Pyridine derivatives as protein kinase inhibitors

Abstract

The present invention relates to compounds suitable for use as kinase inhibitors.

Description

Technical Field

[0001] The present invention belongs to the fields of medicinal chemistry and pharmacy. Background Art

[0002] Protein phosphorylation is the most common form of reversible post-translational modification, and it is estimated that 50% of all proteins are phosphorylated. The phosphorylation state of any given protein is controlled by the coordinated action of specific kinases and phosphatases that add and remove phosphate groups, respectively. In particular, protein kinases are protein phosphotransferases that transfer the phosphate group of ATP to specific amino acid residues. They are generally classified into five categories: tyrosine protein kinases, serine / threonine protein kinases, histidine protein kinases, tryptophan protein kinases, and aspartyl / glutamyl protein kinases.

[0003] Signal transduction networks that utilize phosphorylation to regulate target activity have been shown to be closely related to all aspects of cell function, and the abnormal activation of protein phosphorylation is often a driving factor or direct consequence of diseases. Dysregulation of kinase signaling pathways is associated with cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, and metabolic diseases, by constitutively activating many downstream pathways, such as phosphatidylinositol 3-kinase / v-akt murine thymoma viral oncogene homolog 1 (PIK3 / AKT), mitogen-activated protein kinase / extracellular signal-regulated kinase (MAPK / ERK), and signal transducer and activator of transcription 5 (STAT5). Therefore, protein kinases are important therapeutic targets.

[0004] In tumors, the abnormal oncogenic activation of protein kinases results from various types of genetic and epigenetic changes. These alterations lead to an increase in the specific activity of the kinase itself, its overexpression, or the loss of negative regulation, resulting in uncontrolled cell growth and persistent malignant behavior. The signal transduction networks operating in cancer cells can also lead to congenital or acquired treatment resistance, as they are able to generate the most common or rare oncogenic mutations between different tumors. Therefore, searching for small molecule inhibitors that target altered protein kinase molecules in tumor cells has become a major research focus in academia and pharmaceutical companies.

[0005] Such inhibitors can be products derived (isolated) from sources such as plants, animals, or microorganisms, or can be designed (synthesized) small molecules.

[0006] WO 2004 / 022572 discloses classes of bioactive compounds that interact with kinases, as well as the preparation of these compounds.

[0007] In oncology, there are currently multiple examples of small molecule kinase inhibitors that are both selective and have suitable drug properties, which have produced meaningful clinical benefits. For example, pexidartinib is used to inhibit colony-stimulating factor-1 receptor (CSF1R), KIT proto-oncogene receptor tyrosine kinase (KIT), and FMS-like tyrosine kinase 3 (FLT3), for example, in the treatment of patients with symptomatic tenosynovial giant cell tumor (TGCT); edicotinib is used to inhibit CSF1R and is currently in phase II clinical trials for the treatment of acute myeloid leukemia, cognitive impairment, or Crohn's disease; nintedanib is used to inhibit vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and CSF1R, for example, in the treatment of idiopathic pulmonary fibrosis.

[0008] There is still a great need to develop inhibitors of effective protein kinases for the treatment of various protein kinase-related disorders.

[0009] In this regard, WO 2011 / 090738 A2 discloses compounds capable of inhibiting B-RAF and B-RAF mutants and methods for treating diseases related to the regulation of B-RAF and B-RAF mutants.

[0010] US2009 / 0325945 describes active compounds, particularly certain imidazo[4,5-b]pyridin-2-ones and oxazolo[4,5-b]pyridin-2-ones compounds and analogs, which inhibit RAF (e.g., B-RAF) activity in cells in vitro or in vivo, inhibit receptor tyrosine kinase (RTK) activity in cells in vitro or in vivo, such as FGFR, Tie, VEGFR, and / or Eph activity, such as FGFR-1, FGFR-2, FGFR-3, Tie2, VEGFR-2, and / or EphB2 activity.

[0011] US2015 / 0182526: This document describes therapeutic compounds for the treatment of proliferative disorders, cancers, etc., more particularly certain pyrido[2,3-b]pyrazine-8-substituted compounds, which particularly inhibit RAF (e.g., B-RAF) activity and inhibit receptor tyrosine kinase (RTK) activity.

[0012] However, despite increasing efforts in the development of new protein kinase inhibitor-based therapies, there is still a need for protein kinase inhibitors that can overcome the disadvantages of current protein kinase therapies, such as side effects, limited efficacy, development of drug resistance, and compliance failures. SUMMARY OF THE INVENTION

[0013] The inventors have surprisingly found that the use of a protein kinase inhibitor according to the invention can provide improved treatment of protein kinase-related diseases in disarray by developing a more effective therapy with reduced side effects, limited development of drug resistance, and improved compliance.

[0014] Accordingly, the present invention provides a compound according to any one of formulas (I) to (VII) [hereinafter compound (C)] or an N-oxide, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a stereoisomer thereof, suitable for use as a protein kinase inhibitor.

[0015]

[0016] Wherein:

[0017] - Each A is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, NO2, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, CF3, CN, OR 11 , SR 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, S(O)R 12 , SO2R 12 , SO2N(R 11 )2, S(O)3R 11 , P(=O)(OR 11 )2, P(=O)(R 11 )2NR 11 COR 12 , COR 11 , C(O)OR 11 , CON(R 11 )2, OC(O)R 11 , and OCON(R 11 )2, and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl substituent is further optionally substituted with halo, NO2, C 1-6 alkyl, cycloalkyl, aryl, CF3, N(R 11 )2, COR 11 , CON(R 11 )2, OC(O)R 11 , CN, or OR11 substituted; and wherein R 11 and R 12 each, independently of one another and in each occurrence, is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl and CF3, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl substituents are optionally halogenated, C 1-6 alkyl, cycloalkyl, heterocyclic group, C 1-6 alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2 substituted, wherein R 31 and R 32 each, independently of one another and in each occurrence, is selected from the group consisting of hydrogen and C 1-4 alkyl;

[0018] - Each of -R4 and R’4, independently of one another and in each occurrence, is selected from hydrogen or C 1-6 alkyl, and z is an integer ranging from 0 to 2; provided that when z = 0, then A and R7 may together form a saturated or unsaturated ring moiety;

[0019] - Each of -R7, independently of one another and in each occurrence, is selected from hydrogen, C 1-6 alkyl, cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted by a halogen atom, CF3, N(R 11 )2, CN, or OR 11 substituted; and wherein R 11 each, independently of one another and in each occurrence, is selected from the group consisting of hydrogen, C 1-6 alkyl, and CF3;

[0020] - Each of -R3, independently of one another and in each occurrence, is selected from the group consisting of hydrogen, halogenated, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, CF3, CN, OR 21 , SR 21 , N(R 21 )2, NC(O)R 21 , NCON(R 21 )2, COR 21 , C(O)OR 21 , CON(R 21 )2, OC(O)R 21 , OCON(R 21 )2, OC(R21 )2O, and OC(R 21 )2C(R 22 )2O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl are optionally substituted by one or more substituents selected from halo, C 1-6 alkyl, CF3, N(R 21 )2, CN, or OR 21 ; and wherein each of R 21 and R 22 is independently of one another and at each occurrence selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl, and wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl substituents are optionally substituted by halo, C 1-6 alkyl, cycloalkyl, heterocyclic, aryl, OR 31 or N(R 32 )2, where each of R 31 and R 32 is independently of one another and at each occurrence selected from the group consisting of hydrogen and C 1-4 alkyl; each r is an integer ranging from 0 to 3; provided that when R3 = NR 21 and R7 = H, then R3 and NR7 can together form a saturated or unsaturated ring moiety;

[0021] -Each of -R2 is independently of one another and at each occurrence selected from the group consisting of hydrogen, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, CF3, CN, NO2, OR 21 , SR 21 , N(R 21 )2, COR 21 , C(O)OR 21 , CON(R 21 )2, OC(O)R 21 , OCON(R 21 )2, NC(O)R 21 , NCON(R 21 )2, OC(R 21 )2O and OC(R 21 )2C(R 22 )2O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are optionally substituted by one or more substituents selected from halo, C 1-6 alkyl, C2-6 Alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, CF3, COR 21 , CON(R 21 )2, C(O)OR 21 , N(R 21 )2, CN, or OR 21 substituted, and each optional alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl substituent is further optionally substituted by a heterocyclic group, N(R 11 )2, or OR 11 ; and wherein each of R 21 and R 22 is independently of one another and at each occurrence selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl, and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl substituents are optionally substituted by halo, C 1-6 alkyl, cycloalkyl, heterocyclic group, aryl, OR 31 or N(R 32 )2, wherein each of R 31 and R 32 is independently of one another and at each occurrence selected from the group consisting of: hydrogen and C 1-4 alkyl; each of q is an integer ranging from 0 to 2;

[0022] - Each of -x and y is independently an integer equal to 0 or 1;

[0023] - R8 is independently selected from the group consisting of: C 6-12 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl and heterocyclic group, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic group are optionally substituted by a halogen atom, an aryl group, an aralkyl group, CF3, N(R 11 )2, CN, or OR 11 ; and wherein each of R 11 is independently of one another and at each occurrence selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl and CF3, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl substituents are optionally substituted by halo, C 1-6 alkyl, cycloalkyl, heterocyclic group, alkyl or aryl or heteroaryl amide, OR31 or substituted by N(R 32 )2, where each of R 31 and R 32 is independently of one another and in each occurrence selected from the group consisting of hydrogen and C 1-4 alkyl;

[0024] -R9 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, N(R 11 )2 and CN, where the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic group are optionally substituted by a halogen atom, an aryl group, an aralkyl group, a heterocyclic group, CF3, N(R 11 )2, CN, or OR 11 ; and where each of R 11 is independently of one another and in each occurrence selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl and CF3, where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, heteroaryl optionally substituted by C 1-4 alkyl, aryl, heteroaryl, and aralkyl substituents are optionally substituted by halo, C 1-6 alkyl, cycloalkyl, heterocyclic group, alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2, where each of R 31 and R 32 is independently of one another and in each occurrence selected from the group consisting of hydrogen and C 1-4 alkyl, provided that if x = 1 and y = 0, then R9 is different from the heterocyclic group and from C 1-6 alkyl, where the alkyl is optionally substituted by a heterocyclic group; and provided that if x = 0 and y = 0, then R9 is different from hydrogen and C 1-6 alkyl, where the alkyl is optionally substituted by a heterocyclic group and N(R 11 )2; provided that when x = 0 and y = 0, then R9 and R2 can together form a saturated or unsaturated ring moiety; provided that when x = 0 and y = 0, and when R9 and R2 together form a saturated or unsaturated ring moiety, then R9 is NR 11 ; provided that when x = 1 and y = 1, then R9 is different from N(R 11 )2; and provided that when x = 0, y = 0 and z = 0, then R9 is different from pyrrole;

[0025] - Each of Ts is independently a moiety of the following formula (T-a):

[0026]

[0027] Wherein:

[0028] - Each of Us is independently of one another and at each occurrence is selected from the group consisting of: C, C-halo, C-R, and N; where R is selected from hydrogen, OR 11 , N(R 11 )2, C 1-6 alkyl or cycloalkyl, optionally substituted by a halogen atom, an aryl group or an aralkyl group, where each of R 11 s is independently of one another and at each occurrence is selected from the group consisting of hydrogen or C 1-4 alkyl; provided that at least one U is different from N;

[0029] - Each of Zs is independently of one another and at each occurrence is selected from C(R)2, O, S and NR7, where the Rs are independently of one another and at each occurrence are selected from hydrogen or C 1-6 alkyl, optionally substituted by a halogen atom, an aryl group or an aralkyl group, where R7 is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 1-6 alkenyl, cycloalkyl, heterocyclic group, aryl, aralkyl and CF3;

[0030] - Each of R5s is independently of one another and at each occurrence is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, halo, CF3, OR 11 , SR 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, CON(R 11 )2, and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group, heteroaryl, aralkyl substituent is further optionally substituted by halo, C 1-6 alkyl, cycloalkyl, aryl, heterocyclic group, N(R 11 )2, CN, OR 11 , C(=O)OR 11 , P(=O)(OR 11 )2, P(=O)(R 11 )2, CN or CF3, and where each of R 11 s is independently of one another and at each occurrence is selected from the group consisting of hydrogen, C 1-6Alkyl, cycloalkyl, and heterocyclic group; each of n1 is an integer ranging from 0 to 2;

[0031] - Each X is independently a moiety of the following formula (X-a):

[0032]

[0033] Wherein:

[0034] - Each -V is independently of the others and at each occurrence is selected from the group consisting of: C, C-halo, C-R, and N; wherein R is selected from hydrogen, OR 11 , N(R 11 )2, C 1-6 alkyl or cycloalkyl, which is optionally substituted by a halogen atom, an aryl group or an aralkyl group, wherein each of R 11 is independently of the others and at each occurrence selected from hydrogen or C 1-4 alkyl;

[0035] - Each -R6 is independently of the others and at each occurrence selected from the group consisting of: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, halo, CF3, OR 11 , SR 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, CON(R 11 )2, and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group, heteroaryl, aralkyl substituent is further optionally substituted by halo, C 1-6 alkyl, cycloalkyl, aryl, heterocyclic group, N(R 11 )2, CN, OR 11 , C(=O)OR 11 , P(=O)(OR 11 )2, P(=O)(R 11 )2, CN or CF3, and wherein each of R 11 is independently of the others and at each occurrence selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, and heterocyclic group; each of n2 is an integer ranging from 0 to 4;

[0036] - The dashed bond represents an optional triple bond;

[0037] - R a1 is independently selected from the group consisting of: hydrogen, C 1-6Alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, CF3, CN, OR 11 , SR 11 , N(R 11 )2, COR 11 , C(O)OR 11 , wherein the alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl and aralkyl are optionally halogenated, NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, CF3, CN, OR 11 , SR 11 , N(R 11 )2, COR 11 , and C(O)OR 11 substituted, and each optional alkyl, alkenyl, cycloalkyl, phenyl, heterocyclic group, heteroaryl substituent is further optionally halogenated, NO2, C 1-6 alkyl, cycloalkyl, phenyl, N(R 11 )2, CN, or OR 11 substituted; and wherein each of R 11 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, and aralkyl, wherein the alkyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, and aralkyl substituents are optionally halogenated, C 1-6 alkyl, cycloalkyl or heterocyclic group substituted;

[0038] -R a2 each is independently and at each occurrence selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, CF3, CN, OR 11 , SR 11 , N(R 11 )2, COR 11 , C(O)OR 11 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl and aralkyl are optionally halogenated, NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, CF3, CN, OR 11 , SR 11 , N(R 11 )2, COR 11 , and C(O)OR 11substituted, and each optional alkyl, alkenyl, cycloalkyl, phenyl, heterocyclic, heteroaryl substituent is further optionally halogenated, NO2, C 1-6 alkyl, cycloalkyl, phenyl, N(R 11 )2, CN, or OR 11 substituted; and wherein R 11 each independently selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclic, phenyl, heteroaryl, and aralkyl, wherein the alkyl, cycloalkyl, heterocyclic, phenyl, heteroaryl, and aralkyl substituents are optionally halogenated, C 1-6 alkyl, cycloalkyl or heterocyclic substituted; and wherein n3 is an integer equal to 0 or 1; provided that when the dashed bond represents a triple bond, then n3 is 0;

[0039] wherein the cycloalkyl is a monocyclic, bicyclic or tricyclic ring system of 3-6 ring members per ring; the heterocyclic is a saturated, partially saturated or fully saturated monocyclic, bicyclic or tricyclic containing 3 to 12 carbon atoms and 1 or 2 heteroatoms independently selected from O or N; the aryl is phenyl, naphthyl or anthracenyl, which is an optionally fused carbocyclic ring with a cycloalkyl or heterocyclic of 5-7 ring members; the heteroaryl is a monocyclic structure containing 5 or 6 ring atoms with 1-3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

[0040] The present invention further relates to a pharmaceutical composition comprising a carrier and an effective amount of a compound as defined in any one of the examples herein as an active ingredient.

[0041] The present invention relates to a compound as defined in any one of the examples herein for use as a medicament.

[0042] The present invention relates to a compound as defined in any one of the embodiments herein for use in the treatment of a disease selected from: cancer, metabolic disorders (such as diabetes), inflammatory and autoimmune disorders (such as inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, inflammatory lung diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus and psoriasis and psoriatic arthritis), neurological disorders (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth neuropathy, amyotrophic lateral sclerosis and epilepsy), atherosclerosis and cardiovascular diseases, Sjogren's syndrome, renal transplant rejection, virus-induced diseases, circulatory system diseases, osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, eye diseases (such as retinopathy, age-related macular degeneration and uveitis), chronic and neuropathic pain, and fibroproliferative diseases.

[0043] The present invention relates to a compound as defined in any one of the embodiments herein for use in the treatment of pain sensitization.

[0044] The present invention further relates to a method of inhibiting protein kinase activity in a warm-blooded animal, the method comprising administering to an animal in need thereof a kinase-inhibiting effective amount of a compound according to any one of the embodiments herein.

[0045] The present invention further relates to a method of treating a disease selected from: cancer, metabolic disorders (such as diabetes), inflammatory and autoimmune disorders (such as inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, inflammatory lung diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus and psoriasis and psoriatic arthritis), neurological disorders (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth neuropathy, amyotrophic lateral sclerosis and epilepsy), atherosclerosis and cardiovascular diseases, Sjogren's syndrome, renal transplant rejection, virus-induced diseases, circulatory system diseases, osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, eye diseases (such as retinopathy, age-related macular degeneration and uveitis), chronic and neuropathic pain, and fibroproliferative diseases in a warm-blooded animal, the method comprising administering to an animal in need thereof an effective amount of a compound according to any one of the embodiments herein. Detailed Description

[0046] The first aspect of the present invention relates to a compound according to any one of formulas (I) to (VII) [hereinafter compound (C)] suitable for use as a protein kinase inhibitor, or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer thereof,

[0047]

[0048]

[0049] wherein:

[0050] - Each A is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, NO2, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, CF3, CN, OR 11 , SR 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, S(O)R 12 , SO2R 12 , SO2N(R 11 )2, S(O)3R 11 , P(=O)(OR 11 )2, P(=O)(R 11 )2NR 11 COR 12 , COR 11 , C(O)OR 11 , CON(R 11 )2, OC(O)R 11 , and OCON(R 11 )2, and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl substituent is further optionally substituted with halo, NO2, C 1-6 alkyl, cycloalkyl, aryl, CF3, N(R 11 )2, COR 11 , CON(R 11 )2, OC(O)R 11 , CN, or OR 11 ; and wherein each of R 11 and R 12 is independently of each other and at each occurrence selected from the group consisting of hydrogen, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, and CF3, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl substituents are optionally halogenated, C 1-6 alkyl, cycloalkyl, heterocyclic group, C 1-6 alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2 substituted, wherein R 31 and R 32 each independently of one another and at each occurrence are selected from the group consisting of hydrogen and C 1-4 alkyl;

[0051] - Each of R4 and R’4 is independently of one another and at each occurrence selected from hydrogen or C 1-6 alkyl, and z is an integer ranging from 0 to 2; provided that when z = 0, then A and R7 can together form a saturated or unsaturated ring moiety;

[0052] - Each of R7 is independently of one another and at each occurrence selected from hydrogen, C 1-6 alkyl, cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted by a halogen atom, CF3, N(R 11 )2, CN, or OR 11 substituted; and wherein each of R 11 is independently of one another and at each occurrence selected from the group consisting of hydrogen, C 1-6 alkyl, and CF3;

[0053] - Each of R3 is independently of one another and at each occurrence selected from the group consisting of hydrogen, halogenated, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, CF3, CN, OR 21 , SR 21 , N(R 21 )2, NC(O)R 21 , NCON(R 21 )2, COR 21 , C(O)OR 21 , CON(R 21 )2, OC(O)R 21 , OCON(R 21 )2, OC(R 21 )2O, and OC(R 21 )2C(R 22)2O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl are optionally substituted by one or more substituents selected from halo, C 1-6 alkyl, CF3, N(R 21 )2, CN, or OR 21 ; and wherein each of R 21 and R 22 is independently of each other and in each occurrence selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl, and wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl substituents are optionally substituted by halo, C 1-6 alkyl, cycloalkyl, heterocyclic group, aryl, OR 31 or N(R 32 )2, wherein each of R 31 and R 32 is independently of each other and in each occurrence selected from the group consisting of: hydrogen and C 1-4 alkyl; each r is an integer ranging from 0 to 3; provided that when R3 = NR 21 and R7 = H, then R3 and NR7 can together form a saturated or unsaturated ring moiety;

[0054] -R2 is independently of each other and in each occurrence selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, and heteroaryl, CF3, CN, NO2, OR 21 , SR 21 , N(R 21 )2, COR 21 , C(O)OR 21 , CON(R 21 )2, OC(O)R 21 , OCON(R 21 )2, NC(O)R 21 , NCON(R 21 )2, OC(R 21 )2O and OC(R 21 )2C(R 22 )2O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, and heteroaryl are optionally substituted by one or more substituents selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, CF3, COR21 , CON(R 21 )2, C(O)OR 21 , N(R 21 )2, CN, or OR 21 , and each optional alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl substituent is further optionally substituted by a heterocyclic group, N(R 11 )2, or OR 11 ; and wherein each of R 21 and R 22 is independently of one another and at each occurrence selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl, and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl substituents are optionally halogenated, C 1-6 alkyl, cycloalkyl, heterocyclic, aryl, OR 31 or N(R 32 )2 substituted, wherein each of R 31 and R 32 is independently of one another and at each occurrence selected from the group consisting of: hydrogen and C 1-4 alkyl; each q is an integer ranging from 0 to 2;

[0055] - Each of -x and y is independently an integer equal to 0 or 1;

[0056] - R8 is independently selected from the group consisting of: C 6-12 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl and heterocyclic, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic are optionally substituted by a halogen atom, an aryl group, an aralkyl group, CF3, N(R 11 )2, CN, or OR 11 ; and wherein each of R 11 is independently of one another and at each occurrence selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl and CF3, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl substituents are optionally halogenated, C 1-6 alkyl, cycloalkyl, heterocyclic, alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2 substituted, wherein each of R 31 and R32 Each of which is independently and, in each occurrence, selected from the group consisting of hydrogen and C 1-4 alkyl;

[0057] -R9 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, N(R 11 )2 and CN, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic group are optionally substituted by a halogen atom, an aryl group, an aralkyl group, a heterocyclic group, CF3, N(R 11 )2, CN, or OR 11 ; and wherein each of R 11 is independently and, in each occurrence, selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl and CF3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, optionally substituted heteroaryl by C 1-4 alkyl, aryl, heteroaryl, and aralkyl substituents are optionally substituted by halo, C 1-6 alkyl, cycloalkyl, heterocyclic group, alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2, wherein each of R 31 and R 32 is independently and, in each occurrence, selected from the group consisting of hydrogen and C 1-4 alkyl, provided that if x = 1 and y = 0, then R9 is different from the heterocyclic group and from C 1-6 alkyl, wherein the alkyl is optionally substituted by a heterocyclic group; and provided that if x = 0 and y = 0, then R9 is different from hydrogen and C 1-6 alkyl, wherein the alkyl is optionally substituted by a heterocyclic group and N(R 11 )2; provided that when x = 0 and y = 0, then R9 and R2 may together form a saturated or unsaturated ring moiety; provided that when x = 0 and y = 0, and when R9 and R2 together form a saturated or unsaturated ring moiety, then R9 is NR 11 ; provided that when x = 1 and y = 1, then R9 is different from N(R 11 )2; and provided that when x = 0, y = 0 and z = 0, then R9 is different from pyrrole;

[0058] Each -T is independently a moiety of the following formula (T-a):

[0059]

[0060] Wherein:

[0061] - Each U is independently of one another and, each time it occurs, is selected from the group consisting of: C, C-halo, C-R, and N; where R is selected from hydrogen, OR 11 , N(R 11 )2, C 1-6 alkyl or cycloalkyl, optionally substituted by a halogen atom, an aryl group or an aralkyl group, where each of R 11 is independently of one another and, each time it occurs, is selected from the group consisting of: hydrogen or C 1-4 alkyl; provided that at least one U is different from N;

[0062] - Each Z is independently of one another and, each time it occurs, is selected from C(R)2, O, S and NR7, where the Rs are independently of one another and, each time they occur, are selected from hydrogen or C 1-6 alkyl, optionally substituted by a halogen atom, an aryl group or an aralkyl group, where R7 is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 1-6 alkenyl, cycloalkyl, heterocyclic group, aryl, aralkyl and CF3;

[0063] - Each R5 is independently of one another and, each time it occurs, is selected from the group consisting of: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, halo, CF3, OR 11 , SR 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, CON(R 11 )2, and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group, heteroaryl, aralkyl substituent is further optionally substituted by halo, C 1-6 alkyl, cycloalkyl, aryl, heterocyclic group, N(R 11 )2, CN, OR 11 , C(=O)OR 11 , P(=O)(OR 11 )2, P(=O)(R 11 )2, CN or CF3, and where each of R 11 is independently of one another and, each time it occurs, is selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, and heterocyclic group; each n1 is an integer ranging from 0 to 2;

[0064] - Each X is independently a moiety of formula (X-a) below:

[0065]

[0066] wherein:

[0067] each of -V is independently and at each occurrence selected from the group consisting of C, C-halo, C-R, and N; where R is selected from hydrogen, OR 11 , N(R 11 )2, C 1-6 alkyl or cycloalkyl, optionally substituted by a halogen atom, an aryl group or an aralkyl group, where each of R 11 is independently and at each occurrence selected from hydrogen or C 1-4 alkyl;

[0068] each of -R6 is independently and at each occurrence selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, halo, CF3, OR 11 , SR 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, CON(R 11 )2, and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group, heteroaryl, aralkyl substituent is further optionally substituted by halo, C 1-6 alkyl, cycloalkyl, aryl, heterocyclic group, N(R 11 )2, CN, OR 11 , C(=O)OR 11 , P(=O)(OR 11 )2, P(=O)(R 11 )2, CN or CF3, and where each of R 11 is independently and at each occurrence selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, and heterocyclic group; each of n2 is an integer ranging from 0 to 4;

[0069] - The dashed bond represents an optional triple bond;

[0070] - R a1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, CF3, CN, OR 11 , SR 11 , N(R 11 )2, COR 11 , C(O)OR11 , wherein the alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl are optionally halogenated, NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, CF3, CN, OR 11 , SR 11 , N(R 11 )2, COR 11 , and C(O)OR 11 substituted, and each optional alkyl, alkenyl, cycloalkyl, phenyl, heterocyclic group, heteroaryl substituent is further optionally halogenated, NO2, C 1-6 alkyl, cycloalkyl, phenyl, N(R 11 )2, CN, or OR 11 substituted; and wherein each of R 11 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, and aralkyl, wherein the alkyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, and aralkyl substituents are optionally halogenated, C 1-6 alkyl, cycloalkyl or heterocyclic group substituted;

[0071] -R a2 each is independently and at each occurrence selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, CF3, CN, OR 11 , SR 11 , N(R 11 )2, COR 11 , C(O)OR 11 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl are optionally halogenated, NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, CF3, CN, OR 11 , SR 11 , N(R 11 )2, COR 11 , and C(O)OR 11 substituted, and each optional alkyl, alkenyl, cycloalkyl, phenyl, heterocyclic group, heteroaryl substituent is further optionally halogenated, NO2, C 1-6 alkyl, cycloalkyl, phenyl, N(R 11 )2, CN, or OR 11 substituted; and wherein R 11each selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, and aralkyl, wherein said alkyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, and aralkyl substituents are optionally halogenated, C 1-6 alkyl, cycloalkyl or heterocyclic group substituted; and wherein n3 is an integer equal to 0 or 1; provided that when the dashed bond represents a triple bond, then n3 is 0;

[0072] wherein said cycloalkyl is a monocyclic, bicyclic or tricyclic ring system having 3 to 6 ring members per ring; said heterocyclic group is a saturated, partially saturated or fully saturated monocyclic, bicyclic or tricyclic containing 3 to 12 carbon atoms and 1 or 2 heteroatoms independently selected from O or N; said aryl is phenyl, naphthyl or anthracenyl, which is an optionally fused carbocyclic ring with a cycloalkyl or heterocyclic group having 5 to 7 ring members; said heteroaryl is a monocyclic structure having 5 or 6 ring atoms containing 1 to 3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

[0073] In a preferred embodiment of the present invention, A in the compounds (C) of formulas (I) to (VII) is independently selected from the group consisting of: cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl, wherein said cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl are optionally substituted by one or more substituents independently selected from the group consisting of: halogenated, NO2, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, CF3, CN, OR 11 , SR 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, P(=O)(OR 11 )2, P(=O)(R 11 )2NR 11 COR 12 , COR 11 , C(O)OR 11 , CON(R 11 )2, OC(O)R 11 , and OCON(R 11 )2, and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group, heteroaryl substituent is further optionally halogenated, NO2, C 1-6 alkyl, cycloalkyl, aryl, CF3, N(R 11 )2, CN, or OR 11 substituted; and wherein R11 and R 12 each, independently of one another and in each occurrence, is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and CF3, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl substituents are optionally halogenated, C 1-6 alkyl, cycloalkyl, or heterocycloalkyl substituted. More preferably, A is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl are optionally substituted with one or more substituents independently selected from the group consisting of halogenated, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, CF3, CN, OR 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, P(=O)(R 11 )2, COR 11 , C(O)OR 11 , CON(R 11 )2, OC(O)R 11 , and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl substituent is further optionally substituted with C 1-4 alkyl or cycloalkyl; and wherein each of R 11 and R 12 , independently of one another and in each occurrence, is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and CF3. More preferably, A is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl are optionally substituted with one or more substituents independently selected from the group consisting of halogenated, C 1-6 alkyl, CF3, CN, OR 11 , and P(=O)(R 11 )2; and wherein each of R 11 is, in each occurrence, hydrogen or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and isobutyl.

[0074] In one embodiment of the present invention, A in the compounds (C) of formulas (I) to (VII) is independently selected from the following moieties:

[0075]

[0076] wherein each of the halogenated is F, Cl, Br, or I, and each of R is hydrogen or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and isobutyl, and preferably R is hydrogen, methyl, ethyl, 2-methylpropyl, or tert-butyl.

[0077] In a preferred embodiment of the present invention, each of R4 in the compounds (C) of formulas (I) to (VII) is hydrogen or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, etc. Even more preferably, R4 is hydrogen or methyl.

[0078] In a preferred embodiment of the present invention, each of R4' in the compounds (C) of formulas (I) to (VII) is hydrogen or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, etc. Even more preferably, R4' is hydrogen.

[0079] In a preferred embodiment of the present invention, z in the compounds (C) of formulas (I) to (VII) is an integer equal to 0 or 1. Even more preferably, z is 1.

[0080] In a preferred embodiment of the present invention, each of R7 in the compounds (C) of formulas (I) to (VII) is independently of one another and in each occurrence hydrogen or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, etc. More preferably, each of R7 is independently of one another and in each occurrence hydrogen or methyl. Even more preferably, each of R7 is independently of one another and in each occurrence hydrogen.

[0081] In a preferred embodiment of the present invention, each of R3 in the compounds (C) of formulas (I) to (VII) is independently of one another and in each occurrence selected from the group consisting of: hydrogen, halogenated, C 1-6 alkyl, cycloalkyl, heterocyclic group, CF3, CN, OR 21 , and N(R 21 )2, wherein the alkyl, cycloalkyl, and heterocyclic group are optionally substituted by one or more substituents selected from halogenated, C 1-6 alkyl, CF3, N(R 21 )2, CN, or OR 21 ; and wherein each of R 21 is independently of one another and in each occurrence selected from the group consisting of: hydrogen, C 1-6 alkyl, C 3-6Cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl, and wherein said alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl substituents are optionally halogenated, C 1-6 alkyl, cycloalkyl, heterocyclic group, or aryl substituted. Preferably, R3 is independently selected from the group consisting of: hydrogen, halogenated, C 1-6 alkyl, cycloalkyl, CF3, CN, OR 21 , and N(R 21 )2, wherein said alkyl and cycloalkyl are optionally substituted by one or more substituents selected from halogenated, C 1-6 alkyl, CF3, N(R 21 )2, CN, or OR 21 ; and wherein each of R 21 is independently of one another and at each occurrence selected from the group consisting of: hydrogen, and C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and isobutyl. More preferably, R3 is independently selected from the group consisting of: hydrogen, halogenated, and C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, CF3, CN, OR 21 , and N(R 21 )2, and wherein each of R 21 is independently of one another and at each occurrence selected from the group consisting of: hydrogen, and C 1-4 alkyl. Even more preferably, R3 is independently selected from the group consisting of: hydrogen, halogenated, OC 1-4 alkyl, and C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and isobutyl. Even more preferably, R3 is independently selected from the group consisting of: hydrogen, halogenated, OCH3 and methyl.

[0082] In a preferred embodiment of the present invention, each r in the compounds (C) of formulas (I) to (VII) is an integer equal to 0, 1 or 2. More preferably, each r is an integer equal to 0 or 1. Even more preferably, each r is an integer equal to 1.

[0083] In a preferred embodiment of the present invention, each of R2 in the compounds (C) of formulas (I) to (VII) is independently of one another and at each occurrence selected from the group consisting of: hydrogen, halogenated, C 1-6 alkyl, cycloalkyl, heterocyclic group, aryl, and heteroaryl, CN, OR 21 , and N(R 21 )2, wherein said alkyl, cycloalkyl, heterocyclic group, aryl, and heteroaryl are optionally substituted by one or more substituents selected from halogenated, C 1-6 alkyl, cycloalkyl, N(R 21)2, CN, or OR 21 is substituted with a substituent of; wherein R 21 are each independently and at each occurrence selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl. More preferably, R2 is independently selected from the group consisting of: hydrogen, halo, C 1-4 alkyl, cycloalkyl, heterocyclic group, CN, OR 21 , and N(R 21 )2; wherein R 21 are each independently and at each occurrence selected from the group consisting of: hydrogen, C 1-4 alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and isobutyl) and C 3-6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl). Even more preferably, R2 is independently selected from the group consisting of: hydrogen, halo, C 1-4 alkyl, and N(R 21 )2, wherein R 21 is selected from the group consisting of: hydrogen and C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and isobutyl.

[0084] In a preferred embodiment of the present invention, q in the compounds (C) of formulas (I) to (VII) is equal to 0 or 1.

[0085] According to certain embodiments of the present invention, x in the compounds (C) of formulas (II), (IV) or (VI) is an integer equal to 0 and y is an integer equal to 1.

[0086] According to certain embodiments of the present invention, x in the compounds (C) of formulas (II), (IV) or (VI) is an integer equal to 1 and y is an integer equal to 0.

[0087] According to certain embodiments of the present invention, x in the compounds (C) of formulas (II), (IV) or (VI) is an integer equal to 1 and y is an integer equal to 1.

[0088] According to certain embodiments of the present invention, x in the compounds (C) of formulas (II), (IV) or (VI) is an integer equal to 0 and y is an integer equal to 0.

[0089] In a preferred embodiment of the present invention, R8 in the compound (C) of formula (I) is selected from the group consisting of C 6-12 alkyl, cycloalkyl and heterocyclic group, wherein the alkyl, cycloalkyl, and heterocyclic group are optionally substituted with a halogen atom, CF3, N(R 11 )2, CN, or OR 11is substituted; and wherein each R 11 , independently of one another and in each occurrence, is selected from the group consisting of: hydrogen, C 1-6 -alkyl. More preferably, R8 is C 6-12 -alkyl, wherein said alkyl is optionally substituted with a halogen atom. Even more preferably, R8 is C 6-12 -alkyl.

[0090] In a preferred embodiment of the present invention, R9 in the compound (C) of formula (II) is selected from the group consisting of: hydrogen, C 1-6 -alkyl, cycloalkyl, N(R 11 )2, and CN, wherein said alkyl and cycloalkyl are optionally substituted with a halogen atom, CF3, CN, or OR 11 ; and wherein each R 11 , independently of one another and in each occurrence, is selected from the group consisting of: hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, and CF3, wherein said alkyl and alkenyl substituents are optionally substituted with a heteroaryl group optionally substituted with C 1-4 -alkyl, provided that if x = 0 and y = 0, then R9 is different from hydrogen and C 1-6 -alkyl, wherein said alkyl is optionally substituted with a heterocyclic group and N(R 11 )2; provided that when x = 0 and y = 0, then R9 and R2 may together form a saturated or unsaturated ring moiety; provided that when x = 0 and y = 0, and when R9 and R2 together form a saturated or unsaturated ring moiety, then R9 is NR 11 ; provided that when x = 1 and y = 1, then R9 is different from N(R 11 )2; and provided that when x = 0, y = 0 and z = 0, then R9 is different from pyrrole; more preferably, R9 is selected from the group consisting of: hydrogen, C 1-6 -alkyl, cycloalkyl, N(R 11 )2, and CN, wherein said alkyl and cycloalkyl are optionally substituted with a halogen atom, CF3, CN, or OR 11 ; and wherein each R 11 , independently of one another and in each occurrence, is selected from the group consisting of: hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, and CF3, wherein said alkyl and alkenyl substituents are optionally substituted with a heteroaryl group optionally substituted with C 1-4 -alkyl; provided that if x = 0 and y = 0, then R9 is different from hydrogen and C 1-6 -alkyl, wherein said alkyl is optionally substituted with a heterocyclic group and N(R 11)2-substituted, provided that when x = 0 and y = 0, then R9 and R2 can together form a saturated or unsaturated ring moiety; provided that when x = 0 and y = 0, and when R9 and R2 together form a saturated or unsaturated ring moiety, then R9 is NR 11 ; provided that when x = 1 and y = 1, then R9 is different from N(R 11 )2; and provided that when x = 0, y = 0 and z = 0, then R9 is different from pyrrole; even more preferably, R9 is selected from the group consisting of: hydrogen, C 1-4 alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and isobutyl), C 2-6 alkenyl (such as propene or butene), C 3-6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), N(R 11 )2, and CN, wherein said alkyl, and cycloalkyl are optionally substituted by a halogen atom, CF3, CN, or OR 11 ; and wherein each of R 11 is independently of one another and in each occurrence selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, and CF3, wherein said alkyl, and alkenyl substituents are optionally substituted by a heteroaryl group optionally substituted by C 1-4 alkyl; provided that if x = 0 and y = 0, then R9 is different from hydrogen and C 1-6 alkyl, wherein said alkyl is optionally substituted by a heterocyclic group and N(R 11 )2, and provided that when x = 0 and y = 0, then R9 and R2 can together form a saturated or unsaturated ring moiety; provided that when x = 0 and y = 0, and when R9 and R2 together form a saturated or unsaturated ring moiety, then R9 is NR 11 ; provided that when x = 1 and y = 1, then R9 is different from N(R 11 )2; and provided that when x = 0, y = 0 and z = 0, then R9 is different from pyrrole;

[0091] In a preferred embodiment of the present invention, each of T in the compound (C) of formula (III) or (IV) is independently a moiety of formula (T-a) below:

[0092]

[0093] Wherein:

[0094] - Each of -U is independently of one another and in each occurrence preferably selected from C, C-halo, C-R, or N; wherein R is hydrogen or C 1-4An alkyl group, provided that at least one U is different from N, and more preferably, each U is independently of one another and at each occurrence selected from C, C-R or N; wherein R is hydrogen or C 1-4 An alkyl group, provided that at least one U is different from N.

[0095] Each of -Z is independently of one another and at each occurrence preferably selected from the group consisting of: CH2, and O, S and NR7, wherein R7 is hydrogen, or C 1-4 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and isobutyl. More preferably, each of Z is independently of one another and at each occurrence selected from the group consisting of: CH2, O, and NH.

[0096] Each of -R5 is independently of one another and at each occurrence preferably selected from the group consisting of: C 1-6 Alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl, halo, CF3, OR 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, CON(R 11 )2, and each optional alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl substituent is further optionally substituted by halo, C 1-6 alkyl, cycloalkyl, aryl, heterocyclic, N(R 11 )2, CN, OR 11 , C(=O)OR 11 , P(=O)(OR 11 )2, P(=O)(R 11 )2, CN or CF3, and wherein each of R 11 is independently of one another and at each occurrence selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, and heterocyclic. More preferably, each of R5 is independently of one another and at each occurrence selected from the group consisting of: C 1-4 alkyl, cycloalkyl, heterocyclic, CF3, OR 11 , and each optional alkyl, cycloalkyl, heterocyclic substituent is further optionally substituted by halo, C 1-4 alkyl, cycloalkyl, CN, OC 1-4 alkyl, C(=O)OC 1-4 alkyl, P(=O)(OC 1-4 alkyl)2, P(=O)(C 1-4 alkyl)2.

[0097] -n1 is preferably an integer equal to 0, 1 or 2. More preferably, n1 is an integer equal to 1 or 2.

[0098] In a preferred embodiment of the present invention, each T in the compound (C) of formula (III) or (IV) is independently of one another and in each occurrence selected from the moieties of formulae (T-a-1) to (T-a-11) below:

[0099]

[0100] wherein each R is independently selected from the group consisting of: hydrogen, C 1-4 alkyl, cycloalkyl, heterocyclic group, wherein said C 1-4 alkyl, cycloalkyl and heterocyclic group are optionally substituted with halogen, CN, cycloalkyl, OC 1-4 alkyl, C(=O)OC 1-4 alkyl, P(=O)(C 1-4 alkyl)2, P(=O)(OC 1-4 alkyl)2; preferably R is hydrogen or methyl, and wherein each R5' is independently selected from the group consisting of: hydrogen, C 1-4 alkyl, CF3, and cycloalkyl; and wherein n1 is an integer equal to 1 or 2.

[0101] In a preferred embodiment of the present invention, each X in the compound (C) of formula (V) or (VI) is independently a moiety of formula (X-a) below:

[0102]

[0103] wherein:

[0104] - Each V is independently of one another and in each occurrence selected from the group consisting of: C, C-halogen, C-R, and N; wherein R is hydrogen or C 1-4 alkyl; more preferably, each V is independently of one another and in each occurrence selected from C, C-R or N; wherein R is hydrogen or C 1-4 alkyl.

[0105] - Each R6 is independently of one another and in each occurrence preferably selected from the group consisting of: C 1-6 alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, halogen, CF3, OR 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, CON(R 11 )2, and each optional alkyl, cycloalkyl, aryl, heterocyclic group, heteroaryl, aralkyl substituent is further optionally substituted with halogen, C 1-6 alkyl, cycloalkyl, aryl, heterocyclic group, N(R 11 )2, CN, OR 11, C(=O)OR 11 , P(=O)(OR 11 )2, P(=O)(R 11 )2, CN or CF3 substituted, and wherein each of R 11 is independently of one another and in each occurrence selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, and heterocyclic group. More preferably, each of R6 is independently of one another and in each occurrence selected from the group consisting of: C 1-4 alkyl, cycloalkyl, heterocyclic group, heteroaryl, halogenated, CF3, OR 11 , N(R 11 )2, and each optional alkyl, cycloalkyl, heterocyclic group and heteroaryl substituent is further optionally substituted by halogenated, C 1-4 alkyl, cycloalkyl, heterocyclic group, CN, OC 1-4 alkyl, C(=O)OC 1-4 alkyl, P(=O)(OC 1-4 alkyl)2, P(=O)(C 1-4 alkyl)2 substituted, wherein the heterocyclic group is further optionally substituted by C 1-4 alkyl substituted, and wherein each of R 11 is independently of one another and in each occurrence selected from the group consisting of: hydrogen, and C 1-4 alkyl. Even more preferably, each of R6 is independently of one another and in each occurrence selected from the group consisting of: C 1-4 alkyl, cycloalkyl, heterocyclic group, heteroaryl, halogenated, CF3, OR 11 , N(R 11 )2, and each optional alkyl, cycloalkyl, heterocyclic group and heteroaryl substituent is further optionally substituted by C 1-4 alkyl, or heterocyclic group substituted, wherein the heterocyclic group is further optionally substituted by C 1-4 alkyl substituted, and wherein each of R 11 is independently of one another and in each occurrence selected from the group consisting of: hydrogen, and C 1-4 alkyl.

[0106] -n2 is preferably an integer equal to 0, 1 or 2. More preferably, n1 is an integer equal to 0 or 1.

[0107] In one embodiment of the present invention, each of X in the compound (C) of formula (V) or (VI) is independently selected from the moieties of formula (X-a-1) to (X-a-3) below:

[0108]

[0109] wherein

[0110] -Each of R6’ is independently selected from hydrogen, halo, C 1-4 alkyl, OC 1-4 alkyl, NH2, N(C 1-4 alkyl)2, heterocyclic group, heteroaryl, wherein the C 1-4 alkyl, heteroaryl and heterocyclic group are optionally substituted by halo, C 1-4 alkyl, heterocyclic group (which is optionally substituted by C 1-4 alkyl).

[0111] -n2 is an integer equal to 1 or 2.

[0112] In a preferred embodiment of the present invention, the dashed bond in the compound (C) of formula (VII) represents a triple bond.

[0113] In a preferred embodiment of the present invention, R in the compound (C) of formula (VII) a1 is independently selected from the group consisting of: C 1-4 alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, wherein the alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl and aralkyl are optionally substituted by halo, NO2, C 1-4 alkyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, CF3, CN, OR 11 , N(R 11 )2, and wherein each of R 11 is selected from the group consisting of: hydrogen, or C 1-4 alkyl. More preferably, R a1 is independently selected from the group consisting of: C 1-4 alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, wherein the alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl and aralkyl are optionally substituted by halo, heterocyclic group, aryl, heteroaryl, OR 11 , N(R 11 )2, and wherein each of R 11 is selected from the group consisting of hydrogen and C 1-4 alkyl. Even more preferably, R a1 is independently C 1-4 alkyl, wherein the alkyl is optionally substituted by aryl, heteroaryl, OR 11 , N(R 11 )2, and wherein each of R 11 is selected from the group consisting of: hydrogen, and C 1-4 alkyl.

[0114] In a preferred embodiment of the present invention, R in the compound (C) of formula (VII) a2 is independently selected from the group consisting of: C 1-4Alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, wherein the alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl and aralkyl are optionally halogenated, NO2, C 1-4 alkyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, CF3, CN, OR 11 , N(R 11 ), and wherein each of R 11 is selected from the group consisting of: hydrogen, or C 1-4 alkyl. More preferably, each of R a2 is independently selected from the group consisting of: C 1-4 alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, wherein the alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl and aralkyl are optionally halogenated, heterocyclic group, phenyl, heteroaryl, OR 11 , N(R 11 ), and wherein each of R 11 is selected from the group consisting of: hydrogen, or C 1-4 alkyl. Even more preferably, each of R a2 is independently C 1-4 alkyl, wherein the alkyl is optionally substituted with aryl, heteroaryl, OR 11 , N(R 11 ), and wherein each of R 11 is selected from the group consisting of: hydrogen, and C 1-4 alkyl.

[0115] In a preferred embodiment of the present invention, n3 in the compound (C) of formula (VII) is an integer equal to 0.

[0116] According to one embodiment of the present invention, the compound (C) of formula (II) or its N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer is preferably a compound selected from those of formula (II-a) or (II-b) [compound (C) of class (II) below]:

[0117]

[0118]

[0119] wherein A, R4, R4’, z, R7, R3, r, R2, q and R9 have the same meanings as defined above for formula (II).

[0120] According to one embodiment of the present invention, the compound (C) of formula (III) or its N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer is preferably a compound of formula (III-a) [compound (C) of class (III) below]:

[0121]

[0122] Wherein A, R4, R4', z, R7, R3, r, R2, q, and T have the same meanings as defined above for formula (III).

[0123] According to one embodiment of the present invention, the compound (C) according to formula (IV), or its N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer is preferably a compound selected from those of formulae (IV-a) to (IV-c) [compound (C) of class (IV) below]:

[0124]

[0125] Wherein A, R4, R4', z, R7, R3, r, R2, q, and T have the same meanings as defined above for formula (IV).

[0126] According to one embodiment of the present invention, the compound (C) according to formula (VI), or its N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer is preferably a compound selected from those of formulae (VI-a) to (VI-c) [compound (C) of class (VI) below]:

[0127]

[0128] Wherein A, R4, R4', z, R7, R3, r, R2, q, and X have the same meanings as defined above for formula (VI).

[0129] According to one embodiment of the present invention, the compound (C) according to formula (VII), or its N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer is preferably a compound selected from those of formula (VII-a) or (VII-b) [compound (C) of class (VI) below]:

[0130]

[0131] Wherein A, R4, R4', z, R7, R3, r, R2, q, R a1 、R a2 and n3 have the same meanings as defined above for formula (VII).

[0132] In the compound (C) according to the present invention, preferably R4' and R7 are hydrogen, and r and q are equal to 1. Therefore, the preferred compound (C) of class (II) is selected from those of formulae (II-a-1) to (II-c-1) below:

[0133]

[0134] wherein A, R4, R3, R2, and R9 have the same meanings as defined above for formula (II); wherein R 31 is a heteroaryl, which is optionally substituted by C 1-4 alkyl, wherein R 11 ' is hydrogen or C 1-4 alkyl; and wherein R b is selected from the group consisting of: hydrogen, halo, C 1-4 alkyl, and C 1-6 cycloalkyl.

[0135] wherein the heteroaryl is a monocyclic structure having 5 or 6 ring atoms containing 1-3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

[0136] In one embodiment of the present invention, the compound (C) of class (II) is selected from those of formulae (II-a-1) to (II-c-1).

[0137] In the compound (C) according to the present invention, preferably R4' and R7 are hydrogen, and r and q are equal to 1. Thus, the preferred compounds (C) of class (IV) are selected from those of formulae (IV-a-1) to (IV-c-1) below:

[0138]

[0139]

[0140] wherein A, R4, R3, R2, and T have the same meanings as defined above for formula (IV).

[0141] In one embodiment of the present invention, the compound (C) of class (IV) is selected from those of formulae (IV-a-1) to (IV-c-1).

[0142] In the compound (C) according to the present invention, preferably R4' and R7 are hydrogen, and r and q are equal to 1. Thus, the preferred compounds (C) of class VI are selected from those of formulae (VI-a-1) to (VI-c-1) below:

[0143]

[0144] wherein A, R4, R3, R2, and X have the same meanings as defined above for formula (VI).

[0145] In one embodiment of the present invention, the compound (C) of class (VI) is selected from those of formulae (VI-a-1) to (VI-c-1).

[0146] In the compound (C) according to the present invention, preferably R4' and R7 are hydrogen, and r and q are equal to 1. Accordingly, the preferred compounds (C) of class (VII) are selected from those of formula (VII-a-1) or (VII-b-1) below:

[0147]

[0148]

[0149] wherein A, R4, R3, R2, R a1 , R a2 , and n3 have the same meanings as defined above for formula (VII).

[0150] In one embodiment of the present invention, the compound (C) of class (II) is selected from those of formula (VII-a-1) or (VII-b-1).

[0151] In a preferred embodiment of the present invention, the compound (C) of class (II) according to the present invention is selected from those of formula (II-a-2) or (II-b-2) or (II-c-2) below:

[0152]

[0153] Each of -R9' is selected from the group consisting of: hydrogen, CN, and C 3-6 cycloalkyl, such as cyclopropyl;

[0154] Each of -R9'' is selected from the group consisting of: hydrogen, C 1-4 alkyl, CN, and C 3-6 cycloalkyl, such as cyclopropyl;

[0155] Each of -R2 is independently selected from hydrogen or halo;

[0156] -R q Each of which is independently selected from the group consisting of: hydrogen, CH3, OCH3, and halo, such as F or Cl;

[0157] -R 10 Each of which is independently selected from the group consisting of: H, F, Cl, OCH3, or CF3;

[0158] Each of -U is selected from the group consisting of: C, C-R 10 and N;

[0159] -n 10 is an integer equal to 0, 1, or 2; and

[0160] -R 31Each of ’ is selected from the group consisting of: pyrazinyl, N-methylpyrazinyl, and pyridinyl;

[0161] -R b ’ is selected from the group consisting of: hydrogen, halo, C 1-4 alkyl, and C 1-4 cycloalkyl; preferably R b ’ is selected from the group consisting of: Cl, CH3, and cyclopropyl;

[0162] - The dashed bond represents an optional double bond.

[0163] In a preferred embodiment of the present invention, the compound (C) of class (IV) according to the present invention is selected from those of the following formulae (IV-a-2-1), (IV-a-2-2), (IV-b-2-1), (IV-b-2-2), or (IV-c-2) to (IV-c-2-4):

[0164]

[0165]

[0166] Wherein:

[0167] - T is independently of each other and at each occurrence selected from the moieties of the following formulae (T-a-a) to (T-a-f):

[0168]

[0169] Wherein:

[0170] - Each of R’ is independently hydrogen, C 1-4 alkyl, cycloalkyl selected from the group consisting of cyclopropyl and cyclobutyl; heterocyclic group selected from the group consisting of oxetanyl, tetrahydropyranyl, azetidinyl, and piperidinyl; wherein the alkyl is further optionally substituted by F, OC 1-4 alkyl, P(=O)(OC 1-4 alkyl)2, P(=O)(C 1-4 alkyl)2, CN, cyclopropyl, or cyclobutyl; and wherein the heterocyclic group is further optionally substituted by C(=O)(OC 1-4 alkyl),

[0171] - Each of R”5 is independently selected from the group consisting of: hydrogen, C 1-4 alkyl, CF3, and cyclopropyl;

[0172] - Each of n1 is independently of each other and at each occurrence an integer equal to 0, 1, or 2;

[0173] - R2 is independently hydrogen, halo, or NH2;

[0174] -R q Each of which is independently selected from the group consisting of: H, CH3, OCH3, and halo, such as F or Cl;

[0175] -R 10 Each of which is independently selected from the group consisting of: hydrogen, halo, C 1-4 alkyl, CF3, OC 1-4 alkyl, and CN,

[0176] Each of -U and V is independently C, C-R 10 or N;

[0177] -n 10 is an integer equal to 0, 1, or 2.

[0178] In a preferred embodiment of the present invention, the compound (C) of class (VI) according to the present invention is selected from those of the following formulas (VI-a-2) to (VI-c-2):

[0179]

[0180] wherein

[0181] Each of -R”6 is independently selected from the group consisting of: hydrogen, halo, C 1-4 alkyl, N(R 21 )2, OR 21 ; a heterocyclic group selected from the group consisting of: pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl; pyrazinyl, wherein the heterocyclic group and pyrazinyl are optionally substituted by C 1-4 alkyl, and wherein R 21 is C 1-4 alkyl;

[0182] -R q Each of which is independently selected from the group consisting of: H, CH3, OCH3, and halo, such as F or Cl;

[0183] -R 10 Each of which is independently selected from the group consisting of: hydrogen, halo, OC -4 alkyl, and CN;

[0184] Each of -U is independently C, C-R 10 or N;

[0185] -n 10 is an integer equal to 0, 1, or 2;

[0186] -n2 is an integer equal to 0, 1, or 2.

[0187] In a preferred embodiment of the present invention, the compound (C) of class (VII) according to the present invention is selected from those of the following formula (VII-a-2):

[0188]

[0189] wherein Ra’1 is selected from the group consisting of: benzyl, pyrazinyl, OH, OC 1-4 alkyl, NH2, and NH(C 1-4 alkyl), and wherein R q is selected from the group consisting of: H, CH3, OCH3, and halo, such as F or Cl; preferably R q is H or CH3.

[0190] In a preferred embodiment of the present invention, the compound (C) according to the general formula (II-a) is a compound selected from those of the following formulas (VIII) to (XXXII-3):

[0191]

[0192]

[0193]

[0194]

[0195]

[0196] In a preferred embodiment of the present invention, the compound (C) according to the general formula (II-b) is a compound selected from those of the following formulas (XXXIII) to (XXXIV):

[0197]

[0198] In a preferred embodiment of the present invention, the compound (C) according to the general formula (III-a) is a compound selected from those of the following formulas (XXXV) to (XXXVI):

[0199]

[0200] In a preferred embodiment of the present invention, the compound (C) according to the general formula (IV-a) is a compound selected from those of the following formulas (XXXVII) to (LXXI-2):

[0201]

[0202]

[0203]

[0204]

[0205]

[0206] In a preferred embodiment of the present invention, the compound (C) according to general formula (IV-b) is a compound selected from those of the following formulas (LXXII) to (CV):

[0207]

[0208]

[0209]

[0210]

[0211]

[0212] In a preferred embodiment of the present invention, the compound (C) according to general formula (IV-c) is a compound selected from those of the following formulas (CVI) to (CXCVIII-5):

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225] In a preferred embodiment of the present invention, the compound (C) according to general formula (VI-a) is a compound selected from those of the following formulas (CXCIX) to (CCXII):

[0226]

[0227]

[0228] In a preferred embodiment of the present invention, the compound (C) according to general formula (VI-b) is a compound selected from those of the following formulas (CCXIII) to (CCXV):

[0229]

[0230] In a preferred embodiment of the present invention, the compound (C) according to general formula (VI-c) is a compound selected from those of the following formulas (CCXVI) to (CCLX):

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238] In a preferred embodiment of the present invention, the compound (C) according to general formula (VII-a) is a compound selected from those of the following formulas (CCLXI) to (CCLXVII):

[0239]

[0240]

[0241] The present invention further relates to an in vitro method for inhibiting protein kinase activity, the method comprising contacting a protein kinase with a compound of formulas (I) to (VII) as defined above [compound (C), hereinafter], or its N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer,

[0242]

[0243]

[0244] wherein:

[0245] Each of -A is independently selected from the group consisting of cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl, wherein the cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, NO2, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, CF3, CN, OR 11 , SR 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, S(O)R 12 , SO2R 12 , SO2N(R 11 )2, S(O)3R 11 , P(=O)(OR 11 )2, P(=O)(R 11 )2NR 11 COR 12 , COR 11 , C(O)OR 11 , CON(R 11 )2, OC(O)R 11 , and OCON(R 11 )2, and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group, and heteroaryl substituent is further optionally substituted with halo, NO2, C 1-6 alkyl, cycloalkyl, aryl, CF3, N(R 11 )2, COR 11 , CON(R 11 )2, OC(O)R 11 , CN, or OR 11 ; and wherein each of R 11 and R 12 is independently of one another and at each occurrence selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl and CF3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl substituents are optionally substituted with halo, C 1-6 alkyl, cycloalkyl, heterocyclic group, C 1-6 alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2, where R 31 and R32 each of which is independently of the others and, in each occurrence, selected from the group consisting of hydrogen and C 1-4 alkyl;

[0246] each of -R4 and R’4 is independently of the other and, in each occurrence, selected from hydrogen or C 1-6 alkyl, and z is an integer ranging from 0 to 2; provided that when z = 0, then A and R7 may together form a saturated or unsaturated ring moiety;

[0247] each of -R7 is independently of the others and, in each occurrence, selected from hydrogen, C 1-6 alkyl, cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted by a halogen atom, CF3, N(R 11 )2, CN, or OR 11 ; and wherein R 11 each of which is independently of the others and, in each occurrence, selected from the group consisting of hydrogen, C 1-6 alkyl, and CF3;

[0248] each of -R3 is independently of the others and, in each occurrence, selected from the group consisting of hydrogen, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, CF3, CN, OR 21 , SR 21 , N(R 21 )2, NC(O)R 21 , NCON(R 21 )2, COR 21 , C(O)OR 21 , CON(R 21 )2, OC(O)R 21 , OCON(R 21 )2, OC(R 21 )2O, and OC(R 21 )2C(R 22 )2O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and aralkyl are optionally substituted by one or more substituents selected from halo, C 1-6 alkyl, CF3, N(R 21 )2, CN, or OR 21 ; and wherein R 21 and R 22 each of which is independently of the others and, in each occurrence, selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl, and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl substituents are optionally halogenated, C 1-6 alkyl, cycloalkyl, heterocyclic group, aryl, OR 31 or N(R 32 )2 substituted, wherein R 31 and R 32 each independently of one another and in each occurrence is selected from the group consisting of hydrogen and C 1-4 alkyl; each r is an integer ranging from 0 to 3; provided that when R3 = NR 21 and R7 = H, then R3 and NR7 can together form a saturated or unsaturated ring moiety;

[0249] - Each of -R2 is independently of one another and in each occurrence is selected from the group consisting of hydrogen, halogenated, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, and heteroaryl, CF3, CN, NO2, OR 21 , SR 21 , N(R 21 )2, COR 21 , C(O)OR 21 , CON(R 21 )2, OC(O)R 21 , OCON(R 21 )2, NC(O)R 21 , NCON(R 21 )2, OC(R 21 )2O and OC(R 21 )2C(R 22 )2O, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, and heteroaryl are optionally substituted by one or more substituents selected from halogenated, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, CF3, COR 21 , CON(R 21 )2, C(O)OR 21 , N(R 21 )2, CN, or OR 21 ; and each optional alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl substituent is further optionally substituted by a heterocyclic group, N(R 11 )2, or OR 11 ; and wherein R 21 and R 22Each of which is independently and, in each occurrence, selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl, and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl substituents are optionally halogenated, C 1-6 alkyl, cycloalkyl, heterocyclic group, aryl, OR 31 or N(R 32 )2 substituted, wherein R 31 and R 32 Each of which is independently and, in each occurrence, selected from the group consisting of: hydrogen and C 1-4 alkyl; each q is an integer ranging from 0 to 2;

[0250] - Each of x and y is independently an integer equal to 0 or 1;

[0251] - R8 is independently selected from the group consisting of: C 6-12 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl and heterocyclic group, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic group are optionally substituted by a halogen atom, an aryl group, an aralkyl group, CF3, N(R 11 )2, CN, or OR 11 substituted; and wherein R 11 Each of which is independently and, in each occurrence, selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl and CF3, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl substituents are optionally halogenated, C 1-6 alkyl, cycloalkyl, heterocyclic group, alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2 substituted, wherein R 31 and R 32 Each of which is independently and, in each occurrence, selected from the group consisting of: hydrogen and C 1-4 alkyl;

[0252] - R9 is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, N(R 11) 2 and CN, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic group are optionally substituted by a halogen atom, an aryl group, an aralkyl group, a heterocyclic group, CF3, N(R 11 ) 2, CN, or OR 11 ; and wherein each R 11 is independently of one another and at each occurrence selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl and CF3, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group are optionally substituted by C 1-4 alkyl substituted heteroaryl, aryl, heteroaryl, and aralkyl substituents are optionally halogenated, C 1-6 alkyl, cycloalkyl, heterocyclic group, alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 ) 2, wherein each R 31 and R 32 is independently of one another and at each occurrence selected from the group consisting of: hydrogen and C 1-4 alkyl, provided that if x = 1 and y = 0, then R9 is different from the heterocyclic group and from C 1-6 alkyl, wherein said alkyl is optionally substituted by a heterocyclic group; and provided that if x = 0 and y = 0, then R9 is different from hydrogen and C 1-6 alkyl, wherein said alkyl is optionally substituted by a heterocyclic group and N(R 11 ) 2; provided that when x = 0 and y = 0, then R9 and R2 may together form a saturated or unsaturated ring moiety; provided that when x = 0 and y = 0, and when R9 and R2 together form a saturated or unsaturated ring moiety, then R9 is NR 11 ; provided that when x = 1 and y = 1, then R9 is different from N(R 11 ) 2; and provided that when x = 0, y = 0 and z = 0, then R9 is different from pyrrole;

[0253] Each -T is independently a moiety of formula (T-a) below:

[0254]

[0255] Wherein:

[0256] Each -U is independently of one another and at each occurrence selected from the group consisting of: C, C-halogenated, C-R, and N; wherein R is selected from hydrogen, OR 11 , N(R 11 ) 2, C 1-6An alkyl or cycloalkyl group, optionally substituted by a halogen atom, an aryl group or an aralkyl group, wherein R 11 each of which is independently of one another and in each occurrence is selected from the group consisting of: hydrogen or C 1-4 alkyl; provided that at least one U is different from N;

[0257] each of -Z is independently of one another and in each occurrence is selected from C(R)2, O, S and NR7, wherein R is independently of one another and in each occurrence selected from hydrogen or C 1-6 alkyl, optionally substituted by a halogen atom, an aryl group or an aralkyl group, wherein R7 is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 1-6 alkenyl, cycloalkyl, heterocyclic group, aryl, aralkyl and CF3;

[0258] each of -R5 is independently of one another and in each occurrence is selected from the group consisting of: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, halo, CF3, OR 11 , SR 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, CON(R 11 )2, and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group, heteroaryl, aralkyl substituent is further optionally substituted by halo, C 1-6 alkyl, cycloalkyl, aryl, heterocyclic group, N(R 11 )2, CN, OR 11 , C(=O)OR 11 , P(=O)(OR 11 )2, P(=O)(R 11 )2, CN or CF3, and wherein R 11 each of which is independently of one another and in each occurrence is selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, and heterocyclic group; each of n1 is an integer ranging from 0 to 2;

[0259] each of -X is independently a moiety of formula (X-a) below:

[0260]

[0261] wherein:

[0262] each of -V is independently of one another and in each occurrence is selected from the group consisting of: C, C-halo, C-R, and N; wherein R is selected from hydrogen, OR11 , N(R 11 )2, C 1-6 alkyl or cycloalkyl, optionally substituted by a halogen atom, an aryl group or an aralkyl group, wherein each of R 11 is independently of one another and in each occurrence selected from hydrogen or C 1-4 alkyl;

[0263] Each of -R6 is independently of one another and in each occurrence selected from the group consisting of: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, halo, CF3, OR 11 , SR 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, CON(R 11 )2, and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group, heteroaryl, aralkyl substituent is further optionally substituted by halo, C 1-6 alkyl, cycloalkyl, aryl, heterocyclic group, N(R 11 )2, CN, OR 11 , C(=O)OR 11 , P(=O)(OR 11 )2, P(=O)(R 11 )2, CN or CF3, and wherein each of R 11 is independently of one another and in each occurrence selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, and heterocyclic group; each of n2 is an integer ranging from 0 to 4;

[0264] - The dashed bond represents an optional triple bond;

[0265] - R a1 is independently selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, CF3, CN, OR 11 , SR 11 , N(R 11 )2, COR 11 , C(O)OR 11 , wherein the alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl and aralkyl are optionally substituted by halo, NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, CF3, CN, OR 11 , SR11 , N(R 11 )2, COR 11 , and C(O)OR 11 substituted, and each optional alkyl, alkenyl, cycloalkyl, phenyl, heterocyclic, heteroaryl substituent is further optionally halogenated, NO2, C 1-6 alkyl, cycloalkyl, phenyl, N(R 11 )2, CN, or OR 11 substituted; and wherein each of R 11 is independently selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclic, phenyl, heteroaryl, and aralkyl, wherein said alkyl, cycloalkyl, heterocyclic, phenyl, heteroaryl, and aralkyl substituents are optionally halogenated, C 1-6 alkyl, cycloalkyl or heterocyclic substituted;

[0266] -R a2 each independently of one another and at each occurrence is selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl, CF3, CN, OR 11 , SR 11 , N(R 11 )2, COR 11 , C(O)OR 11 , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl and aralkyl are optionally halogenated, NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic, phenyl, heteroaryl, CF3, CN, OR 11 , SR 11 , N(R 11 )2, COR 11 , and C(O)OR 11 substituted, and each optional alkyl, alkenyl, cycloalkyl, phenyl, heterocyclic, heteroaryl substituent is further optionally halogenated, NO2, C 1-6 alkyl, cycloalkyl, phenyl, N(R 11 )2, CN, or OR 11 substituted; and wherein each of R 11 is independently selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclic, phenyl, heteroaryl, and aralkyl, wherein said alkyl, cycloalkyl, heterocyclic, phenyl, heteroaryl, and aralkyl substituents are optionally halogenated, C 1-6 alkyl, cycloalkyl or heterocyclic substituted; and wherein n3 is an integer equal to 0 or 1; provided that when the dashed bond represents a triple bond, then n3 is 0;

[0267] Wherein the cycloalkyl group is a monocyclic, bicyclic or tricyclic ring system having 3 to 6 ring members per ring; the heterocyclic group is a monocyclic, bicyclic or tricyclic saturated, partially saturated or fully saturated group containing 3 to 12 carbon atoms and 1 or 2 heteroatoms independently selected from O or N; the aryl group is phenyl, naphthyl or anthracenyl, which is an optionally fused carbocyclic ring with a cycloalkyl or heterocyclic group having 5 to 7 ring members; the heteroaryl group is a monocyclic structure having 5 or 6 ring atoms containing 1 to 3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

[0268] It should also be understood that all definitions and preferences described above for compound (C) apply equally to this example and all additional examples described below.

[0269] Unless otherwise stated, the following definitions apply as used above and below.

[0270] The term halo, alone or in combination, means all halogens, i.e., chlorine (Cl), bromine (Br), fluorine (F), iodine (I).

[0271] Unless otherwise stated, the term alkyl, alone or in combination, means an alkane-derived group containing 1 to 15 carbon atoms, e.g., C F-G Alkyl is defined as a straight-chain or branched-chain alkyl group having F to G carbon atoms, e.g., C 1-4 Alkyl is defined as a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms, e.g., methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl. The alkyl group can be a straight-chain alkyl or a branched-chain alkyl. Preferably, the straight-chain or branched-chain alkyl group contains 1-10, more preferably 1 to 8, even more preferably 1-6, and most preferably 1-4 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc. Alkyl also includes straight-chain or branched-chain alkyl groups containing a cycloalkyl moiety or interrupted by a cycloalkyl moiety. The straight-chain or branched-chain alkyl can be attached at any available point to produce a stable compound. Examples thereof include but are not limited to 4-(isopropyl)-cyclohexylethyl or 2-methyl-cyclopropylpentyl.

[0272] The term alkenyl, alone or in combination, means a straight-chain or branched-chain hydrocarbon containing 2 to 15, more preferably 2 to 10, even more preferably 2 to 8, and most preferably 2 to 4 carbon atoms (unless otherwise specified) and at least one, preferably 1 to 3, more preferably 1 to 2, and most preferably one carbon-carbon double bond. Examples of alkenyl groups include vinyl, propenyl, isopropenyl, butenyl, cyclohexenyl, cyclohexenylalkyl, etc. Alkenyl also includes straight-chain or branched-chain alkenyl groups containing a cycloalkyl moiety or interrupted by a cycloalkyl moiety. The carbon-carbon double bond can be contained within the cycloalkyl moiety (except cyclopropyl) or within the straight-chain or branched-chain moiety.

[0273] The term alkynyl, alone or in combination, means a straight-chain or branched-chain hydrocarbon containing 2 to 15, more preferably 2 to 10, even more preferably 2 to 8, and most preferably 2 to 4 carbon atoms and containing at least one, preferably one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl, propynyl, butynyl, etc.

[0274] The term aryl, alone or in combination, means phenyl, naphthyl, or anthracenyl, which is optionally a carbocyclic ring fused with preferably 5 to 7, more preferably 5 to 6 ring members and / or optionally a cycloalkyl or heterocyclic group substituted by 1 to 5 groups or substituents. Aryl can be optionally substituted, where the substituent is attached to the aryl at one point, or where the substituent is attached to the aryl at two points to form a bicyclic system, such as benzodioxolene, benzodioxane, benzimidazole.

[0275] The term heteroaryl, alone or in combination, means a monocyclic aromatic ring structure containing 5 or 6 ring atoms or a bicyclic aromatic group having 8 to 10 atoms containing 1 to 3 heteroatoms independently selected from the group consisting of O, S, and N and optionally substituted by 1 to 5 groups or substituents. Heteroaryl also is intended to include oxidized S or N, such as sulfinyl, sulfonyl, and N-oxides of tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure, thus retaining a stable aromatic ring. More particularly, the term heteroaryl includes, but is not limited to, pyridyl, furyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuryl, isobenzofuryl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzisoxazolyl, benzothienyl, dibenzofuran, and benzodiazepin-2-one-5-yl, etc. -2-one-5-yl, etc.

[0276] The term heterocyclic group, alone or in combination, is intended to mean a saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or tricyclic ring having 3 to 12 carbon atoms and containing 1 or 2 heteroatoms each independently selected from O, S, P or N, and is optionally benzo-fused or fused 5-6 membered heteroaryl and / or optionally substituted (as in the case of cycloalkyl). The heterocycle is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxides of tertiary ring nitrogen. The point of attachment is on a carbon or nitrogen atom. In each case, the heterocyclic group may be condensed with an aryl group to form a bicyclic ring system.

[0277] The term cycloalkyl refers to a monocyclic or polycyclic alkyl group containing 3 to 7 carbon atoms. Preferably, the cycloalkyl group is a monocyclic, bicyclic or tricyclic ring system with 3-6 ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, etc.

[0278] The term aralkyl refers to an organic compound containing an aromatic nucleus bonded to an alkyl group. These alkyl groups include groups such as methyl, ethyl, propyl, butyl, octyl, etc. Thus, the term aralkyl includes aralkyl hydrocarbons, such as alkylbenzenes and various alkylnaphthalenes. It can be seen from the definition of the term aralkyl compound that this term includes compounds such as benzyl, the three isomers of xylenyl, the two isomers of trimethylbenzene, ethylbenzene, p-methylbiphenyl, α-methylnaphthalene, etc.

[0279] The present invention further relates to a pharmaceutical composition comprising a carrier and an effective amount of a compound (C) of formulas (I) to (VII) as specified herein and defined in any one of the examples herein, or of formulas (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or of formula (VII-a-2) as specified herein and defined in any one of the examples herein, or any subgroup of compounds.

[0280] The present invention relates to compounds (C) of formulae (I) to (VII) as specified herein and defined in any of the examples herein, or any subgroup of compounds of formulae (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-c), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2) as specified herein and defined in any of the examples herein, for use as a medicament.

[0281] The present invention relates to compounds (C) of formulae (I) to (VII) as specified herein and defined in any of the examples herein, or any subgroup of compounds of formulae (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or of formula (VII-a-2) as specified herein and defined in any of the examples herein, for use in the treatment of diseases selected from: cancer, metabolic disorders (such as diabetes), inflammatory and autoimmune disorders (such as inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, inflammatory lung diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus and psoriasis and psoriatic arthritis), neurological disorders (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth neuropathy, amyotrophic lateral sclerosis and epilepsy), atherosclerosis and cardiovascular diseases, Sjogren's syndrome, kidney transplant rejection, virus-induced diseases, circulatory system diseases, osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, eye diseases (such as retinopathy, age-related macular degeneration and uveitis), chronic and neuropathic pain, and fibroproliferative diseases.

[0282] The present invention further relates to a method for inhibiting the protein kinase activity of warm-blooded animals, said method comprising administering to an animal in need thereof a kinase-inhibiting effective amount of a compound (C) of formula (I) to (VII) as specified herein and according to any one of the examples herein, or a compound of any subgroup of compounds of formula (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or formula (VII-a-2) as specified herein and according to any one of the examples herein.

[0283] The present invention further relates to a method of inhibiting the protein kinase activity in warm-blooded animals, the method comprising administering to an animal in need thereof a kinase-inhibiting effective amount of a compound (C) of formula (I) to (VII) as specified herein and according to any one of the examples herein, or a compound of any subgroup of compounds of formula (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or formula (VII-a-2) as specified herein and according to any one of the examples herein, wherein the protein kinase is selected from the group consisting of: CSF1R, FLT3, Kit, PDGFRB (PDGFRβ), PDGFRA (PDGFRα), ABL1, ACVR1B (ALK4), AKT1 (PKBα), AMPK A1 / B1 / G1, AURKA (Aurora A), BTK, CDK1 / cyclin B, CHEK1 (CHK1), CSNK1G2 (CK1γ2), CSNK2A1 (CK2α1), DYRK3, EGFR (ErbB1), EPHA2, ERBB2 (HER2), FGFR1, FRAP1 (mTOR), GSK3B (GSK3β), IGF1R, IKBKB (IKKβ), INSR, IRAK4, JAK3, KDR (VEGFR2), LCK, MAP2K1 (MEK1), MAP4K4 (HGK), MAPK1 (ERK2), MAPK14 (p38α), MAPK3 (ERK1), MAPK8 (JNK1), MARK2, MET (cMet), NEK1, PAK4, PHKG2, PIM1, PLK1, PRKACA (PKA), PRKCB1 (PKCβI), ROCK1, RPS6KA3 (RSK2), RPS6KB1 (p70S6K), SRC, SYK, and TEK (Tie2). Preferably, the protein kinase is selected from the group consisting of: CSF1R, FLT3, Kit, PDGFRB (PDGFRβ), PDGFRA (PDGFRα).

[0284] The present invention further relates to a method of treating a disease selected from the following in warm-blooded animals: cancer, metabolic disorders (such as diabetes), inflammatory and autoimmune disorders (such as inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, inflammatory lung disease, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus and psoriasis and psoriatic arthritis), neurological disorders (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth neuropathy, amyotrophic lateral sclerosis and epilepsy), atherosclerosis and cardiovascular diseases, Sjogren's syndrome, kidney transplant rejection, virus-induced diseases, circulatory system diseases, osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, eye diseases (such as retinopathy, age-related macular degeneration and uveitis), chronic and neuropathic pain, and fibroproliferative diseases, the method comprising administering to an animal in need thereof an effective amount of a compound (C) of formula (I) to (VII) as specified herein and according to any one of the examples herein, or of formula (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or of formula (VII-a-2) as specified herein and according to any one of the examples herein, or any subgroup of compounds of formula (VII-a-2).

[0285] It should be noted that the position of a group on any molecular moiety used in the definitions can be at any position of such a moiety, provided that it is chemically stable.

[0286] Unless otherwise specified, the groups used in the definitions of variables include all possible isomers. For example, pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes 1-pentyl, 2-pentyl and 3-pentyl.

[0287] When any variable occurs more than once in any component, each definition is independent. Hereinafter, whenever the term "compound (C) of formula (I) to (VII)", or "compound of the present invention" or a similar term is used, it is intended to include all compounds (C) of formula (I) to (VII), N-oxides, addition salts, and stereochemical isomeric forms. One embodiment comprises the compounds (C) of formula (I) to (VII) as specified herein, or any subgroup of the compounds of formula (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or formula (VII-a-2), and their N-oxides, salts, and possible stereoisomeric forms. Another embodiment comprises the compounds (C) of formula (I) to (VII) as specified herein, or any subgroup of the compounds of formula (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or formula (VII-a-2), and their salts and possible stereoisomeric forms.

[0288] Compounds (C) of formulae (I) to (VII) as specified herein, or any subgroup of compounds of formulae (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or formula (VII-a-2) as specified herein have several chiral centers and exist in stereoisomeric forms. As used herein, the term "stereoisomeric forms" defines all possible compounds formed by the same atoms bonded in the same bond sequence but having different and non-interchangeable three-dimensional structures, as may be possessed by compounds (C) of formulae (I) to (VII) as specified herein, or any subgroup of compounds of formulae (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or formula (VII-a-2) as specified herein.

[0289] Unless otherwise stated or indicated, the chemical designation of a compound (C) of formula (I) to (VII) as specified herein, or of any subgroup of compounds of formula (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or of formula (VII-a-2) as specified herein encompasses a mixture of all possible stereochemical isomeric forms, as may be possessed by said compounds. Said mixture may contain all diastereoisomers and / or enantiomers of the basic molecular structure of said compounds. All stereochemical isomeric forms of the compounds of the present invention, whether in pure form or in admixture with each other, are intended to be embraced within the scope of the present invention.

[0290] A pure stereoisomeric form of a compound (C) of formula (I) to (VII) as specified herein, or of any subgroup of compounds of formula (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or of formula (VII-a-2) as specified herein, and of an intermediate as mentioned herein is defined as being substantially free of isomers of the same basic molecular structure as said compound or intermediate which are other enantiomeric or diastereomeric forms. In particular, the term "stereoisomerically pure" pertains to a compound or intermediate having a stereoisomeric excess of at least 80% (i.e., at least 90% of one isomer and at most 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e., 100% of one isomer and none other), more particularly having a stereoisomeric excess of 90% up to 100%, even more particularly having a stereoisomeric excess of 94% up to 100%, and most particularly having a stereoisomeric excess of 97% up to 100%. The terms "enantiomerically pure" and "diastereomerically pure" should be understood in a similar manner, considering the enantiomeric excess and diastereomeric excess of the mixture under discussion, respectively.

[0291] The pure stereoisomeric forms of the compounds and intermediates of the present invention can be obtained by application procedures known in the art. For example, enantiomers can be separated from each other by selectively crystallizing diastereomeric salts with an optically active acid or base. Examples thereof are tartaric acid, dibenzoyl tartaric acid, xylene tartaric acid, and camphorsulfonic acid. Alternatively, enantiomers can also be separated by chromatographic techniques using a chiral stationary phase. The pure stereochemical isomeric forms can also be derived from the corresponding pure stereochemical isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is required, the compound will be synthesized by a stereospecific preparation method. These methods will advantageously employ enantiomerically pure starting materials.

[0292] The diastereomeric racemates of the compounds (C) of formula (I) to (VII) as specified herein, or of any subgroup of the compounds of formula (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or of formula (VII-a-2) as specified herein can be obtained separately by conventional methods. Suitable physical separation methods that can be advantageously employed are, for example, selective crystallization and chromatography, such as column chromatography.

[0293] For some of the compounds (C) of formula (I) to (VII) as specified herein, or of any subgroup of the compounds of formula (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or of formula (VII-a-2) as specified herein, the absolute stereochemical configuration of the N-oxides, salts, solvates, and intermediates (used in their preparation) has not been determined experimentally.

[0294] Those skilled in the art are able to determine the absolute configuration of such compounds by methods known in the art, such as X-ray diffraction.

[0295] The present invention also aims to include isotopes of all atoms that occur on compounds (C) of formulae (I) to (VII) as specified herein, or any subgroup of compounds of formulae (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or formula (VII-a-2) as specified herein. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general illustration but not limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0296] For therapeutic use, salts of compounds (C) of formulae (I) to (VII) as specified herein, or any subgroup of compounds of formulae (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or formula (VII-a-2) as specified herein are those in which the counterion is pharmaceutically acceptable, and these salts may be referred to as pharmaceutically acceptable acid and base addition salts. However, salts of non-pharmaceutically acceptable acids and bases may also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are included within the scope of the present invention.

[0297] The pharmaceutically acceptable acid and base addition salts as mentioned above are intended to include the compounds (C) of formulas (I) to (VII) as specified herein, or the compounds of any subgroup of the compounds of formulas (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or formula (VII-a-2), or formula (VII-a-2) in the form of pharmaceutically active non-toxic acid and base addition salts that can be formed. The pharmaceutically acceptable acid addition salts can be conveniently obtained by treating the base form with an acid in such a suitable anionic form. Suitable anions include, for example, trifluoroacetate, acetate, benzenesulfonate, benzoate, bicarbonate, hydrogen tartrate, bromide, calcium edetate, camsyiate, carbonate, chloride, citrate, dihydrochloride, edetate, ethanedisulfonate, propionate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxy naphthoate, iodide, hydroxyethylsulfonate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthalenesulfonate, nitrate, pamoate / embonate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, basic acetate, succinate, sulfate, tannate, tartrate, theophyllinate, triethyl iodide, etc. The selected counterion can be introduced using an ion exchange resin. Conversely, the salt form can be converted to the free base form by treatment with a suitable base.

[0298] Compounds (C) of formulae (I) to (VII) as specified herein containing acidic protons, or any subgroup of compounds of formulae (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or formula (VII-a-2), or formula (VII-a-2) can also be converted into their non-toxic metal or amine addition salt forms by treatment with suitable cationic forms of organic and inorganic bases. Suitable basic salts include salts formed with organic cations such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, etc.; and salts formed with metal cations (e.g., aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, etc.). Conversely, the salt forms can be converted into the free form by treatment with a suitable acid.

[0299] The term addition salt as used above also includes solvates that can be formed by compounds (C) of formulae (I) to (VII) as specified herein, or any subgroup of compounds of formulae (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or formula (VII-a-2) and their salts. Such solvates are, for example, hydrates, alcoholates, etc.

[0300] The N-oxide forms of the compounds (C) of the invention of formulas (I) to (VII) as specified herein, or of any subgroup of compounds of formulas (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or formula (VII-a-2) as specified herein are intended to include compounds of formula (I) in which one or several nitrogen atoms are oxidized to the so-called N-oxides.

[0301] It should be understood that the compounds (C) of formulas (I) to (VII) as specified herein, or any subgroup of compounds of formulas (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or formula (VII-a-2) as specified herein may have metal-binding, chelating, complex-forming properties and thus may exist as metal complexes or metal chelates. Such metallized derivatives of the compounds (C) of formulas (I) to (VII) as specified herein, or any subgroup of compounds of formulas (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or formula (VII-a-2) as specified herein are intended to be included within the scope of the present invention.

[0302] Compounds (C) of formulas (I) to (VII) as specified herein, or some of any subgroup of compounds of formulas (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or formula (VII-a-2) may also exist in their tautomeric forms. Although such forms are not explicitly indicated in the above formulas, they are still intended to be included within the scope of the present invention.

[0303] In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound (C) of formula (I) to (VII) as specified herein, or any subgroup of compounds of formula (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or formula (VII-a-2) as specified herein, and a pharmaceutically acceptable carrier. A therapeutically effective amount herein is an amount sufficient to prophylactically counteract, stabilize or mitigate a protein kinase-mediated disorder in a diseased subject or a subject at risk of disease, particularly a protein kinase selected from the group consisting of: CSF1R, FLT3, Kit, PDGFRB (PDGFRβ), PDGFRA (PDGFRα), ABL1, ACVR1B (ALK4), AKT1 (PKBα), AMPK A1 / B1 / G1, AURKA (Aurora A), BTK, CDK1 / cyclin B, CHEK1 (CHK1), CSNK1G2 (CK1γ2), CSNK2A1 (CK2α1), DYRK3, EGFR (ErbB1), EPHA2, ERBB2 (HER2), FGFR1, FRAP1 (mTOR), GSK3B (GSK3β), IGF1R, IKBKB (IKKβ), INSR, IRAK4, JAK3, KDR (VEGFR2), LCK, MAP2K1 (MEK1), MAP4K4 (HGK), MAPK1 (ERK2), MAPK14 (p38α), MAPK3 (ERK1), MAPK8 (JNK1), MARK2, MET (cMet), NEK1, PAK4, PHKG2, PIM1, PLK1, PRKACA (PKA), PRKCB1 (PKCβI), ROCK1, RPS6KA3 (RSK2), RPS6KB1 (p70S6K), SRC, SYK, and TEK (Tie2). Preferably, the protein kinase is selected from the group consisting of: CSF1R, FLT3, Kit, PDGFRB (PDGFRβ), PDGFRA (PDGFRα).

[0304] In particular, examples of protein kinase-mediated disorders include cancer, metabolic disorders (such as diabetes), inflammatory and autoimmune disorders (such as inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, inflammatory lung diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus and psoriasis and psoriatic arthritis), neurological disorders (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth neuropathy, amyotrophic lateral sclerosis and epilepsy), atherosclerosis and cardiovascular diseases, Sjogren's syndrome, kidney transplant rejection, virus-induced diseases, circulatory system diseases, osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, eye diseases (such as retinopathy, age-related macular degeneration and uveitis), chronic and neuropathic pain, and fibroproliferative diseases.

[0305] In still further aspects, the present invention relates to methods of preparing pharmaceutical compositions as specified herein, the methods comprising intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound (C) of formula (I) to (VII) as specified herein, or any subgroup of compounds of formula (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or formula (VII-a-2) as specified herein.

[0306] Accordingly, the compounds (C) of formulae (I) to (VII) as specified herein, or any subgroup of compounds of formulae (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or of formula (VII-a-2) as specified herein can be formulated into various pharmaceutical forms for administration purposes. As suitable compositions, all compositions commonly used for systemic drug administration can be cited. To prepare the pharmaceutical compositions of the present invention, an effective amount of a specific compound as the active ingredient (optionally, also in the form of a salt or a metal complex) is intimately admixed with a pharmaceutically acceptable carrier, which can take a variety of forms depending on the dosage form required for administration. These pharmaceutical compositions are preferably in suitable unit dosage forms, particularly suitable for oral, rectal, transdermal or parenteral injection administration. For example, in preparing compositions for oral dosage forms, any common pharmaceutical vehicle can be used. For example, in the case of liquid oral preparations (such as suspensions, syrups, elixirs, emulsions and solutions), water, ethylene glycol, oils, alcohols, etc. can be used; or in the case of powders, pills, capsules and tablets, solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrants, etc. can be used.

[0307] Due to convenience of administration, tablets and capsules are the most advantageous oral dosage forms, and in such cases a solid pharmaceutical carrier will obviously be used. For parenteral compositions, the carrier will generally comprise at least a large portion of sterile water, although other ingredients (such as ingredients for assisting dissolution) can also be included. For example, injectable solutions can be prepared in which the carrier comprises a saline solution, a glucose solution or a mixture of a saline solution and a glucose solution. Injectable suspensions can also be prepared, in which case a suitable liquid carrier, suspending agent, etc. can be used. Also included are solid form preparations which are intended to be converted into liquid form preparations shortly before use. In compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and / or a suitable wetting agent, optionally in combination with a smaller proportion of suitable additives of any nature which do not have a significant adverse effect on the skin.

[0308] Compounds (C) of formulae (I) to (VII) as specified herein of the present invention, or compounds of any subgroup of compounds of formulae (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or of formula (VII-a-2) as specified herein may also be administered via oral inhalation or insufflation by methods and formulations used in the art for administration via such means. Thus, compounds (C) of formulae (I) to (VII) as specified herein, or compounds of any subgroup of compounds of formulae (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or of formula (VII-a-2) as specified herein can generally be administered to the lungs in the form of a solution, suspension or dry powder (preferably a solution). Any system for delivering a solution, suspension or dry powder via oral inhalation or insufflation is suitable for administering the compounds of the present invention.

[0309] Accordingly, the present invention also provides a pharmaceutical composition suitable for administration by oral inhalation or insufflation, the pharmaceutical composition comprising a compound (C) of formulae (I) to (VII) as specified herein, or a compound of any subgroup of compounds of formulae (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or of formula (VII-a-2) as specified herein, and a pharmaceutically acceptable carrier. Preferably, the compounds of the present invention are administered via an inhaled nebulized or aerosolized dose of a solution.

[0310] The above pharmaceutical compositions can be formulated particularly advantageously in unit dosage forms for ease of administration and to achieve dose uniformity. As used herein, a unit dosage form refers to a physically discrete unit suitable as a unit dose; each unit contains a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, cachets, injectable solutions or suspensions, etc., and divided multi-dose forms thereof.

[0311] Compounds (C) of formula (I) to (VII) as specified herein, or any subgroup of compounds of formula (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b), (II-a-1) to (II-c-1), (IV-a-1) to (IV-c-1), (VI-a-1) to (VI-c-1), (VII-a-1) to (VII-b-1), (II-a-2) to (II-c-2), (IV-a-2-1) to (IV-c-2-4), (IV-a-2) to (VI-c-2), or of formula (VII-a-2) as specified herein exhibit kinase inhibitory properties. Conditions and diseases that can be treated using the compounds and methods of the present invention include protein kinase-mediated diseases such as cancer, metabolic disorders (e.g., diabetes), inflammatory and autoimmune disorders (e.g., inflammatory bowel disease, e.g., Crohn's disease and ulcerative colitis, inflammatory lung diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus and psoriasis and psoriatic arthritis), neurological disorders (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth neuropathy, amyotrophic lateral sclerosis and epilepsy), atherosclerosis and cardiovascular diseases, Sjogren's syndrome, renal transplant rejection, virus-induced diseases, circulatory system diseases, osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, eye diseases (e.g., retinopathy, age-related macular degeneration and uveitis), chronic and neuropathic pain, and fibroproliferative diseases. Many of the compounds of the present invention may exhibit good pharmacokinetic characteristics and have attractive properties in terms of bioavailability (including acceptable half-life, AUC (area under the curve) and peak), and do not have adverse phenomena such as insufficient onset and tissue retention.

[0312] The combination of the present invention can be used as a medicament. The use as a medicament or the method of treatment includes administering to a diseased subject systemically an effective amount of the medicament to counteract the symptoms associated with the disorder. Accordingly, the combination of the present invention can be used for the manufacture of a medicament for treating, preventing or counteracting a disorder or disease associated with a protein kinase, which disorders or diseases include cancer, metabolic disorders (such as diabetes), inflammatory and autoimmune disorders (such as inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, inflammatory lung diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus and psoriasis and psoriatic arthritis), neurological disorders (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth neuropathy, amyotrophic lateral sclerosis and epilepsy), atherosclerosis and cardiovascular diseases, Sjogren's syndrome, renal transplant rejection, virus-induced diseases, circulatory system diseases, osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, eye diseases (such as retinopathy, age-related macular degeneration and uveitis), chronic and neuropathic pain, and fibroproliferative diseases.

[0313] As used herein, the term "therapeutically effective amount" means an amount of an active compound or component or agent that elicits a biological or medical response sought by a researcher, veterinarian, medical doctor or other clinician according to the present invention in a tissue, system, animal or human, including alleviation of the symptoms of the disease being treated.

[0314] Examples

[0315] Example 1: General procedure for the preparation of analogs 49 - 55

[0316]

[0317] Method A1: Under nitrogen, to a solution of a phenol derivative (1 equivalent) in DMF (5 mL / mmol) was added solid cesium carbonate (2.5 equivalents), followed by addition of a 4-chloropyridine derivative (1 equivalent). The reaction mixture was stirred at 110 °C until completion (from 2 h to overnight). After cooling to room temperature, a saturated aqueous solution of NH4Cl was added and the aqueous layer was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (cyclohexane / EtOAc from 100 / 0 to 50 / 50) or (DCM / MeOH from 100 / 0 to 90 / 10), or reverse phase chromatography (H2O / MeOH: 0 to 100%) to give the desired compound.

[0318] Method B1: A solution of NaOH 1N (2.9 mL / mmol) was added to a solution of the appropriate intermediate 47 (1 equivalent) in EtOH or MeOH (2.5 mL / mmol). The reaction mixture was stirred at rt until completion. EtOH or MeOH was removed under reduced pressure, and the crude product was acidified with HCl 1N until pH = 2 - 3. The precipitate was filtered off, washed with water and dried in vacuo over P2O5 to give the desired intermediate 48.

[0319] Method C2: Under nitrogen, DMAP (2.2 equivalents), EDC·HCl (2 equivalents) and the appropriate amine (1.1 - 1.5 equivalents) were added to a suspension of the appropriate intermediate 48 (1 equivalent) in DCM or DMF (10 mL / mmol). The reaction mixture was stirred at room temperature until completion (1 h - overnight). The reaction mixture was diluted with DCM and washed twice with a saturated solution of NH4Cl. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH from 100 / 0 to 90 / 10) and reverse phase chromatography (H2O / MeOH: 0 to 100%) to give the desired compound.

[0320] Method D1: Phenylboronic acid (128 mg, 1.05 mmol), K3PO4 (424 mg, 2 mmol) and Pd(OAc)2 (4 mg, 0.015 mmol) were added to a stirred solution of 2 - bromo - 4 - chloropyridine (192 mg, 1 mmol) in isopropanol / H2O (4 mL / 4 mL). The reaction mixture was stirred at 80 °C in an air atmosphere for 30 minutes. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed twice with a saturated solution of NaCl. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (cyclohexane / EtOAc: 100 / 0 to 90 / 10) to give 162 mg of 4 - chloro - 2 - phenylpyridine 46b in 85% yield.

[0321] Method D2: Under nitrogen, phenylboronic acid (256 mg, 2.1 mmol), solid K3PO4 (849 mg, 4 mmol) and Pd(PPh3)4 (231 mg, 0.2 mmol) were added to a stirred solution of 3 - bromo - 4 - chloropyridine (385 mg, 2 mmol) in dioxane (10 mL). The reaction mixture was stirred at 100 °C for 4 h. The solvent was removed in vacuo, and the crude product was purified by flash column chromatography (cyclohexane / EtOAc, from 100 / 0 to 75 / 25) to give 4 - chloro - 3 - phenyl - pyridine 46c as a yellow oil in 87% yield.

[0322] The following table lists Intermediate 47 prepared by Method A1:

[0323]

[0324] The following table lists Intermediate 48 prepared by Method B1:

[0325]

[0326] The following compounds are examples illustrating Procedure C2:

[0327] N -(Cyclohexylmethyl)-3-(4-pyridyloxy)benzamide (49):

[0328]

[0329] According to General Method C2, Compound 49 as a white solid was synthesized from Intermediate 48a (0.20 mmol) and 1-cyclohexylmethylamine (0.34 mmol) with a yield of 83%. 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 8.51 (t, J = 5.8 Hz, 1H), 8.49 - 8.47 (m, 2H), 7.78 (ddd, J = 7.8 Hz, 1.5 Hz, 1.0 Hz, 1H), 7.64 - 7.61 (m, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.35 (ddd, J = 8.1 Hz, 2.5 Hz, 1.0 Hz, 1H), 6.96 - 6.93 (m, 2H), 3.09 (dd, J = 6.8 Hz, 6.0 Hz, 2H), 1.68 (t, J = 13.5 Hz, 4H), 1.63 - 1.49 (m, 2H), 1.23 - 1.09 (m, 3H), 0.95 - 0.84 (m, 2H).

[0330] N -(Cyclohexylmethyl)-3-[(2-phenyl-4-pyridyl)oxy]benzamide (50):

[0331]

[0332] According to General Method C2, Compound 50 as a white solid was synthesized from Intermediate 48b (0.20 mmol) and 1-cyclohexylmethylamine (0.30 mmol) with a yield of 70%. 11H NMR (400 MHz, CDCl3) δ (ppm): 8.56 (d, J = 5.6 Hz, 1H), 7.94 - 7.88 (m, 2H), 7.66 - 7.61 (m, 1H), 7.57 - 7.54 (m, 1H), 7.52 - 7.39 (m, 4H), 7.28 - 7.24 (m, 2H), 6.79 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 6.14 (bs, 1H), 3.35 - 3.28 (m, 2H), 1.83 - 1.54 (m, 6H), 1.27 - 1.15 (m, 3H), 1.05 - 0.94 (m, 2H).

[0333] Example 2: General Procedure for the Synthesis of Analogs 68 - 101

[0334]

[0335] Method E: Under nitrogen, oxalyl chloride (3 equiv) and 50 μL of DMF were added to a solution of the carboxylic acid derivative (1 equiv) in CH2Cl2 (5 mL / mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give the acyl chloride derivative. Under nitrogen, 2 - amino - 4 - chloropyridine (1 equiv) was added to a solution of this previous intermediate in pyridine (3 mL / mmol) and the reaction mixture was stirred at room temperature until completion (from 2 h to overnight). The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH from 100 / 0 to 95 / 5) to give the desired compound.

[0336] The following compound 65a is an example illustrating Method E:

[0337] N -(4-Chloro-2-pyridyl)-1-methyl-pyrazole-4-carboxamide (65a ) Preparation :

[0338]

[0339] Intermediate 65a as a white powder was synthesized from 1 - methyl - 1H - pyrazole - 4 - carboxylic acid (2.37 mmol) and 2 - amino - 4 - chloropyridine (2.37 mmol) according to the general method E in 84% yield.

[0340] ESI - MS: 237.10 (M + H) + .

[0341] The following table lists the intermediates 65 prepared by Method E:

[0342]

[0343] The following compound 65e is an example illustrating Method C2:

[0344] N -(4-Chloro-2-pyridyl)pyridine-3-carboxamide (65e ) Preparation :

[0345]

[0346] The intermediate 65e as a white powder was synthesized from nicotinic acid (1.28 mmol) and 2-amino-4-chloropyridine (1.16 mmol) according to the general method C2, with a yield of 84%.

[0347] ESI-MS: 234.10 (M+H) + 。

[0348] Method A2: Under nitrogen, cesium carbonate (2.5 equivalents) as a solid was added to a solution of a phenol derivative (1 equivalent) in DMF (2 mL / mmol), and then a 4-chloropyridine derivative (1 equivalent) was added. The reaction mixture was stirred overnight at 140 °C. The reaction mixture was concentrated under reduced pressure to give the desired compound, which was used in the next step without purification.

[0349] The following compound 66a is an example illustrating Method A2:

[0350] Ethyl 3-({2-[(1-methylpyrazole-4-carbonyl)amino]-4-pyridyl}oxy)benzoate (66a) Preparation Preparation :

[0351]

[0352] The intermediate 66a as a brown powder was synthesized from ethyl 3-hydroxy-2-methyl-benzoate (0.91 mmol) and compound 65a (0.91 mmol) according to the general method A2.

[0353] ESI-MS: 381.20 (M+H) + 。

[0354] The following table lists the intermediates 66 prepared by Method A2:

[0355]

[0356] Method B2: To a solution of the appropriate intermediate 66 (1 eq) in EtOH (2.5 mL / mmol) was added a solution of 2N NaOH (2.5 mL / mmol). The reaction mixture was stirred at 50 °C for 1 h. The EtOH was evaporated under reduced pressure and the residue was dissolved in water and washed three times with CH2Cl2. The aqueous layer was then acidified with concentrated HCl until pH = 2 - 3. The resulting precipitate was filtered, washed with H2O and dried over P2O5 to give the desired compound. If desired, the filtrate was evaporated under reduced pressure and purified by reverse phase chromatography (H2O / MeOH from 100 / 0 to 0 / 100) to give a more desired compound.

[0357] The following compound 67a is an example illustrating Method B2:

[0358] Preparation of 2-methyl-3-({2-[(1-methylpyrazole-4-carbonyl)amino]-4-pyridinyl}oxy)benzoic acid (67a):

[0359]

[0360] According to the general method B2, intermediate 67a as a white solid was synthesized from intermediate 66a (0.91 mmol) in 32% yield (over 2 steps).

[0361] ESI-MS: 353.15 (M+H) + 。

[0362] The following table lists intermediates 67 prepared by Method B2:

[0363]

[0364] The following compounds are examples illustrating Method C2:

[0365] N-(4-{3-[(2,6-Difluoro-4-pyridyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)- 1-methyl-pyrazole-4-carboxamide (68):

[0366]

[0367] According to the general method C2, compound 68 as a white solid was synthesized from intermediate 67a (0.42 mmol) and (2,6-difluoro-4-pyridinyl)methanamine (0.63 mmol) in 23% yield. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 10.59 (s, 1H), 9.16 (t, J = 6.0 Hz, 1H), 8.40 (s, 1H), 8.24 (d, J = 5.7 Hz, 1H), 8.09 (s, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.50 - 7.37 (m, 2H), 7.30 - 7.24 (m, 1H), 7.14 (s, 2H), 6.63 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.57 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 2.15 (s, 3H).

[0368] ESI-MS: 479.20 (M + H) + 。

[0369] N-(4-{3-[(4-Cyano-3-fluorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)- 1-methyl-pyrazole-4-carboxamide (69):

[0370]

[0371] Compound 69 as a white solid was synthesized from intermediate 67a (0.10 mmol) and 4-aminomethyl-2-fluorobenzonitrile (0.11 mmol) according to general method C2 in 71% yield. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.59 (s, 1H), 9.14 (t, J = 6.0 Hz, 1H), 8.40 (s, 1H), 8.23 (d, J = 5.7 Hz, 1H), 8.09 (d, J = 0.6 Hz, 1H), 7.97 - 7.88 (m, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 10.4 Hz, 1H), 7.43 - 7.37 (m, 3H), 7.26 (t, J = 4.7 Hz, 1H), 6.63 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.54 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 2.14 (s, 3H).

[0372] ESI-MS: 485.15 (M + H) + 。

[0373] N-(4-{3-[(3,5-Difluorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl- pyrazole-4-carboxamide (70):

[0374]

[0375] Compound 70 as a white solid was synthesized from intermediate 67a (0.10 mmol) and 3,5-difluorobenzylamine (0.11 mmol) according to general method C2 in 64% yield.1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.56 (s, 1H), 9.05 (t, J = 6.1 Hz, 1H), 8.40 (s, 1H), 8.23 (d, J = 5.7 Hz, 1H), 8.09 (s, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.44 - 7.35 (m, 2H), 7.25 (dd, J = 7.3 Hz, 2.0 Hz, 1H), 7.18 - 7.03 (m, 3H), 6.62 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.14 (s, 3H).

[0376] N-(4-{3-[(6-Methoxy-3-pyridyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)- 1-methyl-pyrazole-4-carboxamide (71):

[0377]

[0378] According to the general method C2, compound 71 as a white solid was synthesized from intermediate 67a (0.10 mmol) and (6-methoxypyridin-3-yl)methanamine (0.11 mmol) with a yield of 61%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.56 (s, 1H), 8.95 (t, J = 5.9 Hz, 1H), 8.40 (s, 1H), 8.22 (d, J = 5.7 Hz, 1H), 8.14 (d, J = 2.2 Hz, 1H), 8.09 (s, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 7.40 - 7.19 (m, 3H), 6.81 (d, J = 8.5 Hz, 1H), 6.61 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 2.11 (s, 3H).

[0379] N-(4-{3-[(3-Fluorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl-py razole-4-carboxamide (72):

[0380]

[0381] According to the general method C2, compound 72 as a white solid was synthesized from intermediate 67a (0.09 mmol) and 3-fluorobenzylamine (0.13 mmol) with a yield of 26%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 10.54 (s, 1H), 9.01 (t, J = 6.1 Hz, 1H), 8.40 (s, 1H), 8.23 (d, J = 5.8 Hz, 1H), 8.09 (d, J = 0.6 Hz, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.45 - 7.20 (m, 6H), 7.24 (dd, J = 7.9 Hz, 1.3 Hz, 1H), 6.62 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.46 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.14 (s, 3H).

[0382] ESI-MS: 460.15 (M+H) + 。

[0383] N-(4-{3-[(4-Fluorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl-py razole-4-carboxamide (73):

[0384]

[0385] Compound 73 as a white solid was synthesized from intermediate 67a (0.09 mmol) and 4-fluorobenzylamine (0.13 mmol) according to general method C2, with a yield of 26%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.53 (s, 1H), 9.00 (t, J = 6.0 Hz, 1H), 8.40 (s, 1H), 8.23 (d, J = 5.7 Hz, 1H), 8.09 (d, J = 0.5 Hz, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.46 - 7.32 (m, 3H), 7.26 - 7.04 (m, 4H), 6.62 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.14 (s, 3H).

[0386] ESI-MS: 460.15 (M+H) + 。

[0387] N-(4-{3-[(3-Chlorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl-py razole-4-carboxamide (74):

[0388]

[0389] Compound 74 as a white solid was synthesized from intermediate 67a (0.09 mmol) and 3-chlorobenzylamine (0.13 mmol) according to general method C2, with a yield of 30%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 10.53 (s, 1H), 8.97 (t, J = 6.2 Hz, 1H), 8.40 (s, 1H), 8.23 (d, J = 5.7 Hz, 1H), 8.09 (d, J = 0.5 Hz, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.47 - 7.30 (m, 4H), 7.25 - 7.12 (m, 3H), 6.61 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.43 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 2.13 (s, 3H).

[0390] ESI-MS: 476.10 (M+H) + 。

[0391] N-(4-{3-[(4-Chlorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl-py razole-4-carboxamide (75):

[0392]

[0393] Compound 75 as a white solid was synthesized from intermediate 67a (0.09 mmol) and 4-chlorobenzylamine (0.13 mmol) according to general method C2 with a yield of 30%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.56 (s, 1H), 9.01 (t, J = 6.0 Hz, 1H), 8.40 (s, 1H), 8.23 (d, J = 5.7 Hz, 1H), 8.09 (d, J = 0.4 Hz, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.47 - 7.31 (m, 6H), 7.23 (dd, J = 7.8 Hz, 1.3 Hz, 1H), 6.62 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.43 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.13 (s, 3H).

[0394] ESI-MS: 476.10 (M+H) + 。

[0395] N-{4-[3-(Imidazo[1,2-a]pyridin-6-ylmethylcarbamoyl)-2-methyl-phenoxy]-2-pyridin yl}-1-methyl-pyrazole-4-carboxamide (76):

[0396]

[0397] Compound 76 as a white solid was synthesized from intermediate 67a (0.09 mmol) and imidazo[1,2-a]pyridin-6-ylmethylamine (0.13 mmol) according to general method C2 with a yield of 22%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 10.56 (s, 1H), 9.01 (t, J = 5.9 Hz, 1H), 8.50 (s, 1H), 8.40 (s, 1H), 8.23 (d, J = 5.7 Hz, 1H), 8.09 (d, J = 0.5 Hz, 1H), 7.97 (s, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.58 - 7.52 (m, 2H), 7.45 - 7.32 (m, 2H), 7.29 - 7.19 (m, 2H), 6.62 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.44 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 2.13 (s, 3H).

[0398] ESI-MS: 482.20 (M+H) + 。

[0399] N-{4-[3-(Imidazo[1,2-a]pyridin-7-ylmethylcarbamoyl)-2-methyl-phenoxy]-2-pyridin yl}-1-methyl-pyrazole-4-carboxamide (77):

[0400]

[0401] According to the general method C2, compound 77 as a white solid was synthesized from intermediate 67a (0.09 mmol) and imidazo[1,2-a]pyridin-7-ylmethanamine (0.13 mmol) with a yield of 15%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.56 (s, 1H), 9.05 (t, J = 6.1 Hz, 1H), 8.51 (dd, J = 7.0 Hz, 0.7 Hz, 1H), 8.40 (s, 1H), 8.23 (d, J = 5.7 Hz, 1H), 8.09 (d, J = 0.5 Hz, 1H), 7.90 (s, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.53 (d, J = 1.2 Hz, 1H), 7.47 - 7.35 (m, 3H), 7.25 (dd, J = 7.4 Hz, 1.9 Hz, 1H), 6.89 (dd, J = 7.0 Hz, 1.6 Hz, 1H), 6.62 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.49 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 2.15 (s, 3H).

[0402] ESI-MS: 482.2

[0403] 0 (M+H) + 。

[0404] 1-Methyl-N-[4-(2-methyl-3-{[6-(trifluoromethyl)-3-pyridyl]methylcarbamoyl}phenoxy)- 2-pyridyl]pyrazole-4-carboxamide (78):

[0405]

[0406] According to the general method C2, the compound 78 as a white solid was synthesized from the intermediate 67a (0.09 mmol) and [6-(trifluoromethyl)-3-pyridyl]methylamine (0.13 mmol) in a yield of 44%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.88 (s, 1H), 9.12 (t, J = 5.9 Hz, 1H), 8.76 (s, 1H), 8.27 (d, J = 5.7 Hz, 1H), 8.05 (d, J = 9.3 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.46 - 7.35 (m, 2H), 7.30 - 7.23 (m, 2H), 6.65 (dd, J = 5.7 Hz, 2.3 Hz, 1H), 4.58 (d, J = 5.8 Hz, 2H), 4.04 (s, 3H), 2.14 (s, 3H).

[0407] ESI-MS: 511.15 (M + H) + 。

[0408] N-(4-{3-[(5-Fluoro-6-methoxy-3-pyridyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyr idyl)-1-methyl-pyrazole-4-carboxamide (79):

[0409]

[0410] According to the general method C2, the compound 79 as a white solid was synthesized from the intermediate 67a (0.09 mmol) and (5-fluoro-6-methoxy-3-pyridyl)methylamine (0.13 mmol) in a yield of 38%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.54 (s, 1H), 8.95 (t, J = 5.9 Hz, 1H), 8.40 (s, 1H), 8.23 (d, J = 5.7 Hz, 1H), 8.09 (d, J = 0.4 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.65 (dd, J = 11.4 Hz, 1.9 Hz, 1H), 7.41 - 7.30 (m, 2H), 7.23 (dd, J = 7.8 Hz, 1.4 Hz, 1H), 6.61 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.41 (d, J = 5.9 Hz, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 2.12 (s, 3H).

[0411] ESI-MS: 491.05 (M+H) + 。

[0412] N-(4-{3-[(3-Fluorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl-py razole-3-carboxamide (80):

[0413]

[0414] According to the general method C2, compound 80 as a white solid was synthesized from intermediate 67b (0.11 mmol) and 3-fluorobenzylamine (0.17 mmol) with a yield of 37%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.54 (s, 1H), 9.03 (t, J = 6.0 Hz, 1H), 8.23 (d, J = 5.8 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.45 - 7.34 (m, 3H), 7.29 - 7.14 (m, 3H), 7.09 (td, J = 8.5 Hz, 2.5 Hz, 1H), 6.81 (d, J = 2.3 Hz, 1H), 6.65 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.95 (s, 3H), 2.14 (s, 3H).

[0415] ESI-MS: 460.30 (M+H) + 。

[0416] N-(4-{3-[(4-Fluorophenyl)methylcarbamoyl]-2-methylphenoxy}-2-pyridinyl)-1-methylpyrazole-3-carboxamide (81): N-(4-{3-[(3-Chlorophenyl)methylcarbamoyl]-2-methylphenoxy}-2-pyridinyl)-1-methylpyrazole-3-carboxamide (82):

[0417]

[0418] According to the general method C2, compound 81 as a white solid was synthesized from intermediate 67b (0.11 mmol) and 4-fluorobenzylamine (0.17 mmol) with a yield of 37%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.54 (s, 1H), 8.99 (t, J = 6.1 Hz, 1H), 8.23 (d, J = 5.7 Hz, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.42 - 7.33 (m, 4H), 7.25 (dd, J = 7.8 Hz, 1.4 Hz, 1H), 7.22 - 7.12 (m, 2H), 6.81 (d, J = 2.3 Hz, 1H), 6.65 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.43 (d, J = 6.0 Hz, 2H), 3.95 (s, 3H), 2.13 (s, 3H).

[0419] ESI-MS: 460.25 (M+H) + 。

[0420] N-(4-{3-[(4-Chlorophenyl)methylcarbamoyl]-2-methylphenoxy}-2-pyridinyl)-1-methylpyrazole-3-carboxamide (83): N-{4-[3-(Imidazo[1,2-a]pyridin-6-ylmethylcarbamoyl)-2-methylphenoxy]-2-pyridinyl}-1-methylpyrazole-3-carboxamide (84):

[0421]

[0422] Compound 82 as a white solid was synthesized from intermediate 67b (0.11 mmol) and 3-chlorobenzylamine (0.17 mmol) according to general method C2 in 41% yield. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.54 (s, 1H), 9.03 (t, J = 6.1 Hz, 1H), 8.23 (d, J = 5.7 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.45 - 7.30 (m, 6H), 7.26 (dd, J = 7.8 Hz, 1.2 Hz, 1H), 6.81 (d, J = 2.3 Hz, 1H), 6.65 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.46 (d, J = 6.0 Hz, 2H), 3.95 (s, 3H), 2.14 (s, 3H).

[0423] ESI-MS: 476.10 (M+H) + 。

[0424] N-{4-[3-(Imidazo[1,2-a]pyridin-7-ylmethylcarbamoyl)-2-methylphenoxy]-2-pyridinyl}-1-methylpyrazole-3-carboxamide (85): N-(4-{3-[(3,5-Difluorophenyl)methylcarbamoyl]-2-methylphenoxy}-2-pyridinyl)-1-methylpyrazole-3-carboxamide (86):

[0425]

[0426] Compound 83 as a white solid was synthesized from intermediate 67b (0.11 mmol) and 4-chlorobenzylamine (0.17 mmol) according to general method C2 in 48% yield. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.52 (s, 1H), 8.99 (t, J = 6.0 Hz, 1H), 8.23 (d, J = 5.7 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.44 - 7.32 (m, 6H), 7.25 (dd, J = 7.8 Hz, 1.4 Hz, 1H), 6.80 (d, J = 2.3 Hz, 1H), 6.65 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.44 (d, J = 6.0 Hz, 2H), 3.95 (s, 3H), 2.13 (s, 3H).

[0427] ESI-MS: 476.10 (M+H) + 。

[0428] N-(4-{3-[(6-Methoxy-3-pyridinyl)methylcarbamoyl]-2-methylphenoxy}-2-pyridinyl)-1-methylpyrazole-3-carboxamide (87): 1-Methyl-N-[4-(2-methyl-3-{[6-(trifluoromethyl)-3-pyridinyl]methylcarbamoyl}phenoxy)-2-pyridinyl]pyrazole-3-carboxamide (88):

[0429]

[0430] Compound 84 as a white solid was synthesized from intermediate 67b (0.11 mmol) and imidazo[1,2-a]pyridin-6-ylmethanamine (0.17 mmol) according to general method C2, with a yield of 35%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.52 (s, 1H), 8.99 (t, J = 6.0 Hz, 1H), 8.50 (s, 1H), 8.22 (d, J = 5.8 Hz, 1H), 7.96 (s, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.44 - 7.34 (m, 2H), 7.28 - 7.22 (m, 2H), 6.80 (d, J = 2.3 Hz, 1H), 6.65 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.45 (d, J = 5.8 Hz, 2H), 3.95 (s, 3H), 2.14 (s, 3H).

[0431] ESI-MS: 482.20 (M+H) + 。

[0432] N-(4-{3-[(3-Fluorophenyl)methylcarbamoyl]-2-methylphenoxy}-2-pyridinyl)-2-methylpyrazole-3-carboxamide (89): N-(4-{3-[(4-Fluorophenyl)methylcarbamoyl]-2-methylphenoxy}-2-pyridinyl)-2-methylpyrazole-3-carboxamide (90):

[0433]

[0434] Compound 85 as a white solid was synthesized from intermediate 67b (0.11 mmol) and imidazo[1,2-a]pyridin-7-ylmethanamine (0.17 mmol) according to general method C2, with a yield of 22%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 9.52 (s, 1H), 9.04 (t, J = 6.0 Hz, 1H), 8.51 (dd, J = 7.0 Hz, 0.7 Hz, 1H), 8.23 (d, J = 5.8 Hz, 1H), 7.90 (s, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.53 (d, J = 1.1 Hz, 1H), 7.45 - 7.37 (m, 3H), 7.26 (dd, J = 7.1 Hz, 2.2 Hz, 1H), 6.89 (dd, J = 7.0 Hz, 1.6 Hz, 1H), 6.81 (d, J = 2.3 Hz, 1H), 6.65 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.49 (d, J = 5.9 Hz, 2H), 3.95 (s, 3H), 2.16 (s, 3H).

[0435] ESI-MS: 482.15 (M + H) + 。

[0436] N-(4-{3-[(3-Chlorophenyl)methylcarbamoyl]-2-methylphenoxy}-2-pyridinyl)-2-methylpyrazole-3-carboxamide (91): N-(4-{3-[(4-Chlorophenyl)methylcarbamoyl]-2-methylphenoxy}-2-pyridinyl)-2-methylpyrazole-3-carboxamide (92):

[0437]

[0438] Compound 86 as a white solid was synthesized from intermediate 67b (0.09 mmol) and 3,5-difluorobenzylamine (0.13 mmol) according to the general method C2, with a yield of 49%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.53 (s, 1H), 9.03 (t, J = 6.0 Hz, 1H), 8.23 (d, J = 5.8 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.44 - 7.35 (m, 2H), 7.26 (dd, J = 7.2 Hz, 2.1 Hz, 1H), 7.17 - 7.02 (m, 3H), 6.81 (d, J = 2.3 Hz, 1H), 6.65 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.95 (s, 3H), 2.14 (s, 3H).

[0439] ESI-MS: 478.15 (M + H) + 。

[0440] N-{4-[3-(Imidazo[1,2-a]pyridin-6-ylmethylcarbamoyl)-2-methylphenoxy]-2-pyridinyl}-2-methylpyrazole-3-carboxamide (93): N-{4-[3-(Imidazo[1,2-a]pyridin-7-ylmethylcarbamoyl)-2-methylphenoxy]-2-pyridinyl}-2-methylpyrazole-3-carboxamide (94):

[0441]

[0442] According to the general method C2, the compound 87 as a white solid was synthesized from intermediate 67b (0.09 mmol) and (6-methoxypyridin-3-yl)methanamine (0.13 mmol) with a yield of 45%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.52 (s, 1H), 8.93 (t, J = 5.9 Hz, 1H), 8.22 (d, J = 5.7 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.71 - 7.69 (m, 2H), 7.38 (t, J = 7.7 Hz, 1H), 7.32 (dd, J = 7.6 Hz, 1.3 Hz, 1H), 7.24 (dd, J = 7.9 Hz, 1.2 Hz, 1H), 6.82 - 6.80 (m, 2H), 6.64 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 3.95 (s, 3H), 3.83 (s, 3H), 2.12 (s, 3H).

[0443] ESI-MS: 473.15 (M + H) + 。

[0444] N-(4-{3-[(3,5-Difluorophenyl)methylcarbamoyl]-2-methylphenoxy}-2-pyridinyl)-2-methylpyrazole-3-carboxamide (95): ​

[0445]

[0446] According to the general method C2, the compound 88 as a white solid was synthesized from intermediate 67b (0.09 mmol) and [6-(trifluoromethyl)-3-pyridinyl]methanamine (0.13 mmol) with a yield of 48%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.54 (s, 1H), 9.13 (t, J = 5.9 Hz, 1H), 8.77 (d, J = 1.2 Hz, 1H), 8.23 (d, J = 5.7 Hz, 1H), 8.05 (dd, J = 8.1 Hz, 1.4 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.31 - 7.24 (m, 1H), 6.81 (d, J = 2.3 Hz, 1H), 6.66 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.58 (d, J = 5.8 Hz, 2H), 3.95 (s, 3H), 2.14 (s, 3H).

[0447] ESI-MS: 511.15 (M + H)+ 。

[0448] ​ ​

[0449]

[0450] According to the general method C2, the white solid compound 89 was synthesized from intermediate 67c (0.09 mmol) and 3-fluorobenzylamine (0.13 mmol) with a yield of 33%. 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 10.85 (s, 1H), 9.00 (t, J = 6.1 Hz, 1H), 8.27 (d, J = 5.8 Hz, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.41 - 7.35 (m, 3H), 7.26 - 7.24 (m, 2H), 7.20 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 10.2 Hz, 1H), 7.09 (td, J = 8.3 Hz, 2.0 Hz, 1H), 6.65 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 4.05 (s, 3H), 2.15 (s, 3H).

[0451] ESI-MS: 460.20 (M + H) + 。

[0452] ​ ​

[0453]

[0454] According to the general method C2, the white solid compound 90 was synthesized from intermediate 67c (0.09 mmol) and 4-fluorobenzylamine (0.13 mmol) with a yield of 32%. 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 10.85 (s, 1H), 8.96 (t, J = 6.1 Hz, 1H), 8.29 - 8.24 (m, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.41 - 7.37 (m, 3H), 7.33 (dd, J = 7.6 Hz, 1.1 Hz, 1H), 7.27 - 7.23 (m, 2H), 7.20 - 7.14 (m, 2H), 6.64 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.43 (d, J = 6.0 Hz, 2H), 4.05 (s, 3H), 2.14 (s, 3H).

[0455] ESI-MS: 460.20 (M+H) + 。

[0456] ​ ​

[0457]

[0458] Compound 91 as a white solid was synthesized from intermediate 67c (0.09 mmol) and 3-chlorobenzylamine (0.13 mmol) according to the general method C2 with a yield of 37%. 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 10.85 (s, 1H), 9.00 (t, J = 6.0 Hz, 1H), 8.31 - 8.23 (m, 1H), 7.72 (d, J = 2.3, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.43 - 7.30 (m, 6H), 7.25 (m, 2H), 6.65 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.46 (d, J = 6.0 Hz, 2H), 4.05 (s, 3H), 2.15 (s, 3H).

[0459] ESI-MS: 476.15 (M+H) + 。

[0460] ​ ​

[0461]

[0462] Compound 92 as a white solid was synthesized from intermediate 67c (0.09 mmol) and 4-chlorobenzylamine (0.13 mmol) according to the general method C2 with a yield of 35%. 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 10.85 (s, 1H), 8.98 (t, J = 6.1 Hz, 1H), 8.29 - 8.24 (m, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.42 - 7.33 (m, 5H), 7.26 (d, J = 2.1 Hz, 2H), 7.25 (dd, J = 8.0 Hz, 1.1 Hz, 1H) 6.64 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.44 (d, J = 6.0 Hz, 2H), 4.05 (s, 3H), 2.14 (s, 3H).

[0463] ESI-MS: 476.15 (M+H) + 。

[0464] ​ ​

[0465]

[0466] According to the general method C2, compound 93 as a white solid was synthesized from intermediate 67c (0.09 mmol) and imidazo[1,2-a]pyridin-6-ylmethanamine (0.13 mmol) with a yield of 15%. 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 10.85 (s, 1H), 8.98 (t, J = 6.0 Hz, 1H), 8.52 - 8.49 (m, 1H), 8.26 (d, J = 5.7 Hz, 1H), 7.98 - 7.95 (m, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.58 - 7.54 (m, 2H), 7.50 (d, J = 2.1 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.27 - 7.22 (m, 3H), 6.64 (dd, J = 5.7 Hz, 2.3 Hz, 1H), 4.45 (d, J = 5.8 Hz, 2H), 4.04 (s, 3H), 2.14 (s, 3H).

[0467] ESI-MS: 482.20 (M + H) + 。

[0468] ​ ​

[0469]

[0470] According to the general method C2, compound 94 as a white solid was synthesized from intermediate 67c (0.09 mmol) and imidazo[1,2-a]pyridin-7-ylmethanamine (0.13 mmol) with a yield of 20%. 11H NMR (600 MHz, DMSO-d6) δ (ppm): 10.85 (s, 1H), 9.03 (t, J = 6.0 Hz, 1H), 8.51 (dd, J = 7.0 Hz, 0.9 Hz, 1H), 8.27 (d, J = 5.7 Hz, 1H), 7.91 - 7.88 (m, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.53 (d, J = 1.2 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.45 - 7.36 (m, 3H), 7.28 - 7.24 (m, 2H), 6.89 (dd, J = 7.0 Hz, 1.7 Hz, 1H), 6.65 (dd, J = 5.7 Hz, 2.3 Hz, 1H), 4.49 (d, J = 5.8 Hz, 2H), 4.05 (s, 3H), 2.17 (s, 3H).

[0471] ESI-MS: 482.20 (M+H) + 。

[0472] ​ ​

[0473]

[0474] Compound 95 as a white solid was synthesized from intermediate 67c (0.09 mmol) and 3,5-difluorobenzylamine (0.13 mmol) according to the general method C2 with a yield of 42%. 1 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.85 (s, 1H), 9.02 (t, J = 6.1 Hz, 1H), 8.27 (d, J = 5.7 Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.43 - 7.36 (m, 2H), 7.27 - 7.25 (m, 2H), 7.12 (tt, J = 9.3 Hz, 2.4 Hz, 1H), 7.08 - 7.04 (m, 2H), 6.65 (dd, J = 5.5 Hz, 2.3 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 4.05 (s, 3H), 2.15 (s, 3H).

[0475] ESI-MS: 478.15 (M+H) + 。

[0476] N-(4-{3-[(6-Methoxy-3-pyridinyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridinyl)- 2-methyl-pyrazole-3-carboxamide (96):

[0477]

[0478] Compound 96 as a white solid was synthesized from intermediate 67c (0.09 mmol) and (6-methoxypyridin-3-yl)methanamine (0.13 mmol) according to general method C2, with a yield of 38%. 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 10.85 (s, 1H), 8.92 (t, J = 5.9 Hz, 1H), 8.33 - 8.22 (m, 1H), 8.14 (dd, J = 2.4 Hz, 0.6 Hz, 1H), 7.76 - 7.64 (m, 2H), 7.50 (d, J = 2.1 Hz, 1H), 7.39 - 7.36 (m, 1H), 7.31 (dd, J = 7.6 Hz, 1.1 Hz, 1H), 7.26 - 7.22 (m, 2H), 6.81 (dd, J = 8.5 Hz, 0.6 Hz, 1H), 6.63 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 4.05 (s, 3H), 3.83 (s, 3H), 2.12 (s, 3H).

[0479] ESI-MS: 473.20 (M + H) + 。

[0480] 2-methyl-N-[4-(2-methyl-3-{[6-(trifluoromethyl)-3-pyridinyl]methylcarbamoyl}phenoxy)- 2-pyridinyl]pyrazole-3-carboxamide (97):

[0481]

[0482] Compound 97 as a white solid was synthesized from intermediate 67c (0.09 mmol) and [6-(trifluoromethyl)pyridin-3-yl]methanamine (0.13 mmol) according to general method C2, with a yield of 44%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.88 (s, 1H), 9.12 (t, J = 5.9 Hz, 1H), 8.76 (s, 1H), 8.27 (d, J = 5.7 Hz, 1H), 8.05 (d, J = 9.3 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.28 - 7.25 (m, 2H), 6.65 (dd, J = 5.7 Hz, 2.3 Hz, 1H), 4.58 (d, J = 5.8 Hz, 2H), 4.04 (s, 3H), 2.14 (s, 3H).

[0483] ESI-MS: 511.15 (M + H) + 。

[0484] N-(4-{3-[(5-fluoro-6-methoxy-3-pyridinyl)methylcarbamoyl]-2-methyl-phenoxy}-2-py ridinyl)-2-methyl-pyrazole-3-carboxamide (98):

[0485]

[0486] Compound 98 as a white solid was synthesized from intermediate 67c (0.09 mmol) and (5-fluoro-6-methoxy-3-pyridyl)methylamine (0.13 mmol) according to general method C2, with a yield of 36%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.86 (s, 1H), 8.95 (t, J = 5.8 Hz, 1H), 8.27 (d, J = 5.7 Hz, 1H), 7.98 (d, J = 1.7 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.65 (dd, J = 11.4 Hz, 1.9 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.44 - 7.31 (m, 2H), 7.26 - 7.23 (m, 2H), 6.64 (dd, J = 5.7 Hz, 2.3 Hz, 1H), 4.41 (d, J = 5.9 Hz, 2H), 4.05 (s, 3H), 3.93 (s, 3H), 2.13 (s, 3H).

[0487] ESI-MS: 491.10 (M + H) + 。

[0488] N-{4-[2-Methyl-3-(4-pyridylmethylcarbamoyl)phenoxy]-2-pyridyl}pyridine-3-carboxamide (99):

[0489]

[0490] Compound 99 as a white solid was synthesized from intermediate 67d (0.13 mmol) and 4-(aminomethyl)pyridine (0.19 mmol) according to general method C2, with a yield of 7%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 11.14 (s, 1H), 9.08 - 9.05 (m, 2H), 8.73 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 8.53 (dd, J = 4.4 Hz, 1.5 Hz, 2H), 8.35 - 8.24 (m, 2H), 7.77 (d, J = 2.3 Hz, 1H), 7.52 (dd, J = 7.7 Hz, 5.1 Hz, 1H), 7.45 - 7.39 (m, 2H), 7.35 (d, J = 5.9 Hz, 2H), 7.31 - 7.24 (m, 1H), 6.70 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 2.17 (s, 3H).

[0491] ESI-MS: 440.15 (M + H) + 。

[0492] N-(4-{3-[(2,6-difluoro-4-pyridinyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridinyl) pyridine-3-carboxamide (100):

[0493]

[0494] According to the general method C2, compound 100 as a white solid was synthesized from intermediate 67d (0.13 mmol) and (2,6-difluoro-4-pyridyl)methylamine (0.38 mmol) with a yield of 14%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.14 (s, 1H), 9.12 (t, J = 5.8 Hz, 1H), 9.08 (d, J = 1.7 Hz, 1H), 8.73 (dd, J = 4.8 Hz, 1.5 Hz, 1H), 8.34 - 8.24 (m, 2H), 7.76 (d, J = 2.2 Hz, 1H), 7.52 (dd, J = 7.5 Hz, 4.8 Hz, 1H), 7.48 - 7.40 (m, 2H), 7.28 (dd, J = 7.6 Hz, 1.4 Hz, 1H), 7.13 (s, 2H), 6.71 (dd, J = 5.7 Hz, 2.3 Hz, 1H), 4.57 (d, J = 5.9 Hz, 2H), 2.17 (s, 3H).

[0495] ESI-MS: 476.20 (M + H) + 。

[0496] N-(4-{3-[(4-cyano-3-fluoro-phenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridinyl)py ridine-3-carboxamide (101):

[0497]

[0498] Compound 101 as a white solid was synthesized from intermediate 67d (0.13 mmol) and 4-aminomethyl-2-fluorobenzonitrile (0.14 mmol) according to general method C2 in 8% yield. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 1H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 9.15 - 9.05 (m, 2H), 8.73 (dd, J = 4.7 Hz, 1.5 Hz, 1H), 8.34 - 8.26 (m, 2H), 7.97 - 7.88 (m, 1H), 7.76 (d, J = 2.2 Hz, 1H), 7.55 - 7.38 (m, 5H), 7.30 - 7.25 (m, 1H), 6.70 (dd, J = 5.7 Hz, 2.3 Hz, 1H), 4.55 (d, J = 5.9 Hz, 2H), 2.16 (s, 3H).

[0499] ESI-MS: 482.15 (M + H) + 。

[0500] Example 3: General procedure for the synthesis of analogs 103 - 105

[0501]

[0502] 3-hydroxy-2-methyl-N-(pyridin-4-ylmethyl)benzamide (102 ) Preparation :

[0503]

[0504] Intermediate 102 as a white solid was synthesized from 3-hydroxy-2-methylbenzoic acid (19.6 mmol) and 4-(aminomethyl)pyridine (19.6 mmol) according to general method C3 in 93% yield.

[0505] Method A3: Under nitrogen, t-BuOK (1.5 equivalents) was added to a solution of the phenol derivative (1 equivalent) in DMF (5 mL / mmol). 4-Chloropyridine derivative (1 equivalent) was added and the reaction mixture was stirred at 140 °C until completion (from 24 to 48 hours). The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH from 100 / 0 to 90 / 10) and reverse phase chromatography (H2O / MeOH from 100 / 0 to 0 / 100) to give the desired compound.

[0506] Method F: To a stirred solution of 104 (30 mg, 0.063 mmol) in EtOH / H2O (0.75 mL / 0.25 mL) were added sodium (L)-ascorbate (2 mg, 0.006 mmol), sodium azide (9 mg, 0.126 mmol), copper(I) iodide (3 mg, 0.013 mmol) and DMEDA (2 μL, 0.019 mmol). The reaction mixture was stirred at 100 °C overnight. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH from 100 / 0 to 80 / 20) and reverse phase chromatography (H2O / MeOH: 0 to 100%) to give 6 mg of N-{6-amino-4-[2-methyl-3-(4-pyridylmethylcarbamoyl)phenoxy]-2-pyridyl}-1-methyl-pyrazole-4-carboxamide 105 in 21% yield. 1 H NMR (500 MHz, DMSO-d6) δ (ppm): 9.94 (s, 1H), 9.05 (t, J = 6.1 Hz, 1H), 8.54 - 8.52 (m, 2H), 8.36 (s, 1H), 8.05 (d, J = 0.6 Hz, 1H), 7.40 - 7.29 (m, 4H), 7.19 (dd, J = 7.0 Hz, 2.3 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 5.79 (bs, 2H), 5.56 (d, J = 2.0 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.85 (s, 3H), 2.16 (s, 3H).

[0507] ESI-MS: 458.15 (M+H) + 。

[0508] The following compounds are examples illustrating Method A3:

[0509] 1-methyl-N-{4-[2-methyl-3-(pyridin-4-ylmethylcarbamoyl)phenoxy]-2-pyridinyl}pyrazole- 4-carboxamide (103):

[0510]

[0511] According to the general method A3, compound 103 as a white solid was synthesized from intermediate 102 (0.22 mmol) and 65a (0.22 mmol) in 19% yield. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 10.53 (s, 1H), 9.05 (t, J = 6.0 Hz, 1H), 8.53 (dd, J = 4.5 Hz, 1.5 Hz, 2H), 8.40 (s, 1H), 8.23 (d, J = 5.7 Hz, 1H), 8.09 (s, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.42 - 7.33 (m, 4H), 7.28 - 7.20 (m, 1H), 6.62 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.16 (s, 3H).

[0512] N-{6-chloro-4-[2-methyl-3-(pyridin-4-ylmethylcarbamoyl)phenoxy]-2-pyridinyl}-1-methyl- pyrazole-4-carboxamide (104):

[0513]

[0514] According to the general method A3, compound 104 as a white solid was synthesized from intermediate 102 (0.22 mmol) and 65d (0.22 mmol) with a yield of 23%. 1 1H NMR (500 MHz, DMSO-d6) δ (ppm): 10.84 (s, 1H), 9.10 (t, J = 6.1 Hz, 1H), 8.53 (dd, J = 4.4 Hz, 1.6 Hz, 2H), 8.41 (s, 1H), 8.10 (d, J = 0.5 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.44 - 7.40 (m, 2H), 7.35 (d, J = 6.0 Hz, 2H), 7.33 - 7.28 (m, 1H), 6.73 (d, J = 2.0 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.85 (s, 3H), 2.16 (s, 3H).

[0515] ESI-MS: 477.15 (M + H) + .

[0516] Example 4: General procedure for the synthesis of analogs 106 - 108

[0517]

[0518] 3-[(2-amino-4-pyridinyl)oxy]-2-methyl-N-(pyridin-4-ylmethyl)benzamide (106 ):

[0519]

[0520] Compound 106 as a white solid was synthesized from intermediate 102 (0.39 mmol) and 2-amino-4-chloropyridine (0.39 mmol) according to general method A3 with a yield of 23%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.0 Hz, 1H), 8.54 - 8.52 (m, 2H), 7.79 (d, J = 5.8 Hz, 1H), 7.36 - 7.33 (m, 4H), 7.17 (dd, J = 6.4 Hz, 2.9 Hz, 1H), 6.08 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 5.92 (s, 2H), 5.74 (d, J = 2.2 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 2.13 (s, 3H).

[0521] 3-[(2-amino-4-pyridinyl)oxy]-2-methyl-N-(pyridin-4-ylmethyl)benzamide (107 ):

[0522]

[0523] Compound 107 as a white solid was synthesized from intermediate 102 (0.61 mmol) and 2-amino-4,6-dichloropyridine (0.61 mmol) according to general method A3 with a yield of 30%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.05 (t, J = 6.0 Hz, 1H), 8.53 (d, J = 5.4 Hz, 2H), 7.40 - 7.31 (m, 4H), 7.25 - 7.20 (m, 1H), 6.45 (s, 2H), 6.13 (d, J = 1.9 Hz, 1H), 5.65 (d, J = 1.9 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 2.12 (s, 3H).

[0524] 3-{[2-amino-6-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy}-2-methyl-N-(pyridin-4-ylmethyl) benzamide (108):

[0525]

[0526] Method D3: Under nitrogen, PdCl2dppf (7 mg, 0.009 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-1H-pyrazole (27 mg, 0.13 mmol) and Cs2CO3 1 M (0.215 mL, 0.215 mmol) were added to a stirred solution of 107 (32 mg, 0.086 mmol) in dioxane (1 mL). The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH) and reverse-phase chromatography (H2O / MeOH: 0 to 100%) to give 18 mg of 108 in 51% yield. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.03 (t, J = 6.0 Hz, 1H), 8.54 - 8.52 (m 2H), 8.06 (s, 1H), 7.83 (d, J = 0.6 Hz, 1H), 7.41 - 7.32 (m, 4H), 7.20 (dd, J = 6.7 Hz, 2.6 Hz, 1H), 6.51 (d, J = 2.0 Hz, 1H), 5.92 (s, 2H), 5.49 (d, J = 2.0 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.84 (s, 3H), 2.16 (s, 3H).

[0527] Example 5: General procedure for the synthesis of analogues 110 - 116

[0528]

[0529] Preparation of 3-[(2-bromo-4-pyridyl)oxy]-2-methyl-N-(4-pyridylmethyl)benzamide (109):

[0530]

[0531] According to general method A1, intermediate 109 as a white solid was synthesized from intermediate 102 (5.87 mmol) and 2-bromo-4-chloropyridine (5.87 mmol) in 84% yield.

[0532] ESI-MS: 398.10 - 400.10 (M + H) + 。

[0533] Method G: Under nitrogen, to a solution of 109 (1 equiv) in THF (20 mL / mmol) was added an alkyne derivative (3 equiv), Pd(PPh3)Cl2 (0.1 equiv), CuI (0.2 equiv), and triethylamine (3 equiv). The mixture was stirred at 50 °C overnight. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH from 100 / 0 to 90 / 10) and reverse-phase chromatography (H2O / MeOH from 100 / 0 to 0 / 100) to give the desired compound.

[0534] 2-methyl-3-{[2-(3-phenylprop-1-ynyl)-4-pyridinyl]oxy}-N-(pyridin-4-ylmethyl)benz amide (110):

[0535]

[0536] According to general method G, compound 110 as a white solid was synthesized from intermediate 109 (0.10 mmol) and 3-phenyl-1-propyne (0.30 mmol) in 21% yield. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.03 (t, J = 6.0 Hz, 1H), 8.55 - 8.52 (m, 2H), 8.41 (d, J = 5.7 Hz, 1H), 7.44 - 7.32 (m, 9H), 7.28 - 7.23 (m, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.85 (dd, J = 5.7 Hz, 2.5 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.90 (s, 2H), 2.12 (s, 3H).

[0537] ESI-MS: 434.25 (M+H) + 。

[0538] 3-{[2-(3-hydroxyprop-1-ynyl)-4-pyridinyl]oxy}-2-methyl-N-(pyridin-4-ylmethyl)benz amide (111):

[0539]

[0540] According to general method G, compound 111 as a white solid was synthesized from intermediate 109 (0.10 mmol) and propargyl alcohol (0.30 mmol) in 22% yield. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 9.05 (t, J = 6.0 Hz, 1H), 8.54 - 8.52 (m, 2H), 8.43 (d, J = 5.7 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.34 (d, J = 6.0 Hz, 2H), 7.29 - 7.23 (m, 1H), 6.91 (dd, J = 5.7 Hz, 2.5 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 5.41 (bs, 1H), 4.48 (d, J = 6.0 Hz, 2H), 4.28 (s, 2H), 2.11 (s, 3H).

[0541] ESI-MS: 374.20 (M+H) + 。

[0542] 3-{[2-(3-Aminoprop-1-ynyl)-4-pyridinyl]oxy}-2-methyl-N-(pyridin-4-ylmethyl)benzamide (112):

[0543]

[0544] Compound 112 as a white solid was synthesized from intermediate 109 (0.10 mmol) and propargylamine (0.30 mmol) according to general method G, with a yield of 22%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.05 (t, J = 6.0 Hz, 1H), 8.54 - 8.52 (m, 2H), 8.41 (d, J = 5.7 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.34 (d, J = 5.9 Hz, 2H), 7.26 (dd, J = 8.7 Hz, 4.3 Hz, 1H), 6.90 (dd, J = 5.7 Hz, 2.5 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 3H), 3.47 (s, 2H), 2.11 (s, 4H).

[0545] ESI-MS: 373.20 (M+H) + 。

[0546] 3-{[2-(3-methoxyprop-1-ynyl)-4-pyridinyl]oxy}-2-methyl-N-(pyridin-4-ylmethyl)benz amide (113):

[0547]

[0548] Compound 113 as a white solid was synthesized from intermediate 109 (0.10 mmol) and methyl propargyl ether (0.30 mmol) according to general method G, with a yield of 31%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 9.04 (t, J = 5.9 Hz, 1H), 8.54 - 8.52 (m, 2H), 8.44 (d, J = 5.6 Hz, 1H), 7.41 (d, J = 4.5 Hz, 2H), 7.35 (d, J = 5.7 Hz, 2H), 7.25 (t, J = 4.7 Hz, 1H), 6.93 - 6.86 (m, 2H), 4.48 (d, J = 5.9 Hz, 2H), 4.32 (s, 2H), 3.31 (s, 3H), 2.12 (s, 3H).

[0549] ESI-MS: 388.20 (M+H) + 。

[0550] 2-methyl-3-({2-[3-(methylamino)prop-1-ynyl]-4-pyridinyl}oxy)-N-(pyridin-4-ylmethyl) benzamide (114):

[0551]

[0552] Compound 114 as a white solid was synthesized from intermediate 109 (0.10 mmol) and N-methyl-N-prop-2-ynylamine (0.30 mmol) according to the general method G, with a yield of 18%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.05 (t, J = 5.9 Hz, 1H), 8.54 - 8.52 (m, 2H), 8.41 (d, J = 5.8 Hz, 1H), 7.41 - 7.38 (m, 3H), 7.34 (d, J = 5.8 Hz, 2H), 7.25 (t, J = 4.7 Hz, 1H), 6.87 (dd, J = 5.7 Hz, 2.5 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 4.48 (d, J = 5.9 Hz, 2H), 3.48 (d, J = 5.7 Hz, 2H), 2.30 (d, J = 5.0 Hz, 3H), 2.11 (s, 3H).

[0553] ESI-MS: 387.25 (M+H) + 。

[0554] 3-{[2-(3-imidazol-1-ylprop-1-ynyl)-4-pyridinyl]oxy}-2-methyl-N-(pyridin-4-ylmethyl)benz amide (115):

[0555]

[0556] Compound 115 as a white solid was synthesized from intermediate 109 (0.20 mmol) and 1-(prop-2-yn-1-yl)-1H-imidazole (0.40 mmol) according to the general method G, with a yield of 4%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 9.04 (t, J = 5.9 Hz, 1H), 8.54 - 8.52 (m, 2H), 8.44 (d, J = 5.7 Hz, 1H), 7.73 (s, 1H), 7.41 (d, J = 4.3 Hz, 2H), 7.34 (d, J = 5.8 Hz, 2H), 7.27 - 7.23 (m, 2H), 6.94 - 6.93 (m, 2H), 6.89 (dd, J = 5.7 Hz, 2.5 Hz, 1H), 5.19 (s, 2H), 4.48 (d, J = 5.9 Hz, 2H), 2.11 (s, 3H).

[0557] ESI-MS: 424.30 (M + H) + 。

[0558] 2-methyl-3-({2-[3-(methylamino)prop-1-ynyl]-4-pyridinyl}oxy)-N-(pyridin-4-ylmethyl) benzamide (116):

[0559]

[0560] According to the general method G, compound 116 as a white solid was synthesized from intermediate 109 (0.20 mmol) and 1-(prop-2-yn-1-yl)-1H-pyrazole (0.30 mmol) with a yield of 12%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.04 (t, J = 6.0 Hz, 1H), 8.54 - 8.52 (m, 2H), 8.46 - 8.41 (m, 1H), 7.83 (d, J = 1.8 Hz, 1H), 7.49 (d, J = 1.2 Hz, 1H), 7.40 (d, J = 4.2 Hz, 2H), 7.34 (d, J = 6.0 Hz, 2H), 7.25 (t, J = 4.7 Hz, 1H), 6.98 - 6.88 (m, 2H), 6.30 - 6.29 (m, 1H), 5.30 (s, 2H), 4.48 (d, J = 6.0 Hz, 2H), 2.11 (s, 3H).

[0561] ESI-MS: 424.25 (M + H) + 。

[0562] Example 6: General procedure for the synthesis of analogs 120 - 197, 350 - 355, and 359

[0563]

[0564] The following compound 117a is an example illustrating method A1:

[0565] Preparation of ethyl 3-[(2-chloro-4-pyridinyl)oxy]-2-methylbenzoate (117a):

[0566]

[0567] According to the general method A1, intermediate 117a as a colorless oil was synthesized from ethyl 3-hydroxy-2-methyl-benzoate (6.30 mmol) and 2-chloro-4-nitropyridine (6.30 mmol) in 95% yield.

[0568] ESI-MS: 292.00 (M+H) + 。

[0569] The following table lists intermediate 117 prepared by method A1:

[0570]

[0571]

[0572] The following compound 118a is an example illustrating method D2:

[0573] Preparation of ethyl 2-methyl-3-{[2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl]oxy}benzoate (118a):

[0574]

[0575] According to the general method D2, intermediate 118a as a colorless oil was synthesized from 117a (1.71 mmol) and 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (2.05 mmol) in quantitative yield.

[0576] ESI-MS: 338.15 (M+H) + 。

[0577] The following table lists intermediate 118 prepared by method D2:

[0578]

[0579]

[0580] Method H: Under nitrogen, to a solution of 117 (1 equiv) in dioxane (10 mL / mmol) was added an amine derivative (2 equiv), Pd2dba3 (0.1 equiv), Xantphos (0.2 equiv) and Cs2CO3 (2 equiv). The mixture was stirred at 100 °C until completion (from 2 h to overnight). The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH from 100 / 0 to 90 / 10) to give the desired compound.

[0581] The following compound 118e is an example illustrating method H:

[0582] Preparation of ethyl 2-methyl-3-({2-[(1-methylpyrazol-3-yl)amino]-4-pyridinyl}oxy)benzoate (118e) :

[0583]

[0584] According to the general method H, the intermediate 118e as a yellow oil was synthesized from 117a (1.37 mmol) and 1-methylpyrazol-3-amine (2.74 mmol) in a yield of 90%.

[0585] ESI-MS: 353.05 (M+H) + 。

[0586] The following table lists the intermediate 113 prepared by method H:

[0587]

[0588] Method I: To a stirred solution of 117a (250 mg, 0.86 mmol) in CH3CN (6 mL) were added pyrazole (123 mg, 1.79 mmol), Cs2CO3 (1.12 g, 3.42 mmol), CuI (360 mg, 1.88 mmol) and DMEDA (0.323 mL, 3 mmol). The reaction mixture was stirred at 100 °C for 48 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (cyclohexane / EtOAc from 100 / 0 to 75 / 25) to give 58 mg of ethyl 2-methyl-3-[(2-pyrazol-1-yl-4-pyridyl)oxy]benzoate 118h in a yield of 11%.

[0589] The following compound 119a is an example illustrating method B2:

[0590] Preparation of 2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy}benzoic acid (119a):

[0591]

[0592] According to the general method B2, the intermediate 119a as a white powder was synthesized from 118a (1.88 mmol) in a yield of 79%.

[0593] ESI-MS: 292.00 (M+H) + 。

[0594] The following table lists the intermediate 119 prepared by method B2:

[0595]

[0596]

[0597] The following compounds are examples illustrating Method C2:

[0598] N-[(6-methoxy-3-pyridinyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl] oxy}benzamide (120):

[0599]

[0600] According to the general method C2, compound 120 as a white solid was synthesized from intermediate 119a (0.10 mmol) and (6-methoxypyridin-3-yl)methanamine (0.12 mmol) with a yield of 60%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.91 (t, J = 5.9 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.25 (s, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.96 (s, 1H), 7.69 (dd, J = 8.5 Hz, 2.4 Hz, 1H), 7.39 - 7.28 (m, 2H), 7.24 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 7.9 Hz, 1.0 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.47 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.39 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 2.11 (s, 3H).

[0601] ESI-MS: 430.10 (M + H) + .

[0602] 2-Methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy}-N-(4-pyridinylmethyl)benzamide (121):

[0603]

[0604] According to the general method C2, compound 121 as a white solid was synthesized from intermediate 119a (0.10 mmol) and 4-(aminomethyl)pyridine (0.12 mmol) with a yield of 69%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 9.04 (t, J = 6.0 Hz, 1H), 8.54 - 8.52 (m, 2H), 8.36 (d, J = 5.7 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.43 - 7.32 (m, 4H), 7.25 - 7.22 (m, 2H), 6.49 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.15 (s, 3H).

[0605] ESI-MS: 400.05 (M + H) + 。

[0606] 2-Methyl-3-{[2-(1-methyl-1H-pyrazol-4-yl)-4-pyridinyl]oxy}-N-(pyridin-3-ylmethyl)benzamide (122):

[0607]

[0608] According to general method C2, compound 122 as a white solid was synthesized from intermediate 119a (0.10 mmol) and 3-(aminomethyl)pyridine (0.12 mmol) in 59% yield. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 5.9 Hz, 1H), 8.57 (d, J = 1.7 Hz, 1H), 8.48 (dd, J = 4.7 Hz, 1.4 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.76 (dt, J = 7.8 Hz, 1.8 Hz, 1H) 7.43 - 7.30 (m, 3H), 7.27 - 7.20 (m, 2H), 6.47 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 2.12 (s, 3H).

[0609] ESI-MS: 400.10 (M + H) + 。

[0610] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy} benzamide (123):

[0611]

[0612] According to general method C2, compound 123 as a white solid was synthesized from intermediate 119a (0.10 mmol) and 3,5-difluorobenzylamine (0.12 mmol) in 85% yield. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.0 Hz, 1H), 8.36 (d, J = 5.7 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.42 - 7.34 (m, 2H), 7.26 - 7.22 (m, 2H), 7.17 - 7.03 (m, 3H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.14 (s, 3H).

[0613] ESI-MS: 435.15 (M + H) + 。

[0614] N-[(3-fluorophenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy}benz amide (124):

[0615]

[0616] Compound 124 as a white solid was synthesized from intermediate 119a (0.10 mmol) and 3-fluorobenzylamine (0.12 mmol) according to general method C2 in 82% yield. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.98 (t, J = 6.0 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.25 (s, 1H), 7.96 (d, J = 0.5 Hz, 1H), 7.43 - 7.31 (m, 3H), 7.26 - 7.13 (m, 4H), 7.09 (td, J = 8.4 Hz, 2.3 Hz, 1H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.14 (s, 3H).

[0617] ESI-MS: 417.20 (M + H) + 。

[0618] N-[(4-fluorophenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy}benz amide (125):

[0619]

[0620] Compound 125 as a white solid was synthesized from intermediate 119a (0.10 mmol) and 4-fluorobenzylamine (0.12 mmol) according to general method C2 in 92% yield. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 8.94 (t, J = 6.0 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.25 (s, 1H), 7.96 (d, J = 0.5 Hz, 1H), 7.43 - 7.30 (m, 4H), 7.26 - 7.14 (m, 4H), 6.47 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.43 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.12 (s, 3H).

[0621] ESI-MS: 417.15 (M+H) + 。

[0622] N-[(3-chlorophenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy}benz amide (126):

[0623]

[0624] According to the general method C2, compound 126 as a white solid was synthesized from intermediate 119a (0.10 mmol) and 3-chlorobenzylamine (0.12 mmol) with a yield of 72%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.98 (t, J = 6.0 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.44 - 7.30 (m, 6H), 7.25 (d, J = 2.4 Hz, 1H), 7.22 (dd, J = 7.8 Hz, 1.2 Hz, 1H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.46 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.13 (s, 3H).

[0625] ESI-MS: 433.15 (M+H) + 。

[0626] N-[(4-chlorophenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy}benz amide (127):

[0627]

[0628] According to the general method C2, compound 127 as a white solid was synthesized from intermediate 119a (0.10 mmol) and 4-chlorobenzylamine (0.12 mmol) with a yield of 83%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 8.97 (t, J = 6.0 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.45 - 7.30 (m, 6H), 7.25 - 7.20 (m, 2H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.44 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.13 (s, 3H).

[0629] ESI-MS: 433.05 (M + H) + 。

[0630] N-[(2,4-difluorophenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy} benzamide (128):

[0631]

[0632] According to the general method C2, compound 128 as a white solid was synthesized from intermediate 119a (0.065 mmol) and 2,4-difluorobenzylamine (0.097 mmol) with a yield of 53%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.93 (t, J = 5.6 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.51 - 7.43 (m, 1H), 7.40 - 7.18 (m, 5H), 7.09 (dd, J = 8.5 Hz, 7.0 Hz, 1H), 6.47 (dd, J = 5.6 Hz, 2.2 Hz, 1H), 4.46 (d, J = 5.5 Hz, 2H), 3.86 (s, 3H), 2.11 (s, 3H).

[0633] ESI-MS: 435.15 (M + H) + 。

[0634] N-[(3,4-difluorophenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy} benzamide (129):

[0635]

[0636] According to the general method C2, compound 129 as a white solid was synthesized from intermediate 119a (0.065 mmol) and 3,4-difluorobenzylamine (0.097 mmol) with a yield of 57%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 8.98 (t, J = 6.0 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.47 - 7.30 (m, 4H), 7.27 - 7.17 (m, 3H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.44 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.13 (s, 3H).

[0637] ESI-MS: 435.15 (M + H) + 。

[0638] N-[(4-chloro-3-fluoro-phenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]ox y}benzamide (130):

[0639]

[0640] According to General Method C2, compound 130 as a white solid was synthesized from intermediate 119a (0.065 mmol) and 4-chloro-3-fluorobenzylamine (0.097 mmol) with a yield of 34%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 6.0 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.43 - 7.32 (m, 3H), 7.28 - 7.18 (m, 3H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.46 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.13 (s, 3H).

[0641] ESI-MS: 451.10 (M + H) + 。

[0642] N-(imidazo[1,2-a]pyridin-6-ylmethyl)-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridin yl]oxy}benzamide (131):

[0643]

[0644] According to General Method C2, compound 131 as a white solid was synthesized from intermediate 119a (0.065 mmol) and imidazo[1,2-a]pyridin-6-ylmethylamine (0.097 mmol) with a yield of 57%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 8.97 (t, J = 5.9 Hz, 1H), 8.51 (s, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.25 (s, 1H), 7.97 - 7.95 (m, 2H), 7.57 - 5.55 (m, 2H), 7.41 - 7.32 (m, 2H), 7.26 - 7.20 (m, 3H), 6.47 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.45 (d, J = 5.8 Hz, 2H), 3.86 (s, 3H), 2.13 (s, 3H).

[0645] ESI-MS: 439.15 (M + H) + 。

[0646] N-(imidazo[1,2-a]pyridin-7-ylmethyl)-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridin yl]oxy}benzamide (132):

[0647]

[0648] According to the general method C2, compound 132 as a white solid was synthesized from intermediate 119a (0.065 mmol) and imidazo[1,2-a]pyridin-7-ylmethanamine (0.097 mmol) with a yield of 50%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.0 Hz, 1H), 8.51 (d, J = 7.0 Hz, 1H), 8.36 (d, J = 5.7 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.90 (s, 1H), 7.53 (d, J = 1.0 Hz, 1H), 7.44 (s, 1H), 7.41 - 7.34 (m, 2H), 7.28 - 7.20 (m, 2H), 6.89 (dd, J = 7.0 Hz, Hz 1.5, 1H), 6.49 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.49 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 2.15 (s, 3H).

[0649] ESI-MS: 439.15 (M + H) + 。

[0650] 2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy}-N-{[6-(trifluoromethyl)-3-pyridin yl]methyl}benzamide (133):

[0651]

[0652] Compound 133 as a white solid was synthesized from intermediate 119a (0.065 mmol) and [6-(trifluoromethyl)-3-pyridyl]methanamine (0.097 mmol) according to general method C2, with a yield of 79%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.09 (t, J = 5.9 Hz, 1H), 8.76 (s, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.25 (s, 1H), 8.08 - 8.02 (m, 1H), 7.96 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.27 - 7.20 (m, 2H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.59 (d, J = 5.8 Hz, 2H), 3.86 (s, 3H), 2.14 (s, 3H).

[0653] ESI-MS: 468.15 (M + H) + 。

[0654] N-[(2,3-difluorophenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy} benzamide (134):

[0655]

[0656] Compound 134 as a white solid was synthesized from intermediate 119a (0.074 mmol) and 2,3-difluorobenzylamine (0.111 mmol) according to general method C2, with a yield of 60%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.97 (t, J = 5.8 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.24 (s, 1H), 7.95 (d, J = 0.6 Hz, 1H), 7.40 - 7.29 (m, 3H), 7.28 - 7.18 (m, 4H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.53 (d, J = 5.8 Hz, 2H), 3.86 (s, 3H), 2.13 (s, 3H).

[0657] ESI-MS: 435.15 (M + H) + 。

[0658] N-[(3-methoxyphenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy} benzamide (135):

[0659]

[0660] Compound 135 as a white solid was synthesized from intermediate 119a (0.074 mmol) and 3 - methoxybenzylamine (0.111 mmol) according to the general method C2, with a yield of 78%. 1 H NMR (400 MHz, DMSO - d6) δ (ppm): 8.90 (t, J = 6.0 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.24 (s, 1H), 7.95 (d, J = 0.6 Hz, 1H), 7.43 - 7.16 (m, 5H), 6.98 - 6.90 (m, 2H), 6.86 - 6.80 (m, 1H), 6.49 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.44 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.74 (s, 3H), 2.14 (s, 3H).

[0661] ESI - MS: 429.20 (M + H) + 。

[0662] N-[(4-methoxyphenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy} benzamide (136):

[0663]

[0664] Compound 136 as a white solid was synthesized from intermediate 119a (0.074 mmol) and 4 - methoxybenzylamine (0.111 mmol) according to the general method C2, with a yield of 63%. 1 H NMR (400 MHz, DMSO - d6) δ (ppm): 8.83 (t, J = 6.0 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.24 (s, 1H), 7.95 (d, J = 0.6 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.30 - 7.18 (m, 5H), 6.92 - 6.88 (m, 2H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.38 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.73 (s, 3H), 2.12 (s, 3H).

[0665] ESI - MS: 429.15 (M + H) + 。

[0666] N-[(5-fluoro-3-pyridinyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy} benzamide (137):

[0667]

[0668] According to the general method C2, compound 137 as a white solid was synthesized from intermediate 119a (0.10 mmol) and 5-fluoro-3-pyridinemethanamine (0.15 mmol) with a yield of 50%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 5.9 Hz, 1H), 8.52 - 8.45 (m, 2H), 8.36 (d, J = 5.7 Hz, 1H), 8.24 (s, 1H), 7.95 (d, J = 0.6 Hz, 1H), 7.71 - 7.64 (m, 1H), 7.41 - 7.33 (m, 2H), 7.27 - 7.20 (m, 2H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.53 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 2.13 (s, 3H).

[0669] ESI-MS: 418.15 (M + H) + 。

[0670] N-[(5-fluoro-6-methoxy-3-pyridinyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy}benzamide (138): N-[(5-fluoro-2-methoxy-3-pyridinyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy}benzamide (139):

[0671]

[0672] According to the general method C2, compound 138 as a white solid was synthesized from intermediate 119a (0.10 mmol) and (5-fluoro-6-methoxy-3-pyridinyl)methanamine (0.15 mmol) with a yield of 62%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.91 (t, J = 5.9 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.24 (s, 1H), 7.98 - 7.95 (m, 2H), 7.65 (dd, J = 11.4 Hz, 1.9 Hz, 1H), 7.42 - 7.31 (m, 2H), 7.26 - 7.19 (m, 2H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.41 (d, J = 5.9 Hz, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 2.12 (s, 3H).

[0673] ESI-MS: 448.15 (M + H) + 。

[0674] N-[(3-fluoro-4-methoxyphenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy} benzamide (140):

[0675]

[0676] Compound 139 as a white solid was synthesized from intermediate 119a (0.10 mmol) and 5-fluoro-2-methoxy-3-pyridinemethanamine (0.24 mmol) according to general method C2, with a yield of 40%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.85 (t, J = 5.7 Hz, 1H), 8.36 (d, J = 5.7 Hz, 1H), 8.24 (s, 1H), 8.07 (d, J = 3.0 Hz, 1H), 7.96 (d, J = 0.6 Hz, 1H), 7.57 (dd, J = 8.6 Hz, 3.0 Hz, 1H), 7.41 - 7.36 (m, 2H), 7.24 - 7.21 (m, 2H), 6.49 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.39 (d, J = 5.7 Hz, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 2.15 (s, 3H).

[0677] ESI-MS: 448.20 (M + H) + 。

[0678] N-[(4-fluoro-3-methoxyphenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy} benzamide (141):

[0679]

[0680] Compound 140 as a white solid was synthesized from intermediate 119a (0.10 mmol) and (3-fluoro-4-methoxyphenyl)methanamine (0.15 mmol) according to general method C2, with a yield of 58%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.88 (t, J = 6.0 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.24 (s, 1H), 7.95 (d, J = 0.6 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.31 (dd, J = 7.6 Hz, 1.3 Hz, 1H), 7.24 - 7.09 (m, 5H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.39 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.82 (s, 3H), 2.13 (s, 3H).

[0681] ESI-MS: 447.20 (M + H) + 。

[0682] N-(cyclohexylmethyl)-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy}benzamide 2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy}-N-(tetrahydropyran-4-ylmethyl)benz

[0683]

[0684] Compound 141 as a white solid was synthesized from intermediate 119a (0.10 mmol) and 5-(aminomethyl)-2-fluoroanisole (0.15 mmol) according to general method C2 in 70% yield. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.90 (t, J = 6.0 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.24 (s, 1H), 7.95 (d, J = 0.6 Hz, 1H), 7.42 - 7.30 (m, 2H), 7.25 - 7.12 (m, 4H), 6.92 - 6.88 (m, 1H), 6.49 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.43 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.82 (s, 3H), 2.14 (s, 3H).

[0685] ESI-MS: 447.20 (M + H) + 。

[0686] amide (143): (142)：

[0687]

[0688] Compound 142 as a white solid was synthesized from intermediate 119a (0.10 mmol) and 1-cyclohexylmethylamine (0.15 mmol) according to general method C2 in 69% yield. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.36 - 3.81 (m, 2H), 8.24 (s, 1H), 7.96 (s, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.27 - 7.22 (m, 2H), 7.18 (d, J = 8.0 Hz, 1H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 3.87 (s, 3H), 3.09 (t, J = 6.4 Hz, 2H), 2.13 (s, 3H), 1.77 - 1.47 (m, 6H), 1.27 - 1.12 (m, 3H), 0.99 - 0.89 (m, 2H).

[0689] ESI-MS: 405.20 (M + H) + 。

[0690] N-[(1R)-1-cyclohexylethyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy}benz amide (144):

[0691]

[0692] Compound 143 as a white solid was synthesized from intermediate 119a (0.10 mmol) and 4-(aminomethyl)tetrahydropyran (0.15 mmol) according to general method C2 in a yield of 71%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.39 (t, J = 5.8 Hz, 1H), 8.36 (d, J = 5.7 Hz, 1H), 8.24 (s, 1H), 7.96 (d, J = 0.6 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.28 - 7.21 (m, 2H), 7.19 (dd, J = 8.0 Hz, 1.0 Hz, 1H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 3.89 - 3.82 (m, 5H), 3.27 - 3.24 (m, 2H), 3.18 - 3.12 (m, 2H), 2.13 (s, 3H), 1.80 - 1.74 (m, 1H), 1.63 - 1.60 (m, 2H), 1.26 - 1.16 (m, 2H).

[0693] ESI-MS: 407.15 (M + H) + 。

[0694] N-[(1S)-1-cyclohexylethyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy}benz amide (145):

[0695]

[0696] Compound 144 as a white solid was synthesized from intermediate 119a (0.10 mmol) and (R)-1-cyclohexylethylamine (0.15 mmol) according to general method C2 in a yield of 60%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.36 (d, J = 5.7 Hz, 1H), 8.25 (s, 1H), 8.15 (d, J = 8.7 Hz, 1H), 7.96 (d, J = 0.5 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.27 - 7.14 (m, 3H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 3.92 - 3.76 (m, 4H), 2.12 (s, 3H), 1.83 - 1.57 (m, 5H), 1.38 - 1.33 (m, 1H), 1.24 - 0.92 (m, 8H).

[0697] ESI-MS: 419.20 (M + H) + 。

[0698] 2-methyl-N-[(1-methylpyrazol-4-yl)methyl]-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy} benzamide (146):

[0699]

[0700] According to the general method C2, compound 145 as a white solid was synthesized from intermediate 119a (0.10 mmol) and (S)-1-cyclohexylethylamine (0.15 mmol) with a yield of 54%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.36 (d, J = 5.7 Hz, 1H), 8.25 (s, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.96 (s, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.26 - 7.15 (m, 3H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 3.90 - 3.75 (m, 4H), 2.12 (s, 3H), 1.82 - 1.58 (m, 5H), 1.42 - 1.33 (m, 1H), 1.24 - 1.06 (m, 6H), 1.03 - 0.94 (m, 2H).

[0701] ESI-MS: 419.20 (M + H) + 。

[0702] 2-methyl-N-[(2-methylpyrazol-3-yl)methyl]-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy} benzamide (147):

[0703]

[0704] According to the general method C2, compound 146 as a white solid was synthesized from intermediate 119a (0.10 mmol) and C-(1-methyl-1H-pyrazol-4-yl)-methanamine (0.15 mmol) with a yield of 62%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.69 (t, J = 5.7 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.24 (s, 1H), 7.95 (d, J = 0.6 Hz, 1H), 7.61 (s, 1H), 7.37 - 7.32 (m, 2H), 7.27 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 7.22 (d, J = 2.3 Hz, 1H), 7.18 (dd, J = 8.0 Hz, 1.1 Hz, 1H), 6.47 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.27 (d, J = 5.7 Hz, 2H), 3.86 (s, 3H), 3.79 (s, 3H), 2.12 (s, 3H).

[0705] ESI-MS: 403.15 (M + H) + 。

[0706] 2-methyl-N-[(1-methylpyrazol-3-yl)methyl]-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy}benzamide (148):

[0707]

[0708] According to the general method C2, compound 147 as a white solid was synthesized from intermediate 119a (0.10 mmol) and C-(2-methyl-2H-pyrazol-3-yl)-methanamine (0.15 mmol) with a yield of 69%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.89 (t, J = 5.7 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.24 (s, 1H), 7.95 (d, J = 0.6 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.32 - 7.28 (m, 2H), 7.23 (d, J = 2.3 Hz, 1H), 7.21 (dd, J = 7.9 Hz, 1.2 Hz, 1H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 6.19 (d, J = 1.8 Hz, 1H), 4.51 (d, J = 5.7 Hz, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 2.13 (s, 3H).

[0709] ESI-MS: 403.20 (M+H) + 。

[0710] N-[(4-fluoro-3-methylphenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy} benzamide (149):

[0711]

[0712] According to the general method C2, compound 148 as a white solid was synthesized from intermediate 119a (0.10 mmol) and (1-methyl-1H-pyrazol-3-yl)methanamine (0.15 mmol) with a yield of 72%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 8.74 (t, J = 5.9 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.24 (s, 1H), 7.95 (d, J = 0.6 Hz, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.27 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 7.22 (d, J = 2.3 Hz, 1H), 7.18 (dd, J = 7.9 Hz, 1.1 Hz, 1H), 6.49 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 6.16 (d, J = 2.2 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 3.78 (s, 3H), 2.13 (s, 3H).

[0713] ESI-MS: 403.15 (M+H) + 。

[0714] N-[(3-fluoro-4-methylphenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy} benzamide (150):

[0715]

[0716] Compound 149 as a white solid was synthesized from intermediate 119a (0.10 mmol) and (4-fluoro-3-methylphenyl)methanamine (0.15 mmol) according to general method C2 with a yield of 67%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.88 (t, J = 6.0 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.42 - 7.29 (m, 2H), 7.28 - 7.16 (m, 4H), 7.13 - 7.06 (m, 1H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.40 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.22 (d, J = 1.5 Hz, 3H), 2.13 (s, 3H).

[0717] ESI-MS: 431.15 (M+H) + 。

[0718] 2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy}-N-[(2-oxo-1H-pyridin-3-yl)methyl]benzamide (151): ​

[0719]

[0720] Compound 150 as a white solid was synthesized from intermediate 119a (0.10 mmol) and 3-fluoro-4-methylbenzylamine (0.15 mmol) according to general method C2 with a yield of 69%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.91 (t, J = 6.0 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.24 (s, 1H), 7.95 (d, J = 0.6 Hz, 1H), 7.40 - 7.30 (m, 2H), 7.27 - 7.17 (m, 3H), 7.13 - 7.07 (m, 2H), 6.49 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.42 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.21 (d, J = 1.2 Hz, 3H), 2.13 (s, 3H).

[0721] ESI-MS: 431.15 (M + H) + 。

[0722] ​ ​

[0723]

[0724] Compound 151 as a white solid was synthesized from intermediate 119a (0.10 mmol) and 3-(aminomethyl)-2(1H)-pyridone (0.24 mmol) according to general method C2 with a yield of 40%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 11.62 (bs, 1H), 8.66 (t, J = 5.8 Hz, 1H), 8.36 (d, J = 5.7 Hz, 1H), 8.24 (s, 1H), 7.96 (d, J = 0.6 Hz, 1H), 7.37 - 7.35 (m, 3H), 7.30 (dd, J = 6.5 Hz, 2.0 Hz, 1H), 7.25 - 7.18 (m, 2H), 6.49 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 6.20 (t, J = 6.6 Hz, 1H), 4.21 (d, J = 5.8 Hz, 2H), 3.86 (s, 3H), 2.15 (s, 3H).

[0725] ESI-MS: 416.15 (M + H) + 。

[0726] 2-Methyl-N-[(1-methyl-2-oxo-3-piperidinyl)methyl]-3-{[2-(1-methyl-1H-pyrazol-4-yl)-4-pyridinyl]oxy}benzamide (152): 2-Methyl-N-[(1-methyl-2-oxo-3-pyridinyl)methyl]-3-{[2-(1-methyl-1H-pyrazol-4-yl)-4-pyridinyl]oxy}benzamide (153):

[0727]

[0728] Compound 152 as a white solid was synthesized from intermediate 119a (0.10 mmol) and 3-(aminomethyl)-1-methyl-2-piperidone (0.24 mmol) according to general method C2, with a yield of 69%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.36 (d, J = 5.7 Hz, 1H), 8.30 (t, J = 5.8 Hz, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.28 (d, J = 6.6 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 6.49 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 3.87 (s, 3H), 3.67 - 3.61 (m, 1H), 3.41 - 3.33 (m, 2H), 3.27 - 3.20 (m, 2H), 2.81 (s, 3H), 2.13 (s, 3H), 1.92 - 1.84 (m, 2H), 1.72 - 1.54 (m, 2H).

[0729] ESI-MS: 434.20 (M + H) + 。

[0730] N-[(5-Fluoro-2-pyridinyl)methyl]-2-methyl-3-{[2-(1-methyl-1H-pyrazol-4-yl)-4-pyridinyl]oxy}benzamide (154): N-[(6-(Dimethylphosphoryl)-3-pyridinyl)methyl]-2-methyl-3-{[2-(1-methyl-1H-pyrazol-4-yl)-4-pyridinyl]oxy}benzamide (155):

[0731]

[0732] Compound 153 as a white solid was synthesized from intermediate 119a (0.07 mmol) and 3-(aminomethyl)-1-methyl-2(1H)-pyridone (0.15 mmol) according to general method C2, with a yield of 53%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.69 (t, J = 5.8 Hz, 1H), 8.36 (d, J = 5.8 Hz, 1H), 8.25 (s, 1H), 7.96 (d, J = 0.7 Hz, 1H), 7.63 (dd, J = 6.7 Hz, 1.9 Hz, 1H), 7.41 - 7.33 (m, 3H), 7.27 - 7.18 (m, 2H), 6.49 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 6.24 (t, J = 6.8 Hz, 1H), 4.24 (d, J = 5.8 Hz, 2H), 3.86 (s, 3H), 3.46 (s, 3H), 2.15 (s, 3H).

[0733] ESI-MS: 430.20 (M + H) + 。

[0734] N-[(3,5-Difluorophenyl)methyl]-4-methyl-3-{[2-(1-methyl-1H-pyrazol-4-yl)-4-pyridinyl]oxy}benzamide (156): N-[(3,4-Difluorophenyl)methyl]-4-methyl-3-{[2-(1-methyl-1H-pyrazol-4-yl)-4-pyridinyl]oxy}benzamide (157):

[0735]

[0736] According to general method C2, compound 154 as a white solid was synthesized from intermediate 119a (0.06 mmol) and 5-fluoro-2-pyridinemethanamine (0.10 mmol) with a yield of 41%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.0 Hz, 1H), 8.52 (d, J = 2.9 Hz, 1H), 8.36 (d, J = 5.7 Hz, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 7.73 (td, J = 8.8 Hz, 3.0 Hz, 1H), 7.47 (dd, J = 8.7 Hz, 4.5 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.28 - 7.19 (m, 2H), 6.49 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.54 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.16 (s, 3H).

[0737] ESI-MS: 418.20 (M + H) + 。

[0738] N-[(4-Chloro-3-fluorophenyl)methyl]-4-methyl-3-{[2-(1-methyl-1H-pyrazol-4-yl)-4-pyridinyl]oxy}benzamide (158): N-[(4-Chlorophenyl)methyl]-4-methyl-3-{[2-(1-methyl-1H-pyrazol-4-yl)-4-pyridinyl]oxy}benzamide (159):

[0739]

[0740] According to general method C2, compound 155 as a white solid was synthesized from intermediate 119a (0.10 mmol) and (5-(aminomethyl)pyridin-2-yl)dimethylphosphine oxide (0.29 mmol) with a yield of 78%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.04 (t, J = 5.9 Hz, 1H), 8.75 (s, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.24 (s, 1H), 7.98 - 7.90 (m, 3H), 7.44 - 7.33 (m, 2H), 7.24 - 7.21 (m, 2H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.54 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 2.14 (s, 3H), 1.66 (s, 3H), 1.63 (s, 3H). 31 P NMR (162 MHz, DMSO-d6) δ (ppm): 33.89.

[0741] ESI-MS: 476.10 (M+H) + 。

[0742] N-[(4-Fluorophenyl)methyl]-4-methyl-3-{[2-(1-methyl-1H-pyrazol-4-yl)-4-pyridinyl]oxy}benzamide (352): N-[(3,5-Difluorophenyl)methyl]-2-methyl-5-{[2-(1-methyl-1H-pyrazol-4-yl)-4-pyridinyl]oxy}benzamide (160):

[0743]

[0744] Compound 156 as a white solid was synthesized from intermediate 119b (0.10 mmol) and 3,5-difluorobenzylamine (0.15 mmol) according to general method C2 with a yield of 67%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.10 (t, J = 6.0 Hz, 1H), 8.36 (d, J = 5.7 Hz, 1H), 8.25 (s, 1H), 7.97 (d, J = 0.7 Hz, 1H), 7.79 (dd, J = 7.9 Hz, 1.7 Hz, 1H), 7.64 (d, J = 1.7 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.29 - 7.20 (m, 1H), 7.13 - 7.05 (m, 1H), 7.04 - 6.98 (m, 2H), 6.55 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.46 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 2.20 (s, 3H).

[0745] ESI-MS: 435.00 (M+H) + 。

[0746] N-[(3,4-Difluorophenyl)methyl]-2-methyl-5-{[2-(1-methyl-1H-pyrazol-4-yl)-4-pyridinyl]oxy}benzamide (161): N-[(4-Chloro-3-fluorophenyl)methyl]-2-methyl-5-{[2-(1-methyl-1H-pyrazol-4-yl)-4-pyridinyl]oxy}benzamide (162):

[0747]

[0748] Compound 157 as a white solid was synthesized from intermediate 119b (0.10 mmol) and 3,4-difluorobenzylamine (0.15 mmol) according to general method C2 with a yield of 45%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 9.07 (t, J = 5.9 Hz, 1H), 8.40 - 8.33 (m, 1H), 8.25 (s, 1H), 7.97 (d, J = 0.7 Hz, 1H), 7.78 (dd, J = 7.9 Hz, 1.7 Hz, 1H), 7.63 (d, J = 1.7 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.42 - 7.31 (m, 2H), 7.23 (d, J = 2.1 Hz, 1H), 7.16 - 7.13 (m, 1H), 6.54 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.42 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 2.20 (s, 3H).

[0749] ESI-MS: 435.00 (M + H) + 。

[0750] N-[(4-Chlorophenyl)methyl]-2-methyl-5-{[2-(1-methyl-1H-pyrazol-4-yl)-4-pyridinyl]oxy}benzamide (163): N-[(2-Methoxyphenyl)methyl]-2-methyl-5-{[2-(1-methyl-1H-pyrazol-4-yl)-4-pyridinyl]oxy}benzamide (351):

[0751]

[0752] According to the general method C2, compound 158 as a white solid was synthesized from intermediate 119b (0.10 mmol) and 4-chloro-3-fluorobenzylamine (0.15 mmol) with a yield of 57%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.09 (t, J = 6.0 Hz, 1H), 8.39 - 8.34 (m, 1H), 8.25 (s, 1H), 7.97 (d, J = 0.7 Hz, 1H), 7.79 (dd, J = 7.9 Hz, 1.7 Hz, 1H), 7.63 (d, J = 1.7 Hz, 1H), 7.55 - 7.47 (m, 2H), 7.33 (dd, J = 10.4 Hz, 1.9 Hz, 1H), 7.27 - 7.21 (m, 1H), 7.17 (dd, J = 8.2 Hz, 1.3 Hz, 1H), 6.54 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.44 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 2.20 (s, 3H).

[0753] ESI-MS: 451.05 (M + H) + 。

[0754] 2-Methyl-5-{[2-(1-methyl-1H-pyrazol-4-yl)-4-pyridinyl]oxy}-N-{[3-(trifluoromethyl)phenyl]methyl}benzamide (354): N-[(3,4-Difluorophenyl)methyl]-2-methoxy-5-{[2-(1-methyl-1H-pyrazol-4-yl)-4-pyridinyl]oxy}benzamide (359):

[0755]

[0756] Compound 159 as a white solid was synthesized from intermediate 119b (0.10 mmol) and 4-chlorobenzylamine (0.15 mmol) according to general method C2, with a yield of 92%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.07 (t, J = 6.0 Hz, 1H), 8.38 - 8.34 (m, 1H), 8.25 (s, 1H), 7.97 (d, J = 0.7 Hz, 1H), 7.78 (dd, J = 7.9 Hz, 1.7 Hz, 1H), 7.63 (d, J = 1.7 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.40 - 7.29 (m, 4H), 7.23 (d, J = 2.1 Hz, 1H), 6.54 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.43 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 2.20 (s, 3H).

[0757] ESI-MS: 433.00 (M + H) + 。

[0758] ​ ​

[0759]

[0760] Compound 352 as a white solid was synthesized from intermediate 119b (0.08 mmol) and 4-fluorobenzylamine (0.12 mmol) according to general method C2, with a yield of 80%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.05 (t, J = 6.0 Hz, 1H), 8.36 (d, J = 5.6 Hz, 1H), 8.25 (s, 1H), 7.97 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.36 - 7.31 (m, 2H), 7.23 (d, J = 2.4 Hz, 1H), 7.16 - 7.10 (m, 2H), 6.54 (dd, J = 5.7 Hz, 2.5 Hz, 1H), 4.42 (d, J = 5.8 Hz, 2H), 3.86 (s, 3H), 2.20 (s, 3H).

[0761] ESI-MS: 417.10 (M + H) + 。

[0762] 4-Fluoro-N-[(4-fluorophenyl)methyl]-3-{[2-(1-methylpyrazol-4-yl)-4-pyridinyl]oxy}benzamide (353):

[0763]

[0764] According to the general method C2, the compound 353 as a white solid was synthesized from intermediate 119i (0.08 mmol) and 4-fluorobenzylamine (0.12 mmol) with a yield of 63%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.14 (t, J = 5.9 Hz, 1H), 8.40 (d, J = 5.7 Hz, 1H), 8.28 (s, 1H), 7.99 (s, 1H), 7.94 - 7.87 (m, 2H), 7.61 - 7.56 (m, 1H), 7.37 - 7.30 (m, 3H), 7.19 - 7.10 (m, 2H), 6.71 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.44 (d, J = 5.8 Hz, 2H), 3.86 (s, 3H).

[0765] ESI-MS: 421.05 (M + H) + .

[0766] ​ ​

[0767]

[0768] According to the general method C2, the compound 160 as a white solid was synthesized from intermediate 119c (0.10 mmol) and 3,5-difluorobenzylamine (0.15 mmol) with a yield of 90%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.92 (t, J = 6.0 Hz, 1H), 8.40 - 8.35 (m, 1H), 8.25 (s, 1H), 7.96 (d, J = 0.7 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.27 - 7.23 (m, 2H), 7.19 (dd, J = 8.2 Hz, 2.6 Hz, 1H), 7.14 - 7.07 (m, 1H), 7.07 - 7.02 (m, 2H), 6.66 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.44 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.36 (s, 3H).

[0769] ESI-MS: 435.00 (M + H) + .

[0770] ​ ​

[0771]

[0772] According to the general method C2, compound 161 as a white solid was synthesized from intermediate 119c (0.10 mmol) and 3,4-difluorobenzylamine (0.15 mmol) with a yield of 41%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.90 (t, J = 6.0 Hz, 1H), 8.39 - 8.35 (m, 1H), 8.25 (s, 1H), 7.96 (d, J = 0.7 Hz, 1H), 7.44 - 7.34 (m, 3H), 7.25 (d, J = 2.1 Hz, 1H), 7.22 (d, J = 2.6 Hz, 1H), 7.20 - 7.15 (m, 2H), 6.65 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.41 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 2.35 (s, 3H).

[0773] ESI-MS: 435.05 (M + H) + 。

[0774] ​ ​

[0775]

[0776] According to the general method C2, compound 162 as a white solid was synthesized from intermediate 119c (0.10 mmol) and 4-chloro-3-fluorobenzylamine (0.15 mmol) with a yield of 60%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.92 (t, J = 6.0 Hz, 1H), 8.40 - 8.35 (m, 1H), 8.25 (s, 1H), 7.96 (d, J = 0.7 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.37 - 7.33 (m, 2H), 7.28 - 7.15 (m, 4H), 6.65 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.43 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.35 (s, 3H).

[0777] ESI-MS: 451.05 (M + H) + 。

[0778] ​ ​

[0779]

[0780] Compound 163 as a white solid was synthesized from intermediate 119c (0.10 mmol) and 4-chlorobenzylamine (0.15 mmol) according to general method C2 in 79% yield. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.98 (t, J = 6.0 Hz, 1H), 8.48 - 8.45 (m, 1H), 8.34 (s, 1H), 8.05 (d, J = 0.7 Hz, 1H), 7.51 - 7.41 (m, 5H), 7.34 (d, J = 2.1 Hz, 1H), 7.30 - 7.23 (m, 2H), 6.74 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.50 (d, J = 6.0 Hz, 2H), 3.95 (s, 3H), 2.44 (s, 3H).

[0781] ESI-MS: 433.00 (M + H) + 。

[0782] ​ ​

[0783]

[0784] Compound 351 as a white solid was synthesized from intermediate 119c (0.07 mmol) and 2-methoxybenzylamine (0.10 mmol) according to general method C2 in 71% yield. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.70 (t, J = 5.8 Hz, 1H), 8.37 (d, J = 5.7 Hz, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.28 - 7.21 (m, 3H), 7.20 - 7.16 (m, 2H), 6.98 (d, J = 8.2 Hz, 1H), 6.90 (t, J = 7.4 Hz, 1H), 6.66 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.39 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 3.79 (s, 3H), 2.36 (s, 3H).

[0785] ESI-MS: 429.10 (M + H) + 。

[0786] ​ ​

[0787]

[0788] Compound 354 as a white solid was synthesized from intermediate 119c (0.07 mmol) and 3-(trifluoromethyl)benzylamine (0.10 mmol) according to general method C2 with a yield of 73%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.97 (t, J = 6.0 Hz, 1H), 8.37 (d, J = 5.7 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.72 - 7.53 (m, 4H), 7.36 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 7.21 - 7.16 (m, 2H), 6.66 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.52 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 2.35 (s, 3H).

[0789] ESI-MS: 467.10 (M + H) + 。

[0790] ​ ​

[0791]

[0792] Compound 359 as a white solid was synthesized from intermediate 119j (0.08 mmol) and 3,4-difluorobenzylamine (0.12 mmol) according to general method C2 with a yield of 72%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.87 (t, J = 6.1 Hz, 1H), 8.36 (d, J = 5.7 Hz, 1H), 8.24 (s, 1H), 7.95 (d, J = 0.7 Hz, 1H), 7.49 (d, J = 3.1 Hz, 1H), 7.43 - 7.32 (m, 3H), 7.28 - 7.15 (m, 3H), 6.61 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.47 (d, J = 6.1 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H).

[0793] ESI-MS: 451.10 (M + H) + 。

[0794] N-[(3,5-Difluorophenyl)methyl]-3-methyl-5-{[2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl]oxy} benzamide (164):

[0795]

[0796] Compound 164 as a white solid was synthesized from intermediate 119d (0.10 mmol) and 3,5-difluorobenzylamine (0.15 mmol) according to general method C2 in a yield of 43%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.12 (t, J = 5.9 Hz, 1H), 8.39 (d, J = 5.7 Hz, 1H), 8.27 (s, 1H), 7.97 (d, J = 0.5 Hz, 1H), 7.66 (s, 1H), 7.49 (s, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.22 (s, 1H), 7.13 - 7.07 (m, 1H), 7.04 - 6.99 (m, 2H), 6.68 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.47 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 2.40 (s, 3H).

[0797] ESI-MS: 435.00 (M + H) + 。

[0798] N-[(3,4-Difluorophenyl)methyl]-3-methyl-5-{[2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl]oxy} benzamide (165):

[0799]

[0800] Compound 165 as a white solid was synthesized from intermediate 119d (0.10 mmol) and 3,4-difluorobenzylamine (0.15 mmol) according to general method C2 in a yield of 29%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.09 (t, J = 5.9 Hz, 1H), 8.39 (d, J = 5.7 Hz, 1H), 8.26 (s, 1H), 7.97 (d, J = 0.7 Hz, 1H), 7.66 - 7.64 (m, 1H), 7.48 - 7.47 (m, 1H), 7.42 - 7.32 (m, 2H), 7.28 (d, J = 2.1 Hz, 1H), 7.22 - 7.21 (m, 1H), 7.19 - 7.11 (m, 1H), 6.67 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.43 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 2.39 (s, 3H).

[0801] ESI-MS: 435.00 (M + H) + 。

[0802] N-[(4-Chloro-3-fluorophenyl)methyl]-3-methyl-5-{[2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl]oxy} benzamide (166):

[0803]

[0804] Compound 166 as a white solid was synthesized from Intermediate 119d (0.10 mmol) and 4-chloro-3-fluorobenzylamine (0.15 mmol) according to General Method C2 in 46% yield. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.11 (t, J = 5.9 Hz, 1H), 8.41 - 8.36 (m, 1H), 8.26 (s, 1H), 7.97 (d, J = 0.7 Hz, 1H), 7.66 - 7.65 (m, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.48 - 7.47 (m, 1H), 7.33 (dd, J = 10.4 Hz, 1.9 Hz, 1H), 7.28 (d, J = 2.1 Hz, 1H), 7.22 - 7.21 (m, 1H), 7.18 (dd, J = 8.3 Hz, 1.3 Hz, 1H), 6.67 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.45 (d, J = 5.9, 2H), 3.86 (s, 3H), 2.39 (s, 3H).

[0805] ESI-MS: 451.05 (M + H) + 。

[0806] N-[(4-Chlorophenyl)methyl]-3-methyl-5-{[2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl]oxy}benz amide (167):

[0807]

[0808] Compound 167 as a white solid was synthesized from Intermediate 119d (0.10 mmol) and 4-chlorobenzylamine (0.15 mmol) according to General Method C2 in 53% yield. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.09 (t, J = 5.9 Hz, 1H), 8.41 - 8.37 (m, 1H), 8.26 (s, 1H), 7.97 (d, J = 0.7 Hz, 1H), 7.66 - 7.65 (m, 1H), 7.49 - 7.45 (m, 1H), 7.40 - 7.30 (m, 4H), 7.28 (d, J = 2.0 Hz, 1H), 7.22 - 7.21 (m, 1H), 6.66 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.43 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 2.39 (s, 3H).

[0809] ESI-MS: 433.00 (M + H) + 。

[0810] N-[(3-Fluorophenyl)methyl]-2-methyl-3-({2-[(1-methyl-1H-pyrazol-3-yl)amino]pyridin-4-yl}oxy)benzamide (168):

[0811]

[0812] According to the general method C2, compound 168 as a white solid was synthesized from intermediate 119e (0.09 mmol) and 3-fluorobenzylamine (0.14 mmol) with a yield of 53%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.17 (s, 1H), 8.94 (t, J = 6.0 Hz, 1H), 7.98 (d, J = 5.7 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.42 - 7.31 (m, 3H), 7.22 - 7.13 (m, 3H), 7.08 (td, J = 8.3 Hz, 2.1 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 6.18 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 6.15 (d, J = 2.2 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.67 (s, 3H), 2.14 (s, 3H).

[0813] ESI-MS: 432.15 (M + H) + 。

[0814] N-[(4-Fluorophenyl)methyl]-2-methyl-3-({2-[(1-methyl-1H-pyrazol-3-yl)amino]pyridin-4-yl}oxy) benzamide (169):

[0815]

[0816] According to the general method C2, compound 169 as a white solid was synthesized from intermediate 119e (0.09 mmol) and 4-fluorobenzylamine (0.14 mmol) with a yield of 50%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.17 (s, 1H), 8.91 (t, J = 6.0 Hz, 1H), 7.98 (d, J = 5.8 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.42 - 7.27 (m, 4H), 7.21 - 7.13 (m, 3H), 6.88 (d, J = 2.1 Hz, 1H), 6.17 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 6.15 (d, J = 2.2 Hz, 1H), 4.43 (d, J = 6.0 Hz, 2H), 3.67 (s, 3H), 2.13 (s, 3H).

[0817] ESI-MS: 432.15 (M + H) + 。

[0818] N-[(3-Chlorophenyl)methyl]-2-methyl-3-({2-[(1-methyl-1H-pyrazol-3-yl)amino]pyridin-4-yl}oxy)benzamide (170):

[0819]

[0820] According to the general method C2, compound 170 as a white solid was synthesized from intermediate 119e (0.09 mmol) and 3-chlorobenzylamine (0.14 mmol) with a yield of 63%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.17 (s, 1H), 8.95 (t, J = 6.1 Hz, 1H), 7.98 (d, J = 5.8 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.43 - 7.28 (m, 6H), 7.18 (dd, J = 7.8 Hz, 1.2 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 6.18 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 6.15 (d, J = 2.2 Hz, 1H), 4.46 (d, J = 6.0 Hz, 2H), 3.67 (s, 3H), 2.14 (s, 3H).

[0821] ESI-MS: 448.15 (M + H) + 。

[0822] N-[(4-Chlorophenyl)methyl]-2-methyl-3-({2-[(1-methyl-1H-pyrazol-3-yl)amino]pyridin-4-yl}oxy) benzamide (171):

[0823]

[0824] According to the general method C2, compound 171 as a white solid was synthesized from intermediate 119e (0.09 mmol) and 4-chlorobenzylamine (0.14 mmol) with a yield of 49%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.17 (s, 1H), 8.93 (t, J = 6.0 Hz, 1H), 7.98 (d, J = 5.8 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.43 - 7.28 (m, 6H), 7.18 (dd, J = 7.8 Hz, 1.3 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 6.17 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 6.15 (d, J = 2.2 Hz, 1H), 4.43 (d, J = 6.0 Hz, 2H), 3.67 (s, 3H), 2.13 (s, 3H).

[0825] ESI-MS: 448.15 (M + H) + 。

[0826] 2-Methyl-3-({2-[(1-methyl-1H-pyrazol-3-yl)amino]pyridin-4-yl}oxy)-N-{[6-(trifluoromethyl)- pyridin-3-yl]methyl}benzamide (172):

[0827]

[0828] According to the general method C2, compound 172 as a white solid was synthesized from intermediate 119e (0.09 mmol) and [6-(trifluoromethyl)-3-pyridyl]methanamine (0.14 mmol) with a yield of 57%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.17 (s, 1H), 9.05 (t, J = 5.9 Hz, 1H), 8.76 - 8.75 (m, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 5.8 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.40 - 7.33 (m, 2H), 7.19 (dd, J = 7.0 Hz, 2.4 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 6.18 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 6.15 (d, J = 2.2 Hz, 1H), 4.58 (d, J = 5.9 Hz, 2H), 3.67 (s, 3H), 2.14 (s, 3H).

[0829] ESI-MS: 483.15 (M + H) + 。

[0830] N-(Imidazo[1,2-a]pyridin-6-ylmethyl)-2-methyl-3-({2-[(1-methyl-1H-pyrazol-3-yl)amino]- pyridin-4-yl}oxy)benzamide (173):

[0831]

[0832] According to the general method C2, compound 173 as a white solid was synthesized from intermediate 119e (0.09 mmol) and imidazo[1,2-a]pyridin-6-ylmethanamine (0.14 mmol) with a yield of 50%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 9.17 (s, 1H), 8.93 (t, J = 5.9 Hz, 1H), 8.50 - 8.49 (m, 1H), 7.99 - 7.95 (m, 2H), 7.57 - 7.54 (m, 2H), 7.46 (d, J = 2.2 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.25 (dd, J = 9.3 Hz, 1.7 Hz, 1H), 7.18 (dd, J = 7.4 Hz, 1.8 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 6.17 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 6.15 (d, J = 2.2 Hz, 1H), 4.44 (d, J = 5.8 Hz, 2H), 3.67 (s, 3H), 2.13 (s, 3H).

[0833] ESI-MS: 454.15 (M+H) + 。

[0834] N-(Imidazo[1,2-a]pyridin-7-ylmethyl)-2-methyl-3-({2-[(1-methyl-1H-pyrazol-3-yl)amino]- pyridin-4-yl}oxy)benzamide (174):

[0835]

[0836] Compound 174 as a white solid was synthesized from intermediate 119e (0.09 mmol) and imidazo[1,2-a]pyridin-7-ylmethanamine (0.14 mmol) according to the general method C2 with a yield of 41%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.17 (s, 1H), 8.98 (t, J = 6.0 Hz, 1H), 8.51 (dd, J = 7.0 Hz, 0.7 Hz, 1H), 7.98 (d, J = 5.8 Hz, 1H), 7.90 (s, 1H), 7.53 (d, J = 1.1 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.44 (s, 1H), 7.40 - 7.33 (m, 2H), 7.19 (dd, J = 7.4 Hz, 1.8 Hz, 1H), 6.90 - 6.87 (m, 2H), 6.18 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 6.15 (d, J = 2.2 Hz, 1H), 4.49 (d, J = 5.9 Hz, 2H), 3.67 (s, 3H), 2.16 (s, 3H).

[0837] ESI-MS: 454.15 (M+H) + 。

[0838] N-[(5-Fluoropyridin-3-yl)methyl]-2-methyl-3-({2-[(1-methyl-1H-pyrazol-3-yl)amino]pyridin-4- yl}oxy)benzamide (175):

[0839]

[0840] According to the general method C2, compound 175 as a white solid was synthesized from intermediate 119e (0.06 mmol) and 5-fluoro-3-pyridinemethanamine (0.09 mmol) with a yield of 37%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.17 (s, 1H), 9.00 (t, J = 5.9 Hz, 1H), 8.49 (d, J = 2.8 Hz, 1H), 8.47 - 8.46 (m, 1H), 7.98 (d, J = 5.8 Hz, 1H), 7.69 - 7.65 (m, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.39 - 7.32 (m, 2H), 7.19 (dd, J = 7.2 Hz, 2.0 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 6.18 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 6.15 (d, J = 2.2 Hz, 1H), 4.52 (d, J = 5.9 Hz, 2H), 3.67 (s, 3H), 2.13 (s, 3H).

[0841] ESI-MS: 433.20 (M + H) + 。

[0842] N-[(3,4-Difluorophenyl)methyl]-2-fluoro-5-({2-[(1-methyl-1H-pyrazol-3-yl)amino]pyridin-4-yl}oxy) benzamide (355):

[0843]

[0844] According to the general method C2, compound 355 as a white solid was synthesized from intermediate 119k (0.08 mmol) and 3,4-difluorobenzylamine (0.11 mmol) with a yield of 30%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.21 (s, 1H), 8.98 (t, J = 5.0 Hz, 1H), 8.01 (d, J = 5.7 Hz, 1H), 7.49 - 7.33 (m, 6H), 7.22 - 7.14 (m, 1H), 6.93 (d, J = 2.1 Hz, 1H), 6.30 (dd, J = 5.7 Hz, 2.3 Hz, 1H), 6.16 (d, J = 2.2 Hz, 1H), 4.44 (d, J = 6.0 Hz, 2H), 3.67 (s, 3H).

[0845] ESI-MS: 454.00 (M + H) + 。

[0846] N-[(5-Fluoro-6-methoxypyridin-3-yl)methyl]-2-methyl-3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]- pyridin-4-yl}oxy)benzamide (176):

[0847]

[0848] According to the general method C2, compound 176 as a white solid was synthesized from intermediate 119e (0.06 mmol) and (5-fluoro-6-methoxy-3-pyridyl)methylamine (0.09 mmol) with a yield of 59%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.17 (s, 1H), 8.90 (t, J = 5.9 Hz, 1H), 7.98 - 7.96 (m, 2H), 7.64 (dd, J = 11.4 Hz, 1.9 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.37 - 7.28 (m, 2H), 7.17 (dd, J = 7.8 Hz, 1.2 Hz, 1H), 6.87 (d, J = 2.1 Hz, 1H), 6.17 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 6.14 (d, J = 2.2 Hz, 1H), 4.41 (d, J = 5.9 Hz, 2H), 3.93 (s, 3H), 3.67 (s, 3H), 2.12 (s, 3H).

[0849] ESI-MS: 463.25 (M + H) + 。

[0850] N-[(5-Fluoro-2-methoxypyridin-3-yl)methyl]-2-methyl-3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]- pyridin-4-yl}oxy)benzamide (177):

[0851]

[0852] According to the general method C2, compound 177 as a white solid was synthesized from intermediate 119e (0.06 mmol) and 5-fluoropyridine-3-methylamine (0.09 mmol) with a yield of 48%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.17 (s, 1H), 8.84 (t, J = 5.8 Hz, 1H), 8.07 (d, J = 3.0 Hz, 1H), 7.98 (d, J = 5.8 Hz, 1H), 7.55 (dd, J = 8.6 Hz, 3.0 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.39 - 7.34 (m, 2H), 7.21 - 7.17 (m, 1H), 6.88 (d, J = 2.1 Hz, 1H), 6.18 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 6.15 (d, J = 2.2 Hz, 1H), 4.38 (d, J = 5.7 Hz, 2H), 3.91 (s, 3H), 3.67 (s, 3H), 2.14 (s, 3H).

[0853] ESI-MS: 463.20 (M+H) + 。

[0854] N-(Imidazo[1,2-a]pyridin-6-ylmethyl)-2-methyl-3-({2-[(1-methylpyrazol-4-yl)amino]- 4-pyridyl}oxy)benzamide (178):

[0855]

[0856] Compound 178 as a white solid was synthesized from intermediate 119f (0.09 mmol) and imidazo[1,2-a]pyridin-6-ylmethanamine (0.14 mmol) according to general method C2 with a yield of 53%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.95 (t, J = 5.9 Hz, 1H), 8.74 (s, 1H), 8.50 (s, 1H), 7.99 - 7.96 (m, 2H), 7.86 (s, 1H), 7.57 - 7.55 (m, 2H), 7.38 - 7.31 (m, 3H), 7.24 (dd, J = 9.3 Hz, 1.6 Hz, 1H), 7.19 (dd, J = 7.4 Hz, 1.8 Hz, 1H), 6.23 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 5.93 (d, J = 2.1 Hz, 1H), 4.44 (d, J = 5.9 Hz, 2H), 3.76 (s, 3H), 2.12 (s, 3H).

[0857] ESI-MS: 454.15 (M+H) + 。

[0858] N-(Imidazo[1,2-a]pyridin-7-ylmethyl)-2-methyl-3-({2-[(1-methylpyrazol-4-yl)amino]- 4-pyridyl}oxy)benzamide (179):

[0859]

[0860] Compound 179 as a white solid was synthesized from intermediate 119f (0.09 mmol) and imidazo[1,2-a]pyridin-7-ylmethanamine (0.14 mmol) according to general method C2 with a yield of 46%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 6.0 Hz, 1H), 8.75 (s, 1H), 8.51 (d, J = 7.0 Hz, 1H), 7.99 (d, J = 5.8 Hz, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 7.53 (d, J = 1.1 Hz, 1H), 7.44 (s, 1H), 7.40 - 7.33 (m, 2H), 7.31 (s, 1H), 7.21 (dd, J = 7.3 Hz, 2.0 Hz, 1H), 6.88 (dd, J = 7.0 Hz, 1.6 Hz, 1H), 6.24 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 5.94 (d, J = 2.2 Hz, 1H), 4.49 (d, J = 5.9 Hz, 2H), 3.76 (s, 3H), 2.15 (s, 3H).

[0861] ESI-MS: 454.15 (M+H) + 。

[0862] 2-Methyl-3-({2-[(1-methylpyrazol-4-yl)amino]-4-pyridyl}oxy)-N-{[6-(trifluoromethyl)- 3-pyridyl]methyl}benzamide (180):

[0863]

[0864] Compound 180 as a white solid was synthesized from intermediate 119f (0.09 mmol) and [6-(trifluoromethyl)-3-pyridyl]methylamine (0.14 mmol) according to the general method C2, with a yield of 58%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.07 (t, J = 5.9 Hz, 1H), 8.76 - 8.74 (m, 2H), 8.04 (dd, J = 8.0 Hz, 1.5 Hz, 1H), 7.99 (d, J = 5.8 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.86 (s, 1H), 7.39 - 7.34 (m, 2H), 7.31 (s, 1H), 7.21 (dd, J = 6.7 Hz, 2.6 Hz, 1H), 6.24 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 5.93 (d, J = 2.2 Hz, 1H), 4.58 (d, J = 5.9 Hz, 2H), 3.76 (s, 3H), 2.12 (s, 3H).

[0865] ESI-MS: 483.15 (M+H) + 。

[0866] N-[(5-Fluoro-3-pyridyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-4-yl)amino]-4-pyridin yl}oxy)benzamide (181):

[0867]

[0868] According to the general method C2, compound 181 as a white solid was synthesized from intermediate 119f (0.09 mmol) and 5-fluoro-3-pyridinemethanamine (0.14 mmol) in a yield of 73%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 5.9 Hz, 1H), 8.73 (s, 1H), 8.49 (d, J = 2.8 Hz, 1H), 8.47 - 8.46 (m, 1H), 7.99 (d, J = 5.8 Hz, 1H), 7.86 (s, 1H), 7.69 - 7.65 (m, 1H), 7.39 - 7.33 (m, 2H), 7.31 (d, J = 0.6 Hz, 1H), 7.20 (dd, J = 7.2 Hz, 2.1 Hz, 1H), 6.23 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 5.94 (d, J = 2.2 Hz, 1H), 4.52 (d, J = 5.9 Hz, 2H), 3.77 (s, 3H), 2.12 (s, 3H).

[0869] ESI-MS: 433.20 (M + H) + 。

[0870] N-[(5-Fluoro-6-methoxy-3-pyridyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-4-yl)amm ino]-4-pyridyl}oxy)benzamide (182):

[0871]

[0872] According to the general method C2, compound 182 as a white solid was synthesized from intermediate 119f (0.09 mmol) and (5-fluoro-6-methoxy-3-pyridinyl)methanamine (0.14 mmol) in a yield of 86%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.90 (t, J = 5.8 Hz, 1H), 8.72 (s, 1H), 7.99 - 7.97 (m, 2H), 7.86 (s, 1H), 7.64 (dd, J = 11.4 Hz, 1.9 Hz, 1H), 7.37 - 7.29 (m, 3H), 7.19 (dd, J = 7.8 Hz, 1.3 Hz, 1H), 6.23 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 5.94 (d, J = 2.1 Hz, 1H), 4.41 (d, J = 5.9 Hz, 2H), 3.93 (s, 3H), 3.77 (s, 3H), 2.11 (s, 3H).

[0873] ESI-MS: 463.20 (M + H) + 。

[0874] N-[(5-Fluoro-2-methoxy-3-pyridyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-4-yl)amm ino]-4-pyridyl}oxy)benzamide (183):

[0875]

[0876] According to general method C2, compound 183 as a white solid was synthesized from intermediate 119f (0.09 mmol) and 5-fluoro-2-methoxy-3-pyridinemethanamine (0.14 mmol) with a yield of 70%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.84 (t, J = 5.8 Hz, 1H), 8.73 (s, 1H), 8.07 (d, J = 3.0 Hz, 1H), 7.99 (d, J = 5.8 Hz, 1H), 7.86 (s, 1H), 7.55 (dd, J = 8.6 Hz, 3.0 Hz, 1H), 7.39 - 7.34 (m, 2H), 7.31 (d, J = 0.5 Hz, 1H), 7.22 - 7.18 (m, 1H), 6.24 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 5.94 (d, J = 2.2 Hz, 1H), 4.38 (d, J = 5.7 Hz, 2H), 3.91 (s, 3H), 3.77 (s, 3H), 2.13 (s, 3H).

[0877] ESI-MS: 463.20 (M + H) + 。

[0878] N-[(3-Fluorophenyl)methyl]-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl}ox y)benzamide (184):

[0879]

[0880] According to general method C2, compound 184 as a white solid was synthesized from intermediate 119g (0.15 mmol) and 3-fluorobenzylamine (0.23 mmol) with a yield of 18%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.95 (t, J = 6.1 Hz, 1H), 8.75 (s, 1H), 8.00 (d, J = 5.8 Hz, 1H), 7.43 - 7.32 (m, 3H), 7.27 (d, J = 1.9 Hz, 1H), 7.23 - 7.13 (m, 3H), 7.09 (td, J = 8.4 Hz, 2.4 Hz, 1H), 6.36 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 6.16 (d, J = 1.9 Hz, 1H), 6.12 (d, J = 2.2 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.61 (s, 3H), 2.13 (s, 3H).

[0881] ESI-MS: 432.15 (M+H) + 。

[0882] N-[(4-Fluorophenyl)methyl]-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl}ox y)benzamide (185):

[0883]

[0884] Compound 185 as a white solid was synthesized from intermediate 119 g (0.15 mmol) and 4-fluorobenzylamine (0.23 mmol) according to General Method C2, with a yield of 21%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.92 (t, J = 6.0 Hz, 1H), 8.75 (s, 1H), 8.00 (d, J = 5.8 Hz, 1H), 7.40 - 7.34 (m, 3H), 7.31 (dd, J = 7.6 Hz, 1.3 Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H), 7.22 - 7.14 (m, 3H), 6.36 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 6.16 (d, J = 1.9 Hz, 1H), 6.11 (d, J = 2.2 Hz, 1H), 4.43 (d, J = 6.0 Hz, 2H), 3.61 (s, 3H), 2.12 (s, 3H).

[0885] ESI-MS: 432.15 (M+H) + 。

[0886] N-[(3-Chlorophenyl)methyl]-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl}ox y)benzamide (186):

[0887]

[0888] Compound 186 as a white solid was synthesized from intermediate 119 g (0.15 mmol) and 3-chlorobenzylamine (0.23 mmol) according to General Method C2, with a yield of 13%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 8.96 (t, J = 6.0 Hz, 1H), 8.75 (s, 1H), 8.00 (d, J = 5.8 Hz, 1H), 7.41 - 7.36 (m, 3H), 7.34 - 7.30 (m, 3H), 7.27 (d, J = 1.9 Hz, 1H), 7.22 (dd, J = 7.8 Hz, 1.2 Hz, 1H), 6.36 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 6.16 (d, J = 1.9 Hz, 1H), 6.12 (d, J = 2.2 Hz, 1H), 4.46 (d, J = 6.0 Hz, 2H), 3.61 (s, 3H), 2.13 (s, 3H).

[0889] ESI-MS: 448.10 (M + H) + 。

[0890] N-[(4-Chlorophenyl)methyl]-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl}ox y)benzamide (187):

[0891]

[0892] Compound 187 as a white solid was synthesized from intermediate 119 g (0.15 mmol) and 4-chlorobenzylamine (0.23 mmol) according to general method C2 with a yield of 18%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.17 (s, 1H), 8.94 (t, J = 6.0 Hz, 1H), 8.75 (s, 1H), 8.00 (d, J = 5.8 Hz, 1H), 7.43 - 7.30 (m, 6H), 7.27 (d, J = 1.9 Hz, 1H), 7.21 (dd, J = 7.8 Hz, 1.3 Hz, 1H), 6.36 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 6.16 (d, J = 1.9 Hz, 1H), 6.11 (d, J = 2.2 Hz, 1H), 4.43 (d, J = 6.0 Hz, 2H), 3.61 (s, 3H), 2.12 (s, 3H).

[0893] ESI-MS: 448.15 (M + H) + 。

[0894] N-(Imidazo[1,2-a]pyridin-6-ylmethyl)-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amino]- 4-pyridyl}oxy)benzamide (188):

[0895]

[0896] Compound 188 as a white solid was synthesized from intermediate 119 g (0.15 mmol) and imidazo[1,2-a]pyridin-6-ylmethanamine (0.23 mmol) according to General Method C2 with a yield of 18%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.94 (t, J = 5.9 Hz, 1H), 8.75 (s, 1H), 8.50 (s, 1H), 7.99 (d, J = 5.8 Hz, 1H), 7.96 (s, 1H), 7.57 - 7.54 (m, 2H), 7.39 - 7.32 (m, 2H), 7.27 (d, J = 1.9 Hz, 1H), 7.26 - 7.20 (m, 2H), 6.35 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 6.16 (d, J = 1.9 Hz, 1H), 6.11 (d, J = 2.2 Hz, 1H), 4.44 (d, J = 5.8 Hz, 2H), 3.61 (s, 3H), 2.13 (s, 3H).

[0897] ESI-MS: 454.15 (M + H) + 。

[0898] N-(Imidazo[1,2-a]pyridin-7-ylmethyl)-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amino]- 4-pyridyl}oxy)benzamide (189):

[0899]

[0900] Compound 189 as a white solid was synthesized from intermediate 119 g (0.15 mmol) and imidazo[1,2-a]pyridin-7-ylmethanamine (0.23 mmol) according to General Method C2 with a yield of 13%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.0 Hz, 1H), 8.75 (s, 1H), 8.51 (d, J = 6.9 Hz, 1H), 8.00 (d, J = 5.8 Hz, 1H), 7.90 (s, 1H), 7.53 (d, J = 1.1 Hz, 1H), 7.44 (s, 1H), 7.41 - 7.34 (m, 2H), 7.27 (d, J = 1.9 Hz, 1H), 7.23 (dd, J = 7.3 Hz, 1.9 Hz, 1H), 6.88 (dd, J = 7.0 Hz, 1.6 Hz, 1H), 6.37 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 6.16 (d, J = 1.9 Hz, 1H), 6.12 (d, J = 2.2 Hz, 1H), 4.49 (d, J = 5.9 Hz, 2H), 3.61 (s, 3H), 2.15 (s, 3H).

[0901] ESI-MS: 454.15 (M + H)+ 。

[0902] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl} oxy)benzamide (190):

[0903]

[0904] According to the general method C2, compound 190 as a white solid was synthesized from intermediate 119 g (0.15 mmol) and 3,5-difluorobenzylamine (0.23 mmol) with a yield of 16%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.0 Hz, 1H), 8.75 (s, 1H), 8.00 (d, J = 5.8 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.27 (d, J = 1.9 Hz, 1H), 7.23 (dd, J = 7.4 Hz, 1.8 Hz, 1H), 7.13 (tt, J = 9.4 Hz, 2.3 Hz, 1H), 7.08 - 7.03 (m, 2H), 6.36 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 6.16 (d, J = 1.9 Hz, 1H), 6.12 (d, J = 2.1 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.61 (s, 3H), 2.13 (s, 3H).

[0905] ESI-MS: 450.10 (M + H) + 。

[0906] N-[(6-Methoxy-3-pyridyl)methyl]-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amino]-4-pyr idyl}oxy)benzamide (191):

[0907]

[0908] According to the general method C2, compound 191 as a white solid was synthesized from intermediate 119 g (0.15 mmol) and (6-methoxypyridin-3-yl)methylamine (0.23 mmol) with a yield of 15%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 8.88 (t, J = 6.0 Hz, 1H), 8.74 (s, 1H), 8.13 (d, J = 2.0 Hz, 1H), 7.99 (d, J = 5.8 Hz, 1H), 7.69 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 7.30 - 7.27 (m, 2H), 7.20 (dd, J = 7.9 Hz, 1.1 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.35 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 6.16 (d, J = 1.9 Hz, 1H), 6.11 (d, J = 2.2 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 3.83 (s, 3H), 3.61 (s, 3H), 2.11 (s, 3H).

[0909] ESI-MS: 445.15 (M + H) + 。

[0910] 2-Methyl-3-({2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)-N-{[6-(trifluoromethyl)- {[3-Pyridinyl]methyl}benzamide (192):

[0911]

[0912] Compound 192 as a white solid was synthesized from intermediate 119 g (0.15 mmol) and [6-(trifluoromethyl)-3-pyridinyl]methanamine (0.23 mmol) according to the general method C2 with a yield of 10%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.08 (t, J = 5.9 Hz, 1H), 8.77 (s, 2H), 8.04 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 5.8 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.40 - 7.35 (m, 2H), 7.27 (d, J = 1.8 Hz, 1H), 7.23 (dd, J = 6.8 Hz, 2.5 Hz, 1H), 6.36 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 6.16 (d, J = 1.8 Hz, 1H), 6.11 (d, J = 2.1 Hz, 1H), 4.58 (d, J = 5.8 Hz, 2H), 3.61 (s, 3H), 2.13 (s, 3H).

[0913] ESI-MS: 483.15 (M + H) + 。

[0914] N-[(5-Fluoro-3-pyridinyl)methyl]-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amino]-4-pyridin yl}oxy)benzamide (193):

[0915]

[0916] According to the general method C2, compound 193 as a white solid was synthesized from intermediate 119 g (0.09 mmol) and 5-fluoro-3-pyridinemethanamine (0.14 mmol) with a yield of 13%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 5.9 Hz, 1H), 8.75 (s, 1H), 8.49 (d, J = 2.8 Hz, 1H), 8.47 (s, 1H), 8.00 (d, J = 5.8 Hz, 1H), 7.69 - 7.65 (m, 1H), 7.40 - 7.34 (m, 2H), 7.27 (d, J = 1.9 Hz, 1H), 7.22 (dd, J = 7.2 Hz, 2.1 Hz, 1H), 6.36 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 6.16 (d, J = 1.9 Hz, 1H), 6.11 (d, J = 2.2 Hz, 1H), 4.52 (d, J = 5.9 Hz, 2H), 3.61 (s, 3H), 2.12 (s, 3H).

[0917] ESI-MS: 433.20 (M + H) + 。

[0918] N-[(5-Fluoro-6-methoxy-3-pyridinyl)methyl]-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amin o]-4-pyridinyl}oxy)benzamide (194):

[0919]

[0920] According to the general method C2, compound 194 as a white solid was synthesized from intermediate 119 g (0.09 mmol) and (5-fluoro-6-methoxy-3-pyridinyl)methanamine (0.14 mmol) with a yield of 19%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.91 (t, J = 5.9 Hz, 1H), 8.75 (s, 1H), 8.00 (d, J = 5.8 Hz, 1H), 7.97 (d, J = 1.7 Hz, 1H), 7.64 (dd, J = 11.4 Hz, 1.9 Hz, 1H), 7.38 - 7.30 (m, 2H), 7.27 (d, J = 1.9 Hz, 1H), 7.21 (dd, J = 7.8 Hz, 1.3 Hz, 1H), 6.35 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 6.16 (d, J = 1.9 Hz, 1H), 6.11 (d, J = 2.2 Hz, 1H), 4.41 (d, J = 5.8 Hz, 2H), 3.93 (s, 3H), 3.61 (s, 3H), 2.11 (s, 3H).

[0921] ESI-MS: 463.25 (M+H) + 。

[0922] N-[(5-Fluoro-2-methoxy-3-pyridinyl)methyl]-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amin o]-4-pyridinyl}oxy)benzamide (195):

[0923]

[0924] According to the general method C2, compound 195 as a white solid was synthesized from intermediate 119 g (0.09 mmol) and 5-fluoro-2-methoxy-3-pyridinemethanamine (0.14 mmol) with a yield of 14%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.85 (t, J = 5.7 Hz, 1H), 8.75 (s, 1H), 8.07 (d, J = 3.0 Hz, 1H), 8.00 (d, J = 5.8 Hz, 1H), 7.55 (dd, J = 8.6 Hz, 3.0 Hz, 1H), 7.40 - 7.35 (m, 2H), 7.27 (d, J = 1.9 Hz, 1H), 7.25 - 7.20 (m, 1H), 6.36 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 6.16 (d, J = 1.9 Hz, 1H), 6.12 (d, J = 2.2 Hz, 1H), 4.38 (d, J = 5.7 Hz, 2H), 3.91 (s, 3H), 3.61 (s, 3H), 2.14 (s, 3H).

[0925] ESI-MS: 463.25 (M+H) + 。

[0926] N-[(5-Fluoro-6-methoxy-3-pyridinyl)methyl]-2-methyl-3-({2-[(2-methyl-1,2,3-triazol-4-yl)amin o]-4-pyridinyl}oxy)benzamide (350):

[0927]

[0928] According to the general method C2, compound 350 as a white solid was synthesized from intermediate 119 l (0.08 mmol) and (5-fluoro-6-methoxy-3-pyridyl)methanamine (0.12 mmol) with a yield of 56%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 9.59 (s, 1H), 8.90 (t, J = 5.8 Hz, 1H), 8.06 (d, J = 5.9 Hz, 1H), 7.97 (s, 1H), 7.80 (s, 1H), 7.68 - 7.61 (m, 1H), 7.38 - 7.30 (m, 2H), 7.21 - 7.18 (m, 1H), 6.47 (d, J = 2.2 Hz, 1H), 6.30 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 4.41 (d, J = 5.6 Hz, 2H), 4.00 (s, 3H), 3.93 (s, 3H), 2.11 (s, 3H).

[0929] ESI-MS: 464.05 (M+H) + 。

[0930] N-[(6-Methoxy-3-pyridinyl)methyl]-2-methyl-3-[(2-pyrazol-1-yl-4-pyridinyl)oxy]benz amide (196):

[0931]

[0932] Compound 196 as a white solid was synthesized from intermediate 119h (0.09 mmol) and 6-methoxypyridin-3-yl)methanamine (0.14 mmol) according to general method C2 with a yield of 53%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 5.9 Hz, 1H), 8.59 (d, J = 2.5 Hz, 1H), 8.37 (d, J = 5.7 Hz, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.75 (d, J = 1.1 Hz, 1H), 7.69 (dd, J = 8.5 Hz, 2.4 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.36 - 7.29 (m, 2H), 7.18 (d, J = 2.3 Hz, 1H), 6.93 (dd, J = 5.7 Hz, 2.3 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.55 - 6.54 (m, 1H), 4.38 (d, J = 5.9 Hz, 2H), 3.82 (s, 3H), 2.11 (s, 3H).

[0933] ESI-MS: 416.05 (M+H) + 。

[0934] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-[(2-pyrazol-1-yl-4-pyridinyl)oxy]benzamide (197)：

[0935]

[0936] Compound 197 as a white solid was synthesized from intermediate 119h (0.09 mmol) and 3,5-difluorobenzylamine (0.14 mmol) according to General Method D with a yield of 74%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.09 (s, 1H), 8.59 (d, J = 1.9 Hz, 1H), 8.37 (d, J = 5.6 Hz, 1H), 7.75 (s, 1H), 7.46 - 7.32 (m, 3H), 7.19 - 7.06 (m, 4H), 6.95 - 6.93 (m, 1H), 6.55 (s, 1H), 4.47 (d, J = 5.8 Hz, 2H), 2.14 (s, 3H).

[0937] ESI-MS: 421.05 (M + H) + 。

[0938] Example 7: General Procedure for the Synthesis of Analogues 200 - 247

[0939]

[0940] 3-[(2-Chloro-4-pyridinyl)oxy]-2-methyl-benzoic acid (198 ) Preparation :

[0941]

[0942] Intermediate 198 as a white solid was synthesized from 117a (1.37 mmol) in quantitative yield according to General Method B2.

[0943] The following table lists intermediate 199 prepared by Method C2:

[0944]

[0945] The following compounds are examples illustrating Method D2:

[0946] N-[(6-Methoxy-3-pyridinyl)methyl]-2-methyl-3-{[2-(4-pyridinyl)-4-pyridinyl]oxy}benz amide (200):

[0947]

[0948] Compound 200 as a white solid was synthesized from intermediate 199a (0.07 mmol) and pyridine-4-boronic acid hydrate (0.10 mmol) according to General Method D2 with a yield of 61%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 8.89 (t, J = 5.9 Hz, 1H), 8.70 - 8.68 (m, 2H), 8.59 (d, J = 5.6 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 8.02 - 8.00 (m, 2H), 7.71 - 7.68 (m, 2H), 7.39 (t, J = 7.8 Hz, 1H), 7.32 (dd, J = 7.6 Hz, 1.3 Hz, 1H), 7.25 (dd, J = 7.9 Hz, 1.2 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.76 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.39 (d, J = 5.9 Hz, 2H), 3.83 (s, 3H), 2.13 (s, 3H).

[0949] ESI-MS: 427.10 (M+H) + 。

[0950] N-[(6-Methoxy-3-pyridinyl)methyl]-2-methyl-3-{[2-(3-pyridinyl)-4-pyridinyl]oxy}benz amide (201):

[0951]

[0952] Compound 201 as a white solid was synthesized from intermediate 199a (0.07 mmol) and pyridine-3-boronic acid (0.10 mmol) according to the general method D2 with a yield of 61%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.21 (d, J = 1.6 Hz, 1H), 8.89 (t, J = 5.9 Hz, 1H), 8.64 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 8.56 (d, J = 5.7 Hz, 1H), 8.40 - 8.37 (m, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 7.63 (d, J = Hz 2.2, 1H), 7.51 (ddd, J = 8.0 Hz, 4.8 Hz, 0.7 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.32 (dd, J = 7.6 Hz, 1.3 Hz, 1H), 7.25 (dd, J = 7.9 Hz, 1.2 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.71 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.39 (d, J = 5.9 Hz, 2H), 3.83 (s, 3H), 2.13 (s, 3H).

[0953] ESI-MS: 427.10 (M+H) + 。

[0954] N-[(6-Methoxy-3-pyridinyl)methyl]-2-methyl-3-[(2-pyrimidin-5-yl-4-pyridinyl)oxy]benz amide (202):

[0955]

[0956] According to the general method D2, compound 202 as a white solid was synthesized from intermediate 199a (0.07 mmol) and pyrimidine-5-boronic acid (0.10 mmol) in a yield of 72%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.41 (s, 2H), 9.26 (s, 1H), 8.89 (t, J = 5.9 Hz, 1H), 8.59 (d, J = 5.7 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H), 7.70 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.32 (dd, J = 7.6 Hz, 1.3 Hz, 1H), 7.25 (dd, J = 7.9 Hz, 1.2 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.72 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.39 (d, J = 5.9 Hz, 2H), 3.83 (s, 3H), 2.13 (s, 3H).

[0957] ESI-MS: 428.05 (M+H) + 。

[0958] N-[(6-Methoxy-3-pyridinyl)methyl]-2-methyl-3-{[2-(2-methylpyrazol-3-yl)-4-pyridinyl] oxy}benzamide (203):

[0959]

[0960] According to the general method D2, compound 203 as a white solid was synthesized from intermediate 199a (0.07 mmol) and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (0.10 mmol) in a yield of 43%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 8.89 (t, J = 5.9 Hz, 1H), 8.53 (d, J = 5.7 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.69 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.32 - 7.30 (m, 2H), 7.24 (dd, J = 7.9 Hz, 1.2 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 6.71 (dd, J = 5.7 Hz, 2.5 Hz, 1H), 4.39 (d, J = 5.9 Hz, 2H), 4.11 (s, 3H), 3.83 (s, 3H), 2.12 (s, 3H).

[0961] ESI-MS: 430.10 (M+H) + 。

[0962] 3-{[2-(3,5-Dimethylisoxazol-4-yl)-4-pyridinyl]oxy}-N-[(6-methoxy-3-pyridinyl)meth yl]-2-methyl-benzamide (204):

[0963]

[0964] According to the general method D2, compound 204 as a white solid was synthesized from intermediate 199a (0.07 mmol) and 3,5-dimethylisoxazole-4-boronic acid pinacol ester (0.10 mmol) with a yield of 35%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.88 (t, J = 5.9 Hz, 1H), 8.52 (d, J = 5.7 Hz, 1H), 8.14 (d, J = 1.9 Hz, 1H), 7.69 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.31 (dd, J = 7.6 Hz, 1.3 Hz, 1H), 7.25 (dd, J = 7.9 Hz, 1.2 Hz, 1H), 6.99 (d, J = 2.2 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.73 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.39 (d, J = 5.9 Hz, 2H), 3.83 (s, 3H), 2.31 (s, 3H), 2.12 (s, 3H).

[0965] ESI-MS: 445.10 (M+H) + 。

[0966] 3-{[2-(1,3-Dimethylpyrazol-4-yl)-4-pyridinyl]oxy}-N-[(6-methoxy-3-pyridinyl)meth yl]-2-methyl-benzamide (205):

[0967]

[0968] According to the general method D2, the compound 205 as a white solid was synthesized from intermediate 199a (0.07 mmol) and 1,3-dimethyl-1H-pyrazole-4-boronic acid pinacol ester (0.10 mmol) with a yield of 86%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.88 (t, J = 5.9 Hz, 1H), 8.39 (d, J = 5.7 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 8.10 (s, 1H), 7.69 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.30 (dd, J = 7.6 Hz, 1.3 Hz, 1H), 7.21 (dd, J = 7.9 Hz, 1.2 Hz, 1H), 7.01 (d, J = 2.3 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.54 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.39 (d, J = 5.9 Hz, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 2.35 (s, 3H), 2.11 (s, 3H).

[0969] ESI-MS: 444.15 (M + H) + 。

[0970] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(4-pyridinyl)-4-pyridinyl]oxy}benzamide (206)：

[0971]

[0972] According to the general method D2, the compound 206 as a white solid was synthesized from intermediate 199b (0.08 mmol) and pyridine-4-boronic acid hydrate (0.12 mmol) with a yield of 67%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.03 (t, J = 6.0 Hz, 1H), 8.70 - 8.68 (m, 2H), 8.60 (d, J = 5.6 Hz, 1H), 8.03 - 8.01 (m, 2H), 7.73 (d, J = 2.3 Hz, 1H), 7.44 - 7.38 (m, 2H), 7.29 (dd, J = 7.1 Hz, 2.2 Hz, 1H), 7.13 (tt, J = 9.4 Hz, 2.3 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.77 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 2.15 (s, 3H).

[0973] ESI-MS: 432.20 (M+H) + 。

[0974] N -[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(3-pyridinyl)-4-pyridinyl]oxy}benzamide (207)：

[0975]

[0976] Compound 207 as a white solid was synthesized from intermediate 199b (0.07 mmol) and pyridine-3-boronic acid (0.12 mmol) according to general method D2 in 85% yield. 1 H NMR (500 MHz, DMSO-d6) δ (ppm): 9.22 (d, J = 1.7 Hz, 1H), 9.04 (t, J = 6.0 Hz, 1H), 8.64 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 8.57 (d, J = 5.7 Hz, 1H), 8.41 - 8.38 (m, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.51 (ddd, J = 8.0 Hz, 4.8 Hz, 0.7 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.28 (dd, J = 7.5 Hz, 1.8 Hz, 1H), 7.14 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.09 - 7.05 (m, 2H), 6.71 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 2.15 (s, 3H).

[0977] ESI-MS: 432.05 (M+H) + 。

[0978] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-[(2-pyrimidin-5-yl-4-pyridyl)oxy]benzamide (208):

[0979]

[0980] Compound 208 as a white solid was synthesized from intermediate 199b (0.08 mmol) and pyrimidine-5-boronic acid (0.12 mmol) according to general method D2 in 85% yield. 11H NMR (500 MHz, DMSO-d6) δ (ppm): 9.43 (s, 2H), 9.26 (s, 1H), 9.03 (t, J = 6.0 Hz, 1H), 8.60 (d, J = 5.7 Hz, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.28 (dd, J = 7.3 Hz, 2.0 Hz, 1H), 7.16 - 7.11 (m, 1H), 7.09 - 7.05 (m, 2H), 6.73 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 2.15 (s, 3H).

[0981] ESI-MS: 433.05 (M+H) + 。

[0982] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(2-methylpyrazol-3-yl)-4-pyridinyl]oxy} benzamide (209):

[0983]

[0984] Compound 209 as a white solid was synthesized from intermediate 199b (0.08 mmol) and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (0.12 mmol) according to the general method D2 with a yield of 45%. 1 1H NMR (500 MHz, DMSO-d6) δ (ppm): 9.04 (t, J = 6.1 Hz, 1H), 8.54 (d, J = 5.8 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.34 (d, J = 2.4 Hz, 1H), 7.27 (dd, J = 7.5 Hz, 1.8 Hz, 1H), 7.16 - 7.11 (m, 1H), 7.09 - 7.04 (m, 2H), 6.75 (d, J = 2.0 Hz, 1H), 6.71 (dd, J = 5.7 Hz, 2.5 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 4.12 (s, 3H), 2.14 (s, 3H).

[0985] ESI-MS: 435.15 (M+H) + 。

[0986] N-[(3,5-Difluorophenyl)methyl]-3-{[2-(3,5-dimethylisoxazol-4-yl)-4-pyridinyl]oxy}- 2-methyl-benzamide (210):

[0987]

[0988] Compound 210, a white solid, was synthesized from intermediate 199b (0.08 mmol) and 3,5-dimethylisoxazole-4-boronic acid pinacol ester (0.12 mmol) according to general method D2, with a yield of 35%. 1 H NMR (500 MHz, DMSO-d6) δ (ppm): 9.02 (t, J = 6.0 Hz, 1H), 8.53 (d, J = 5.7 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.29 (dd, J = 7.4 Hz, 1.9 Hz, 1H), 7.14 - 7.11 (m, 1H), 7.08 - 7.04 (m, 2H), 7.00 (d, J = 2.3 Hz, 1H), 6.74 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 2.31 (s, 3H), 2.14 (s, 3H).

[0989] ESI-MS: 450.20 (M + H) + 。

[0990] N-[(3,5-Difluorophenyl)methyl]-3-{[2-(1,3-dimethylpyrazol-4-yl)-4-pyridinyl]oxy}-2- methyl-benzamide (211):

[0991]

[0992] Compound 211, a white solid, was synthesized from intermediate 199b (0.08 mmol) and 1,3-dimethyl-1H-pyrazole-4-boronic acid pinacol ester (0.12 mmol) according to general method D2, with a yield of 80%. 1 H NMR (500 MHz, DMSO-d6) δ (ppm): 9.02 (t, J = 6.0 Hz, 1H), 8.40 (d, J = 5.7 Hz, 1H), 8.12 (s, 1H), 7.41 - 7.35 (m, 2H), 7.24 (dd, J = 7.5 Hz, 1.8 Hz, 1H), 7.14 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.08 - 7.04 (m, 2H), 7.03 (d, J = 2.3 Hz, 1H), 6.55 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.77 (s, 3H), 2.35 (s, 3H), 2.13 (s, 3H).

[0993] ESI-MS: 449.90 (M + H) + 。

[0994] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-3-yl)-4-pyridinyl]oxy} benzamide (212):

[0995]

[0996] According to the general method D2, the white solid compound 212 was synthesized from intermediate 199b (0.06 mmol) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.10 mmol) with a yield of 64%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.07 (t, J = 6.0 Hz, 1H), 8.46 (d, J = 5.7 Hz, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.44 - 7.38 (m, 2H), 7.27 (dd, J = 7.4 Hz, 1.8 Hz, 1H), 7.20 (d, J = 2.5 Hz, 1H), 7.13 (tt, J = 9.4 Hz, 2.3 Hz, 1H), 7.10 - 7.04 (m, 2H), 6.89 (dd, J = 5.7 Hz, 2.5 Hz, 1H), 6.77 (d, J = 2.2 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.85 (s, 3H), 2.13 (s, 3H).

[0997] ESI-MS: 435.10 (M + H) + .

[0998] N-[(3,5-Difluorophenyl)methyl]-3-{[2-(1,5-dimethylpyrazol-4-yl)-4-pyridinyl]oxy}-2- methyl-benzamide (213):

[0999]

[1000] According to the general method D2, the white solid compound 213 was synthesized from intermediate 199b (0.07 mmol) and 1,3-dimethyl-1H-pyrazole-4-boronic acid pinacol ester (0.10 mmol) with a yield of 70%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 6.0 Hz, 1H), 8.40 (d, J = 5.8 Hz, 1H), 7.81 (s, 1H), 7.41 - 7.35 (m, 2H), 7.23 (dd, J = 7.4 Hz, 1.9 Hz, 1H), 7.16 - 7.04 (m, 4H), 6.51 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.76 (s, 3H), 2.55 (s, 3H), 2.14 (s, 3H).

[1001] ESI-MS: 449.20 (M + H) + .

[1002] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(1H-pyrazol-4-yl)-4-pyridinyl]oxy}benzamide (214):

[1003]

[1004] According to the general method D2, the white solid compound 214 was synthesized from intermediate 199b (0.07 mmol) and 1H-pyrazole-4-boronic acid pinacol ester (0.10 mmol) in a yield of 41%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 13.06 (bs, 1H), 8.99 (t, J = 6.0 Hz, 1H), 8.36 (d, J = 5.8 Hz, 1H), 8.17 (bs, 2H), 7.41 - 7.33 (m, 3H), 7.22 (dd, J = 7.4 Hz, 1.9 Hz, 1H), 7.13 (tt, J = 9.5 Hz, 2.4 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.46 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 2.15 (s, 3H).

[1005] ESI-MS: 421.10 (M + H) + 。

[1006] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(1-tetrahydropyran-4-ylpyrazol-4-yl)-4-pyridin yl]oxy}benzamide (215):

[1007]

[1008] According to the general method D2, the white solid compound 215 was synthesized from intermediate 199b (0.07 mmol) and 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.10 mmol) in a yield of 42%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.0 Hz, 1H), 8.37 - 8.35 (m, 2H), 8.00 (s, 1H), 7.42 - 7.34 (m, 2H), 7.30 (d, J = 2.3 Hz, 1H), 7.22 (dd, J = 7.3 Hz, 1.8 Hz, 1H), 7.16 - 7.04 (m, 3H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 - 4.38 (m, 3H), 3.98 - 3.94 (m, 2H), 3.50 - 3.43 (m, 2H), 2.14 (s, 3H), 2.00 - 1.91 (m, 4H).

[1009] ESI-MS: 505.20 (M + H)+ 。

[1010] 3-{[2-(1-Cyclopropylpyrazol-4-yl)-4-pyridinyl]oxy}-N-[(3,5-difluorophenyl)methyl]-2-meth yl-benzamide (216):

[1011]

[1012] Compound 216 as a white solid was synthesized from intermediate 199b (0.07 mmol) and 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.10 mmol) according to general method D2 in 63% yield. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.0 Hz, 1H), 8.36 - 8.35 (m, 2H), 7.96 (d, J = 0.6 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.30 (d, J = 2.4 Hz, 1H), 7.22 (dd, J = 7.2 Hz, 2.1 Hz, 1H), 7.13 - 7.04 (m, 3H), 6.47 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.79 - 3.74 (m, 1H), 2.14 (s, 3H), 1.10 - 0.95 (m, 4H).

[1013] ESI-MS: 461.20 (M + H) + 。

[1014] 3-({2-[1-(Difluoromethyl)pyrazol-4-yl]-4-pyridinyl}oxy)-N-[(3,5-difluorophenyl)methyl]- 2-methyl-benzamide (217):

[1015]

[1016] Compound 217 as a white solid was synthesized from intermediate 199b (0.06 mmol) and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.10 mmol) according to general method D2 in 100% yield. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.0 Hz, 1H), 8.82 (s, 1H), 8.43 (d, J = 5.7 Hz, 1H), 8.35 (s, 1H), 7.85 (t, J = 59.0 Hz, 1H), 7.49 (d, J = 2.3 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.24 (dd, J = 7.2 Hz, 2.2 Hz, 1H), 7.16 - 7.04 (m, 3H), 6.57 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 2.15 (s, 3H).

[1017] ESI-MS: 471.20 (M+H) + 。

[1018] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-[(2-phenyl-4-pyridinyl)oxy]benzamide (218):

[1019]

[1020] Compound 218 as a white solid was synthesized from intermediate 199b (0.05 mmol) and phenylboronic acid (0.08 mmol) according to the general method D2, with a yield of 82%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.0 Hz, 1H), 8.54 (d, J = 5.8 Hz, 1H), 8.03 - 8.01 (m, 2H), 7.50 - 7.36 (m, 6H), 7.27 (dd, J = 7.4 Hz, 1.9 Hz, 1H), 7.16 - 7.09 (m, 1H), 7.08 - 7.04 (m, 2H), 6.71 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 2.16 (s, 3H).

[1021] ESI-MS: 431.05 (M+H) + 。

[1022] N-[(3,5-Difluorophenyl)methyl]-3-{[2-(2-fluorophenyl)-4-pyridyl]oxy}-2-methyl-benzamide (219):

[1023]

[1024] Compound 219 as a white solid was synthesized from intermediate 199b (0.05 mmol) and 2-fluorophenylboronic acid (0.08 mmol) according to the general method D2, with a yield of 74%. 11H NMR (600 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 6.1 Hz, 1H), 8.60 - 8.58 (m, 1H), 7.93 (td, J = 7.9 Hz, 1.8 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.42 - 7.37 (m, 2H), 7.34 - 7.27 (m, 3H), 7.23 - 7.22 (m, 1H), 7.12 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.08 - 7.04 (m, 2H), 6.86 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 2.15 (s, 3H).

[1025] ESI-MS: 449.05 (M + H) + 。

[1026] N-[(3,5-Difluorophenyl)methyl]-3-{[2-(3-fluorophenyl)-4-pyridinyl]oxy}-2-methyl-benzamide (220):

[1027]

[1028] Compound 220 as a white solid was synthesized from intermediate 199b (0.05 mmol) and 3-fluorobenzeneboronic acid (0.08 mmol) according to the general method D2, with a yield of 83%. 1 1H NMR (600 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 6.1 Hz, 1H), 8.55 - 8.54 (m, 1H), 7.90 - 7.85 (m, 2H), 7.61 - 7.60 (m, 1H), 7.54 - 7.51 (m, 1H), 7.42 - 7.37 (m, 2H), 7.30 - 7.26 (m, 2H), 7.12 (tt, J = 9.3 Hz, 2.4 Hz, 1H), 7.08 - 7.05 (m, 2H), 6.71 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 2.16 (s, 3H).

[1029] ESI-MS: 449.05 (M + H) + 。

[1030] N-[(3,5-Difluorophenyl)methyl]-3-{[2-(4-fluorophenyl)-4-pyridinyl]oxy}-2-methyl-benzamide (221):

[1031]

[1032] Compound 221 as a white solid was synthesized from Intermediate 199b (0.05 mmol) and 4-fluorophenylboronic acid (0.08 mmol) according to General Method D2 in a yield of 91%. 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 6.0 Hz, 1H), 8.52 (d, J = 5.7 Hz, 1H), 8.10 - 8.07 (m, 2H), 7.50 (d, J = 2.3 Hz, 1H), 7.42 - 7.3 (m, 2H), 7.31 - 7.25 (m, 3H), 7.12 (tt, J = 9.3 Hz, 2.4 Hz, 1H), 7.08 - 7.05 (m, 2H), 6.69 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 2.16 (s, 3H).

[1033] ESI-MS: 449.05 (M + H) + 。

[1034] N-[(3,5-Difluorophenyl)methyl]-3-{[2-(2-methoxyphenyl)-4-pyridinyl]oxy}-2-methyl-benz amide (222):

[1035]

[1036] Compound 222 as a white solid was synthesized from Intermediate 199b (0.05 mmol) and 2-methoxyphenylboronic acid (0.08 mmol) according to General Method D2 in a yield of 75%. 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 6.1 Hz, 1H), 8.53 (dd, J = 5.7 Hz, 0.4 Hz, 1H), 7.78 (dd, J = 7.7 Hz, 1.8 Hz, 1H), 7.42 - 7.36 (m, 3H), 7.27 - 7.25 (m, 2H), 7.14 - 7.02 (m, 5H), 6.85 (dd, J = 5.7 Hz, 2.5 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.74 (s, 3H), 2.15 (s, 3H).

[1037] ESI-MS: 461.05 (M + H) + 。

[1038] N-[(3,5-Difluorophenyl)methyl]-3-{[2-(3-methoxyphenyl)-4-pyridinyl]oxy}-2-methyl-benz amide (223):

[1039]

[1040] According to the general method D2, the white solid compound 223 was synthesized from intermediate 199b (0.05 mmol) and 3-methoxyphenylboronic acid (0.08 mmol) with a yield of 84%. 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 6.0 Hz, 1H), 8.53 (d, J = 5.6 Hz, 1H), 7.60 - 7.59 (m, 1H), 7.57 (dd, J = 7.7 Hz, 0.9 Hz, 1H), 7.51 (d, J = 2.3 Hz, 1H), 7.42 - 7.37 (m, 3H), 7.26 (d, J = 7.7 Hz, 1H), 7.14 - 7.10 (m, 1H), 7.08 - 7.05 (m, 2H), 7.02 - 7.00 (m, 1H), 6.70 - 6.68 (m, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.82 (s, 3H), 2.16 (s, 3H).

[1041] ESI-MS: 461.05 (M + H) + 。

[1042] N-[(3,5-Difluorophenyl)methyl]-3-{[2-(4-methoxyphenyl)-4-pyridinyl]oxy}-2-methyl-benz amide (224):

[1043]

[1044] According to the general method D2, the white solid compound 224 was synthesized from intermediate 199b (0.05 mmol) and 4-methoxyphenylboronic acid (0.08 mmol) with a yield of 92%. 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 6.1 Hz, 1H), 8.48 - 8.47 (m, 1H), 8.00 - 7.97 (m, 2H), 7.41 - 7.36 (m, 3H), 7.26 (dd, J = 7.7 Hz, 1.4 Hz, 1H), 7.12 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.08 - 7.05 (m, 2H), 7.03 - 7.00 (m, 2H), 6.63 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.81 (s, 3H), 2.15 (s, 3H).

[1045] ESI-MS: 461.05 (M + H) + 。

[1046] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(o-tolyl)-4-pyridinyl]oxy}benzoyl amide (225):

[1047]

[1048] Compound 225 as a white solid was synthesized from Intermediate 199b (0.05 mmol) and o-tolylboronic acid (0.08 mmol) according to General Method D2 in 83% yield. 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.0 Hz, 1H), 8.54 (dd, J = 5.7 Hz, 0.5 Hz, 1H), 7.41 - 7.23 (m, 7H), 7.12 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.07 - 7.04 (m, 2H), 6.86 (dd, J = 2.5 Hz, 0.5 Hz, 1H), 6.84 (dd, J = 5.7 Hz, 2.5 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 2.27 (s, 3H), 2.15 (s, 3H).

[1049] ESI-MS: 445.05 (M + H) + 。

[1050] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(m-tolyl)-4-pyridyl]oxy}benzamide (226):

[1051]

[1052] Compound 226 as a white solid was synthesized from Intermediate 199b (0.05 mmol) and 3-tolylboronic acid (0.08 mmol) according to General Method D2 in 83% yield. 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 6.1 Hz, 1H), 8.52 (dd, J = 5.7 Hz, 0.4 Hz, 1H), 7.87 (s, 1H), 7.79 (d, J = 7 Hz.8, 1H), 7.48 - 7.46 (m, 1H), 7.42 - 7.34 (m, 3H), 7.27 - 7.24 (m, 2H), 7.12 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.08 - 7.05 (m, 2H), 6.69 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 2.38 (s, 3H), 2.16 (s, 3H).

[1053] ESI-MS: 445.05 (M + H) + 。

[1054] N -[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-( p-tolu yl)-4-pyridinyl]oxy}benzoyl amide (227):

[1055]

[1056] According to the general method D2, the compound 227 as a white solid was synthesized from the intermediate 199b (0.05 mmol) and 4-tolylboronic acid (0.08 mmol) in a yield of 91%. 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 6.1 Hz, 1H), 8.51 - 8.50 (m, 1H), 7.92 - 7.91 (m, 2H), 7.44 (d, J = 2.0 Hz, 1H), 7.42 - 7.36 (m, 2H), 7.29 - 7.25 (m, 3H), 7.12 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.08 - 7.05 (m, 2H), 6.67 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 2.35 (s, 3H), 2.15 (s, 3H).

[1057] ESI-MS: 445.05 (M + H) + .

[1058] The following compounds are examples illustrating method H:

[1059] N-[(6-Methoxy-3-pyridinyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-4-yl)amino]-4-pyr idinyl}oxy)benzamide (228):

[1060]

[1061] According to the general method H, the compound 228 as a white solid was synthesized from the intermediate 199a (0.09 mmol) and 1-methyl-1H-pyrazol-4-ylamine (0.18 mmol) in a yield of 54%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.89 (t, J = 5.9 Hz, 1H), 8.74 (s, 1H), 8.13 (d, J = 2.3 Hz, 1H), 7.98 (d, J = 5.8 Hz, 1H), 7.86 (s, 1H), 7.69 (dd, J = 8.5 Hz, 2.4 Hz, 1H), 7.37 - 7.26 (m, 3H), 7.18 (dd, J = 7.9 Hz, 1.0 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.23 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 5.93 (d, J = 2.2 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 2.10 (s, 3H).

[1062] ESI-MS: 445.25 (M+H) + 。

[1063] N-[(6-Methoxy-3-pyridinyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-3-yl)amino]-4-pyr idinyl}oxy)benzamide (229):

[1064]

[1065] Compound 229 as a white solid was synthesized from intermediate 199a (0.09 mmol) and 1-methylpyrazol-3-amine (0.18 mmol) according to General Method H with a yield of 44%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.18 (s, 1H), 8.89 (t, J = 5.9 Hz, 1H), 8.13 (d, J = 2.3 Hz, 1H), 7.97 (d, J = 5.8 Hz, 1H), 7.69 (dd, J = 8.5 Hz, 2.4 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.27 (dd, J = 7.6 Hz, 1.1 Hz, 1H), 7.17 (dd, J = 7.9 Hz, 1.0 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.17 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 6.14 (d, J = 2.2 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 3.83 (s, 3H), 3.67 (s, 3H), 2.11 (s, 3H).

[1066] ESI-MS: 445.90 (M+H) + 。

[1067] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-4-yl)amino]-4-pyridinyl} oxy)benzamide (230):

[1068]

[1069] Compound 230 as a white solid was synthesized from intermediate 199b (0.08 mmol) and 1-methyl-1H-pyrazol-4-ylamine (0.15 mmol) according to General Method H with a yield of 72%. 11H NMR (500 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.1 Hz, 1H), 8.76 (s, 1H), 7.99 (d, J = 5.8 Hz, 1H), 7.87 (s, 1H), 7.39 - 7.33 (m, 2H), 7.31 (d, J = 0.6 Hz, 1H), 7.21 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.16 - 7.11 (m, 1H), 7.08 - 7.03 (m, 2H), 6.24 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 5.93 (d, J = 2.2 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.76 (s, 3H), 2.12 (s, 3H).

[1070] ESI-MS: 450.25 (M + H) + 。

[1071] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-3-yl)amino]-4-pyridinyl} oxy)benzamide (231):

[1072]

[1073] Compound 231 as a white solid was synthesized from intermediate 199b (0.08 mmol) and 1-methylpyrazol-3-amine (0.15 mmol) according to general method H with a yield of 63%. 1 1H NMR (500 MHz, DMSO-d6) δ (ppm): 9.21 (s, 1H), 9.01 (t, J = 6.1 Hz, 1H), 7.98 (d, J = 5.8 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.39 - 7.33 (m, 2H), 7.20 (dd, J = 7.7 Hz, 1.5 Hz, 1H), 7.15 - 7.11 (m, 1H), 7.08 - 7.04 (m, 2H), 6.88 (d, J = 1.6 Hz, 1H), 6.18 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 6.14 (d, J = 2.1 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.67 (s, 3H), 2.13 (s, 3H).

[1074] ESI-MS: 450.25 (M + H) + 。

[1075] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(2-pyridinylamino)-4-pyridinyl]oxy}benz amide (232):

[1076]

[1077] Compound 232 as a white solid was synthesized from intermediate 199b (0.10 mmol) and 2-aminopyridine (0.20 mmol) according to general method H, with a yield of 33%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.70 (s, 1H), 9.01 (t, J = 6.1 Hz, 1H), 8.15 - 8.13 (m, 1H), 8.10 (d, J = 5.8 Hz, 1H), 7.65 - 7.59 (m, 2H), 7.43 (d, J = 2.3 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.22 (dd, J = 7.3 Hz, 2.0 Hz, 1H), 7.13 (tt, J = 9.3 Hz, 2.3 Hz, 1H), 7.08 - 7.04 (m, 2H), 6.85 - 6.82 (m, 1H), 6.32 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 2.15 (s, 3H).

[1078] ESI-MS: 447.15 (M + H) + 。

[1079] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(4-pyridinylamino)-4-pyridinyl]oxy}benz amide (233):

[1080]

[1081] Compound 233 as a white solid was synthesized from intermediate 199b (0.10 mmol) and 4-aminopyridine (0.20 mmol) according to general method H, with a yield of 44%. 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 9.48 (s, 1H), 8.98 (t, J = 6.0 Hz, 1H), 8.27 (d, J = 6.4 Hz, 2H), 8.17 (d, J = 5.8 Hz, 1H), 7.61 - 7.60 (m, 2H), 7.42 - 7.37 (m, 2H), 7.26 (dd, J = 7.5 Hz, 1.6 Hz, 1H), 7.13 (tt, J = 9.4 Hz, 2.3 Hz, 1H), 7.08 - 7.04 (m, 2H), 6.55 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 6.21 (d, J = 2.2 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 2.14 (s, 3H).

[1082] ESI-MS: 447.15 (M + H) + 。

[1083] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(pyrimidin-2-ylamino)-4-pyridinyl]oxy}benz amide (234):

[1084]

[1085] Compound 234 as a white solid was synthesized from intermediate 199b (0.08 mmol) and pyrimidin-2-amine (0.17 mmol) according to general method H with a yield of 32%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.87 (s, 1H), 9.00 (t, J = 6.1 Hz, 1H), 8.51 (s, 1H), 8.50 (s, 1H), 8.14 (d, J = 5.7 Hz, 1H), 7.95 (d, J = 2.1 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.23 (dd, J = 7.4 Hz, 1.8 Hz, 1H), 7.13 (tt, J = 9.5 Hz, 2.4 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.93 (t, J = 4.8 Hz, 1H), 6.37 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 2.15 (s, 3H).

[1086] ESI-MS: 448.05 (M + H) + 。

[1087] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(pyrimidin-4-ylamino)-4-pyridinyl]oxy}benz amide (235):

[1088]

[1089] Compound 235 as a white solid was synthesized from intermediate 199b (0.08 mmol) and 4-aminopyrimidine (0.17 mmol) according to general method H with a yield of 50%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.21 (s, 1H), 9.00 (t, J = 6.1 Hz, 1H), 8.65 (d, J = 0.8 Hz, 1H), 8.41 - 8.39 (m, 1H), 8.18 (d, J = 5.8 Hz, 1H), 7.70 (dd, J = 5.9 Hz, 1.2 Hz, 1H), 7.42 - 7.34 (m, 3H), 7.24 (dd, J = 7.1 Hz, 2.2 Hz, 1H), 7.12 (tt, J = 9.5 Hz, 2.4 Hz, 1H), 7.09 - 7.03 (m, 2H), 6.47 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 2.14 (s, 3H).

[1090] ESI-MS: 448.05 (M + H)+ .

[1091] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(pyrimidin-5-ylamino)-4-pyridinyl]oxy}benz amide (236):

[1092]

[1093] Compound 236 as a white solid was synthesized from intermediate 199b (0.08 mmol) and 5-aminopyrimidine (0.17 mmol) according to general method H, with a yield of 19%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.40 (s, 1H), 9.08 (s, 2H), 8.99 (t, J = 6.0 Hz, 1H), 8.69 (s, 1H), 8.13 (d, J = 5.8 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.26 (dd, J = 7.3 Hz, 2.0 Hz, 1H), 7.13 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.09 - 7.03 (m, 2H), 6.53 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 6.15 (d, J = 2.1 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 2.14 (s, 3H).

[1094] ESI-MS: 448.05 (M + H) + .

[1095] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(1H-pyrazol-3-ylamino)-4-pyridinyl]oxy} benzamide (237):

[1096]

[1097] Compound 237 as a white solid was synthesized from intermediate 199b (0.08 mmol) and 3-aminopyrazole (0.17 mmol) according to general method H, with a yield of 17%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 12.00 (bs, 1H), 9.22 (s, 1H), 8.98 (t, J = 6.0 Hz, 1H), 8.00 (d, J = 5.8 Hz, 1H), 7.51 (d, J = 1.7 Hz, 1H), 7.39 - 7.31 (m, 2H), 7.21 - 7.03 (m, 4H), 6.83 (bs, 1H), 6.18 (dd, J = 5.6 Hz, 1.8 Hz, 2H), 4.47 (d, J = 6.0 Hz, 2H), 2.14 (s, 3H).

[1098] ESI-MS: 436.00 (M + H) + .

[1099] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[(1-methyl-1,2,4-triazol-3-yl)amino]-4- pyridinyl}oxy)benzamide (238):

[1100]

[1101] According to general method H, compound 238 as a white solid was synthesized from intermediate 199b (0.08 mmol) and 1-methyl-1H-1,2,4-triazol-3-amine (0.17 mmol) with a yield of 77%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.63 (s, 1H), 8.98 (t, J = 6.0 Hz, 1H), 8.20 (s, 1H), 8.04 (d, J = 5.7 Hz, 1H), 7.51 (d, J = 2.2 Hz, 1H), 7.40 - 7.33 (m, 2H), 7.20 (dd, J = 7.4 Hz, 1.8 Hz, 1H), 7.12 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.10 - 7.03 (m, 2H), 6.21 (dd, J = 5.7 Hz, 2.3 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.73 (s, 3H), 2.14 (s, 3H).

[1102] ESI-MS: 451.05 (M + H) + 。

[1103] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[(2-methyltriazol-4-yl)amino]-4-pyridinyl} oxy)benzamide (239):

[1104]

[1105] According to general method H, compound 239 as a white solid was synthesized from intermediate 199b (0.08 mmol) and 2-methyltriazol-4-amine (0.15 mmol) with a yield of 57%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.61 (s, 1H), 8.99 (t, J = 6.0 Hz, 1H), 8.06 (d, J = 5.8 Hz, 1H), 7.81 (s, 1H), 7.41 - 7.34 (m, 2H), 7.21 (dd, J = 7.3 Hz, 2.0 Hz, 1H), 7.13 (tt, J = 9.4 Hz, 2.3 Hz, 1H), 7.08 - 7.03 (m, 2H), 6.48 (d, J = 2.2 Hz, 1H), 6.31 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 4.00 (s, 3H), 2.14 (s, 3H).

[1106] ESI-MS: 451.10 (M+H) + 。

[1107] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[(1-methyltriazol-4-yl)amino]-4-pyridinyl} oxy)benzamide (240):

[1108]

[1109] Compound 240 as a white solid was synthesized from intermediate 199b (0.08 mmol) and 1-methyl-1,2,3-triazol-4-amine (0.15 mmol) according to General Method H with a yield of 30%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.63 (s, 1H), 8.98 (t, J = 6.0 Hz, 1H), 8.10 (s, 1H), 8.05 (d, J = 5.8 Hz, 1H), 7.40 - 7.34 (m, 2H), 7.20 (dd, J = 7.3 Hz, 2.0 Hz, 1H), 7.13 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.09 - 7.03 (m, 2H), 6.36 (d, J = 2.2 Hz, 1H), 6.29 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 4.00 (s, 3H), 2.14 (s, 3H).

[1110] ESI-MS: 451.10 (M+H) + 。

[1111] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(2-methylaniline)-4-pyridinyl]oxy}benzoyl amide (241):

[1112]

[1113] Compound 241 as a white solid was synthesized from intermediate 199b (0.06 mmol) and o-toluidine (0.13 mmol) according to General Method H with a yield of 64%. 11H NMR (600 MHz, DMSO-d6) δ (ppm): 8.96 (t, J = 6.1 Hz, 1H), 8.15 (s, 1H), 7.94 (d, J = 5.7 Hz, 1H), 7.51 (dd, J = 8.0 Hz, 0.9 Hz, 1H), 7.38 - 7.32 (m, 2H), 7.21 (dd, J = 7.8 Hz, 1.3 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.14 - 7.08 (m, 2H), 7.07 - 7.03 (m, 2H), 6.95 (td, J = 7.4 Hz, 1.2 Hz, 1H), 6.25 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 6.11 (d, J = 2.2 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 2.17 (s, 3H), 2.14 (s, 3H).

[1114] ESI-MS: 460.05 (M + H) + 。

[1115] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(3-methylaniline)-4-pyridinyl]oxy}benzoyl amide (242):

[1116]

[1117] Compound 242 as a white solid was synthesized from intermediate 199b (0.06 mmol) and m-toluidine (0.13 mmol) according to general method H with a yield of 74%. 1 1H NMR (600 MHz, DMSO-d6) δ (ppm): 8.97 (t, J = 6.1 Hz, 1H), 8.89 (s, 1H), 8.05 (d, J = 5.8 Hz, 1H), 7.41 - 7.35 (m, 4H), 7.23 (dd, J = 7.7 Hz, 1.4 Hz, 1H), 7.14 - 7.04 (m, 4H), 6.69 - 6.67 (m, 1H), 6.37 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 6.12 (d, J = 2.2 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 2.24 (s, 3H), 2.15 (s, 3H).

[1118] ESI-MS: 460.10 (M + H) + 。

[1119] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(4-methylaniline)-4-pyridinyl]oxy}benzoyl amide (243):

[1120]

[1121] Compound 243 as a white solid was synthesized from intermediate 199b (0.06 mmol) and p-toluidine (0.13 mmol) according to general method H, with a yield of 74%. 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 8.97 (t, J = 6.1 Hz, 1H), 8.85 (s, 1H), 8.02 (d, J = 5.8 Hz, 1H), 7.49 - 7.46 (m, 2H), 7.40 - 7.34 (m, 2H), 7.22 (dd, J = 7.8 Hz, 1.4 Hz, 1H), 7.12 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.08 - 7.04 (m, 2H), 7.02 (d, J = 8.1 Hz, 2H), 6.34 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 6.09 (d, J = 2.2 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 2.22 (s, 3H), 2.14 (s, 3H).

[1122] ESI-MS: 460.10 (M + H) + 。

[1123] N-[(3,5-Difluorophenyl)methyl]-3-{[2-(2-methoxyaniline)-4-pyridinyl]oxy}-2-methyl-ben zamide (244):

[1124]

[1125] Compound 244 as a white solid was synthesized from intermediate 199b (0.06 mmol) and o-anisidine (0.13 mmol) according to general method H, with a yield of 47%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.96 (t, J = 6.1 Hz, 1H), 8.15 (s, 1H), 8.11 (dd, J = 7.8 Hz, 1.7 Hz, 1H), 8.00 (d, J = 5.8 Hz, 1H), 7.40 - 7.33 (m, 2H), 7.20 (dd, J = 7.4 Hz, 1.9 Hz, 1H), 7.13 (tt, J = 9.4 Hz, 2.3 Hz, 1H), 7.09 - 7.03 (m, 2H), 6.98 - 6.83 (m, 3H), 6.39 (d, J = 2.2 Hz, 1H), 6.31 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.79 (s, 3H), 2.14 (s, 3H).

[1126] ESI-MS: 476.10 (M + H) + 。

[1127] N-[(3,5-Difluorophenyl)methyl]-3-{[2-(3-methoxyaniline)-4-pyridinyl]oxy}-2-methyl-benzamide (245):

[1128]

[1129] Compound 245 as a white solid was synthesized from intermediate 199b (0.06 mmol) and m-anisidine (0.13 mmol) according to general method H, with a yield of 84%. 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 8.98 - 8.96 (m, 2H), 8.06 (d, J = 5.8 Hz, 1H), 7.41 - 7.35 (m, 3H), 7.23 (dd, J = 7.7 Hz, 1.4 Hz, 1H), 7.14 - 7.09 (m, 3H), 7.08 - 7.04 (m, 2H), 6.45 (dt, J = 6.7 Hz, 2.4 Hz, 1H), 6.39 (dd, J = 5.8 Hz, 2.3 Hz, 1H), 6.12 (d, J = 2.2 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.70 (s, 3H), 2.14 (s, 3H).

[1130] ESI-MS: 476.10 (M + H) + 。

[1131] N-[(3,5-Difluorophenyl)methyl]-3-{[2-(4-methoxyaniline)-4-pyridinyl]oxy}-2-methyl-benzene carboxamide (246):

[1132]

[1133] Compound 246 as a white solid was synthesized from intermediate 199b (0.06 mmol) and p-anisidine (0.13 mmol) according to general method H, with a yield of 81%. 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 8.97 (t, J = 6.1 Hz, 1H), 8.75 (s, 1H), 7.99 (d, J = 5.8 Hz, 1H), 7.59 - 7.46 (m, 2H), 7.40 - 7.34 (m, 2H), 7.22 (dd, J = 7.8 Hz, 1.4 Hz, 1H), 7.12 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.08 - 7.04 (m, 2H), 6.84 - 6.81 (m, 2H), 6.30 (dd, J = 5.8 Hz, 2.2 Hz, 1H), 6.04 (d, J = 2.2 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.69 (s, 3H), 2.14 (s, 3H).

[1134] ESI-MS: 476.10 (M + H) + 。

[1135] N-[(3,5-Difluorophenyl)methyl]-3-({2-[(6-methoxy-2-pyridinyl)amino]-4-pyridinyl}oxy )-2-methyl-benzamide (247):

[1136]

[1137] Compound 247, obtained as a white solid in 68% yield, was synthesized from Intermediate 199b (0.06 mmol) and 2-amino-6-methoxypyridine (0.13 mmol) according to General Method H. 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 9.65 (s, 1H), 8.95 (t, J = 6.1 Hz, 1H), 8.13 - 8.12 (m, 1H), 7.50 - 7.47 (m, 2H), 7.37 - 7.35 (m, 2H), 7.25 - 7.22 (m, 1H), 7.12 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.08 - 7.04 (m, 2H), 6.89 (d, J = 7.5 Hz, 1H), 6.56 (dd, J = 5.7 Hz, 2.3 Hz, 1H), 6.18 (dd, J = 7.9 Hz, 0.6 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.34 (s, 3H), 2.14 (s, 3H).

[1138] ESI-MS: 477.10 (M + H) + 。

[1139] Example 8: General Procedure for the Synthesis of Analogs 248 - 261

[1140]

[1141] Method I: Under nitrogen, to a solution of 214 (1 equiv) in DMF (10 mL / mmol) was added an R1-X derivative, an R1-OMs derivative, or an R1-OTs derivative (1 - 2 equiv) and Cs2CO3 (1.5 equiv). The mixture was stirred at 90 °C overnight. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH from 100 / 0 to 95 / 5) and reverse-phase chromatography (H2O / MeOH from 100 / 0 to 0 / 100) to give the desired compound.

[1142] The following compound 248 is an example illustrating Method I:

[1143] N-[(3,5-Difluorophenyl)methyl]-3-{[2-(1-isopropylpyrazol-4-yl)-4-pyridinyl]oxy}-2-methyl -benzamide (248):

[1144]

[1145] According to General Method I, compound 248 as a white solid was synthesized from intermediate 214 (0.05 mmol) and 2-iodopropane (0.05 mmol) with a yield of 50%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.0 Hz, 1H), 8.36 (d, J = 5.7 Hz, 1H), 8.33 (s, 1H), 7.97 (s, 1H), 7.41 - 7.35 (m, 2H), 7.29 (d, J = 2.3 Hz, 1H), 7.22 (dd, J = 7.4 Hz, 1.8 Hz, 1H), 7.13 (tt, J = 9.5 Hz, 2.3 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.55 - 4.47 (m, 3H), 2.14 (s, 3H), 1.44 (d, J = 6.7 Hz, 6H).

[1146] ESI-MS: 463.10 (M + H) + 。

[1147] tert-Butyl 3-[4-(4-{3-[(3,5-difluorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridinyl)pyraz ol-1-yl]azetidine-1-carboxylate (249):

[1148]

[1149] According to General Method I, compound 249 as a white solid was synthesized from intermediate 214 (0.10 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (0.11 mmol) with a yield of 76%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.0 Hz, 1H), 8.46 (s, 1H), 8.38 (d, J = 5.7 Hz, 1H), 8.12 (s, 1H), 7.41 - 7.35 (m, 2H), 7.31 (d, J = 2.3 Hz, 1H), 7.23 (dd, J = 7.3 Hz, 2.0 Hz, 1H), 7.13 (tt, J = 9.5 Hz, 2.4 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.51 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 5.27 - 5.20 (m, 1H), 4.48 (d, J = 6.0 Hz, 2H), 4.30 (t, J = 8.2 Hz, 2H), 4.15 (bs, 2H), 2.14 (s, 3H), 1.41 (s, 9H).

[1150] ESI-MS: 576.20 (M + H) + 。

[1151] Ethyl 3-{[4-(4-{3-[(3,5-difluorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridinyl)pyraz ol-1-yl]methyl}azetidine-1-carboxylate (250): tert-Butyl N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[1-(oxetan-3-yl)pyrazol-4-yl]-4-pyridinyl}oxy)benzamide (251):

[1152]

[1153] According to General Method I, compound 250 as a white solid was synthesized from intermediate 214 (0.10 mmol) and tert-butyl 3-(bromomethyl)azetidine-1-carboxylate (0.11 mmol) with a yield of 63%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.0 Hz, 1H), 8.37 - 8.35 (m, 2H), 8.00 (s, 1H), 7.41 - 7.34 (m, 2H), 7.27 (d, J = 2.3 Hz, 1H), 7.22 (dd, J = 7.3 Hz, 1.9 Hz, 1H), 7.13 (tt, J = 9.5 Hz, 2.4 Hz, 1H), 7.10 - 7.04 (m, 2H), 6.49 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 4.35 (d, J = 7.2 Hz, 2H), 3.88 (t, J = 7.3 Hz, 2H), 3.68 (bs, 2H), 3.04 - 2.94 (m, 1H), 2.14 (s, 3H), 1.36 (s, 9H).

[1154] ESI-MS: 590.30 (M+H) + 。

[1155] N-[(3,5-Difluorophenyl)methyl]-3-({2-[1-(2-methoxyethyl)pyrazol-4-yl]-4-pyridinyl}oxy )-2-methyl-benzamide (252):

[1156]

[1157] According to General Method I, compound 251 as a white solid was synthesized from intermediate 214 (0.05 mmol) and 3-bromooxetane (0.06 mmol) with a yield of 35%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (bs, 1H), 8.46 (s, 1H), 8.38 (d, J = 5.3 Hz, 1H), 8.13 (s, 1H), 7.41 - 7.31 (m, 3H), 7.23 (d, J = 7.0 Hz, 1H), 7.15 - 7.06 (m, 3H), 6.51 (d, J = 3.6 Hz, 1H), 5.62 - 5.57 (m, 1H), 4.93 - 4.91 (m, 4H), 4.48 (d, J = 5.4 Hz, 2H), 2.14 (s, 3H).

[1158] ESI-MS: 477.10 (M+H) + 。

[1159] N-[(3,5-Difluorophenyl)methyl]-3-({2-[1-(dimethylphosphorylmethyl)pyrazol-4-yl]-4-pyridin yl}oxy)-2-methyl-benzamide (253):

[1160]

[1161] According to General Method I, compound 252 as a white solid was synthesized from intermediate 214 (0.05 mmol) and 2-bromoethyl methyl ether (0.06 mmol) with a yield of 78%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 5.8 Hz, 1H), 8.36 (d, J = 5.7 Hz, 1H), 8.26 (s, 1H), 7.99 (s, 1H), 7.41 - 7.35 (m, 2H), 7.27 - 7.22 (m, 2H), 7.15 - 7.05 (m, 3H), 6.49 (d, J = 5.0 Hz, 1H), 4.48 (d, J = 5.9 Hz, 2H), 4.28 (t, J = 5.1 Hz, 2H), 3.70 (t, J = 5.1 Hz, 2H), 3.23 (s, 3H), 2.14 (s, 3H).

[1162] ESI-MS: 479.10 (M+H) + 。

[1163] 3-({2-[1-(di-tert-butoxyphosphorylmethyl)pyrazol-4-yl]-4-pyridinyl}oxy)-N-[(3,5-difluoro phenyl)methyl]-2-methyl-benzamide (254):

[1164]

[1165] According to General Method I, compound 253 as a white solid was synthesized from intermediate 214 (0.05 mmol) and 1-{[(dimethylphosphoryl)methoxy]sulfonyl}-4-methylbenzene (0.06 mmol) with a yield of 75%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 6.0 Hz, 1H), 8.38 (d, J = 5.7 Hz, 1H), 8.28 (s, 1H), 8.07 (s, 1H), 7.41 - 7.35 (m, 2H), 7.28 (d, J = 2.3 Hz, 1H), 7.23 (dd, J = 7.4 Hz, 1.8 Hz, 1H), 7.13 (tt, J = 9.5 Hz, 2.3 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.52 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.69 (d, J = 7.5 Hz, 2H), 4.48 (d, J = 6.0 Hz, 2H), 2.14 (s, 3H), 1.46 (s, 3H), 1.42 (s, 3H). 31 31P NMR (162 MHz, DMSO-d6) δ (ppm): 38.43.

[1166] ESI-MS: 511.10 (M + H) + .

[1167] 3-({2-[1-(cyclopropylmethyl)pyrazol-4-yl]-4-pyridinyl}oxy)-N-[(3,5-difluorophenyl)meth yl]-2-methyl-benzamide (255):

[1168]

[1169] According to the general method I, compound 254 as a white solid was synthesized from intermediate 214 (0.12 mmol) and 4-methylbenzenesulfonic acid (di-tert-butoxyphosphoryl) methyl ester (0.24 mmol) with a yield of 51%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.0 Hz, 1H), 8.37 (d, J = 5.7 Hz, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.41 - 7.35 (m, 2H), 7.24 (dd, J = 7.2 Hz, 2.2 Hz, 2H), 7.16 - 7.10 (m, 1H), 7.09 - 7.04 (m, 2H), 6.52 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.53 (d, J = 11.8 Hz, 2H), 4.48 (d, J = 6.0 Hz, 2H), 2.15 (s, 3H), 1.39 (s, 18H). 31 31P NMR (162 MHz, DMSO-d6) δ (ppm): 10.07.

[1170] ESI-MS: 627.15 (M + H) + .

[1171] 3-({2-[1-(2,2-difluoroethyl)pyrazol-4-yl]-4-pyridinyl}oxy)-N-[(3,5-difluorophenyl)methyl]-2-methyl-benzamide (256):

[1172]

[1173] According to General Method I, compound 255 as a white solid was synthesized from intermediate 214 (0.05 mmol) and cyclopropylmethyl bromide (0.06 mmol) with a yield of 56%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.0 Hz, 1H), 8.36 (d, J = 5.7 Hz, 1H), 8.33 (s, 1H), 7.98 - 7.97 (m, 1H), 7.41 - 7.35 (m, 2H), 7.28 (d, J = 2.3 Hz, 1H), 7.22 (dd, J = 7.4 Hz, 1.9 Hz, 1H), 7.13 (tt, J = 9.5 Hz, 2.4 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.99 (d, J = 7.1 Hz, 2H), 2.15 (s, 3H), 1.31 - 1.21 (m, 1H), 0.56 - 0.51 (m, 2H), 0.40 - 0.36 (m, 2H).

[1174] ESI-MS: 475.10 (M + H) + 。

[1175] 3-{[2-(1-cyclobutylpyrazol-4-yl)-4-pyridinyl]oxy}-N-[(3,5-difluorophenyl)methyl]-2-meth yl-benzamide (257):

[1176]

[1177] According to General Method I, compound 256 as a white solid was synthesized from intermediate 214 (0.05 mmol) and 2-iodo-1,1-difluoroethane (0.06 mmol) with a yield of 50%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.0 Hz, 1H), 8.38 (d, J = 5.7 Hz, 1H), 8.35 (s, 1H), 8.09 (d, J = 0.4 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.30 (d, J = 2.3 Hz, 1H), 7.23 (dd, J = 7.3 Hz, 1.9 Hz, 1H), 7.13 (tt, J = 9.5 Hz, 2.4 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.54 - 6.25 (m, 2H), 4.66 (td, J = 15.1 Hz, 3.7 Hz, 2H), 4.48 (d, J = 6.0 Hz, 2H), 2.14 (s, 3H).

[1178] ESI-MS: 485.10 (M + H) + 。

[1179] 3-({2-[1-(cyclobutylmethyl)pyrazol-4-yl]-4-pyridinyl}oxy)-N-[(3,5-difluorophenyl)meth yl]-2-methyl-benzamide (258):

[1180]

[1181] According to General Method I, compound 257 as a white solid was synthesized from intermediate 214 (0.05 mmol) and cyclobutyl bromide (0.06 mmol) with a yield of 39%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.0 Hz, 1H), 8.39 (d, J = 0.5 Hz, 1H), 8.37 - 8.35 (m, 1H), 8.01 (d, J = 0.5 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.29 (d, J = 2.1 Hz, 1H), 7.22 (dd, J = 7.4 Hz, 1.9 Hz, 1H), 7.13 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.85 (p, J = 8.5 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 2.50 - 2.35 (m, 4H), 2.14 (s, 3H), 1.82 - 1.73 (m, 2H).

[1182] ESI-MS: 475.10 (M + H) + 。

[1183] 3-({2-[1-(2-cyanoethyl)pyrazol-4-yl]-4-pyridinyl}oxy)-N-[(3,5-difluorophenyl)meth yl]-2-methyl-benzamide (259):

[1184]

[1185] According to General Method I, compound 258 as a white solid was synthesized from intermediate 214 (0.05 mmol) and (bromomethyl)cyclobutane (0.06 mmol) with a yield of 43%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.0 Hz, 1H), 8.36 - 8.35 (m, 1H), 8.27 (d, J = 0.5 Hz, 1H), 7.96 (d, J = 0.6 Hz, 1H), 7.41 - 7.35 (m, 2H), 7.27 (d, J = 2.2 Hz, 1H), 7.22 (dd, J = 7.4 Hz, 1.9 Hz, 1H), 7.13 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.47 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 4.14 (d, J = 7.3 Hz, 2H), 2.76 (dt, J = 14.9 Hz, 7.5 Hz, 1H), 2.14 (s, 3H), 2.00 - 1.94 (m, 2H), 1.89 - 1.72 (m, 4H).

[1186] ESI-MS: 489.10 (M + H) + 。

[1187] 3-({2-[1-(cyanomethyl)pyrazol-4-yl]-4-pyridinyl}oxy)-N-[(3,5-difluorophenyl)methyl]- ​

[1188]

[1189] According to General Method I, compound 259 as a white solid was synthesized from intermediate 214 (0.05 mmol) and 3-bromopropionitrile (0.06 mmol) with a yield of 56%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.1 Hz, 1H), 8.39 - 8.37 (m, 2H), 8.07 (d, J = 0.6 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.28 (d, J = 2.2 Hz, 1H), 7.23 (dd, J = 7.4 Hz, 1.9 Hz, 1H), 7.13 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.52 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 4.42 (t, J = 6.4 Hz, 2H), 3.10 (t, J = 6.4 Hz, 2H), 2.15 (s, 3H).

[1190] ESI-MS: 474.10 (M+H) + 。

[1191] ​ 2-Methyl-benzamide (260):

[1192]

[1193] According to General Method I, compound 260 as a white solid was synthesized from intermediate 214 (0.05 mmol) and 2-iodoacetonitrile (0.07 mmol) with a yield of 14%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.0 Hz, 1H), 8.40 - 8.38 (m, 2H), 8.15 (d, J = 0.6 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.32 (d, J = 2.2 Hz, 1H), 7.24 (dd, J = 7.3 Hz, 2.0 Hz, 1H), 7.13 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.09 - 7.03 (m, 2H), 6.54 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 5.53 (s, 2H), 4.48 (d, J = 6.0 Hz, 2H), 2.14 (s, 3H).

[1194] ESI-MS: 460.10 (M+H) + 。

[1195] 4-[4-(4-{3-[(3,5-Difluorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridinyl)py razol-1-yl]piperidine-1-carboxylic acid tert-Butyl ester (261):

[1196]

[1197] According to General Method I, compound 261 as a white solid was synthesized from intermediate 214 (0.10 mmol) and tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (0.11 mmol) with a yield of 70%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.0 Hz, 1H), 8.37 - 8.35 (m, 2H), 8.00 (s, 1H), 7.41 - 7.35 (m, 2H), 7.29 (d, J = 2.3 Hz, 1H), 7.22 (dd, J = 7.4 Hz, 1.9 Hz, 1H), 7.13 (tt, J = 9.5 Hz, 2.4 Hz, 1H), 7.10 - 7.04 (m, 2H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 4.42 - 4.34 (m, 1H), 4.04 (d, J = 11.8 Hz, 2H), 2.91 (bs, 2H), 2.14 (s, 3H), 2.02 (d, J = 10.2 Hz, 2H), 1.85 - 1.75 (m, 2H), 1.42 (s, 9H).

[1198] ESI-MS: 604.40 (M+H) + 。

[1199] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[1-(4-piperidinyl)pyrazol-4-yl]-4-pyridinyl} oxy)benzamide (262):

[1200]

[1201] To a stirred solution of compound 261 (25 mg, 0.04 mmol) in dioxane (2 mL) was added HCl (4 N in dioxane, 0.41 mL, 10 equiv) and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and washed with saturated solution of NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (DCM / MeOH from 100 / 0 to 90 / 10) and reverse phase chromatography (H2O / MeOH from 100 / 0 to 0 / 100) to give the desired compound as a white solid in 33% yield. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.0 Hz, 1H), 8.36 (d, J = 5.7 Hz, 1H), 8.32 (s, 1H), 7.99 (s, 1H), 7.41 - 7.34 (m, 2H), 7.29 (d, J = 2.3 Hz, 1H), 7.22 (dd, J = 7.3 Hz, 1.8 Hz, 1H), 7.16 - 7.10 (m, 1H), 7.09 - 7.14 (m, 2H), 6.48 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 4.28 - 4.19 (m, 1H), 3.07 (d, J = 12.3 Hz, 2H), 2.61 (d, J = 10.8, 2H), 2.14 (s, 3H), 1.98 (d, J = 10.2, 2H), 1.87 - 1.78 (m, 2H).

[1202] ESI-MS: 504.10 (M+H) + 。

[1203] Example 9: General procedure for the synthesis of analogues 263 - 277

[1204]

[1205] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[2-(1-methylpyrazol-4-yl)-4-pyridinyl]-4- pyridinyl}oxy)benzamide (263):

[1206]

[1207] According to the general method D2, in a two-step procedure, compound 263 as a white solid was synthesized from intermediate 199b (0.08 mmol), 2-chloropyridine-4-boronic acid (0.08 mmol), and 1-methylpyrazole-4-boronic acid pinacol ester (0.15 mmol) with a yield of 23%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.1 Hz, 1H), 8.61 - 8.59 (m, 2H), 8.40 (s, 1H), 8.29 - 8.28 (m, 1H), 8.10 (d, J = 0.7 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.81 (dd, J = 5.2 Hz, 1.7 Hz, 1H), 7.44 - 7.38 (m, 2H), 7.29 (dd, J = 7.3 Hz, 2.0 Hz, 1H), 7.16 - 7.10 (m, 1H), 7.09 - 7.04 (m, 2H), 6.71 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.90 (s, 3H), 2.17 (s, 3H).

[1208] ESI-MS: 512.10 (M+H) + 。

[1209] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[6-(1-methylpyrazol-4-yl)-3-pyridinyl]-4- pyridinyl}oxy)benzamide (264):

[1210]

[1211] According to the general method D2, the compound 264 as a white solid was synthesized in a two-step procedure from intermediate 199b (0.08 mmol), (6-chloropyridin-3-yl)boronic acid (0.08 mmol), and 1-methylpyrazole-4-boronic acid pinacol ester (0.15 mmol) with a yield of 15%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.16 (dd, J = 2.3 Hz, 0.7 Hz, 1H), 9.01 (t, J = 6.1 Hz, 1H), 8.55 (d, J = 5.7 Hz, 1H), 8.38 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 8.35 (s, 1H), 8.06 (d, J = 0.6 Hz, 1H), 7.74 (dd, J = 8.3 Hz, 0.6 Hz, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.27 (dd, J = 7.3 Hz, 2.0 Hz, 1H), 7.16 - 7.10 (m, 1H), 7.09 - 7.04 (m, 2H), 6.67 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.90 (s, 3H), 2.16 (s, 3H).

[1212] ESI-MS: 512.10 (M+H) + 。

[1213] N-[(3,5-Difluorophenyl)methyl]-3-{[2-(2-fluoro-4-pyridinyl)-4-pyridinyl]oxy}-2-methyl-ben zamide (265a):

[1214]

[1215] According to the general method D2, the compound 265a as a white solid was synthesized from intermediate 199b (1.16 mmol) and 2-fluoropyridin-4-ylboronic acid (1.39 mmol) with a yield of 100%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 5.9 Hz, 1H), 8.61 (d, J = 5.6 Hz, 1H), 8.36 (d, J = 5.3 Hz, 1H), 8.02 (d, J = 5.2 Hz, 1H), 7.85 (d, J = 2. Hz 3, 1H), 7.82 (s, 1H), 7.44 - 7.38 (m, 2H), 7.28 (dd, J = 6.9 Hz, 2.2 Hz, 1H), 7.16 - 7.04 (m, 3H), 6.78 (dd, J = 5.6 Hz, 1.9 Hz, 1H), 4.48 (d, J = 5.9 Hz, 2H), 2.16 (s, 3H).

[1216] ESI-MS: 450.05 (M+H) + 。

[1217] N-[(3,5-Difluorophenyl)methyl]-3-{[2-(6-fluoro-3-pyridinyl)-4-pyridinyl]oxy}-2-methyl-ben zamide (265b):

[1218]

[1219] Compound 265b as a white solid was synthesized from intermediate 199b (0.77 mmol) and 6-fluoro-3-pyridylboronic acid (0.93 mmol) according to the general method D2 with a yield of 100%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 6.0 Hz, 1H), 8.90 (d, J = 2.5 Hz, 1H), 8.64 - 8.59 (m, 1H), 8.57 - 8.55 (m, 1H), 7.69 (d, J = 2.1 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.31 (dd, J = 8.6 Hz, 2.4 Hz, 1H), 7.27 (dd, J = 7.2 Hz, 2.1 Hz, 1H), 7.13 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.70 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 2.16 (s, 3H).

[1220] ESI-MS: 450.05 (M+H) + 。

[1221] Method J: To a solution of 265 (1 equiv) in dioxane (10 mL / mmol) was added an amine derivative (16 equiv) and DIEA (6 equiv). The mixture was stirred at 100 °C until completion (from 2 h to overnight). The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH from 100 / 0 to 90 / 10) and reverse-phase chromatography (H2O / MeOH from 100 / 0 to 0 / 100) to give the desired compound.

[1222] The following compound 266 is an example illustrating Method J:

[1223] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(2-pyrrolidin-1-yl-4-pyridinyl)-4-pyridin yl]oxybenzamide (266):

[1224]

[1225] According to the general method J, compound 266 as a white solid was synthesized from intermediate 265a (0.07 mmol) and pyrrolidine (0.53 mmol) in 55% yield. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.0 Hz, 1H), 8.55 (d, J = 5.8 Hz, 1H), 8.14 (dd, J = 5.3 Hz, 0.6 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.27 (dd, J = 7.3 Hz, 2.0 Hz, 1H), 7.16 - 7.04 (m, 5H), 6.71 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.46 - 3.43 (m, 4H), 2.15 (s, 3H), 1.98 - 1.94 (m, 4H).

[1226] ESI-MS: 501.10 (M + H) + 。

[1227] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[2-(1-piperidinyl)-4-pyridinyl]-4-pyridinyl} oxy)benzamide (267):

[1228]

[1229] According to the general method J, compound 267 as a white solid was synthesized from intermediate 265a (0.07 mmol) and piperidine (0.53 mmol) in 50% yield. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.0 Hz, 1H), 8.55 (d, J = 5.6 Hz, 1H), 8.18 (d, J = 5.2 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.43 - 7.36 (m, 3H), 7.26 (dd, J = 7.2 Hz, 2.0 Hz, 1H), 7.17 - 7.04 (m, 4H), 6.69 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.60 - 3.58 (m, 4H), 2.16 (s, 3H), 1.62 - 1.55 (m, 6H).

[1230] ESI-MS: 515.15 (M + H) + 。

[1231] N-[(3,5-Difluorophenyl)methyl]-3-({2-[2-(dimethylamino)-4-pyridinyl]-4-pyridinyl}oxy yl)-2-methyl-benzamide (268):

[1232]

[1233] Compound 268 as a white solid was synthesized from intermediate 265a (0.07 mmol) and dimethylamine (2M THF, 0.67 mmol) according to general method J with a yield of 47%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.0 Hz, 1H), 8.56 (d, J = 5.6 Hz, 1H), 8.18 - 8.16 (m, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.27 (dd, J = 8.1 Hz, 2.7 Hz, 2H), 7.15 - 7.04 (m, 4H), 6.71 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.09 (s, 6H), 2.15 (s, 3H).

[1234] ESI-MS: 475.10 (M + H) + 。

[1235] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(2-morpholino-4-pyridinyl)-4-pyridinyl]oxy yl}benzamide (269):

[1236]

[1237] Compound 269 as a white solid was synthesized from intermediate 265a (0.07 mmol) and morpholine (1.07 mmol) according to general method J with a yield of 50%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.1 Hz, 1H), 8.55 (d, J = 5.7 Hz, 1H), 8.23 (d, J = 5.6 Hz, 1H), 7.75 (d, J = 2.2 Hz, 1H), 7.46 (s, 1H), 7.43 - 7.37 (m, 2H), 7.29 (dd, J = 5.2 Hz, 1.3 Hz, 1H), 7.26 (dd, J = 7.3 Hz, 2.0 Hz, 1H), 7.13 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.69 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.73 - 3.71 (m, 4H), 3.54 - 3.51 (m, 4H), 2.16 (s, 3H).

[1238] ESI-MS: 517.15 (M + H) + 。

[1239] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[2-(4-methylpiperazin-1-yl)-4-pyridinyl]-4- pyridinyl}oxy)benzamide (270):

[1240]

[1241] Compound 270 as a white solid was synthesized from intermediate 265a (0.07 mmol) and 1-methylpiperazine (1.07 mmol) according to general method J with a yield of 40%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.0 Hz, 1H), 8.55 (d, J = 5.8 Hz, 1H), 8.21 - 8.19 (m, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.45 (s, 1H), 7.43 - 7.37 (m, 2H), 7.27 - 7.23 (m, 2H), 7.13 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.69 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.57 - 3.55 (m, 4H), 2.42 - 2.40 (m, 4H), 2.22 (s, 3H), 2.16 (s, 3H).

[1242] ESI-MS: 530.15 (M + H) + 。

[1243] 3-{[2-(2-amino-4-pyridinyl)-4-pyridinyl]oxy}-N-[(3,5-difluorophenyl)methyl]-2-methyl- benzamide (271):

[1244]

[1245] Compound 271 as a white solid was synthesized from intermediate 265a (0.07 mmol) and NH4OH (1.5 mL) according to general method J, with a yield of 34%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.1 Hz, 1H), 8.55 (d, J = 5.8 Hz, 1H), 7.98 (dd, J = 5.4 Hz, 0.6 Hz, 1H), 7.43 - 7.37 (m, 3H), 7.28 (dd, J = 7.3 Hz, 2.0 Hz, 1H), 7.16 - 7.04 (m, 4H), 7.02 (dd, J = 5.4 Hz, 1.6 Hz, 1H), 6.78 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 6.03 (s, 2H), 4.48 (d, J = 6.0 Hz, 2H), 2.15 (s, 3H).

[1246] ESI-MS: 447.05 (M + H) + 。

[1247] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(6-pyrrolidin-1-yl-3-pyridinyl)-4-pyridin yl]oxy}benzamide (272):

[1248]

[1249] Compound 272 as a white solid was synthesized from intermediate 265b (0.07 mmol) and pyrrolidine (1.06 mmol) according to general method J, with a yield of 55%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.0 Hz, 1H), 8.75 (d, J = 1.9 Hz, 1H), 8.43 (d, J = 5.6 Hz, 1H), 8.13 (dd, J = 8.9 Hz, 2.5 Hz, 1H), 7.42 - 7.35 (m, 3H), 7.24 (dd, J = 7.5 Hz, 1.8 Hz, 1H), 7.16 - 7.10 (m, 1H), 7.09 - 7.04 (m, 2H), 6.55 - 6.50 (m, 2H), 4.48 (d, J = 6.0 Hz, 2H), 3.45 - 3.42 (m, 4H), 2.15 (s, 3H), 1.97 - 1.94 (m, 4H).

[1250] ESI-MS: 501.10 (M + H) + 。

[1251] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[6-(1-piperidinyl)-3-pyridinyl]-4-pyridinyl} oxy)benzamide (273):

[1252]

[1253] Compound 273, a white solid, was synthesized from intermediate 265b (0.07 mmol) and piperidine (1.06 mmol) according to General Method J in 65% yield. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 6.0 Hz, 1H), 8.75 (d, J = 2.2 Hz, 1H), 8.44 (d, J = 5.8 Hz, 1H), 8.13 (dd, J = 9.0 Hz, 2.5 Hz, 1H), 7.42 - 7.35 (m, 3H), 7.24 (dd, J = 7.4 Hz, 1.8 Hz, 1H), 7.16 - 7.04 (m, 3H), 6.87 (d, J = 8.9 Hz, 1H), 6.56 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.61 - 3.58 (m, 4H), 2.15 (s, 3H), 1.63 - 1.54 (m, 6H).

[1254] ESI-MS: 515.20 (M + H) + 。

[1255] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-{[2-(6-morpholino-3-pyridinyl)-4-pyridinyl]oxy yl}benzamide (274):

[1256]

[1257] Compound 274, a white solid, was synthesized from intermediate 265b (0.07 mmol) and morpholine (1.06 mmol) according to General Method J in 65% yield. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 6.0 Hz, 1H), 8.80 (d, J = 2.2 Hz, 1H), 8.46 (d, J = 5.7 Hz, 1H), 8.20 (dd, J = 9.0 Hz, 2.5 Hz, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.40 - 7.36 (m, 2H), 7.25 (dd, J = 7.4 Hz, 1.9 Hz, 1H), 7.13 (tt, J = 9.5 Hz, 2.4 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.91 (d, J = 9.0 Hz, 1H), 6.57 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.72 - 3.69 (m, 4H), 3.55 - 3.52 (m, 4H), 2.15 (s, 3H).

[1258] ESI-MS: 517.15 (M + H) +。

[1259] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[6-(4-methylpiperazin-1-yl)-3-pyridinyl]-4- pyridinyl}oxy)benzamide (275):

[1260]

[1261] Compound 275 as a white solid was synthesized from intermediate 265b (0.07 mmol) and 1-methylpiperazine (1.06 mmol) according to general method J with a yield of 52%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 6.0 Hz, 1H), 8.77 (d, J = 2.1 Hz, 1H), 8.45 (d, J = 5.8 Hz, 1H), 8.16 (dd, J = 9.0 Hz, 2.5 Hz, 1H), 7.43 (d, J = 2.2 Hz, 1H), 7.42 - 7.36 (m, 2H), 7.25 (dd, J = 7.4 Hz, 1.9 Hz, 1H), 7.16 - 7.10 (m, 1H), 7.09 - 7.04 (m, 2H), 6.90 (d, J = 9.0 Hz, 1H), 6.57 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.58 - 3.55 (m, 4H), 2.40 - 2.38 (m, 4H), 2.22 (s, 3H), 2.15 (s, 3H).

[1262] ESI-MS: 530.15 (M + H) + 。

[1263] N-[(3,5-Difluorophenyl)methyl]-3-({2-[6-(dimethylamino)-3-pyridinyl]-4-pyridinyl}oxy )-2-methyl-benzamide (276):

[1264]

[1265] Compound 276 as a white solid was synthesized from intermediate 265b (0.07 mmol) and dimethylamine (2M THF, 1.06 mmol) according to general method J with a yield of 72%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.0 Hz, 1H), 8.76 (dd, J = 2.5 Hz, 0.6 Hz, 1H), 8.44 (d, J = 5.8 Hz, 1H), 8.14 (dd, J = 9.0 Hz, 2.5 Hz, 1H), 7.42 - 7.35 (m, 3H), 7.24 (dd, J = 7.5 Hz, 1.8 Hz, 1H), 7.16 - 7.10 (m, 1H), 7.09 - 7.04 (m, 2H), 6.71 (dd, J = 9.0 Hz, 0.5 Hz, 1H), 6.55 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.08 (s, 6H), 2.15 (s, 3H).

[1266] ESI-MS: 475.10 (M + H) + 。

[1267] 3-{[2-(6-Amino-3-pyridinyl)-4-pyridinyl]oxy}-N-[(3,5-difluorophenyl)methyl]-2-methyl- benzamide (277):

[1268]

[1269] Compound 277 as a white solid was synthesized from intermediate 265b (0.07 mmol) and NH4OH (1.5 mL) according to General Procedure J with a yield of 69%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 6.0 Hz, 1H), 8.60 - 8.59 (m, 1H), 8.42 (d, J = 5.8 Hz, 1H), 8.01 (dd, J = 8.7 Hz, 2.5 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.34 (d, J = 2.2 Hz, 1H), 7.24 (dd, J = 7.5 Hz, 1.8 Hz, 1H), 7.13 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.55 (dd, J = 5.7 Hz, 2.4 Hz, 1H), 6.49 (dd, J = 8.7 Hz, 0.6 Hz, 1H), 6.28 (s, 2H), 4.48 (d, J = 6.0 Hz, 2H), 2.15 (s, 3H).

[1270] ESI-MS: 447.05 (M + H) + 。

[1271] Example 10: General Procedure for the Synthesis of Analogs 278 - 283

[1272]

[1273] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[3-(1-methylpyrazol-4-yl)phenyl]-4-pyridin yl}oxy)benzamide (278):

[1274]

[1275] According to the general method D2, the white solid compound 278 was synthesized from intermediate 199b (0.06 mmol), (3-bromophenyl)boronic acid (0.06 mmol) and 1-methylpyrazole-4-boronic acid pinacol ester (0.13 mmol) in a two-step procedure with a yield of 10%. 1 H NMR (600 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 6.0 Hz, 1H), 8.54 (d, J = 5.6 Hz, 1H), 8.26 (s, 1H), 8.23 (t, J = 1.6 Hz, 1H), 7.95 (d, J = 0.8 Hz, 1H), 7.85 - 7.83 (m, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.64 - 7.62 (m, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.27 (dd, J = 7.8 Hz, 1.4 Hz, 1H), 7.12 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.09 - 7.05 (m, 2H), 6.66 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.88 (s, 3H), 2.17 (s, 3H).

[1276] ESI-MS: 511.10 (M + H) + 。

[1277] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[3-(2-methylpyrazol-3-yl)phenyl]-4-pyridin yl}oxy)benzamide (279):

[1278]

[1279] According to the general method D2, the white solid compound 279 was synthesized from intermediate 199b (0.08 mmol), (3-bromophenyl)boronic acid (0.08 mmol) and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (0.15 mmol) in a two-step procedure with a yield of 6%. 11H NMR (600 MHz, DMSO-d6) δ (ppm): 8.99 (t, J = 6.0 Hz, 1H), 8.56 - 8.55 (m, 1H), 8.15 (t, J = 2.0 Hz, 1H), 8.10 - 8.08 (m, 1H), 7.64 (d, J = 2.1 Hz, 1H), 7.62 - 7.60 (m, 2H), 7.49 (d, J = 1.9 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.27 (dd, J = 7.7 Hz, 1.4 Hz, 1H), 7.12 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.09 - 7.05 (m, 2H), 6.70 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 6.49 (d, J = 1.9 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.88 (s, 3H), 2.16 (s, 3H).

[1280] ESI-MS: 511.15 (M + H) + 。

[1281] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[3-(1-methylpyrazol-3-yl)phenyl]-4-pyridin yl}oxy)benzamide (280):

[1282]

[1283] Compound 280, obtained as a white solid in 10% yield, was synthesized from Intermediate 199b (0.08 mmol), (3-bromophenyl)boronic acid (0.08 mmol), and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.15 mmol) according to General Method D2 in a two-step procedure. 11H NMR (600 MHz, DMSO-d6) δ (ppm): 9.00 (t, J = 6.0 Hz, 1H), 8.56 - 8.55 (m, 1H), 8.48 (t, J = 1.6 Hz, 1H), 7.90 (ddd, J = 7.8 Hz, 1.8 Hz, 1.1 Hz, 1H), 7.85 (ddd, J = 7.7 Hz, 1.6 Hz, 1.1 Hz, 1H), 7.75 (d, J = 2.2 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.28 (dd, J = 7.8 Hz, 1.3 Hz, 1H), 7.12 (tt, J = 9.3 Hz, 2.4 Hz, 1H), 7.09 - 7.05 (m, 2H), 6.78 (d, J = 2.2 Hz, 1H), 6.70 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.90 (s, 3H), 2.17 (s, 3H).

[1284] ESI-MS: 511.10 (M + H) + 。

[1285] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[4-(1-methylpyrazol-4-yl)phenyl]-4-pyridin yl}oxy)benzamide (281):

[1286]

[1287] According to the general method D2, in a two-step procedure, compound 281 as a white solid was synthesized from intermediate 199b (0.10 mmol), (4-bromophenyl)boronic acid (0.15 mmol), and 1-methylpyrazole-4-boronic acid pinacol ester (0.21 mmol) with a yield of 4%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.0 Hz, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.21 (s, 1H), 8.03 (d, J = 8.5 Hz, 2H), 7.93 (d, J = 0.6 Hz, 1H), 7.66 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 2.3 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.27 (dd, J = 7.4 Hz, 1.8 Hz, 1H), 7.16 - 7.10 (m, 1H), 7.09 - 7.04 (m, 2H), 6.66 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.88 (s, 3H), 2.16 (s, 3H).

[1288] ESI-MS: 511.10 (M+H) + 。

[1289] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[4-(2-methylpyrazol-3-yl)phenyl]-4-pyridin yl}oxy)benzamide (282):

[1290]

[1291] According to the general method D2, the white solid compound 282 was synthesized in a two-step procedure from intermediate 199b (0.10 mmol), (4-bromophenyl)boronic acid (0.15 mmol), and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (0.21 mmol) with a yield of 4%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.02 (t, J = 6.0 Hz, 1H), 8.57 (d, J = 5.7 Hz, 1H), 8.15 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 2.3 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.29 (dd, J = 7.3 Hz, 1.9 Hz, 1H), 7.15 - 7.10 (m, 1H), 7.09 - 7.04 (m, 2H), 6.74 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 6.48 (d, J = 1.9 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.90 (s, 3H), 2.17 (s, 3H).

[1292] ESI-MS: 511.10 (M+H) + 。

[1293] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[4-(1-methylpyrazol-3-yl)phenyl]-4-pyridin yl}oxy)benzamide (283):

[1294]

[1295] According to the general method D2, the white solid compound 283 was synthesized in a two-step procedure from intermediate 199b (0.10 mmol), (4-bromophenyl)boronic acid (0.15 mmol), and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.21 mmol) with a yield of 4%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.1 Hz, 1H), 8.53 (d, J = 5.6 Hz, 1H), 8.06 (d, J = 8.6 Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H), 7.76 (d, J = 2.2 Hz, 1H), 7.53 (d, J = 2.3 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.28 (dd, J = 7.4 Hz, 1.8 Hz, 1H), 7.15 - 7.10 (m, 1H), 7.09 - 7.04 (m, 2H), 6.76 (d, J = 2.3 Hz, 1H), 6.69 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.90 (s, 3H), 2.17 (s, 3H).

[1296] ESI-MS: 511.10 (M + H) + 。

[1297] Example 11: General Procedure for the Synthesis of Analogs 285 - 290

[1298]

[1299] N-[(3,5-Difluorophenyl)methyl]-3-{[2-(4-formylphenyl)-4-pyridinyl]oxy}-2-methyl-benz amide (284a ) Preparation :

[1300]

[1301] According to General Method D2, intermediate 284a as a white solid was synthesized from 199b (0.39 mmol) in quantitative yield.

[1302] ESI-MS: 459.05 (M + H) + 。

[1303] The following table lists intermediate 284 prepared by Method D2:

[1304]

[1305] Method K: To a solution of 284 (1 equiv) in MeOH (10 mL / mmol) was added an amine derivative (1.3 equiv), AcOH (2% v / v), and NaBH3CN. The mixture was stirred at room temperature until completion (from 1 h to overnight). The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH from 100 / 0 to 90 / 10) and reverse-phase chromatography (H2O / MeOH from 100 / 0 to 0 / 100) to give the desired compound.

[1306] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[4-(pyrrolidin-1-ylmethyl)phenyl]-4-pyridin yl}oxy)benzamide (285):

[1307]

[1308] According to general method K, the white solid compound 285 was synthesized from intermediate 284a (0.05 mmol) and pyrrolidine (0.07 mmol) with a yield of 25%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.0 Hz, 1H), 8.52 (d, J = 5.6 Hz, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 2.2 Hz, 1H), 7.43 - 7.37 (m, 4H), 7.27 (dd, J = 7.3 Hz, 1.9 Hz, 1H), 7.15 - 7.04 (m, 3H), 6.69 (dd, J = 5.6 Hz, 2.3 Hz, 1H), 4.48 (d, J = 5.9 Hz, 2H), 3.61 (s, 2H), 2.43 (bs, 4H), 2.16 (s, 3H), 1.70 (bs, 4H).

[1309] ESI-MS: 514.15 (M + H) + 。

[1310] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[4-(morpholinomethyl)phenyl]-4-pyridinyl}oxy benzamide (286):

[1311]

[1312] According to general method K, the white solid compound 286 was synthesized from intermediate 284a (0.07 mmol) and morpholine (0.09 mmol) with a yield of 26%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.0 Hz, 1H), 8.52 (d, J = 5.7 Hz, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 2.3 Hz, 1H), 7.41 - 7.37 (m, 4H), 7.27 (dd, J = 7.4 Hz, 1.9 Hz, 1H), 7.13 (tt, J = 9.5 Hz, 2.4 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.69 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.59 - 3.56 (m, 4H), 3.51 (s, 2H), 2.38 - 2.35 (m, 4H), 2.15 (s, 3H).

[1313] ESI-MS: 530.15 (M + H)+ 。

[1314] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-[(2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}- 4-pyridinyl)oxy]benzamide (287):

[1315]

[1316] According to general method K, compound 287 as a white solid was synthesized from intermediate 284a (0.07 mmol) and 1-methylpiperazine (0.09 mmol) with a yield of 31%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.1 Hz, 1H), 8.52 (d, J = 5.7 Hz, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 2.3 Hz, 1H), 7.43 - 7.37 (m, 4H), 7.27 (dd, J = 7.4 Hz, 1.9 Hz, 1H), 7.16 - 7.10 (m, 1H), 7.09 - 7.04 (m, 2H), 6.69 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.49 (s, 2H), 2.56 - 2.50 (m, 4H), 2.40 - 2.30 (m, 4H), 2.15 (s, 3H), 2.14 (s, 3H).

[1317] ESI-MS: 543.20 (M + H) + 。

[1318] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[3-(pyrrolidin-1-ylmethyl)phenyl]-4-pyridin yl}oxy)benzamide (288):

[1319]

[1320] According to general method K, compound 288 as a white solid was synthesized from intermediate 284b (0.06 mmol) and pyrrolidine (0.09 mmol) with a yield of 44%. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.0 Hz, 1H), 8.53 (d, J = 5.7 Hz, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 7.50 - 7.37 (m, 5H), 7.27 (dd, J = 7.4 Hz, 1.9 Hz, 1H), 7.13 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.70 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.69 (s, 2H), 2.52 (bs, 4H), 2.16 (s, 3H), 1.74 (bs, 4H).

[1321] ESI-MS: 514.15 (M+H) + 。

[1322] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-({2-[3-(morpholinomethyl)phenyl]-4-pyridinyl}oxy benzamide (289):

[1323]

[1324] Compound 289 as a white solid was synthesized from intermediate 284b (0.07 mmol) and morpholine (0.09 mmol) according to general method K, with a yield of 40%. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.0 Hz, 1H), 8.53 (d, J = 5.7 Hz, 1H), 7.99 (bs, 1H), 7.88 - 7.86 (m, 1H), 7.48 (d, J = 2.2 Hz, 1H), 7.45 - 7.37 (m, 4H), 7.27 (dd, J = 7.4 Hz, 1.9 Hz, 1H), 7.16 - 7.10 (m, 1H), 7.09 - 7.04 (m, 2H), 6.70 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.58 - 3.56 (m, 4H), 3.53 (s, 2H), 2.38 - 2.36 (s, 4H), 2.16 (s, 3H).

[1325] ESI-MS: 530.15 (M+H) + 。

[1326] N-[(3,5-Difluorophenyl)methyl]-2-methyl-3-[(2-{3-[(4-methylpiperazin-1-yl)methyl]phenyl}- 4-pyridyloxy)benzamide (290):

[1327]

[1328] Compound 290, a white solid, was synthesized from intermediate 284b (0.07 mmol) and 1-methylpiperazine (0.09 mmol) according to general method K with a yield of 36%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (t, J = 6.1 Hz, 1H), 8.53 (d, J = 5.7 Hz, 1H), 7.97 (s, 1H), 7.88 - 7.84 (m, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.44 - 7.34 (m, 4H), 7.27 (dd, J = 7.5 Hz, 1.8 Hz, 1H), 7.13 (tt, J = 9.4 Hz, 2.4 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.70 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.51 (s, 2H), 2.52 - 2.50 (m, 4H), 2.37 - 2.30 (m, 4H), 2.16 (s, 3H), 2.14 (s, 3H).

[1329] ESI-MS: 543.20 (M + H) + 。

[1330] Example 12: General Procedure for the Synthesis of Analogs 292 - 29...

Claims

1. A compound (C) or its N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer, wherein the compound (C) is selected from those of formulae (I) to (VII): Wherein: Each of -A is independently selected from the group consisting of cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl, wherein the cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, NO2, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, CF3, CN, OR 11 , SR 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, S(O)R 12 , SO2R 12 , SO2N(R 11 )2, S(O)3R 11 , P(=O)(OR 11 )2, P(=O)(R 11 )2NR 11 COR 12 , COR 11 , C(O)OR 11 , CON(R 11 )2, OCON(R 11 ), and OCON(R 11 )2, and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group, and heteroaryl substituent is further optionally substituted with halo, NO2, C 1-6 alkyl, cycloalkyl, aryl, CF3, N(R 11 )2, COR 11 , CON(R 11 )2, OCON(R 11 ), CN, or OR 11 ; and wherein each of R 11 and R 12 is independently of one another and at each occurrence selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl and CF3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl substituents are optionally substituted with halo, C 1-6 alkyl, cycloalkyl, heterocyclic group, C 1-6 alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2, where R 31 and R 32 each independently of one another and, each time it occurs, is selected from the group consisting of hydrogen and C 1-4 alkyl group. - Each of R4 and R'4 is independently of one another and, each time it appears, is selected from hydrogen or C 1-6 alkyl, and z is an integer ranging from 0 to 2; Provided that when z = 0, then A and R7 can together form a saturated or unsaturated ring moiety; -Each of R7 is independently of one another and, each time it appears, is selected from hydrogen, C 1-6 alkyl, cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted by a halogen atom, CF3, N(R 11 )2, CN, or OR 11 ; and wherein each of R 11 is independently of one another and, each time it appears, is selected from the group consisting of: hydrogen, C 1-6 alkyl, and CF3; -Each of R3 is independently of one another and, each time it appears, is selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, CF3, CN, OR 21 , SR 21 , N(R 21 )2, NC(O)R 21 , NCON(R 21 )2, COR 21 , C(O)OR 21 , CON(R 21 )2, OC(O)R 21 , OCON(R 21 )2, OC(R 21 )2O, and OC(R 21 )2C(R 22 )2O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl are optionally substituted with one or more substituents selected from halo, C 1-6 alkyl, CF3, N(R 21 )2, CN, or OR 21 ; and wherein each of R 21 and R 22 is independently of one another and, each time it appears, is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl, and wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl substituents are optionally substituted with halo, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, OR 31 or N(R 32 )2, wherein each of R 31 and R 32 is independently of one another and, each time it appears, is selected from the group consisting of: hydrogen and C 1-4 alkyl; and each r is an integer ranging from 0 to 3; provided that when R3 = NR 21 and R7 = H, then R3 and NR7 may together form a saturated or unsaturated ring moiety; - Each of R2 is independently of the others and, in each occurrence, is selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, CF3, CN, NO2, OR 21 , SR 21 , N(R 21 )2, COR 21 , C(O)OR 21 , CON(R 21 )2, OC(O)R 21 , OCON(R 21 )2, NC(O)R 21 , NCON(R 21 )2, OC(R 21 )2O and OC(R 21 )2C(R 22 )2O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, CF3, COR 21 , CON(R 21 )2, C(O)OR 21 , N(R 21 )2, CN, or OR 21 , and each optional alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl substituent is further optionally substituted with heterocycloalkyl, N(R 11 )2, or OR 11 ; and wherein each of R 21 and R 22 is independently of the others and, in each occurrence, is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl, and wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl substituents are optionally substituted with halo, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, OR 31 or N(R 32 )2, wherein each of R 31 and R 32 is independently of the others and, in each occurrence, is selected from the group consisting of: hydrogen and C 1-4 alkyl; and each q is an integer ranging from 0 to 2; - Each of x and y is independently an integer equal to 0 or 1; -R8 is independently selected from the group consisting of: C 6-12 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, and heterocyclic group, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic group are optionally substituted by a halogen atom, an aryl group, an aralkyl group, CF3, N(R 11 )2, CN, or OR 11 ; and wherein each of R 11 is independently of one another and at each occurrence selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, and CF3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl substituents are optionally substituted by halo, C 1-6 alkyl, cycloalkyl, heterocyclic group, alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2, wherein each of R 31 and R 32 is independently of one another and at each occurrence selected from the group consisting of: hydrogen and C 1-4 alkyl; -R9 is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, N(R 11 )2 and CN, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic group are optionally substituted by a halogen atom, an aryl group, an aralkyl group, a heterocyclic group, CF3, N(R 11 )2, CN, or OR 11 ; and wherein each of R 11 is independently of one another and in each occurrence selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl and CF3, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, heteroaryl optionally substituted by C 1-4 alkyl, aryl, heteroaryl, and aralkyl substituents are optionally substituted by halo, C 1-6 alkyl, cycloalkyl, heterocyclic group, alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2, wherein each of R 31 and R 32 is independently of one another and in each occurrence selected from the group consisting of: hydrogen and C 1-4 alkyl, provided that if x = 1 and y = 0, then R9 is different from a heterocyclic group and different from C 1-6 alkyl, wherein said alkyl is optionally substituted by a heterocyclic group; and provided that if x = 0 and y = 0, then R9 is different from hydrogen and C 1-6 alkyl, wherein said alkyl is optionally substituted by a heterocyclic group and N(R 11 )2; provided that when x = 0 and y = 0, then R9 and R2 can together form a saturated or unsaturated ring moiety; Provided that when x = 0 and y = 0, and when R9 and R2 together form a saturated or unsaturated ring moiety, then R9 is NR 11 ; provided that when x = 1 and y = 1, then R9 is different from N(R 11 )2; and provided that when x = 0, y = 0 and z = 0, then R9 is different from pyrrole. - Each of T is independently a moiety of formula (T-a) below: Wherein: -Each U is independently of one another and, each time it occurs, is selected from the group consisting of: C, C-halo, C-R, and N; where R is selected from hydrogen, OR 11 , N(R 11 )2, C 1-6 alkyl or cycloalkyl, optionally substituted by a halogen atom, an aryl group or an aralkyl group, where each R 11 is independently of one another and, each time it occurs, is selected from the group consisting of: hydrogen or C 1-4 alkyl; provided that at least one U is different from N; -Z is each independently, at each occurrence, selected from C(R)2, O, S, and NR7, where R is independently, at each occurrence, selected from hydrogen or C 1-6 alkyl, which is optionally substituted by a halogen atom, an aryl group, or an aralkyl group, where R7 is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 1-6 alkenyl, cycloalkyl, heterocyclic group, aryl, aralkyl, and CF3; -Each R5 is independently of one another and, each time it occurs, is selected from the group consisting of: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, halo, CF3, OR 11 , SR 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, CON(R 11 )2, and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl substituent is further optionally substituted by halo, C 1-6 alkyl, cycloalkyl, aryl, heterocycloalkyl, N(R 11 )2, CN, OR 11 , C(=O)OR 11 , P(=O)(OR 11 )2, P(=O)(R 11 )2, CN or CF3, and wherein each R 11 is independently of one another and, each time it occurs, is selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, and heterocycloalkyl; and each n1 is an integer ranging from 0 to 2; - Each of X is independently a moiety of formula (X-a) below: Wherein: Each of -V is independently of one another and, each time it occurs, is selected from the group consisting of: C, C-halo, C-R, and N; where R is selected from hydrogen, OR 11 , N(R 11 )2, C 1-6 alkyl or cycloalkyl, which is optionally substituted by a halogen atom, an aryl group or an aralkyl group, where each of R 11 is independently of one another and, each time it occurs, is selected from hydrogen or C 1-4 alkyl; -Each R6, independently of one another and in each occurrence, is selected from the group consisting of: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, halo, CF3, OR 11 , SR 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, CON(R 11 )2, and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, aralkyl substituent is further optionally substituted by halo, C 1-6 alkyl, cycloalkyl, aryl, heterocycloalkyl, N(R 11 )2, CN, OR 11 , C(=O)OR 11 , P(=O)(OR 11 )2, P(=O)(R 11 )2, CN or CF3, and wherein each R 11 , independently of one another and in each occurrence, is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, and heterocycloalkyl; and each n2 is an integer ranging from 0 to 4; - The dashed bond represents an optional triple bond; -R a1 independently selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, CF3, CN, OR 11 SR 11 N(R 11 )2, COR 11 C(O)OR 11 , wherein said alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl and aralkyl are optionally halogenated, NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, CF3, CN, OR 11 SR 11 N(R 11 )2, COR 11 and C(O)OR 11 substituted, and each optional alkyl, alkenyl, cycloalkyl, phenyl, heterocyclic group, heteroaryl substituent is further optionally halogenated, NO2, C 1-6 alkyl, cycloalkyl, phenyl, N(R 11 )2, CN, or OR 11 substituted; and wherein each of R 11 is selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, and aralkyl, wherein said alkyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, and aralkyl substituents are optionally halogenated, C 1-6 alkyl, cycloalkyl or heterocyclic group substituted. -R a2 Each of which is independently of one another and, each time it appears, is selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, CF3, CN, OR 11 、SR 11 、N(R 11 )2、COR 11 、C(O)OR 11 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl and aralkyl are optionally halogenated, NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, CF3, CN, OR 11 、SR 11 、N(R 11 )2、COR 11 、and C(O)OR 11 substituted, and each optional alkyl, alkenyl, cycloalkyl, phenyl, heterocyclic group, heteroaryl substituent is further optionally halogenated, NO2, C 1-6 alkyl, cycloalkyl, phenyl, N(R 11 )2、CN、or OR 11 substituted; and wherein each of R 11 is selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, and aralkyl, wherein the alkyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, and aralkyl substituents are optionally halogenated, C 1-6 alkyl, cycloalkyl or heterocyclic group substituted; and wherein n3 is an integer equal to 0 or 1; provided that when the dashed bond represents a triple bond, then n3 is 0; Wherein the cycloalkyl is a monocyclic, bicyclic or tricyclic ring system having 3 to 6 ring members per ring; the heterocyclic group is a saturated, partially saturated or fully saturated monocyclic, bicyclic or tricyclic containing 3 to 12 carbon atoms and 1 or 2 heteroatoms independently selected from O or N; the aryl is phenyl, naphthyl or anthracenyl, which is an optionally fused carbocyclic ring with a cycloalkyl or heterocyclic group having 5 to 7 ring members; the heteroaryl is a monocyclic structure having 5 or 6 ring atoms containing 1 to 3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

2. The compound (C) or its N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer according to claim 1, wherein x and y are as defined in claim 1 and wherein: Each of -A is independently selected from the group consisting of cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl, wherein the cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, NO2, C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, CF3, CN, OR 11 , SR 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, P(=O)(OR 11 )2, P(=O)(R 11 )2NR 11 COR 12 , COR 11 , C(O)OR 11 , CON(R 11 )2, OCON(R 11 ), and OCON(R 11 )2, and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group, heteroaryl substituent is further optionally substituted with halo, NO2, C 1-6 alkyl, cycloalkyl, aryl, CF3, N(R 11 )2, CN, or OR 11 ; and wherein each of R 11 and R 12 is independently of each other and at each occurrence selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl and CF3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and aralkyl substituents are optionally substituted with halo, C 1-6 alkyl, cycloalkyl, or heterocyclic group; - Each of R4 and R'4 is independently of one another and in each occurrence selected from hydrogen or C 1-6 alkyl; and wherein z is an integer equal to 1; - Each of -R7 is independently of one another and, each time it appears, is hydrogen or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, etc.; - Each of R3 is independently of one another and, each time it appears, is selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, CF3, CN, OR 21 , and N(R 21 )2, wherein said alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, C 1-6 alkyl, CF3, N(R 21 )2, CN, or OR 21 ; and wherein each of R 21 is independently of one another and, each time it appears, is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl, and wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl substituents are optionally substituted with halo, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, or aryl; each r is an integer equal to 0 or 1; - Each R2 is independently of the others and, each time it appears, is selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, CN, OR 21 , and N(R 21 )2, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from halo, C 1-6 alkyl, cycloalkyl, N(R 21 )2, CN, or OR 21 ; wherein each R 21 is independently of the others and, each time it appears, is selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl. - R8 is selected from the group consisting of: C 6-12 alkyl, cycloalkyl, and heterocyclic group, wherein said alkyl, cycloalkyl, and heterocyclic group are optionally substituted by a halogen atom, CF3, N(R 11 )2, CN, or OR 11 ; and wherein each of R 11 is independently of one another and in each occurrence selected from the group consisting of: hydrogen, and C 1-6 alkyl. -R9 is selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, N(R 11 )2, and CN, wherein said alkyl and cycloalkyl are optionally substituted with a halogen atom, CF3, CN, or OR 11 ; and wherein each of R 11 is independently of one another and at each occurrence selected from the group consisting of: hydrogen, C 1-6 alkyl, C 2-6 alkenyl, and CF3, wherein said alkyl and alkenyl substituents are optionally substituted with a heteroaryl group optionally substituted with C 1-4 alkyl, provided that if x = 0 and y = 0, then R9 is different from hydrogen and C 1-6 alkyl, wherein said alkyl is optionally substituted with a heterocyclic group and N(R 11 )2, and provided that when x = 0 and y = 0, then R9 and R2 may together form a saturated or unsaturated ring moiety; Provided that when x = 0 and y = 0, and when R9 and R2 together form a saturated or unsaturated ring moiety, then R9 is NR 11 ; provided that when x = 1 and y = 1, then R9 is different from N(R 11 )2; and provided that when x = 0, y = 0 and z = 0, then R9 is different from pyrrole. - Each of T is independently a moiety of formula (T-a) below: Wherein: -Each U is independently of one another and, each time it occurs, is selected from C, C-halo, C-R, or N; where R is hydrogen or C 1-4 alkyl, provided that at least one U is different from N, and more preferably, each U is independently of one another and, each time it occurs, is selected from C, C-R or N; where R is hydrogen or C 1-4 alkyl, provided that at least one U is different from N; -Z, each independently of the others and preferably, each time it appears, selected from the group consisting of: CH2, and O, S and NR7, where R7 is hydrogen, or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and isobutyl; -Each of R5 is independently of one another and preferably, each occurrence, is selected from the group consisting of: C 1-6 alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, halogenated, CF3, OR 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, CON(R 11 )2, and each optional alkyl, cycloalkyl, aryl, heterocyclic group, heteroaryl, aralkyl substituent is further optionally substituted by halogenated, C 1-6 alkyl, cycloalkyl, aryl, heterocyclic group, N(R 11 )2, CN, OR 11 , C(=O)OR 11 , P(=O)(OR 11 )2, P(=O)(R 11 )2, CN or CF3, and wherein each of R 11 is independently of one another and each occurrence is selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, and heterocyclic group; each of n1 is an integer equal to 1 or 2; - Each of X is independently a moiety of formula (X-a) below: Wherein: Each of -V is independently of one another and, in each occurrence, is selected from the group consisting of: C, C-halo, C-R, and N; where R is hydrogen or C 1-4 alkyl; -Each of R6 is independently of one another and preferably, each occurrence, is selected from the group consisting of: C 1-6 alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, halo, CF3, OR 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, CON(R 11 )2, and each optional alkyl, cycloalkyl, aryl, heterocyclic group, heteroaryl, aralkyl substituent is further optionally substituted by halo, C 1-6 alkyl, cycloalkyl, aryl, heterocyclic group, N(R 11 )2, CN, OR 11 , C(=O)OR 11 , P(=O)(OR 11 )2, P(=O)(R 11 )2, CN or CF3, and wherein each of R 11 is independently of one another and each occurrence is selected from the group consisting of: hydrogen, C 1-6 alkyl, cycloalkyl, and heterocyclic group; and wherein n2 is an integer equal to 0, 1 or 2; - The dashed bond represents an optional triple bond; -R a1 Independently selected from the group consisting of: C 1-4 alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, wherein said alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl and aralkyl are optionally halogenated, NO2, C 1-4 alkyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, CF3, CN, OR 11 , N(R 11 ), and wherein each of R 11 is independently selected from the group consisting of: hydrogen, or C 1-4 alkyl; -R a2 Each of which is independently selected from the group consisting of: C 1-4 alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, aralkyl, wherein the alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl and aralkyl are optionally halogenated, NO2, C 1-4 alkyl, cycloalkyl, heterocyclic group, phenyl, heteroaryl, CF3, CN, OR 11 , N(R 11 ), and wherein each of R 11 is selected from the group consisting of: hydrogen, or C 1-4 alkyl. Wherein the cycloalkyl is a monocyclic, bicyclic or tricyclic ring system having 3 to 6 ring members per ring; the heterocyclic group is a saturated, partially saturated or fully saturated monocyclic, bicyclic or tricyclic containing 3 to 12 carbon atoms and 1 or 2 heteroatoms independently selected from O or N; the aryl is phenyl, naphthyl or anthracenyl, which is an optionally fused carbocyclic ring with a cycloalkyl or heterocyclic group having 5 to 7 ring members; the heteroaryl is a monocyclic structure having 5 or 6 ring atoms containing 1 to 3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

3. The compound (C) of formula (II) or (III) or its N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer according to claim 1, wherein the compound is a compound of formula (II-a) or (II-b) [compound (C) of class (II) below] or a compound of formula (III-a) [compound (C) of class (III) below]: Wherein A, R4, R4’, z, R7, R3, r, R2, q, R9 and T are as defined in claim 1 or claim 2.

4. A compound (C) of formula (IV) or formula (VI) according to claim 1, or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer thereof, wherein the compound is a compound of formula (IV-a) to (IV-c) [compound (C) of class (IV) below] or a compound of formula (VI-a) to (VI-c) [compound (C) of class (VI) below]: wherein A, R4, R4’, z, R7, R3, r, R2, q, T, and X are as defined in claim 1 or claim 2.

5. A compound (C) of formula (VII) according to claim 1, or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer thereof, wherein the compound is a compound of formula (VII-a) or (VII-b) [compound (C) of class (VII) below]: wherein A, R4, R4’, z, R7, R3, r, R2, q, R a1 , R a2 and n3 are as defined in claim 1 or claim 2.

6. A compound (C) of formula (II) according to claim 1, or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer thereof, wherein the compound is a compound of formula (II-a-1) or (II-b-1) or (II-c-1) [compound (C) of class (II) below]: wherein A, R4, R3, R2, and R9 have the same meanings as defined above for formula (II); wherein R 31 is a heteroaryl, which is optionally substituted by C 1-4 alkyl, wherein R 11 ' is hydrogen or C 1-4 alkyl; and wherein R b is selected from the group consisting of: hydrogen, halo, C 1-4 alkyl, and C 1-6 cycloalkyl. wherein the heteroaryl is a monocyclic structure having 5 or 6 ring atoms containing 1-3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

7. A compound (C) of formula (IV) or (VI) according to claim 1, or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer thereof, wherein the compound is a compound of formula (IV-a-1) to (IV-c-1) [compound (C) of class (IV) below] or a compound of formula (VI-a-1) to (VI-c-1) [compound (C) of class (VI) below]: wherein A, R4, R3, R2, T, and X are as defined in claim 1 or claim 2.

8. A compound (C) of formula (VII) according to claim 1, or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer thereof, wherein the compound is a compound of formula (VII-a-1) or (VII-b-1) [compound (C) of class (VII) below]: wherein A, R4, R3, R2, R a1 , R a2 , and n3 are as defined in claim 1 or claim 2.

9. A compound (C) of formula (II) according to claim 1, or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer thereof, wherein the compound is a compound of formula (II-a-2), or (II-b-2), or (II-c-2) [compound (C) of class (II) below]: wherein: Each of -R9’ is selected from the group consisting of: hydrogen, CN, and C 3-6 cycloalkyl, such as cyclopropyl; Each of "-R9" is selected from the group consisting of: hydrogen, C 1-4 alkyl, CN, and C 3-6 cycloalkyl, such as cyclopropyl; - Each R2 is independently selected from hydrogen or halo; -R q each of which is independently selected from the group consisting of hydrogen, CH3, OCH3, and halo, such as F or Cl; -R 10 each independently selected from the group consisting of: H, F, Cl, OCH3, or CF3; Each of -U is selected from the group consisting of: C, C-R 10 and N; -n 10 is an integer equal to 0, 1 or 2; -R 31 each of which is selected from the group consisting of: pyrazinyl, N-methylpyrazinyl, and pyridinyl. -R b ’ is selected from the group consisting of: hydrogen, halogenated, C 1-4 alkyl, and C 1-4 cycloalkyl; preferably R b ’ is selected from the group consisting of: Cl, CH3, and cyclopropyl; - The dashed bond represents an optional double bond.

10. The compound (C) of formula (IV) according to claim 1, or its N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer, wherein the compound is a compound of formula (IV-a-2-1), (IV-a-2-2), (IV-b-2-1), (IV-b-2-2), or (IV-c-2-1) to (IV-c-2-4) [compound (C) of class (IV) below]: Wherein: - T are each independently and each occurrence is selected from the moieties of formula (T-a-a) to (T-a-f) below: Wherein: -Each R’ is independently hydrogen, C 1-4 alkyl, cycloalkyl selected from the group consisting of cyclopropyl and cyclobutyl; heterocyclic group selected from the group consisting of: oxetanyl, tetrahydropyranyl, azetidinyl, and piperidinyl; wherein said alkyl is further optionally substituted by F, OC 1-4 alkyl, P(=O)(OC 1-4 alkyl)2, P(=O)(C 1-4 alkyl)2, CN, cyclopropyl, or cyclobutyl; and wherein said heterocyclic group is further optionally substituted by C(=O)(OC 1-4 alkyl), -R”5 is each independently selected from the group consisting of: hydrogen, C 1-4 alkyl, CF3 and cyclopropyl; - Each of n1 is independently and each occurrence is an integer equal to 0, 1 or 2. - R2 is independently hydrogen, halo, or NH2; -R q each independently selected from the group consisting of: H, CH3, OCH3, and halo, such as F or Cl; -R 10 each independently selected from the group consisting of: hydrogen, halo, C 1-4 alkyl, CF3, OC 1-4 alkyl, CN, - Each of U and V is independently C, C-R 10 or N; -n 10 is an integer equal to 0, 1, or 2.

11. The compound (C) of formula (VI) according to claim 1, or its N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer, wherein the compound is a compound of formula (VI-a-2) to (VI-c-2) [compound (C) of class (VI) below]: Where -R”6 is each independently selected from the group consisting of: hydrogen, halo, C 1-4 alkyl, N(R 21 )2, OR 21 ; a heterocyclic group selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and pyrazinyl, wherein the heterocyclic group and the pyrazinyl group are optionally substituted by C 1-4 alkyl, and wherein R 21 is C 1-4 alkyl. -R q each independently selected from the group consisting of: H, CH3, OCH3, and halo, such as F or Cl. -R 10 each independently selected from the group consisting of: hydrogen, halo, OC -4 alkyl, and CN; Each of -U is independently C, C-R 10 or N; -n 10 is an integer equal to 0, 1 or 2; - n2 is an integer equal to 0, 1 or 2.

12. The compound (C) of formula (VII) according to claim 1, or its N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer, wherein the compound is a compound of formula (VII-a-2) [compound (C) of class (VI) below]: where Ra’1 is selected from the group consisting of: benzyl, pyrazinyl, OH, OC 1-4 alkyl, NH2, and NH(C 1-4 alkyl), and where R q is selected from the group consisting of: H, CH3, OCH3, and halo, such as F or Cl; preferably R q is H or CH3.

13. The compound (C) of formula (IV-a-1), (IV-b-1), or (IV-c-1), (VI-a-1), (VI-b-1) or (VI-c-2) according to claim 7, or its N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer, wherein the compounds of formula (IV-a-1), (IV-b-1), (IV-c-1), (VI-a-1), (VI-b-1) or (VI-c-2) are compounds according to formula (XXXVII) to (CCLX) below:

14. A pharmaceutical composition comprising a carrier and a compound (C) according to any one of claims 1 to 13 as an active ingredient.

15. The compound (C) according to any one of claims 1 to 13 for use as a medicament.

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