H, 2 x CH2), 3.05 - 2.91 (m, 4H, 2 x CH2), 2.74 - 2.63 (m, 2H, CH2).19 F NMR (376 MHz, DMSO-d6) δ -112.9 (s). HRMS (EI-MS) m / z C 21 H 21 FN5OS [M+H] + Calculated value: 410.1445, Measured value: 410.1440.

[0401] Example 86: N-(3-chlorophenyl)-4-(5,7,8,9-tetrahydrothiopyrano)[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (155) The reaction was carried out as described in general procedure G using amine 151 (70 mg, 0.26 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 10 / 90 to give compound 155 (89 mg, 81%) as a brown solid. f (CH2Cl2 / acetone 40 / 60) 0.28. Mp: decomposition 206°C. 1 H NMR (250 MHz, MeOD-d4) δ 8.59 (s, 1H, CH), 7.74 - 7.67 (m, 1H, CH), 7.42 - 7.33 (m, 1H, CH), 7.23 - 7.12 (m, 2H, 2 x CH), 6.06 (s, 2H, CH), 4.33 - 4.24 (m, 2H, CH2), 3.82 (t, J = 5.6 Hz, 2H, CH2), 3.77 (s, 2H, CH2), 3.11 - 2.96 (m, 4H, 2 x CH2), 2.73 (s, 2H, CH2). HRMS (EI-MS) m / z C 21 H 21 ClN5OS [M+H] + Calculated value: 426.1150, Measured value: 426.1147.

[0402] Example 87: N-(3-bromophenyl)-4-(5,7,8,9-tetrahydrothiopyrano)[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (156) The reaction was carried out as described in general procedure G using amine 151 (70 mg, 0.26 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 10 / 90 to give compound 156 (99 mg, 82%) as a brown solid. f (CH2Cl2 / acetone 40 / 60) 0.28. Mp: decomposition 220°C. 1 H NMR (250 MHz, MeOD-d4) δ 8.61 (s, 1H, CH), 7.56 (d, J = 2.2 Hz, 1H, CH), 7.32 (d, J = 8.4 Hz, 1H, CH), 7.24 (t, J = 8.0 Hz, 1H, CH), 7.01 (d, J = 7.7 Hz, 1H, CH), 6.12 - 6.04 (m, 1H, CH), 4.34 - 4.24 (m, 2H, CH2), 3.83 (t, J = 5.6 Hz, 2H, CH2), 3.77 (s, 2H, CH2), 3.12 - 2.93 (m, 4H, 2 x CH2), 2.79 - 2.67 (m, 2H, CH2). HRMS (EI-MS) m / z C 21 H 21 BrN5OS [M+H] + Calculated value: 470.0645, Measured value: 470.0639.

[0403] Example 88: N-(3-fluorophenyl)-4-(5,7,8,9-tetrahydropyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (157) The reaction was carried out as described in general procedure G using amine 152 (60 mg, 0.16 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 20 / 80 to give compound 157 (42 mg, 67%) as a beige solid. f (CH2Cl2 / acetone 50 / 50) 0.25. Mp: 223-225°C. 1 H NMR (400 MHz, DMSO-d6) δ 12.02 (br s, 1H, NH), 8.78 (br s, 1H, NH), 8.62 (s, 1H, CH), 7.48 (dt, J = 12.3 Hz, J = 2.2 Hz, 1H, CH), 7.32 - 7.21 (m, 2H, 2 x CH), 6.79 - 6.71 (m, 1H, CH), 6.11 - 6.06 (m, 1H, CH), 4.69 (s, 2H, CH2), 4.30 - 4.14 (m, 2H, CH2), 3.96 (t, J = 5.6 Hz, 2H, CH2), 3.71 (t, J = 5.6 Hz, 2H, CH2), 2.86 - 2.78 (m, 2H, CH2), 2.71 - 2.62 (m, 2H, CH2). 19 F NMR (376 MHz, DMSO-d6) δ -112.9 (s). HRMS (EI-MS) m / z C 21 H 21 FN5O2[M+H] + Calculated value: 394.1674, Measured value: 394.1673.

[0404] Example 89: N-(3-chlorophenyl)-4-(5,7,8,9-tetrahydropyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (158) The reaction was carried out as described in general procedure G using amine 152 (60 mg, 0.16 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 20 / 80 to give compound 158 (47 mg, 72%) as a beige solid. f (CH2Cl2 / acetone 50 / 50) 0.28. Mp: 224-226°C. 1 H NMR (400 MHz, DMSO-d6) δ 12.03 (br s, 1H, NH), 8.76 (br s, 1H, NH), 8.62 (s, 1H, CH), 7.69 (t, J = 2.2 Hz, 1H, CH), 7.44 (dd, J = 8.2 Hz, J = 2.1 Hz, 1H, CH), 7.26 (t, J = 8.1 Hz, 1H, CH), 6.98 (dd, J = 7.8 Hz, J = 2.1 Hz, 1H, CH), 6.13 - 6.06 (m, 1H, CH), 4.69 (s, 2H, CH2), 4.26 - 4.17 (m, 2H, CH2), 3.96 (t, J = HRMS (EI-MS) m / z C 21 H 21 ClNO2[M+H] + Calculated value: 410.1378, Measured value: 410.1377.

[0405] Example 90: N-(3-bromophenyl)-4-(5,7,8,9-tetrahydropyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (159) The reaction was carried out as described in general procedure G using amine 152 (60 mg, 0.16 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 80 / 20 to 20 / 80 to give compound 159 (52 mg, 71%) as a beige solid. f (CH2Cl2 / acetone 50 / 50) 0.27. Mp: 219-221°C. 1 H NMR (400 MHz, DMSO-d6) δ 12.03 (br s, 1H, NH), 8.74 (br s, 1H, NH), 8.62 (s, 1H, CH), 7.83 (t, J = 2.1 Hz, 1H, CH), 7.49 (dd, J = 8.1 Hz, J = 2.0 Hz, 1H, CH), 7.20 (t, J = 8.0 Hz, 1H, CH), 7.11 (dd, J = 7.9 Hz, J = 1.9 Hz, 1H, CH), 6.13 - 6.04 (m, 1H, CH), 4.69 (s, 2H, CH2), 4.25 - 4.16 (m, 2H, CH2), 3.96 (t, J = HRMS (EI-MS) m / z C 21 H 21 BrNO2[M+H] + Calculated value: 454.0873, Measured value: 454.0870.

[0406] Example 91: N-(3-fluorophenyl)-4-(6-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (160) The reaction was carried out as described in general procedure G using amine 153 (40 mg, 0.15 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / MeOH 98 / 2 to 82 / 18 to give compound 160 (41 mg, 68%) as a beige solid. f (CH2Cl2 / MeOH 85 / 15)0.16. Mp: decomposition 191℃. 1 H NMR (400 MHz, DMSO-d6) δ 12.25 (br s, 1H, NH), 8.90 (br s, 1H, NH), 8.67 (s, 1H, CH), 7.51 (d, J = 12.3 Hz, 1H, CH), 7.39 - 7.16 (m, 2H, 2 x CH), 6.75 (t, J = 8.6 Hz, 1H, CH), 6.19 - 6.00 (m, 1H, CH), 4.26 (s, 2H, CH2), 4.11 (s, 2H, CH2), 3.75 (s, 2H, CH2), 3.40 - 3.28 (m, 2H, CH2), 3.07 (s, 2H, CH2), 2.80 (s, 3H, NCH3), 2.71 (s, 2H, CH2). 19 F NMR (376 MHz, DMSO-d6) δ -112.9 (s). HRMS (EI-MS) m / z C 22 H 24 FN6O [M+H] + Calculated value: 407.1990, Measured value: 407.1988.

[0407] Example 92: N-(3-chlorophenyl)-4-(6-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (161) The reaction was carried out as described in general procedure G using amine 153 (70 mg, 0.26 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / MeOH 98 / 2 to 82 / 18 to give compound 161 (58 mg, 5%) as a beige solid. f (CH2Cl2 / MeOH 85 / 15)0.16. Mp: decomposition 193℃. 1 H NMR (400 MHz, DMSO-d6) δ 12.21 (br s, 1H, NH), 8.93 (br s, 1H, NH), 8.65 (s, 1H, CH), 7.73 (s, 1H, CH), 7.49 (d, J = 8.4 Hz, 1H, CH), 7.26 (t, J = 8.1 Hz, 1H, CH), 6.98 (d, J = 8.1 Hz, 1H, CH), 6.13 - 6.05 (m, 1H, CH), 4.26 (s, 2H, CH2), 3.99 (s, 2H, CH2), 3.79 - 3.70 (m, 2H, CH2), 3.28 - 3.16 (m, 2H, CH2), 3.04 (s, 2H, CH2), 2.78 - 2.64 (m, 5H, NCH3+ CH2). HRMS (EI-MS) m / z C 22 H 24 ClNO [M+H] + Calculated value: 423.1695, Measured value: 423.1694.

[0408] Example 93: N-(3-bromophenyl)-4-(6-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (162) The reaction was carried out as described in general procedure G using amine 153 (70 mg, 0.26 mmol) in anhydrous CHCl (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / MeOH 98 / 2 to 82 / 18 to give compound 162 (61 mg, 50%) as a beige solid. f (CH2Cl2 / MeOH 85 / 15)0.17. Mp: decomposition 191℃. 1 H NMR (400 MHz, DMSO-d6) δ 12.05 (br s, 1H, NH), 8.90 (br s, 1H, NH), 8.61 (s, 1H, CH), 7.87 (s, 1H, CH), 7.54 (d, J = 8.5 Hz, 1H, CH), 7.20 (t, J = 8.0 Hz, 1H, CH), 7.11 (d, J = 8.0 Hz, 1H, CH), 6.14 - 6.05 (m, 1H, CH), 4.23 (s, 2H, CH2), 3.79 - 3.58 (m, 4H, 2 x CH2), 2.90 (s, 4H, 2 x CH2), 2.72 - 2.62 (m, 2H, CH2), 2.50 (s, 3H, NCH3). HRMS (EI-MS) m / z C 22 H 24 BrNO [M+H] + Calculated value: 467.1189, Measured value: 467.1183.

[0409] Family 8. Fluorescent probes synthesized from LIMK / Rock inhibitors for cellular assays

[0410] [ka]

[0411] tert-Butyl N-[3-[3-(3-aminophenyl)phenoxy]propyl]carbamate (163) Compound 37 (377 mg, 1.01 mmol) was suspended in 30 mL of EtOAc in a hydrogenation reactor. Pd / C (11 mg, 0.10 mmol, 0.1 equiv.) was then added, and the reaction was stirred under 10 bar of hydrogen for 48 hours. The reaction mixture was then filtered through Celite and concentrated under reduced pressure to give compound 163 as a yellow oil (0.345 g, quantitative), which was used in the next step without further purification. f (EP / Et2O 80 / 20) 0.11. 1 H NMR (400 MHz, MeOD-d4) δ 7.29 (t, J = 7.9 Hz, 1H, CH), 7.18 - 7.07 (m, 3H, CH), 6.98 (t, J = 1.8 Hz, 1H, CH), 6.95 - 6.90 (m, 1H, CH), 6.89 - 6.85 (m, 1H, CH), 6.73 - 6.67 (m, 1H, CH), 4.03 (t, J = 6.3 Hz, 2H, CH2), 3.23 (q, J = 6.3 Hz 2H, CH2), 1.93 (p, J = 6.3 Hz, 2H, CH2), 1.44 (s, 9H, 3 x CH3). HRMS (EI-MS) m / z C 20 H 27 N2O3[M+H] + Calculated value: 343.2016, Measured value: 343.2011.

[0412] tert-Butyl (3-((3'-(4-(5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridine-1-carboxamido)-[1,1'-biphenyl]-3-yl)oxy)propyl)carbamate (164) The reaction was carried out as described in general procedure H using compound 163 (309 mg, 0.90 mmol) and amine 107.HCl (300 mg, 1.08 mmol, 1.2 equiv.) in THF (13 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 50 / 50 to give compound 164 (350 mg, 64%) as a beige solid. f (CH2Cl2 / acetone 50 / 50) 0.41. Mp: decomposition 120°C. 1 H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H, NH), 8.64 (s, 1H, NH), 8.58 (s, 1H, CH), 7.80 (t, J = 1.88 Hz, 1H, CH), 7.59 - 7.54 (m, 1H, CH), 7.40 - 7.29 (m, 2H, CH), 7.27 - 7.21 (m, 1H, CH), 7.20 - 7.16 (m, 1H, CH), 7.14 - 7.10 (m, 1H, CH), 6.96 - 6.88 (m, 2H, CH + NH), 6.66 - 6.56 (m, 1H, CH), 4.28 (d, J = 3.0 Hz, 2H, CH2), 4.04 (t, J = 6.3 Hz, 2H, CH2), 3.73 (t, J = 5.6 Hz, 2H, CH2), 3.11 (q, J = 6.6 Hz, 2H, CH2), 2.95 - 2.83 (m, 4H, 2 x CH2), 2.79 - 2.72 (m, 2H, CH2), 2.43 (p, J = 7.28 Hz, 2H, CH2), 1.86 (p, J = 6.6 Hz, 2H, CH2), 1.37 (s, 9H, 3 x CH3). HRMS (EI-MS) m / z C 35 H 41 N6O4[M+H] + Calculated value: 609.3184, Measured value: 609.3180.

[0413] tert-Butyl N-[3-[3-[3-[[4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carbonyl]amino]phenyl]phenoxy]propyl]carbamate (165) The reaction was carried out as described in general procedure H using compound 163 (210 mg, 0.61 mmol) and amine 70.HCl (205 mg, 0.74 mmol, 1.2 equiv.) in THF (13 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 50 / 50 to give compound 165 (152 mg, 41%) as a beige solid. f (CH2Cl2 / acetone 50 / 50) 0.36. Mp: decomposition 113°C. 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H, NH), 8.65 (s, 2H, NH + CH), 7.80 (s, 1H, CH), 7.55 (d, J = 8.0 Hz, 1H, CH), 7.40 - 7.29 (m, 2H, CH), 7.26 - 7.22 (m, 2H, 2 x CH), 7.18 (d, J = 7.8 Hz, 1H, CH), 7.12 (s, 1H, CH), 6.96 - 6.86 (m, 2H, NH + CH), 6.32 - 6.26 (m, 1H, CH), 4.30 - 4.20 (m, 2H, CH2), 4.04 (t, J = 6.3 Hz, 2H, CH2), 3.77 (t, J = 5.6 Hz, 2H, CH2), 3.11 (q, J = 6.5 Hz, 2H, CH2), 2.81 - 2.66 (m, 2H, CH2), 1.93 - 1.80 (m, 3H, CH + CH2), 1.37 (s, 9H, 3 x CH3), 0.86 - 0.76 (m, 2H, CH2), 0.66 - 0.57 (m, 2H, CH2). HRMS (EI-MS) m / z C 35 H 41 N6O4[M+H] +Calculated value: 609.3184, Measured value: 609.3180.

[0414] tert-Butyl N-[3-[3-[3-[[4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carbonyl]amino]phenyl]phenoxy]propyl]carbamate (166) The reaction was carried out as described in general procedure H using compound 163 (300 mg, 0.88 mmol) and amine 4 (263 mg, 1.05 mmol, 1.2 equiv.) in THF (13 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCl / acetone from 90 / 10 to 50 / 50 to give compound 166 (294 mg, 58%) as a beige solid. f (CH2Cl2 / acetone 50 / 50) 0.32. Mp: decomposition 105°C. 1 H NMR (250 MHz, DMSO-d6) δ 11.83 (s, 1H, NH), 8.67 (s, 1H, NH), 8.65 (s, 1H, CH), 7.81 (s, 1H, CH), 7.57 (d, J = 7.9 Hz, 1H, CH), 7.42 - 7.08 (m, 6H, 6 x CH), 6.97 - 6.84 (m, 2H, CH + NH), 6.06 (s, 1H, CH), 4.35 - 4.20 (m, 2H, CH2), 4.04 (t, J = 6.0 Hz, 2H, CH2), 3.76 (t, J = 5.5 Hz, 2H, CH2), 3.21 - 3.02 (m, HRMS (EI-MS) m / z C 33 H 39 N6O4[M+H] + Calculated value: 583.3027, Measured value: 583.3018.

[0415] N-(3'-(3-(3-(5,5-difluoro-7,9-dimethyl-5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborin-3-yl)propanamido)propoxy)-[1,1'-biphenyl]-3-yl)-4-(5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (167) A solution of HCl (4N in dioxane, 0.164 mL, 8 equiv.) was added slowly to a solution of urea 164 (50 mg, 0.08 mmol) in CHCl (3 mL) at 0 °C and stirred at room temperature until the reaction was complete by TLC. The solvent was then evaporated under reduced pressure, and the crude amine salt was used in the next step without further purification. Anhydrous DMF (10 mL) was added, and the reaction was placed under Ar. DIPEA (0.086 mL, 0.49 mmol, 6.0 equiv.), HOBt (33 mg, 0.25 mmol, 3.0 equiv.), and 3-(5,5-difluoro-7,9-dimethyl-5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborin-3-yl)propanoic acid (26 mg, 0.09 mmol, 1.1 equiv.) were then added, followed by EDC (38 mg, 43 μL, 0.25 mmol, 3.0 equiv.). The reaction was stirred overnight at room temperature. The reaction mixture was diluted with water (3 mL), and the aqueous layer was extracted with AcOEt (3 × 10 mL). The combined organic layers were washed with brine, dried over MgSO4, and the solvent was removed under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Cl2 / acetone from 100 / 0 to 70 / 30 to give compound 167 (16 mg, 25%) as a red solid. f (CH2Cl2 / acetone 50 / 50) 0.18. Mp: decomposition 103°C. 11H NMR (400 MHz, CDCl3) δ (ppm) 9.63 (s, 1H, NH), 8.71 (s, 1H, CH), 7.57 (s, 1H, CH), 7.53 - 7.47 (m, 1H, CH), 7.34 (t, J = 7.9 Hz, 1H, CH), 7.29 - 7.23 (m, 2H, 2 x CH), 7.19 - 7.14 (m, 1H, CH), 7.06 - 7.03 (m, 1H, CH), 6.94 (s, 1H, CH), 6.82 - 6.78 (m, 2H, NH + CH), 6.76 (d, J = 3.9 Hz, 1H, CH), 6.54 - 6.50 (m, 1H, CH), 6.24 (d, J = 4.0 Hz, 1H, CH), 6.14 (t, J = 5.7 Hz, 1H, NH), 6.06 (s, 1H, CH), 4.30 (d, J = 3.0 Hz, 2H, CH2), 3.93 (t, J = 6.1 Hz, 2H, CH2), 3.79 (t, J = 5.6 Hz, 2H, CH2), 3.42 (q, J = 6.2 Hz, 2H, CH2), 3.27 (t, J = 7.4 Hz, 2H, CH2), 2.95 (t, J = 7.2 Hz, 2H, CH2), 2.92 - 2.83 (m, 4H, 2 x CH2), 2.66 (t, J = 7.3 Hz, 2H, CH2), 2.58 - 2.43 (m, 5H, CH2+ CH3), 2.17 (s, 3H, CH3), 1.92 (p, J = 6.3 Hz, 2H, CH2). HRMS (EI-MS) m / z C 44 H 46 BF2N8O3[M+H] + Calculated value: 783.3749, Measured value: 783.3754.

[0416] N-(3'-(3-(3-(5,5-difluoro-7,9-dimethyl-5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborin-3-yl)propanamido)propoxy)-[1,1'-biphenyl]-3-yl)-4-(5-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (168) A solution of HCl (4N in dioxane, 0.26 mL, 8 equiv.) was added slowly to a solution of urea 165 (81 mg, 0.13 mmol) in CHCl (3 mL) at 0 °C and stirred at room temperature until the reaction was complete by TLC. The solvent was then evaporated under reduced pressure, and the crude amine salt was used in the next step without further purification. Anhydrous DMF (10 mL) was added, and the reaction was placed under Ar. DIPEA (0.140 mL, 0.80 mmol, 6.0 equiv.), HOBt (54 mg, 0.40 mmol, 3.0 equiv.), and 3-(5,5-difluoro-7,9-dimethyl-5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborin-3-yl)propanoic acid (43 mg, 0.15 mmol, 1.1 equiv.) were added, followed by EDC (71.2 μL, 0.40 mmol, 3.0 equiv.). The reaction was stirred overnight at room temperature. The reaction mixture was diluted with water (3 mL), and the aqueous layer was extracted with AcOEt (3 × 10 mL). The combined organic layers were washed with brine, dried over MgSO4, and the solvent was removed under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Cl2 / MeOH 100 / 0 to 90 / 10 to give compound 168 (25 mg, 24%) as a red solid. f (CH2Cl2 / acetone 90 / 10) 0.52. Mp: decomposition 138°C. 11H NMR (250 MHz, CDCl3) δ 10.18 (brs, 1H, NH), 8.80 (s, 1H, CH), 7.60 - 7.54 (m, 1H, CH), 7.50 (d, J = 8.0 Hz, 1H, CH), 7.33 (t, J = 7.8 Hz, 1H, CH), 7.26 (t, J = 7.9 Hz, 2H, 2 x CH), 7.15 (d, J = 7.8 Hz, 1H, CH), 7.04 - 7.01 (m, 1H, CH), 7.01 - 6.95 (m, 2H, CH + NH), 6.94 (s, 1H, CH), 6.82 - 6.73 (m, 2H, 2 x CH), 6.28 - 6.15 (m, 3H, 2 x CH, NH), 6.05 (s, 1H, CH), 4.32 - 4.18 (m, 2H, CH2), 3.91 (t, J = 6.1 Hz, 2H, CH2), 3.82 (t, J = 5.5 Hz, 2H, CH2), 3.41 (q, J = 6.3 Hz, 2H, CH2), 3.26 (t, J = 7.3 Hz, 2H, CH2), 2.84 (s, 2H, CH2), 2.65 (t, J = 7.3 Hz, 2H, CH2), 2.48 (s, 3H, CH3), 2.16 (s, 3H, CH3), 1.91 (p, J = 6.0 Hz, 2H, CH2), 1.85 - 1.74 (m, 1H, CH), 0.91 - 0.78 (m, 2H, CH2), 0.62 - 0.51 (m, 2H, CH2). HRMS (EI-MS) m / z C 44 H 46 BF2N8O3[M+H] + Calculated value: 783.3749, Measured value: 783.3755.

[0417] N-(3'-(3-(3-(5,5-difluoro-7,9-dimethyl-5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborin-3-yl)propanamido)propoxy)-[1,1'-biphenyl]-3-yl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (169) A solution of HCl (4N in dioxane, 0.34 mL, 8 equiv.) was added slowly to a solution of urea 166 (100 mg, 0.17 mmol) in CHCl (4 mL) at 0 °C and stirred at room temperature until the reaction was complete by TLC. The solvent was then evaporated under reduced pressure, and the crude amine salt was used in the next step without further purification. Anhydrous DMF (12 mL) was added, and the reaction was placed under Ar. DIPEA (0.18 mL, 1.03 mmol, 6.0 equiv.), HOBt (70 mg, 0.52 mmol, 3.0 equiv.), and 3-(5,5-difluoro-7,9-dimethyl-5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborin-3-yl)propanoic acid (55 mg, 0.19 mmol, 1.1 equiv.) were added, followed by EDC (91 μL, 0.52 mmol, 3.0 equiv.). The reaction was stirred overnight at room temperature. The reaction mixture was diluted with water (4 mL), and the aqueous layer was extracted with AcOEt (3 × 15 mL). The combined organic layers were washed with brine, dried over MgSO4, and the solvent was removed under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Cl2 / MeOH 100 / 0 to 90 / 10 to give compound 169 (37 mg, 28%) as a red solid. f (CH2Cl2 / acetone 95 / 5) 0.25. Mp: 130°C. 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H, NH), 8.80 (s, 1H, CH), 7.60 - 7.55 (m, 1H, CH), 7.52 - 7.48 (m, 1H, CH), 7.34 (t, J = 7.9 Hz, 1H, CH), 7.30 - 7.23 (m, 2H, CH), 7.19 - 7.14 (m, 1H, CH), 7.08 (brs, 1H, CH), 7.04 (t, J = 2.1 Hz, 1H, CH), 6.95 (brs, 1H, CH), 6.86 (brs, 1H, NH), 6.80 (dd, J = 8.2, 2.5 Hz, 1H, CH), 6.75 (d, J = 4.0 Hz, 1H, CH), 6.23 (d, J = 4.0 Hz, 1H, CH), 6.16 (t, J = 5.9 Hz, 1H, NH), 6.06 (s, 1H, CH), 5.99 (s, 1H, CH), 4.27 (d, J = 2.9 Hz, 2H, CH2), 3.93 (t, J = 6.2 Hz, 2H, CH2), 3.82 (t, J = 5.6 Hz, 2H, CH2), 3.42 (q, J = 6.3 Hz, 2H, CH2), 3.26 (t, J = 7.4 Hz, 2H, CH2), 2.87 - 2.77 (m, 2H, CH2), 2.65 HRMS (EI-MS): m / z C 42 H 44 BF2N8O3[M+H]+ calculated value: 757.3593; measured value: 757.3592.

[0418] Biological research 1.インビトロアッセイ 1.1. Blockage of LIMK1 and LIMK2 Inhibition of LIMK1 and LIMK2 was measured with the Lanthascreen® Eu Binding Assay (Life Technologies). This TR-FRET assay is based on the competition between a fluorescent tracer and the inhibitor being tested, allowing the determination of the inhibition constant, K.

[0419] 133 compounds were tested. Twelve of these compounds had a Ki of less than 10 nM, and approximately 50 had a Ki of less than 50 nM. The reference compounds LIMKi3 and LX7101 had Ki values of 8 and 3.9 nM, respectively, and the IC of the Pyr1 compounds tested in breast cancer tumors was 1.2. 50 These results are very promising, as the IL-1 and IL-2 activity are 50 nM and 75 nM, respectively, for LIMK1 and LIMK2.

[0420] 1.2. Inhibition of ROCK1 and ROCK2 ROCK1 and ROCK2 inhibition was also evaluated, but at a single concentration of 1 μM. These tests were performed using the "Z'Lyte®" assay, based on inhibition of basal phosphorylation measured by FRET (Life Technologies).

[0421] Based on this assay, compounds were classified into two groups: (i) compounds that selectively inhibit LIMK and (ii) potential "dual" compounds that inhibit both LIMK and ROCK.

[0422] 1.3. Selectivity in a panel of 100 kinases The selectivity of compounds against LIMK1 and LIMK2 was tested at a concentration of 1 μM against 100 representative kinases by Eurofins Kinase Screening & Profiling Services.

[0423] Eighteen compounds were tested. Six of them were highly selective, inhibiting only LIMK1 and LIMK2 by 80% or more. These compounds are promising candidates for future in vivo assays. Selective compounds avoid potentially harmful off-target and secondary effects. In particular, we hope to develop compounds that do not target ROCK1 and ROCK2, kinases upstream of LIMK1 / 2, which have many physiological targets. LIMK1 and LIMK2 are actually downstream in the signaling pathway, and the only downstream effector is their quasi-specific substrate, cofilin. By selectively targeting LIMK1 and LIMK2, we should be able to avoid side effects.

[0424] 2. Intracellular Assay The following six intracellular assays were used to characterize the activity of our compounds. 1. Determination of cytotoxicity against several cell lines 2. Remodeling of the actin cytoskeleton by measuring the levels of phospho-cofilin. Cofilin is a classic substrate of LIMK. 3. Actin cytoskeleton dynamics by visualization of stress fibers induced by LIMK2 overexpression 4. Migration characteristics measured by wound healing assay 5. Visualization of Microtubule Dynamics in the Spindle 6. Dendritic Plasticity by Size Measurement

[0425] 2.1.Cytotoxicity The cytotoxicity of our compounds was assessed using Promega's CellTiter-Glo® Luminescent Cell Viability assay, which is based on ATP production by viable cells. Two cell lines were studied: HeLa and MPNST (malignant peripheral nerve sheath tumor, a tumor associated with the genetic disease neurofibromatosis type 1). Day 1: Cell preparation in 96-well plates HeLa cells are seeded at 10,000 cells per well in 100 μL of DMEM. MPNST cells are seeded at 30,000 cells per well in 100 μL of DMEM.

[0426] Day 2: Incubation with inhibitors For each inhibitor, prepare a 1 mM solution in DMEM from a 10 mM stock solution. Serially dilute this solution with DMEM to concentrations of 10, 20, 30, 40, 50, 60, 70, 80, 90, and 100 μM. Remove the cell culture medium and add 100 μL of the inhibitor solution at different concentrations. Control conditions: (i) 100 μL of 1:100 DMSO, (ii) 100 μL of DMEM. Incubation for 48 hours at 37°C in a CO2 and humid atmosphere.

[0427] Day 4: Determination of cytotoxicity by Promega CellTiter-Glo® Luminescent Cell Viability assay, plates read on a Mithras instrument. Remove the plate from the incubator. Add 100 μL of reagent to each well. Incubate the plate at 22°C for 30 minutes. Prepare standards containing ATP diluted in DMEM: 100 μL of 1 μM, 100 nM, and 10 nM, loaded in triplicate on the same plate. Read luminescence on the Mitras instrument.

[0428] Interpretation of data. The luminescence value is directly related to the amount of ATP present in the cell, which in turn is related to the number of viable cells. Data are normalized, with 100% corresponding to the control condition, 1:100 DMSO.

[0429] Fifty compounds were tested in the HeLa cell line. The EC 50 The EC (inhibitor concentration corresponding to half of the viable cells) of LIMKi3 and Pyr1 for HeLa cells is 9 μM and 1 μM, respectively. 50The EC values of the compounds of the present invention are 15 μM to 35 μM, compared to 17 compounds tested in MPNST cell lines. 50 The EC values range from 35 to 90 μM (Table 1). Compared with published data, T56-LIMKi, a compound developed by Y. Kloog, has an EC value of approximately 20 μM against MPNST cell lines. 50 It has the following characteristics.

[0430] [Table 9]

[0431] 2.2. Actin cytoskeleton remodeling by measuring phospho-cofilin levels Cofilin is a classical substrate of LIMK. LIMK inhibits cofilin by phosphorylating serine 3. Because cofilin is an actin-depolymerizing factor (ADF), its inactivation blocks actin cytoskeleton remodeling.

[0432] The effect of the compounds on the phosphorylation level of cofilin was measured by Western blot using a specific antibody, anti-phospho-Ser3-cofilin.

[0433] HeLa and MPNST cell lines were studied. Day 1: Cell preparation in 6-well plates HeLa cells are seeded at 150,000 cells per well in 2 mL of DMEM. MPNST cells are seeded at 500,000 cells per well in 2 mL of DMEM. Day 3: Incubation with inhibitors and lysis Add 5 μL of a 10 mM stock solution or 5 μL of DMSO (control) to the culture medium of the cultured cells => final concentration: 25 μM. Incubate for 2 hours at 37°C in a CO2 and humid atmosphere.

[0434] Melting: Remove the medium. Wash the cells twice with 1 mL of PBS and incubate them with 150 μL of lysis buffer (50 mM Tris / HCl, pH 7.5, 100 mM NaCl, 5 mM EDTA, 0.1% Triton X-100, 50 mM NaF, 10 mM sodium pyrophosphate, 1 mM Na3VO4, 20 mM p-nitrophenyl phosphate, 20 mM β-glycerophosphate, 10 mg / mL aprotinin, 0.05 mg / mL okapidic acid, 1 mg / mL leupeptin, 1 mM PMSF) on ice for 10 min. Collect the cells (with a cell scraper), transfer them to a tube, and centrifuge them at 10,000 × g for 10 min at 4 °C. Remove 60 μL of the supernatant and add 20 μL of Laemmli buffer 4x. Samples were heated at 95°C for 5 minutes, spun at 10,000 x g for 5 minutes, and analyzed by Western blot using antibodies: anti-phospho-Ser3-cofilin (#3313) and anti-cofilin (#3312) from Cell Signaling Technology (Figure 1 shows an example of a Western blot of HeLa cells after treatment with multiple inhibitors. The antibodies used in this experiment are anti-phospho-Ser3-cofilin (top) and anti-cofilin (bottom).

[0435] The control condition corresponds to cells incubated with DMSO (solvent in which the inhibitor is diluted). The rate of phospho-cofilin is quantified and divided by the rate of total cofilin, normalizing it using the control condition DMSO (100% phosphorylation). Each sample is analyzed twice to increase reproducibility, and the best molecule is tested twice in two independent experiments.

[0436] [Table 10]

[0437] 70 compounds have been tested in HeLa cell lines. Over 80% inhibition of cofilin phosphorylation is observed. 50 compounds are more potent than LIMKi3, and 24 of these compounds are more potent than LX7101.

[0438] Twenty compounds were tested in MPNST cell lines. Cofilin phosphorylation was inhibited by 60-80%. Nine compounds were more effective than LIMKi3 and LX7101. Furthermore, three compounds that performed poorly in HeLa cell lines (60% inhibition of phospho-cofilin) were highly effective in MPNST cell lines (80% inhibition of phospho-cofilin). These data suggest that some compounds selectively inhibit certain cell lines, potentially targeting specific diseases.

[0439] In conclusion, the compounds of the present invention are highly active in cells against the direct phosphorylation of cofilin by LIMK.

[0440] Cofilin phosphorylation was also tested using another technology, Promega's LUMIT™ technology. LUMIT™ technology is a luminescence-detection-based immunoassay. It requires the use of two different secondary antibodies, one conjugated to the small subunit and the other to the large subunit of nanoluciferase. Once these two antibodies are immobilized on the analyte, the intact nanoluciferase is reconstituted and activated, generating a bright luminescent signal in the presence of substrate. We have optimized the conditions for measuring phospho-cofilin with this assay. We are currently testing our compounds with this new technology to confirm our results obtained by Western blot.

[0441] 2.3. Actin cytoskeleton dynamics induced by LIMK2 overexpression as visualized by stress fibers Next, another approach was developed to directly test the efficacy of the compounds of the present invention in live cells by imaging. In HeLa cells, stress fibers induced by LIMK2 overexpression were visualized by immunofluorescence. Indeed, when LIMK2 is overproduced, cofilin is phosphorylated, resulting in its inhibition. Cofilin is no longer able to depolymerize actin filaments, and stress fibers are observed.

[0442] Day 1: Cell preparation in 6-well plates HeLa cells are seeded at 30,000 cells per well in 2 mL of DMEM.

[0443] Day 2: Transfection Remove the medium from the cells and add 1.5 mL of DMEM. In an Eppendorf tube, add 150 μL of OptiMEM. Dilute 2.5 μg of DNA (plasmid preparation) in 150 μL of OptiMEM. Mix the + reagent (Invitrogen) and add 7.5 μL of + reagent to the mixture. Homogenize by inversion. Incubate at room temperature for 5 minutes. Mix Lipofectamine LTX (Invitrogen). In a new tube, add 7.5 μL of Lipofectamine LTX to 150 μL of OptiMEM. Homogenize by inversion. Incubate at room temperature for 5 minutes. Add the OptiMEM-AND mixture to the OptiMEM-Lipofectamine mixture. Homogenize by inversion. Incubate at room temperature for 30 minutes. The OptiMEM-ADN-Lipofectamine mixture is added on top of the cells, dropwise anywhere in the well, without stirring to prevent complex disruption. Incubate for 4-5 hours. Change the medium.

[0444] Day 3: Seed cells into 4-well plates. Treat cells with trypsin to detach them from the plate. Seed 20,000 cells per well in 500 μL of DMEM.

[0445] Day 4: Incubation with inhibitors and labeling Cells are incubated with 25 μM of inhibitor (ie 1.25 μL of a 10 mM stock solution) or 1.25 μL of DMSO (control) for 2 hours at 37° C. under CO 2 and a humid atmosphere. Labeling: Remove medium. Wash 3 times with 500 μL PBS 1x. Add 250 μL of PBS / 4% PFA. Incubate at room temperature for 20 minutes. Remove PBS / PFA. Wash 3 times with 500 μL PBS 1×. Add 250 μL of PBS / 0.5% Triton. Incubate at room temperature for 15 minutes. Remove PBS / Triton. Wash 3 times with 500 μL PBS 1×. Add 250 μL of primary antibody (anti-HA from Roche Applied Science) diluted in PBS / 1% BSA. Incubate for 1 hour at room temperature. Remove primary antibody. Wash three times with 500 μL of PBS / 0.5% BSA. Add 250 μL of secondary antibody (FITC anti-rat) or 250 μL of phalloidin conjugated to AlexaFluor 568 diluted in PBS / 1% BSA. Incubate for 1 hour at room temperature without light. Remove medium and wash 3 times with 500 μL PBS / 0.5% BSA. implementation Mount the coverslip with one drop of Vectashield (5 μL). Seal the coverslip with nail polish to prevent drying and movement under the microscope. Store at -4°C for 2-3 days, then store at -20°C in the dark.

[0446] Overexpression of LIMK2 induces the formation of stress fibers, which are insensitive to DMSO treatment. Treating cells with our compounds results in much fewer stress fibers (Figure 2—Confocal imaging of the actin cytoskeleton. HeLa cells were transfected with a plasmid that allows overproduction of LIMK2 and treated with 25 μM of inhibitor or DMSO (control) for 2 hours. Stress fibers were visualized by immunofluorescence via phalloidin labeling, which binds to filamentous actin (stress fibers appear as thick white lines within the cells)). Thus, our compounds inhibit stress fiber formation induced by overexpression of LIMK2.

[0447] This second test further demonstrates the effectiveness of our compounds on the dynamics of actin filament polymerization in living cells.

[0448] 2.4. Migration characteristics measured by wound healing assay The effect of the compounds of the invention on cell migration was measured by a wound healing assay: a scratch wound was made in the cell monolayer and the rate at which the cells migrated to fill the gap was measured.

[0449] U2OS cells were seeded at a density of 40,000 cells per well (96-well plate) and grown overnight. Five hours before wound healing, cells were starved in 0.5% fetal bovine serum. Wound healing was performed using WoundMaker™ (Essen BioScience). Inhibitors were added to the medium at a final concentration of 2.5 μM. Data were acquired and analyzed every hour for 24 hours using an IncuCyte® S3 (Sartorius, Essen BioScience, MI 9021).

[0450] The results are shown in Figure 3. Eight compounds were tested. Four of them showed a strong tendency to inhibit migration of U2OS cells upon scratching compared to the reference LIMKi3. One compound was particularly effective (compound 15). These data indicate that the tested compounds are effective at preventing cell migration, a property that plays a key role in the formation of metastases.

[0451] 2.5. Visualization of microtubule dynamics through mitotic spindle assembly LIMK1 and LIMK2 also affect microtubule dynamics, but the molecular actors involved in this process are still unknown. To observe microtubule dynamics, microtubules are labeled with anti-tubulin antibodies and the mitotic spindle is observed.

[0452] U2OS cells were plated on coverslips and grown for 24 hours. Inhibitors were added to the culture medium at a final concentration of 2.5 μM for 24 hours. Cells were then fixed with 4% formaldehyde, permeabilized with TBS-0.5% Triton-X100, and microtubules were labeled with anti-tubulin antibodies.

[0453] Three compounds were tested. Compound 15 appeared to have a strong effect on microtubule dynamics: astral microtubules disappeared, spindle poles split, and microtubules depolymerized, as free tubulin diffused into the cytoplasm and polymerized microtubule structures were lost (see Figure 4).

[0454] 2.6. Dendritic plasticity measured by size The effects of compounds of the invention on cytoskeletal dynamics were also evaluated in specialized cells (NSC34, a mouse motor neuron-like hybrid cell line) to assess their effects on dendritic plasticity for neurological applications.

[0455] 40,000 NSC34 cells were seeded in 1 mL of DMEM / well (12-well plate) for 24 hours. Cells were then grown without serum and induced to differentiate in the presence of 25 μM inhibitors for 24 hours. Dendrites were visualized by microscopy.

[0456] Ten compounds were tested, four of which strongly affected neurite size and plasticity.

[0457] 3. In vivo assay in an ALS (amyotrophic lateral sclerosis) mouse model We studied the in vivo effects of compound 110 using SOD1-G93A transgenic mice (Jackson Laboratory, B6.Cg-Tg(SOD1*G93A)1Gur / J), a commonly used preclinical model of ALS. These mice express a copy of a human SOD1 transgene carrying the G93A mutation and recapitulate many of the pathological features of human ALS, including progressive paralysis and early death. Mice were given 10 mg / kg of compound 110 (n = 13) or vehicle solution (control, n = 14) via intraperitoneal injection twice weekly from 8 weeks of age until the endpoint. Body weight was monitored twice weekly from week 8 until the endpoint. The endpoint (survival) was determined when mice were unable to right themselves within 30 seconds (three times) after being placed on their backs. Several tests were performed to assess motor behavior. Hindlimb function was assessed twice weekly using a scoring system, NeuroScore (ranging from 1 for slightly abnormal to 4 for paralysis), by observing mice in three consecutive states: hanging by the tail, walking, and lying on their side. The rotarod test, which assesses balance and motor coordination, was performed by placing the mice on a rotating cylinder (5 min, 3 trials). The grid test was performed by placing the mice on a metal grid that was later inverted to assess muscle strength (cutoff time 90 s). The results are shown in Figures 5 and 6.

[0458] We demonstrated that Compound 110 had a significant effect in delaying the onset of weight loss and motor symptoms (the early stage and first decay of the neuroscore in the rotarod test). No improvement in the subsequent development of the disease phenotype and in the disease endpoint (survival) was observed.

[0459] [Table 11A]

[0460] [Table 11B]

[0461] [Table 12A]

[0462] [Table 12B]

[0463] [Table 13A]

[0464] [Table 13B]

[0465] [Table 14]

[0466] [Table 15]

[0467] [Table 16]

[0468] Table 17

Claims

1. A compound having the following formula (I): 【Chemical 1】 [In the formula, - "a" is a single bond and "b" is a double bond, or "a" is a double bond and "b" is a single bond; -R 1 is H, (C 1 ~C 6 ) alkyl groups, halogens, and (C 3 ~C 7 ) cycloalkyl groups; -R 2 is H, and (C 1 ~C 6 ) alkyl groups, - or R 1 and R 2 together with the carbon atoms that carry them, (C 5 ~C 7 ) cycloalkyl group or (C 5 ~C 7 ) heterocycloalkyl group, wherein the heterocycloalkyl group is 1 ~C 6 ) optionally substituted with alkyl groups; - n is 0, 1, or 2; - each Ri may be the same or different, (C 1 ~C 6 ) alkyl groups, R is optionally fused with an aryl group (C 3 ~C 7 ) selected from the group consisting of a cycloalkyl group, an aryl group, a heteroaryl group, a heterocycloalkyl group fused to an aryl group, and an aryl group fused to a heterocycloalkyl group, wherein the aryl group and the heteroaryl group contain at least one substituent R selected from the group consisting of 3 is optionally replaced by ・ H、 ・ (C 1 ~C 6 ) alkyl, wherein said alkyl is optionally interrupted by at least one heteroatom; heterocycloalkyl, aryl, wherein said aryl is optionally substituted with at least one substituent; heteroaryl, wherein said heteroaryl is optionally substituted with at least one substituent; - halogens, ・Haro (C 1 ~C 6 ) alkyl, aryloxy, wherein said aryloxy is optionally substituted with at least one substituent; heteroaryloxy, wherein said heteroaryloxy is optionally substituted with at least one substituent; -O-halo(C 1 ~C 6 ) alkyl, ・ Cyano, ・ (C 1 ~C 6 ) alkoxy, -X-NR a R b , where X is (C 1 ~C 6 ) alkylene groups, —OC(═O)—, —C(═O)—, and —NHC(═O)—; R a and R b are each independently H or (C 1 ~C 6 ) alkyl group, -X'-Rc, where X' is -C(=O)- or -O-(C 1 ~C 6 ) alkylene group, and Rc is a cycloalkyl group optionally substituted with at least one halogen, or Rc is SO 2 CH 3 Or at least one (C 1 ~C 6 ) a heterocycloalkyl group optionally substituted with an alkyl group, and -OX 2 -NR e R f , where X 2 (C 1 ~C 6 ) alkylene group, and R e and R f are independently H or (C 1 ~C 6 ) alkyl group, or R e and R f at least one of which contains a carbamate (Boc) or one fluorophore, or is SO2CH3] or a pharmaceutically acceptable salt, racemate, diastereomer or enantiomer thereof.

2. R is (C 3 ~C 7 ) a cycloalkyl group.

3. R is at least one substituent R as defined in claim 1 3 2. The compound of claim 1, wherein R is an aryl group optionally substituted with R.

4. 4. The compound of claim 1 or 3, having the following formula (II): 【Chemistry 2】 (In the formula, - a, b, n, R i , R 1 , and R 2 is as defined in claim 1, m is 1 or 2, and each R 3 are the same or different and are as defined in claim 1).

5. 5. The compound of any one of claims 1, 3 or 4, having the following formula (III): 【Chemistry 3】 (In the formula, - a, b, n, R i , R 1 , R 2 , and R 3 is as defined in claim 1, -R 4 is H, halogen or aryloxy).

6. A compound having the following formula (IV): 【Chemistry 4】 (In the formula, -R 1 is H or (C 1 ~C 6 ) alkyl group, -R 3 teeth, ・ H、 ・ (C 1 ~C 6 ) alkyl, aryl, wherein said aryl is optionally substituted with at least one substituent; heteroaryl, - halogens, ・Haro (C 1 ~C 6 ) alkyl, aryloxy, wherein said aryloxy is optionally substituted with at least one substituent; -O-halo(C 1 ~C 6 ) alkyl, ・ Cyano, ・ (C 1 ~C 6 ) alkoxy, and -OC(=O)-NR a R b , where R a and R b are each independently H or (C 1 ~C 6 ) alkyl group, is selected from the group consisting of -R 4 is H, halogen, or aryloxy; or R 3 and R 4 together with the carbon atoms that carry them form a phenyl group or a heterocycloalkyl group).

7. The compound of any one of claims 1, 3 and 4, having the following formula (V): 【Chemistry 5】 (In the formula, - "a" is a single bond and "b" is a double bond, or "a" is a double bond and "b" is a single bond; -R 1 is (C 1 ~C 6 ) alkyl groups, -R 5 is (C 1 ~C 6 ) alkyl groups, -R 6 is H or (C 1 ~C 6 ) alkyl groups, -R 3 teeth, halogens, and Aryloxy (selected from the group consisting of:

8. The compound of any one of claims 1, 3 and 4, having the following formula (VI): 【Chemistry 6】 (In the formula, R 3 is a halogen).

9. The compound of any one of claims 1, 3 and 4, having the following formula (VII): 【Chemistry 7】 (In the formula, -R 1 is a halogen, -R 3 is -OC(=O)-NR a R b where R a and R b are each independently H or (C 1 ~C 6 ) alkyl group).

10. The compound of any one of claims 1, 3 and 4, having the following formula (VIII): 【Chemistry 8】 (In the formula, -R 1 (C 3 ~C 7 ) a cycloalkyl group, -R 3 teeth, aryl, wherein said aryl is optionally substituted with at least one substituent; heteroaryl, - halogens, aryloxy, wherein said aryloxy is optionally substituted with at least one substituent, and -OC(=O)-NR a R b , where R a and R b are each independently H or (C 1 ~C 6 ) alkyl group, (selected from the group consisting of:

11. The compound of any one of claims 1, 3 and 4, having the following formula (IX): 【Chemistry 9】 (In the formula, -R 1 (C 1 ~C 6 ) alkyl group, -R 2 (C 1 ~C 6 ) alkyl group, -R 3 teeth, ・ H、 aryl, wherein said aryl is optionally substituted with at least one substituent; - halogens, ・ (C 1 ~C 6 ) alkoxy, and -OC(=O)-NR a R b , where R a and R b are each independently H or (C 1 ~C 6 ) alkyl group, (selected from the group consisting of:

12. The compound of any one of claims 1, 3 and 4, having the following formula (X): 【Chemistry 10】 (In the formula, - p is 0, 1, or 2; -R 3 teeth, ・ H、 ・ (C 1 ~C 6 ) alkyl, wherein said alkyl is optionally interrupted by at least one heteroatom; heterocycloalkyl, aryl, wherein said aryl is optionally substituted with at least one substituent; heteroaryl, - halogens, aryloxy, ・Haro (C 1 ~C 6 ) alkyl, ・ Cyano, ・ (C 1 ~C 6 ) alkoxy, and -X-NR a R b , where X is (C 1 ~C 6 ) alkylene groups, —OC(═O)—, —C(═O)—, and NH—C(═O)—; R a and R b are each independently H or (C 1 ~C 6 ) alkyl group, (selected from the group consisting of:

13. The compound of any one of claims 1, 3 and 4, having the following formula (XI): 【Chemistry 11】 (In the formula, - X 1 is -O-, -S-, or -N((C 1 ~C 6 ) alkyl)-, -R 3 is a halogen).

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof. medicine.

15. Cancer, virion infection, ocular hypertension and glaucoma formation, neurofibromatosis type 1 and type 2, psoriatic lesions, From inflammatory diseases and hyperalgesia, central sensitization and chronic pain, reproductive erectile dysfunction, and neurological disorders 14. A method according to any one of claims 1 to 13 for use in the treatment of a condition selected from the group consisting of: Item 1. The compound according to item 1.

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