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 is in the field of medicinal chemistry and medicine. [Background technology]

[0002] Protein phosphorylation is the most common form of reversible post-translational modification, with an estimated 50% of all proteins undergoing phosphorylation. The phosphorylation state of any given protein is controlled by the coordinated action of specific kinases and phosphatases, which add and remove phosphates, respectively. In particular, protein kinases are a type of protein phosphotransferase that transfer the phosphate of ATP to specific amino acid residues. These can be conventionally divided into five classes: tyrosine protein kinases, serine / threonine protein kinases, histidine protein kinases, tryptophan protein kinases, and aspartyl / glutamoyl protein kinases.

[0003] Signaling networks that utilize phosphorylation to regulate target activity have been shown to be critically involved in all aspects of cellular function, and aberrant activation of protein phosphorylation is frequently either a driver or a direct consequence of disease. Dysregulation of kinase signaling pathways is associated with cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, and metabolic disorders through the constitutive activation of many downstream pathways, including phosphatidyl-inositol 3-kinase / v-akt murine thymoma viral oncogene homolog 1 (PIK3 / AKT), mitogen-activated protein kinase (MAPK) / extracellular signal-regulated kinase (ERK), and signal transducer and activator of transcription 5 (STAT5). Consequently, protein kinases represent important therapeutic targets.

[0004] In tumors, abnormal oncogenic activation of protein kinases results from multiple types of genetic and epigenetic alterations. These alterations result in increased specific activity of the kinase itself, its overexpression, or loss of negative regulation, leading to uncontrolled cell proliferation and persistent malignant behavior. Signaling networks operating in cancer cells can also contribute to innate or acquired resistance to treatment, as they can generate the most common oncogenic mutations or rare oncogenic mutations that vary from tumor to tumor. Therefore, the search 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 may be (isolated) products derived from sources such as plants, animals or microorganisms, or may be designed (synthetic) small molecules.

[0006] WO 2004 / 022572 discloses a class of biologically active compounds that interact with kinases, and the preparation of these compounds.

[0007] In oncology, there are now multiple examples of small molecule kinase inhibitors with both selectivity and favorable pharmacological properties that produce meaningful clinical benefit. 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), e.g., in the treatment of patients with symptomatic tenosynovial giant cell tumor (TGCT); edicotinib is used to inhibit CSF1R and acute myeloid leukemia, cognitive impairment, or Crohn's disease and is currently in Phase II; or nintedanib is used to inhibit vascular endothelial growth factor receptor (VEGFR), fibroplast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and CSF1R, e.g., in the treatment of idiopathic pulmonary fibrosis.

[0008] There remains a great need to develop potent inhibitors of protein kinases that are useful in treating a variety of protein kinase-associated pathologies.

[0009] In this sense, WO 2011 / 090738 A2 discloses compounds capable of inhibiting B-RAF and B-RAF mutations, as well as methods for treating diseases associated with the regulation of B-RAF and B-RAF mutations.

[0010] U.S. Patent Application Publication No. 2009 / 0325945 describes active compounds, specifically certain imidazo[4,5-b]pyridin-2-one and oxazolo[4,5-b]pyridin-2-one compounds and analogs, that inhibit RAF (e.g., B-RAF) activity in cells in vitro or in vivo, receptor tyrosine kinase (RTK) activity, such as FGFR, Tie, VEGFR, or Eph activity, such as FGFR-1, FGFR-2, FGFR-3, Tie2, VEGFR-2, and / or EphB2 activity, in cells in vitro or in vivo.

[0011] US Patent Application Publication No. 2015 / 0182526: This document describes, inter alia, therapeutic compounds and more specifically certain pyrido[2,3-b]pyrazine-8-substituted compounds for treating proliferative disorders, cancer, and the like, that inhibit RAF (e.g., B-RAF) activity and inhibit receptor tyrosine kinase (RTK) activity. Summary of the Invention [Problem to be solved by the invention]

[0012] However, despite the considerable efforts being made to develop novel protein kinase inhibitor-based therapies, there remains a need for protein kinase inhibitors that can overcome the disadvantages of current protein kinase treatments, such as side effects, limited efficacy, the emergence of resistance, and non-compliance. [Means for solving the problem]

[0013] The inventors have surprisingly found that the use of protein kinase inhibitors according to the present invention makes it possible to improve the treatment of dysregulated protein kinase-related diseases by developing treatments that are more effective, have reduced side effects, limit the emergence of resistance and promote compliance.

[0014] Accordingly, the present invention provides a compound suitable for use as a protein kinase inhibitor according to any one of formulas (I) to (VII) [hereinafter compound (C)], or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof. TIFF2025539843000001.tif185170, wherein: each A is independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl, and said aralkyl are independently selected from the group consisting of halo, NO, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, OR 11 , S.R. 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 , C.O.R. 11 , C(O)OR 11 , CON(R 11 )2, OC(O)R 11 and OCON(R 11and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl substituent may further be selected from the group consisting of halo, NO, 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, independently of each other, when they occur, are optionally replaced by R 11 and R 12 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, C 1-6 alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2, optionally replaced by R 31 and R 32 Each of, independently of the other, when it occurs, is selected from hydrogen and C 1-4 is selected from the group consisting of alkyl, - Each of R4 and R'4, when occurring, independently of each other, is hydrogen or C 1-6 alkyl, z is an integer ranging from 0 to 2, with the proviso that when z=0, A and R7 together may form a saturated or unsaturated cyclic moiety; Each occurrence of -R7 is independently hydrogen, C 1-6 alkyl, cycloalkyl, wherein the alkyl and cycloalkyl are selected from halogen atoms, CF, N(R 11 )2, CN, or OR 11 optionally replaced by R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C1-6 selected from the group consisting of alkyl and CF3; Each occurrence of -R3, independently of the others, is selected from hydrogen, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, CF3, CN, OR 21 , S.R. 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 said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl and said aralkyl are selected from the group consisting of halo, C 1-6 Alkyl, CF3, N(R 21 )2, CN, or OR 21 and R 21 and R 22 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, OR 31 or N(R 32 )2, optionally replaced by R 31 and R 32 Each of, independently of the other, when it occurs, is selected from hydrogen and C 1-4alkyl, and each r is an integer ranging from 0 to 3, with the proviso that R3 = NR 21 and provided that when R7=H, R3 and NR7 may together form a saturated or unsaturated cyclic moiety; Each occurrence of -R2, independently of the other, is selected from hydrogen, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, CF3, CN, NO2, OR 21 , S.R. 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, said alkenyl, said alkynyl, said cycloalkyl, said heterocyclyl, said aryl and said heteroaryl are selected from the group consisting of halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, 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, heterocyclyl, aryl, or heteroaryl substituent may further be selected from heterocyclyl, N(R 11 )2 OR 11 optionally replaced by R 21 and R 22 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, OR 31 or N(R 32 )2, optionally replaced by R 31 and R 32 Each of, independently of the other, when it occurs, is selected from 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 C 6-12 Alkyl, C 2-6 Alkenyl, C 2-6 Independently selected from alkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl, and the heterocyclyl are selected from halogen atoms, aryl groups, aralkyl groups, CF, N(R 11 )2, CN, or OR 11 is optionally replaced by R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are selected from the group consisting of halo, C 1-6 alkyl, cycloalkyl, heterocyclyl, alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2, optionally replaced by R 31 and R 32 Each of, independently of the other, when it occurs, is selected from hydrogen and C 1-4 is selected from the group consisting of alkyl, -R9 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, N(R 11 )2 and CN, and the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocyclyl are selected from the group consisting of a halogen atom, an aryl group, an aralkyl group, a heterocyclyl group, CF3, N(R 11 )2, CN, or OR 11 is optionally replaced by R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF3; 1-4 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and heteroaryl optionally substituted with alkyl, aryl, heteroaryl, and aralkyl substituents are optionally substituted with halo, C 1-6 alkyl, cycloalkyl, heterocyclyl, alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2, optionally replaced by R 31 and R 32 Each of, independently of the other, when it occurs, is selected from hydrogen and C 1-4 alkyl, with the proviso that x=1 and y=0, R9 is selected from the group consisting of heterocyclyl and C 1-6 The alkyl is optionally substituted with heterocyclyl, provided that x=0 and y=0, R9 is selected from hydrogen and C 1-6 The alkyl is distinct from heterocyclyl and N(R 11 )2, with the proviso that when x=0 and y=0, R9 and R2 together may form a saturated or unsaturated cyclic moiety, with the proviso that when x=0 and y=0, R9 and R2 together form a saturated or unsaturated cyclic moiety, and R9 is NR 11However, under the condition that x=1 and y=1, R9 is N(R 11 )2, provided that x=0, y=0 and z=0, R9 is different from pyrrole, Each of -T is independently a moiety of formula (Ta) herein: TIFF2025539843000002.tif29170 formula, Each occurrence of -U is independently selected from the group consisting of C, C-halo, CR, and N, where R is a halogen atom, a hydrogen optionally substituted with an aryl or aralkyl group, OR 11 , N(R 11 )2, C 1-6 alkyl or cycloalkyl; R 11 Each of, independently of the other, when it occurs, is hydrogen or C 1-4 alkyl, with the proviso that at least one U is different from N; Each Z, independently of the other, when it occurs, is selected from C(R), O, S, and NR, where R, independently of the other, when it occurs, is hydrogen or C optionally substituted with a halogen atom, an aryl group, or an aralkyl group. 1-6 alkyl; R7 is selected from hydrogen, C 1-6 Alkyl, C 1-6 selected from the group consisting of alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF3; - Each of R5, when occurring, independently of one another, is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, CF3, OR 11 , S.R. 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, CON(R 11 and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent may further be selected from the group consisting of halo, C 1-6Alkyl, cycloalkyl, aryl, heterocyclyl, 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 optionally further substituted with R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, and each n1 is an integer ranging from 0 to 2; Each of -X is independently a moiety of formula (Xa) as used herein: TIFF2025539843000003.tif29170 formula, Each V, when present, is independently selected from the group consisting of C, C-halo, CR, and N, where R is a halogen atom, a hydrogen optionally substituted with an aryl or aralkyl group, OR 11 , N(R 11 )2, C 1-6 alkyl or cycloalkyl; R 11 Each of, independently of the other, when it occurs, is hydrogen or C 1-4 alkyl, Each of R6 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, CF3, OR 11 , S.R. 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, CON(R 11 )2, wherein each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent is selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, 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 R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, and each n2 is an integer ranging from 0 to 4; -The dash bond represents any triple bond, -R a1 is hydrogen, C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, COR 11 , C(O)OR 11 wherein the alkyl, the cycloalkyl, the heterocyclyl, the aryl, the heteroaryl, and the aralkyl are independently selected from the group consisting of halo, NO, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, COR 11 and C(O)OR 11 and each optional alkyl, alkenyl, cycloalkyl, phenyl, heterocyclyl, heteroaryl substituent is optionally substituted by halo, NO, C 1-6 Alkyl, cycloalkyl, phenyl, N(R 11 )2, CN or OR 11 and optionally further replaced by R 11 Each of these is hydrogen, C 1-6 selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl and aralkyl, wherein said alkyl, said cycloalkyl, said heterocyclyl, said phenyl, said heteroaryl and said aralkyl substituents are selected from the group consisting of halo, C 1-6 optionally substituted with alkyl, cycloalkyl, or heterocyclyl; -R a2Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, COR 11 , C(O)OR 11 wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, the heteroaryl, and the aralkyl are selected from the group consisting of halo, NO, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, COR 11 and C(O)OR 11 and each optional alkyl, alkenyl, cycloalkyl, phenyl, heterocyclyl, heteroaryl substituent is optionally substituted by halo, NO, C 1-6 Alkyl, cycloalkyl, phenyl, N(R 11 )2, CN or OR 11 and optionally further replaced by R 11 Each of these is hydrogen, C 1-6 selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl and aralkyl, wherein said alkyl, said cycloalkyl, said heterocyclyl, said phenyl, said heteroaryl and said aralkyl substituents are selected from the group consisting of halo, C 1-6 optionally substituted with alkyl, cycloalkyl, or heterocyclyl, and n3 is an integer equal to 0 or 1, provided that when the dashed bond is a triple bond, then n3 is 0; The cycloalkyl is a monocyclic, bicyclic, or tricyclic ring system having 3 to 6 ring members per ring; the heterocyclyl is a saturated, partially saturated, or fully saturated monocyclic, bicyclic, or tricyclic ring containing 3 to 12 carbon atoms, in which one or two heteroatoms are independently selected from O or N; the aryl is a phenyl, naphthyl, or anthracenyl optionally carbocyclically fused with a cycloalkyl or heterocyclyl having 5 to 7 ring members, in which the heteroaryl is a monocyclic ring structure containing 5 to 6 ring atoms or a bicyclic aromatic group having 8 to 10 atoms, in which one to three heteroatoms are independently selected from O or N.

[0015] 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 embodiments presented herein as an active ingredient.

[0016] The present invention relates to a compound as defined in any one of the embodiments presented herein for use as a medicament.

[0017] The present invention relates to a method for treating cancer, metabolic diseases (e.g., diabetes), inflammatory and autoimmune diseases (e.g., inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, inflammatory lung diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, psoriasis and psoriatic arthritis), neurological diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis, epilepsy), arteriosclerosis and cardiovascular diseases, Sjogren's syndrome, renal transplant rejection. The present invention relates to a compound as defined in any one of the embodiments presented herein for use in the treatment of a disease selected from: osteoporosis, osteoarthritis, rheumatoid art ...

[0018] The present invention relates to a compound as defined in any one of the embodiments presented herein for use in the treatment of pain sensitization.

[0019] The present invention further relates to a method for inhibiting protein kinase activity in a warm-blooded animal, said method comprising administering to an animal in need of treatment an effective kinase-inhibiting amount of a compound according to any one of the embodiments presented herein.

[0020] The present invention relates to the treatment of warm-blooded animals with cancer, metabolic diseases (e.g., diabetes), inflammatory and autoimmune diseases (e.g., inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, inflammatory lung diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, psoriasis and psoriatic arthritis), neurological diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis, epilepsy), arteriosclerosis and cardiovascular diseases, Sjogren's syndrome, renal transplant rejection, viral infections, and the like. The present invention further relates to a method of treating a disease selected from cancer-induced diseases, cardiovascular diseases, hyperresorption (osteolysis) and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, ophthalmic diseases (e.g., retinopathy, age-related macular degeneration, and uveitis), chronic pain and neuropathic pain, and fibroproliferative diseases, said method comprising administering to an animal in need of treatment an effective amount of a compound according to any one of the embodiments presented herein. DETAILED DESCRIPTION OF THE INVENTION

[0021] A first aspect of the present invention relates to a compound suitable for use as a protein kinase inhibitor according to any one of formulas (I) to (VII) [hereinafter compound (C)], or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof, TIFF2025539843000004.tif197170 formula (I) During the ceremony, Each A is independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein said cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl are independently selected from halo, NO, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, OR 11 , S.R. 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 , C.O.R. 11 , C(O)OR 11 , CON(R 11 )2, OC(O)R 11 , and OCON(R 11 and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl substituent may further be selected from the group consisting of halo, NO, 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, independently of each other, when they occur, are optionally replaced by R 11 and R 12 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, C 1-6 alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2, optionally replaced by R 31 and R 32 Each of, independently of the other, when it occurs, is selected from hydrogen and C 1-4 is selected from the group consisting of alkyl, - Each of R4 and R'4, when occurring, independently of each other, is hydrogen or C 1-6 alkyl, z is an integer ranging from 0 to 2, with the proviso that when z=0, A and R7 together may form a saturated or unsaturated cyclic moiety; Each occurrence of -R7 is independently hydrogen, C 1-6 alkyl, cycloalkyl, wherein the alkyl and cycloalkyl are selected from halogen atoms, CF, N(R 11 )2, CN, or OR 11 optionally replaced by R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 selected from the group consisting of alkyl and CF3; Each occurrence of -R3, independently of the others, is selected from hydrogen, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, CF3, CN, OR 21 , S.R. 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 said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl and said aralkyl are selected from the group consisting of halo, C 1-6 Alkyl, CF3, N(R 21 )2, CN, or OR 21 and R 21 and R 22 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, OR 31 or N(R 32 )2, optionally replaced by R 31 and R 32 Each of, independently of the other, when it occurs, is selected from hydrogen and C 1-4 alkyl, and each r is an integer ranging from 0 to 3, with the proviso that R3 = NR 21 and provided that when R7=H, R3 and NR7 may together form a saturated or unsaturated cyclic moiety; Each occurrence of -R2, independently of the other, is selected from hydrogen, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, CF3, CN, NO2, OR 21 , S.R. 21 , N(R 21 )2, COR 21 , C(O)OR 21 , CON(R21 )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, said alkenyl, said alkynyl, said cycloalkyl, said heterocyclyl, said aryl and said heteroaryl are selected from the group consisting of halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, 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, heterocyclyl, aryl, or heteroaryl substituent may further be selected from heterocyclyl, N(R 11 )2 OR 11 optionally replaced by R 21 and R 22 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, OR 31 or N(R 32 )2, optionally replaced by R 31 and R 32 Each of, independently of the other, when it occurs, is selected from 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 C 6-12 Alkyl, C 2-6 Alkenyl, C 2-6 Independently selected from alkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl, and the heterocyclyl are selected from halogen atoms, aryl groups, aralkyl groups, CF, N(R 11 )2, CN, or OR 11 is optionally replaced by R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are selected from the group consisting of halo, C 1-6 alkyl, cycloalkyl, heterocyclyl, alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2, optionally replaced by R 31 and R 32 Each of, independently of the other, when it occurs, is selected from hydrogen and C 1-4 is selected from the group consisting of alkyl, -R9 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, N(R 11 )2 and CN, and the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocyclyl are selected from the group consisting of a halogen atom, an aryl group, an aralkyl group, a heterocyclyl group, CF3, N(R 11 )2, CN, or OR 11 Optionally replaced by ; and R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF3; 1-4 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and heteroaryl optionally substituted with alkyl, aryl, heteroaryl, and aralkyl substituents are optionally substituted with halo, C 1-6 alkyl, cycloalkyl, heterocyclyl, alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2, optionally replaced by R 31 and R 32 Each of, independently of the other, when it occurs, is selected from hydrogen and C 1-4 alkyl, with the proviso that x=1 and y=0, R9 is selected from the group consisting of heterocyclyl and C 1-6 The alkyl is optionally substituted with heterocyclyl, provided that x=0 and y=0, R9 is selected from hydrogen and C 1-6 The alkyl is distinct from heterocyclyl and N(R 11 )2, with the proviso that when x=0 and y=0, R9 and R2 together may form a saturated or unsaturated cyclic moiety, with the proviso that when x=0 and y=0, R9 and R2 together form a saturated or unsaturated cyclic moiety, and R9 is NR 11 However, under the condition that x=1 and y=1, R9 is N(R 11 )2, provided that x=0, y=0 and z=0, R9 is different from pyrrole, Each of -T is independently a moiety of formula (Ta) herein: TIFF2025539843000005.tif27170 formula, Each occurrence of -U is independently selected from the group consisting of C, C-halo, CR, and N, where R is a halogen atom, a hydrogen optionally substituted with an aryl or aralkyl group, OR 11 , N(R 11 )2, C 1-6alkyl or cycloalkyl; R 11 Each of, independently of the other, when it occurs, is hydrogen or C 1-4 alkyl, with the proviso that at least one U is different from N; Each Z, independently of the other, when it occurs, is selected from C(R), O, S, and NR, where R, independently of the other, when it occurs, is hydrogen or C optionally substituted with a halogen atom, an aryl group, or an aralkyl group. 1-6 alkyl; R7 is selected from hydrogen, C 1-6 Alkyl, C 1-6 selected from the group consisting of alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF3; - Each of R5, when occurring, independently of one another, is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, CF3, OR 11 , S.R. 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, CON(R 11 and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent may further be selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, 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 optionally further substituted with R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, and each n1 is an integer ranging from 0 to 2; Each of -X is independently a moiety of formula (Xa) as used herein: TIFF2025539843000006.tif28170 formula, Each V, when present, is independently selected from the group consisting of C, C-halo, CR, and N, where R is a halogen atom, a hydrogen optionally substituted with an aryl or aralkyl group, OR 11 , N(R 11 )2, C 1-6 alkyl or cycloalkyl; R 11 Each of, independently of the other, when it occurs, is hydrogen or C 1-4 alkyl, Each of R6 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, CF3, OR 11 , S.R. 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, CON(R 11 )2, wherein each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent is selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, 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 R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, and each n2 is an integer ranging from 0 to 4; -The dashed bond represents an optional triple bond; -R a1 is hydrogen, C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, CF3, CN, OR 11 , S.R. 11 , N(R11 )2, COR 11 , C(O)OR 11 wherein the alkyl, the cycloalkyl, the heterocyclyl, the aryl, the heteroaryl, and the aralkyl are independently selected from the group consisting of halo, NO, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, COR 11 and C(O)OR 11 and each optional alkyl, alkenyl, cycloalkyl, phenyl, heterocyclyl, heteroaryl substituent is optionally substituted by halo, NO, C 1-6 Alkyl, cycloalkyl, phenyl, N(R 11 )2, CN or OR 11 and optionally further replaced by R 11 Each of these is hydrogen, C 1-6 selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl and aralkyl, wherein said alkyl, said cycloalkyl, said heterocyclyl, said phenyl, said heteroaryl and said aralkyl substituents are selected from the group consisting of halo, C 1-6 optionally substituted with alkyl, cycloalkyl, or heterocyclyl; -R a2 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, COR 11 , C(O)OR 11 wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, the heteroaryl, and the aralkyl are selected from the group consisting of halo, NO, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, COR 11 and C(O)OR 11 and each optional alkyl, alkenyl, cycloalkyl, phenyl, heterocyclyl, heteroaryl substituent is optionally substituted by halo, NO, C 1-6 Alkyl, cycloalkyl, phenyl, N(R 11 )2, CN or OR 11 and optionally further replaced by R 11 Each of these is hydrogen, C 1-6 selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl and aralkyl, wherein said alkyl, said cycloalkyl, said heterocyclyl, said phenyl, said heteroaryl and said aralkyl substituents are selected from the group consisting of halo, C 1-6 optionally substituted with alkyl, cycloalkyl, or heterocyclyl, and n3 is an integer equal to 0 or 1, provided that when the dashed bond is a triple bond, then n3 is 0; The cycloalkyl is a monocyclic, bicyclic, or tricyclic ring system having 3 to 6 ring members per ring; the heterocyclyl is a saturated, partially saturated, or fully saturated monocyclic, bicyclic, or tricyclic ring containing 3 to 12 carbon atoms, in which one or two heteroatoms are independently selected from O or N; the aryl is a phenyl, naphthyl, or anthracenyl optionally carbocyclically fused with a cycloalkyl or heterocyclyl having 5 to 7 ring members; and the heteroaryl is a monocyclic ring structure containing 5 to 6 ring atoms or a bicyclic aromatic group having 8 to 10 atoms, in which one to three heteroatoms are independently selected from O or N.

[0022] In a preferred embodiment of the present invention, A in the compound (C) of formulas (I) to (VII) is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl, and the cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are each independently selected from halo, NO, C1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, OR 11 , S.R. 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 , C.O.R. 11 , C(O)OR 11 , CON(R 11 )2, OC(O)R 11 , and OCON(R 11 )2, wherein each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl substituent is selected from the group consisting of halo, NO, C 1-6 Alkyl, cycloalkyl, aryl, CF3, N(R 11 )2, CN or OR 11 and optionally further replaced by R 11 and R 12 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are selected from the group consisting of halo, C 1-6 More preferably, A is independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl, and said aralkyl are independently selected from the group consisting of halo, C 1-6Alkyl, cycloalkyl, heterocyclyl, 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, heterocyclyl, heteroaryl substituent is optionally substituted with one or more substituents independently selected from the group consisting of: 1-4 is optionally further substituted with alkyl or cycloalkyl, R 11 and R 12 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 More preferably, A is independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF3, wherein said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl, and said aralkyl are independently selected from the group consisting of halo, C 1-6 Alkyl, CF3, CN, OR 11 , and P(=O)(R 11 )2, optionally substituted with one or more substituents independently selected from the group consisting of: 11 Each of the following, when it occurs, is hydrogen or a C alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and isobutyl. 1-4 It is alkyl.

[0023] In one embodiment of the present invention, A in compound (C) of formula (I)-(VII) is independently selected from the following moieties: TIFF2025539843000007.tif116170 wherein each halo is F, Cl, Br, or I, and each R is hydrogen or a C alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and isobutyl. 1-4 alkyl, preferably R is hydrogen, methyl, ethyl, 2-methylpropyl or tert-butyl.

[0024] In a preferred embodiment of the present invention, each of R4 in the compound (C) of formulas (I) to (VII) is hydrogen or a C methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, etc. 1-4 Even more preferably, R4 is hydrogen or methyl.

[0025] In a preferred embodiment of the present invention, R4 in compound (C) of formula (I) to (VII) ’ Each of the C groups is hydrogen or methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, etc. 1-4 Even more preferably, R4' is hydrogen.

[0026] In a preferred embodiment of the present invention, z in compounds (C) of formulae (I) to (VII) is an integer equal to 0 or 1. Even more preferably, z is 1.

[0027] In a preferred embodiment of the present invention, each R7 in the compound (C) of formula (I) to (VII) is, independently of one another, when it occurs, hydrogen or a C group such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, etc. 1-4 More preferably, each R7, independently of each other, when it occurs, is hydrogen or methyl. Even more preferably, each R7, independently of each other, when it occurs, is hydrogen.

[0028] In a preferred embodiment of the present invention, each R3 in the compound (C) of the formulas (I) to (VII) is, independently of each other, selected from the group consisting of hydrogen, halo, C 1-6Alkyl, cycloalkyl, heterocyclyl, CF3, CN, OR 21 and N(R 21 )2, wherein said alkyl, said cycloalkyl and said heterocyclyl are selected from the group consisting of halo, C 1-6 Alkyl, CF3, N(R 21 )2, CN or OR 21 and R 21 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are selected from the group consisting of halo, C 1-6 Optionally substituted with alkyl, cycloalkyl, heterocyclyl or aryl, preferably R3 is hydrogen, halo, C 1-6 Alkyl, cycloalkyl, CF3, CN, OR 21 and N(R 21 )2, wherein said alkyl and said cycloalkyl are independently selected from halo, C 1-6 Alkyl, CF3, N(R 21 )2, CN or OR 21 and R 21 Each of the following, when occurring, independently of one another, is selected from hydrogen and C groups such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and isobutyl. 1-4 More preferably, R3 is selected from the group consisting of hydrogen, halo, and methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, CF3, CN, OR 21 and N(R 21 )2 etc. 1-4 alkyl; R 21 Each of, independently of the other, when it occurs, is selected from hydrogen and C 1-4 More preferably, R3 is selected from the group consisting of hydrogen, halo, OC 1-4C alkyl and C such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and isobutyl 1-4 Even more preferably, R3 is independently selected from the group consisting of hydrogen, halo, OCH3, and methyl.

[0029] In a preferred embodiment of the present invention, each r in 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.

[0030] In a preferred embodiment of the present invention, each R2 in the compound (C) of the formulas (I) to (VII) is, independently of each other, selected from the group consisting of hydrogen, halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, CN, OR 21 , and N(R 21 )2, wherein the alkyl, the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, N(R 21 )2, CN, or OR 21 and R 21 are, independently of each other, hydrogen, C 1-6 More preferably, R2 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl. More preferably, R2 is selected from the group consisting of hydrogen, halo, C 1-4 Alkyl, cycloalkyl, heterocyclyl, CN, OR 21 and N(R 21 )2, and R 21 are, independently of one another, when they occur, C such as hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and isobutyl. 1-4 Alkyl, and C such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl 3-6Even more preferably, R2 is selected from the group consisting of hydrogen, halo, C 1-4 Alkyl and N(R 21 )2, and R 21 is hydrogen and C such as methyl, ethyl, propyl, isopropyl, isopropyl, butyl, tert-butyl and isobutyl. 1-4 alkyl.

[0031] In a preferred embodiment of the present invention, q in the compounds (C) of formulae (I) to (VII) is an integer equal to 0 or 1.

[0032] According to one particular embodiment of the invention, in the compound (C) of formula (II), (IV) or (VI), x is an integer equal to 0 and y is an integer equal to 1.

[0033] According to one particular embodiment of the invention, in compound (C) of formula (II), (IV) or (VI), x is an integer equal to 1 and y is an integer equal to 0.

[0034] According to one particular embodiment of the invention, x of compound (C) of formula (II), (IV) or (VI) is an integer equal to 1 and y is an integer equal to 1.

[0035] According to one particular embodiment of the invention, in the compound (C) of formula (II), (IV) or (VI), x is an integer equal to 0 and y is an integer equal to 0.

[0036] In a preferred embodiment of the present invention, R in compound (C) of formula (I) is C 6-12 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, wherein the alkyl, cycloalkyl, and heterocyclyl are selected from the group consisting of halogen atoms, CF, N(R 11 )2, CN, or OR 11 is optionally replaced by R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6More preferably, R is selected from the group consisting of C 6-12 More preferably, R is C 6-12 It is alkyl.

[0037] In a preferred embodiment of the present invention, R9 in the compound (C) of formula (II) is hydrogen, C 1-6 Alkyl, cycloalkyl, N(R 11 )2 and CN, wherein said alkyl and said cycloalkyl are selected from the group consisting of a halogen atom, CF3, CN or OR 11 is optionally replaced by R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl and CF3, wherein said alkyl and said alkenyl substituents are selected from the group consisting of C 1-4 and optionally substituted with alkyl, heteroaryl, with the proviso that when x=0 and y=0, R9 is selected from hydrogen and C 1-6 The alkyl is distinct from heterocyclyl and N(R 11 )2, with the proviso that when x=0 and y=0, R9 and R2 together may form a saturated or unsaturated cyclic moiety, with the proviso that when x=0 and y=0 and R9 and R2 together form a saturated or unsaturated cyclic moiety, R9 is NR 11 where R9 is the sum of N(R 11 )2, with the proviso that when x=0, y=0 and z=0, R9 is different from pyrrole. More preferably, R9 is hydrogen, C 1-6 Alkyl, cycloalkyl, N(R 11 )2, and CN, wherein said alkyl and said cycloalkyl are selected from the group consisting of a halogen atom, CF3, CN, or OR 11 is optionally replaced by R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 Alkyl, C 2-6alkenyl and CF3, wherein said alkyl and said alkenyl substituents are selected from the group consisting of C 1-4 and optionally substituted with alkyl, heteroaryl, with the proviso that when x=0 and y=0, R9 is selected from hydrogen and C 1-6 The alkyl is different from heterocyclyl and N(R 11 )2, with the proviso that when x=0 and y=0, R9 and R2 together may form a saturated or unsaturated cyclic moiety, with the proviso that when x=0 and y=0 and when R9 and R2 together form a saturated or unsaturated cyclic moiety, R9 is NR 11 where R9 is the sum of N(R 11 )2, with the proviso that when x=0, y=0 and z=0, R9 is different from pyrrole. More preferably, R9 is a C methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and isobutyl. 1-4 C alkyl, propene or butene 2-6 Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, N(R 11 )2 and C such as CN 3-6 cycloalkyl, wherein said alkyl and said cycloalkyl are selected from the group consisting of a halogen atom, CF, CN, or OR 11 is optionally replaced by R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl and CF3, wherein said alkyl and said alkenyl substituents are selected from the group consisting of C 1-4 and optionally substituted with alkyl, heteroaryl, with the proviso that when x=0 and y=0, R9 is selected from hydrogen and C 1-6 The alkyl is distinct from heterocyclyl and N(R 11 )2, with the proviso that when x=0 and y=0, R9 and R2 together may form a saturated or unsaturated cyclic moiety, with the proviso that when x=0 and y=0 and R9 and R2 together form a saturated or unsaturated cyclic moiety, R9 is NR 11where R9 is the sum of N(R 11 )2, except that when x=0, y=0 and z=0, R9 is different from pyrrole.

[0038] In a preferred embodiment of the present invention, in compound (C) of formula (III) or (IV), each T is independently a moiety of formula (Ta) herein below: TIFF2025539843000008.tif27170 formula, Each of -U is preferably, independently of one another, when it occurs, selected from C, C-halo, CR or N, R is hydrogen or C 1-4 alkyl with the proviso that at least one U is different from N, more preferably each of U, independently of each other, when occurring, is selected from C, CR or N, and R is hydrogen or C 1-4 alkyl, with the proviso that at least one U is different from N; Each -Z, independently of the other, when it occurs, is preferably CH and O, S and NR 7’ and R7 is selected from the group consisting of hydrogen or C such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and isobutyl. 1-4 alkyl, more preferably each Z, independently of the other, at each occurrence is selected from the group consisting of CH, O, and NH; Each of R5, independently of the others, when it occurs, is preferably C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, CF3, OR 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, CON(R 11 )2, wherein each optional alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent is selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, 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 R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 More preferably, each R5, independently of the other, when occurring, is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl. 1-4 Alkyl, cycloalkyl, heterocyclyl, CF3, OR 11 and each optional alkyl, cycloalkyl, heterocyclyl substituent is selected from the group consisting of 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, -n1 is preferably an integer equal to 0, 1 or 2, more preferably n1 is an integer equal to 1 or 2.

[0039] In a preferred embodiment of the present invention, each T in the compound (C) of formula (III) or (IV) is, independently of one another, selected from the moieties of formulae (Ta-1) to (Ta-11) herein below, when they occur: TIFF2025539843000009.tif95170In the formula, each R is hydrogen, C 1-4 alkyl, cycloalkyl, and heterocyclyl, 1-4 Alkyl, said cycloalkyl and said heterocyclyl are selected from halo, 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), preferably R is hydrogen or methyl, and each R is hydrogen, C 1-4 n1 is independently selected from the group consisting of alkyl, CF3, and cycloalkyl, and n1 is an integer equal to 1 or 2.

[0040] In a preferred embodiment of the present invention, in compound (C) of formula (V) or (VI), each X is independently a moiety of formula (Xa) as defined herein: TIFF2025539843000010.tif28170 formula, Each V, when present, is independently selected from the group consisting of C, C-halo, CR, and N, and R is hydrogen or C 1-4 alkyl, and more preferably each V, independently of the other, when it occurs, is selected from C, CR or N, and R is hydrogen or C 1-4 is alkyl, Each of R6, independently of the others, when it occurs, is preferably C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, CF3, OR 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, CON(R 11 )2, wherein each optional alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent is selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, 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 R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 More preferably, each R6, independently of the other, when occurring, is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl. 1-4 Alkyl, cycloalkyl, heterocyclyl, heteroaryl, halo, CF3, OR 11 , N(R 11 )2, wherein each optional alkyl, cycloalkyl, heterocyclyl, and heteroaryl substituent is selected from the group consisting of halo, C 1-4Alkyl, cycloalkyl, heterocyclyl, 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, wherein said heterocyclyl is 1-4 is optionally further substituted with alkyl, R 11 Each of, independently of the other, when it occurs, is selected from hydrogen and C 1-4 alkyl, and even more preferably, each R6, independently of the other, when occurring, is selected from the group consisting of C 1-4 Alkyl, cycloalkyl, heterocyclyl, heteroaryl, halo, CF3, OR 11 , N(R 11 )2, and each optional alkyl, cycloalkyl, heterocyclyl, and heteroaryl substituent is selected from the group consisting of C 1-4 and optionally further substituted with alkyl or heterocyclyl, said heterocyclyl being 1-4 is optionally further substituted with alkyl, R 11 Each of the 1-4 is selected from the group consisting of alkyl, -n2 is preferably an integer equal to 0, 1 or 2, and more preferably n1 is an integer equal to 0 or 1.

[0041] In one embodiment of the present invention, in compound (C) of formula (V) or (VI), each X is independently selected from the cyclic moieties of formulas (Xa-1) to (Xa-3) herein below: TIFF2025539843000011.tif28170 formula, Each of -R6' is hydrogen, halo, C 1-4 Alkyl, OC 1-4 Alkyl, NH2, N(C 1-4 alkyl), heterocyclyl, and heteroaryl; 1-4 Alkyl, the heteroaryl and the heterocyclyl are optionally substituted with halo, C 1-4 Alkyl, C 1-4Optionally substituted heterocyclyl which is optionally substituted with alkyl. -n2 is an integer equal to 1 or 2.

[0042] In a preferred embodiment of the present invention, the dashed bond in compound (C) of formula (VII) represents a triple bond.

[0043] In a preferred embodiment of the present invention, R in compound (C) of formula (VII) a1 is C 1-4 Independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein said alkyl, said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl, and said aralkyl are selected from the group consisting of halo, NO, C 1-4 Alkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, CF3, CN, OR 11 , N(R 11 )2, optionally replaced by R 11 Each of 1-4 alkyl. More preferably, R a1 is C 1-4 independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein said alkyl, said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl, and said aralkyl are independently selected from the group consisting of halo, heterocyclyl, aryl, heteroaryl, OR 11 , N(R 11 )2, optionally replaced by R 11 Each of the 1-4 Even more preferably, R a1 independently C 1-4 alkyl, wherein the alkyl is selected from aryl, heteroaryl, OR 11 , N(R 11 )2, optionally replaced by R 11 Each of the 1-4 alkyl.

[0044] In a preferred embodiment of the present invention, R in compound (C) of formula (VII) a2 is C 1-4 Independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein said alkyl, said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl, and said aralkyl are selected from the group consisting of halo, NO, C 1-4 Alkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, CF3, CN, OR 11 , N(R 11 )2, optionally replaced by R 11 Each of 1-4 alkyl. More preferably, R a2 is C 1-4 independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein said alkyl, said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl, and said aralkyl are independently selected from the group consisting of halo, heterocyclyl, phenyl, heteroaryl, OR 11 , N(R 11 )2, optionally replaced by R 11 Each of 1-4 Even more preferably, R a2 independently C 1-4 alkyl, wherein the alkyl is selected from aryl, heteroaryl, OR 11 , N(R 11 )2, optionally replaced by R 11 Each of the 1-4 alkyl.

[0045] In a preferred embodiment of the present invention, n3 of compound (C) of formula (VII) is an integer equal to 0.

[0046] According to one embodiment of the present invention, the compound (C) according to formula (II) or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof is preferably a compound selected from among formula (II-a) or (II-b) [hereinafter compounds (C) of class (II)]: TIFF2025539843000012.tif55170 wherein A, R4, R4', z, R7, R3, r, R2, q and R9 have the same meanings as defined above for formula (II).

[0047] According to one embodiment of the present invention, the compound (C) according to formula (III), or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof, is preferably a compound of formula (III-a) [hereinafter, compound (C) of class (III)]: TIFF2025539843000013.tif34170 wherein A, R4, R4', z, R7, R3, r, R2, q and T have the same meanings as defined above for formula (III).

[0048] According to one embodiment of the present invention, the compound (C) according to formula (IV) or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof is preferably a compound selected from among formulae (IV-a) to (IV-c) [hereinafter compounds (C) of class (IV)]: TIFF2025539843000014.tif88170 wherein A, R4, R4', z, R7, R3, r, R2, q and T have the same meanings as defined above for formula (IV).

[0049] According to one embodiment of the present invention, the compound (C) according to formula (VI) or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof is preferably a compound selected from among formulae (VI-a) to (VI-c) [hereinafter compounds (C) of class (VI)]: TIFF2025539843000015.tif82170 wherein A, R4, R4', z, R7, R3, r, R2, q and X have the same meanings as defined above for formula (VI).

[0050] According to one embodiment of the present invention, the compound (C) according to formula (VII) or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof is preferably a compound selected from among formula (VII-a) or (VII-c) [hereinafter compounds (C) of class (VI)]: TIFF2025539843000016.tif65170In formula, A, R4, R4', z, R7, R3, r, R2, q, R a1 , R a2 and n3 have the same meaning as defined above for formula (VII).

[0051] In the compounds (C) according to the present invention, preferably R4' and R7 are hydrogen, and r and q are equal to 1. Therefore, preferred compounds (C) of class (II) herein are selected from those of the following formulae (II-a-1) to (II-c-1): TIFF2025539843000017.tif92170 wherein A, R4, R3, R2 and R9 have the same meanings as defined above for formula (II), and R 31 is C 1-4 heteroaryl optionally substituted with alkyl; R 11 ' is hydrogen or C 1-4 alkyl, and R b is hydrogen, halo, C 1-4 Alkyl and C 1-6 cycloalkyl; wherein the heteroaryl is a monocyclic ring structure containing 5 to 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms and containing 1 to 3 heteroatoms independently selected from O or N.

[0052] In one embodiment of the present invention, the compounds (C) of class (II) are selected from those of formulae (II-a-1) to (II-c-1).

[0053] In the compounds (C) according to the invention, preferably R4' and R7 are hydrogen and r and q are equal to 1. Therefore, preferred compounds (C) of class (IV) are selected herein from those of the following formulae (IV-a-1) to (IV-c-1): TIFF2025539843000018.tif89170 formula, A, R 4、 R3, R2 and T have the same meanings as defined above for formula (IV).

[0054] In one embodiment of the present invention, the compounds (C) of class (IV) are selected from those of formulae (IV-a-1) to (IV-c-1):

[0055] In the compounds (C) according to the invention, preferably R4' and R7 are hydrogen and r and q are equal to 1. Therefore, preferred compounds (C) of class VI herein are selected from those of the following formulae (VI-a-1) to (VI-c-1): TIFF2025539843000019.tif91170 formula, A, R 4、 R3, R2 and X have the same meanings as defined above for formula (VI).

[0056] In one embodiment of the present invention, the compounds (C) of class (VI) are selected from those of formulae (VI-a-1) to (VI-c-1):

[0057] In the compounds (C) according to the invention, preferably R4' and R7 are hydrogen and r and q are equal to 1. Therefore, preferred compounds (C) of class (VII) are selected herein from the following formulae (VII-a-1) to (VII-c-1): TIFF2025539843000020.tif65170 formula, A, R 4、 R3, R2, R a1 , R a2 and n3 have the same meaning as defined above for formula (VII).

[0058] In one embodiment of the present invention, the compounds (C) of class (II) are selected from those of formula (VII-a-1) or (VII-b-1):

[0059] In a preferred embodiment of the present invention, the compounds (C) of class (II) according to the present invention are selected from the following formulae (II-a-2) or (II-b-2) or (II-c-2) TIFF2025539843000021.tif98170 formula, Each of -R9' is a C such as hydrogen, CN and cyclopropyl. 3-6 cycloalkyl; Each of -R9'' is hydrogen, C 1-4 C such as alkyl, CN and cyclopropyl 3-6 cycloalkyl; each R2 is independently selected from hydrogen or halo; -R q each is independently selected from the group consisting of hydrogen, CH3, OCH3, and halo, such as F or Cl; -R 10 are each independently selected from the group consisting of H, F, Cl, OCH3, or CF3; -U is C, CR 10 and N, -n 10 is an integer equal to 0, 1, or 2, -R 31 each of ' is selected from the group consisting of pyrazyl, N-methylpyrazyl, and pyridyl; -R b ' is 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; -The dash bond represents an optional double bond.

[0060] In a preferred embodiment of the present invention, the compounds (C) of class (IV) according to the present invention are selected from 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) herein: TIFF2025539843000022.tif155170TIFF2025539843000023.tif91170In the formula, -T are, independently of each other, when they occur, selected herein from the moieties of the following formulae (Taa) to (Taf): TIFF2025539843000024.tif62170 formula, Each R' is independently hydrogen, C 1-4 cycloalkyl selected from the group consisting of alkyl, cyclopropyl, and cyclobutyl; heterocyclyl selected from the group consisting of oxetanyl, tetrahydropyranyl, azetidinyl, and piperidinyl, wherein the alkyl is selected from the group consisting of F, OC 1-4 Alkyl, P(=O)(OC 1-4 alkyl)2, P(=O)(C 1-4 alkyl), CN, cyclopropyl or cyclobutyl, and said heterocyclyl is C(=O)(OC 1-4 alkyl), Each of R″5 is hydrogen, C 1-4 independently selected from the group consisting of alkyl, CF3, and cyclopropyl; - each n1, independently of the others, when occurring, is an integer equal to 0, 1 or 2; -R2 is independently hydrogen, halo, or NH2; -R q each is independently selected from the group consisting of H, CH3, OCH3, and halo, such as F or Cl; -R 10 Each of these is hydrogen, halo, C 1-4 Alkyl, CF3, OC 1-4 independently selected from the group consisting of alkyl and CN; - each of U and V is independently C, CR 10 or N, -n 10 is an integer equal to 0, 1, or 2.

[0061] In a preferred embodiment of the present invention, the compounds (C) of class (VI) according to the present invention are selected from the following formula (VI-a-2) or (VI-c-2), TIFF2025539843000025.tif91170 formula, Each R"6 is hydrogen, halo, C 1-4 Alkyl, N(R 21 )2, OR 21 , heterocyclyl selected from the group consisting of pyrrolidyl, piperidyl, morpholinyl, piperazyl, and pyrazyl; wherein the heterocyclyl and pyrazyl are C 1-4 optionally substituted with alkyl, R 21 is C 1-4 is alkyl, -R q each is independently selected from the group consisting of H, CH3, OCH3, and halo, such as F or Cl; -R 10 Each of these is hydrogen, halo, OC -4 independently selected from the group consisting of alkyl and CN; - each of U independently represents C, CR 10 or N, -n 10 is an integer equal to 0, 1, or 2, -n2 is an integer equal to 0, 1 or 2.

[0062] In a preferred embodiment of the present invention, the compounds (C) of class (VII) according to the present invention are selected from the following formula (VII-a-2) herein: TIFF2025539843000026.tif27170In the formula, Ra'1 is benzyl, pyrazyl, OH, OC 1-4 Alkyl, NH2, and NH(C 1-4 alkyl), and R qis selected from the group consisting of H, CH, OCH, and halo such as F or Cl, preferably R q is H or CH3.

[0063] In a preferred embodiment of the present invention, the compound (C) according to the general formula (II-a) herein is a compound selected from the following formulae (VIII) to (XXXII-3): TIFF2025539843000027.tif27170TIFF2025539843000028.tif190170TIFF2025539843000029.tif215170TIFF20255398430 00030.tif183170TIFF2025539843000031.tif182170TIFF2025539843000032.tif196170TIFF2025539843000033.tif38170

[0064] In a preferred embodiment of the present invention, the compound (C) according to general formula (II-b) herein is a compound selected from the following formulae (XXXIII) to (XXXIV): TIFF2025539843000034.tif48170

[0065] In a preferred embodiment of the present invention, the compound (C) according to general formula (III-a) herein is a compound selected from the following formulae (XXXV) to (XXXVI): TIFF2025539843000035.tif66170

[0066] In a preferred embodiment of the present invention, the compound (C) according to the general formula (IV-b) herein is a compound selected from the following formulae (XXXVII) to (LXXI-2): TIFF2025539843000036.tif210170TIFF2025539843000037.tif207170TIFF2025539843 000038.tif208170TIFF2025539843000039.tif200170TIFF2025539843000040.tif40170

[0067] In a preferred embodiment of the present invention, the compound (C) according to general formula (IV-b) herein is a compound selected from the following formulae (LXXII) to (CV): TIFF2025539843000041.tif134170TIFF2025539843000042.tif214170TIFF20255398430 00043.tif194170TIFF2025539843000044.tif203170TIFF2025539843000045.tif157170

[0068] In a preferred embodiment of the present invention, the compound (C) according to general formula (IV-c) herein is a compound selected from the following formulae (CVI) to (CXCVIII-5): TIFF2025539843000046.tif42170TIFF2025539843000047.tif219170TIFF2025539843000048.tif219170TIFF20255398430 00049.tif214170TIFF2025539843000050.tif219170TIFF2025539843000051.tif201170TIFF2025539843000052.tif214170 TIFF2025539843000053.tif206170TIFF2025539843000054.tif205170TIFF2025539843000055.tif208170TIFF2025539843 000056.tif212170TIFF2025539843000057.tif202170TIFF2025539843000058.tif206170TIFF2025539843000059.tif95170

[0069] In a preferred embodiment of the present invention, the compound (C) according to general formula (VI-a) herein is a compound selected from the following formulae (CXCIX) to (CCXII): TIFF2025539843000060.tif80170TIFF2025539843000061.tif215170TIFF2025539843000062.tif78170

[0070] In a preferred embodiment of the present invention, the compound (C) according to general formula (VI-b) herein is a compound selected from the following formulae (CCXIII) to (CCXV): TIFF2025539843000063.tif78170

[0071] In a preferred embodiment of the present invention, the compound (C) according to general formula (VI-c) herein is a compound selected from the following formulae (CCXVI) to (CCLX): TIFF2025539843000064.tif216170TIFF2025539843000065.tif207170TIFF2025539843000066.tif218170TIFF20255398430 00067.tif183170TIFF2025539843000068.tif214170TIFF2025539843000069.tif203170TIFF2025539843000070.tif143170

[0072] In a preferred embodiment of the present invention, the compound (C) according to general formula (VII-a) herein is a compound selected from the following formulae (CCLXI) to (CCLXVII): TIFF2025539843000071.tif49170TIFF2025539843000072.tif122170

[0073] The present invention further relates to an in vitro method of inhibiting protein kinase activity, comprising contacting the protein kinase with a compound of formula (I) to (VII) as defined above [hereinafter Compound (C)], or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer thereof, TIFF2025539843000073.tif59170TIFF2025539843000074.tif146170In the formula, each A is independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl, and said aralkyl are independently selected from the group consisting of halo, NO, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, OR 11 , S.R. 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 , C.O.R. 11 , C(O)OR 11 , CON(R 11 )2, OC(O)R 11 , and OCON(R 11 and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl substituent may further be selected from the group consisting of halo, NO, 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, independently of each other, when they occur, are optionally replaced by R 11 and R 12 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, C 1-6 alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2, optionally replaced by R 31 and R 32 Each of, independently of the other, when it occurs, is selected from hydrogen and C 1-4 is selected from the group consisting of alkyl, - Each of R4 and R'4, when occurring, independently of each other, is hydrogen or C 1-6 alkyl, z is an integer ranging from 0 to 2, with the proviso that when z=0, A and R7 together may form a saturated or unsaturated cyclic moiety; Each occurrence of -R7 is independently hydrogen, C 1-6 alkyl, cycloalkyl, wherein the alkyl and cycloalkyl are selected from halogen atoms, CF, N(R 11 )2, CN, or OR 11 optionally replaced by R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 selected from the group consisting of alkyl and CF3; Each occurrence of -R3, independently of the others, is selected from hydrogen, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, CF3, CN, OR 21 , S.R. 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 said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl and said aralkyl are selected from the group consisting of halo, C 1-6 Alkyl, CF3, N(R 21 )2, CN, or OR 21 and R 21 and R 22 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, OR 31 or N(R 32 )2, optionally replaced by R 31 and R 32 Each of, independently of the other, when it occurs, is selected from hydrogen and C 1-4 alkyl, and each r is an integer ranging from 0 to 3, with the proviso that R3 = NR 21 and provided that when R7=H, R3 and NR7 may together form a saturated or unsaturated cyclic moiety; Each occurrence of -R2, independently of the other, is selected from hydrogen, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, CF3, CN, NO2, OR 21 , S.R. 21 , N(R 21 )2, COR 21 , C(O)OR 21 , CON(R21 )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, said alkenyl, said alkynyl, said cycloalkyl, said heterocyclyl, said aryl and said heteroaryl are selected from the group consisting of halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, 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, heterocyclyl, aryl, or heteroaryl substituent may further be selected from heterocyclyl, N(R 11 )2 OR 11 optionally replaced by R 21 and R 22 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, OR 31 or N(R 32 )2, optionally replaced by R 31 and R 32 Each of, independently of the other, when it occurs, is selected from 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 C 6-12 Alkyl, C 2-6 Alkenyl, C 2-6 Independently selected from alkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl, and the heterocyclyl are selected from halogen atoms, aryl groups, aralkyl groups, CF, N(R 11 )2, CN, or OR 11 is optionally replaced by R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are selected from the group consisting of halo, C 1-6 alkyl, cycloalkyl, heterocyclyl, alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2, optionally replaced by R 31 and R 32 Each of, independently of the other, when it occurs, is selected from hydrogen and C 1-4 is selected from the group consisting of alkyl, -R9 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, N(R 11 )2 and CN, and the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocyclyl are selected from the group consisting of a halogen atom, an aryl group, an aralkyl group, a heterocyclyl group, CF3, N(R 11 )2, CN, or OR 11 is optionally replaced by R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF3; 1-4 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and heteroaryl optionally substituted with alkyl, aryl, heteroaryl, and aralkyl substituents are optionally substituted with halo, C 1-6 alkyl, cycloalkyl, heterocyclyl, alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2, optionally replaced by R 31 and R 32 Each of, independently of the other, when it occurs, is selected from hydrogen and C 1-4 alkyl, with the proviso that x=1 and y=0, R9 is selected from the group consisting of heterocyclyl and C 1-6 The alkyl is optionally substituted with heterocyclyl, provided that x=0 and y=0, R9 is selected from hydrogen and C 1-6 The alkyl is distinct from heterocyclyl and N(R 11 )2, with the proviso that when x=0 and y=0, R9 and R2 together may form a saturated or unsaturated cyclic moiety, with the proviso that when x=0 and y=0, R9 and R2 together form a saturated or unsaturated cyclic moiety, and R9 is NR 11 However, under the condition that x=1 and y=1, R9 is N(R 11 )2, provided that x=0, y=0 and z=0, R9 is different from pyrrole, Each of -T is independently a moiety of formula (Ta) herein: TIFF2025539843000075.tif28170 formula, Each occurrence of -U is independently selected from the group consisting of C, C-halo, CR, and N, where R is a halogen atom, a hydrogen optionally substituted with an aryl or aralkyl group, OR 11 , N(R 11 )2, C 1-6alkyl or cycloalkyl; R 11 Each of, independently of the other, when it occurs, is hydrogen or C 1-4 alkyl, with the proviso that at least one U is different from N; Each Z, independently of the other, when it occurs, is selected from C(R), O, S, and NR, where R, independently of the other, when it occurs, is hydrogen or C optionally substituted with a halogen atom, an aryl group, or an aralkyl group. 1-6 alkyl; R7 is selected from hydrogen, C 1-6 Alkyl, C 1-6 selected from the group consisting of alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF3; - Each of R5, when occurring, independently of one another, is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, CF3, OR 11 , S.R. 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, CON(R 11 and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent may further be selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, 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 optionally further substituted with R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, and each n1 is an integer ranging from 0 to 2; Each of -X is independently a moiety of formula (Xa) as used herein: TIFF2025539843000076.tif28170 formula, Each V, when present, is independently selected from the group consisting of C, C-halo, CR, and N, where R is a halogen atom, a hydrogen optionally substituted with an aryl or aralkyl group, OR 11 , N(R 11 )2, C 1-6 alkyl or cycloalkyl; R 11 Each of, independently of the other, when it occurs, is hydrogen or C 1-4 alkyl, Each of R6 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, CF3, OR 11 , S.R. 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, CON(R 11 )2, wherein each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent is selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, 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 R 11 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, and each n2 is an integer ranging from 0 to 4; -The dashed bond represents an optional triple bond; -R a1 is hydrogen, C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, CF3, CN, OR 11 , S.R. 11 , N(R11 )2, COR 11 , C(O)OR 11 wherein the alkyl, the cycloalkyl, the heterocyclyl, the aryl, the heteroaryl, and the aralkyl are independently selected from the group consisting of halo, NO, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, COR 11 and C(O)OR 11 and each optional alkyl, alkenyl, cycloalkyl, phenyl, heterocyclyl, heteroaryl substituent is optionally substituted by halo, NO, C 1-6 Alkyl, cycloalkyl, phenyl, N(R 11 )2, CN or OR 11 and optionally further replaced by R 11 Each of these is hydrogen, C 1-6 selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl and aralkyl, wherein said alkyl, said cycloalkyl, said heterocyclyl, said phenyl, said heteroaryl and said aralkyl substituents are selected from the group consisting of halo, C 1-6 optionally substituted with alkyl, cycloalkyl, or heterocyclyl; -R a2 Each of, independently of the other, when it occurs, is selected from hydrogen, C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, COR 11 , C(O)OR 11 wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, the heteroaryl, and the aralkyl are selected from the group consisting of halo, NO, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, COR 11 and C(O)OR 11 and each optional alkyl, alkenyl, cycloalkyl, phenyl, heterocyclyl, heteroaryl substituent is optionally substituted by halo, NO, C 1-6 Alkyl, cycloalkyl, phenyl, N(R 11 )2, CN or OR 11 and optionally further replaced by R 11 Each of these is hydrogen, C 1-6 selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl and aralkyl, wherein said alkyl, said cycloalkyl, said heterocyclyl, said phenyl, said heteroaryl and said aralkyl substituents are selected from the group consisting of halo, C 1-6 optionally substituted with alkyl, cycloalkyl, or heterocyclyl, and n3 is an integer equal to 0 or 1, provided that when the dashed bond is a triple bond, then n3 is 0; The cycloalkyl is a monocyclic, bicyclic, or tricyclic ring system having 3 to 6 ring members per ring; the heterocyclyl is a saturated, partially saturated, or fully saturated monocyclic, bicyclic, or tricyclic ring containing 3 to 12 carbon atoms, in which one or two heteroatoms are independently selected from O or N; the aryl is a phenyl, naphthyl, or anthracenyl optionally carbocyclically fused with a cycloalkyl or heterocyclyl having 5 to 7 ring members; and the heteroaryl is a monocyclic ring structure containing 5 to 6 ring atoms or a bicyclic aromatic group having 8 to 10 atoms, in which one to three heteroatoms are independently selected from O or N.

[0074] It is further understood that all definitions and preferences as set forth for compound (C) above apply equally to this embodiment and all further embodiments, as described below.

[0075] As used above and below, the following definitions apply unless otherwise stated.

[0076] The term halo, alone or in combination, means all halogens, ie, chloro (Cl), bromo (Br), fluoro (F), and iodo (I).

[0077] The term alkyl, alone or in combination, unless otherwise specified, means a radical derived from an alkane containing 1 to 15 carbon atoms, e.g., C F-G Alkyl defines a linear or branched alkyl radical having F to G carbon atoms, e.g., C 1-4 Alkyl defines a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, and 2-methyl-1-propyl. The alkyl group can be a straight-chain or branched alkyl. Preferably, the straight-chain or branched alkyl group contains 1 to 10, more preferably 1 to 8, even more preferably 1 to 6, and most preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, and t-butyl. Alkyl also includes straight-chain or branched alkyl groups containing or interrupted by a cycloalkyl moiety. The straight-chain or branched alkyl group can be attached at any available point to produce a stable compound. Examples include, but are not limited to, 4-(isopropyl)-cyclohexylethyl or 2-methyl-cyclopropylpentyl.

[0078] The term alkenyl, alone or in combination, unless otherwise specified, refers to a straight-chain or branched 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 at least one, preferably 1 to 3, more preferably 1 to 2, and most preferably 1 carbon-carbon double bond. Examples of alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, cyclohexenyl, cyclohexenylalkyl, and the like. Alkenyl also includes straight-chain or branched alkenyl groups containing or interrupted by a cycloalkyl moiety. The carbon-carbon double bond can be contained within the cycloalkyl moiety or within either the straight-chain or branched moiety, except for cyclopropyl.

[0079] The term alkynyl, alone or in combination, means a straight 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, and the like.

[0080] The term aryl, alone or in combination, means phenyl, naphthyl, or anthracenyl optionally carbocyclically fused with a cycloalkyl or heterocyclyl, preferably of 5 to 7, more preferably 5 to 6 ring members, and / or optionally substituted with 1 to 5 groups or substituents. The aryl is optionally substituted, whereby the substituent may be attached at one point to the aryl, or whereby the substituent is attached at two points to the aryl to form a bicyclic ring system, e.g., benzodioxole, benzodioxane, benzimidazole.

[0081] 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 and containing 1 to 3 heteroatoms independently selected from O, S, and N, and optionally substituted with 1 to 5 groups or substituents. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl, and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable aromatic ring is maintained. More specifically, the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzisoxazolyl, benzothienyl, dibenzofuran, and benzodiazepin-2-one-5-yl, and the like.

[0082] The term heterocyclyl, alone or in combination, is intended to denote a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic ring having 3 to 12 carbon atoms and containing one or two heteroatoms, each independently selected from O, S, P, or N, and is optionally benzofused or fused heteroaryl of 5 to 6 ring members and / or optionally substituted as in the case of cycloalkyl. Heterocyclyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl, and N-oxide of a tertiary ring nitrogen. The point of attachment is at a carbon atom or a nitrogen atom. In each case, the heterocyclyl can be fused with an aryl to form a bicyclic ring system.

[0083] The term cycloalkyl refers to a cyclic or polycyclic alkyl group containing from 3 to 7 carbon atoms. Preferably, the cycloalkyl group is a monocyclic, bicyclic, or tricyclic ring system of 3 to 6 ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, etc.

[0084] The term aralkyl refers to an organic compound containing an aromatic nucleus to which an alkyl radical is attached. These alkyl radicals include radicals such as methyl, ethyl, propyl, butyl, and octyl. Therefore, the term aralkyl is considered to include aralkyl hydrocarbons such as alkylbenzenes and various alkylnaphthalenes. From this definition of the term aralkyl compound, the term is considered to include compounds such as benzyl, the three isomeric xylyls, the two isomeric trimethylbenzenes, ethylbenzene, p-methylbiphenyl, and α-methylnaphthalene.

[0085] The present invention relates to a compound (C) comprising a carrier and a compound (C) of formula (I) to (VII) as described herein, or a compound (C) 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), as described herein and as defined in any one of the embodiments presented herein. and an effective amount of an active ingredient of any compound from the subgroup of compounds of formula (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).

[0086] The present invention relates to compound (C) of formula (I) to (VII) as described in the present invention or any compound of the 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-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 (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 described herein and as defined in any one of the embodiments presented herein, for use as a medicament.

[0087] The present invention relates to compounds (C) of formula (I) to (VII) as described herein, or 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) as described herein. , (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 a compound of any of the subgroups of compounds of formula (VII-a-2), and which are useful in treating cancer, metabolic diseases (e.g., diabetes), inflammatory diseases and autoimmune diseases (e.g., inflammatory diseases such as Crohn's disease and ulcerative colitis), and psoriasis and psoriatic arthritis), neurological diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis, epilepsy), arteriosclerosis and cardiovascular diseases, Sjogren's syndrome, renal transplant rejection, virus-induced diseases, cardiovascular diseases, hyperresorption (osteolysis) and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, ophthalmological diseases (e.g., retinopathy, age-related macular degeneration and uveitis), chronic pain and neuropathic pain, and fibroproliferative diseases.

[0088] The present invention further relates to a method of inhibiting protein kinase activity in a warm-blooded animal, said method comprising administering to the animal in need of treatment an effective kinase-inhibiting amount of a compound (C) of (I)-(VII), or a compound of formula (II-a)-(II-b), (III-a), (IV-a)-(IV-c), (VI-a)-(VI-c), (VII-a), (VII-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (III-j ... and any of the subgroups of compounds of formula (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), including administration of a compound according to any one of the embodiments presented herein.

[0089] The present invention further relates to a method of inhibiting protein kinase activity in a warm-blooded animal, said method comprising administering to the animal in need of treatment a kinase-inhibiting effective amount of compound (C) of (I)-(VII), or a compound of formula (II-a)-(II-b), (III-a), (IV-a)-(IV-c), (VI-a)-(VI-c), (VII-a), (VII-b), (II-a-1)-(II-c-1), (IV-a-1)-(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 any of the subgroups of compounds of formula (VII-a-2), and the protein kinase is CSF1R, FLT3, Kit, PDGFRB (PDGFR beta), PDGFRA (PDGFR alpha), ABL1, ACVR1B (ALK4), AKT1 (PKB alpha), AMPK A1 / B1 / G1, AURKA (Aurora A), BTK, CDK1 / cyclin B, CHEK1 (CHK1), CSNK1G2 (CK1 gamma 2), CSNK2A1 (CK2 alpha 1), DYRK3, EGFR (ErbB1), EPHA2, ERBB2 (HER2), FGFR1, FRAP1 (mTOR), GSK3B (GSK3 beta), IGF1R, IKBKB (IKK beta), INSR, IRAK4, JAK3, KDR (VEGFR2), LCK, MAP2 Preferably, the protein kinase is selected from the group consisting of CSF1R, FLT3, Kit, PDGFRB (PDGFR beta), and PDGFRA (PDGFR alpha).

[0090] The present invention relates to the use of a compound of formula (I) or (II) for the treatment of a disease in a warm-blooded animal selected from the group consisting of cancer, metabolic diseases (e.g. diabetes), inflammatory and autoimmune diseases (e.g. inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, inflammatory lung diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, psoriasis and psoriatic arthritis), neurological diseases (e.g. Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis, epilepsy), arteriosclerosis and cardiovascular diseases, Sjogren's syndrome, renal transplant rejection, virus-induced diseases, cardiovascular diseases, hyperresorption (osteolysis) and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, ophthalmic diseases (e.g. retinopathy, age-related macular degeneration and uveitis), chronic pain and neuropathic pain, and fibroproliferative diseases. The present invention further relates to a method for treating a disease as defined herein, comprising administering to an animal in need of treatment according to any one of the embodiments presented herein, a compound (C) of formula (I) to (VII) as described in the present invention, or a compound (C) of formula (II-a) to (II-b), (III-a), (IV-a) to (IV-c), (VI-a) to (VI-c), (VII-a), (VII-b) as described herein. (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 the administration of an effective amount of a compound of any of the subgroups of compounds of formula (VII-a-2).

[0091] The radical moiety on any molecular moiety used in the definitions may occur anywhere on such moiety as long as it is chemically stable.

[0092] The radicals used in the definitions of the variables include all possible isomers unless otherwise indicated, for example, pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl, pentyl includes 1-pentyl, 2-pentyl and 3-pentyl.

[0093] When any variable occurs more than one time in any constituent, each definition is independent. Whenever used hereinafter, the term "compound (C) of formula (I)-(VII)" or "the compound" or similar terms is meant to include compound (C) of formula (I)-(VII), N-oxides, addition salts and all stereochemically isomeric forms. One embodiment includes compounds (C) of formulae (I) to (VII) as described in the present invention, 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 (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 described herein, as well as N-oxides, salts, as their possible stereoisomeric forms. Another embodiment includes compounds (C) of formulae (I) to (VII) as described in the present invention, 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 (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 described herein, as well as salts as their possible stereoisomeric forms.

[0094] The present invention relates to compounds (C) of formulae (I) to (VII) as described herein, or any of the compounds of the subgroups 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 (VI-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 described herein, which have several chiral centers and exist as stereochemical isomers. The term "stereochemically isomeric" as used herein refers to a compound (C) of formula (I) to (VII) as described in the present invention, or a compound (C) 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 ... This defines all possible compounds that may be possessed by any of the compounds of the subgroups of compounds of formula (VII-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), which are composed of the same atoms bonded in the same bond sequence, but have different, non-interchangeable, three-dimensional structures.

[0095] Unless otherwise stated or supported, the chemical names of compounds (C) of formulae (I) to (VII) as described in the present invention or any of the compounds of the subgroups 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 (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 described herein encompass mixtures of all possible stereochemical isomers that said compounds may possess. Said mixtures may contain all diastereomers and / or enantiomers of the basic molecular structure of said compounds. Stereoisomeric forms of the compounds of the invention, either in pure form or mixed with one another, are intended to be encompassed within the scope of the present invention.

[0096] Compound (C) of formula (I) to (VII) as described in the present invention, 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 (VI-c-1), (VII-a-1) to (VII-b-1), (II- Pure stereoisomeric forms of any of the compounds of the subgroup of compounds of formula (II-a-2), (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 intermediates as referred to herein are defined as isomers that are substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compound or intermediate. In particular, "stereoisomerically pure" relates to compounds or intermediates having a stereoisomeric excess of at least 80% (i.e., a minimum of 90% of one isomer and a maximum of 10% of the other possible isomers) up to 100% (i.e., 100% of one isomer and no other isomers), more particularly to compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more particularly to compounds or intermediates having a stereoisomeric excess of 94% up to 100%, and most particularly to compounds or intermediates having a stereoisomeric excess of 97% up to 100%. The terms "enantiomerically pure" and "diastereomerically pure" should be understood similarly, but taking into account the enantiomeric excess and diastereomeric excess, respectively, of the mixture in question.

[0097] Pure stereoisomeric forms of the compounds and intermediates of the present invention can be obtained by applying procedures known in the art. For example, enantiomers can be separated from each other by selective crystallization of diastereomeric salts with optically active acids or bases. Examples of this are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, and carphorsulfonic acid. Alternatively, enantiomers can be separated by chromatographic techniques using chiral stationary phases. The pure stereochemically isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, when a specific stereoisomer is desired, the compound is synthesized by stereospecific preparation methods. These methods advantageously utilize enantiomerically pure starting materials.

[0098] The diastereomeric racemates of compound (C) of formula (I) to (VII) as described in the present invention or any of the compounds of the 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 (VI-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 described herein can be obtained separately by conventional methods. Suitable physical separation methods which may be advantageously employed are, for example, selective crystallization and chromatography, such as column chromatography.

[0099] Compound (C) of formula (I) to (VII) as described in the present invention, or 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) The absolute stereochemical configuration of some of the compounds, N-oxides, salts, solvates and intermediates used in the preparation of any of the compounds of the subgroups of formula (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) has not been experimentally determined.

[0100] A person skilled in the art is able to determine the absolute configuration of such compounds using art-known methods such as, for example, X-ray analysis.

[0101] The present invention is also intended to include all isotopes of atoms presently present in the compounds (C) of formulae (I) to (VII) as described herein, or any of the compounds of the subgroups 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 (VI-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 described herein. Isotopes include atoms having the same atomic number but different mass numbers. Common examples and limitations include isotopes of hydrogen, such as tritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0102] For therapeutic use, the compounds (C) of formula (I) to (VII) as described in the present invention or 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), (VI-a-1) to (VI-c-1) as described herein may be used. Salts of compounds of any of the subgroups of compounds of formula (VII-a-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), in which the counterion is pharmaceutically acceptable, may be referred to as pharmaceutically acceptable acid and base addition salts. However, salts of acids and bases that are not pharmaceutically acceptable are also used, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the scope of the present invention.

[0103] The pharmaceutically acceptable acid and base addition salts as referred to herein above can be used in combination with compounds (C) of formula (I) to (VII) as described in the present invention, or 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), (VII-a-1) to (IV-c-1), (VII-a-1) to (VII ...b), (VII-a-1) to (VII-b), (VII-a-1) to (VII-b), (VII-a-1) to (VII-b), (VII-a-1) to (VII-b), (VII-a The term "compounds" is intended to include therapeutically active non-toxic acid and base addition salts such as those that can be formed by any of the compounds of the subgroup of compounds of formula (VII-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). Pharmaceutically acceptable acid addition salts can be obtained conventionally by treating the base form with such a suitable acid in anionic form. Suitable anions include, for example, trifluoroacetate, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estrus, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcylate, hydrabamine, hydrobromide, hydrochloride, hydroxybenzoate ... Examples of counterions include naphthylic acid, iodide, isethionic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, mesylic acid, methyl bromide, methyl nitrate, methyl sulfate, muconic acid, naphthalenesulfonic acid, nitric acid, pamoic acid (embonic acid), pantothenic acid, phosphoric acid / pyrophosphate, polygalacturonic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid, teoclic acid, and triiodide. 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 an appropriate base.

[0104] Compound (C) of formula (I) to (VII) as described in the present invention, containing an acidic proton, 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- The compounds of any of the subgroups of compounds of formula (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 in cationic form into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Suitable base salts include those formed with organic cations such as benzathine, chloroprocaine, chlorine, diethanolamine, ethylenediamine, meglumine, procaine, and the like, and those formed with metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and the like. Conversely, the salt forms can be converted into the free form by treatment with an appropriate acid.

[0105] The term addition salt as used herein above also includes compounds (C) of formulae (I) to (VII) as described in the present invention or any of the compounds of the 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 (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 described herein, as well as solvates which these salts are able to form. Such solvates are for example hydrates, alcoholates and the like.

[0106] The present compounds (C) of formula (I) to (VII) as described in the present invention or 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 ... The N-oxide forms of the present compounds of any of the subgroups of compounds of formula (II-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) are meant to include compounds of formula (I) in which one or more nitrogen atoms are oxidized to the so-called N-oxide.

[0107] Compound (C) of formula (I) to (VII) as described in the present invention, or any compound of the 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 (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 described herein, may have metal binding, chelating, complexing properties and may therefore exist as a metal complex or metal chelate. Such metallated derivatives of compound (C) of formula (I) to (VII) as described in the present invention or of any of the subgroups 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 (VI-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 described herein are intended to be included within the scope of the present invention.

[0108] Some of the compounds (C) of formulae (I) to (VII) as described in the present invention or any of the compounds of the subgroups 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 (VI-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 described herein may also exist in their tautomeric forms. Such forms, although not explicitly indicated in the above formula, are intended to be included within the scope of the present invention.

[0109] In a further aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of compound (C) of formula (I) to (VII) as described herein, or any compound from the subgroup of compounds (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 (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 described herein, and a pharmaceutically acceptable carrier. A therapeutically effective amount in this context refers to an amount of a gene that specifically targets a gene encoding CSF1R, FLT3, Kit, PDGFRB (PDGFR beta), PDGFRA (PDGFR alpha), ABL1, ACVR1B (ALK4), AKT1 (PKB alpha), AMPK A1 / B1 / G1, AURKA (Aurora A), BTK, CDK1 / cyclin B, CHEK1 (CHK1), CSNK1G2 (CK1 gamma 2), CSNK2A1 (CK2 alpha 1), DYRK3, EGFR (ErbB1), EPHA2, ERBB2 (HER2), FGFR1, FRAP1 (mTOR), GSK3B (GSK3 beta), IGF1R, IKBKB (IKK beta), INSR, IRAK4, JAK3, KDR (VEGFR2), LCK, MAP2K1 (MEK1), MAP4K4 (HGK), MAPK1 (ERK2), MAPK14 ( p38 alpha), MAPK3 (ERK1), MAPK8 (JNK1), MARK2, MET (cMet), NEK1, PAK4, PHKG2, PIM1, PLK1, PRKACA (PKA), PRKCB1 (PKC beta I), ROCK1, RPS6KA3 (RSK2), RPS6KB1 (p70S6K), SRC, SYK, and TEK (Tie2), and is an amount sufficient to act prophylactically against a protein kinase selected from the group consisting of: ROCK1, RPS6KA3 (RSK2), RPS6KB1 (p70S6K), SRC, SYK, and TEK (Tie2), thereby stabilizing or alleviating a disease mediated by the protein kinase.Preferably, the protein kinase is selected from the group consisting of CSF1R, FLT3, Kit, PDGFRB (PDGFR beta), PDGFRA (PDGFR alpha).

[0110] Examples of diseases mediated by protein kinases include, inter alia, cancer, metabolic diseases (e.g., diabetes), inflammatory and autoimmune diseases (e.g., inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, inflammatory lung diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, psoriasis and psoriatic arthritis), neurological diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis, epilepsy), arteriosclerosis and cardiovascular diseases, Sjogren's syndrome, renal transplant rejection, virus-induced diseases, cardiovascular diseases, hyperresorption (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 pain and neuropathic pain, and fibroproliferative diseases.

[0111] In yet a further aspect, the present invention provides a compound (C) of formula (I) to (VII) as described herein, or (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-2), (IV-a-2) to (IV-c-3), (IV-a-3) to (IV-c-4), (IV-a-4) to (IV-c-5), (IV-a-5) to (IV-c-6), (IV-a-6) to (IV-c-7), (IV-a-7) to (IV-c-8), (IV-a-8) to (IV-c-9), (IV-a-9) to (IV-c-10), (IV-a-9) to (IV-c-11), (IV-a-9) to (IV-c-12), (IV-a-9) to (IV-c-13), (IV-a-9) to (IV-c-14), (IV-a-9) to (IV-c-15), (IV-a-9) to (IV-c-16), (IV-a-9) to (IV-c-17), (IV-a-9) to (IV-c-18), (IV-a-9) to (IV-c-19 ... and a compound of any of the subgroups of compounds of formula (VI-a-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).

[0112] Thus, compound (C) of formula (I) to (VII) as described in the present invention, or any compound of the 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 (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 described herein, may be formulated into various pharmaceutical forms for administration purposes. Suitable compositions include all compositions commonly used for systemic drug administration. To prepare the pharmaceutical compositions of the present invention, an effective amount of a specific compound, optionally in addition salt form or metal complex form, is combined in intimate admixture with a pharmaceutically acceptable carrier as the active ingredient, which may take a wide variety of forms depending on the desired form of preparation for administration. These pharmaceutical compositions are desirable in that they are in a single dosage form suitable for oral administration, rectal administration, transdermal administration, or parenteral injection. For example, when preparing compositions in oral dosage form, any of the usual pharmaceutical vehicles may be used, such as water, glycols, oils, alcohols for oral liquid preparations such as suspensions, syrups, elixirs, emulsions, and solutions, or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents, and the like for powders, pills, capsules, and tablets.

[0113] Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are clearly employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, although other ingredients, for example, to aid solubility, may be included. For example, injectable solutions can be prepared in which the carrier comprises saline, glucose solution, or a mixture of saline and glucose solution. Injectable suspensions can also be prepared, where appropriate liquid carriers, suspending agents, and the like are available. Also included are solid form preparations that are intended to be converted to liquid form preparations upon use. In compositions suitable for transdermal administration, the carrier optionally comprises minor amounts of penetration enhancers and / or suitable wetting agents, optionally combined with suitable additives of any nature that do not introduce significant adverse effects on the skin.

[0114] Compound (C) of the present invention of formula (I) to (VII) as described herein, or any of the subgroups 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 (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 described herein, may also be administered via oral inhalation or insufflation according to methods and formulations available in the art for administration by this method. Thus, compound (C) of formula (I) to (VII) generally as described in the present invention, or any compound of the 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 (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 described herein, may also be administered to the lungs in the form of a solution, suspension or dry powder, with a solution being preferred. Any system developed to deliver solutions, suspensions, or dry powders via oral inhalation or insufflation is suitable for administering the present compounds.

[0115] Therefore, the present invention also provides a therapeutically effective amount of a compound (C) of formula (I) to (VII) as described in the present invention, or (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 ...

[0013] The present invention provides a pharmaceutical composition adapted for administration by inhalation or insufflation through the oral cavity, comprising a compound of any of the subgroups of compounds of formula (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 the compounds of formula (VII-a-2), and a pharmaceutically acceptable carrier. Preferably, the compounds of the invention are administered via inhaling a solution in a nebulized or aerosolized dose.

[0116] In order to facilitate administration and uniformity of dosage, it is particularly advantageous to prepare the above-mentioned pharmaceutical composition in unit dosage form.As used herein, unit dosage form refers to a physically separate unit suitable for uniform dosage, and each unit contains a predetermined amount of active ingredient calculated to produce desired therapeutic effect in combination with required pharmaceutical carrier.Examples of such unit dosage form are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injection solutions or suspensions, etc., and divided multiples thereof.

[0117] Compound (C) of formula (I) to (VII) as described in the present invention or any compound of the 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 (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 described herein exhibits kinase inhibitory properties. Diseases and disorders that can be treated using the compounds and methods of the present invention include protein kinase-mediated diseases such as cancer, metabolic diseases (e.g., diabetes), inflammatory and autoimmune diseases (e.g., inflammatory bowel diseases such as Crohn's disease, ulcerative colitis, inflammatory lung diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, psoriasis and psoriatic arthritis), neurological diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis, epilepsy), arteriosclerosis and cardiovascular disease, Sjogren's syndrome, renal transplant rejection, virus-induced diseases, circulatory diseases, hyperresorption (osteolysis) and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, ophthalmic diseases (e.g., retinopathy, age-related macular degeneration and uveitis), chronic pain and neuropathic pain, and fibroproliferative diseases. Many of the compounds of the present invention may exhibit favorable pharmacokinetic profiles and have attractive properties with respect to bioavailability, including acceptable half-lives, AUCs (area under the curve) and peak values, and lack unfavorable phenomena such as insufficient rapid release and tissue retention.

[0118] The combination of the present invention can be used as a medicine. Said use as a medicine or a method of treatment includes the systemic administration of an effective amount to a diseased subject to combat the condition related to the disease.As a result, the combination of the present invention can be used to treat cancer, metabolic diseases (e.g., diabetes), inflammatory diseases and autoimmune diseases (e.g., inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, inflammatory lung diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, psoriasis and psoriatic arthritis), neurological diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis, epilepsy), arteriosclerosis and cardiovascular diseases, Sjogren's syndrome, They can be used in the manufacture of a medicament useful for treating, preventing, or combating diseases or disorders associated with protein kinases including renal transplant rejection, virally induced diseases, cardiovascular diseases, hyperresorption (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 pain and neuropathic pain, and fibroproliferative disorders.

[0119] As used herein, a "therapeutically effective amount" means an amount of an active compound, ingredient, or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal, or human that is desired by a researcher, veterinarian, physician, or other clinician in light of the present invention, including alleviation of the symptoms of the disease being treated. [Example]

[0120] Example 1: General procedure for the preparation of analogs 49-55 TIFF2025539843000077.tif114170

[0121] Method A1: Under nitrogen, solid cesium carbonate (2.5 equiv.) was added to a solution of the phenol derivative (1 equiv.) in DMF (5 mL / mmol), followed by the 4-chloropyridine derivative (1 equiv.). The reaction mixture was stirred at 110 °C until completion (2 h to overnight). After cooling at 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 was purified by flash column chromatography (cyclohexane / EtOAc, 100 / 0 to 50 / 50) or (DCM / MeOH, 100 / 0 to 90 / 10) or reverse-phase chromatography (HO / MeOH: 0 to 100%) to give the expected compound.

[0122] Method B1: To a solution of the appropriate intermediate 47 (1 equiv.) in EtOH or MeOH (2.5 mL / mmol) was added a solution of NaOH 1N (2.9 mL / mmol). The reaction mixture was stirred at rt until completion. EtOH or MeOH was removed under reduced pressure and the crude was acidified with HCl 1N to pH = 2-3. The precipitate was filtered off, washed with water and dried over PO in vacuo to give the expected intermediate 48.

[0123] Method C2: To a suspension of the appropriate intermediate 48 (1 equiv.) in DCM or DMF (10 mL / mmol) under nitrogen, DMAP (2.2 equiv.), EDC.HCl (2 equiv.), and the appropriate amine (1.1–1.5 equiv.) were added. 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 was purified by flash column chromatography (DCM / MeOH, 100 / 0–90 / 10) and reverse-phase chromatography (HO / MeOH: 0–100%) to give the expected compound.

[0124] Method D1: To a stirred solution of 2-bromo-4-chloropyridine (192 mg, 1 mmol) in isopropanol / HO (4 mL / 4 mL) was added phenylboronic acid (128 mg, 1.05 mmol), KPO (424 mg, 2 mmol), and Pd(OAc) (4 mg, 0.015 mmol). The reaction mixture was stirred at 80 °C under air for 30 min. After cooling at room temperature, the reaction mixture was diluted with EtOAc and washed twice with a saturated solution of NaCl. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The crude 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.

[0125] Method D2: To a stirred solution of 3-bromo-4-chloropyridine (385 mg, 2 mmol) in dioxane (10 mL) under nitrogen, phenylboronic acid (256 mg, 2.1 mmol), solid KPO (849 mg, 4 mmol), and Pd(PPh) (231 mg, 0.2 mmol) were added. The reaction mixture was stirred at 100 °C for 4 h. The solvent was removed under reduced pressure, and the crude was purified by flash column chromatography (cyclohexane / EtOAc, 100 / 0 to 75 / 25) to give 4-chloro-3-phenyl-pyridine 46c as a yellow oil in 87% yield.

[0126] The following table shows intermediate 47 prepared from Method A1.

[0127] TIFF2025539843000078.tif100170

[0128] The following table shows intermediate 48 prepared from Method B1.

[0129] TIFF2025539843000079.tif100170

[0130] The following compounds are examples illustrating procedure C2:

[0131] N-(cyclohexylmethyl)-3-(4-pyridyloxy)benzamide (49): TIFF2025539843000080.tif23170 Compound 49 was synthesized from intermediate 48a (0.20 mmol) and 1-cyclohexylmethanamine (0.34 mmol) according to general method C2 as a white solid in 83% yield. 1 H NMR(600MHz,DMSO-d6)δ(ppm):8.51(t,J=5.8Hz,1H),8.49-8.47(m,2H),7.78(dd d,J=7.8Hz,1.5Hz,1.0Hz,1H),7.64-7.61(m,1H),7.57(t,J=7.9Hz,1H),7.35(dd d,J=8.1Hz,2.5Hz,1.0Hz,1H),6.96-6.93(m,2H),3.09(dd,J=6.8Hz,6.0Hz,2H), 1.68(t,J=13.5Hz,4H),1.63-1.49(m,2H),1.23-1.09(m,3H),0.95-0.84(m,2H).

[0132] N-(cyclohexylmethyl)-3-[(2-phenyl-4-pyridyl)oxy]benzamide (50): TIFF2025539843000081.tif22170 Compound 50 was synthesized from intermediate 48b (0.20 mmol) and 1-cyclohexylmethanamine (0.30 mmol) according to general method C2 as a white solid in 70% yield. 1 H NMR(400MHz,CDCl3)δ(ppm):8.56(d,J=5.6Hz,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=5.6Hz,2.4Hz,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).

[0133] Example 2: General procedure for the synthesis of analogs 68-101 TIFF2025539843000082.tif89170

[0134] Method E: Under nitrogen, to a solution of the carboxylic acid derivative (1 equiv.) in CHCl (5 mL / mmol) was added oxalyl chloride (3 equiv.) and 50 μL of DMF. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give the chloride acyl derivative. To a solution of this intermediate in pyridine (3 mL / mmol) under nitrogen, 2-amino-4-chloropyridine (1 equiv.) was added, and the reaction mixture was stirred at room temperature until completion (2 h to overnight). The reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography (DCM / MeOH, 100 / 0 to 95 / 5) to give the expected compound.

[0135] The following compound 65a is an example illustrating Method E:

[0136] Preparation of N-(4-chloro-2-pyridyl)-1-methyl-pyrazole-4-carboxamide (65a): TIFF2025539843000083.tif22170 Intermediate 65a was synthesized from 1-methyl-1H-pyrazole-4-carboxylic acid (2.37 mmol) and 2-amino-4-chloropyridine (2.37 mmol) according to general procedure E as a white powder in 84% yield. ESI-MS: 237.10 (M+H) + .

[0137] The following table shows intermediate 65 prepared from Method E.

[0138] TIFF2025539843000084.tif126170

[0139] The following compound 65e is an example illustrating Method C2:

[0140] Preparation of N-(4-chloro-2-pyridyl)pyridine-3-carboxamide (65e): TIFF2025539843000085.tif19170 Intermediate 65e was synthesized from nicotinic acid (1.28 mmol) and 2-amino-4-chloropyridine (1.16 mmol) as a white powder in 84% yield according to general method C2. ESI-MS: 234.10 (M+H) + .

[0141] Method A2: Under nitrogen, to a solution of the phenol derivative (1 equivalent) in DMF (2 mL / mmol) was added solid cesium carbonate (2.5 equivalents), followed by the 4-chloropyridine derivative (1 equivalent). The reaction mixture was stirred at 140° C. overnight. The reaction mixture was concentrated under reduced pressure to give the expected compound, which was used in the next step without purification.

[0142] The following compound 66a is an example illustrating Method A2:

[0143] Preparation of ethyl 3-({2-[(1-methylpyrazole-4-carbonyl)amino]-4-pyridyl}oxy)benzoate (66a) TIFF2025539843000086.tif24170 Intermediate 66a was synthesized from ethyl 3-hydroxy-2-methyl-benzoate (0.91 mmol) and compound 65a (0.91 mmol) as a brown powder according to general method A2. ESI-MS: 381.20 (M+H) + .

[0144] The following table shows intermediate 66 prepared from Method A2.

[0145] TIFF2025539843000087.tif47170

[0146] TIFF2025539843000088.tif85170

[0147] Method B2: To a solution of the appropriate intermediate 66 (1 equiv.) in EtOH (2.5 mL / mmol) was added a solution of NaOH 2N (2.5 mL / mmol). The reaction mixture was stirred at 50 °C for 1 h. EtOH was evaporated under reduced pressure, and the residue was dissolved in water and washed three times with CHCl. ​​The aqueous layer was then acidified with concentrated HCl to pH = 2-3. The resulting precipitate was filtered, washed with H2O, and dried over P2O5 to give the expected compound. If necessary, the filtrate was evaporated under reduced pressure and purified by reverse-phase chromatography (H2O / MeOH, 100 / 0 to 0 / 100) to give more of the expected compound.

[0148] The following compound 67a is an example illustrating Method B2:

[0149] Preparation of 2-methyl-3-({2-[(1-methylpyrazole-4-carbonyl)amino]-4-pyridyl}oxy)benzoic acid (67a): TIFF2025539843000089.tif24170 Intermediate 67a was synthesized from intermediate 66a (0.91 mmol) according to general method B2 in 32% yield (in two steps) as a white solid. ESI-MS: 353.15 (M+H) + .

[0150] The following table shows intermediate 67 prepared from Method B2.

[0151] TIFF2025539843000090.tif122170

[0152] The following compounds are examples illustrating Method C2:

[0153] N-(4-{3-[(2,6-difluoro-4-pyridyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl-pyrazole-4-carboxamide (68): TIFF2025539843000091.tif26170 Compound 68 was synthesized from intermediate 67a (0.42 mmol) and (2,6-difluoro-4-pyridyl)methanamine (0.63 mmol) according to general method C2 as a white solid in 23% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.59(s,1H),9.16(t,J=6.0Hz,1H),8.40(s,1H),8.24(d,J=5.7Hz,1H),8.09(s,1H),7.75(d,J=2.3Hz, 1H),7.50-7.37(m,2H),7.30-7.24(m,1H),7.14(s,2H),6.63(dd,J=5.7Hz,2.4Hz,1H),4.57(d,J=5.9Hz,2H),3.86(s,3H),2.15(s,3H). ESI-MS: 479.20 (M+H) + .

[0154] N-(4-{3-[(4-cyano-3-fluoro-phenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl-pyrazole-4-carboxamide (69): TIFF2025539843000092.tif26170 Compound 69 was synthesized from intermediate 67a (0.10 mmol) and 4-aminomethyl-2-fluorobenzonitrile (0.11 mmol) according to general method C2 as a white solid in 71% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.59(s,1H),9.14(t,J=6.0Hz,1H),8.40(s,1 H),8.23(d,J=5.7Hz,1H),8.09(d,J=0.6Hz,1H),7.97-7.88(m,1H),7.74(d,J= 2.3Hz,1H),7.48(d,J=10.4Hz,1H),7.43-7.37(m,3H),7.26(t,J=4.7Hz,1H),6 .63(dd,J=5.7Hz,2.4Hz,1H),4.54(d,J=5.9Hz,2H),3.86(s,3H),2.14(s,3H). ESI-MS: 485.15 (M+H) + .

[0155] N-(4-{3-[(3,5-difluorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl-pyrazole-4-carboxamide (70): TIFF2025539843000093.tif27170 Compound 70 was synthesized from intermediate 67a (0.10 mmol) and 3,5-difluorobenzylamine (0.11 mmol) according to general method C2 as a white solid in 64% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.56(s,1H),9.05(t,J=6.1Hz,1H),8.40(s,1H),8.23(d,J=5.7Hz,1H),8.09(s,1H),7.75(d,J=2.3Hz,1H),7.44 -7.35(m,2H),7.25(dd,J=7.3Hz,2.0Hz,1H),7.18-7.03(m,3H),6.62(dd,J=5.7Hz,2.4Hz,1H),4.47(d,J=6.0Hz,2H),3.86(s,3H),2.14(s,3H).

[0156] N-(4-{3-[(6-methoxy-3-pyridyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl-pyrazole-4-carboxamide (71): TIFF2025539843000094.tif22170 Compound 71 was synthesized from intermediate 67a (0.10 mmol) and (6-methoxypyridin-3-yl)methanamine (0.11 mmol) according to general method C2 as a white solid in 61% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):10.56(s,1H),8.95(t,J=5.9Hz,1H),8.40(s,1H), 8.22(d,J=5.7Hz,1H),8.14(d,J=2.2Hz,1H),8.09(s,1H),7.74(d,J=2.3Hz,1H),7 .69(dd,J=8.5Hz,2.5Hz,1H),7.40-7.19(m,3H),6.81(d,J=8.5Hz,1H),6.61(dd,J =5.7Hz,2.4Hz,1H),4.38(d,J=5.9Hz,2H),3.86(s,3H),3.83(s,3H),2.11(s,3H).

[0157] N-(4-{3-[(3-difluorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl-pyrazole-4-carboxamide (72): TIFF2025539843000095.tif27170 Compound 72 was synthesized from intermediate 67a (0.09 mmol) and 3-fluorobenzylamine (0.13 mmol) according to general method C2 as a white solid in 26% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.54(s,1H),9.01(t,J=6.1Hz,1H),8.40(s,1H),8.23(d,J=5.8Hz,1H),8.09(d,J=0.6Hz,1H),7.75(d,J=2. 3Hz,1H),7.45-7.20(m,6H),7.24(dd,J=7.9Hz,1.3Hz,1H),6.62(dd,J=5.7Hz,2.4Hz,1H),4.46(d,J=6.0Hz,2H),3.86(s,3H),2.14(s,3H). ESI-MS: 460.15 (M+H) + .

[0158] N-(4-{3-[(4-difluorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl-pyrazole-4-carboxamide (73): TIFF2025539843000096.tif29170 Compound 73 was synthesized from intermediate 67a (0.09 mmol) and 4-fluorobenzylamine (0.13 mmol) according to general method C2 as a white solid in 26% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.53(s,1H),9.00(t,J=6.0Hz,1H),8.40(s,1H),8.23(d,J=5.7Hz,1H),8.09(d,J=0.5Hz,1H),7.75(d ,J=2.3Hz,1H),7.46-7.32(m,3H),7.26-7.04(m,4H),6.62(dd,J=5.7Hz,2.4Hz,1H),4.47(d,J=6.0Hz,2H),3.86(s,3H),2.14(s,3H). ESI-MS: 460.15 (M+H) + .

[0159] N-(4-{3-[(3-chlorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl-pyrazole-4-carboxamide (74): TIFF2025539843000097.tif27170 Compound 74 was synthesized from intermediate 67a (0.09 mmol) and 3-chlorobenzylamine (0.13 mmol) according to general method C2 as a white solid in 30% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.53(s,1H),8.97(t,J=6.2Hz,1H),8.40(s,1H),8.23(d,J=5.7Hz,1H),8.09(d,J=0.5Hz,1H),7.75(d ,J=2.3Hz,1H),7.47-7.30(m,4H),7.25-7.12(m,3H),6.61(dd,J=5.7Hz,2.4Hz,1H),4.43(d,J=5.9Hz,2H),3.86(s,3H),2.13(s,3H). ESI-MS: 476.10 (M+H) + .

[0160] N-(4-{3-[(4-chlorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl-pyrazole-4-carboxamide (75): TIFF2025539843000098.tif27170 Compound 75 was synthesized from intermediate 67a (0.09 mmol) and 4-chlorobenzylamine (0.13 mmol) according to general method C2 as a white solid in 30% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.56(s,1H),9.01(t,J=6.0Hz,1H),8.40(s,1H),8.23(d,J=5.7Hz,1H),8.09(d,J=0.4Hz,1H),7.75(d,J=2. 3Hz,1H),7.47-7.31(m,6H),7.23(dd,J=7.8Hz,1.3Hz,1H),6.62(dd,J=5.7Hz,2.4Hz,1H),4.43(d,J=6.0Hz,2H),3.86(s,3H),2.13(s,3H). ESI-MS: 476.10 (M+H) + .

[0161] N-{4-[3-(imidazo[1,2-a]pyridin-6-ylmethylcarbamoyl)-2-methyl-phenoxy]-2-pyridyl}-1-methyl-pyrazole-4-carboxamide (76): TIFF2025539843000099.tif26170 Compound 76 was synthesized from intermediate 67a (0.09 mmol) and imidazo[1,2-a]pyridin-6-ylmethanamine (0.13 mmol) according to general method C2 as a white solid in 22% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):10.56(s,1H),9.01(t,J=5.9Hz,1H),8.50(s,1 H),8.40(s,1H),8.23(d,J=5.7Hz,1H),8.09(d,J=0.5Hz,1H),7.97(s,1H),7.7 4(d,J=2.3Hz,1H),7.58-7.52(m,2H),7.45-7.32(m,2H),7.29-7.19(m,2H),6 .62(dd,J=5.7Hz,2.4Hz,1H),4.44(d,J=5.9Hz,2H),3.86(s,3H),2.13(s,3H). ESI-MS: 482.20 (M+H) + .

[0162] N-{4-[3-(imidazo[1,2-a]pyridin-7-ylmethylcarbamoyl)-2-methyl-phenoxy]-2-pyridyl}-1-methyl-pyrazole-4-carboxamide (77): TIFF2025539843000100.tif24170 Compound 77 was synthesized from intermediate 67a (0.09 mmol) and imidazo[1,2-a]pyridin-7-ylmethanamine (0.13 mmol) according to general method C2 as a white solid in 15% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.56(s,1H),9.05(t,J=6.1Hz,1H),8.51(dd,J=7.0Hz,0.7Hz, 1H),8.40(s,1H),8.23(d,J=5.7Hz,1H),8.09(d,J=0.5Hz,1H),7.90(s,1H),7.75(d,J=2.3Hz, 1H),7.53(d,J=1.2Hz,1H),7.47-7.35(m,3H),7.25(dd,J=7.4Hz,1.9Hz,1H),6.89(dd,J=7.0H z,1.6Hz,1H),6.62(dd,J=5.7Hz,2.4Hz,1H),4.49(d,J=5.9Hz,2H),3.86(s,3H),2.15(s,3H). ESI-MS: 482.2 0(M+H) + .

[0163] 1-Methyl-N-[4-(2-methyl-3-{[6-(trifluoromethyl)-3-pyridyl]methylcarbamoyl}phenoxy)-2-pyridyl]pyrazole-4-carboxamide (78): TIFF2025539843000101.tif26170

[0164] Compound 78 was synthesized from intermediate 67a (0.09 mmol) and [6-(trifluoromethyl)-3-pyridyl]methanamine (0.13 mmol) according to general procedure C2 as a white solid in 44% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.88(s,1H),9.12(t,J=5.9Hz,1H),8.76(s,1 H),8.27(d,J=5.7Hz,1H),8.05(d,J=9.3Hz,1H),7.91(d,J=8.1Hz,1H),7.71(d ,J=2.3Hz,1H),7.50(d,J=2.1Hz,1H),7.46-7.35(m,2H),7.30-7.23(m,2H),6 .65(dd,J=5.7Hz,2.3Hz,1H),4.58(d,J=5.8Hz,2H),4.04(s,3H),2.14(s,3H). ESI-MS: 511.15 (M+H) + .

[0165] N-(4-{3-[(5-fluoro-6-methoxy-3-pyridyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl-pyrazole-4-carboxamide (79): TIFF2025539843000102.tif28170 Compound 79 was synthesized from intermediate 67a (0.09 mmol) and (5-fluoro-6-methoxy-3-pyridyl)methanamine (0.13 mmol) according to general method C2 as a white solid in 38% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):10.54(s,1H),8.95(t,J=5.9Hz,1H),8.40(s,1H),8.23 (d,J=5.7Hz,1H),8.09(d,J=0.4Hz,1H),7.98(d,J=1.8Hz,1H),7.74(d,J=2.3Hz,1H),7 .65(dd,J=11.4Hz,1.9Hz,1H),7.41-7.30(m,2H),7.23(dd,J=7.8Hz,1.4Hz,1H),6.61( dd,J=5.7Hz,2.4Hz,1H),4.41(d,J=5.9Hz,2H),3.93(s,3H),3.86(s,3H),2.12(s,3H). ESI-MS: 491.05 (M+H) + .

[0166] N-(4-{3-[(3-difluorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl-pyrazole-3-carboxamide (80): TIFF2025539843000103.tif26170 Compound 80 was synthesized from intermediate 67b (0.11 mmol) and 3-fluorobenzylamine (0.17 mmol) according to general method C2 as a white solid in 37% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.54(s,1H),9.03(t,J=6.0Hz,1H),8.23(d,J =5.8Hz,1H),7.87(d,J=2.3Hz,1H),7.71(d,J=2.3Hz,1H),7.45-7.34(m,3H) ,7.29-7.14(m,3H),7.09(td,J=8.5Hz,2.5Hz,1H),6.81(d,J=2.3Hz,1H),6. 65(dd,J=5.7Hz,2.4Hz,1H),4.47(d,J=6.0Hz,2H),3.95(s,3H),2.14(s,3H). ESI-MS: 460.30 (M+H) + .

[0167] N-(4-{3-[(4-difluorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl-pyrazole-3-carboxamide (81): TIFF2025539843000104.tif28170 Compound 81 was synthesized from intermediate 67b (0.11 mmol) and 4-fluorobenzylamine (0.17 mmol) according to general method C2 as a white solid in 37% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.54(s,1H),8.99(t,J=6.1Hz,1H),8.23(d,J =5.7Hz,1H),7.88(d,J=2.3Hz,1H),7.71(d,J=2.3Hz,1H),7.42-7.33(m,4H) ,7.25(dd,J=7.8Hz,1.4Hz,1H),7.22-7.12(m,2H),6.81(d,J=2.3Hz,1H),6. 65(dd,J=5.7Hz,2.4Hz,1H),4.43(d,J=6.0Hz,2H),3.95(s,3H),2.13(s,3H). ESI-MS: 460.25 (M+H) + .

[0168] N-(4-{3-[(3-chlorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl-pyrazole-3-carboxamide (82): TIFF2025539843000105.tif26170 Compound 82 was synthesized from intermediate 67b (0.11 mmol) and 3-chlorobenzylamine (0.17 mmol) according to general method C2 as a white solid in 41% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.54(s,1H),9.03(t,J=6.1Hz,1H),8.23(d,J=5.7Hz,1H),7.87(d,J=2.3Hz,1H),7.71(d,J=2.3Hz,1H),7.45-7. 30(m,6H),7.26(dd,J=7.8Hz,1.2Hz,1H),6.81(d,J=2.3Hz,1H),6.65(dd,J=5.7Hz,2.4Hz,1H),4.46(d,J=6.0Hz,2H),3.95(s,3H),2.14(s,3H). ESI-MS: 476.10 (M+H) + .

[0169] N-(4-{3-[(4-chlorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl-pyrazole-3-carboxamide (83): TIFF2025539843000106.tif28170 Compound 83 was synthesized from intermediate 67b (0.11 mmol) and 4-chlorobenzylamine (0.17 mmol) according to general method C2 as a white solid in 48% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.52(s,1H),8.99(t,J=6.0Hz,1H),8.23(d,J=5.7Hz,1H),7.87(d,J=2.3Hz,1H),7.71(d,J=2.3Hz,1H),7.44-7. 32(m,6H),7.25(dd,J=7.8Hz,1.4Hz,1H),6.80(d,J=2.3Hz,1H),6.65(dd,J=5.7Hz,2.4Hz,1H),4.44(d,J=6.0Hz,2H),3.95(s,3H),2.13(s,3H). ESI-MS: 476.10 (M+H) + .

[0170] N-{4-[3-(imidazo[1,2-a]pyridin-6-ylmethylcarbamoyl)-2-methyl-phenoxy]-2-pyridyl}-1-methyl-pyrazole-3-carboxamide (84): TIFF2025539843000107.tif24170 Compound 84 was synthesized from intermediate 67b (0.11 mmol) and imidazo[1,2-a]pyridin-6-ylmethanamine (0.17 mmol) according to general method C2 as a white solid in 35% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.52(s,1H),8.99(t,J=6.0Hz,1H),8.50(s,1H), 8.22(d,J=5.8Hz,1H),7.96(s,1H),7.87(d,J=2.3Hz,1H),7.70(d,J=2.3Hz,1H) ,7.59-7.52(m,2H),7.44-7.34(m,2H),7.28-7.22(m,2H),6.80(d,J=2.3Hz,1H) ,6.65(dd,J=5.7Hz,2.4Hz,1H),4.45(d,J=5.8Hz,2H),3.95(s,3H),2.14(s,3H). ESI-MS: 482.20 (M+H) + .

[0171] N-{4-[3-(imidazo[1,2-a]pyridin-7-ylmethylcarbamoyl)-2-methyl-phenoxy]-2-pyridyl}-1-methyl-pyrazole-3-carboxamide (85): TIFF2025539843000108.tif25170 Compound 85 was synthesized from intermediate 67b (0.11 mmol) and imidazo[1,2-a]pyridin-7-ylmethanamine (0.17 mmol) according to general method C2 as a white solid in 22% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.52(s,1H),9.04(t,J=6.0Hz,1H),8.51(dd,J=7.0Hz,0.7Hz,1H ),8.23(d,J=5.8Hz,1H),7.90(s,1H),7.87(d,J=2.3Hz,1H),7.72(d,J=2.3Hz,1H),7.53(d,J=1. 1Hz,1H),7.45-7.37(m,3H),7.26(dd,J=7.1Hz,2.2Hz,1H),6.89(dd,J=7.0Hz,1.6Hz,1H),6.81( d,J=2.3Hz,1H),6.65(dd,J=5.7Hz,2.4Hz,1H),4.49(d,J=5.9Hz,2H),3.95(s,3H),2.16(s,3H). ESI-MS: 482.15 (M+H) + .

[0172] N-(4-{3-[(3,5-difluorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl-pyrazole-3-carboxamide (86): TIFF2025539843000109.tif34170 Compound 86 was synthesized from intermediate 67b (0.09 mmol) and 3,5-difluorobenzylamine (0.13 mmol) according to general method C2 as a white solid in 49% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.53(s,1H),9.03(t,J=6.0Hz,1H),8.23(d,J =5.8Hz,1H),7.87(d,J=2.3Hz,1H),7.71(d,J=2.3Hz,1H),7.44-7.35(m,2H) ,7.26(dd,J=7.2Hz,2.1Hz,1H),7.17-7.02(m,3H),6.81(d,J=2.3Hz,1H),6. 65(dd,J=5.7Hz,2.4Hz,1H),4.47(d,J=6.0Hz,2H),3.95(s,3H),2.14(s,3H). ESI-MS: 478.15 (M+H) + .

[0173] N-(4-{3-[(6-methoxy-3-pyridyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-1-methyl-pyrazole-3-carboxamide (87): TIFF2025539843000110.tif27170 Compound 87 was synthesized from intermediate 67b (0.09 mmol) and (6-methoxypyridin-3-yl)methanamine (0.13 mmol) according to general method C2 as a white solid in 45% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.52(s,1H),8.93(t,J=5.9Hz,1H),8.22(d,J=5.7Hz,1H ),8.14(d,J=2.0Hz,1H),7.87(d,J=2.3Hz,1H),7.71-7.69(m,2H),7.38(t,J=7.7Hz,1H) ,7.32(dd,J=7.6Hz,1.3Hz,1H),7.24(dd,J=7.9Hz,1.2Hz,1H),6.82-6.80(m,2H),6.64 (dd,J=5.7Hz,2.4Hz,1H),4.38(d,J=5.9Hz,2H),3.95(s,3H),3.83(s,3H),2.12(s,3H). ESI-MS: 473.15 (M+H) + .

[0174] 1-Methyl-N-[4-(2-methyl-3-{[6-(trifluoromethyl)-3-pyridyl]methylcarbamoyl}phenoxy)-2-pyridyl]pyrazole-3-carboxamide (88): TIFF2025539843000111.tif31170 Compound 88 was synthesized from intermediate 67b (0.09 mmol) and [6-(trifluoromethyl)-3-pyridyl]methanamine (0.13 mmol) according to general method C2 as a white solid in 48% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.54(s,1H),9.13(t,J=5.9Hz,1H),8.77(d,J=1.2Hz,1H ),8.23(d,J=5.7Hz,1H),8.05(dd,J=8.1Hz,1.4Hz,1H),7.91(d,J=8.1Hz,1H),7.87(d,J =2.3Hz,1H),7.70(d,J=2.3Hz,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=5.7Hz,2.4Hz,1H),4.58(d,J=5.8Hz,2H),3.95(s,3H),2.14(s,3H). ESI-MS: 511.15 (M+H) + .

[0175] N-(4-{3-[(3-difluorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-2-methyl-pyrazole-3-carboxamide (89): TIFF2025539843000112.tif21170 Compound 89 was synthesized from intermediate 67b (0.09 mmol) and 3-fluorobenzylamine (0.13 mmol) according to general method C2 as a white solid in 33% yield. 1 H NMR(600MHz,DMSO-d6)δ(ppm):10.85(s,1H),9.00(t,J=6.1Hz,1H),8.27(d,J=5.8 Hz,1H),7.72(d,J=2.2Hz,1H),7.50(d,J=2.1Hz,1H),7.41-7.35(m,3H),7.26-7.24 (m,2H),7.20(d,J=7.6Hz,1H),7.16(d,J=10.2Hz,1H),7.09(td,J=8.3Hz,2.0Hz,1 H),6.65(dd,J=5.7Hz,2.4Hz,1H),4.47(d,J=6.0Hz,2H),4.05(s,3H),2.15(s,3H). ESI-MS: 460.20 (M+H) + .

[0176] N-(4-{3-[(4-difluorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-2-methyl-pyrazole-3-carboxamide (90): TIFF2025539843000113.tif21170 Compound 90 was synthesized from intermediate 67c (0.09 mmol) and 4-fluorobenzylamine (0.13 mmol) according to general procedure C2 as a white solid in 32% yield. 1 H NMR(600MHz,DMSO-d6)δ(ppm):10.85(s,1H),8.96(t,J=6.1Hz,1H),8.29-8 .24(m,1H),7.72(d,J=2.2Hz,1H),7.50(d,J=2.1Hz,1H),7.41-7.37(m,3H) ,7.33(dd,J=7.6Hz,1.1Hz,1H),7.27-7.23(m,2H),7.20-7.14(m,2H),6.64 (dd,J=5.7Hz,2.4Hz,1H),4.43(d,J=6.0Hz,2H),4.05(s,3H),2.14(s,3H). ESI-MS: 460.20 (M+H) + .

[0177] N-(4-{3-[(3-chlorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-2-methyl-pyrazole-3-carboxamide (91): TIFF2025539843000114.tif22170 Compound 91 was synthesized from intermediate 67c (0.09 mmol) and 3-chlorobenzylamine (0.13 mmol) according to general method C2 as a white solid in 37% yield. 1 H NMR(600MHz,DMSO-d6)δ(ppm):10.85(s,1H),9.00(t,J=6.0Hz,1H),8.31-8.23(m,1H),7.72(d,J=2.3,1H),7.50(d,J=2. 1Hz,1H),7.43-7.30(m,6H),7.25(m,2H),6.65(dd,J=5.7Hz,2.4Hz,1H),4.46(d,J=6.0Hz,2H),4.05(s,3H),2.15(s,3H). ESI-MS: 476.15 (M+H) + .

[0178] N-(4-{3-[(4-chlorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-2-methyl-pyrazole-3-carboxamide (92): TIFF2025539843000115.tif23170 Compound 92 was synthesized from intermediate 67c (0.09 mmol) and 4-chlorobenzylamine (0.13 mmol) according to general method C2 as a white solid in 35% yield. 1 H NMR(600MHz,DMSO-d6)δ(ppm):10.85(s,1H),8.98(t,J=6.1Hz,1H),8.29-8.24(m,1H),7.72(d,J=2.2Hz,1H),7.50(d,J=2.1Hz,1H),7.42-7.3 3(m,5H),7.26(d,J=2.1Hz,2H),7.25(dd,J=8.0Hz,1.1Hz,1H)6.64(dd,J=5.7Hz,2.4Hz,1H),4.44(d,J=6.0Hz,2H),4.05(s,3H),2.14(s,3H). ESI-MS: 476.15 (M+H) + .

[0179] N-{4-[3-(imidazo[1,2-a]pyridin-6-ylmethylcarbamoyl)-2-methyl-phenoxy]-2-pyridyl}-2-methyl-pyrazole-3-carboxamide (93): TIFF2025539843000116.tif23170 Compound 93 was synthesized from intermediate 67c (0.09 mmol) and imidazo[1,2-a]pyridin-6-ylmethanamine (0.13 mmol) according to general method C2 as a white solid in 15% yield. 1H NMR(600MHz,DMSO-d6)δ(ppm):10.85(s,1H),8.98(t,J=6.0Hz,1H),8.52-8.4 9(m,1H),8.26(d,J=5.7Hz,1H),7.98-7.95(m,1H),7.71(d,J=2.3Hz,1H),7.5 8-7.54(m,2H),7.50(d,J=2.1Hz,1H),7.41-7.34(m,2H),7.27-7.22(m,3H),6 .64(dd,J=5.7Hz,2.3Hz,1H),4.45(d,J=5.8Hz,2H),4.04(s,3H),2.14(s,3H). ESI-MS: 482.20 (M+H) + .

[0180] N-{4-[3-(imidazo[1,2-a]pyridin-7-ylmethylcarbamoyl)-2-methyl-phenoxy]-2-pyridyl}-2-methyl-pyrazole-3-carboxamide (94): TIFF2025539843000117.tif21170 Compound 94 was synthesized from intermediate 67c (0.09 mmol) and imidazo[1,2-a]pyridin-7-ylmethanamine (0.13 mmol) according to general method C2 as a white solid in 20% yield. 1 H NMR(600MHz,DMSO-d6)δ(ppm):10.85(s,1H),9.03(t,J=6.0Hz,1H),8.51(dd,J=7.0Hz,0. 9Hz,1H),8.27(d,J=5.7Hz,1H),7.91-7.88(m,1H),7.72(d,J=2.3Hz,1H),7.53(d,J=1.2H) z,1H),7.50(d,J=2.1Hz,1H),7.45-7.36(m,3H),7.28-7.24(m,2H),6.89(dd,J=7.0Hz,1. 7Hz,1H),6.65(dd,J=5.7Hz,2.3Hz,1H),4.49(d,J=5.8Hz,2H),4.05(s,3H),2.17(s,3H). ESI-MS: 482.20 (M+H) + .

[0181] N-(4-{3-[(3,5-difluorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-2-methyl-pyrazole-3-carboxamide (95): TIFF2025539843000118.tif26170 Compound 95 was synthesized from intermediate 67c (0.09 mmol) and 3,5-difluorobenzylamine (0.13 mmol) according to general method C2 as a white solid in 42% yield. 1 H NMR(600MHz,DMSO-d6)δ(ppm):10.85(s,1H),9.02(t,J=6.1Hz,1H),8.27(d ,J=5.7Hz,1H),7.72(d,J=2.3Hz,1H),7.50(d,J=2.1Hz,1H),7.43-7.36(m,2 H),7.27-7.25(m,2H),7.12(tt,J=9.3Hz,2.4Hz,1H),7.08-7.04(m,2H),6.6 5(dd,J=5.5Hz,2.3Hz,1H),4.47(d,J=6.0Hz,2H),4.05(s,3H),2.15(s,3H). ESI-MS: 478.15 (M+H) + .

[0182] N-(4-{3-[(6-methoxy-3-pyridyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-2-methyl-pyrazole-3-carboxamide (96): TIFF2025539843000119.tif22170 Compound 96 was synthesized from intermediate 67c (0.09 mmol) and (6-methoxypyridin-3-yl)methanamine (0.13 mmol) according to general procedure C2 as a white solid in 38% yield. 1H NMR(600MHz,DMSO-d6)δ(ppm):10.85(s,1H),8.92(t,J=5.9Hz,1H),8.33-8.22(m,1H),8 .14(dd,J=2.4Hz,0.6Hz,1H),7.76-7.64(m,2H),7.50(d,J=2.1Hz,1H),7.39-7.36(m,1H ),7.31(dd,J=7.6Hz,1.1Hz,1H),7.26-7.22(m,2H),6.81(dd,J=8.5Hz,0.6Hz,1H),6.63 (dd,J=5.7Hz,2.4Hz,1H),4.38(d,J=5.9Hz,2H),4.05(s,3H),3.83(s,3H),2.12(s,3H). ESI-MS: 473.20 (M+H) + .

[0183] 2-Methyl-N-[4-(2-methyl-3-{[6-(trifluoromethyl)-3-pyridyl]methylcarbamoyl}phenoxy)-2-pyridyl]pyrazole-3-carboxamide (97): TIFF2025539843000120.tif26170 Compound 97 was synthesized from intermediate 67c (0.09 mmol) and [6-(trifluoromethyl)-3-pyridyl]methanamine (0.13 mmol) according to general method C2 as a white solid in 44% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.88(s,1H),9.12(t,J=5.9Hz,1H),8.76(s,1 H),8.27(d,J=5.7Hz,1H),8.05(d,J=9.3Hz,1H),7.91(d,J=8.1Hz,1H),7.71(d ,J=2.3Hz,1H),7.50(d,J=2.1Hz,1H),7.44-7.36(m,2H),7.28-7.25(m,2H),6 .65(dd,J=5.7Hz,2.3Hz,1H),4.58(d,J=5.8Hz,2H),4.04(s,3H),2.14(s,3H). ESI-MS: 511.15 (M+H) + .

[0184] N-(4-{3-[(5-fluoro-6-methoxy-3-pyridyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)-2-methyl-pyrazole-3-carboxamide (98): TIFF2025539843000121.tif21170 Compound 98 was synthesized from intermediate 67c (0.09 mmol) and (5-fluoro-6-methoxy-3-pyridyl)methanamine (0.13 mmol) according to general method C2 as a white solid in 36% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.86(s,1H),8.95(t,J=5.8Hz,1H),8.27(d,J=5 .7Hz,1H),7.98(d,J=1.7Hz,1H),7.71(d,J=2.3Hz,1H),7.65(dd,J=11.4Hz,1.9H z,1H),7.50(d,J=2.1Hz,1H),7.44-7.31(m,2H),7.26-7.23(m,2H),6.64(dd,J= 5.7Hz,2.3Hz,1H),4.41(d,J=5.9Hz,2H),4.05(s,3H),3.93(s,3H),2.13(s,3H). ESI-MS: 491.10 (M+H) + .

[0185] N-{4-[2-methyl-3-(4-pyridylmethylcarbamoyl)phenoxy]-2-pyridyl}pyridine-3-carboxamide (99): TIFF2025539843000122.tif23170 Compound 99 was synthesized from intermediate 67d (0.13 mmol) and 4-(aminomethyl)pyridine (0.19 mmol) according to general method C2 as a white solid in 7% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):11.14(s,1H),9.08-9.05(m,2H),8.73(dd,J=4.8H z,1.6Hz,1H),8.53(dd,J=4.4Hz,1.5Hz,2H),8.35-8.24(m,2H),7.77(d,J=2.3Hz, 1H),7.52(dd,J=7.7Hz,5.1Hz,1H),7.45-7.39(m,2H),7.35(d,J=5.9Hz,2H),7.3 1-7.24(m,1H),6.70(dd,J=5.7Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),2.17(s,3H). ESI-MS: 440.15 (M+H) + .

[0186] N-(4-{3-[(2,6-difluoro-4-pyridyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)pyridine-3-carboxamide (100): TIFF2025539843000123.tif27170 Compound 100 was synthesized from intermediate 67d (0.13 mmol) and (2,6-difluoro-4-pyridyl)methanamine (0.38 mmol) according to general method C2 as a white solid in 14% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):11.14(s,1H),9.12(t,J=5.8Hz,1H),9.08(d,J=1. 7Hz,1H),8.73(dd,J=4.8Hz,1.5Hz,1H),8.34-8.24(m,2H),7.76(d,J=2.2Hz,1H) ,7.52(dd,J=7.5Hz,4.8Hz,1H),7.48-7.40(m,2H),7.28(dd,J=7.6Hz,1.4Hz,1H) ,7.13(s,2H),6.71(dd,J=5.7Hz,2.3Hz,1H),4.57(d,J=5.9Hz,2H),2.17(s,3H). ESI-MS: 476.20 (M+H) + .

[0187] N-(4-{3-[(4-cyano-3-fluoro-phenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)pyridine-3-carboxamide (101): TIFF2025539843000124.tif22170 Compound 101 was synthesized from intermediate 67d (0.13 mmol) and 4-aminomethyl-2-fluorobenzonitrile (0.14 mmol) according to general method C2 as a white solid in 8% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):1H NMR(400MHz,DMSO)δ 11.14(s,1H),9.15-9.05(m,2H),8.73(dd,J=4.7Hz,1.5Hz,1H),8.34-8.26(m,2H),7.97-7.88(m,1H),7.76(d,J=2 .2Hz,1H),7.55-7.38(m,5H),7.30-7.25(m,1H),6.70(dd,J=5.7Hz,2.3Hz,1H),4.55(d,J=5.9Hz,2H),2.16(s,3H). ESI-MS: 482.15 (M+H) + .

[0188] Example 3: General procedure for the synthesis of analogs 103-105 TIFF2025539843000125.tif104170

[0189] Preparation of 3-hydroxy-2-methyl-N-(4-pyridylmethyl)benzamide (102): TIFF2025539843000126.tif19170 Intermediate 102 was synthesized from 3-hydroxy-2-methylbenzoic acid (19.6 mmol) and 4-(aminomethyl)pyridine (19.6 mmol) as a white solid in 93% yield according to general method C3.

[0190] Method A3: Under nitrogen, t-BuOK (1.5 equiv.) was added to a solution of the phenol derivative (1 equiv.) in DMF (5 mL / mmol). The 4-chloropyridine derivative (1 equiv.) was added, and the reaction mixture was stirred at 140 °C until completion (24-48 h). The reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography (DCM / MeOH, 100 / 0 to 90 / 10) and reverse-phase chromatography (HO / MeOH, 100 / 0 to 0 / 100) to give the expected compound.

[0191] Method F: To a stirred solution of 104 (30 mg, 0.063 mmol) in EtOH / HO (0.75 mL / 0.25 mL) was added (L) sodium ascorbate (2 mg, 0.006 mmol), sodium azide (9 mg, 0.126 mmol), copper 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 was purified by flash column chromatography (DCM / MeOH, 100 / 0 to 80 / 20) and reverse-phase chromatography (HO / 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(500MHz,DMSO-d6)δ(ppm):9.94(s,1H),9.05(t,J=6.1Hz,1H),8.54-8.52(m,2H),8.36(s,1H),8.05(d,J=0.6Hz,1H),7.40-7.29(m,4H) ,7.19(dd,J=7.0Hz,2.3Hz,1H),7.07(d,J=2.0Hz,1H),5.79(bs,2H),5.56(d,J=2.0Hz,1H),4.47(d,J=6.0Hz,2H),3.85(s,3H),2.16(s,3H). ESI-MS: 458.15 (M+H) + .

[0192] The following compounds are examples illustrating Method A3:

[0193] 1-Methyl-N-{4-[2-methyl-3-(4-pyridylmethylcarbamoyl)phenoxy]-2-pyridyl}pyrazole-4-carboxamide (103): TIFF2025539843000127.tif21170 Compound 103 was synthesized from intermediate 102 (0.22 mmol) and 65a (0.22 mmol) according to general method A3 as a white solid in 19% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.53(s,1H),9.05(t,J=6.0Hz,1H),8.53(dd,J=4.5Hz,1.5Hz,2H),8.40(s,1H),8.23(d,J=5.7Hz,1H),8.09(s,1 H),7.75(d,J=2.3Hz,1H),7.42-7.33(m,4H),7.28-7.20(m,1H),6.62(dd,J=5.7Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),3.86(s,3H),2.16(s,3H).

[0194] N-{6-chloro-4-[2-methyl-3-(4-pyridylmethylcarbamoyl)phenoxy]-2-pyridyl}-1-methyl-pyrazole-4-carboxamide (104): TIFF2025539843000128.tif29170 Compound 104 was synthesized from intermediate 102 (0.22 mmol) and 65d (0.22 mmol) according to general method A3 as a white solid in 23% yield. 1 H NMR(500MHz,DMSO-d6)δ(ppm):10.84(s,1H),9.10(t,J=6.1Hz,1H),8.53(dd,J=4.4Hz,1.6Hz,2H),8.41(s,1H),8.10(d,J=0.5Hz,1H),7.73(d,J =2.0Hz,1H),7.44-7.40(m,2H),7.35(d,J=6.0Hz,2H),7.33-7.28(m,1H) ,6.73(d,J=2.0Hz,1H),4.48(d,J=6.0Hz,2H),3.85(s,3H),2.16(s,3H). ESI-MS: 477.15 (M+H) +.

[0195] Example 4: General procedure for the synthesis of analogs 106-108 TIFF2025539843000129.tif107170

[0196] 3-[(2-amino-4-pyridyl)oxy]-2-methyl-N-(4-pyridylmethyl)benzamide (106): TIFF2025539843000130.tif22170 Compound 106 was synthesized from intermediate 102 (0.39 mmol) and 2-amino-4-chloropyridine (0.39 mmol) according to general method A3 as a white solid in 23% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.54-8.52(m,2H),7.79(d,J=5.8Hz,1H),7.36-7.33(m,4H),7.17(dd, J=6.4Hz,2.9Hz,1H),6.08(dd,J=5.8Hz,2.3Hz,1H),5.92(s,2H),5.74(d,J=2.2Hz,1H),4.47(d,J=6.0Hz,2H),2.13(s,3H).

[0197] 3-[(2-amino-4-pyridyl)oxy]-2-methyl-N-(4-pyridylmethyl)benzamide (107): TIFF2025539843000131.tif24170 Compound 107 was synthesized from intermediate 102 (0.61 mmol) and 2-amino-4,6-dichloropyridine (0.61 mmol) according to general method A3 as a white solid in 30% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.05(t,J=6.0Hz,1H),8.53(d,J=5.4Hz,2H),7.40-7.31(m,4H),7.25-7. 20(m,1H),6.45(s,2H),6.13(d,J=1.9Hz,1H),5.65(d,J=1.9Hz,1H),4.47(d,J=6.0Hz,2H),2.12(s,3H).

[0198] 3-{[2-amino-6-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}-2-methyl-N-(4-pyridylmethyl)benzamide (108): Method D3: To a stirred dioxane (1 mL) solution of 107 (32 mg, 0.086 mmol) under nitrogen, PdCl2dppf (7 mg, 0.009 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-1H-pyrazole) (27 mg, 0.13 mmol), and Cs2CO3 1M (0.215 mL, 0.215 mmol) were added. The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography (DCM / MeOH) and reverse-phase chromatography (HO / MeOH: 0-100%) to give 18 mg of 108 in 51% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.03(t,J=6.0Hz,1H),8.54-8.52(m 2H),8.06(s,1H),7.83(d,J=0.6Hz,1H),7.41-7.32(m,4H),7.20(dd,J=6.7Hz,2.6Hz,1H),6.51(d, J=2.0Hz,1H),5.92(s,2H),5.49(d,J=2.0Hz,1H),4.47(d,J=6.0Hz,2H),3.84(s,3H),2.16(s,3H).

[0199] Example 5: General procedure for the synthesis of analogs 110-116 TIFF2025539843000133.tif88170

[0200] Preparation of 3-[(2-bromo-4-pyridyl)oxy]-2-methyl-N-(4-pyridylmethyl)benzamide (109): TIFF2025539843000134.tif21170 Compound 109 was synthesized from intermediate 102 (5.87 mmol) and 2-bromo-4-chloropyridine (5.87 mmol) according to general method A1 as a white solid in 84% yield. ESI-MS: 398.10-400.10 (M+H) + .

[0201] Method G: Under nitrogen, to a solution of 109 (1 equiv.) in THF (20 mL / mmol) was added the 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 was purified by flash column chromatography (DCM / MeOH, 100 / 0 to 90 / 10) and reverse-phase chromatography (HO / MeOH, 100 / 0 to 0 / 100) to give the expected compound.

[0202] 2-Methyl-3-{[2-(3-phenylprop-1-ynyl)-4-pyridyl]oxy}-N-(4-pyridylmethyl)benzamide (110): TIFF2025539843000135.tif20170 Compound 110 was synthesized from intermediate 109 (0.10 mmol) and 3-phenyl-1-propyne (0.30 mmol) according to general method G as a white solid in 21% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.03(t,J=6.0Hz,1H),8.55-8.52(m,2H),8.41(d,J=5.7Hz,1H),7.44-7.32(m,9H),7.2 8-7.23(m,1H),6.89(d,J=2.4Hz,1H),6.85(dd,J=5.7Hz,2.5Hz,1H),4.48(d,J=6.0Hz,2H),3.90(s,2H),2.12(s,3H). ESI-MS: 434.25 (M+H) + .

[0203] 3-{[2-(3-hydroxyprop-1-ynyl)-4-pyridyl]oxy}-2-methyl-N-(4-pyridylmethyl)benzamide (111): TIFF2025539843000136.tif23170 Compound 111 was synthesized from intermediate 109 (0.10 mmol) and propargyl alcohol (0.30 mmol) according to general method G as a white solid in 22% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.05(t,J=6.0Hz,1H),8.54-8.52(m,2H),8.43(d,J=5.7Hz,1H),7.44-7.39(m,2H),7.34(d,J=6.0Hz,2H) ,7.29-7.23(m,1H),6.91(dd,J=5.7Hz,2.5Hz,1H),6.80(d,J=2.4Hz,1H),5.41(bs,1H),4.48(d,J=6.0Hz,2H),4.28(s,2H),2.11(s,3H). ESI-MS: 374.20 (M+H) + .

[0204] 3-{[2-(3-aminopropyl)-4-pyridyl]oxy}-2-methyl-N-(4-pyridylmethyl)benzamide (112): TIFF2025539843000137.tif23170 Compound 112 was synthesized from intermediate 109 (0.10 mmol) and propargylamine (0.30 mmol) according to general method G as a white solid in 22% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.05(t,J=6.0Hz,1H),8.54-8.52(m,2H),8.41(d,J=5.7Hz,1H),7.44-7.39(m,2H),7.34(d,J=5.9Hz,2H) ),7.26(dd,J=8.7Hz,4.3Hz,1H),6.90(dd,J=5.7Hz,2.5Hz,1H),6.75(d,J=2.4Hz,1H),4.48(d,J=6.0Hz,3H),3.47(s,2H),2.11(s,4H). ESI-MS: 373.20 (M+H) + .

[0205] 3-{[2-(3-methoxyprop-1-ynyl)-4-pyridyl]oxy}-2-methyl-N-(4-pyridylmethyl)benzamide (113): TIFF2025539843000138.tif22170 Compound 113 was synthesized from intermediate 109 (0.10 mmol) and propargyl ether methyl (0.30 mmol) according to general method G as a white solid in 31% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.04(t,J=5.9Hz,1H),8.54-8.52(m,2H),8.44(d,J=5.6Hz,1H),7.41(d,J=4.5Hz,2H),7.3 5(d,J=5.7Hz,2H),7.25(t,J=4.7Hz,1H),6.93-6.86(m,2H),4.48(d,J=5.9Hz,2H),4.32(s,2H),3.31(s,3H),2.12(s,3H). ESI-MS: 388.20 (M+H) + .

[0206] 2-Methyl-3-({2-[3-(methylamino)prop-1-ynyl]-4-pyridyl}oxy)-N-(4-pyridylmethyl)benzamide (114): TIFF2025539843000139.tif24170 Compound 114 was synthesized from intermediate 109 (0.10 mmol) and N-methyl-N-propynyl-2-amine (0.30 mmol) according to general method G as a white solid in 18% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.05(t,J=5.9Hz,1H),8.54-8.52(m,2H),8.41(d,J=5.8Hz,1H),7.41-7.38(m,3H),7.34(d,J=5.8Hz,2H),7.25(t,J =4.7Hz,1H),6.87(dd,J=5.7Hz,2.5Hz,1H),6.80(d,J=2.4Hz,1H),4.48(d,J=5.9Hz,2H),3.48(d,J=5.7Hz,2H),2.30(d,J=5.0Hz,3H),2.11(s,3H). ESI-MS: 387.25 (M+H) + .

[0207] 3-{[2-(3-imidazol-1-ylprop-1-ynyl)-4-pyridyl]oxy}-2-methyl-N-(4-pyridylmethyl)benzamide (115): TIFF2025539843000140.tif22170 Compound 115 was synthesized from intermediate 109 (0.20 mmol) and 1-(2-prop-1-yl)-1H-imidazole (0.40 mmol) according to general method G as a white solid in 4% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.04(t,J=5.9Hz,1H),8.54-8.52(m,2H),8.44(d,J=5.7Hz,1H),7.73(s,1H),7.41(d,J=4.3Hz,2H),7.34 (d,J=5.8Hz,2H),7.27-7.23(m,2H),6.94-6.93(m,2H),6.89(dd,J=5.7Hz,2.5Hz,1H),5.19(s,2H),4.48(d,J=5.9Hz,2H),2.11(s,3H). ESI-MS: 424.30 (M+H) + .

[0208] 2-Methyl-3-({2-[3-(methylamino)prop-1-ynyl]-4-pyridyl}oxy)-N-(4-pyridylmethyl)benzamide (116): TIFF2025539843000141.tif25170 Compound 116 was synthesized from intermediate 109 (0.20 mmol) and 1-(2-prop-1-yl)-1H-pyrazole (0.30 mmol) according to general method G as a white solid in 12% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.04(t,J=6.0Hz,1H),8.54-8.52(m,2H),8.46-8.41(m,1H),7.83(d,J=1.8Hz,1H),7.49(d,J=1.2Hz,1H),7.40(d, J=4.2Hz,2H),7.34(d,J=6.0Hz,2H),7.25(t,J=4.7Hz,1H),6.98-6.88(m ,2H),6.30-6.29(m,1H),5.30(s,2H),4.48(d,J=6.0Hz,2H),2.11(s,3H). ESI-MS: 424.25 (M+H) + .

[0209] Example 6: General procedure for the synthesis of analogs 120-197, 350-355 and 359 TIFF2025539843000142.tif93170

[0210] The following compound 117a is an example illustrating Method A1:

[0211] Preparation of ethyl 3-[(2-chloro-4-pyridyl)oxy]-2-methyl-benzoate (117a): TIFF2025539843000143.tif21170 Intermediate 117a was synthesized from ethyl 3-hydroxy-2-methyl-benzoate (6.30 mmol) and 2-chloro-4-nitropyridine (6.30 mmol) according to general method A1 as a colorless oil in 95% yield. ESI-MS: 292.00 (M+H) + .

[0212] The following table shows intermediate 117 prepared from Method A1.

[0213] TIFF2025539843000144.tif162170

[0214] The following compound 118a is an example illustrating Method D2:

[0215] Preparation of ethyl 2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzoate (118a): TIFF2025539843000145.tif22170 Intermediate 118a was synthesized from 117a (1.71 mmol) and 1-methylpyrazole-4-boronic acid pinacol ester (2.05 mmol) as a colorless oil in quantitative yield following general method D2. ESI-MS: 338.15 (M+H) + .

[0216] The following table shows intermediate 118 prepared from Method D2.

[0217] TIFF2025539843000146.tif117170

[0218] TIFF2025539843000147.tif50170

[0219] Method H: Under nitrogen, to a solution of 117 (1 equiv.) in dioxane (10 mL / mmol) was added the 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 (2 h to overnight). The reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography (DCM / MeOH, 100 / 0 to 90 / 10) to give the expected compound.

[0220] The following compound 118e is an example illustrating Method H:

[0221] Preparation of ethyl 2-methyl-3-({2-[(1-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzoate (118e): TIFF2025539843000148.tif23170 Intermediate 118e was synthesized from 117a (1.37 mmol) and 1-methylpyrazol-3-amine (2.74 mmol) following general method H as a yellow oil in 90% yield. ESI-MS: 353.05 (M+H) + .

[0222] The following table shows intermediate 113 prepared from Method H.

[0223] TIFF2025539843000149.tif45170

[0224] TIFF2025539843000150.tif94170

[0225] Method I: To a stirred solution of 117a (250 mg, 0.86 mmol) in CHCN (6 mL) was added pyrazole (123 mg, 1.79 mmol), CsCO (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 was purified by flash column chromatography (cyclohexane / EtOAc, 100 / 0 to 75 / 25) to give 58 mg of ethyl 2-methyl-3-[(2-pyrazol-1-yl-4-pyridyl)oxy]benzoate 118h in 11% yield.

[0226] The following compound 119a is an example illustrating Method B2:

[0227] Preparation of 2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzoic acid (119a): TIFF2025539843000151.tif21170 Compound 119a was synthesized from intermediate 118a (1.88 mmol) as a white powder in 79% yield according to general method B2. ESI-MS: 292.00 (M+H) + .

[0228] The following table shows intermediate 119 prepared from Method B2.

[0229] TIFF2025539843000152.tif204170

[0230] TIFF2025539843000153.tif96170

[0231] The following compounds are examples illustrating Method C2:

[0232] N-[(6-methoxy-3-pyridyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (120): TIFF2025539843000154.tif22170

[0233] Compound 120 was synthesized from intermediate 119a (0.10 mmol) and (6-methoxypyridin-3-yl)methanamine (0.12 mmol) according to general procedure C2 as a white solid in 60% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.91(t,J=5.9Hz,1H),8.35(d,J=5.7Hz,1H),8.25(s,1 H),8.14(d,J=2.2Hz,1H),7.96(s,1H),7.69(dd,J=8.5Hz,2.4Hz,1H),7.39-7.28(m,2 H),7.24(d,J=2.3Hz,1H),7.20(dd,J=7.9Hz,1.0Hz,1H),6.81(d,J=8.5Hz,1H),6.47( dd,J=5.7Hz,2.4Hz,1H),4.39(d,J=5.9Hz,2H),3.86(s,3H),3.83(s,3H),2.11(s,3H). ESI-MS: 430.10 (M+H) + .

[0234] 2-Methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}-N-(4-pyridylmethyl)benzamide (121): TIFF2025539843000155.tif22170 Compound 121 was synthesized from intermediate 119a (0.10 mmol) and 4-(aminomethyl)pyridine (0.12 mmol) according to general method C2 as a white solid in 69% yield.1 H NMR(400MHz,DMSO-d6)δ(ppm):9.04(t,J=6.0Hz,1H),8.54-8.52(m,2H),8.36(d,J=5.7Hz,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=5.7Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),3.86(s,3H),2.15(s,3H). ESI-MS: 400.05 (M+H) + .

[0235] 2-Methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}-N-(3-pyridylmethyl)benzamide (122): TIFF2025539843000156.tif23170 Compound 122 was synthesized from intermediate 119a (0.10 mmol) and 3-(aminomethyl)pyridine (0.12 mmol) according to general method C2 as a white solid in 59% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.00(t,J=5.9Hz,1H),8.57(d,J=1.7Hz,1H),8.48(dd,J=4.7Hz,1.4Hz,1H),8.35(d,J=5.7Hz,1H),8.25(s,1H),7.96(s, 1H),7.76(dt,J=7.8Hz,1.8Hz,1H)7.43-7.30(m,3H),7.27-7.20(m,2H),6.4 7(dd,J=5.7Hz,2.4Hz,1H),4.48(d,J=5.9Hz,2H),3.86(s,3H),2.12(s,3H). ESI-MS: 400.10 (M+H) + .

[0236] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (123): TIFF2025539843000157.tif28170 Compound 123 was synthesized from intermediate 119a (0.10 mmol) and 3,5-difluorobenzylamine (0.12 mmol) according to general method C2 as a white solid in 85% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=6.0Hz,1H),8.36(d,J=5.7Hz,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=5.7Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),3.86(s,3H),2.14(s,3H). ESI-MS: 435.15 (M+H) + .

[0237] N-[(3-fluorophenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (124): TIFF2025539843000158.tif21170 Compound 124 was synthesized from intermediate 119a (0.10 mmol) and 3-fluorobenzylamine (0.12 mmol) according to general method C2 as a white solid in 82% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.98(t,J=6.0Hz,1H),8.35(d,J=5.7Hz,1H),8.25(s,1H),7.96(d,J=0.5Hz,1H),7.43-7.31(m,3H) ,7.26-7.13(m,4H),7.09(td,J=8.4Hz,2.3Hz,1H),6.48(dd,J=5.7Hz,2.4Hz,1H),4.47(d,J=6.0Hz,2H),3.86(s,3H),2.14(s,3H). ESI-MS: 417.20 (M+H) + .

[0238] N-[(4-fluorophenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (125): TIFF2025539843000159.tif23170 Compound 125 was synthesized from intermediate 119a (0.10 mmol) and 4-fluorobenzylamine (0.12 mmol) according to general method C2 as a white solid in 92% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.94(t,J=6.0Hz,1H),8.35(d,J=5.7Hz,1H),8.25(s,1H),7.96(d,J=0.5Hz,1H),7. 43-7.30(m,4H),7.26-7.14(m,4H),6.47(dd,J=5.7Hz,2.4Hz,1H),4.43(d,J=6.0Hz,2H),3.86(s,3H),2.12(s,3H). ESI-MS: 417.15 (M+H) + .

[0239] N-[(3-chlorophenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (126): TIFF2025539843000160.tif21170 Compound 126 was synthesized from intermediate 119a (0.10 mmol) and 3-chlorobenzylamine (0.12 mmol) according to general method C2 as a white solid in 72% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.98(t,J=6.0Hz,1H),8.35(d,J=5.7Hz,1H),8.25(s,1H),7.96(s,1H),7.44-7.30(m,6H),7.25( d,J=2.4Hz,1H),7.22(dd,J=7.8Hz,1.2Hz,1H),6.48(dd,J=5.7Hz,2.4Hz,1H),4.46(d,J=6.0Hz,2H),3.86(s,3H),2.13(s,3H). ESI-MS: 433.15 (M+H) + .

[0240] N-[(4-chlorophenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (127): TIFF2025539843000161.tif20170 Compound 127 was synthesized from intermediate 119a (0.10 mmol) and 4-chlorobenzylamine (0.12 mmol) according to general method C2 as a white solid in 83% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.97(t,J=6.0Hz,1H),8.35(d,J=5.7Hz,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=5.7Hz,2.4Hz,1H),4.44(d,J=6.0Hz,2H),3.86(s,3H),2.13(s,3H). ESI-MS: 433.05 (M+H) + .

[0241] N-[(2,4-difluorophenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (128): TIFF2025539843000162.tif22170 Compound 128 was synthesized from intermediate 119a (0.065 mmol) and 2,4-difluorobenzylamine (0.097 mmol) according to general method C2 as a white solid in 53% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.93(t,J=5.6Hz,1H),8.35(d,J=5.7Hz,1H),8.25(s,1H),7.96(s,1H),7.51-7.43(m,1H),7.4 0-7.18(m,5H),7.09(dd,J=8.5Hz,7.0Hz,1H),6.47(dd,J=5.6Hz,2.2Hz,1H),4.46(d,J=5.5Hz,2H),3.86(s,3H),2.11(s,3H). ESI-MS: 435.15 (M+H) + .

[0242] N-[(3,4-difluorophenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (129): TIFF2025539843000163.tif21170 Compound 129 was synthesized from intermediate 119a (0.065 mmol) and 3,4-difluorobenzylamine (0.097 mmol) according to general method C2 as a white solid in 57% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.98(t,J=6.0Hz,1H),8.35(d,J=5.7Hz,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=5.7Hz,2.4Hz,1H),4.44(d,J=6.0Hz,2H),3.86(s,3H),2.13(s,3H). ESI-MS: 435.15 (M+H) + .

[0243] N-[(4-chloro-3-fluoro-phenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (130): TIFF2025539843000164.tif21170 Compound 130 was synthesized from intermediate 119a (0.065 mmol) and 4-chloro-3-fluorobenzylamine (0.097 mmol) according to general method C2 as a white solid in 34% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.00(t,J=6.0Hz,1H),8.35(d,J=5.7Hz,1H),8.25(s,1H),7.96(s,1H),7.58(t,J=8.0Hz,1 H),7.43-7.32(m,3H),7.28-7.18(m,3H),6.48(dd,J=5.7Hz,2.4Hz,1H),4.46(d,J=6.0Hz,2H),3.86(s,3H),2.13(s,3H). ESI-MS: 451.10 (M+H) + .

[0244] N-(imidazo[1,2-a]pyridin-6-ylmethyl)-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (131): TIFF2025539843000165.tif22170 Compound 131 was synthesized from intermediate 119a (0.065 mmol) and imidazo[1,2-a]pyridin-6-ylmethanamine (0.097 mmol) according to general method C2 as a white solid in 57% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.97(t,J=5.9Hz,1H),8.51(s,1H),8.35(d,J=5.7Hz,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=5.7Hz,2.4Hz,1H),4.45(d,J=5.8Hz,2H),3.86(s,3H),2.13(s,3H). ESI-MS: 439.15 (M+H) + .

[0245] N-(imidazo[1,2-a]pyridin-7-ylmethyl)-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (132): TIFF2025539843000166.tif21170 Compound 132 was synthesized from intermediate 119a (0.065 mmol) and imidazo[1,2-a]pyridin-7-ylmethanamine (0.097 mmol) according to general method C2 as a white solid in 50% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=6.0Hz,1H),8.51(d,J=7.0Hz,1H),8.36(d,J=5.7Hz,1H),8.25(s,1H),7. 96(s,1H),7.90(s,1H),7.53(d,J=1.0Hz,1H),7.44(s,1H),7.41-7.34(m,2H),7.28-7.20(m,2H),6.89(dd,J=7.0Hz ,Hz 1.5,1H),6.49(dd,J=5.7Hz,2.4Hz,1H),4.49(d,J=5.9Hz,2H),3.86(s,3H),2.15(s,3H). ESI-MS: 439.15 (M+H) + .

[0246] 2-Methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}-N-{[6-(trifluoromethyl)-3-pyridyl]methyl}benzamide (133): TIFF2025539843000167.tif27170 Compound 133 was synthesized from intermediate 119a (0.065 mmol) and [6-(trifluoromethyl)-3-pyridyl]methanamine (0.097 mmol) according to general method C2 as a white solid in 79% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.09(t,J=5.9Hz,1H),8.76(s,1H),8.35(d,J=5.7Hz,1H),8.25(s,1H),8.08-8.02(m,1H),7.96(s,1H),7. 92(d,J=8.1Hz,1H),7.43-7.35(m,2H),7.27-7.20(m,2H),6.48(dd,J=5.7Hz,2.4Hz,1H),4.59(d,J=5.8Hz,2H),3.86(s,3H),2.14(s,3H). ESI-MS: 468.15 (M+H) + .

[0247] N-[(2,3-difluorophenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (134): TIFF2025539843000168.tif22170 Compound 134 was synthesized from intermediate 119a (0.074 mmol) and 2,3-difluorobenzylamine (0.111 mmol) according to general method C2 as a white solid in 60% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.97(t,J=5.8Hz,1H),8.35(d,J=5.7Hz,1H),8.24(s,1H),7.95(d,J=0.6Hz,1H),7. 40-7.29(m,3H),7.28-7.18(m,4H),6.48(dd,J=5.7Hz,2.4Hz,1H),4.53(d,J=5.8Hz,2H),3.86(s,3H),2.13(s,3H). ESI-MS: 435.15 (M+H) + .

[0248] N-[(3-methoxyphenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (135): TIFF2025539843000169.tif23170 Compound 135 was synthesized from intermediate 119a (0.074 mmol) and 3-methoxybenzylamine (0.111 mmol) according to general method C2 as a white solid in 78% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.90(t,J=6.0Hz,1H),8.35(d,J=5.7Hz,1H),8.24(s,1H),7.95(d,J=0.6Hz,1H),7.43-7.16(m,5H), 6.98-6.90(m,2H),6.86-6.80(m,1H),6.49(dd,J=5.7Hz,2.4Hz,1H),4.44(d,J=6.0Hz,2H),3.86(s,3H),3.74(s,3H),2.14(s,3H). ESI-MS: 429.20 (M+H) + .

[0249] N-[(4-methoxyphenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (136): TIFF2025539843000170.tif22170 Compound 136 was synthesized from intermediate 119a (0.074 mmol) and 4-methoxybenzylamine (0.111 mmol) according to general method C2 as a white solid in 63% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.83(t,J=6.0Hz,1H),8.35(d,J=5.7Hz,1H),8.24(s,1H),7.95(d,J=0.6Hz,1H),7.36(t,J=7.8Hz,1H) ),7.30-7.18(m,5H),6.92-6.88(m,2H),6.48(dd,J=5.7Hz,2.4Hz,1H),4.38(d,J=6.0Hz,2H),3.86(s,3H),3.73(s,3H),2.12(s,3H). ESI-MS: 429.15 (M+H) + .

[0250] N-[(5-fluoro-3-pyridyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (137): TIFF2025539843000171.tif22170 Compound 137 was synthesized from intermediate 119a (0.10 mmol) and 5-fluoro-3-pyridinemethanamine (0.15 mmol) according to general method C2 as a white solid in 50% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=5.9Hz,1H),8.52-8.45(m,2H),8.36(d,J=5.7Hz,1H),8.24(s,1H),7.95(d,J=0.6Hz,1H),7. 71-7.64(m,1H),7.41-7.33(m,2H),7.27-7.20(m,2H),6.48(dd,J=5.7Hz,2.4Hz,1H),4.53(d,J=5.9Hz,2H),3.86(s,3H),2.13(s,3H). ESI-MS: 418.15 (M+H) + .

[0251] N-[(5-fluoro-6-methoxy-3-pyridyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (138): TIFF2025539843000172.tif22170 Compound 138 was synthesized from intermediate 119a (0.10 mmol) and (5-fluoro-6-methoxy-3-pyridyl)methanamine (0.15 mmol) according to general method C2 as a white solid in 62% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.91(t,J=5.9Hz,1H),8.35(d,J=5.7Hz,1H),8.24(s,1H),7.98-7.95(m,2H),7.65(dd,J=11.4Hz,1.9Hz, 1H),7.42-7.31(m,2H),7.26-7.19(m,2H),6.48(dd,J=5.7Hz,2.4Hz,1H),4.41(d,J=5.9Hz,2H),3.93(s,3H),3.86(s,3H),2.12(s,3H). ESI-MS: 448.15 (M+H) + .

[0252] N-[(5-fluoro-2-methoxy-3-pyridyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (139): TIFF2025539843000173.tif23170 Compound 139 was synthesized from intermediate 119a (0.10 mmol) and 5-fluoro-2-methoxy-3-pyridinemethanamine (0.24 mmol) according to general method C2 as a white solid in 40% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.85(t,J=5.7Hz,1H),8.36(d,J=5.7Hz,1H),8.24(s,1H),8.07(d,J=3.0Hz,1H),7.96(d,J=0.6Hz,1H),7.57(dd,J=8 .6Hz,3.0Hz,1H),7.41-7.36(m,2H),7.24-7.21(m,2H),6.49(dd,J=5.7Hz ,2.4Hz,1H),4.39(d,J=5.7Hz,2H),3.91(s,3H),3.86(s,3H),2.15(s,3H). ESI-MS: 448.20 (M+H) + .

[0253] N-[(3-fluoro-4-methoxy-phenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (140): TIFF2025539843000174.tif21170 Compound 140 was synthesized from intermediate 119a (0.10 mmol) and (3-fluoro-4-methoxyphenyl)methanamine (0.15 mmol) according to general method C2 as a white solid in 58% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.88(t,J=6.0Hz,1H),8.35(d,J=5.7Hz,1H),8.24(s,1H),7.95(d,J=0.6Hz,1H),7.37(t,J=7.8Hz,1H),7.3 1(dd,J=7.6Hz,1.3Hz,1H),7.24-7.09(m,5H),6.48(dd,J=5.7Hz,2.4Hz,1H),4.39(d,J=6.0Hz,2H),3.86(s,3H),3.82(s,3H),2.13(s,3H). ESI-MS: 447.20 (M+H) + .

[0254] N-[(4-fluoro-3-methoxy-phenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (141): TIFF2025539843000175.tif22170 Compound 141 was synthesized from intermediate 119a (0.10 mmol) and 5-(aminomethyl)-2-fluoroanisole (0.15 mmol) according to general method C2 as a white solid in 70% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.90(t,J=6.0Hz,1H),8.35(d,J=5.7Hz,1H),8.24(s,1H),7.95(d,J=0.6Hz,1H),7.42-7.30(m,2H), 7.25-7.12(m,4H),6.92-6.88(m,1H),6.49(dd,J=5.7Hz,2.4Hz,1H),4.43(d,J=6.0Hz,2H),3.86(s,3H),3.82(s,3H),2.14(s,3H). ESI-MS: 447.20 (M+H) + .

[0255] N-(cyclohexylmethyl)-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (142): TIFF2025539843000176.tif22170 Compound 142 was synthesized from intermediate 119a (0.10 mmol) and 1-cyclohexylmethanamine (0.15 mmol) according to general method C2 as a white solid in 69% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.36-3.81(m,2H),8.24(s,1H),7.96(s,1H),7.35(t,J=7.8Hz,1H),7.27-7.22(m,2H),7.18(d,J=8.0Hz,1H ),6.48(dd,J=5.7Hz,2.4Hz,1H),3.87(s,3H),3.09(t,J=6.4Hz,2H),2.13(s,3H),1.77-1.47(m,6H),1.27-1.12(m,3H),0.99-0.89(m,2H). ESI-MS: 405.20 (M+H) + .

[0256] 2-Methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}-N-(tetrahydropyran-4-ylmethyl)benzamide (143): TIFF2025539843000177.tif20170 Compound 143 was synthesized from intermediate 119a (0.10 mmol) and 4-(aminomethyl)tetrahydropyran (0.15 mmol) according to general method C2 as a white solid in 71% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.39(t,J=5.8Hz,1H),8.36(d,J=5.7Hz,1H),8.24(s,1 H),7.96(d,J=0.6Hz,1H),7.35(t,J=7.7Hz,1H),7.28-7.21(m,2H),7.19(dd,J=8.0Hz ,1.0Hz,1H),6.48(dd,J=5.7Hz,2.4Hz,1H),3.89-3.82(m,5H),3.27-3.24(m,2H),3.1 8-3.12(m,2H),2.13(s,3H),1.80-1.74(m,1H),1.63-1.60(m,2H),1.26-1.16(m,2H). ESI-MS: 407.15 (M+H) + .

[0257] N-[(1R)-1-cyclohexylethyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (144): TIFF2025539843000178.tif23170 Compound 144 was synthesized from intermediate 119a (0.10 mmol) and (R)-1-cyclohexylmethanamine (0.15 mmol) according to general method C2 as a white solid in 60% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.36(d,J=5.7Hz,1H),8.25(s,1H),8.15(d,J=8.7Hz,1H),7.96(d,J=0.5Hz,1H),7.35(t,J=7.8Hz,1H),7. 27-7.14(m,3H),6.48(dd,J=5.7Hz,2.4Hz,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). ESI-MS: 419.20 (M+H) + .

[0258] N-[(1S)-1-cyclohexylethyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (145): TIFF2025539843000179.tif21170 Compound 145 was synthesized from intermediate 119a (0.10 mmol) and (S)-1-cyclohexylmethanamine (0.15 mmol) according to general method C2 as a white solid in 54% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.36(d,J=5.7Hz,1H),8.25(s,1H),8.15(d,J=8.8Hz,1H),7.96(s,1H),7.35(t,J=7.7Hz,1H),7.26-7.15(m,3H) ),6.48(dd,J=5.7Hz,2.4Hz,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). ESI-MS: 419.20 (M+H) + .

[0259] 2-Methyl-N-[(1-methylpyrazol-4-yl)methyl]-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (146): TIFF2025539843000180.tif23170 Compound 146 was synthesized from intermediate 119a (0.10 mmol) and (C)-(1-methyl-1H-pyrazol-4-yl)-methanamine (0.15 mmol) according to general method C2 as a white solid in 62% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.69(t,J=5.7Hz,1H),8.35(d,J=5.7Hz,1H),8.2 4(s,1H),7.95(d,J=0.6Hz,1H),7.61(s,1H),7.37-7.32(m,2H),7.27(dd,J=7.6H z,1.2Hz,1H),7.22(d,J=2.3Hz,1H),7.18(dd,J=8.0Hz,1.1Hz,1H),6.47(dd,J= 5.7Hz,2.4Hz,1H),4.27(d,J=5.7Hz,2H),3.86(s,3H),3.79(s,3H),2.12(s,3H). ESI-MS: 403.15 (M+H) + .

[0260] 2-Methyl-N-[(2-methylpyrazol-3-yl)methyl]-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (147): TIFF2025539843000181.tif21170 Compound 147 was synthesized from intermediate 119a (0.10 mmol) and (C)-(2-methyl-2H-pyrazol-3-yl)-methanamine (0.15 mmol) according to general method C2 as a white solid in 69% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.89(t,J=5.7Hz,1H),8.35(d,J=5.7Hz,1H),8.2 4(s,1H),7.95(d,J=0.6Hz,1H),7.36(t,J=7.8Hz,1H),7.32-7.28(m,2H),7.23(d ,J=2.3Hz,1H),7.21(dd,J=7.9Hz,1.2Hz,1H),6.48(dd,J=5.7Hz,2.4Hz,1H),6.1 9(d,J=1.8Hz,1H),4.51(d,J=5.7Hz,2H),3.86(s,3H),3.83(s,3H),2.13(s,3H). ESI-MS: 403.20 (M+H) + .

[0261] 2-Methyl-N-[(1-methylpyrazol-3-yl)methyl]-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (148): TIFF2025539843000182.tif21170 Compound 148 was synthesized from intermediate 119a (0.10 mmol) and (1-methyl-1H-pyrazol-3-yl)-methanamine (0.15 mmol) according to general method C2 as a white solid in 72% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.74(t,J=5.9Hz,1H),8.35(d,J=5.7Hz,1H),8.24(s,1H), 7.95(d,J=0.6Hz,1H),7.59(d,J=2.1Hz,1H),7.35(t,J=7.7Hz,1H),7.27(dd,J=7.6Hz,1. 2Hz,1H),7.22(d,J=2.3Hz,1H),7.18(dd,J=7.9Hz,1.1Hz,1H),6.49(dd,J=5.7Hz,2.4Hz, 1H),6.16(d,J=2.2Hz,1H),4.38(d,J=5.9Hz,2H),3.86(s,3H),3.78(s,3H),2.13(s,3H). ESI-MS: 403.15 (M+H) + .

[0262] N-[(4-fluoro-3-methyl-phenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (149): TIFF2025539843000183.tif22170 Compound 149 was synthesized from intermediate 119a (0.10 mmol) and (4-fluoro-3-methylphenyl)methanamine (0.15 mmol) according to general method C2 as a white solid in 67% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.88(t,J=6.0Hz,1H),8.35(d,J=5.7Hz,1H),8.24(s,1H),7.95(s,1H),7.42-7.29(m,2H),7.28-7.1 6(m,4H),7.13-7.06(m,1H),6.48(dd,J=5.7Hz,2.4Hz,1H),4.40(d,J=6.0Hz,2H),3.86(s,3H),2.22(d,J=1.5Hz,3H),2.13(s,3H). ESI-MS: 431.15 (M+H) + .

[0263] N-[(3-fluoro-4-methyl-phenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (150): TIFF2025539843000184.tif24170 Compound 150 was synthesized from intermediate 119a (0.10 mmol) and 3-fluoro-4-methylbenzylamine (0.15 mmol) according to general method C2 as a white solid in 69% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.91(t,J=6.0Hz,1H),8.35(d,J=5.7Hz,1H),8.24(s,1H),7.95(d,J=0.6Hz,1H),7.40-7.30(m,2H),7.27 -7.17(m,3H),7.13-7.07(m,2H),6.49(dd,J=5.7Hz,2.4Hz,1H),4.42(d,J=6.0Hz,2H),3.86(s,3H),2.21(d,J=1.2Hz,3H),2.13(s,3H). ESI-MS: 431.15 (M+H) + .

[0264] 2-Methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}-N-[(2-oxo-1H-pyridin-3-yl)methyl]benzamide (151): TIFF2025539843000185.tif22170 Compound 151 was synthesized from intermediate 119a (0.10 mmol) and 3-(aminomethyl)-2(1H)-pyridinone (0.24 mmol) according to general method C2 as a white solid in 40% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):11.62(bs,1H),8.66(t,J=5.8Hz,1H),8.36(d,J=5.7Hz,1H),8.24(s,1H),7.96(d,J=0.6Hz,1H),7.37-7.35(m,3H),7. 30(dd,J=6.5Hz,2.0Hz,1H),7.25-7.18(m,2H),6.49(dd,J=5.7Hz,2.4Hz,1 H),6.20(t,J=6.6Hz,1H),4.21(d,J=5.8Hz,2H),3.86(s,3H),2.15(s,3H). ESI-MS: 416.15 (M+H) + .

[0265] 2-Methyl-N-[(1-methyl-2-oxo-3-piperidyl)methyl]-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (152): TIFF2025539843000186.tif22170 Compound 152 was synthesized from intermediate 119a (0.10 mmol) and 3-(aminomethyl)-1-methyl-2-piperidinone (0.24 mmol) according to general method C2 as a white solid in 69% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.36(d,J=5.7Hz,1H),8.30(t,J=5.8Hz,1H),8.24(s,1H), 7.96(s,1H),7.35(t,J=7.8Hz,1H),7.28(d,J=6.6Hz,1H),7.23(d,J=2.4Hz,1H),7.19(d, J=7.9Hz,1H),6.49(dd,J=5.7Hz,2.4Hz,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). ESI-MS: 434.20 (M+H) + .

[0266] 2-Methyl-N-[(1-methyl-2-oxo-3-pyridyl)methyl]-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (153): TIFF2025539843000187.tif22170 Compound 153 was synthesized from intermediate 119a (0.07 mmol) and 3-(aminomethyl)-1-methyl-2(1-H)-pyridinone (0.15 mmol) according to general method C2 as a white solid in 53% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.69(t,J=5.8Hz,1H),8.36(d,J=5.8Hz,1H),8.25(s,1H),7.96(d,J=0.7Hz,1H),7.63(dd,J=6.7Hz,1.9Hz,1H),7.41 -7.33(m,3H),7.27-7.18(m,2H),6.49(dd,J=5.7Hz,2.4Hz,1H),6.24(t,J =6.8Hz,1H),4.24(d,J=5.8Hz,2H),3.86(s,3H),3.46(s,3H),2.15(s,3H). ESI-MS: 430.20 (M+H) + .

[0267] N-[(5-fluoro-2-pyridyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (154): TIFF2025539843000188.tif22170 Compound 154 was synthesized from intermediate 119a (0.06 mmol) and 5-fluoro-2-pyridinemethanamine (0.10 mmol) according to general method C2 as a white solid in 41% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.52(d,J=2.9Hz,1H), 8.36(d,J=5.7Hz,1H),8.24(s,1H),7.96(s,1H),7.73(td,J=8.8Hz,3.0Hz,1 H),7.47(dd,J=8.7Hz,4.5Hz,1H),7.43-7.35(m,2H),7.28-7.19(m,2H),6.4 9(dd,J=5.7Hz,2.4Hz,1H),4.54(d,J=6.0Hz,2H),3.86(s,3H),2.16(s,3H). ESI-MS: 418.20 (M+H) + .

[0268] N-[(6-dimethylphosphoryl-3-pyridyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (155): TIFF2025539843000189.tif27170 Compound 155 was synthesized from intermediate 119a (0.10 mmol) and (5-(aminomethyl)pyridin-2-yl)dimethylphosphine oxide (0.29 mmol) according to general method C2 as a white solid in 78% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.04(t,J=5.9Hz,1H),8.75(s,1H),8.35(d,J=5.7Hz,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=5.7Hz,2.4Hz,1H),4.54(d,J=5.9Hz,2H),3.86(s,3H),2.14(s,3H),1.66(s,3H),1.63(s,3H). 31 P NMR(162MHz,DMSO-d6)δ(ppm):33.89. ESI-MS: 476.10 (M+H) + .

[0269] N-[(3,5-difluorophenyl)methyl]-4-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (156): TIFF2025539843000190.tif27170 Compound 156 was synthesized from intermediate 119b (0.10 mmol) and 3,5-difluorobenzylamine (0.15 mmol) according to general method C2 as a white solid in 67% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.10(t,J=6.0Hz,1H),8.36(d,J=5.7Hz,1H),8.25 (s,1H),7.97(d,J=0.7Hz,1H),7.79(dd,J=7.9Hz,1.7Hz,1H),7.64(d,J=1.7Hz,1 H),7.51(d,J=8.3Hz,1H),7.29-7.20(m,1H),7.13-7.05(m,1H),7.04-6.98(m,2H ),6.55(dd,J=5.7Hz,2.4Hz,1H),4.46(d,J=5.9Hz,2H),3.86(s,3H),2.20(s,3H). ESI-MS: 435.00 (M+H) + .

[0270] N-[(3,4-difluorophenyl)methyl]-4-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (157): TIFF2025539843000191.tif22170 Compound 157 was synthesized from intermediate 119b (0.10 mmol) and 3,4-difluorobenzylamine (0.15 mmol) according to general method C2 as a white solid in 45% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.07(t,J=5.9Hz,1H),8.40-8.33(m,1H),8.25(s, 1H),7.97(d,J=0.7Hz,1H),7.78(dd,J=7.9Hz,1.7Hz,1H),7.63(d,J=1.7Hz,1H), 7.50(d,J=8.4Hz,1H),7.42-7.31(m,2H),7.23(d,J=2.1Hz,1H),7.16-7.13(m,1H ),6.54(dd,J=5.7Hz,2.4Hz,1H),4.42(d,J=5.9Hz,2H),3.86(s,3H),2.20(s,3H). ESI-MS: 435.00 (M+H) + .

[0271] N-[(4-chloro-3-fluoro-phenyl)methyl]-4-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (158): TIFF2025539843000192.tif23170 Compound 158 was synthesized from intermediate 119b (0.10 mmol) and 4-chloro-3-fluorobenzylamine (0.15 mmol) according to general method C2 as a white solid in 57% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.09(t,J=6.0Hz,1H),8.39-8.34(m,1H),8.25(s,1H), 7.97(d,J=0.7Hz,1H),7.79(dd,J=7.9Hz,1.7Hz,1H),7.63(d,J=1.7Hz,1H),7.55-7.4 7(m,2H),7.33(dd,J=10.4Hz,1.9Hz,1H),7.27-7.21(m,1H),7.17(dd,J=8.2Hz,1.3Hz ,1H),6.54(dd,J=5.7Hz,2.4Hz,1H),4.44(d,J=5.9Hz,2H),3.86(s,3H),2.20(s,3H). ESI-MS: 451.05 (M+H) + .

[0272] N-[(4-chlorophenyl)methyl]-4-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (159): TIFF2025539843000193.tif22170 Compound 159 was synthesized from intermediate 119b (0.10 mmol) and 4-chlorobenzylamine (0.15 mmol) according to general method C2 as a white solid in 92% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.07(t,J=6.0Hz,1H),8.38-8.34(m,1H),8.2 5(s,1H),7.97(d,J=0.7Hz,1H),7.78(dd,J=7.9Hz,1.7Hz,1H),7.63(d,J=1. 7Hz,1H),7.50(d,J=8.4Hz,1H),7.40-7.29(m,4H),7.23(d,J=2.1Hz,1H),6. 54(dd,J=5.7Hz,2.4Hz,1H),4.43(d,J=5.9Hz,2H),3.86(s,3H),2.20(s,3H). ESI-MS: 433.00 (M+H) + .

[0273] N-[(4-fluorophenyl)methyl]-4-methyl-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (352): TIFF2025539843000194.tif23170 Compound 352 was synthesized from intermediate 119b (0.08 mmol) and 4-fluorobenzylamine (0.12 mmol) according to general method C2 as a white solid in 80% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.05(t,J=6.0Hz,1H),8.36(d,J=5.6Hz,1H),8 .25(s,1H),7.97(s,1H),7.78(d,J=7.8Hz,1H),7.63(d,J=1.6Hz,1H),7.50(d ,J=8.2Hz,1H),7.36-7.31(m,2H),7.23(d,J=2.4Hz,1H),7.16-7.10(m,2H),6 .54(dd,J=5.7Hz,2.5Hz,1H),4.42(d,J=5.8Hz,2H),3.86(s,3H),2.20(s,3H). ESI-MS: 417.10 (M+H) + .

[0274] 4-Fluoro-N-[(4-fluorophenyl)methyl]-3-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (353): TIFF2025539843000195.tif22170 Compound 353 was synthesized from intermediate 119i (0.08 mmol) and 4-fluorobenzylamine (0.12 mmol) according to general method C2 as a white solid in 63% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.14(t,J=5.9Hz,1H),8.40(d,J=5.7Hz,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=5.7Hz,2.4Hz,1H),4.44(d,J=5.8Hz,2H),3.86(s,3H). ESI-MS: 421.05 (M+H) + .

[0275] N-[(3,5-difluorophenyl)methyl]-2-methyl-5-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (160): TIFF2025539843000196.tif26170 Compound 160 was synthesized from intermediate 119c (0.10 mmol) and 3,5-difluorobenzylamine (0.15 mmol) according to general method C2 as a white solid in 90% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.92(t,J=6.0Hz,1H),8.40-8.35(m,1H),8.25(s,1H),7.96(d,J=0.7Hz,1H),7.36(d,J=8.4Hz,1H),7.27-7.23(m,2H) ,7.19(dd,J=8.2Hz,2.6Hz,1H),7.14-7.07(m,1H),7.07-7.02(m,2H),6.66 (dd,J=5.7Hz,2.4Hz,1H),4.44(d,J=6.0Hz,2H),3.86(s,3H),2.36(s,3H). ESI-MS: 435.00 (M+H) + .

[0276] N-[(3,4-difluorophenyl)methyl]-2-methyl-5-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (161): TIFF2025539843000197.tif22170 Compound 161 was synthesized from intermediate 119c (0.10 mmol) and 3,4-difluorobenzylamine (0.15 mmol) according to general method C2 as a white solid in 41% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.90(t,J=6.0Hz,1H),8.39-8.35(m,1H),8.25(s,1H),7.96(d,J=0.7Hz,1 H),7.44-7.34(m,3H),7.25(d,J=2.1Hz,1H),7.22(d,J=2.6Hz,1H),7.20-7.15(m,2H),6.65(dd,J=5.7Hz ,2.4Hz,1H),4.41(d,J=5.9Hz,2H),3.86(s,3H),2.35(s,3H). ESI-MS: 435.05 (M+H) + .

[0277] N-[(4-chloro-3-fluoro-phenyl)methyl]-2-methyl-5-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (162): TIFF2025539843000198.tif23170 Compound 162 was synthesized from intermediate 119c (0.10 mmol) and 4-chloro-3-fluorobenzylamine (0.15 mmol) according to general method C2 as a white solid in 60% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.92(t,J=6.0Hz,1H),8.40-8.35(m,1H),8.25(s,1H),7.96(d,J=0.7Hz,1H),7.54(t,J=8.0H) z,1H),7.37-7.33(m,2H),7.28-7.15(m,4H),6.65(dd,J=5.7Hz,2.4Hz,1H),4.43(d,J=6.0Hz,2H),3.86(s,3H),2.35(s,3H). ESI-MS: 451.05 (M+H) + .

[0278] N-[(4-chlorophenyl)methyl]-2-methyl-5-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (163): TIFF2025539843000199.tif22170 Compound 163 was synthesized from intermediate 119c (0.10 mmol) and 4-chlorobenzylamine (0.15 mmol) according to general method C2 as a white solid in 79% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.98(t,J=6.0Hz,1H),8.48-8.45(m,1H),8.34(s,1H),8.05(d,J=0.7Hz,1H),7.51-7.41(m,5 H),7.34(d,J=2.1Hz,1H),7.30-7.23(m,2H),6.74(dd,J=5.7Hz,2.4Hz,1H),4.50(d,J=6.0Hz,2H),3.95(s,3H),2.44(s,3H). ESI-MS: 433.00 (M+H) + .

[0279] N-[(2-methoxyphenyl)methyl]-2-methyl-5-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (351): TIFF2025539843000200.tif23170 Compound 351 was synthesized from intermediate 119c (0.07 mmol) and 2-methoxybenzylamine (0.10 mmol) according to general method C2 as a white solid in 71% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.70(t,J=5.8Hz,1H),8.37(d,J=5.7Hz,1H) ,8.26(s,1H),7.97(s,1H),7.35(d,J=8.2Hz,1H),7.28-7.21(m,3H),7.20- 7.16(m,2H),6.98(d,J=8.2Hz,1H),6.90(t,J=7.4Hz,1H),6.66(dd,J=5.7H z,2.4Hz,1H),4.39(d,J=5.9Hz,2H),3.86(s,3H),3.79(s,3H),2.36(s,3H). ESI-MS: 429.10 (M+H) + .

[0280] 2-Methyl-5-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}-N-{[3-(trifluoromethyl)phenyl]methyl}benzamide (354): TIFF2025539843000201.tif21170 Compound 354 was synthesized from intermediate 119c (0.07 mmol) and 3-trifluorobenzylamine (0.10 mmol) according to general method C2 as a white solid in 73% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.97(t,J=6.0Hz,1H),8.37(d,J=5.7Hz,1H),8.25(s,1H),7.96(s,1H),7.72-7.53(m,4H),7.36(d,J= 7.8Hz,1H),7.26(d,J=2.3Hz,1H),7.21-7.16(m,2H),6.66(dd,J=5.7Hz,2.4Hz,1H),4.52(d,J=6.0Hz,2H),3.86(s,3H),2.35(s,3H). ESI-MS: 467.10 (M+H) + .

[0281] N-[(3,4-difluorophenyl)methyl]-2-methoxy-5-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (359): TIFF2025539843000202.tif22170 Compound 359 was synthesized from intermediate 119j (0.08 mmol) and 3,4-difluorobenzylamine (0.12 mmol) according to general method C2 as a white solid in 72% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.87(t,J=6.1Hz,1H),8.36(d,J=5.7Hz,1H),8.24(s,1H),7.95(d,J=0.7Hz,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=5.7Hz,2.4Hz,1H),4.47(d,J=6.1Hz,2H),3.94(s,3H),3.86(s,3H). ESI-MS: 451.10 (M+H)+ .

[0282] N-[(3,5-difluorophenyl)methyl]-3-methyl-5-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (164): TIFF2025539843000203.tif27170 Compound 164 was synthesized from intermediate 119d (0.10 mmol) and 3,5-difluorobenzylamine (0.15 mmol) according to general method C2 as a white solid in 43% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.12(t,J=5.9Hz,1H),8.39(d,J=5.7Hz,1H),8.27(s,1H),7.97(d,J=0.5Hz,1H),7.66(s,1H),7.49(s,1H),7.28(d ,J=2.2Hz,1H),7.22(s,1H),7.13-7.07(m,1H),7.04-6.99(m,2H),6.68( dd,J=5.7Hz,2.4Hz,1H),4.47(d,J=5.9Hz,2H),3.86(s,3H),2.40(s,3H). ESI-MS: 435.00 (M+H) + .

[0283] N-[(3,4-difluorophenyl)methyl]-3-methyl-5-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (165): TIFF2025539843000204.tif26170 Compound 165 was synthesized from intermediate 119d (0.10 mmol) and 3,4-difluorobenzylamine (0.15 mmol) according to general method C2 as a white solid in 29% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.09(t,J=5.9Hz,1H),8.39(d,J=5.7Hz,1H),8 .26(s,1H),7.97(d,J=0.7Hz,1H),7.66-7.64(m,1H),7.48-7.47(m,1H),7.42 -7.32(m,2H),7.28(d,J=2.1Hz,1H),7.22-7.21(m,1H),7.19-7.11(m,1H),6. 67(dd,J=5.7Hz,2.4Hz,1H),4.43(d,J=5.9Hz,2H),3.86(s,3H),2.39(s,3H). ESI-MS: 435.00 (M+H) + .

[0284] N-[(4-chloro-3-fluoro-phenyl)methyl]-3-methyl-5-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (166): TIFF2025539843000205.tif26170 Compound 166 was synthesized from intermediate 119d (0.10 mmol) and 4-chloro-3-fluorobenzylamine (0.15 mmol) according to general method C2 as a white solid in 46% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.11(t,J=5.9Hz,1H),8.41-8.36(m,1H),8.26(s,1H),7 .97(d,J=0.7Hz,1H),7.66-7.65(m,1H),7.53(t,J=8.0Hz,1H),7.48-7.47(m,1H),7.33( dd,J=10.4Hz,1.9Hz,1H),7.28(d,J=2.1Hz,1H),7.22-7.21(m,1H),7.18(dd,J=8.3Hz,1 .3Hz,1H),6.67(dd,J=5.7Hz,2.4Hz,1H),4.45(d,J=5.9,2H),3.86(s,3H),2.39(s,3H). ESI-MS: 451.05 (M+H) + .

[0285] N-[(4-chlorophenyl)methyl]-3-methyl-5-{[2-(1-methylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (167): TIFF2025539843000206.tif27170 Compound 167 was synthesized from intermediate 119d (0.10 mmol) and 4-chlorobenzylamine (0.15 mmol) according to general method C2 as a white solid in 53% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.09(t,J=5.9Hz,1H),8.41-8.37(m,1H),8.26(s,1H),7.97(d,J=0.7Hz,1H),7.66-7.65(m,1H),7.49-7.45(m,1 H),7.40-7.30(m,4H),7.28(d,J=2.0Hz,1H),7.22-7.21(m,1H),6.66(dd,J=5.7Hz,2.4Hz,1H),4.43(d,J=5.9Hz,2H),3.86(s,3H),2.39(s,3H). ESI-MS: 433.00 (M+H) + .

[0286] N-[(3-fluorophenyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (168): TIFF2025539843000207.tif21170 Compound 168 was synthesized from intermediate 119e (0.09 mmol) and 3-fluorobenzylamine (0.14 mmol) according to general method C2 as a white solid in 53% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.17(s,1H),8.94(t,J=6.0Hz,1H),7.98(d,J =5.7Hz,1H),7.46(d,J=2.2Hz,1H),7.42-7.31(m,3H),7.22-7.13(m,3H),7. 08(td,J=8.3Hz,2.1Hz,1H),6.88(d,J=2.1Hz,1H),6.18(dd,J=5.8Hz,2.3Hz ,1H),6.15(d,J=2.2Hz,1H),4.47(d,J=6.0Hz,2H),3.67(s,3H),2.14(s,3H). ESI-MS: 432.15 (M+H) + .

[0287] N-[(4-fluorophenyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (169): TIFF2025539843000208.tif22170 Compound 169 was synthesized from intermediate 119e (0.09 mmol) and 4-fluorobenzylamine (0.14 mmol) according to general method C2 as a white solid in 50% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.17(s,1H),8.91(t,J=6.0Hz,1H),7.98(d,J=5.8Hz,1H),7.46(d,J=2.2Hz,1H),7.42-7.27(m,4H),7.21- 7.13(m,3H),6.88(d,J=2.1Hz,1H),6.17(dd,J=5.8Hz,2.3Hz,1H),6.15(d,J=2.2Hz,1H),4.43(d,J=6.0Hz,2H),3.67(s,3H),2.13(s,3H). ESI-MS: 432.15 (M+H) + .

[0288] N-[(3-chlorophenyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (170): TIFF2025539843000209.tif22170 Compound 170 was synthesized from intermediate 119e (0.09 mmol) and 3-chlorobenzylamine (0.14 mmol) according to general method C2 as a white solid in 63% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.17(s,1H),8.95(t,J=6.1Hz,1H),7.98(d,J=5.8Hz,1H),7.46(d,J=2.2Hz,1H),7.43-7.28(m,6H),7.18(dd,J= 7.8Hz,1.2Hz,1H),6.88(d,J=2.1Hz,1H),6.18(dd,J=5.8Hz,2.3Hz,1H),6.15(d,J=2.2Hz,1H),4.46(d,J=6.0Hz,2H),3.67(s,3H),2.14(s,3H). ESI-MS: 448.15 (M+H) + .

[0289] N-[(4-chlorophenyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (171): TIFF2025539843000210.tif21170 Compound 171 was synthesized from intermediate 119e (0.09 mmol) and 4-chlorobenzylamine (0.14 mmol) according to general method C2 as a white solid in 49% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.17(s,1H),8.93(t,J=6.0Hz,1H),7.98(d,J=5.8Hz,1H),7.46(d,J=2.2Hz,1H),7.43-7.28(m,6H),7.18(dd,J= 7.8Hz,1.3Hz,1H),6.88(d,J=2.1Hz,1H),6.17(dd,J=5.8Hz,2.3Hz,1H),6.15(d,J=2.2Hz,1H),4.43(d,J=6.0Hz,2H),3.67(s,3H),2.13(s,3H). ESI-MS: 448.15 (M+H) + .

[0290] 2-Methyl-3-({2-[(1-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)-N-{[6-(trifluoromethyl)-3-pyridyl]methyl}benzamide (172): TIFF2025539843000211.tif23170 Compound 172 was synthesized from intermediate 119e (0.09 mmol) and [6-(trifluoromethyl)-3-pyridyl]methanamine (0.14 mmol) according to general method C2 as a white solid in 57% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.17(s,1H),9.05(t,J=5.9Hz,1H),8.76-8.75(m,1H),8 .04(d,J=8.1Hz,1H),7.98(d,J=5.8Hz,1H),7.91(d,J=8.0Hz,1H),7.46(d,J=2.2Hz,1H) ,7.40-7.33(m,2H),7.19(dd,J=7.0Hz,2.4Hz,1H),6.88(d,J=2.1Hz,1H),6.18(dd,J=5. 8Hz,2.3Hz,1H),6.15(d,J=2.2Hz,1H),4.58(d,J=5.9Hz,2H),3.67(s,3H),2.14(s,3H). ESI-MS: 483.15 (M+H) + .

[0291] N-(imidazo[1,2-a]pyridin-6-ylmethyl)-2-methyl-3-({2-[(1-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (173): TIFF2025539843000212.tif22170 Compound 173 was synthesized from intermediate 119e (0.09 mmol) and imidazo[1,2-a]pyridin-6-ylmethanamine (0.14 mmol) according to general method C2 as a white solid in 50% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.17(s,1H),8.93(t,J=5.9Hz,1H),8.50-8.49(m,1H),7. 99-7.95(m,2H),7.57-7.54(m,2H),7.46(d,J=2.2Hz,1H),7.38-7.31(m,2H),7.25(dd,J =9.3Hz,1.7Hz,1H),7.18(dd,J=7.4Hz,1.8Hz,1H),6.88(d,J=2.1Hz,1H),6.17(dd,J=5. 8Hz,2.3Hz,1H),6.15(d,J=2.2Hz,1H),4.44(d,J=5.8Hz,2H),3.67(s,3H),2.13(s,3H). ESI-MS: 454.15 (M+H) + .

[0292] N-(imidazo[1,2-a]pyridin-7-ylmethyl)-2-methyl-3-({2-[(1-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (174): TIFF2025539843000213.tif24170 Compound 174 was synthesized from intermediate 119e (0.09 mmol) and imidazo[1,2-a]pyridin-7-ylmethanamine (0.14 mmol) according to general method C2 as a white solid in 41% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.17(s,1H),8.98(t,J=6.0Hz,1H),8.51(dd,J=7.0Hz,0.7H z,1H),7.98(d,J=5.8Hz,1H),7.90(s,1H),7.53(d,J=1.1Hz,1H),7.46(d,J=2.2Hz,1H),7. 44(s,1H),7.40-7.33(m,2H),7.19(dd,J=7.4Hz,1.8Hz,1H),6.90-6.87(m,2H),6.18(dd,J =5.8Hz,2.3Hz,1H),6.15(d,J=2.2Hz,1H),4.49(d,J=5.9Hz,2H),3.67(s,3H),2.16(s,3H). ESI-MS: 454.15 (M+H) + .

[0293] N-[(5-fluoro-3-pyridyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (175): TIFF2025539843000214.tif23170 Compound 175 was synthesized from intermediate 119e (0.06 mmol) and 5-fluoro-3-pyridinemethanamine (0.09 mmol) according to general method C2 as a white solid in 37% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.17(s,1H),9.00(t,J=5.9Hz,1H),8.49(d,J=2.8Hz,1H ),8.47-8.46(m,1H),7.98(d,J=5.8Hz,1H),7.69-7.65(m,1H),7.46(d,J=2.2Hz,1H),7 .39-7.32(m,2H),7.19(dd,J=7.2Hz,2.0Hz,1H),6.88(d,J=2.1Hz,1H),6.18(dd,J=5.8 Hz,2.3Hz,1H),6.15(d,J=2.2Hz,1H),4.52(d,J=5.9Hz,2H),3.67(s,3H),2.13(s,3H). ESI-MS: 433.20 (M+H) + .

[0294] N-[(3,4-difluorophenyl)methyl]-2-fluoro-5-({2-[(1-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (355): TIFF2025539843000215.tif22170 Compound 355 was synthesized from intermediate 119k (0.08 mmol) and 3,4-difluorobenzylamine (0.11 mmol) according to general method C2 as a white solid in 30% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.21(s,1H),8.98(t,J=5.0Hz,1H),8.01(d,J=5.7Hz,1H),7.49-7.33(m,6H),7.22-7.14 (m,1H),6.93(d,J=2.1Hz,1H),6.30(dd,J=5.7Hz,2.3Hz,1H),6.16(d,J=2.2Hz,1H),4.44(d,J=6.0Hz,2H),3.67(s,3H). ESI-MS: 454.00 (M+H) + .

[0295] N-[(5-fluoro-6-methoxy-3-pyridyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-4-yl)amino]-4-pyridyl}oxy)benzamide (176): TIFF2025539843000216.tif23170 Compound 176 was synthesized from intermediate 119e (0.06 mmol) and (5-fluoro-6-methoxy-3-pyridyl)methanamine (0.09 mmol) according to general method C2 as a white solid in 59% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.17(s,1H),8.90(t,J=5.9Hz,1H),7.98-7.96(m,2 H),7.64(dd,J=11.4Hz,1.9Hz,1H),7.46(d,J=2.2Hz,1H),7.37-7.28(m,2H),7.17 (dd,J=7.8Hz,1.2Hz,1H),6.87(d,J=2.1Hz,1H),6.17(dd,J=5.8Hz,2.3Hz,1H),6. 14(d,J=2.2Hz,1H),4.41(d,J=5.9Hz,2H),3.93(s,3H),3.67(s,3H),2.12(s,3H). ESI-MS: 463.25 (M+H) + .

[0296] N-[(5-fluoro-2-methoxy-3-pyridyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-4-yl)amino]-4-pyridyl}oxy)benzamide (177): TIFF2025539843000217.tif22170 Compound 177 was synthesized from intermediate 119e (0.06 mmol) and 5-fluoro-3-pyridinemethanamine (0.09 mmol) according to general method C2 as a white solid in 48% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.17(s,1H),8.84(t,J=5.8Hz,1H),8.07(d,J=3.0Hz, 1H),7.98(d,J=5.8Hz,1H),7.55(dd,J=8.6Hz,3.0Hz,1H),7.46(d,J=2.2Hz,1H),7.39 -7.34(m,2H),7.21-7.17(m,1H),6.88(d,J=2.1Hz,1H),6.18(dd,J=5.8Hz,2.3Hz,1H) ,6.15(d,J=2.2Hz,1H),4.38(d,J=5.7Hz,2H),3.91(s,3H),3.67(s,3H),2.14(s,3H). ESI-MS: 463.20 (M+H) + .

[0297] N-(imidazo[1,2-a]pyridin-6-ylmethyl)-2-methyl-3-({2-[(1-methylpyrazol-4-yl)amino]-4-pyridyl}oxy)benzamide (178): TIFF2025539843000218.tif22170 Compound 178 was synthesized from intermediate 119f (0.09 mmol) and imidazo[1,2-a]pyridin-6-ylmethanamine (0.14 mmol) according to general method C2 as a white solid in 53% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.95(t,J=5.9Hz,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(d d,J=9.3Hz,1.6Hz,1H),7.19(dd,J=7.4Hz,1.8Hz,1H),6.23(dd,J=5.8Hz,2.2H z,1H),5.93(d,J=2.1Hz,1H),4.44(d,J=5.9Hz,2H),3.76(s,3H),2.12(s,3H). ESI-MS: 454.15 (M+H) + .

[0298] N-(imidazo[1,2-a]pyridin-7-ylmethyl)-2-methyl-3-({2-[(1-methylpyrazol-4-yl)amino]-4-pyridyl}oxy)benzamide (179): TIFF2025539843000219.tif22170 Compound 179 was synthesized from intermediate 119f (0.09 mmol) and imidazo[1,2-a]pyridin-7-ylmethanamine (0.14 mmol) according to general method C2 as a white solid in 46% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.00(t,J=6.0Hz,1H),8.75(s,1H),8.51(d,J=7.0Hz,1H),7. 99(d,J=5.8Hz,1H),7.90(s,1H),7.86(s,1H),7.53(d,J=1.1Hz,1H),7.44(s,1H),7.40-7.33 (m,2H),7.31(s,1H),7.21(dd,J=7.3Hz,2.0Hz,1H),6.88(dd,J=7.0Hz,1.6Hz,1H),6.24(dd, J=5.8Hz,2.2Hz,1H),5.94(d,J=2.2Hz,1H),4.49(d,J=5.9Hz,2H),3.76(s,3H),2.15(s,3H). ESI-MS: 454.15 (M+H) + .

[0299] 2-Methyl-3-({2-[(1-methylpyrazol-4-yl)amino]-4-pyridyl}oxy)-N-{[6-(trifluoromethyl)-3-pyridyl]methyl}benzamide (180): TIFF2025539843000220.tif23170 Compound 180 was synthesized from intermediate 119f (0.09 mmol) and [6-(trifluoromethyl)-3-pyridyl]methanamine (0.14 mmol) according to general method C2 as a white solid in 58% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.07(t,J=5.9Hz,1H),8.76-8.74(m,2H),8.04(dd ,J=8.0Hz,1.5Hz,1H),7.99(d,J=5.8Hz,1H),7.92(d,J=8.1Hz,1H),7.86(s,1H),7 .39-7.34(m,2H),7.31(s,1H),7.21(dd,J=6.7Hz,2.6Hz,1H),6.24(dd,J=5.8Hz,2 .2Hz,1H),5.93(d,J=2.2Hz,1H),4.58(d,J=5.9Hz,2H),3.76(s,3H),2.12(s,3H). ESI-MS: 483.15 (M+H) + .

[0300] N-[(5-fluoro-3-pyridyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-4-yl)amino]-4-pyridyl}oxy)benzamide (181): TIFF2025539843000221.tif23170 Compound 181 was synthesized from intermediate 119f (0.09 mmol) and 5-fluoro-3-pyridinemethanamine (0.14 mmol) according to general method C2 as a white solid in 73% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.00(t,J=5.9Hz,1H),8.73(s,1H),8.49(d,J=2.8Hz, 1H),8.47-8.46(m,1H),7.99(d,J=5.8Hz,1H),7.86(s,1H),7.69-7.65(m,1H),7.39- 7.33(m,2H),7.31(d,J=0.6Hz,1H),7.20(dd,J=7.2Hz,2.1Hz,1H),6.23(dd,J=5.8Hz ,2.2Hz,1H),5.94(d,J=2.2Hz,1H),4.52(d,J=5.9Hz,2H),3.77(s,3H),2.12(s,3H). ESI-MS: 433.20 (M+H) + .

[0301] N-[(5-fluoro-6-methoxy-3-pyridyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-4-yl)amino]-4-pyridyl}oxy)benzamide (182): TIFF2025539843000222.tif23170 Compound 182 was synthesized from intermediate 119f (0.09 mmol) and (5-fluoro-6-methoxy-3-pyridyl)methanamine (0.14 mmol) according to general method C2 as a white solid in 86% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.90(t,J=5.8Hz,1H),8.72(s,1H),7.99-7.97(m,2H),7.86(s,1H),7.64(dd,J=11.4Hz,1.9Hz,1H),7.37-7.29(m,3H) ),7.19(dd,J=7.8Hz,1.3Hz,1H),6.23(dd,J=5.8Hz,2.2Hz,1H),5.94(d,J =2.1Hz,1H),4.41(d,J=5.9Hz,2H),3.93(s,3H),3.77(s,3H),2.11(s,3H). ESI-MS: 463.20 (M+H) + .

[0302] N-[(5-fluoro-2-methoxy-3-pyridyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-4-yl)amino]-4-pyridyl}oxy)benzamide (183): TIFF2025539843000223.tif23170 Compound 183 was synthesized from intermediate 119f (0.09 mmol) and 5-fluoro-2-methoxy-3-pyridinemethanamine (0.14 mmol) according to general method C2 as a white solid in 70% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.84(t,J=5.8Hz,1H),8.73(s,1H),8.07(d,J=3.0H z,1H),7.99(d,J=5.8Hz,1H),7.86(s,1H),7.55(dd,J=8.6Hz,3.0Hz,1H),7.39-7.3 4(m,2H),7.31(d,J=0.5Hz,1H),7.22-7.18(m,1H),6.24(dd,J=5.8Hz,2.2Hz,1H),5 .94(d,J=2.2Hz,1H),4.38(d,J=5.7Hz,2H),3.91(s,3H),3.77(s,3H),2.13(s,3H). ESI-MS: 463.20 (M+H) + .

[0303] N-[(3-fluorophenyl)methyl]-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (184): TIFF2025539843000224.tif22170 Compound 184 was synthesized from intermediate 119g (0.15 mmol) and 3-fluorobenzylamine (0.23 mmol) according to general method C2 as a white solid in 18% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.95(t,J=6.1Hz,1H),8.75(s,1H),8.00(d,J =5.8Hz,1H),7.43-7.32(m,3H),7.27(d,J=1.9Hz,1H),7.23-7.13(m,3H),7. 09(td,J=8.4Hz,2.4Hz,1H),6.36(dd,J=5.8Hz,2.2Hz,1H),6.16(d,J=1.9Hz ,1H),6.12(d,J=2.2Hz,1H),4.47(d,J=6.0Hz,2H),3.61(s,3H),2.13(s,3H). ESI-MS: 432.15 (M+H) + .

[0304] N-[(4-fluorophenyl)methyl]-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (185): TIFF2025539843000225.tif22170 Compound 185 was synthesized from intermediate 119g (0.15 mmol) and 4-fluorobenzylamine (0.23 mmol) according to general method C2 as a white solid in 21% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.92(t,J=6.0Hz,1H),8.75(s,1H),8.00(d,J =5.8Hz,1H),7.40-7.34(m,3H),7.31(dd,J=7.6Hz,1.3Hz,1H),7.27(d,J=1. 9Hz,1H),7.22-7.14(m,3H),6.36(dd,J=5.8Hz,2.2Hz,1H),6.16(d,J=1.9Hz ,1H),6.11(d,J=2.2Hz,1H),4.43(d,J=6.0Hz,2H),3.61(s,3H),2.12(s,3H). ESI-MS: 432.15 (M+H) + .

[0305] N-[(3-chlorophenyl)methyl]-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (186): TIFF2025539843000226.tif21170 Compound 186 was synthesized from intermediate 119g (0.15 mmol) and 3-chlorobenzylamine (0.23 mmol) according to general method C2 as a white solid in 13% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.96(t,J=6.0Hz,1H),8.75(s,1H),8.00(d,J =5.8Hz,1H),7.41-7.36(m,3H),7.34-7.30(m,3H),7.27(d,J=1.9Hz,1H),7. 22(dd,J=7.8Hz,1.2Hz,1H),6.36(dd,J=5.8Hz,2.2Hz,1H),6.16(d,J=1.9Hz ,1H),6.12(d,J=2.2Hz,1H),4.46(d,J=6.0Hz,2H),3.61(s,3H),2.13(s,3H). ESI-MS: 448.10 (M+H) + .

[0306] N-[(4-chlorophenyl)methyl]-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (187): TIFF2025539843000227.tif21170 Compound 187 was synthesized from intermediate 119g (0.15 mmol) and 4-chlorobenzylamine (0.23 mmol) according to general method C2 as a white solid in 18% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.17(s,1H),8.94(t,J=6.0Hz,1H),8.75(s, 1H),8.00(d,J=5.8Hz,1H),7.43-7.30(m,6H),7.27(d,J=1.9Hz,1H),7.21( dd,J=7.8Hz,1.3Hz,1H),6.36(dd,J=5.8Hz,2.2Hz,1H),6.16(d,J=1.9Hz,1 H),6.11(d,J=2.2Hz,1H),4.43(d,J=6.0Hz,2H),3.61(s,3H),2.12(s,3H). ESI-MS: 448.15 (M+H) + .

[0307] N-(imidazo[1,2-a]pyridin-6-ylmethyl)-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (188): TIFF2025539843000228.tif22170 Compound 188 was synthesized from intermediate 119g (0.15 mmol) and imidazo[1,2-a]pyridin-6-ylmethanamine (0.23 mmol) according to general method C2 as a white solid in 18% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.94(t,J=5.9Hz,1H),8.75(s,1H),8.50(s,1H), 7.99(d,J=5.8Hz,1H),7.96(s,1H),7.57-7.54(m,2H),7.39-7.32(m,2H),7.27( d,J=1.9Hz,1H),7.26-7.20(m,2H),6.35(dd,J=5.8Hz,2.2Hz,1H),6.16(d,J=1. 9Hz,1H),6.11(d,J=2.2Hz,1H),4.44(d,J=5.8Hz,2H),3.61(s,3H),2.13(s,3H). ESI-MS: 454.15 (M+H) + .

[0308] N-(imidazo[1,2-a]pyridin-7-ylmethyl)-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (189): TIFF2025539843000229.tif22170 Compound 189 was synthesized from intermediate 119g (0.15 mmol) and imidazo[1,2-a]pyridin-7-ylmethanamine (0.23 mmol) according to general method C2 as a white solid in 13% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.75(s,1H),8.51(d,J=6.9Hz,1H),8.00(d ,J=5.8Hz,1H),7.90(s,1H),7.53(d,J=1.1Hz,1H),7.44(s,1H),7.41-7.34(m,2H),7.27(d,J=1.9 Hz,1H),7.23(dd,J=7.3Hz,1.9Hz,1H),6.88(dd,J=7.0Hz,1.6Hz,1H),6.37(dd,J=5.8Hz,2.2Hz,1 H),6.16(d,J=1.9Hz,1H),6.12(d,J=2.2Hz,1H),4.49(d,J=5.9Hz,2H),3.61(s,3H),2.15(s,3H). ESI-MS: 454.15 (M+H) + .

[0309] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (190): TIFF2025539843000230.tif24170 Compound 190 was synthesized from intermediate 119g (0.15 mmol) and 3,5-difluorobenzylamine (0.23 mmol) according to general method C2 as a white solid in 16% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.75(s,1H),8.00(d,J=5.8Hz ,1H),7.41-7.34(m,2H),7.27(d,J=1.9Hz,1H),7.23(dd,J=7.4Hz,1.8Hz,1H),7.13( tt,J=9.4Hz,2.3Hz,1H),7.08-7.03(m,2H),6.36(dd,J=5.8Hz,2.2Hz,1H),6.16(d,J =1.9Hz,1H),6.12(d,J=2.1Hz,1H),4.47(d,J=6.0Hz,2H),3.61(s,3H),2.13(s,3H). ESI-MS: 450.10 (M+H) + .

[0310] N-[(6-methoxy-3-pyridyl)methyl]-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (191): TIFF2025539843000231.tif23170 Compound 191 was synthesized from intermediate 119g (0.15 mmol) and (6-methoxypyridin-3-yl)methanamine (0.23 mmol) according to general procedure C2 as a white solid in 15% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.88(t,J=6.0Hz,1H),8.74(s,1H),8.13(d,J=2.0Hz,1H),7.99(d,J=5.8H z,1H),7.69(dd,J=8.5Hz,2.5Hz,1H),7.36(t,J=7.7Hz,1H),7.30-7.27(m,2H),7.20(dd,J=7.9Hz,1.1Hz ,1H),6.81(d,J=8.1Hz,1H),6.35(dd,J=5.8Hz,2.2Hz,1H),6.16(d,J=1.9Hz,1H),6 .11(d,J=2.2Hz,1H),4.38(d,J=5.9Hz,2H),3.83(s,3H),3.61(s,3H),2.11(s,3H). ESI-MS: 445.15 (M+H) + .

[0311] 2-Methyl-3-({2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)-N-{[6-(trifluoromethyl)-3-pyridyl]methyl}benzamide (192): TIFF2025539843000232.tif25170 Compound 192 was synthesized from intermediate 119g (0.15 mmol) and [6-(trifluoromethyl)-3-pyridyl]methanamine (0.23 mmol) according to general method C2 as a white solid in 10% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.08(t,J=5.9Hz,1H),8.77(s,2H),8.04(d,J=9.0H z,1H),8.00(d,J=5.8Hz,1H),7.92(d,J=8.1Hz,1H),7.40-7.35(m,2H),7.27(d,J=1 .8Hz,1H),7.23(dd,J=6.8Hz,2.5Hz,1H),6.36(dd,J=5.8Hz,2.2Hz,1H),6.16(d,J= 1.8Hz,1H),6.11(d,J=2.1Hz,1H),4.58(d,J=5.8Hz,2H),3.61(s,3H),2.13(s,3H). ESI-MS: 483.15 (M+H) + .

[0312] N-[(5-fluoro-3-pyridyl)methyl]-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (193): TIFF2025539843000233.tif21170 Compound 193 was synthesized from intermediate 119g (0.09 mmol) and 5-fluoro-3-pyridinemethanamine (0.14 mmol) according to general method C2 as a white solid in 13% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=5.9Hz,1H),8.75(s,1H),8.49(d,J=2.8Hz, 1H),8.47(s,1H),8.00(d,J=5.8Hz,1H),7.69-7.65(m,1H),7.40-7.34(m,2H),7.27(d ,J=1.9Hz,1H),7.22(dd,J=7.2Hz,2.1Hz,1H),6.36(dd,J=5.8Hz,2.2Hz,1H),6.16(d, J=1.9Hz,1H),6.11(d,J=2.2Hz,1H),4.52(d,J=5.9Hz,2H),3.61(s,3H),2.12(s,3H). ESI-MS: 433.20 (M+H) + .

[0313] N-[(5-fluoro-6-methoxy-3-pyridyl)methyl]-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (194): TIFF2025539843000234.tif23170 Compound 194 was synthesized from intermediate 119g (0.09 mmol) and (5-fluoro-6-methoxy-3-pyridyl)methanamine (0.14 mmol) according to general method C2 as a white solid in 19% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.91(t,J=5.9Hz,1H),8.75(s,1H),8.00(d,J=5.8Hz,1H) ,7.97(d,J=1.7Hz,1H),7.64(dd,J=11.4Hz,1.9Hz,1H),7.38-7.30(m,2H),7.27(d,J=1.9 Hz,1H),7.21(dd,J=7.8Hz,1.3Hz,1H),6.35(dd,J=5.8Hz,2.2Hz,1H),6.16(d,J=1.9Hz, 1H),6.11(d,J=2.2Hz,1H),4.41(d,J=5.8Hz,2H),3.93(s,3H),3.61(s,3H),2.11(s,3H). ESI-MS: 463.25 (M+H) + .

[0314] N-[(5-fluoro-2-methoxy-3-pyridyl)methyl]-2-methyl-3-({2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (195): TIFF2025539843000235.tif22170 Compound 195 was synthesized from intermediate 119g (0.09 mmol) and 5-fluoro-2-methoxy-3-pyridinemethanamine (0.14 mmol) according to general method C2 as a white solid in 14% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.85(t,J=5.7Hz,1H),8.75(s,1H),8.07(d,J=3.0Hz, 1H),8.00(d,J=5.8Hz,1H),7.55(dd,J=8.6Hz,3.0Hz,1H),7.40-7.35(m,2H),7.27(d, J=1.9Hz,1H),7.25-7.20(m,1H),6.36(dd,J=5.8Hz,2.2Hz,1H),6.16(d,J=1.9Hz,1H) ,6.12(d,J=2.2Hz,1H),4.38(d,J=5.7Hz,2H),3.91(s,3H),3.61(s,3H),2.14(s,3H). ESI-MS: 463.25 (M+H) + .

[0315] N-[(5-fluoro-6-methoxy-3-pyridyl)methyl]-2-methyl-3-({2-[(2-methyltriazol-4-yl)amino]-4-pyridyl}oxy)benzamide (350): TIFF2025539843000236.tif22170 Compound 350 was synthesized from intermediate 119l (0.08 mmol) and (5-fluoro-6-methoxy-3-pyridyl)methanamine (0.12 mmol) according to general method C2 as a white solid in 56% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.59(s,1H),8.90(t,J=5.8Hz,1H),8.06(d,J=5.9Hz,1H),7.97(s,1H),7.80(s,1H),7.68-7.61(m,1H),7.38-7.3 0(m,2H),7.21-7.18(m,1H),6.47(d,J=2.2Hz,1H),6.30(dd,J=5.8Hz,2 .3Hz,1H),4.41(d,J=5.6Hz,2H),4.00(s,3H),3.93(s,3H),2.11(s,3H). ESI-MS: 464.05 (M+H) + .

[0316] N-[(6-methoxy-3-pyridyl)methyl]-2-methyl-3-[(2-pyrazol-1-yl-4-pyridyl)oxy]benzamide (196): TIFF2025539843000237.tif24170 Compound 196 was synthesized from intermediate 119h (0.09 mmol) and (6-methoxypyridin-3-yl)methanamine (0.14 mmol) according to general method C2 as a white solid in 53% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.00(t,J=5.9Hz,1H),8.59(d,J=2.5Hz,1H),8.37(d,J=5. 7Hz,1H),8.14(d,J=2.2Hz,1H),7.75(d,J=1.1Hz,1H),7.69(dd,J=8.5Hz,2.4Hz,1H),7.41 (t,J=7.7Hz,1H),7.36-7.29(m,2H),7.18(d,J=2.3Hz,1H),6.93(dd,J=5.7Hz,2.3Hz,1H), 6.81(d,J=8.5Hz,1H),6.55-6.54(m,1H),4.38(d,J=5.9Hz,2H),3.82(s,3H),2.11(s,3H). ESI-MS: 416.05 (M+H) + .

[0317] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-[(2-pyrazol-1-yl-4-pyridyl)oxy]benzamide (197): TIFF2025539843000238.tif27170 Compound 197 was synthesized from intermediate 119h (0.09 mmol) and 3,5-difluorobenzylamine (0.14 mmol) according to general method D as a white solid in 74% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.09(s,1H),8.59(d,J=1.9Hz,1H),8.37(d,J=5.6Hz,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=5.8Hz,2H),2.14(s,3H). ESI-MS: 421.05 (M+H) + .

[0318] Example 7: General procedure for the synthesis of analogs 200-247 TIFF2025539843000239.tif99170

[0319] Preparation of 3-[(2-chloro-4-pyridyl)oxy]-2-methyl-benzoic acid (198): TIFF2025539843000240.tif22170 Intermediate 198 was synthesized from 117a (1.37 mmol) as a white solid in quantitative yield following general method B2.

[0320] The following table shows intermediate 199 prepared from Method C2.

[0321] TIFF2025539843000241.tif59170

[0322] The following compounds are examples illustrating Method D2:

[0323] N-[(6-methoxy-3-pyridyl)methyl]-2-methyl-3-{[2-(4-pyridyl)-4-pyridyl]oxy}benzamide (200): TIFF2025539843000242.tif23170 Compound 200 was synthesized from intermediate 199a (0.07 mmol) and pyridine-4-boronic acid hydrate (0.10 mmol) according to general method D2 as a white solid in 61% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.89(t,J=5.9Hz,1H),8.70-8.68(m,2H),8.59(d,J=5. 6Hz,1H),8.14(d,J=2.0Hz,1H),8.02-8.00(m,2H),7.71-7.68(m,2H),7.39(t,J=7.8H) z,1H),7.32(dd,J=7.6Hz,1.3Hz,1H),7.25(dd,J=7.9Hz,1.2Hz,1H),6.81(d,J=8.5Hz ,1H),6.76(dd,J=5.6Hz,2.4Hz,1H),4.39(d,J=5.9Hz,2H),3.83(s,3H),2.13(s,3H). ESI-MS: 427.10 (M+H) + .

[0324] N-[(6-methoxy-3-pyridyl)methyl]-2-methyl-3-{[2-(3-pyridyl)-4-pyridyl]oxy}benzamide (201): TIFF2025539843000243.tif21170 Compound 201 was synthesized from intermediate 199a (0.07 mmol) and pyridine-3-boronic acid (0.10 mmol) according to general method D2 as a white solid in 61% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.21(d,J=1.6Hz,1H),8.89(t,J=5.9Hz,1H),8.64(dd,J=4.8Hz,1. 6Hz,1H),8.56(d,J=5.7Hz,1H),8.40-8.37(m,1H),8.14(d,J=2.0Hz,1H),7.70(dd,J=8.5Hz,2.5Hz ,1H),7.63(d,J=Hz 2.2,1H),7.51(ddd,J=8.0Hz,4.8Hz,0.7Hz,1H),7.38(t,J=7.8Hz,1H),7.32(dd,J=7.6Hz ,1.3Hz,1H),7.25(dd,J=7.9Hz,1.2Hz,1H),6.81(d,J=8.5Hz,1H),6.71(dd,J=5.7Hz,2.4Hz,1H),4.39(d,J=5.9Hz,2H),3.83(s,3H),2.13(s,3H). ESI-MS: 427.10 (M+H)+ .

[0325] N-[(6-methoxy-3-pyridyl)methyl]-2-methyl-3-[(2-pyrimidin-5-yl-4-pyridyl)oxy]benzamide (202): TIFF2025539843000244.tif22170 Compound 202 was synthesized from intermediate 199a (0.07 mmol) and pyrimidine-5-boronic acid (0.10 mmol) according to general method D2 as a white solid in 72% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.41(s,2H),9.26(s,1H),8.89(t,J=5.9Hz,1H),8.59(d,J= 5.7Hz,1H),8.14(d,J=2.0Hz,1H),7.80(d,J=2.2Hz,1H),7.70(dd,J=8.5Hz,2.5Hz,1H),7.3 9(t,J=7.8Hz,1H),7.32(dd,J=7.6Hz,1.3Hz,1H),7.25(dd,J=7.9Hz,1.2Hz,1H),6.81(d,J= 8.5Hz,1H),6.72(dd,J=5.7Hz,2.4Hz,1H),4.39(d,J=5.9Hz,2H),3.83(s,3H),2.13(s,3H). ESI-MS: 428.05 (M+H) + .

[0326] N-[(6-methoxy-3-pyridyl)methyl]-2-methyl-3-{[2-(2-methylpyrazol-3-yl)-4-pyridyl]oxy}benzamide (203): TIFF2025539843000245.tif23170 Compound 203 was synthesized from intermediate 199a (0.07 mmol) and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (0.10 mmol) according to general method D2 as a white solid in 43% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.89(t,J=5.9Hz,1H),8.53(d,J=5.7Hz,1H),8.14(d,J=2.0 Hz,1H),7.69(dd,J=8.5Hz,2.5Hz,1H),7.46(d,J=2.0Hz,1H),7.38(t,J=7.8Hz,1H),7.32- 7.30(m,2H),7.24(dd,J=7.9Hz,1.2Hz,1H),6.81(d,J=8.5Hz,1H),6.73(d,J=2.0Hz,1H),6 .71(dd,J=5.7Hz,2.5Hz,1H),4.39(d,J=5.9Hz,2H),4.11(s,3H),3.83(s,3H),2.12(s,3H). ESI-MS: 430.10 (M+H) + .

[0327] 3-{[2-(3,5-dimethylisoxazol-4-yl)-4-pyridyl]oxy}-N-[(6-methoxy-3-pyridyl)methyl]-2-methyl-benzamide (204): TIFF2025539843000246.tif25170 Compound 204 was synthesized from intermediate 199a (0.07 mmol) and 3,5-dimethylisoxazole-4-boronic acid pinacol ester (0.10 mmol) according to general method D2 as a white solid in 35% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.88(t,J=5.9Hz,1H),8.52(d,J=5.7Hz,1H),8.14(d,J=1 .9Hz,1H),7.69(dd,J=8.5Hz,2.5Hz,1H),7.38(t,J=7.8Hz,1H),7.31(dd,J=7.6Hz,1.3H z,1H),7.25(dd,J=7.9Hz,1.2Hz,1H),6.99(d,J=2.2Hz,1H),6.81(d,J=8.5Hz,1H),6.73 (dd,J=5.7Hz,2.4Hz,1H),4.39(d,J=5.9Hz,2H),3.83(s,3H),2.31(s,3H),2.12(s,3H). ESI-MS: 445.10 (M+H) + .

[0328] 3-{[2-(1,3-dimethylpyrazol-4-yl)-4-pyridyl]oxy]-N-[(6-methoxy-3-pyridyl)methyl]-2-methyl-benzamide (205): TIFF2025539843000247.tif23170 Compound 205 was synthesized from intermediate 199a (0.07 mmol) and 1,3-dimethyl-1H-pyrazole-4-boronic acid pinacol ester (0.10 mmol) according to general method D2 as a white solid in 86% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.88(t,J=5.9Hz,1H),8.39(d,J=5.7Hz,1H),8.14(d,J=2.0Hz, 1H),8.10(s,1H),7.69(dd,J=8.5Hz,2.5Hz,1H),7.36(t,J=7.8Hz,1H),7.30(dd,J=7.6Hz,1.3H z,1H),7.21(dd,J=7.9Hz,1.2Hz,1H),7.01(d,J=2.3Hz,1H),6.81(d,J=8.5Hz,1H),6.54(dd,J =5.7Hz,2.4Hz,1H),4.39(d,J=5.9Hz,2H),3.83(s,3H),3.77(s,3H),2.35(s,3H),2.11(s,3H). ESI-MS: 444.15 (M+H) + .

[0329] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(4-pyridyl)-4-pyridyl]oxy}benzamide (206): TIFF2025539843000248.tif25170 Compound 206 was synthesized from intermediate 199b (0.08 mmol) and pyridine-4-boronic acid hydrate (0.12 mmol) according to general method D2 as a white solid in 67% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.03(t,J=6.0Hz,1H),8.70-8.68(m,2H),8. 60(d,J=5.6Hz,1H),8.03-8.01(m,2H),7.73(d,J=2.3Hz,1H),7.44-7.38(m, 2H),7.29(dd,J=7.1Hz,2.2Hz,1H),7.13(tt,J=9.4Hz,2.3Hz,1H),7.09-7.0 4(m,2H),6.77(dd,J=5.6Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),2.15(s,3H). ESI-MS: 432.20 (M+H) + .

[0330] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(3-pyridyl)-4-pyridyl]oxy}benzamide (207): TIFF2025539843000249.tif27170 Compound 207 was synthesized from intermediate 199b (0.07 mmol) and pyridine-3-boronic acid (0.12 mmol) according to general method D2 as a white solid in 85% yield. 1 H NMR(500MHz,DMSO-d6)δ(ppm):9.22(d,J=1.7Hz,1H),9.04(t,J=6.0Hz,1H),8.64(dd,J=4.8Hz ,1.6Hz,1H),8.57(d,J=5.7Hz,1H),8.41-8.38(m,1H),7.66(d,J=2.3Hz,1H),7.51(ddd,J=8.0 Hz,4.8Hz,0.7Hz,1H),7.43-7.37(m,2H),7.28(dd,J=7.5Hz,1.8Hz,1H),7.14(tt,J=9.4Hz,2. 4Hz,1H),7.09-7.05(m,2H),6.71(dd,J=5.7Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),2.15(s,3H). ESI-MS: 432.05 (M+H) + .

[0331] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-[(2-pyrimidin-5-yl-4-pyridyl)oxy]benzamide (208): TIFF2025539843000250.tif30170 Compound 208 was synthesized from intermediate 199b (0.08 mmol) and pyrimidine-5-boronic acid (0.12 mmol) according to general method D2 as a white solid in 85% yield. 1 H NMR(500MHz,DMSO-d6)δ(ppm):9.43(s,2H),9.26(s,1H),9.03(t,J=6.0Hz,1H),8.60(d,J=5.7Hz,1H),7.84(d,J=2.2Hz,1H),7.43-7.38(m, 2H),7.28(dd,J=7.3Hz,2.0Hz,1H),7.16-7.11(m,1H),7.09-7.05(m,2H),6.73(dd,J=5.7Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),2.15(s,3H). ESI-MS: 433.05 (M+H) + .

[0332] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(2-methylpyrazol-3-yl)-4-pyridyl]oxy}benzamide (209): TIFF2025539843000251.tif27170 Compound 209 was synthesized from intermediate 199b (0.08 mmol) and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (0.12 mmol) according to general method D2 as a white solid in 45% yield. 1H NMR(500MHz,DMSO-d6)δ(ppm):9.04(t,J=6.1Hz,1H),8.54(d,J=5.8Hz,1H),7 .47(d,J=2.0Hz,1H),7.42-7.37(m,2H),7.34(d,J=2.4Hz,1H),7.27(dd,J=7.5 Hz,1.8Hz,1H),7.16-7.11(m,1H),7.09-7.04(m,2H),6.75(d,J=2.0Hz,1H),6 .71(dd,J=5.7Hz,2.5Hz,1H),4.47(d,J=6.0Hz,2H),4.12(s,3H),2.14(s,3H). ESI-MS: 435.15 (M+H) + .

[0333] N-[(3,5-difluorophenyl)methyl]-3-{[2-(3,5-dimethylisoxazol-4-yl)-4-pyridyl]oxy}-2-methyl-benzamide (210): TIFF2025539843000252.tif28170 Compound 210 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 as a white solid in 35% yield. 1 H NMR(500MHz,DMSO-d6)δ(ppm):9.02(t,J=6.0Hz,1H),8.53(d,J=5.7Hz,1H),7.42-7.37(m,2H),7.29(dd,J=7.4Hz,1.9Hz,1H),7.14-7 .11(m,1H),7.08-7.04(m,2H),7.00(d,J=2.3Hz,1H),6.74(dd,J=5.7Hz,2.4Hz,1H),4.47(d,J=6.0Hz,2H),2.31(s,3H),2.14(s,3H). ESI-MS: 450.20 (M+H) + .

[0334] N-[(3,5-difluorophenyl)methyl]-3-{[2-(1,3-dimethylpyrazol-4-yl)-4-pyridyl]oxy}-2-methyl-benzamide (211): TIFF2025539843000253.tif27170 Compound 211 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 as a white solid in 80% yield. 1 H NMR(500MHz,DMSO-d6)δ(ppm):9.02(t,J=6.0Hz,1H),8.40(d,J=5.7Hz,1H), 8.12(s,1H),7.41-7.35(m,2H),7.24(dd,J=7.5Hz,1.8Hz,1H),7.14(tt,J=9 .4Hz,2.4Hz,1H),7.08-7.04(m,2H),7.03(d,J=2.3Hz,1H),6.55(dd,J=5.7H z,2.4Hz,1H),4.47(d,J=6.0Hz,2H),3.77(s,3H),2.35(s,3H),2.13(s,3H). ESI-MS: 449.90 (M+H) + .

[0335] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(1-methylpyrazol-3-yl)-4-pyridyl]oxy}benzamide (212): TIFF2025539843000254.tif31170 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) according to general method D2 in 64% yield as a white solid. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.07(t,J=6.0Hz,1H),8.46(d,J=5.7Hz,1H),7.74(d,J=2.2Hz, 1H),7.44-7.38(m,2H),7.27(dd,J=7.4Hz,1.8Hz,1H),7.20(d,J=2.5Hz,1H),7.13(tt,J=9.4Hz ,2.3Hz,1H),7.10-7.04(m,2H),6.89(dd,J=5.7Hz,2.5Hz,1H),6.77(d,J=2.2Hz,1H),4.47(d,J=6.0Hz,2H),3.85(s,3H),2.13(s,3H). ESI-MS: 435.10 (M+H) + .

[0336] N-[(3,5-difluorophenyl)methyl]-3-{[2-(1,5-dimethylpyrazol-4-yl)-4-pyridyl]oxy}-2-methyl-benzamide (213): TIFF2025539843000255.tif27170 Compound 213 was synthesized from intermediate 199b (0.07 mmol) and 1,3-dimethyl-1H-pyrazole-4-boronic acid pinacol ester (0.10 mmol) according to general method D2 as a white solid in 70% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.00(t,J=6.0Hz,1H),8.40(d,J=5.8Hz,1H),7.81(s,1H),7.41-7.35(m,2H),7.23(dd,J=7.4H) z,1.9Hz,1H),7.16-7.04(m,4H),6.51(dd,J=5.7Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),3.76(s,3H),2.55(s,3H),2.14(s,3H). ESI-MS: 449.20 (M+H) + .

[0337] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(1H-pyrazol-4-yl)-4-pyridyl]oxy}benzamide (214): TIFF2025539843000256.tif27170 Compound 214 was synthesized from intermediate 199b (0.07 mmol) and 1H-pyrazole-4-boronic acid pinacol ester (0.10 mmol) according to general method D2 as a white solid in 41% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):13.06(bs,1H),8.99(t,J=6.0Hz,1H),8.36(d,J=5.8Hz,1H),8.17(bs,2H),7.41-7.33(m,3H),7.22(dd,J=7.4Hz ,1.9Hz,1H),7.13(tt,J=9.5Hz,2.4Hz,1H),7.09-7.04(m,2H),6.46(dd,J=5.7Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),2.15(s,3H). ESI-MS: 421.10 (M+H) + .

[0338] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(1-tetrahydropyran-4-ylpyrazol-4-yl)-4-pyridyl]oxy}benzamide (215): TIFF2025539843000257.tif27170 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) according to general method D2 as a white solid in 42% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.37-8.35(m,2H),8.00(s,1H),7.42-7.34(m,2H),7.30(d,J=2.3Hz,1H),7.22(dd,J=7.3Hz,1. 8Hz,1H),7.16-7.04(m,3H),6.48(dd,J=5.7Hz,2.4Hz,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). ESI-MS: 505.20 (M+H) + .

[0339] 3-{[2-(1-cyclopropylpyrazol-4-yl)-4-pyridyl]oxy}-N-[(3,5-difluorophenyl)methyl]-2-methyl-benzamide (216): TIFF2025539843000258.tif27170 Compound 216 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 as a white solid in 63% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.36-8.35(m,2H),7.96(d,J=0.6Hz,1H),7.41-7.34(m,2H),7.30(d,J=2.4Hz,1H),7.22(dd ,J=7.2Hz,2.1Hz,1H),7.13-7.04(m,3H),6.47(dd,J=5.7Hz,2.4Hz,1H), 4.48(d,J=6.0Hz,2H),3.79-3.74(m,1H),2.14(s,3H),1.10-0.95(m,4H). ESI-MS: 461.20 (M+H) + .

[0340] 3-({2-[1-(difluoromethyl)pyrazol-4-yl]-4-pyridyl}oxy)-N-[(3,5-difluorophenyl)methyl]-2-methyl-benzamide (217): TIFF2025539843000259.tif26170 Compound 217 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 as a white solid. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.82(s,1H),8.43(d,J=5.7Hz,1H),8.35(s,1H),7.85(t,J=59.0Hz,1H),7.49(d,J=2.3H) z,1H),7.42-7.37(m,2H),7.24(dd,J=7.2Hz,2.2Hz,1H),7.16-7.04(m,3H),6.57(dd,J=5.7Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),2.15(s,3H). ESI-MS: 471.20 (M+H) + .

[0341] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-[(2-phenyl-4-pyridyl)oxy]benzamide (218): TIFF2025539843000260.tif27170 Compound 218 was synthesized from intermediate 199b (0.05 mmol) and benzeneboronic acid (0.08 mmol) according to general method D2 as a white solid in 82% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=6.0Hz,1H),8.54(d,J=5.8Hz,1H),8.03-8.01(m,2H),7.50-7.36(m,6H),7.27(dd,J =7.4Hz,1.9Hz,1H),7.16-7.09(m,1H),7.08-7.04(m,2H),6.71(dd,J=5.6Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),2.16(s,3H). ESI-MS: 431.05 (M+H) + .

[0342] N-[(3,5-difluorophenyl)methyl]-3-{[2-(2-fluorophenyl)-4-pyridyl]oxy}-2-methyl-benzamide (219): TIFF2025539843000261.tif26170 Compound 219 was synthesized from intermediate 199b (0.05 mmol) and 2-fluorobenzeneboronic acid (0.08 mmol) according to general method D2 as a white solid in 74% yield. 1 H NMR(600MHz,DMSO-d6)δ(ppm):9.00(t,J=6.1Hz,1H),8.60-8.58(m,1H),7.93(td,J=7.9Hz,1.8Hz,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=9.4Hz,2.4Hz,1H),7.08-7.04 (m,2H),6.86(dd,J=5.7Hz,2.4Hz,1H),4.47(d,J=6.0Hz,2H),2.15(s,3H). ESI-MS: 449.05 (M+H) + .

[0343] N-[(3,5-difluorophenyl)methyl]-3-{[2-(3-fluorophenyl)-4-pyridyl]oxy}-2-methyl-benzamide (220): TIFF2025539843000262.tif27170 Compound 220 was synthesized from intermediate 199b (0.05 mmol) and 3-fluorobenzeneboronic acid (0.08 mmol) according to general method D2 as a white solid in 83% yield. 1 H NMR(600MHz,DMSO-d6)δ(ppm):9.00(t,J=6.1Hz,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=9.3Hz,2.4Hz,1H),7.08-7.05(m,2H),6.71(dd,J=5.6Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),2.16(s,3H). ESI-MS: 449.05 (M+H) + .

[0344] N-[(3,5-difluorophenyl)methyl]-3-{[2-(4-fluorophenyl)-4-pyridyl]oxy}-2-methyl-benzamide (221): TIFF2025539843000263.tif29170 Compound 221 was synthesized from intermediate 199b (0.05 mmol) and 4-fluorobenzeneboronic acid (0.08 mmol) according to general method D2 as a white solid in 91% yield. 1 H NMR(600MHz,DMSO-d6)δ(ppm):9.00(t,J=6.0Hz,1H),8.52(d,J=5.7Hz,1H),8.10-8.07(m,2H),7.50(d,J=2.3Hz,1H),7.42-7.3(m,2H), 7.31-7.25(m,3H),7.12(tt,J=9.3Hz,2.4Hz,1H),7.08-7.05(m,2H),6.69(dd,J=5.6Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),2.16(s,3H). ESI-MS: 449.05 (M+H) + .

[0345] N-[(3,5-difluorophenyl)methyl]-3-{[2-(2-methoxyphenyl)-4-pyridyl]oxy}-2-methyl-benzamide (222): TIFF2025539843000264.tif28170 Compound 222 was synthesized from intermediate 199b (0.05 mmol) and 2-methoxybenzeneboronic acid (0.08 mmol) according to general method D2 as a white solid in 75% yield. 1 H NMR(600MHz,DMSO-d6)δ(ppm):9.00(t,J=6.1Hz,1H),8.53(dd,J=5.7Hz,0.4Hz,1H),7.78(dd,J=7.7Hz,1.8Hz,1H),7.42-7.36 (m,3H),7.27-7.25(m,2H),7.14-7.02(m,5H),6.85(dd,J=5.7Hz,2.5Hz,1H),4.48(d,J=6.0Hz,2H),3.74(s,3H),2.15(s,3H). ESI-MS: 461.05 (M+H) + .

[0346] N-[(3,5-difluorophenyl)methyl]-3-{[2-(3-methoxyphenyl)-4-pyridyl]oxy}-2-methyl-benzamide (223): TIFF2025539843000265.tif27170 Compound 223 was synthesized from intermediate 199b (0.05 mmol) and 3-methoxybenzeneboronic acid (0.08 mmol) according to general method D2 as a white solid in 84% yield. 1 H NMR(600MHz,DMSO-d6)δ(ppm):9.00(t,J=6.0Hz,1H),8.53(d,J=5.6Hz,1H),7.60-7.59(m,1H),7.57(dd,J=7.7Hz,0.9Hz ,1H),7.51(d,J=2.3Hz,1H),7.42-7.37(m,3H),7.26(d,J=7.7Hz,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=6.0Hz,2H),3.82(s,3H),2.16(s,3H). ESI-MS: 461.05 (M+H) + .

[0347] N-[(3,5-difluorophenyl)methyl]-3-{[2-(4-methoxyphenyl)-4-pyridyl]oxy}-2-methyl-benzamide (224): TIFF2025539843000266.tif29170 Compound 224 was synthesized from intermediate 199b (0.05 mmol) and 4-methoxybenzeneboronic acid (0.08 mmol) according to general method D2 as a white solid in 92% yield. 1H NMR(600MHz,DMSO-d6)δ(ppm):9.00(t,J=6.1Hz,1H),8.48-8.47(m,1H),8.00-7.97(m,2H),7.41-7.36(m,3H),7.26(d d,J=7.7Hz,1.4Hz,1H),7.12(tt,J=9.4Hz,2.4Hz,1H),7.08-7.05(m,2H),7.03-7.00(m,2H),6.63(dd,J=5.6Hz,2.4Hz ,1H),4.48(d,J=6.0Hz,2H),3.81(s,3H),2.15(s,3H). ESI-MS: 461.05 (M+H) + .

[0348] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(o-tolyl)-4-pyridyl]oxy}benzamide (225): TIFF2025539843000267.tif27170 Compound 225 was synthesized from intermediate 199b (0.05 mmol) and o-tolylboronic acid (0.08 mmol) according to general method D2 as a white solid in 83% yield. 1 H NMR(600MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.54(dd,J=5.7Hz,0.5Hz,1H),7.41-7.23(m,7H),7.12(tt,J=9.4Hz,2.4Hz,1H ),7.07-7.04(m,2H),6.86(dd,J=2.5Hz,0.5Hz,1H),6.84(dd,J=5.7Hz,2.5Hz,1H),4.47(d,J=6.0Hz,2H),2.27(s,3H),2.15(s,3H). ESI-MS: 445.05 (M+H) + .

[0349] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(m-tolyl)-4-pyridyl]oxy}benzamide (226): TIFF2025539843000268.tif29170 Compound 226 was synthesized from intermediate 199b (0.05 mmol) and 3-tolylboronic acid (0.08 mmol) according to general method D2 as a white solid in 83% yield. 1 H NMR(600MHz,DMSO-d6)δ(ppm):9.00(t,J=6.1Hz,1H),8.52(dd,J=5.7Hz,0.4Hz ,1H),7.87(s,1H),7.79(d,J=7Hz.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,2.4Hz,1H),7.08-7.05(m,2H),6.69(dd,J=5.6Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),2.38(s,3H),2.16(s,3H). ESI-MS: 445.05 (M+H) + .

[0350] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(p-tolyl)-4-pyridyl]oxy}benzamide (227): TIFF2025539843000269.tif27170 Compound 227 was synthesized from intermediate 199b (0.05 mmol) and 4-tolylboronic acid (0.08 mmol) according to general method D2 as a white solid in 91% yield. 1 H NMR(600MHz,DMSO-d6)δ(ppm):9.00(t,J=6.1Hz,1H),8.51-8.50(m,1H),7.92-7.91(m,2H),7.44(d,J=2.0Hz,1H),7.42-7.36(m,2H),7.29-7 .25(m,3H),7.12(tt,J=9.4Hz,2.4Hz,1H),7.08-7.05(m,2H),6.67(dd,J=5.6Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),2.35(s,3H),2.15(s,3H). ESI-MS: 445.05 (M+H) + .

[0351] The following compounds are examples illustrating Method H:

[0352] N-[(6-methoxy-3-pyridyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-4-yl)amino]-4-pyridyl}oxy)benzamide (228): TIFF2025539843000270.tif23170 Compound 228 was synthesized from intermediate 199a (0.09 mmol) and 1-methyl-1H-pyrazol-4-ylamine (0.18 mmol) according to general method H as a white solid in 54% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.89(t,J=5.9Hz,1H),8.74(s,1H),8.13(d,J=2.3Hz,1 H),7.98(d,J=5.8Hz,1H),7.86(s,1H),7.69(dd,J=8.5Hz,2.4Hz,1H),7.37-7.26(m,3 H),7.18(dd,J=7.9Hz,1.0Hz,1H),6.81(d,J=8.5Hz,1H),6.23(dd,J=5.8Hz,2.2Hz,1H ),5.93(d,J=2.2Hz,1H),4.38(d,J=5.9Hz,2H),3.83(s,3H),3.76(s,3H),2.10(s,3H). ESI-MS: 445.25 (M+H) + .

[0353] N-[(6-methoxy-3-pyridyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (229): TIFF2025539843000271.tif22170 Compound 229 was synthesized from intermediate 199a (0.09 mmol) and 1-methylpyrazol-3-amine (0.18 mmol) according to general method H as a white solid in 44% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.18(s,1H),8.89(t,J=5.9Hz,1H),8.13(d,J=2.3Hz,1H),7.97(d,J=5. 8Hz,1H),7.69(dd,J=8.5Hz,2.4Hz,1H),7.46(d,J=2.2Hz,1H),7.34(t,J=7.8Hz,1H),7.27(dd,J=7.6H z,1.1Hz,1H),7.17(dd,J=7.9Hz,1.0Hz,1H),6.87(d,J=2.0Hz,1H),6.81(d,J=8.5Hz,1H),6.17(dd,J= 5.8Hz,2.3Hz,1H),6.14(d,J=2.2Hz,1H),4.38(d,J=5.9Hz,2H),3.83(s,3H),3.67(s,3H),2.11(s,3H). ESI-MS: 445.90 (M+H) + .

[0354] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-4-yl)amino]-4-pyridyl}oxy)benzamide (230): TIFF2025539843000272.tif25170 Compound 230 was synthesized from intermediate 199b (0.08 mmol) and 1-methyl-1H-pyrazol-4-ylamine (0.15 mmol) according to general method H as a white solid in 72% yield. 1 H NMR(500MHz,DMSO-d6)δ(ppm):9.01(t,J=6.1Hz,1H),8.76(s,1H),7.99(d,J=5 .8Hz,1H),7.87(s,1H),7.39-7.33(m,2H),7.31(d,J=0.6Hz,1H),7.21(dd,J=7 .6Hz,1.6Hz,1H),7.16-7.11(m,1H),7.08-7.03(m,2H),6.24(dd,J=5.8Hz,2.2 Hz,1H),5.93(d,J=2.2Hz,1H),4.47(d,J=6.0Hz,2H),3.76(s,3H),2.12(s,3H). ESI-MS: 450.25 (M+H) + .

[0355] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[(1-methylpyrazol-3-yl)amino]-4-pyridyl}oxy)benzamide (231): TIFF2025539843000273.tif24170 Compound 231 was synthesized from intermediate 199b (0.08 mmol) and 1-methylpyrazol-3-amine (0.15 mmol) according to general method H as a white solid in 63% yield. 1 H NMR(500MHz,DMSO-d6)δ(ppm):9.21(s,1H),9.01(t,J=6.1Hz,1H),7.98(d,J=5.8 Hz,1H),7.46(d,J=2.2Hz,1H),7.39-7.33(m,2H),7.20(dd,J=7.7Hz,1.5Hz,1H), 7.15-7.11(m,1H),7.08-7.04(m,2H),6.88(d,J=1.6Hz,1H),6.18(dd,J=5.8Hz,2 .3Hz,1H),6.14(d,J=2.1Hz,1H),4.47(d,J=6.0Hz,2H),3.67(s,3H),2.13(s,3H). ESI-MS: 450.25 (M+H) + .

[0356] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(2-pyridylamino)-4-pyridyl]oxy}benzamide (232): TIFF2025539843000274.tif25170 Compound 232 was synthesized from intermediate 199b (0.10 mmol) and 2-aminopyridine (0.20 mmol) according to general method H as a white solid in 33% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.70(s,1H),9.01(t,J=6.1Hz,1H),8.15-8.13(m,1H ),8.10(d,J=5.8Hz,1H),7.65-7.59(m,2H),7.43(d,J=2.3Hz,1H),7.41-7.34(m,2H) ,7.22(dd,J=7.3Hz,2.0Hz,1H),7.13(tt,J=9.3Hz,2.3Hz,1H),7.08-7.04(m,2H),6 .85-6.82(m,1H),6.32(dd,J=5.8Hz,2.3Hz,1H),4.48(d,J=6.0Hz,2H),2.15(s,3H). ESI-MS: 447.15 (M+H) + .

[0357] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(4-pyridylamino)-4-pyridyl]oxy}benzamide (233): TIFF2025539843000275.tif24170 Compound 233 was synthesized from intermediate 199b (0.10 mmol) and 4-aminopyridine (0.20 mmol) according to general method H as a white solid in 44% yield. 1 H NMR(600MHz,DMSO-d6)δ(ppm):9.48(s,1H),8.98(t,J=6.0Hz,1H),8.27(d,J=6. 4Hz,2H),8.17(d,J=5.8Hz,1H),7.61-7.60(m,2H),7.42-7.37(m,2H),7.26(dd, J=7.5Hz,1.6Hz,1H),7.13(tt,J=9.4Hz,2.3Hz,1H),7.08-7.04(m,2H),6.55(dd ,J=5.8Hz,2.2Hz,1H),6.21(d,J=2.2Hz,1H),4.48(d,J=6.0Hz,2H),2.14(s,3H). ESI-MS: 447.15 (M+H) + .

[0358] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(pyrimidin-2-ylamino)-4-pyridyl]oxy}benzamide (234): TIFF2025539843000276.tif26170 Compound 234 was synthesized from intermediate 199b (0.08 mmol) and pyridin-2-amine (0.17 mmol) according to general method H as a white solid in 32% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.87(s,1H),9.00(t,J=6.1Hz,1H),8.51(s,1H),8 .50(s,1H),8.14(d,J=5.7Hz,1H),7.95(d,J=2.1Hz,1H),7.41-7.34(m,2H),7.23( dd,J=7.4Hz,1.8Hz,1H),7.13(tt,J=9.5Hz,2.4Hz,1H),7.09-7.04(m,2H),6.93(t ,J=4.8Hz,1H),6.37(dd,J=5.7Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),2.15(s,3H). ESI-MS: 448.05 (M+H) + .

[0359] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(pyrimidin-4-ylamino)-4-pyridyl]oxy}benzamide (235): TIFF2025539843000277.tif23170 Compound 235 was synthesized from intermediate 199b (0.08 mmol) and 4-aminopyridine (0.17 mmol) according to general method H as a white solid in 50% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.21(s,1H),9.00(t,J=6.1Hz,1H),8.65(d,J=0.8 Hz,1H),8.41-8.39(m,1H),8.18(d,J=5.8Hz,1H),7.70(dd,J=5.9Hz,1.2Hz,1H),7 .42-7.34(m,3H),7.24(dd,J=7.1Hz,2.2Hz,1H),7.12(tt,J=9.5Hz,2.4Hz,1H),7. 09-7.03(m,2H),6.47(dd,J=5.8Hz,2.3Hz,1H),4.48(d,J=6.0Hz,2H),2.14(s,3H). ESI-MS: 448.05 (M+H) + .

[0360] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(pyrimidin-5-ylamino)-4-pyridyl]oxy}benzamide (236): TIFF2025539843000278.tif24170 Compound 236 was synthesized from intermediate 199b (0.08 mmol) and 5-aminopyridine (0.17 mmol) according to general method H as a white solid in 19% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.40(s,1H),9.08(s,2H),8.99(t,J=6.0Hz,1 H),8.69(s,1H),8.13(d,J=5.8Hz,1H),7.42-7.37(m,2H),7.26(dd,J=7.3Hz ,2.0Hz,1H),7.13(tt,J=9.4Hz,2.4Hz,1H),7.09-7.03(m,2H),6.53(dd,J=5 .8Hz,2.2Hz,1H),6.15(d,J=2.1Hz,1H),4.48(d,J=6.0Hz,2H),2.14(s,3H). ESI-MS: 448.05 (M+H) + .

[0361] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(1H-pyrazol-3-ylamino)-4-pyridyl]oxy}benzamide (237): TIFF2025539843000279.tif24170 Compound 237 was synthesized from intermediate 199b (0.08 mmol) and 3-aminopyrazole (0.17 mmol) according to general method H as a white solid in 17% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):12.00(bs,1H),9.22(s,1H),8.98(t,J=6.0Hz,1H),8.00(d,J=5.8Hz,1H),7.51(d,J=1.7Hz, 1H),7.39-7.31(m,2H),7.21-7.03(m,4H),6.83(bs,1H),6.18(dd,J=5.6Hz,1.8Hz,2H),4.47(d,J=6.0Hz,2H),2.14(s,3H). ESI-MS: 436.00 (M+H) + .

[0362] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[(1-methyl-1,2,4-triazol-3-yl)amino]-4-pyridyl}oxy)benzamide (238): TIFF2025539843000280.tif24170 Compound 238 was synthesized from intermediate 199b (0.08 mmol) and 1-methyl-1H-1,2,4-triazol-3-amine (0.17 mmol) according to general method H as a white solid in 77% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.63(s,1H),8.98(t,J=6.0Hz,1H),8.20(s,1H),8 .04(d,J=5.7Hz,1H),7.51(d,J=2.2Hz,1H),7.40-7.33(m,2H),7.20(dd,J=7.4Hz ,1.8Hz,1H),7.12(tt,J=9.4Hz,2.4Hz,1H),7.10-7.03(m,2H),6.21(dd,J=5.7Hz ,2.3Hz,1H),4.47(d,J=6.0Hz,2H),3.73(s,3H),2.14(s,3H). ESI-MS: 451.05 (M+H) + .

[0363] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[(2-methyltriazol-4-yl)amino]-4-pyridyl}oxy)benzamide (239): TIFF2025539843000281.tif25170 Compound 239 was synthesized from intermediate 199b (0.08 mmol) and 2-methyltriazol-4-amine (0.15 mmol) according to general method H as a white solid in 57% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.61(s,1H),8.99(t,J=6.0Hz,1H),8.06(d,J =5.8Hz,1H),7.81(s,1H),7.41-7.34(m,2H),7.21(dd,J=7.3Hz,2.0Hz,1H), 7.13(tt,J=9.4Hz,2.3Hz,1H),7.08-7.03(m,2H),6.48(d,J=2.2Hz,1H),6.3 1(dd,J=5.8Hz,2.3Hz,1H),4.47(d,J=6.0Hz,2H),4.00(s,3H),2.14(s,3H). ESI-MS: 451.10 (M+H) + .

[0364] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[(1-methyltriazol-4-yl)amino]-4-pyridyl}oxy)benzamide (240): TIFF2025539843000282.tif24170 Compound 240 was synthesized from intermediate 199b (0.08 mmol) and 1-methyltriazol-4-amine (0.15 mmol) according to general method H as a white solid in 30% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.63(s,1H),8.98(t,J=6.0Hz,1H),8.10(s,1 H),8.05(d,J=5.8Hz,1H),7.40-7.34(m,2H),7.20(dd,J=7.3Hz,2.0Hz,1H), 7.13(tt,J=9.4Hz,2.4Hz,1H),7.09-7.03(m,2H),6.36(d,J=2.2Hz,1H),6.2 9(dd,J=5.8Hz,2.3Hz,1H),4.47(d,J=6.0Hz,2H),4.00(s,3H),2.14(s,3H). ESI-MS: 451.10 (M+H) + .

[0365] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(2-methylanilino)-4-pyridyl]oxy}benzamide (241): TIFF2025539843000283.tif24170 Compound 241 was synthesized from intermediate 199b (0.06 mmol) and o-toluidine (0.13 mmol) according to general method H as a white solid in 64% yield. 1 H NMR(600MHz,DMSO-d6)δ(ppm):8.96(t,J=6.1Hz,1H),8.15(s,1H),7.94(d,J=5.7Hz,1H),7.51(dd,J=8.0Hz ,0.9Hz,1H),7.38-7.32(m,2H),7.21(dd,J=7.8Hz,1.3Hz,1H),7.16(d,J=7.5Hz,1H),7.14-7.08(m,2H),7.07-7.03(m,2H),6.95 (td,J=7.4Hz,1.2Hz,1H),6.25(dd,J=5.8Hz,2.3Hz,1H),6.11(d,J=2.2Hz,1H),4.47(d,J=6.0Hz,2H),2.17(s,3H),2.14(s,3H). ESI-MS: 460.05 (M+H) + .

[0366] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(3-methylanilino)-4-pyridyl]oxy}benzamide (242): TIFF2025539843000284.tif26170 Compound 242 was synthesized from intermediate 199b (0.06 mmol) and m-toluidine (0.13 mmol) according to general method H as a white solid in 74% yield. 1H NMR(600MHz,DMSO-d6)δ(ppm):8.97(t,J=6.1Hz,1H),8.89(s,1H),8.05(d,J=5.8Hz,1H),7.41-7.35(m,4H),7.23(dd,J=7.7Hz,1.4Hz,1H), 7.14-7.04(m,4H),6.69-6.67(m,1H),6.37(dd,J=5.8Hz,2.3Hz,1H),6.12(d,J=2.2Hz,1H),4.47(d,J=6.0Hz,2H),2.24(s,3H),2.15(s,3H). ESI-MS: 460.10 (M+H) + .

[0367] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(4-methylanilino)-4-pyridyl]oxy}benzamide (243): TIFF2025539843000285.tif24170 Compound 243 was synthesized from intermediate 199b (0.06 mmol) and p-poluidine (0.13 mmol) according to general method H as a white solid in 74% yield. 1 H NMR(600MHz,DMSO-d6)δ(ppm):8.97(t,J=6.1Hz,1H),8.85(s,1H),8.02(d,J=5.8Hz ,1H),7.49-7.46(m,2H),7.40-7.34(m,2H),7.22(dd,J=7.8Hz,1.4Hz,1H),7.12(tt ,J=9.4Hz,2.4Hz,1H),7.08-7.04(m,2H),7.02(d,J=8.1Hz,2H),6.34(dd,J=5.8Hz, 2.2Hz,1H),6.09(d,J=2.2Hz,1H),4.47(d,J=6.0Hz,2H),2.22(s,3H),2.14(s,3H). ESI-MS: 460.10 (M+H) + .

[0368] N-[(3,5-difluorophenyl)methyl]-3-{[2-(2-methoxyanilino)-4-pyridyl]oxy}-2-methyl-benzamide (244): TIFF2025539843000286.tif27170 Compound 244 was synthesized from intermediate 199b (0.06 mmol) and o-anisidine (0.13 mmol) according to general method H as a white solid in 47% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.96(t,J=6.1Hz,1H),8.15(s,1H),8.11(dd,J=7.8Hz ,1.7Hz,1H),8.00(d,J=5.8Hz,1H),7.40-7.33(m,2H),7.20(dd,J=7.4Hz,1.9Hz,1H), 7.13(tt,J=9.4Hz,2.3Hz,1H),7.09-7.03(m,2H),6.98-6.83(m,3H),6.39(d,J=2.2Hz ,1H),6.31(dd,J=5.8Hz,2.2Hz,1H),4.47(d,J=6.0Hz,2H),3.79(s,3H),2.14(s,3H). ESI-MS: 476.10 (M+H) + .

[0369] N-[(3,5-difluorophenyl)methyl]-3-{[2-(3-methoxyanilino)-4-pyridyl]oxy}-2-methyl-benzamide (245): TIFF2025539843000287.tif26170 Compound 245 was synthesized from intermediate 199b (0.06 mmol) and m-anisidine (0.13 mmol) according to general method H as a white solid in 84% yield. 1 H NMR(600MHz,DMSO-d6)δ(ppm):8.98-8.96(m,2H),8.06(d,J=5.8Hz,1H),7.41-7.35(m,3H),7.23(dd,J=7.7Hz,1.4Hz,1H),7.14-7.09(m,3H),7.08 -7.04(m,2H),6.45(dt,J=6.7Hz,2.4Hz,1H),6.39(dd,J=5.8Hz,2.3Hz,1H ),6.12(d,J=2.2Hz,1H),4.48(d,J=6.0Hz,2H),3.70(s,3H),2.14(s,3H). ESI-MS: 476.10 (M+H) + .

[0370] N-[(3,5-difluorophenyl)methyl]-3-{[2-(4-methoxyanilino)-4-pyridyl]oxy}-2-methyl-benzamide (246): TIFF2025539843000288.tif24170 Compound 246 was synthesized from intermediate 199b (0.06 mmol) and p-anisidine (0.13 mmol) according to general method H as a white solid in 81% yield. 1 H NMR(600MHz,DMSO-d6)δ(ppm):8.97(t,J=6.1Hz,1H),8.75(s,1H),7.99(d,J=5.8H z,1H),7.59-7.46(m,2H),7.40-7.34(m,2H),7.22(dd,J=7.8Hz,1.4Hz,1H),7.12( tt,J=9.4Hz,2.4Hz,1H),7.08-7.04(m,2H),6.84-6.81(m,2H),6.30(dd,J=5.8Hz, 2.2Hz,1H),6.04(d,J=2.2Hz,1H),4.47(d,J=6.0Hz,2H),3.69(s,3H),2.14(s,3H). ESI-MS: 476.10 (M+H) + .

[0371] N-[(3,5-difluorophenyl)methyl]-3-({2-[(6-methoxy-2-pyridyl)amino]-4-pyridyl}oxy)-2-methyl-benzamide (247): TIFF2025539843000289.tif25170 Compound 247 was synthesized from intermediate 199b (0.06 mmol) and 2-amino-6-methoxypyridine (0.13 mmol) according to general method H as a white solid in 68% yield. 1H NMR(600MHz,DMSO-d6)δ(ppm):9.65(s,1H),8.95(t,J=6.1Hz,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=9.4Hz,2 .4Hz,1H),7.08-7.04(m,2H),6.89(d,J=7.5Hz,1H),6.56(dd,J=5.7Hz,2.3Hz,1H ),6.18(dd,J=7.9Hz,0.6Hz,1H),4.47(d,J=6.0Hz,2H),3.34(s,3H),2.14(s,3H). ESI-MS: 477.10 (M+H) + .

[0372] Example 8: General procedure for the synthesis of analogs 248-261 TIFF2025539843000290.tif48170

[0373] Method I: Under nitrogen, to a solution of 214 (1 equiv.) in DMF (10 mL / mmol) was added the R1-X derivative, R1-OMs derivative, or 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 was purified by flash column chromatography (DCM / MeOH, 100 / 0 to 95 / 5) and reverse-phase chromatography (HO / MeOH, 100 / 0 to 0 / 100) to give the expected compound.

[0374] The following compound 248 is an example illustrating Method I:

[0375] N-[(3,5-difluorophenyl)methyl]-3-{[2-(1-isopropylpyrazol-4-yl)-4-pyridyl]oxy}-2-methyl-benzamide (248): TIFF2025539843000291.tif25170 Compound 248 was synthesized from intermediate 214 (0.05 mmol) and 2-iodopropane (0.05 mmol) according to general method I as a white solid in 50% yield.1 H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.36(d,J=5.7Hz,1H),8 .33(s,1H),7.97(s,1H),7.41-7.35(m,2H),7.29(d,J=2.3Hz,1H),7.22(dd,J =7.4Hz,1.8Hz,1H),7.13(tt,J=9.5Hz,2.3Hz,1H),7.09-7.04(m,2H),6.48(d d,J=5.7Hz,2.4Hz,1H),4.55-4.47(m,3H),2.14(s,3H),1.44(d,J=6.7Hz,6H). ESI-MS: 463.10 (M+H) + .

[0376] tert-Butyl 3-[4-(4-{3-[(3,5-difluorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)pyrazol-1-yl]azetidine-1-carboxylate (249): TIFF2025539843000292.tif26170 Compound 249 was synthesized from intermediate 214 (0.10 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (0.11 mmol) according to general method I as a white solid in 76% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.46(s,1H),8.38(d,J=5.7Hz,1H), 8.12(s,1H),7.41-7.35(m,2H),7.31(d,J=2.3Hz,1H),7.23(dd,J=7.3Hz,2.0Hz,1H),7.13 (tt,J=9.5Hz,2.4Hz,1H),7.09-7.04(m,2H),6.51(dd,J=5.7Hz,2.4Hz,1H),5.27-5.20(m, 1H),4.48(d,J=6.0Hz,2H),4.30(t,J=8.2Hz,2H),4.15(bs,2H),2.14(s,3H),1.41(s,9H). ESI-MS: 576.20 (M+H) + .

[0377] tert-Butyl 3-{[4-(4-{3-[(3,5-difluorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)pyrazol-1-yl]methyl}-1-carboxylate (250): TIFF2025539843000293.tif29170 Compound 250 was synthesized from intermediate 214 (0.10 mmol) and tert-butyl 3-(bromomethyl)azetidine-1-carboxylate (0.11 mmol) according to general method I as a white solid in 63% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.37-8.35(m,2H),8.00(s,1H),7.41- 7.34(m,2H),7.27(d,J=2.3Hz,1H),7.22(dd,J=7.3Hz,1.9Hz,1H),7.13(tt,J=9.5Hz,2.4Hz ,1H),7.10-7.04(m,2H),6.49(dd,J=5.7Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),4.35(d,J=7. 2Hz, 2H), 3.88 (t, J=7.3Hz, 2H), 3.68 (bs, 2H), 3.04-2.94 (m, 1H), 2.14 (s, 3H), 1.36 (s, 9H). ESI-MS: 590.30 (M+H) + .

[0378] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[1-(oxetan-3-yl)pyrazol-4-yl]-4-pyridyl}oxy)benzamide (251): TIFF2025539843000294.tif26170 Compound 251 was synthesized from intermediate 214 (0.05 mmol) and 3-bromooxetane (0.06 mmol) according to general method I as a white solid in 35% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.99(bs,1H),8.46(s,1H),8.38(d,J=5.3Hz,1H),8.13(s,1H),7.41-7.31(m,3H),7.23(d,J=7 .0Hz,1H),7.15-7.06(m,3H),6.51(d,J=3.6Hz,1H),5.62-5.57(m,1H),4.93-4.91(m,4H),4.48(d,J=5.4Hz,2H),2.14(s,3H). ESI-MS: 477.10 (M+H) + .

[0379] N-[(3,5-difluorophenyl)methyl]-3-({2-[1-(2-methoxyethyl)pyrazol-4-yl]-4-pyridyl}oxy)-2-methyl-benzamide (252): TIFF2025539843000295.tif29170 Compound 252 was synthesized from intermediate 214 (0.05 mmol) and 2-bromoethyl methyl ether (0.06 mmol) according to general method I as a white solid in 78% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=5.8Hz,1H),8.36(d,J=5.7Hz,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=5.0Hz,1H),4.48(d,J=5.9Hz,2H),4.28(t,J=5.1Hz,2H),3.70(t,J=5.1Hz,2H),3.23(s,3H),2.14(s,3H). ESI-MS: 479.10 (M+H) + .

[0380] N-[(3,5-difluorophenyl)methyl]-3-({2-[1-(dimethylphosphorylmethyl)pyrazol-4-yl]-4-pyridyl}oxy)-2-methyl-benzamide (253): TIFF2025539843000296.tif26170 Compound 253 was synthesized from intermediate 214 (0.05 mmol) and 1-{[(dimethylphosphoryl)methoxy]sulfonyl}-4-methylbenzene (0.06 mmol) according to general method I as a white solid in 75% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.00(t,J=6.0Hz,1H),8.38(d,J=5.7Hz,1H),8.28(s,1H),8.07(s ,1H),7.41-7.35(m,2H),7.28(d,J=2.3Hz,1H),7.23(dd,J=7.4Hz,1.8Hz,1H),7.13(tt,J=9.5Hz ,2.3Hz,1H),7.09-7.04(m,2H),6.52(dd,J=5.7Hz,2.4Hz,1H),4.69(d,J= 7.5Hz,2H),4.48(d,J=6.0Hz,2H),2.14(s,3H),1.46(s,3H),1.42(s,3H). 31 P NMR(162MHz,DMSO-d6)δ(ppm):38.43. ESI-MS: 511.10 (M+H) + .

[0381] 3-({2-[1-(ditert-butoxyphosphorylmethyl)pyrazol-4-yl]-4-pyridyl}oxy)-N-[(3,5-difluorophenyl)methyl]-2-methyl-benzamide (254): TIFF2025539843000297.tif32170 Compound 254 was synthesized from intermediate 214 (0.12 mmol) and (di-tert-butoxyphorolyl)methyl 4-methylbenzenesulfonate (0.24 mmol) according to general method I as a white solid in 51% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.37(d,J=5.7Hz,1H),8.18(s,1H),8.01(s,1H),7.41-7.35(m,2H),7.24(dd,J=7.2Hz,2.2Hz, 2H),7.16-7.10(m,1H),7.09-7.04(m,2H),6.52(dd,J=5.7Hz,2.4Hz,1H), 4.53(d,J=11.8Hz,2H),4.48(d,J=6.0Hz,2H),2.15(s,3H),1.39(s,18H). 31 P NMR(162MHz,DMSO-d6)δ(ppm):10.07. ESI-MS: 627.15 (M+H) + .

[0382] 3-({2-[1-(cyclopropylmethyl)pyrazol-4-yl]-4-pyridyl}oxy)-N-[(3,5-difluorophenyl)methyl]-2-methyl-benzamide (255): TIFF2025539843000298.tif26170 Compound 255 was synthesized from intermediate 214 (0.05 mmol) and cyclopropylmethyl bromide (0.06 mmol) according to general method I as a white solid in 56% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.36(d,J=5.7Hz,1H),8.33(s,1H),7.98 -7.97(m,1H),7.41-7.35(m,2H),7.28(d,J=2.3Hz,1H),7.22(dd,J=7.4Hz,1.9Hz,1H),7.13(t t,J=9.5Hz,2.4Hz,1H),7.09-7.04(m,2H),6.48(dd,J=5.7Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H) ),3.99(d,J=7.1Hz,2H),2.15(s,3H),1.31-1.21(m,1H),0.56-0.51(m,2H),0.40-0.36(m,2H). ESI-MS: 475.10 (M+H) + .

[0383] 3-({2-[1-(2,2-difluoroethyl)pyrazol-4-yl]-4-pyridyl}oxy)-N-[(3,5-difluorophenyl)methyl]-2-methyl-benzamide (256): TIFF2025539843000299.tif26170 Compound 256 was synthesized from intermediate 214 (0.05 mmol) and 2-iodo-1,1-difluoroethane (0.06 mmol) according to general method I as a white solid in 50% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.38(d,J=5.7Hz,1H),8.3 5(s,1H),8.09(d,J=0.4Hz,1H),7.42-7.35(m,2H),7.30(d,J=2.3Hz,1H),7.23(d d,J=7.3Hz,1.9Hz,1H),7.13(tt,J=9.5Hz,2.4Hz,1H),7.09-7.04(m,2H),6.54- 6.25(m,2H),4.66(td,J=15.1Hz,3.7Hz,2H),4.48(d,J=6.0Hz,2H),2.14(s,3H). ESI-MS: 485.10 (M+H) + .

[0384] 3-{[2-(1-cyclobutylpyrazol-4-yl)-4-pyridyl]oxy}-N-[(3,5-difluorophenyl)methyl]-2-methyl-benzamide (257): TIFF2025539843000300.tif27170 Compound 257 was synthesized from intermediate 214 (0.05 mmol) and cyclobutyl bromide (0.06 mmol) according to general method I as a white solid in 39% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.39(d,J=0.5Hz,1H),8.37-8.35(m,1 H),8.01(d,J=0.5Hz,1H),7.41-7.34(m,2H),7.29(d,J=2.1Hz,1H),7.22(dd,J=7.4Hz,1.9H z,1H),7.13(tt,J=9.4Hz,2.4Hz,1H),7.09-7.04(m,2H),6.48(dd,J=5.7Hz,2.4Hz,1H),4.8 5(p,J=8.5Hz,1H),4.48(d,J=6.0Hz,2H),2.50-2.35(m,4H),2.14(s,3H),1.82-1.73(m,2H). ESI-MS: 475.10 (M+H) + .

[0385] 3-({2-[1-(cyclobutylmethyl)pyrazol-4-yl]-4-pyridyl}oxy)-N-[(3,5-difluorophenyl)methyl]-2-methyl-benzamide (258): TIFF2025539843000301.tif28170 Compound 258 was synthesized from intermediate 214 (0.05 mmol) and (bromomethyl)cyclobutane (0.06 mmol) according to general method I as a white solid in 43% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.36-8.35(m,1H),8.27(d,J=0.5Hz,1H),7.96 (d,J=0.6Hz,1H),7.41-7.35(m,2H),7.27(d,J=2.2Hz,1H),7.22(dd,J=7.4Hz,1.9Hz,1H),7.13(tt, J=9.4Hz,2.4Hz,1H),7.09-7.04(m,2H),6.47(dd,J=5.7Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),4.14( d,J=7.3Hz,2H),2.76(dt,J=14.9Hz,7.5Hz,1H),2.14(s,3H),2.00-1.94(m,2H),1.89-1.72(m,4H). ESI-MS: 489.10 (M+H) + .

[0386] 3-({2-[1-(2-cyanoethyl)pyrazol-4-yl]-4-pyridyl}oxy)-N-[(3,5-difluorophenyl)methyl]-2-methyl-benzamide (259): TIFF2025539843000302.tif28170 Compound 259 was synthesized from intermediate 214 (0.05 mmol) and 3-bromopropionitrile (0.06 mmol) according to general method I as a white solid in 56% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.1Hz,1H),8.39-8.37(m,2H),8.07(d,J =0.6Hz,1H),7.42-7.35(m,2H),7.28(d,J=2.2Hz,1H),7.23(dd,J=7.4Hz,1.9Hz,1 H),7.13(tt,J=9.4Hz,2.4Hz,1H),7.09-7.04(m,2H),6.52(dd,J=5.7Hz,2.4Hz,1H ),4.48(d,J=6.0Hz,2H),4.42(t,J=6.4Hz,2H),3.10(t,J=6.4Hz,2H),2.15(s,3H). ESI-MS: 474.10 (M+H) + .

[0387] 3-({2-[1-(cyanomethyl)pyrazol-4-yl]-4-pyridyl}oxy)-N-[(3,5-difluorophenyl)methyl]-2-methyl-benzamide (260): TIFF2025539843000303.tif30170 Compound 260 was synthesized from intermediate 214 (0.05 mmol) and 2-iodoacetonitrile (0.07 mmol) according to general method I as a white solid in 14% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.40-8.38(m,2H),8.15(d,J=0.6Hz,1H),7.42-7.35(m,2H),7.32(d,J=2.2Hz,1H),7.24(dd,J= 7.3Hz,2.0Hz,1H),7.13(tt,J=9.4Hz,2.4Hz,1H),7.09-7.03(m,2H),6.54 (dd,J=5.7Hz,2.4Hz,1H),5.53(s,2H),4.48(d,J=6.0Hz,2H),2.14(s,3H). ESI-MS: 460.10 (M+H) + .

[0388] 4-[4-(4-{3-[(3,5-difluorophenyl)methylcarbamoyl]-2-methyl-phenoxy}-2-pyridyl)pyrazol-1-yl]piperidine-1-carboxylate tert-methyl (261): TIFF2025539843000304.tif27170 Compound 261 was synthesized from intermediate 214 (0.10 mmol) and tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (0.11 mmol) according to general method I as a white solid in 70% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.37-8.35(m,2H),8.00(s,1H),7.41-7.35 (m,2H),7.29(d,J=2.3Hz,1H),7.22(dd,J=7.4Hz,1.9Hz,1H),7.13(tt,J=9.5Hz,2.4Hz,1H),7.10 -7.04(m,2H),6.48(dd,J=5.7Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),4.42-4.34(m,1H),4.04(d,J =11.8Hz,2H),2.91(bs,2H),2.14(s,3H),2.02(d,J=10.2Hz,2H),1.85-1.75(m,2H),1.42(s,9H). ESI-MS: 604.40 (M+H) + .

[0389] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[1-(4-piperidyl)pyrazol-4-yl]-4-pyridyl}oxy)benzamide (262): TIFF2025539843000305.tif28170 To a stirred solution of compound 261 (25 mg, 0.04 mmol) in dioxane (2 mL) was added HCl (4N in dioxane, 0.41 mL, 10 equiv.), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with a 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, 100 / 0 to 90 / 10) and reverse-phase chromatography (HO / MeOH, 100 / 0 to 0 / 100) to give the expected compound as a white solid in 33% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.36(d,J=5.7Hz,1H),8.32(s,1H),7.99( s,1H),7.41-7.34(m,2H),7.29(d,J=2.3Hz,1H),7.22(dd,J=7.3Hz,1.8Hz,1H),7.16-7.10(m,1H) ),7.09-7.14(m,2H),6.48(dd,J=5.7Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),4.28-4.19(m,1H),3. 07(d,J=12.3Hz,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). ESI-MS: 504.10 (M+H) + .

[0390] Example 9: General procedure for the synthesis of analogs 263-277 TIFF2025539843000306.tif118170

[0391] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[2-(1-methylpyrazol-4-yl)-4-pyridyl]-4-pyridyl}oxy)benzamide (263): TIFF2025539843000307.tif26170 Compound 263 was synthesized in a two-step procedure 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) according to general method D2 as a white solid in 23% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=6.1Hz,1H),8.61-8.59(m,2H),8.40(s,1H),8 .29-8.28(m,1H),8.10(d,J=0.7Hz,1H),7.92(d,J=2.3Hz,1H),7.81(dd,J=5.2Hz,1.7H z,1H),7.44-7.38(m,2H),7.29(dd,J=7.3Hz,2.0Hz,1H),7.16-7.10(m,1H),7.09-7.04 (m,2H),6.71(dd,J=5.6Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),3.90(s,3H),2.17(s,3H). ESI-MS: 512.10 (M+H) + .

[0392] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[6-(1-methylpyrazol-4-yl)-3-pyridyl]-4-pyridyl}oxy)benzamide (264): TIFF2025539843000308.tif37170 Compound 264 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) as a white solid in 15% yield according to general method D2. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.16(dd,J=2.3Hz,0.7Hz,1H),9.01(t,J=6.1Hz,1H),8.55(d,J=5.7 Hz,1H),8.38(dd,J=8.4Hz,2.4Hz,1H),8.35(s,1H),8.06(d,J=0.6Hz,1H),7.74(dd,J=8.3Hz,0.6H z,1H),7.65(d,J=2.2Hz,1H),7.44-7.37(m,2H),7.27(dd,J=7.3Hz,2.0Hz,1H),7.16-7.10(m,1H), 7.09-7.04(m,2H),6.67(dd,J=5.7Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),3.90(s,3H),2.16(s,3H). ESI-MS: 512.10 (M+H) + .

[0393] N-[(3,5-difluorophenyl)methyl]-3-{[2-(2-fluoro-4-pyridyl)-4-pyridyl]oxy}-2-methyl-benzamide (265a): TIFF2025539843000309.tif25170 Compound 265a was synthesized from intermediate 199b (1.16 mmol) and 2-fluoropyridin-4-ylboronic acid (1.39 mmol) according to general method D2 as a white solid in 100% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.00(t,J=5.9Hz,1H),8.61(d,J=5.6Hz,1H),8.36(d,J=5.3Hz,1H),8.02(d,J=5.2Hz,1H),7.85(d,J=2.Hz) 3,1H),7.82(s,1H),7.44-7.38(m,2H),7.28(dd,J=6.9Hz,2.2Hz,1H),7.16-7 .04(m,3H),6.78(dd,J=5.6Hz,1.9Hz,1H),4.48(d,J=5.9Hz,2H),2.16(s,3H). ESI-MS: 450.05 (M+H) + .

[0394] N-[(3,5-difluorophenyl)methyl]-3-{[2-(6-fluoro-3-pyridyl)-4-pyridyl]oxy}-2-methyl-benzamide (265b): TIFF2025539843000310.tif28170 Compound 265b was synthesized from intermediate 199b (0.77 mmol) and 6-fluoro-3-pyridineboronic acid (0.93 mmol) according to general method D2 as a white solid in 100% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.00(t,J=6.0Hz,1H),8.90(d,J=2.5Hz,1H),8.64-8.59(m,1H),8.57-8.55(m,1H),7.6 9(d,J=2.1Hz,1H),7.43-7.37(m,2H),7.31(dd,J=8.6Hz,2.4Hz,1H),7.27(dd,J=7.2Hz,2.1Hz,1H),7.13(tt,J=9.4Hz ,2.4Hz,1H),7.09-7.04(m,2H),6.70(dd,J=5.7Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),2.16(s,3H). ESI-MS: 450.05 (M+H) + .

[0395] Method J: To a solution of 265 (1 equiv.) in dioxane (10 mL / mmol) was added the amine derivative (16 equiv.) and DIEA (6 equiv.). The mixture was stirred at 100 °C until completion (2 h to overnight). The reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography (DCM / MeOH, 100 / 0 to 90 / 10) and reverse-phase chromatography (HO / MeOH, 100 / 0 to 0 / 100) to give the expected compound.

[0396] The following compound 266 is an example illustrating Method J:

[0397] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(2-pyrrolidin-1-yl-4-pyridyl)-4-pyridyl]oxybenzamide (266): TIFF2025539843000311.tif27170 Compound 266 was synthesized from intermediate 265a (0.07 mmol) and pyrrolidine (0.53 mmol) according to general method J as a white solid in 55% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=6.0Hz,1H),8.55(d,J=5.8Hz,1H),8.14(dd,J=5.3Hz,0.6Hz,1H),7.64(d,J=2.2Hz,1H),7.43-7.37(m,2H),7. 27(dd,J=7.3Hz,2.0Hz,1H),7.16-7.04(m,5H),6.71(dd,J=5.6Hz,2.4Hz,1H ),4.48(d,J=6.0Hz,2H),3.46-3.43(m,4H),2.15(s,3H),1.98-1.94(m,4H). ESI-MS: 501.10 (M+H) + .

[0398] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[2-(1-piperidyl)-4-pyridyl]-4-pyridyl}oxy)benzamide (267): TIFF2025539843000312.tif27170 Compound 267 was synthesized from intermediate 265a (0.07 mmol) and piperidine (0.53 mmol) according to general method J as a white solid in 50% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=6.0Hz,1H),8.55(d,J=5.6Hz,1H),8.18(d,J=5.2Hz,1H),7.70(d,J=2.3Hz,1H),7.43-7.36(m,3H),7.26(d d,J=7.2Hz,2.0Hz,1H),7.17-7.04(m,4H),6.69(dd,J=5.6Hz,2.4Hz,1H), 4.48(d,J=6.0Hz,2H),3.60-3.58(m,4H),2.16(s,3H),1.62-1.55(m,6H). ESI-MS: 515.15 (M+H) + .

[0399] N-[(3,5-difluorophenyl)methyl]-3-({2-[2-(dimethylamino)-4-pyridyl]-4-pyridyl}oxy)-2-methyl-benzamide (268): TIFF2025539843000313.tif26170 Compound 268 was synthesized from intermediate 265a (0.07 mmol) and dimethylamine (2M THF, 0.67 mmol) according to general method J as a white solid in 47% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=6.0Hz,1H),8.56(d,J=5.6Hz,1H),8.18-8.16(m,1H),7.66(d,J=2.3Hz,1H),7.43-7.37(m,2 H),7.27(dd,J=8.1Hz,2.7Hz,2H),7.15-7.04(m,4H),6.71(dd,J=5.6Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),3.09(s,6H),2.15(s,3H). ESI-MS: 475.10 (M+H) + .

[0400] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(2-morpholino-4-pyridyl)-4-pyridyl]oxy}benzamide (269): TIFF2025539843000314.tif26170 Compound 269 was synthesized from intermediate 265a (0.07 mmol) and morpholine (1.07 mmol) according to general method J as a white solid in 50% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=6.1Hz,1H),8.55(d,J=5.7Hz,1H),8.23(d,J=5.6H z,1H),7.75(d,J=2.2Hz,1H),7.46(s,1H),7.43-7.37(m,2H),7.29(dd,J=5.2Hz,1.3Hz,1H), 7.26(dd,J=7.3Hz,2.0Hz,1H),7.13(tt,J=9.4Hz,2.4Hz,1H),7.09-7.04(m,2H),6.69(dd,J= 5.6Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),3.73-3.71(m,4H),3.54-3.51(m,4H),2.16(s,3H). ESI-MS: 517.15 (M+H) + .

[0401] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[2-(4-methylpiperazin-1-yl)-4-pyridyl]-4-pyridyl}oxy)benzamide (270): TIFF2025539843000315.tif27170 Compound 270 was synthesized from intermediate 265a (0.07 mmol) and 1-methylpiperazine (1.07 mmol) according to general method J as a white solid in 40% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=6.0Hz,1H),8.55(d,J=5.8Hz,1H),8.21-8.19(m,1H),7.74(d,J=2.2Hz,1H),7.4 5(s,1H),7.43-7.37(m,2H),7.27-7.23(m,2H),7.13(tt,J=9.4Hz,2.4Hz,1H),7.09-7.04(m,2H),6.69(dd,J=5.6Hz,2.4Hz ,1H),4.48(d,J=6.0Hz,2H),3.57-3.55(m,4H),2.42-2.40(m,4H),2.22(s,3H),2.16(s,3H). ESI-MS: 530.15 (M+H) + .

[0402] 3-{[2-(2-amino-4-pyridyl)-4-pyridyl]oxy}-N-[(3,5-difluorophenyl)methyl]-2-methyl-benzamide (271): TIFF2025539843000316.tif28170 Compound 271 was synthesized from intermediate 265a (0.07 mmol) and NH4OH (1.5 mL) according to general method J as a white solid in 34% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=6.1Hz,1H),8.55(d,J=5.8Hz,1H),7.98(dd,J=5.4Hz,0.6Hz,1H),7.43-7.37(m,3H),7.28(dd,J=7.3H z,2.0Hz,1H),7.16-7.04(m,4H),7.02(dd,J=5.4Hz,1.6Hz,1H),6.78(dd,J=5.6Hz,2.4Hz,1H),6.03(s,2H),4.48(d,J=6.0Hz,2H),2.15(s,3H). ESI-MS: 447.05 (M+H) + .

[0403] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(6-pyrrolidin-1-yl-3-pyridyl)-4-pyridyl]oxy}benzamide (272): TIFF2025539843000317.tif35170 Compound 272 was synthesized from intermediate 265b (0.07 mmol) and pyrrolidine (1.06 mmol) according to general method J as a white solid in 55% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=6.0Hz,1H),8.75(d,J=1.9Hz,1H),8.43(d,J=5.6Hz,1H),8.13(dd,J=8.9Hz ,2.5Hz,1H),7.42-7.35(m,3H),7.24(dd,J=7.5Hz,1.8Hz,1H),7.16-7.10(m,1H),7.09-7.04(m, 2H),6.55-6.50(m,2H),4.48(d,J=6.0Hz,2H),3.45-3.42(m,4H),2.15(s,3H),1.97-1.94(m,4H). ESI-MS: 501.10 (M+H) + .

[0404] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[6-(1-piperidyl)-3-pyridyl]-4-pyridyl}oxy)benzamide (273): TIFF2025539843000318.tif37170 Compound 273 was synthesized from intermediate 265b (0.07 mmol) and piperidine (1.06 mmol) according to general method J as a white solid in 65% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.00(t,J=6.0Hz,1H),8.75(d,J=2.2Hz,1H),8.44 (d,J=5.8Hz,1H),8.13(dd,J=9.0Hz,2.5Hz,1H),7.42-7.35(m,3H),7.24(dd,J=7. 4Hz,1.8Hz,1H),7.16-7.04(m,3H),6.87(d,J=8.9Hz,1H),6.56(dd,J=5.7Hz,2.4 Hz,1H),4.48(d,J=6.0Hz,2H),3.61-3.58(m,4H),2.15(s,3H),1.63-1.54(m,6H). ESI-MS: 515.20 (M+H) + .

[0405] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(6-morpholino-3-pyridyl)-4-pyridyl]oxy}benzamide (274): TIFF2025539843000319.tif35170 Compound 274 was synthesized from intermediate 265b (0.07 mmol) and morpholine (1.06 mmol) according to general method J as a white solid in 65% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.00(t,J=6.0Hz,1H),8.80(d,J=2.2Hz,1H),8.46(d,J=5.7Hz, 1H),8.20(dd,J=9.0Hz,2.5Hz,1H),7.45(d,J=2.3Hz,1H),7.40-7.36(m,2H),7.25(dd,J=7.4Hz ,1.9Hz,1H),7.13(tt,J=9.5Hz,2.4Hz,1H),7.09-7.04(m,2H),6.91(d,J=9.0Hz,1H),6.57(dd, J=5.7Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),3.72-3.69(m,4H),3.55-3.52(m,4H),2.15(s,3H). ESI-MS: 517.15 (M+H) + .

[0406] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[6-(4-methylpiperazin-1-yl)-3-pyridyl]-4-pyridyl}oxy)benzamide (275): TIFF2025539843000320.tif37170 Compound 275 was synthesized from intermediate 265b (0.07 mmol) and 1-methylpiperazine (1.06 mmol) according to general method J as a white solid in 52% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.00(t,J=6.0Hz,1H),8.77(d,J=2.1Hz,1H),8.45(d,J=5.8Hz,1 H),8.16(dd,J=9.0Hz,2.5Hz,1H),7.43(d,J=2.2Hz,1H),7.42-7.36(m,2H),7.25(dd,J=7.4Hz, 1.9Hz,1H),7.16-7.10(m,1H),7.09-7.04(m,2H),6.90(d,J=9.0Hz,1H),6.57(dd,J=5.7Hz,2.4 Hz,1H),4.48(d,J=6.0Hz,2H),3.58-3.55(m,4H),2.40-2.38(m,4H),2.22(s,3H),2.15(s,3H). ESI-MS: 530.15 (M+H) + .

[0407] N-[(3,5-difluorophenyl)methyl]-3-({2-[6-(dimethylamino)-3-pyridyl]-4-pyridyl}oxy)-2-methyl-benzamide (276): TIFF2025539843000321.tif32170 Compound 276 was synthesized from intermediate 265b (0.07 mmol) and dimethylamine (2M THF, 1.06 mmol) according to general method J as a white solid in 72% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=6.0Hz,1H),8.76(dd,J=2.5Hz,0.6Hz,1H) ,8.44(d,J=5.8Hz,1H),8.14(dd,J=9.0Hz,2.5Hz,1H),7.42-7.35(m,3H),7.24(dd,J =7.5Hz,1.8Hz,1H),7.16-7.10(m,1H),7.09-7.04(m,2H),6.71(dd,J=9.0Hz,0.5Hz, 1H),6.55(dd,J=5.7Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),3.08(s,6H),2.15(s,3H). ESI-MS: 475.10 (M+H) + .

[0408] 3-{[2-(6-amino-3-pyridyl)-4-pyridyl]oxy}-N-[(3,5-difluorophenyl)methyl]-2-methyl-benzamide (277): TIFF2025539843000322.tif29170 Compound 277 was synthesized from intermediate 265b (0.07 mmol) and NH4OH (1.5 mL) according to general method J as a white solid in 69% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.00(t,J=6.0Hz,1H),8.60-8.59(m,1H),8.42(d,J=5.8Hz,1H),8 .01(dd,J=8.7Hz,2.5Hz,1H),7.42-7.35(m,2H),7.34(d,J=2.2Hz,1H),7.24(dd,J=7.5Hz,1.8Hz ,1H),7.13(tt,J=9.4Hz ,2.4Hz,1H),7.09-7.04(m,2H),6.55(dd,J=5.7Hz,2.4Hz,1H),6.49(dd,J=8.7Hz,0.6Hz,1H),6.28(s,2H),4.48(d,J=6.0Hz,2H),2.15(s,3H). ESI-MS: 447.05 (M+H) + .

[0409] Example 10: General procedure for the synthesis of analogs 278-283 TIFF2025539843000323.tif118170

[0410] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[3-(1-methylpyrazol-4-yl)phenyl]-4-pyridyl}oxy)benzamide (278): TIFF2025539843000324.tif26170 Compound 278 was synthesized in a two-step procedure from intermediate 199b (0.06 mmol), (3-bromophenyl)boronic acid (0.06 mmol) and 1-methylpyrazole-4-boronic acid pinacol ester (0.13 mmol) as a white solid in 10% yield according to general method D2. 1H NMR(600MHz,DMSO-d6)δ(ppm):9.00(t,J=6.0Hz,1H),8.54(d,J=5.6Hz,1H),8.26(s,1H),8.23(t,J =1.6Hz,1H),7.95(d,J=0.8Hz,1H),7.85-7.83(m,1H),7.66(d,J=2.3Hz,1H),7.64-7.62(m,1H),7.4 5(t,J=7.7Hz,1H),7.43-7.37(m,2H),7.27(dd,J=7.8Hz,1.4Hz,1H),7.12(tt,J=9.4Hz,2.4Hz,1H) ,7.09-7.05(m,2H),6.66(dd,J=5.6Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),3.88(s,3H),2.17(s,3H). ESI-MS: 511.10 (M+H) + .

[0411] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[3-(2-methylpyrazol-3-yl)phenyl]-4-pyridyl}oxy)benzamide (279): TIFF2025539843000325.tif27170 Compound 279 was synthesized in a two-step procedure 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) as a white solid in 6% yield according to general method D2. 1H NMR(600MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.56-8.55(m,1H),8.15(t,J=2.0Hz,1H), 8.10-8.08(m,1H),7.64(d,J=2.1Hz,1H),7.62-7.60(m,2H),7.49(d,J=1.9Hz,1H),7.42-7.37( m,2H),7.27(dd,J=7.7Hz,1.4Hz,1H),7.12(tt,J=9.4Hz,2.4Hz,1H),7.09-7.05(m,2H),6.70(d d,J=5.6Hz,2.4Hz,1H),6.49(d,J=1.9Hz,1H),4.48(d,J=6.0Hz,2H),3.88(s,3H),2.16(s,3H). ESI-MS: 511.15 (M+H) + .

[0412] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[3-(1-methylpyrazol-3-yl)phenyl]-4-pyridyl}oxy)benzamide (280): TIFF2025539843000326.tif27170 Compound 280 was synthesized in a two-step procedure 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) as a white solid in 10% yield according to general method D2. 1H NMR(600MHz,DMSO-d6)δ(ppm):9.00(t,J=6.0Hz,1H),8.56-8.55(m,1H),8.48(t,J=1.6Hz,1H),7.90(ddd,J=7. 8Hz,1.8Hz,1.1Hz,1H),7.85(ddd,J=7.7Hz,1.6Hz,1.1Hz,1H),7.75(d,J=2.2Hz,1H),7.58(d,J=2.2Hz,1H),7. 49(t,J=7.7Hz,1H),7.43-7.37(m,2H),7.28(dd,J=7.8Hz,1.3Hz,1H),7.12(tt,J=9.3Hz,2.4Hz,1H),7.09-7.0 5(m,2H),6.78(d,J=2.2Hz,1H),6.70(dd,J=5.6Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),3.90(s,3H),2.17(s,3H). ESI-MS: 511.10 (M+H) + .

[0413] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[4-(1-methylpyrazol-4-yl)phenyl]-4-pyridyl}oxy)benzamide (281): TIFF2025539843000327.tif39170 Compound 281 was synthesized in a two-step procedure from intermediate 199b (0.10 mmol), (4-bromophenyl)boronic acid (0.15 mmol) and 1-methylpyrazole-4-boronic acid pinacol ester (0.21 mmol) as a white solid in 4% yield according to general method D2. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=6.0Hz,1H),8.52(d,J=5.6Hz,1H),8.21(s,1H ),8.03(d,J=8.5Hz,2H),7.93(d,J=0.6Hz,1H),7.66(d,J=8.5Hz,2H),7.51(d,J=2.3Hz ,1H),7.43-7.37(m,2H),7.27(dd,J=7.4Hz,1.8Hz,1H),7.16-7.10(m,1H),7.09-7.04( m,2H),6.66(dd,J=5.6Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),3.88(s,3H),2.16(s,3H). ESI-MS: 511.10 (M+H) + .

[0414] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[4-(2-methylpyrazol-3-yl)phenyl]-4-pyridyl}oxy)benzamide (282): TIFF2025539843000328.tif37170 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) as a white solid in 4% yield according to general method D2. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.02(t,J=6.0Hz,1H),8.57(d,J=5.7Hz,1H),8.15(d,J=8. 4Hz,2H),7.65(d,J=8.4Hz,2H),7.56(d,J=2.3Hz,1H),7.49(d,J=1.9Hz,1H),7.44-7.37( m,2H),7.29(dd,J=7.3Hz,1.9Hz,1H),7.15-7.10(m,1H),7.09-7.04(m,2H),6.74(dd,J=5 .6Hz,2.4Hz,1H),6.48(d,J=1.9Hz,1H),4.48(d,J=6.0Hz,2H),3.90(s,3H),2.17(s,3H). ESI-MS: 511.10 (M+H) + .

[0415] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[4-(1-methylpyrazol-3-yl)phenyl]-4-pyridyl}oxy)benzamide (283): TIFF2025539843000329.tif37170 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) as a white solid in 4% yield according to general method D2. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=6.1Hz,1H),8.53(d,J=5.6Hz,1H),8.06(d,J=8. 6Hz,2H),7.88(d,J=8.5Hz,2H),7.76(d,J=2.2Hz,1H),7.53(d,J=2.3Hz,1H),7.43-7.37( m,2H),7.28(dd,J=7.4Hz,1.8Hz,1H),7.15-7.10(m,1H),7.09-.704(m,2H),6.76(d,J=2. 3Hz,1H),6.69(dd,J=5.6Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),3.90(s,3H),2.17(s,3H). ESI-MS: 511.10 (M+H) + .

[0416] Example 11: General procedure for the synthesis of analogs 285-290 TIFF2025539843000330.tif110170

[0417] Preparation of N-[(3,5-difluorophenyl)methyl]-3-{[2-(4-formylphenyl)-4-pyridyl]oxy}-2-methyl-benzamide (284a): TIFF2025539843000331.tif32170 Intermediate 284a was synthesized from 199b (0.39 mmol) as a white solid in quantitative yield following general method D2. ESI-MS: 459.05 (M+H) + .

[0418] The following table shows intermediate 284 prepared from Method D2.

[0419] TIFF2025539843000332.tif78170

[0420] Method K: To a solution of 284 (1 equiv.) in MeOH (10 mL / mmol) was added the amine derivative (1.3 equiv.), AcOH (2% v / v), and NaBH3CN. The mixture was stirred at room temperature until completion (1 h to overnight). The reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography (DCM / MeOH 100 / 0 to 90 / 10) and reverse-phase chromatography (HO / MeOH, 100 / 0 to 0 / 100) to give the expected compound.

[0421] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[4-(pyrrolidin-1-ylmethyl)phenyl]-4-pyridyl}oxy)benzamide (285): TIFF2025539843000333.tif28170 Compound 285 was synthesized from intermediate 284a (0.05 mmol) and pyrrolidine (0.07 mmol) according to general method K as a white solid in 25% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=6.0Hz,1H),8.52(d,J=5.6Hz,1H),7.96(d,J=8.2Hz,2H),7.45(d,J=2.2Hz,1H),7.43-7.37(m,4H),7.27(dd ,J=7.3Hz,1.9Hz,1H),7.15-7.04(m,3H),6.69(dd,J=5.6Hz,2.3Hz,1H),4. 48(d,J=5.9Hz,2H),3.61(s,2H),2.43(bs,4H),2.16(s,3H),1.70(bs,4H). ESI-MS: 514.15 (M+H) + .

[0422] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[4-(morpholinomethyl)phenyl]-4-pyridyl}oxy)benzamide (286): TIFF2025539843000334.tif26170 Compound 286 was synthesized from intermediate 284a (0.07 mmol) and morpholine (0.09 mmol) according to general method K as a white solid in 26% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=6.0Hz,1H),8.52(d,J=5.7Hz,1H),7.97(d,J=8.3Hz, 2H),7.46(d,J=2.3Hz,1H),7.41-7.37(m,4H),7.27(dd,J=7.4Hz,1.9Hz,1H),7.13(tt,J=9.5Hz ,2.4Hz,1H),7.09-7.04(m,2H),6.69(dd,J=5.6Hz,2.4Hz,1H),4.48(d,J=6 .0Hz,2H),3.59-3.56(m,4H),3.51(s,2H),2.38-2.35(m,4H),2.15(s,3H). ESI-MS: 530.15 (M+H) + .

[0423] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-[(2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-4-pyridyl)oxy]benzamide (287): TIFF2025539843000335.tif28170 Compound 287 was synthesized from intermediate 284a (0.07 mmol) and 1-methylpiperazine (0.09 mmol) according to general method K as a white solid in 31% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=6.1Hz,1H),8.52(d,J=5.7Hz,1H),7.96(d,J=8.3Hz,2H),7.45(d,J=2.3 Hz,1H),7.43-7.37(m,4H),7.27(dd,J=7.4Hz,1.9Hz,1H),7.16-7.10(m,1H),7.09-7.04(m,2H),6.69(dd,J=5.6Hz ,2.4Hz,1H),4.48(d,J=6.0Hz,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). ESI-MS: 543.20 (M+H) + .

[0424] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[3-(pyrrolidin-1-ylmethyl)phenyl]-4-pyridyl}oxy)benzamide (288): TIFF2025539843000336.tif27170 Compound 288 was synthesized from intermediate 284b (0.06 mmol) and pyrrolidine (0.09 mmol) according to general method K as a white solid in 44% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=6.0Hz,1H),8.53(d,J=5.7Hz,1H),8.04(s,1H),7.90(s,1H),7.50-7.37(m,5H),7.27(dd,J=7.4Hz,1.9Hz ,1H),7.13(tt,J=9.4Hz,2.4Hz,1H),7.09-7.04(m,2H),6.70(dd,J=5.6Hz,2.4Hz, 1H),4.48(d,J=6.0Hz,2H),3.69(s,2H),2.52(bs,4H),2.16(s,3H),1.74(bs,4H). ESI-MS: 514.15 (M+H) + .

[0425] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[3-(morpholinomethyl)phenyl]-4-pyridyl}oxy)benzamide (289): TIFF2025539843000337.tif25170 Compound 289 was synthesized from intermediate 284b (0.07 mmol) and morpholine (0.09 mmol) according to general method K as a white solid in 40% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=6.0Hz,1H),8.53(d,J=5.7Hz,1H),7.99(bs ,1H),7.88-7.86(m,1H),7.48(d,J=2.2Hz,1H),7.45-7.37(m,4H),7.27(dd,J=7.4Hz ,1.9Hz,1H),7.16-7.10(m,1H),7.09-7.04(m,2H),6.70(dd,J=5.6Hz,2.4Hz,1H),4. 48(d,J=6.0Hz,2H),3.58-3.56(m,4H),3.53(s,2H),2.38-2.36(s,4H),2.16(s,3H). ESI-MS: 530.15 (M+H) + .

[0426] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-[(2-{3-[(4-methylpiperazin-1-yl)methyl]phenyl}-4-pyridyl)oxy]benzamide (290): TIFF2025539843000338.tif28170 Compound 290 was synthesized from intermediate 284b (0.07 mmol) and 1-methylpiperazine (0.09 mmol) according to general method K as a white solid in 36% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.01(t,J=6.1Hz,1H),8.53(d,J=5.7Hz,1H),7.97(s,1H),7 .88-7.84(m,1H),7.46(d,J=2.2Hz,1H),7.44-7.34(m,4H),7.27(dd,J=7.5Hz,1.8Hz,1H), 7.13(tt,J=9.4Hz,2.4Hz,1H),7.09-7.04(m,2H),6.70(dd,J=5.6Hz,2.4Hz,1H),4.48(d,J =6.0Hz,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). ESI-MS: 543.20 (M+H) + .

[0427] Example 12: General procedure for the synthesis of analogs 292-297 TIFF2025539843000339.tif107170

[0428] Preparation of N-[(3,5-difluorophenyl)methyl]-2-methyl-3-(1-oxidopyridin-1-ium-4-yl)oxy-benzamide (291): TIFF2025539843000340.tif25170 Compound 291 was synthesized from intermediate 41 (0.77 mmol) and 4-chloropyridine-N-oxide (0.77 mmol) according to general method A as a white solid in 59% yield. ESI-MS: 371.05 (M+H) + .

[0429] Method L: To a solution of 291 (1 equiv.) in CHCl (10 mL / mmol) was added the amine derivative (1.3 equiv.), DIPEA (3.8 equiv.), and Brop or PyBrop (1.3 equiv.). The mixture was stirred at room temperature until completion (1 h to overnight). The reaction mixture was diluted with DCM and washed twice with a saturated solution of NaHCO. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography (DCM / MeOH, 100 / 0 to 90 / 10) and reverse-phase chromatography (HO / MeOH, 100 / 0 to 0 / 100) to give the expected compound.

[0430] The following compounds are examples illustrating Method L:

[0431] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(methylamino)-4-pyridyl]oxy}benzamide (292): TIFF2025539843000341.tif25170 Compound 292 was synthesized from intermediate 291 (0.08 mmol) and dimethylamine (2M THF, 0.10 mmol) according to general method L as a white solid in 32% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),7.87(d,J=5.8Hz,1H),7.37-7.30(m,2H),7.17-7.03(m,4H),6.47(q,J =4.7Hz,1H),6.06(dd,J=5.8Hz,2.2Hz,1H),5.75(d,J=2.2Hz,1H),4.46(d,J=6.0Hz,2H),2.70(d,J=4.8Hz,3H),2.11(s,3H). ESI-MS: 384.10 (M+H) + .

[0432] 3-{[2-(cyanopropylamino)-4-pyridyl]oxy}-N-[(3,5-difluorophenyl)methyl]-2-methyl-benzamide (293): TIFF2025539843000342.tif25170 Compound 293 was synthesized from intermediate 291 (0.08 mmol) and cyclopropylamine (0.11 mmol) according to general method L as a white solid in 30% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),7.87(d,J=5.7Hz,1H) ,7.38-7.31(m,2H),7.18-7.10(m,2H),7.09-7.03(m,2H),6.82(d,J=2.0Hz, 1H),6.04(dd,J=5.7Hz,2.1Hz,1H),5.97(d,J=1.9Hz,1H),4.46(d,J=5.9Hz ,2H),2.40-2.43(m,1H),2.12(s,3H),0.64-0.59(m,2H),0.38-0.34(m,2H). ESI-MS: 410.10 (M+H) + .

[0433] 3-[(2-anilino-4-pyridyl)oxy]-N-[(3,5-difluorophenyl)methyl]-2-methyl-benzamide (294): TIFF2025539843000343.tif25170 Compound 294 was synthesized from intermediate 291 (0.05 mmol) and aniline (0.11 mmol) according to general method L as a white solid in 13% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.98(s,2H),8.05(d,J=5.8Hz,1H),7.61(d,J=8.0Hz,2H),7.41-7.35(m,2H), 7.24-7.05(m,6H),6.86(t,J=7.3Hz,1H),6.39-6.38(m,1H),6.13(s,1H),4.48(d,J=5.8Hz,2H),2.15(s,3H). ESI-MS: 446.10 (M+H) + .

[0434] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(3-pyridylamino)-4-pyridyl]oxy}benzamide (295): TIFF2025539843000344.tif26170 Compound 295 was synthesized from intermediate 291 (0.05 mmol) and 3-aminopyridine (0.27 mmol) according to general method L as a white solid in 37% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.20(s,1H),8.99(t,J=5.9Hz,1H),8.72(d,J=2.5 Hz,1H),8.17(ddd,J=8.4Hz,2.6Hz,1.5Hz,1H),8.10-8.06(m,2H),7.43-7.36(m, 2H),7.26-7.23(m,2H),7.13(tt,J=9.4Hz,2.3Hz,1H),7.09-7.04(m,2H),6.46(d d,J=5.8Hz,2.2Hz,1H),6.13(d,J=2.2Hz,1H),4.48(d,J=6.0Hz,2H),2.15(s,3H). ESI-MS: 447.10 (M+H) + .

[0435] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(4-methylpyrazol-1-yl)-4-pyridyl]oxy}benzamide (296): TIFF2025539843000345.tif26170 Compound 296 was synthesized from intermediate 291 (0.07 mmol) and 4-methylpyrazole (0.34 mmol) according to general method L as a white solid in 38% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.08(t,J=6.0Hz,1H),8.37(s,1H),8.34(d,J=5.7Hz,1H),7.57(s,1H),7.45-7.40(m,2H),7.31(dd,J=7 .0Hz,2.3Hz,1H),7.16-7.09(m,2H),7.09-7.04(m,2H),6.90(dd,J=5.7Hz,2.4Hz,1H),4.47(d,J=6.0Hz,2H),2.14(s,3H),2.08(s,3H). ESI-MS: 435.10 (M+H) + .

[0436] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(3-methylpyrazol-1-yl)-4-pyridyl]oxy}benzamide (297): TIFF2025539843000346.tif29170 Compound 297 was synthesized from intermediate 291 (0.16 mmol) and 3-methylpyrazole (0.78 mmol) according to general method L as a white solid in 15% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.06(t,J=6.0Hz,1H),8.47(d,J=2.4Hz,1H),8.33(d,J=5.7Hz,1H),7.46-7.40(m,2H),7.31(dd,J=7.3Hz,2.0Hz, 1H),7.16-7.09(m,2H),7.08-7.04(m,2H),6.88(dd,J=5.7Hz,2.4Hz,1H) ,6.35(d,J=2.5Hz,1H),4.48(d,J=6.0Hz,2H),2.22(s,3H),2.15(s,3H). ESI-MS: 435.20 (M+H) + .

[0437] Example 13: General procedure for the synthesis of analogs 302-309 TIFF2025539843000347.tif95170

[0438] Method M: To a stirred solution of 117a (400 mg, 1.37 mmol) in CHCl (6 mL / mmol) was added m-CPBA (77%, 922 mg, 4.11 mmol), and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with DCM and washed twice with a saturated solution of NaHCO. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography (CHCl / MeOH, 100 / 0 to 93 / 7) to give 356 mg of ethyl 3-(2-chloro-1-oxido-pyridin-1-nium-4-yl)oxy-2-methyl-benzoate 298 as a yellow oil in 85% yield. ESI-MS: 308.00 (M+H). + .

[0439] Method N: To a stirred solution of 298 (1 equiv.) in DMF (10 mL / mmol) was added the amine derivative (1-3 equiv.) and K2CO3 (1.2 equiv.). The reaction mixture was stirred at 100 °C overnight. The reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography (DCM / MeOH, 100 / 0 to 94 / 6) to give the expected compound.

[0440] The following compound 299 is an example illustrating Method N:

[0441] Preparation of ethyl 2-methyl-3-[1-oxido-2-(triazol-2-yl)pyridin-1-nium-4-yl]oxy-benzoate (299a) and ethyl 2-methyl-3-[1-oxido-2-(triazol-1-yl)pyridin-1-nium-4-yl]oxy-benzoate (299b): TIFF2025539843000348.tif22170 Intermediates 299a and 299b were synthesized from 298 (1.02 mmol) and 1H-1,2,3-triazole (6.02 mmol) as white solids in 33% and 23% yields, respectively, following general method N. ESI-MS: 341.00 (M+H) + .

[0442] The following table shows intermediate 299 prepared from Method N.

[0443] TIFF2025539843000349.tif143170

[0444] Method O: To a stirred solution of 299 (1 equiv.) in DMF (10 mL / mmol) was added PPh3 (2 equiv.), and the reaction mixture was stirred at 135 °C overnight. The reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography (DCM / MeOH, 100 / 0 to 96 / 4) to give the expected compound.

[0445] Preparation of ethyl 2-methyl-3-{[2-(triazol-2-yl)-4-pyridyl]oxy}benzoate (300a): TIFF2025539843000350.tif20170

[0446] Intermediate 300a was synthesized from 299a (0.32 mmol) and PPh3 (0.64 mmol) according to general method O as a white solid in 70% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.47(d,J=5.7Hz,1H),8.14(s,2H),7.81-7.76(m,1H),7.50-7.45(m,2H),7.3 0(d,J=2.2Hz,1H),7.03(dd,J=5.7Hz,2.3Hz,1H),4.33(q,J=7.1Hz,2H),2.32(s,3H),1.33(t,J=7.1Hz,3H). ESI-MS: 325.05 (M+H) + .

[0447] The following table shows intermediates 300 prepared from Method O.

[0448] TIFF2025539843000351.tif146170

[0449] The following table shows intermediate 301 prepared from Method B2.

[0450] TIFF2025539843000352.tif140170

[0451] The following compounds are examples illustrating Method C2:

[0452] N-[(6-methoxy-3-pyridyl)methyl]-2-methyl-3-{[2-(triazol-2-yl)-4-pyridyl]oxy}benzamide (302): TIFF2025539843000353.tif24170 Compound 302 was synthesized from intermediate 301a (0.07 mmol) and 6-methoxypyridin-3-yl)methanamine (0.10 mmol) as a white solid in 79% yield according to general method C2. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.95(t,J=5.9Hz,1H),8.47(d,J=5.7Hz,1H),8.14(s,3H),7.69(dd,J=8.5Hz,2.5Hz,1H),7.41(t,J=7 .8Hz,1H),7.36-7.30(m,3H),7.03(dd,J=5.7Hz,2.3Hz,1H),6.81(d,J=8.5Hz,1H),4.39(d,J=5.9Hz,2H),3.83(s,3H),2.12(s,3H). ESI-MS: 417.05 (M+H) + .

[0453] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(triazol-2-yl)-4-pyridyl]oxy}benzamide (303): TIFF2025539843000354.tif25170 Compound 303 was synthesized from intermediate 301a (0.07 mmol) and 3,5-difluorobenzylamine (0.10 mmol) according to general method C2 as a white solid in 82% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.05(t,J=6.1Hz,1H),8.47(d,J=5.7Hz,1H),8.14(s,2H),7.46-7.41(m,2H),7.34(dd, J=7.0Hz,2.4Hz,1H),7.32(d,J=2.2Hz,1H),7.15-7.09(m,1H),7.09-7.03(m,3H),4.48(d,J=6.0Hz,2H),2.15(s,3H). ESI-MS: 422.05 (M+H) + .

[0454] N-[(6-methoxy-3-pyridyl)methyl]-2-methyl-3-{[2-(triazol-1-yl)-4-pyridyl]oxy}benzamide (304): TIFF2025539843000355.tif24170 Compound 304 was synthesized from intermediate 301b (0.07 mmol) and 6-methoxypyridin-3-yl)methanamine (0.10 mmol) as a white solid in 68% yield according to general method C2. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.97(t,J=5.9Hz,1H),8.84(d,J=1.2Hz,1H),8. 49(d,J=5.8Hz,1H),8.14(d,J=2.0Hz,1H),7.97(d,J=1.2Hz,1H),7.70(dd,J=8 .5Hz,2.5Hz,1H),7.45-7.40(m,2H),7.37-7.32(m,2H),7.07(dd,J=5.8Hz,2.3 Hz,1H),6.81(d,J=8.5Hz,1H),4.39(d,J=5.9Hz,2H),3.83(s,3H),2.13(s,3H). ESI-MS: 417.05 (M+H) + .

[0455] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(triazol-1-yl)-4-pyridyl]oxy}benzamide (305): TIFF2025539843000356.tif26170 Compound 305 was synthesized from intermediate 301b (0.07 mmol) and 3,5-difluorobenzylamine (0.10 mmol) according to general method C2 as a white solid in 64% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.07(t,J=6.1Hz,1H),8.85(d,J=1.2Hz,1H),8.50(d,J=5.8Hz,1H),7.98(d,J=1.2 Hz,1H),7.48-7.42(m,3H),7.36(dd,J=7.1Hz,2.3Hz,1H),7.15-7.04(m,4H),4.48(d,J=6.0Hz,2H),2.16(s,3H). ESI-MS: 422.10 (M+H) + .

[0456] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(3-methyl-1,2,4-triazol-1-yl)-4-pyridyl]oxy}benzamide (306): TIFF2025539843000357.tif31170 Compound 306 was synthesized from intermediate 301c (0.06 mmol) and 3,5-difluorobenzylamine (0.10 mmol) according to general method C2 as a white solid in 65% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.21(s,1H),9.07(t,J=6.0Hz,1H),8.42(d,J=5.7Hz,1H),7.47-7.42(m,2H),7.33(dd,J=6.9Hz,2.4Hz, 1H),7.13(tt,J=9.4Hz,2.3Hz,1H),7.09-7.05(m,3H),7.01(dd,J=5.7Hz,2.3Hz,1H),4.48(d,J=6.0Hz,2H),2.32(s,3H),2.14(s,3H). ESI-MS: 436.15 (M+H) + .

[0457] N-[(6-methoxy-3-pyridyl)methyl]-2-methyl-3-{[2-(3-methyl-1,2,4-triazol-1-yl)-4-pyridyl]oxy}benzamide (307): TIFF2025539843000358.tif26170 Compound 307 was synthesized from intermediate 301c (0.06 mmol) and 6-methoxypyridin-3-yl)methanamine (0.10 mmol) as a white solid in 54% yield according to general method C2. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.21(s,1H),8.97(t,J=5.9Hz,1H),8.41(d,J=5.7Hz, 1H),8.14(d,J=2.2Hz,1H),7.69(dd,J=8.5Hz,2.4Hz,1H),7.42(t,J=7.7Hz,1H),7.36 -7.34(m,1H),7.32-7.29(m,1H),7.05(d,J=2.3Hz,1H),7.00(dd,J=5.7Hz,2.3Hz,1H) ,6.81(d,J=8.5Hz,1H),4.39(d,J=5.9Hz,2H),3.83(s,3H),2.32(s,3H),2.11(s,3H). ESI-MS: 431.15 (M+H) + .

[0458] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(4-methyltriazol-2-yl)-4-pyridyl]oxy}benzamide (308): TIFF2025539843000359.tif30170 Compound 308 was synthesized from intermediate 301d (0.11 mmol) and 3,5-difluorobenzylamine (0.16 mmol) according to general method C2 as a white solid in 81% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.07(t,J=6.1Hz,1H),8.43(d,J=5.7Hz,1H),7.91(s,1H), 7.47-7.40(m,2H),7.34(dd,J=7.0Hz,2.3Hz,1H),7.23(d,J=2.2Hz,1H),7.13(tt,J=9.4Hz ,2.3Hz,1H),7.09-7.04(m,2H),7.01(dd,J=5.7Hz,2.3Hz,1H),4.47(d,J=6.0Hz,2H),2.33(s,3H),2.14(s,3H). ESI-MS: 436.10 (M+H) + .

[0459] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(4-methyltriazol-1-yl)-4-pyridyl]oxy}benzamide (309): TIFF2025539843000360.tif25170 Compound 309 was synthesized from intermediate 301e (0.11 mmol) and 3,5-difluorobenzylamine (0.16 mmol) according to general method C2 as a white solid in 59% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.09(t,J=6.0Hz,1H),8.58(d,J=0.8Hz,1H),8.47(d,J=5.8Hz,1H),7.47-7.41(m,2H), 7.37-7.34(m,2H),7.13(tt,J=9.5Hz,2.3Hz,1H),7.09-7.04(m,3H),4.48(d,J=6.0Hz,2H),2.32(s,3H),2.15(s,3H). ESI-MS: 436.15 (M+H) + .

[0460] Example 14: General procedure for the synthesis of analogs 310-314 TIFF2025539843000361.tif113170

[0461] Method P: Compound 41 (515 mg, 1.86 mmol) and 4-chloropyridine-2-carbonitrile (198 mg, 1.43 mmol) were dissolved in DMF (10 mL / mmol) in an oven-dried screw-cap test tube. K2CO3 (395 mg, 2.90 mmol) was added, and the reaction mixture was stirred and heated at 85 °C under microwave irradiation for 8 h. The reaction mixture was diluted with EtOAc and washed twice with a saturated solution of NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography (CHCl2 / MeOH, 100 / 0 to 95 / 5) to give 321 mg of 3-[(2-cyano-4-pyridyl)oxy]-N-[(3,5-difluorophenyl)methyl]-2-methyl-benzamide 310 as a white powder in 59% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.99(t,J=6.0Hz,1H),8.60(dd,J=5.8Hz,0.4Hz,1H),7.62(dd,J=2.5Hz, 0.4Hz,1H),7.45-7.40(m,2H),7.30-7.26(m,1H),7.16-7.04(m,4H),4.48(d,J=6.0Hz,2H),2.11(s,3H). ESI-MS: 436.15 (M+H) + .

[0462] Method Q: To a stirred solution of 310 (20 mg, 0.05 mmol) in DMF (1 mL) was added NH4Cl (6 mg, 0.11 mmol) and sodium azide (7 mg, 0.11 mmol). The reaction mixture was stirred at 90 °C 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 was purified by flash column chromatography (CHCl2 / MeOH, 100 / 0 to 80 / 20) and reverse-phase chromatography (HO / MeOH, 100 / 0 to 0 / 100) to give 3 mg of N-[(3,5-difluorophenyl)methyl]-2-methyl-3-{[2-(1H-tetrazol-5-yl)-4-pyridyl]oxy}benzamide 311 as a beige solid in 14% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.09(t,J=6.0Hz,1H),8.63(d,J=5.7Hz,1H),7.49(d,J=2.3Hz,1H),7. 47-7.40(m,2H),7.32(dd,J=7.3Hz,2.0Hz,1H),7.15-7.03(m,4H),4.48(d,J=6.0Hz,2H),2.15(s,3H). ESI-MS: 423.00 (M+H) + .

[0463] Method R: To a stirred solution of 310 (1 equiv.) in n-propanol (10 mL / mmol) was added NaOMe (25% in MeOH, 1.2 equiv.), and the reaction mixture was stirred at 50°C for 1.5 h. NHOAc was then added, and the reaction mixture was stirred at 70°C for 1 h. The reaction mixture was diluted with EtOAc and washed twice with water and brine. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give the amidine derivative, which was used directly in the next step. The compound was dissolved in DMF (10 mL / mmol) and KCO (2 equiv.), and the bromo derivative (1.2–2 equiv.) was added. The reaction mixture was stirred at 90°C for 3 h. The reaction mixture was diluted with EtOAc and washed twice with a saturated solution of NHCl. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography (CH2Cl2 / MeOH, 100 / 0 to 90 / 10) and reverse phase chromatography (H2O / MeOH, 100 / 0 to 0 / 100) to give the expected compound.

[0464] The following compounds are examples illustrating Method R:

[0465] N-[(3,5-difluorophenyl)methyl]-3-{[2-(4,5-dimethyl-1H-imidazol-2-yl)-4-pyridyl]oxy}-2-methyl-benzamide (312): TIFF2025539843000362.tif30170 Compound 312 was synthesized from intermediate 310 (0.07 mmol) and 3-bromo-2-butanone (0.13 mmol) according to general method R as a white solid in 23% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):12.33(bs,1H),9.07(t,J=6.0Hz,1H),8.43(d,J=5.7Hz,1H),7.45-7.38(m,2H),7.28(dd,J=7.6 Hz,1.7Hz,1H),7.16-7.04(m,4H),6.91(dd,J=5.7Hz,2.6Hz,1H),4.47(d,J=6.0Hz,2H),2.14(s,3H),2.12(s,3H),2.01(s,3H). ESI-MS: 449.10 (M+H) + .

[0466] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridyl}oxy)benzamide (313): TIFF2025539843000363.tif27170 Compound 313 was synthesized from intermediate 310 (0.05 mmol) and 3-bromo-1,1,1-trifluoroacetone (0.06 mmol) according to general method R as a white solid in 23% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):13.47(bs,1H),9.07(t,J=6.0Hz,1H),8.55(d,J=5.7Hz,1H),7.84(s,1H),7.46-7.39(m,2H),7 .35(d,J=2.4Hz,1H),7.32(dd,J=7.5Hz,1.5Hz,1H),7.1-7.09(m,1H),7.09-7.03(m,3H),4.47(d,J=6.0Hz,2H),2.15(s,3H). ESI-MS: 489.10 (M+H) + .

[0467] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridyl}oxy)benzamide (314): TIFF2025539843000364.tif27170 Compound 314 was synthesized from intermediate 310 (0.07 mmol) and 2-bromo-1-cyclopropylethanone (0.13 mmol) according to general method R as a white solid in 26% yield. ESI-MS: 461.10 (M+H) + .

[0468] Example 15: General procedure for the synthesis of analogue 318 TIFF2025539843000365.tif94170

[0469] Preparation of ethyl 3-[(2-acetyl-4-pyridyl)oxy]-2-methyl-benzoate (315): TIFF2025539843000366.tif20170 Intermediate 315 was synthesized from ethyl 3-hydroxy-2-methyl-benzoate (0.96 mmol) and 1-(4-chloro-2-pyridyl)ethanone (0.64 mmol) according to general method P as an orange oil in 40% yield. ESI-MS: 299.95 (M+H) + .

[0470] Method S: To a stirred solution of 315 (20 mg, 0.07 mmol) in THF (1 mL) was added t-BuOK (1 M THF, 0.134 mL, 0.13 mmol) at 0 °C. After 5 min, ethyl trifluoroacetate (16 μL, 0.13 mmol) was added, and the reaction mixture was stirred at 70 °C for 4 h. After cooling to room temperature, t-BuOK (1 M THF, 0.134 mL, 0.13 mmol) and ethyl trifluoroacetate (16 μL, 0.13 mmol) were added, and the reaction mixture was stirred at 70 °C overnight. The reaction mixture was diluted with EtOAc and washed twice with a saturated solution of NH Cl. The organic layer was dried over Na SO , filtered, and concentrated under reduced pressure. The intermediate was dissolved in EtOH (1 mL), and hydrazine hydrate was added (9 μL, 0.18 mmol). The reaction mixture was stirred at 80 °C overnight. The reaction mixture was concentrated under reduced pressure and ethyl 2-methyl-3-({2-[3-(trifluoromethyl)-1H-pyrazol-5-yl]-4-pyridyl}oxy)benzoate 316 was used directly in the next step without purification. ESI-MS: 392.00 (M+H) + .

[0471] Preparation of 2-methyl-3-({2-[3-(trifluoromethyl)-1H-pyrazol-5-yl]-4-pyridyl}oxy)benzoic acid (317): TIFF2025539843000367.tif31170 Intermediate 317 was synthesized from 316 according to general method B2. ESI-MS: 363.95 (M+H) + .

[0472] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-({2-[3-(trifluoromethyl)-1H-pyrazol-5-yl]-4-pyridyl}oxy)benzamide (318): TIFF2025539843000368.tif33170 Compound 318 was synthesized from intermediate 317 and 3,5-difluorobenzylamine according to general method C2 in 9% yield as a white solid. 1 H NMR(600MHz,DMSO-d6)δ(ppm):14.34(bs,1H),9.00(t,J=5.9Hz,1H),8.50(d,J=5.7Hz,1H),7.60(s,1H),7.42-7.38(m,2H),7.31(s,1H),7.27 (dd,J=7.5Hz,1.8Hz,1H),7.12(tt,J=9.3Hz,2.3Hz,1H),7.09-7.04(m,2H),6.73(dd,J=5.7Hz,2.4Hz,1H),4.48(d,J=6.0Hz,2H),2.15(s,3H). ESI-MS: 489.10 (M+H) + .

[0473] Example 16: General procedure for the synthesis of analogs 321 and 322 TIFF2025539843000369.tif105170

[0474] Method T: To a stirred solution of 4-bromo-7-azaindole (2.5 g, 12.69 mmol) in dichloromethane (40 mL) was added DMAP (155 mg, 1.27 mmol), triethylamine (2.1 mL, 15.23 mmol), and tosyl chloride (2.66 g, 13.96 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the crude was purified by flash column chromatography (cyclohexane / EtOAc, 100 / 0 to 60 / 40) to give 3.914 g of 4-bromo-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine 319 as a yellow powder in 88% yield. ESI-MS: 350.85-352.80 (M+H) + .

[0475] Method U: Under nitrogen, to a stirred solution of intermediate 319 (200 mg, 0.57 mmol) in toluene (10 mL) was added intermediate 41 (237 mg, 0.85 mmol), K2CO3 (197 mg, 1.42 mmol), X-Phos (54 mg, 0.11 mmol), and Pd2(dba)3 (52 mg, 0.06 mmol). The reaction mixture was stirred at 100 °C overnight. The reaction mixture was diluted with EtOAc and washed twice with a saturated solution of NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography (cyclohexane / EtOAc, 100 / 0 to 50 / 50) to give 200 mg of N-[(3,5-difluorophenyl)methyl]-2-methyl-3-[1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-4-yl]oxy-benzamide 320 as a white powder in 93% yield. ESI-MS: 548.10 (M+H) + .

[0476] N-[(3,5-difluorophenyl)methyl]-2-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzamide (321): TIFF2025539843000370.tif25170 Compound 321 was synthesized from intermediate 320 (0.49 mmol) and NaOH (2.46 mmol) according to general method B2 as a white solid in 87% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):11.74(bs,1H),9.02(t,J=6.0,1H),8.06(d,J=5.4,1H),7.39-7.32(m,3H),7.20( dd,J=6.7,2.6,1H),7.15-7.02(m,3H),6.26(d,J=5.4,1H),6.23(d,J=3.4,1H),4.47(d,J=6.0,2H),2.15(s,3H). ESI-MS: 394.05 (M+H) + .

[0477] Method V: To a stirred solution of intermediate 321 (30 mg, 0.08 mmol) in acetonitrile (0.15 mL) was added pyrazole (18 mg, 0.27 mmol), I (48 mg, 0.19 mmol), and a saturated aqueous solution of ammonium formate (0.15 mL). The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with EtOAc and washed with a saturated solution of NaSO. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography (DCM / MeOH, 100 / 0 to 94 / 6) and reverse-phase chromatography (HO / MeOH, 100 / 0 to 0 / 100) to give N-[(3,5-difluorophenyl)methyl]-2-methyl-3-[(2-pyrazol-1-yl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]benzamide 322 as a white powder in 11% yield. 1 H NMR(400MHz,DMSO-d6)δ(ppm):12.68(bs,1H),9.02(t,J=6.1,1H),8.47(d,J=2.4,1H),8.06(d,J=5.5,1H),7.81(d,J=1.5,1H),7.40-7.34 (m,2H),7.22(dd,J=6.9,2.4,1H),7.16-7.05(m,3H),6.59-6.58(m,1H),6.49(s,1H),6.31(d,J=5.5,1H),4.48(d,J=6.0,2H),2.18(s,3H). ESI-MS: 460.00 (M+H) + .

[0478] Example 17: Gen...

Claims

1. Compound (C) or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof, wherein said compound (C) is selected from the group consisting of formulas (I) to (VII): During the ceremony, -A's are each independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, and said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl, and said aralkyl are each independently selected from the group consisting of halo, NO ２ , C １－６ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF ３ , C.N., O.R. １１ , S.R. １１ , N(R １１ ) ２ , OC(R １１ ) ２ O, OC (R １１ ) ２ C (R １１ ) ２ O, S(O)R １２ , S.O. ２ R １２ , S.O. ２ N (R １１ ) ２ , S(O) ３ R １１ , P(=O)(OR １１ ) ２ , P(=O)(R １１ ) ２ NR １１ COR １２ , C.O.R. １１ , C(O)OR １１ , CON(R １１ ) ２ , O.C.(O.)R １１ , and OCON (R １１ ) ２ and wherein each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl substituent is independently selected from the group consisting of halo, NO ２ , C １－６ Alkyl, cycloalkyl, aryl, CF ３ , N(R １１ ) ２ , C.O.R. １１ , CON(R １１ ) ２ , O.C.(O.)R １１ , CN, or OR １１ and optionally further substituted with R １１ and R １２ Each of these, when occurring, independently of one another, is selected from the group consisting of hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF ３ wherein said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl and said aralkyl substituents are selected from the group consisting of halo, C １－６ Alkyl, cycloalkyl, heterocyclyl, C １－６ alkyl or aryl or heteroaryl amide, OR ３１ or N(R ３２ ) ２ and optionally substituted with R ３１ and R ３２ Each of, independently of the other, when occurring, is selected from hydrogen and C １－４ is selected from the group consisting of alkyl, -R ４ and R' ４ Each of, independently of the other, when occurring, is hydrogen or C １－６ alkyl, z is an integer ranging from 0 to 2, provided that when z=0, A and R ７ may together form a saturated or unsaturated cyclic moiety, -R ７ Each of these, when occurring, independently of one another, is selected from the group consisting of hydrogen, C １－６ alkyl, cycloalkyl, wherein the alkyl and cycloalkyl are selected from halogen atoms, CF ３ , N(R １１ ) ２ , CN, or OR １１ and optionally substituted with R １１ Each of these, when occurring, independently of one another, is selected from the group consisting of hydrogen, C １－６ Alkyl and CF ３ is selected from the group consisting of -R ３ Each of these, when occurring, independently of one another, is selected from hydrogen, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, CF ３ , C.N., O.R. ２１ , S.R. ２１ , N(R ２１ ) ２ , NC(O)R ２１ , NCON(R ２１ ) ２ , C.O.R. ２１ , C(O)OR ２１ , CON(R ２１ ) ２ , O.C.(O.)R ２１ , OCON (R ２１ ) ２、 OC (R ２１ ) ２ O, and OC(R ２１ ) ２ C (R ２２ ) ２ and wherein said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl and said aralkyl are selected from the group consisting of halo, C １－６ Alkyl, CF ３ , N(R ２１ ) ２ , CN, or OR ２１ and R ２１ and R ２２ Each of these, when occurring, independently of one another, is selected from the group consisting of hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl, wherein said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl and said aralkyl substituents are selected from the group consisting of halo, C １－６ Alkyl, cycloalkyl, heterocyclyl, aryl, OR ３１ or N(R ３２ ) ２ and optionally substituted with R ３１ and R ３２ Each of, independently of the other, when occurring, is selected from hydrogen and C １－４ alkyl, each r is an integer ranging from 0 to 3, with the proviso that R ３ =NR ２１ , and R ７ Under the condition that R = H, ３ and NR ７ may together form a saturated or unsaturated cyclic moiety, -R ２ Each of these, when occurring, independently of one another, is selected from hydrogen, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, CF ３ , C.N., N.O. ２ , OR ２１ , S.R. ２１ , N(R ２１ ) ２ , C.O.R. ２１ , C(O)OR ２１ , CON(R ２１ ) ２ , O.C.(O.)R ２１ , OCON (R ２１ ) ２ , NC(O)R ２１ , NCON(R ２１ ) ２ , OC(R ２１ ) ２ O and OC(R ２１ ) ２ C (R ２２ ) ２ and wherein said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocyclyl, said aryl and said heteroaryl are selected from the group consisting of halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, cycloalkyl, heterocyclyl, CF ３ , C.O.R. ２１ , CON(R ２１ ) ２ , C(O)OR ２１ , N(R ２１ ) ２ , CN, or OR ２１ and each optional alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituent may further be selected from heterocyclyl, N(R １１ ) ２ OR １１ and optionally substituted with R ２１ and R ２２ Each of, when occurring, independently of the other, is selected from hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl, wherein said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl and said aralkyl substituents are selected from the group consisting of halo, C １－６ Alkyl, cycloalkyl, heterocyclyl, aryl, OR ３１ or N(R ３２ ) ２ and optionally substituted with R ３１ and R ３２ Each of, independently of the other, when it occurs, is selected from hydrogen and C １－４ alkyl, each q is an integer ranging from 0 to 2; - each of x and y is independently an integer equal to 0 or 1; -R ８ But C ６－１２ Alkyl, C ２－６ Alkenyl, C ２－６ Independently selected from alkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl, and the heterocyclyl are selected from halogen atoms, aryl groups, aralkyl groups, CF ３ , N(R １１ ) ２ , CN, or OR １１ and R １１ Each of these, when occurring, independently of one another, is selected from the group consisting of hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF ３ wherein said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl and said aralkyl substituents are selected from the group consisting of halo, C １－６ alkyl, cycloalkyl, heterocyclyl, alkyl or aryl or heteroaryl amide, OR ３１ or N(R ３２ ) ２ and optionally substituted with R ３１ and R ３２ Each of, independently of the other, when occurring, is selected from hydrogen and C １－４ is selected from the group consisting of alkyl, -R ９ But hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, cycloalkyl, heterocyclyl, N(R １１ ) ２ and CN, wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl, and the heterocyclyl are selected from the group consisting of a halogen atom, an aryl group, an aralkyl group, a heterocyclyl group, CF ３ , N(R １１ ) ２ , CN, or OR １１ and R １１ Each of, when occurring, independently of the other, is selected from hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF ３ and C １－４ The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and heteroaryl optionally substituted with alkyl, aryl, heteroaryl, and aralkyl substituents are each independently selected from the group consisting of halo, C １－６ alkyl, cycloalkyl, heterocyclyl, alkyl or aryl or heteroaryl amide, OR ３１ or N(R ３２ ) ２ and optionally substituted with R ３１ and R ３２ Each of, independently of the other, when occurring, is selected from hydrogen and C １－４ alkyl, with the proviso that x=1 and y=0, R ９ is heterocyclyl and C １－６ R is an alkyl group that is optionally substituted with a heterocyclyl group, provided that x=0 and y=0. ９ is hydrogen and C １－６ The alkyl is different from heterocyclyl and N(R １１ ) ２ with the proviso that x=0 and y=0, R ９ and R ２ can together form a saturated or unsaturated cyclic moiety, provided that x=0 and y=0, R ９ and R ２ together form a saturated or unsaturated cyclic moiety, and R ９ But NR １１ where x=1 and y=1, R ９ is N(R １１ ) ２ However, under the condition that x=0, y=0 and z=0, R ９ Unlike pyrrole, -each T is independently a moiety of formula (Ta) During the ceremony, Each of -U, independently of the others, when it occurs, is selected from the group consisting of C, C-halo, C-R, and N, where R is a hydrogen optionally substituted with a halogen atom, an aryl group, or an aralkyl group, OR １１ , N(R １１ ) ２ , C １－６ alkyl or cycloalkyl; R １１ Each of, independently of the other, when occurring, is hydrogen or C １－４ alkyl, with the proviso that at least one U is different from N; Each of Z, independently of the others, when it occurs, is C(R) ２ , O, S and NR ７ and R, independently of each other when they occur, is selected from hydrogen or C optionally substituted with halogen atoms, aryl groups or aralkyl groups. １－６ alkyl, and R ７ But hydrogen, C １－６ Alkyl, C １－６ Alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF ３ is selected from the group consisting of -R ５ Each of, independently of the other, when occurring, is １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, CF ３ , OR １１ , S.R. １１ , N(R １１ ) ２ , COOR １１ , CO(R １１ ) ２ , CON(R １１ ) ２ and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent is selected from the group consisting of halo, C １－６ Alkyl, cycloalkyl, aryl, heterocyclyl, N(R １１ ) ２ , C.N., O.R. １１ , C(=O)OR １１ , P(=O)(OR １１ ) ２ , P(=O)(R １１ ) ２ , CN or CF ３ and optionally further substituted with R １１ Each of these, when occurring, independently of one another, is selected from the group consisting of hydrogen, C １－６ selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, and each n1 is an integer ranging from 0 to 2; -each X is independently a moiety of formula (Xa) During the ceremony, Each occurrence of -V is independently selected from the group consisting of C, C-halo, C-R, and N, where R is a hydrogen optionally substituted with a halogen atom, an aryl group, or an aralkyl group, OR １１ , N(R １１ ) ２ , C １－６ alkyl or cycloalkyl; R １１ Each of, independently of the other, when occurring, is hydrogen or C １－４ alkyl, -R ６ Each of, independently of the other, when occurring, is １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, CF ３ , OR １１ , S.R. １１ , N(R １１ ) ２ , COOR １１ , CO(R １１ ) ２ , CON(R １１ ) ２ and each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent is selected from the group consisting of halo, C １－６ Alkyl, cycloalkyl, aryl, heterocyclyl, N(R １１ ) ２ , C.N., O.R. １１ , C(=O)OR １１ , P(=O)(OR １１ ) ２ , P(=O)(R １１ ) ２ , CN or CF ３ and optionally further substituted with R １１ Each of these, when occurring, independently of one another, is selected from the group consisting of hydrogen, C １－６ selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, and each n2 is an integer ranging from 0 to 4; - the dashed bond represents an optional triple bond; -R ａ１ But hydrogen, C １－６ Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, CF ３ , C.N., O.R. １１ , S.R. １１ , N(R １１ ) ２ , C.O.R. １１ , C(O)OR １１ wherein said alkyl, said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl and said aralkyl are independently selected from the group consisting of halo, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, CF ３ , C.N., O.R. １１ , S.R. １１ , N(R １１ ) ２ , C.O.R. １１ and C(O)OR １１ and each optional alkyl, alkenyl, cycloalkyl, phenyl, heterocyclyl, heteroaryl substituent is optionally substituted by halo, NO ２ , C １－６ Alkyl, cycloalkyl, phenyl, N(R １１ ) ２ , CN or OR １１ and optionally further substituted with R １１ Each of １－６ selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl and aralkyl, wherein said alkyl, said cycloalkyl, said heterocyclyl, said phenyl, said heteroaryl and said aralkyl substituents are selected from the group consisting of halo, C １－６ optionally substituted with alkyl, cycloalkyl, or heterocyclyl; -R ａ２ Each of, when occurring, independently of the other, is selected from hydrogen, C １－６ Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, CF ３ , C.N., O.R. １１ , S.R. １１ , N(R １１ ) ２ , C.O.R. １１ , C(O)OR １１ wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, the heteroaryl and the aralkyl are selected from the group consisting of halo, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, CF ３ , C.N., O.R. １１ , S.R. １１ , N(R １１ ) ２ , C.O.R. １１ and C(O)OR １１ and each optional alkyl, alkenyl, cycloalkyl, phenyl, heterocyclyl, heteroaryl substituent is optionally substituted by halo, NO ２ , C １－６ Alkyl, cycloalkyl, phenyl, N(R １１ ) ２ , CN or OR １１ and optionally further substituted with R １１ Each of １－６ selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl and aralkyl, wherein said alkyl, said cycloalkyl, said heterocyclyl, said phenyl, said heteroaryl and said aralkyl substituents are selected from the group consisting of halo, C １－６ optionally substituted with alkyl, cycloalkyl, or heterocyclyl, and n3 is an integer equal to 0 or 1, with the proviso that when the dashed bond is a triple bond, then n3 is 0; Compound (C), or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer thereof, wherein said cycloalkyl is a monocyclic, bicyclic, or tricyclic ring system of 3 to 6 ring members per ring; said heterocyclyl is a saturated, partially saturated, or fully saturated monocyclic, bicyclic, or tricyclic ring containing 3 to 12 carbon atoms, one or two heteroatoms being independently selected from O or N; said aryl is phenyl, naphthyl, or anthracenyl optionally carbocyclically fused with a cycloalkyl or heterocyclyl of 5 to 7 ring members; and said heteroaryl is a monocyclic ring structure containing 5 to 6 ring atoms or a bicyclic aromatic group having 8 to 10 atoms and containing 1 to 3 heteroatoms independently selected from O or N.

2. x and y are as defined in claim 1; -A's are each independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, and said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl, and said aralkyl are each independently selected from the group consisting of halo, NO ２ , C １－６ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF ３ , C.N., O.R. １１ , S.R. １１ , N(R １１ ) ２ , OC(R １１ ) ２ O, OC (R １１ ) ２ C (R １１ ) ２ O, P(=O)(OR １１ ) ２ , P(=O)(R １１ ) ２ NR １１ COR １２ , C.O.R. １１ , C(O)OR １１ , CON(R １１ ) ２ , O.C.(O.)R １１ , and OCON (R １１ ) ２ and wherein each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl substituent is selected from the group consisting of halo, NO ２ , C １－６ Alkyl, cycloalkyl, aryl, CF ３ , N(R １１ ) ２ , CN, or OR １１ and optionally further substituted with R １１ and R １２ Each of, when occurring, independently of the other, is selected from hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF ３ wherein said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl and said aralkyl substituents are selected from the group consisting of halo, C １－６ optionally substituted with alkyl, cycloalkyl, or heterocyclyl; -R ４ and R' ４ Each of, independently of the other, when occurring, is hydrogen or C １－６ alkyl, z is an integer equal to 1; -R ７ Each of these, independently of the other, when it occurs, is hydrogen or a C group such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, etc. １－４ is alkyl, -R ３ Each of these, when occurring, independently of one another, is selected from hydrogen, halo, C １－６ Alkyl, cycloalkyl, heterocyclyl, CF ３ , C.N., O.R. ２１ and N(R ２１ ) ２ wherein said alkyl, said cycloalkyl and said heterocyclyl are selected from the group consisting of halo, C １－６ Alkyl, CF ３ , N(R ２１ ) ２ , CN or OR ２１ and R ２１ Each of, when occurring, independently of the other, is selected from hydrogen, C １－６ Alkyl, C ３－６ cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein said alkyl, said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl, and said aralkyl substituents are selected from the group consisting of halo, C １－６ optionally substituted with alkyl, cycloalkyl, heterocyclyl, or aryl, and each r is an integer equal to 0 or 1; -R ２ Each of these, when occurring, independently of one another, is selected from hydrogen, halo, C １－６ Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, CN, OR ２１ , and N(R ２１ ) ２ wherein said alkyl, said cycloalkyl, said heterocyclyl, said aryl and said heteroaryl are selected from the group consisting of halo, C １－６ Alkyl, cycloalkyl, N(R ２１ ) ２ , CN, or OR ２１ and R ２１ are, independently of one another, hydrogen, C １－６ selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl; -R ８が , C ６－１２ is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, wherein the alkyl, cycloalkyl, and heterocyclyl are selected from the group consisting of a halogen atom, CF ３ , N(R １１ ) ２ , CN, or OR １１ and R １１ Each of, independently of the other, when it occurs, is selected from hydrogen and C １－６ is selected from the group consisting of alkyl, -R ９ But hydrogen, C １－６ Alkyl, cycloalkyl, N(R １１ ) ２ and CN, wherein the alkyl and the cycloalkyl are selected from the group consisting of a halogen atom, CF ３ , CN, or OR １１ and R １１ Each of, when occurring, independently of the other, is selected from hydrogen, C １－６ Alkyl, C ２－６ Alkenyl and CF ３ wherein said alkyl and said alkenyl substituents are selected from the group consisting of: １－４ and optionally substituted with alkyl, heteroaryl, with the proviso that when x=0 and y=0, then R ９ is hydrogen and C １－６ The alkyl is different from heterocyclyl and N(R １１ ) ２ with the proviso that when x=0 and y=0, R ９ and R ２ may together form a saturated or unsaturated cyclic moiety, provided that when x=0 and y=0 and R ９ and R ２ together form a saturated or unsaturated cyclic moiety, R ９ But NR １１ where x=1 and y=1, then R ９ But N(R １１ ) ２ where x=0, y=0 and z=0, R ９ However, unlike pyrrole, -each T is independently a moiety of formula (Ta) During the ceremony, Each of -U, independently of the others, when it occurs, is selected from C, C-halo, C-R or N, where R is hydrogen or C １－４ alkyl with the proviso that at least one U is different from N, more preferably each of U, independently of one another, when occurring, is selected from C, C—R or N, where R is hydrogen or C １－４ alkyl, with the proviso that at least one U is different from N; Each of the Z's, independently of one another, when occurring, is preferably CH ２ and O, S and NR ７ and R ７ is hydrogen or a C group such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and isobutyl １－４ is alkyl, -R ５ Each of, independently of the other, when occurring, is preferably C １－６ Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, CF ３ , OR １１ , N(R １１ ) ２ , COOR １１ , CO(R １１ ) ２ , CON(R １１ ) ２ and each optional alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent is selected from the group consisting of halo, C １－６ Alkyl, cycloalkyl, aryl, heterocyclyl, N(R １１ ) ２ , C.N., O.R. １１ , C(=O)OR １１ , P(=O)(OR １１ ) ２ , P(=O)(R １１ ) ２ , CN or CF ３ and optionally further substituted with R １１ Each of these, when occurring, independently of one another, is selected from the group consisting of hydrogen, C １－６ selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, and each n1 is an integer equal to 1 or 2; Each of -X is independently a moiety of formula (Xa) below: During the ceremony, Each V, independently of the others, when it occurs, is selected from the group consisting of C, C-halo, C—R and N, where R is hydrogen or C １－４ is alkyl, -R ６ Each of, independently of the other, when occurring, is preferably C １－６ Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, CF ３ , OR １１ , N(R １１ ) ２ , COOR １１ , CO(R １１ ) ２ , CON(R １１ ) ２ and each optional alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent is selected from the group consisting of halo, C １－６ Alkyl, cycloalkyl, aryl, heterocyclyl, N(R １１ ) ２ , C.N., O.R. １１ , C(=O)OR １１ , P(=O)(OR １１ ) ２ , P(=O)(R １１ ) ２ , CN or CF ３ and optionally further substituted with R １１ Each of these, when occurring, independently of one another, is selected from the group consisting of hydrogen, C １－６ selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, and n2 is an integer equal to 0, 1, or 2; - the dashed bond represents an optional triple bond; -R ａ１ But C １－４ Independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein said alkyl, said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl, and said aralkyl are independently selected from the group consisting of halo, NO ２ , C １－４ Alkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, CF ３ , C.N., O.R. １１ , N(R １１ ) ２ and R １１ Each of is hydrogen or C １－４ is selected from the group consisting of alkyl, -R ａ２ But C １－４ Independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein said alkyl, said cycloalkyl, said heterocyclyl, said aryl, said heteroaryl, and said aralkyl are independently selected from the group consisting of halo, NO ２ , C １－４ Alkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, CF ３ , C.N., O.R. １１ , N(R １１ ) ２ and R １１ Each of is hydrogen or C １－４ is selected from the group consisting of alkyl, 2. The compound (C) of claim 1, wherein said cycloalkyl is a monocyclic, bicyclic, or tricyclic ring system of 3 to 6 ring members per ring; said heterocyclyl is a saturated, partially saturated, or fully saturated monocyclic, bicyclic, or tricyclic ring containing 3 to 12 carbon atoms, one or two heteroatoms being independently selected from O or N; said aryl is phenyl, naphthyl, or anthracenyl optionally carbocyclically fused with a cycloalkyl or heterocyclyl of 5 to 7 ring members; and said heteroaryl is a monocyclic ring structure containing 5 to 6 ring atoms or a bicyclic aromatic group having 8 to 10 atoms, containing one to three heteroatoms independently selected from O or N, or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer thereof.

3. The compound is of formula (II-a) or (II-b) [hereinafter referred to as compound (C) of class (II)], or of formula (III-a) [hereinafter referred to as compound (C) of class (III)], In the formula, A, R ４ , R ４ ', z, R ７ , R ３ , r, R ２ , q, R ９ and T is as defined in claim 1 or claim 2, or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof.

4. the compound is one of formulas (IV-a) to (IV-c) [hereinafter referred to as compound (C) of class (IV)] or one of formulas (VI-a) to (VI-c) [hereinafter referred to as compound (C) of class (VI)], In the formula, A, R ４ , R ４ ', z, R ７ , R ３ , r, R ２ 10. The compound (C) of formula (IV) or formula (VI) according to claim 1, wherein q, T and X are as defined in claim 1 or claim 2, or an N-oxide, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate or a stereoisomer thereof.

5. The compound is of formula (VII-a) or (VII-b) [hereinafter referred to as compound (C) of class (VII)], In the formula, A, R ４ , R ４ ', z, R ７ , R ３ , r, R ２ , q, R ａ１ , R ａ２ and n3 is as defined in claim 1 or claim 2, or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof.

6. The compound is of formula (II-a-1) or (II-b-1) or (II-c-1) [hereinafter referred to as compound (C) of class (II)], In the formula, A, R ４ , R ３ , R ２ and R ９ has the same meaning as defined above for formula (II), and R ３１ is C １－４ heteroaryl optionally substituted with alkyl; R １１ ' is hydrogen or C １－４ alkyl, and R ｂ is hydrogen, halo, C １－４ Alkyl and C １－６ cycloalkyl; 2. The compound (C) of formula (II) according to claim 1, wherein said heteroaryl is a monocyclic ring structure containing 5 to 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms and containing 1 to 3 heteroatoms independently selected from O or N, or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer thereof.

7. the compound is one of formulas (IV-a-1) to (IV-c-1) [hereinafter referred to as compound (C) of class (IV)] or one of formulas (VI-a-1) to (VI-c-1) [hereinafter referred to as compound (C) of class (VI)], In the formula, A, R ４、 R ３ , R ２ 10. The compound (C) of formula (IV) or (VI) according to claim 1, wherein T and X are as defined in claim 1 or claim 2, or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof.

8. The compound is of formula (VII-a-1) or (VII-b-1) [hereinafter referred to as compound (C) of class (VII)], In the formula, A, R ４、 R ３ , R ２ , R ａ１ , R ａ２ and n3 is as defined in claim 1 or claim 2, or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof.

9. The compound is of formula (II-a-2) or (II-b-2) or (II-c-2) [hereinafter referred to as compound (C) of class (II)], During the ceremony, -R ９ Each of the ' is a C such as hydrogen, CN and cyclopropyl. ３－６ cycloalkyl; -R ９ Each of １－４ C such as alkyl, CN and cyclopropyl ３－６ cycloalkyl; -R ２ are each independently selected from hydrogen or halo; -R ｑ Each of ３ , OCH ３ and halo, such as F or Cl; -R １０ Each of ３ , or CF ３ are independently selected from the group consisting of Each of the -U is C, C-R １０ and N, -n １０ is an integer equal to 0, 1 or 2, -R ３１ each of ' is selected from the group consisting of pyrazyl, N-methylpyrazyl, and pyridyl; -R ｂ ' is hydrogen, halo, C １－４ Alkyl and C １－４ cycloalkyl, preferably R ｂ ', Cl, CH ３ and cyclopropyl; - the dashed bond represents an optional double bond, or a compound (C) of formula (II) according to claim 1, or an N-oxide, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate or a stereoisomer thereof.

10. The compound is represented by 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) [hereinafter referred to as compound (C) of class (IV)], During the ceremony, -T, independently of each other, when it occurs, is selected from the moieties of the following formulae (Taa) to (Taf): During the ceremony, Each R' is independently hydrogen, C １－４ cycloalkyl selected from the group consisting of alkyl, cyclopropyl, and cyclobutyl; heterocyclyl selected from the group consisting of oxetanyl, tetrahydropyranyl, azetidinyl, and piperidinyl, wherein the alkyl is selected from the group consisting of F, OC １－４ Alkyl, P(=O)(OC １－４ alkyl) ２ , P(=O)(C １－４ alkyl) ２ , CN, cyclopropyl or cyclobutyl, wherein said heterocyclyl is C(═O)(OC １－４ alkyl), -R” ５ Each of １－４ Alkyl, CF ３ and cyclopropyl, - each n1, independently of the others, when occurring, is an integer equal to 0, 1 or 2; -R ２ are independently hydrogen, halo, or NH ２ and -R ｑ Each of ３ , OCH ３ and halo, such as F or Cl; -R １０ Each of １－４ Alkyl, CF ３ , O.C. １－４ independently selected from the group consisting of alkyl, CN; - each of U and V independently represents C, C-R １０ or N, -n １０ is an integer equal to 0, 1 or 2, or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof.

11. The compound is represented by formula (VI-a-2) to (VI-c-2) [hereinafter referred to as compound (C) of class (VI)], During the ceremony, -R” ６ Each of １－４ Alkyl, N(R ２１ ) ２ , OR ２１ , heterocyclyl selected from the group consisting of pyrrolidyl, piperidyl, morpholinyl, piperazyl, and pyrazyl; The heterocyclyl and the pyrazyl are C １－４ optionally substituted with alkyl, R ２１ is C １－４ is alkyl, -R ｑ Each of ３ , OCH ３ and halo, such as F or Cl; -R １０ Each of －４ independently selected from the group consisting of 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, -n ２ is an integer equal to 0, 1 or 2, or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof.

12. The compound is of formula (VII-a-2) [hereinafter referred to as compound (C) of class (VI)], In the formula, Ra' １ Benzyl, pyrazyl, OH, OC １－４ Alkyl, NH ２ , and NH(C １－４ alkyl), and R ｑ But H, CH ３ , OCH ３ and halo such as F or Cl, preferably R ｑ is H or CH ３ 2. The compound (C) of formula (VII) according to claim 1, which is: or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof.

13. 8. Compound (C) of formula (IV-a-1), (IV-b-1), (IV-c-1), (VI-a-1), (VI-b-1) or (VI-c-2) according to claim 7, wherein the compound of formula (IV-a-1), (IV-b-1), (IV-c-1), (VI-a-1), (VI-b-1) or (VI-c-2) is a compound according to the following formulas (XXXVII) to (CCLX):

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

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

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