Isoquinoline 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 relates to the fields of medicinal chemistry and pharmacology. [Background technology]

[0002] Protein phosphorylation is the most common form of reversible post-translational modification, with an estimated 50% of all proteins being phosphorylated. 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 transfers the phosphate of ATP to specific amino acid residues. They 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 use 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 often 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 diseases through constitutive activation of many downstream pathways, such as phosphatidylinositol 3-kinase / v-akt murine thymoma viral oncogene homolog 1 (PIK3 / AKT), mitogen-activated protein kinase / extracellular signal-regulated kinase (MAPK / ERK), and signal transducer and activator of transcription 5 (STAT5). As a result, protein kinases are important therapeutic targets.

[0004] In tumors, aberrant oncogenic activation of protein kinases stems 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. The signaling networks operating in cancer cells can also generate the most common or rare oncogenic mutations, which vary from tumor to tumor, contributing to innate or acquired resistance to treatment. 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 products derived (isolated) from sources such as plants, animals or microorganisms, or may be designed (synthetic) small molecules.

[0006] US Patent No. 5,949,999 discloses a class of biologically active compounds that interact with kinases, and the preparation of these compounds.

[0007] In oncology, there are currently several examples of small molecule kinase inhibitors with both selectivity and suitable pharmaceutical properties that have provided significant clinical benefit. For example, imatinib is used to inhibit BCR-ABL1 in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia with the Philadelphia chromosome; crizotinib and other ALK kinase inhibitors are used for cancers driven by ALK fusions; lapatinib for ERBB2 / HER2 amplified tumors; gefitinib and erlotinib for EGFR-mutated tumors; and vemurafenib for BRAF-mutated tumors.

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

[0009] In this sense, US Pat. No. 5,629,999 discloses adenosine compounds for use in the treatment of hypertension, cerebrovascular disease, heart disease or renal insufficiency.

[0010] Patent Document 3 discloses a composition that regulates cellular aging and is useful for treating Alzheimer's disease or atherosclerosis, the composition comprising an inhibitor of protein kinase A such as adenosine 3'5'-cyclin phosphorothioate.

[0011] Patent Document 4 discloses adenosine kinase inhibitor compounds 149-175, 413-431, and 241-266 for use in the treatment of cardiovascular and cerebrovascular diseases, inflammation, arthritis, and cancer.

[0012] US Pat. No. 5,629,499 discloses a method of cardioprotection by using partial or full agonists of the adenosine A1 receptor.

[0013] US Patent No. 6,213,999 discloses ligands of the C5a receptor for use in the treatment of diseases associated with metalloprotease activity, such as arthritis, cancer, cardiovascular disorders, skin disorders, inflammatory or allergic conditions.

[0014] US Patent No. 6,299,949 discloses compounds capable of inhibiting B-RAF and B-RAF mutations, and methods for treating diseases associated with B-RAF and B-RAF mutation regulation.

[0015] Patent document 8 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, and receptor tyrosine kinase (RTK) activity such as FGFR, Tie, VEGFR and / or Eph activity, for example FGFR-1, FGFR-2, FGFR-3, Tie2, VEGFR-2 and / or EphB2 activity in cells in vitro or in vivo.

[0016] Patent document 9 describes therapeutic compounds for treating proliferative disorders, cancer, and the like, more specifically pyrido[2,3-b]pyrazine-8 substituted compounds, which, inter alia, inhibit RAF (e.g., B-RAF) activity and inhibit receptor tyrosine kinase (RTK) activity.

[0017] Non-Patent Document 1 reviews small molecule VEGFR inhibitors.

[0018] Patent Document 10 discloses novel kinase inhibitors, pharmaceutical compositions, and uses and methods for preventing or treating cell proliferative disorders and / or disorders associated with FLT3 and c-Kit. This document also discloses uses and methods for preventing or treating disorders responsive to FLT3 kinase inhibition. [Prior art documents] [Patent documents]

[0019] [Patent Document 1] International Publication No. 2004 / 022572 Pamphlet [Patent Document 2] European Patent No. 0269574 [Patent Document 3] International Publication No. 2003 / 104482 Pamphlet [Patent Document 4] International Publication No. 1996 / 040705 Pamphlet [Patent Document 5] International Publication No. 2001 / 040245 Pamphlet [Patent Document 6] International Publication No. 2005 / 117882 Pamphlet [Patent Document 7] International Publication No. 2011 / 090738 Brochure [Patent Document 8] US Patent Application Publication No. 2009 / 0325945 [Patent Document 9] US Patent Application Publication No. 2015 / 0182526 [Patent Document 10] International Publication No. 2017 / 049462 Brochure [Non-patent literature]

[0020] [Non-Patent Document 1] J. Zhang et Al.(Mini-Reviews in Medicinal Chemistry,2011,11,920-946) Summary of the Invention [Problem to be solved by the invention]

[0021] However, despite increasing efforts to develop new protein kinase inhibitor-based therapies, there is still a need for protein kinase inhibitors that can overcome the shortcomings of current protein kinase treatments, such as side effects, limited efficacy, the emergence of resistance, and poor compliance.

[0022] The inventors have surprisingly found that the use of protein kinase inhibitors according to the present invention makes it possible to provide improved treatments for dysregulated protein kinase-associated diseases by developing treatments that are more effective, have reduced side effects, limit the emergence of resistance and facilitate compliance. [Means for solving the problem]

[0023] Accordingly, the present invention provides a compound of general formula (Ia) [hereinafter Compound (C)], or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof, suitable for use as a kinase inhibitor: [ka]

[0024] During the ceremony, -A is hydrogen, C 1-15 Alkyl, C 2-15 Alkenyl, C2-15 Independently selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl are optionally selected from halo, NO, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF, 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, SO2NR 11 COR 12 , SO2NR 11 CO2R 12 , SO2NR 11 CON(R 11 )2, NR 11 COR 12 , N.R. 11 CO2R 12 , N.R. 11 CON(R 11 )2, NR 11 C(NR 11 )NHR 11 , C.O.R. 11 , C(O)OR 11 , CON(R 11 )2, CONR 11 SO2R 12 , N.R. 11 SO2R 12 , SO2NR 11 CO2R 12 , OCONR 11 SO2R 12 ,OC(O)R 11 , C(O)OCH2OC(O)R 11 , and OCON(R 11)2, each optional alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, heteroaryl substituent optionally being substituted with one or more substituents independently selected from the group consisting of halo, NO2, alkyl, cycloalkyl, aryl, CF3, N(R 11 ) 2, alkyl or aryl or heteroaryl amide, NR 11 COR 12 , N.R. 11 SO2R 12 , C.O.R. 11 , CON(R 11 )2, NR 11 CON(R 11 )2, OC(O)R 11 , OC(O)N(R 11 )2, S(O)3R 11 , P(O)(OR 11 )2, SR 11 , S(O)R 12 , SO2R 12 , SO2N(R 11 )2, CN, or OR 11 wherein R 11 and R 12 are each, independently of one another, a hydrogen, a C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 and CF3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF3 substituents are optionally selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2 (wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}. - X and V are each, independently of one another and at each occurrence, selected from O, S or NR7, where R7 is hydrogen, C1-12 Alkyl, C 2-12 Alkenyl, C 2-12 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl; 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are optionally substituted with halogen atoms, aryl groups, aralkyl groups, CF, N(R 11 )2, CN or OR 11 where R 11 are each, independently of one another, a hydrogen, a C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 and CF3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF3 substituents are optionally selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2 (wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl))};t is equal to 0 or 1; -Z is each O, S, NR8, where R8 is hydrogen, optionally substituted with a halogen atom, an aryl group, or an aralkyl group. 1-12 selected from alkyl); -W, each selected from C-halo, CR, N, O, S, or NR7, where R is hydrogen, OR 11 , N(R 11 )2, optionally substituted with halogen atoms, aryl groups or aralkyl groups 1-10 alkyl or cycloalkyl, wherein each R 11are each, independently of one another, and at each occurrence, hydrogen or C 1-4 alkyl); wherein R7 is hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl; 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl optionally contain a halogen atom, an aryl or aralkyl group, OR 31 or N(R 32 )2 (wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; -l is equal to 0 or 1, respectively; R1 and R2 are each, independently of each other and at each occurrence, hydrogen, halo, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 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 )O and OC(R 21 )2C(R 22 )2O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of halo, C 1-15 Alkyl, CF3, N(R 21)2, CN, or OR 21 and is substituted with one or more substituents selected from the group consisting of 21 and R 22 are each, independently of one another, a hydrogen, a C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 and selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, aryl, OR 31 or N(R 32 )2, wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; each p is an integer ranging from 0 to 4; each q is an integer ranging from 0 to 2; - R3 each independently of the other and at each occurrence is selected from hydrogen, halo, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, CF3, CN, NO2, 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of halo, C 1-15 Alkyl, CF3, N(R 21)2, CN, or OR 21 and is substituted with one or more substituents selected from the group consisting of 21 and R 22 are each, independently of one another, a hydrogen, a C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 and selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, aryl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; each r is an integer ranging from 0 to 3; provided that R3 = NR 21 , when V=NH, and t=1, in which case R3 and V together may form a saturated or unsaturated cyclic moiety; -R4 and R ´ Each 4, independently of one another and at each occurrence, is hydrogen, CF3, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 alkynyl, cycloalkyl, and heterocyclyl; 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl and heterocyclyl are optionally substituted with halogen atoms, aryl groups, aralkyl groups, OR 13 , S.R. 13 , N(R 13 )2, CF3 or CN, where each R 13 are each, independently of one another and at each occurrence, a hydrogen atom, optionally a halogen atom, an aryl group, an aralkyl group, OR 31 or N(R 32 )2 is substituted with C 1-12Alkyl, C 2-12 Alkenyl, C 2-12 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or aralkyl, wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; x is an integer ranging from 0 to 7, provided that when x=0 and V=NR7, then A and R7 together may form a saturated or unsaturated cyclic moiety.

[0025] The present invention further relates to a pharmaceutical composition comprising a carrier and, as an active ingredient, an effective amount of a compound defined in any one of the embodiments presented herein.

[0026] The present invention relates to a compound as defined in any one of the embodiments presented herein for use as a medicament.

[0027] 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 cancer, metabolic disorders (such as diabetes), inflammatory and autoimmune disorders (e.g., inflammatory bowel diseases, e.g., Crohn's disease and ulcerative colitis, inflammatory lung diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, and psoriasis and psoriatic arthritis), neurological disorders (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth neuropathy, amyotrophic lateral sclerosis, and epilepsy), atherosclerosis and cardiovascular disease, Sjogren's syndrome, renal allograft rejection, virally induced diseases, circulatory diseases, osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, ophthalmic diseases (such as retinopathy, age-related macular degeneration, and uveitis), chronic and neuropathic pain, and fibroproliferative diseases.

[0028] 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.

[0029] The present invention further relates to a method of inhibiting protein kinase activity in a warm-blooded animal, comprising administering to an animal in need thereof an effective kinase-inhibiting amount of a compound according to any one of the embodiments presented herein.

[0030] The present invention further provides a method for the treatment of various diseases in warm-blooded animals, including cancer, metabolic disorders (such as diabetes), inflammatory and autoimmune disorders (e.g., inflammatory bowel disease, e.g., Crohn's disease and ulcerative colitis, inflammatory lung disease, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, and psoriasis and psoriatic arthritis), neurological disorders (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth neuropathy, amyotrophic lateral sclerosis, and epilepsy), atherosclerosis and cardiovascular disease, Sjogren's syndrome, and the like. The present invention relates to a method for treating a disease selected from the group consisting of renal allograft rejection, virally induced diseases, circulatory diseases, osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, ophthalmic diseases (such as retinopathy, age-related macular degeneration and uveitis), chronic and neuropathic pain, and fibroproliferative diseases, comprising administering to an animal in need thereof an effective amount of a compound according to any one of the embodiments presented herein. DETAILED DESCRIPTION OF THE INVENTION

[0031] A first aspect of the present invention relates to a compound of general formula (I'a) [hereinafter compound (C)], or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof, suitable for use as a kinase inhibitor: [ka]

[0032] During the ceremony, -A is hydrogen, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15Independently selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl are optionally selected from halo, NO, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF, 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, SO2NR 11 COR 12 , SO2NR 11 CO2R 12 , SO2NR 11 CON(R 11 )2, NR 11 COR 12 , N.R. 11 CO2R 12 , N.R. 11 CON(R 11 )2, NR 11 C(NR 11 )NHR 11 , C.O.R. 11 , C(O)OR 11 , CON(R 11 )2, CONR 11 SO2R 12 , N.R. 11 SO2R 12 , SO2NR 11 CO2R 12 , OCONR 11 SO2R 12 ,OC(O)R 11 , C(O)OCH2OC(O)R 11 , and OCON(R 11)2, each optional alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, heteroaryl substituent optionally being substituted with one or more substituents independently selected from the group consisting of halo, NO2, alkyl, cycloalkyl, aryl, CF3, N(R 11 ) 2, alkyl or aryl or heteroaryl amide, NR 11 COR 12 , N.R. 11 SO2R 12 , C.O.R. 11 , CON(R 11 )2, NR 11 CON(R 11 )2, OC(O)R 11 , OC(O)N(R 11 )2, S(O)3R 11 , P(O)(OR 11 )2, SR 11 , S(O)R 12 , SO2R 12 , SO2N(R 11 )2, CN, or OR 11 wherein R 11 and R 12 are each, independently of one another, a hydrogen, a C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 and CF3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF3 substituents are optionally selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2 (wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}. - X and V are each, independently of one another and at each occurrence, selected from O, S or NR7, where R7 is hydrogen, C1-12 Alkyl, C 2-12 Alkenyl, C 2-12 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl; 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are optionally substituted with halogen atoms, aryl groups, aralkyl groups, CF, N(R 11 )2, CN or OR 11 where R 11 are each, independently of one another, a hydrogen, a C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 and CF3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF3 substituents are optionally selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2 (wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl))};t is equal to 0 or 1; -Z is each O, S, NR8, where R8 is hydrogen, optionally substituted with a halogen atom, an aryl group, or an aralkyl group. 1-12 selected from alkyl); -W, each selected from C-halo, CR, N, O, S, or NR7, where R is hydrogen, OR 11 , N(R 11 )2, optionally substituted with halogen atoms, aryl groups or aralkyl groups 1-10 alkyl or cycloalkyl, wherein each R 11are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl); wherein R7 is hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl; 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl optionally contain a halogen atom, an aryl or aralkyl group, OR 31 or N(R 32 )2 (wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; -l is equal to 0 or 1, respectively; R1 and R2 are each, independently of each other and at each occurrence, hydrogen, halo, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 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 )O and OC(R 21 )2C(R 22 )2O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of halo, C 1-15 Alkyl, CF3, N(R 21)2, CN, or OR 21 and is substituted with one or more substituents selected from the group consisting of 21 and R 22 are each, independently of one another, a hydrogen, a C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 and selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, aryl, OR 31 or N(R 32 )2, wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; each p is an integer ranging from 0 to 4; each q is an integer ranging from 0 to 2; - R3 each independently of the other and at each occurrence is hydrogen, halo, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, CF3, CN, NO2, 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 )O and OC(R 21 )2C(R 22 )2O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of halo, C 1-15 Alkyl, CF3, N(R 21)2, CN, or OR 21 and is substituted with one or more substituents selected from the group consisting of 21 and R 22 are each, independently of one another, a hydrogen, a C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 and selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, aryl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; each r is an integer ranging from 0 to 3; provided that R3 = NR 21 , when V=NH, and t=1, in which case R3 and V together may form a saturated or unsaturated cyclic moiety; -R4 and R ´ Each 4, independently of one another and at each occurrence, is hydrogen, CF3, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 alkynyl, cycloalkyl, and heterocyclyl; 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl and heterocyclyl are optionally substituted with halogen atoms, aryl groups, aralkyl groups, OR 13 , S.R. 13 , N(R 13 )2, CF3 or CN, where each R 13 are each, independently of one another and at each occurrence, a hydrogen atom, optionally a halogen atom, an aryl group, an aralkyl group, OR 31 or N(R 32 )2 is substituted with C 1-12Alkyl, C 2-12 Alkenyl, C 2-12 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or aralkyl, wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; x is an integer ranging from 0 to 7, provided that when x=0 and V=NR7, then A and R7 together may form a saturated or unsaturated cyclic moiety.

[0033] A second aspect of the present invention relates to a compound of general formula (Ia) [hereinafter Compound (C)], or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof, suitable for use as a kinase inhibitor: [ka]

[0034] During the ceremony, -A is C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Independently selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl are optionally selected from halo, NO, C 1-6 Alkyl, C 2-5 Alkenyl, 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, SO2NR 11 COR 12 , SO2NR11 CO2R 12 , SO2NR 11 CON(R 11 )2, NR 11 COR 12 , N.R. 11 CO2R 12 , N.R. 11 CON(R 11 )2, NR 11 C(NR 11 )NHR 11 , C.O.R. 11 , C(O)OR 11 , CON(R 11 )2, CONR 11 SO2R 12 , N.R. 11 SO2R 12 , SO2NR 11 CO2R 12 , OCONR 11 SO2R 12 ,OC(O)R 11 , C(O)OCH2OC(O)R 11 , and OCON(R 11 and each optional alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, heteroaryl substituent is optionally substituted with one or more substituents independently selected from the group consisting of halo, NO, C 1-6 Alkyl, cycloalkyl, aryl, CF3, N(R 11 ) 2, alkyl or aryl or heteroaryl amide, NR 11 COR 12 , N.R. 11 SO2R 12 , C.O.R. 11 , CON(R 11 )2, NR 11 CON(R 11 )2, OC(O)R 11 , OC(O)N(R 11 )2, S(O)R 12 , SO2R 12 , SO2N(R 11 )2, CN, or OR 11 wherein R 11 and R 12 are each, independently of one another, a hydrogen, a C1-6 Alkyl, C 2-5 Alkenyl, C 2-5 and CF3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF3 substituents are optionally selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2 (wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}. -R7 is each hydrogen or C 1-6 is alkyl; R1 and R2 are each, independently of each other and at each occurrence, hydrogen, halo, C 1-6 Alkyl, C 2-5 Alkenyl, C 2-5 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 )O and OC(R 21 )2C(R 22 )2O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of halo, C 1-6 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, cycloalkyl, heterocyclyl, CF3, COR 21, CON(R 21 )2, C(O)OR 21 , N(R 21 )2, CN, and OR 21 and each optional alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituent is optionally substituted with one or more substituents selected from heterocyclyl, N(R 11 )2 OR 11 and further substituted with {wherein R 21 and R 22 are each, independently of one another, a hydrogen, a C 1-6 Alkyl, C 2-5 Alkenyl, C 2-5 selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl substituents are optionally selected from halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, OR 31 or N(R 32 )2, wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; each p is an integer ranging from 0 to 4; each q is an integer ranging from 0 to 2; - R3 each independently of the other and at each occurrence is selected from hydrogen, halo, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, 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 )O and OC(R 21 )2C(R 22 )2O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally selected from the group consisting of halo, C 1-15 Alkyl, CF3, N(R 21 )2, CN, or OR 21 and is substituted with one or more substituents selected from the group consisting of 21 and R 22 are each, independently of one another, a hydrogen, a C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 and selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, aryl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; each r is an integer ranging from 0 to 3; provided that R3 = NR 21 and when R7 = H, then R3 and NR7 together may form a saturated or unsaturated cyclic moiety; -R4 and R ´ Each 4, independently of one another and at each occurrence, is hydrogen, CF3, C 1-6 Alkyl, C 2-5 Alkenyl, C 2-5 and selected from the group consisting of alkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally substituted with halogen atoms, aryl groups, aralkyl groups, OR 13 , S.R. 13 , N(R 13 )2, CF3 or CN, where R13 are each independently a hydrogen atom, optionally a halogen atom, an aryl group, an aralkyl group, OR 31 or N(R 32 )2 is substituted with C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or aralkyl, wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; x is an integer ranging from 0 to 7, provided that when x=0, A and R7 together may form a saturated or unsaturated cyclic moiety; The cycloalkyl is a monocyclic, bicyclic, or tricyclic ring system of 3 to 7 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 and 1 or 2 heteroatoms independently selected from O or N; the aryl is a phenyl, naphthyl, or anthracenyl optionally carbocyclically fused to a cycloalkyl or heterocyclyl of 5 to 7 ring members; and the heteroaryl is a monocyclic ring structure containing 5 or 6 ring atoms, including 1 to 3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

[0035] According to one embodiment of the present invention, compound (C) is preferably a compound of general formula (Ia) [hereinafter compound (C)], or an N-oxide, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate or a stereoisomer thereof:

[0036] During the ceremony, -A's are each independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl, and the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from halo, NO, C 1-6 Alkyl, C 2-5Alkenyl, C 2-5 Alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COR 11 , C(O)OR 11 , SO2N(R 11 )2, and CON(R 11 and each optional alkyl, alkenyl, cycloalkyl, phenyl, heterocyclyl, heteroaryl substituent is optionally substituted with one or more substituents independently selected from the group consisting of halo, NO, C 1-6 Alkyl, cycloalkyl, phenyl, N(R 11 )2, CN, or OR 11 wherein R 11 are hydrogen and C 1-6 selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, and aralkyl, wherein the alkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, and aralkyl substituents are optionally selected from halo, C 1-6 substituted with alkyl, cycloalkyl, or heterocyclyl). -R7 is each hydrogen or C 1-6 is alkyl, R1 and R2 are each, independently of each other and at each occurrence, hydrogen, halo, C 1-6 Alkyl, C 2-5 Alkenyl, C 2-5 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 )O and OC(R 21 )2C(R 22 )2O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, CF3, COR 21 , N(R 21 )2, CN, CONR 21 , C(O)OR 21 , and OR 21 and each optional alkyl substituent is optionally substituted with one or more substituents selected from heterocyclyl, N(R 11 )2 OR 11 wherein R 21 and R 22 are each, independently of one another, a hydrogen, a C 1-6 Alkyl, C 2-5 Alkenyl, C 2-5 and selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, and aralkyl substituents are optionally selected from halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, phenyl, OR 31 or N(R 32 )2, wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; each p is an integer ranging from 0 to 4; each q is an integer ranging from 0 to 2; - R3 each independently of the other and at each occurrence is hydrogen, halo, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, CF3, CN, OR21 , 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 the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally selected from the group consisting of halo, C 1-15 Alkyl, CF3, N(R 21 )2, CN, or OR 21 and is substituted with one or more substituents selected from the group consisting of 21 and R 22 are each, independently of one another, a hydrogen, a C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 and selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, aryl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; each r is an integer ranging from 0 to 3; provided that R3 = NR 21 , when R7=H, then R3 and NR7 together may form a saturated or unsaturated cyclic moiety; -R4 and R ´ Each 4, independently of one another and at each occurrence, is hydrogen, C 1-6 Alkyl, and C 2-6alkenyl, wherein C 1-6 Alkyl, and C 2-6 alkenyl is optionally substituted with a halogen atom; x is an integer ranging from 0 to 7, provided that when x=0, A and R7 together may form a saturated or unsaturated cyclic moiety; The cycloalkyl is a monocyclic, bicyclic, or tricyclic ring system of 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 and 1 or 2 heteroatoms independently selected from O or N; the aryl is a phenyl, naphthyl, or anthracenyl optionally carbocyclically fused to a cycloalkyl or heterocyclyl of 5 to 7 ring members; and the heteroaryl is a monocyclic ring structure containing 5 or 6 ring atoms, including 1 to 3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

[0037] In a preferred embodiment of the present invention, A is C 1-10 Independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl are optionally selected from halo, NO, C 1-6 Alkyl, C 2-5 Alkenyl, 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, COR 11 , C(O)OR 11 , and CON(R 11 and each optional alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, heteroaryl substituent is optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6Alkyl, cycloalkyl, aryl, N(R 11 )2, CN, or OR 11 wherein R 11 are each, independently of one another, a hydrogen, a C 1-6 More preferably, A is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally substituted with halo, alkyl, cycloalkyl, or heterocyclyl. 1-6 independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl are optionally selected from the group consisting of halo, OR 11 , C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, SR 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COR 11 , C(O)OR 11 , and CON(R 11 )2, wherein R 11 are each, independently of one another, a hydrogen, a C 1-4 Most preferably, A is independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of halo, OC 1-4 Alkyl 、 C 1-4 Alkyl 、 Cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, OCH2O, OCH2CH2O, COR 11, COOR 11 , and CON(R 11 )2, wherein R 11 are each, independently of one another, a hydrogen, a C 1-4 In one embodiment of compound (C) according to the present invention, A in compound (C) of general formula (Ia) or (I'a) is independently selected from the following moieties: [ka] wherein each Halo is F, Cl, Br, Br, or I, and each R is hydrogen and C 1-4 alkyl, preferably R is hydrogen, methyl, ethyl, 2-methylpropyl or tert-butyl).

[0038] In a preferred embodiment of the compound (C) according to the present invention, X in the compound (C) of general formula (I'a) is independently selected from O or NR7, where R7 is hydrogen or C 1-6 It is selected from alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, etc., and preferably X is O in the compound (C) of general formula (Ia).

[0039] In a preferred embodiment of the compound (C) according to the present invention, Y in the compound (C) of general formula (I'a) is NR7, where R7 is hydrogen or C 1-6 It is selected from alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, etc., and preferably Y in compound (C) of general formula (Ia) is NR7 (wherein R7 is hydrogen or methyl).

[0040] In a preferred embodiment of the compound (C) according to the present invention, V in the compound (C) of general formula (I'a) is independently selected from O or NR7, where R7 is hydrogen or C 1-6 alkyl, preferably V in the compound (C) of general formula (I'a) is NR7, where R7 is hydrogen or C 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, etc.), more preferably Y in compound (C) of general formula (I'a) is NR7 (wherein R7 is hydrogen or methyl).

[0041] In a preferred embodiment of the compound (C) according to the present invention, R7 in the compound (C) of general formula (Ia) is hydrogen or C 1-4 Preferably R7 is selected from alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, etc., more preferably R7 is hydrogen or methyl.

[0042] In a preferred embodiment of compound (C) according to the present invention, Z in compound (C) of general formula (I'a) is independently selected from O or S, preferably Z in compound (C) of general formula (Ia) is O.

[0043] In a preferred embodiment of the present invention, W in the compound (C) of the general formula (I'a) is C.

[0044] In a preferred embodiment of the present invention, R1 in the compound (C) of the general formula (I'a), independently of one another and at each occurrence, is selected from the group consisting of halo, C 1-10 Alkyl, C 1-10 Cycloalkyl, aryl, heterocyclyl, heteroaryl, CF3, CN, OR 21 , and N(R 21 )2, wherein the alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl groups are optionally selected from the group consisting of halo, C 1-10 Alkyl, C 1-10 Cycloalkyl, CF3, N(R 21 )2, CN, and OR 21and further substituted with one or more substituents selected from the group consisting of 21 are each, independently of one another, a hydrogen, a C 1-10 Alkyl, C 1-10 and R is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and aralkyl, wherein the alkyl, heterocyclyl, aryl, and aralkyl substituents are optionally substituted with halo, alkyl, cycloalkyl, heterocyclyl, or aryl; preferably, R is selected from the group consisting of halo, C 1-4 Alkyl, cycloalkyl, heterocyclyl, OR 21 , and N(R 21 )2, wherein R 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, or C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; more preferably, R is Cl, Br, F, OMe, and N(R 21 )2, wherein R 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, or C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl).

[0045] In a preferred embodiment of the present invention, R1 in the compound (C) of the general formula (Ia) is, independently of one another and at each occurrence, hydrogen, halo, C 1-6 Alkyl, C 1-6 Cycloalkyl, aryl, heterocyclyl, heteroaryl, CF3, CN, OR 21 , N(R 21 )2, and CON(R 21 )2, wherein the alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl groups are optionally selected from the group consisting of halo, C1-6 Alkyl, C 1-6 Cycloalkyl, heterocyclyl, CF3, COR 21 , N(R 21 )2, CN and OR 21 and each optional alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituent is optionally selected from heterocyclyl, N(R 11 )2 OR 11 wherein R 21 are each, independently of one another, a hydrogen, a C 1-6 Alkyl, C 1-6 is selected from the group consisting of cycloalkyl, heterocyclyl, phenyl, and aralkyl, wherein the alkyl, heterocyclyl, phenyl, and aralkyl substituents are optionally selected from halo, C 1-6 substituted with alkyl, cycloalkyl, heterocyclyl, or phenyl); preferably, R is hydrogen, halo, C 1-4 Alkyl, cycloalkyl, heterocyclyl, heteroaryl, CN OR 21 , N(R 21 )2 and CON(R 21 )2, wherein the alkyl, cycloalkyl, heterocyclyl, and heteroaryl groups are optionally selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Cycloalkyl, heterocyclyl, CF3, COR 21 , N(R 21 )2, CN and OR 21 and each optional alkyl substituent is optionally further substituted with one or more substituents selected from heterocyclyl, N(R 11 )2 OR 11 wherein R 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, and optionally halo, C 3-6cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); more preferably, R1 is hydrogen, Cl, Br, F, heterocyclyl, heteroaryl, CF3, CN, OR 21 , N(R 21 )2 and CON(R 21 )2, wherein the heterocyclyl or heteroaryl group is optionally selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Cycloalkyl, heterocyclyl, CF3, COR 21 , N(R 21 )2, CN and OR 21 and each optional alkyl substituent is optionally further substituted with one or more substituents selected from heterocyclyl, N(R 11 )2 OR 11 wherein R 21 are each, independently of one another, a hydrogen, a C 1-4 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, and optionally halo, C 3-6 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl).

[0046] In a preferred embodiment of the present invention, R2 in the compound (C) of the general formula (Ia) or (I'a) is, independently of one another and at each occurrence, hydrogen, halo, C 1-10 Alkyl, C 1-10 Cycloalkyl, aryl, heterocyclyl, heteroaryl, CN, OR 21 , and N(R 21 )2, wherein the alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl groups are optionally selected from the group consisting of halo, C 1-10 Alkyl, C 1-10 Cycloalkyl, N(R 21 )2, CN, and OR 21 and further substituted with one or more substituents selected from the group consisting of 21are each, independently of one another, a hydrogen, a C 1-10 Alkyl, C 1-10 and R2 is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and aralkyl, wherein the alkyl, heterocyclyl, aryl, and aralkyl substituents are optionally substituted with halo, alkyl, cycloalkyl, heterocyclyl, or aryl; preferably, R2 is hydrogen, C 1-4 Alkyl, cycloalkyl, heterocyclyl, OR 21 , and N(R 21 )2, wherein R 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, or C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; more preferably, R2 is hydrogen and N(R 21 )2, wherein R 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, or C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl).

[0047] In a preferred embodiment of the present invention, R3 in the compound (C) of the general formula (Ia) or (I'a) is, independently of one another and at each occurrence, hydrogen, halo, C 1-10 Alkyl, C 1-10 Cycloalkyl, heterocyclyl, CF3, CN, OR 21 , and N(R 21 )2, wherein the alkyl, cycloalkyl, and heterocyclyl groups are optionally selected from the group consisting of halo, C 1-10 Alkyl, C 1-10 Cycloalkyl, CF3, N(R 21 )2, CN, and OR 21and further substituted with one or more substituents selected from the group consisting of 21 are each, independently of one another, a hydrogen, a C 1-10 Alkyl, C 1-10 and R is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and aralkyl, wherein the alkyl, heterocyclyl, aryl, and aralkyl substituents are optionally substituted with halo, alkyl, cycloalkyl, heterocyclyl, or aryl; preferably, R is selected from the group consisting of hydrogen, halo, C 1-4 Alkyl, cycloalkyl, heterocyclyl, OR 21 , and N(R 21 )2, wherein R 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, or C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; more preferably, R3 is hydrogen, Cl, Br, F, OMe, N(R 21 )2, and C 1-4 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, where R 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, or C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Even more preferably, R3 is independently selected from the group consisting of F, methyl, or OCH3.

[0048] In a preferred embodiment of the present invention, R4 in the compound (C) of the general formula (Ia) or (I'a) is hydrogen, C 1-6 Alkyl, and C 2-5and alkenyl, wherein the alkyl and alkenyl are optionally substituted with halogen atoms. More preferably, R4 is each independently of the other and at each occurrence selected from the group consisting of hydrogen and C 1-4 It is preferably selected from the group consisting of alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, etc. Even more preferably, R4 is hydrogen.

[0049] In a preferred embodiment of the present invention, R'4 in the compound (C) of the general formula (Ia) or (I'a) is hydrogen, C 1-6 Alkyl, and C 2-5 alkenyl, wherein the alkyl and alkenyl are optionally substituted with halogen atoms. More preferably, R'4 are each, independently of each other, selected at each occurrence from the group consisting of hydrogen and C 1-4 It is selected from the group consisting of alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, etc. Even more preferably, R'4 is hydrogen.

[0050] In a preferred embodiment of the present invention, p is an integer ranging from 0 to 2.

[0051] In a preferred embodiment of the present invention, q is an integer ranging from 0 to 1.

[0052] In a preferred embodiment of the present invention, r is an integer ranging from 0 to 2.

[0053] In a preferred embodiment of the present invention, t is an integer equal to one.

[0054] In a preferred embodiment of the present invention, l is an integer equal to one.

[0055] In a preferred embodiment of the present invention, x is an integer ranging from 0 to 4. More preferably, x is an integer equal to 0, 1 or 2. Even more preferably, x is an integer equal to 0 or 1. Even more preferably, x is an integer equal to 1.

[0056] It will be further understood that all preferred embodiments described above also apply to all further embodiments, as described below.

[0057] In one embodiment of the present invention, compound (C) according to general formula (Ia) or (Ia'), or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof, for use as a kinase inhibitor is used in the treatment of diseases mediated by protein kinases, such as 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), The protein kinase is selected from the group consisting of 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), RTK, SRC, SYK, and TEK (Tie2). Preferably, the protein kinase is selected from the group consisting of CSF1R, FLT3, Kit, PDGFRB (PDGFR beta), and PDGFRA (PDGFR alpha).

[0058] According to one embodiment of the present invention, compound (C), or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof, for use as a kinase inhibitor is preferably a compound selected from among formulae (IIa) to (IXa) [hereinafter referred to as compounds (C) of class (I)]: [ka] TIFF0007633702000006.tif39170

[0059] During the ceremony, R1, R2, R3, R 4、 R', p, q, r, x have the same meaning as above, and the dashed bond represents an optional double bond; -T is selected from CH, NR, O or S, where R is hydrogen, optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-10 alkyl or cycloalkyl); preferably, T is selected from CH2 or O; -U is each independently and at each occurrence selected from C-halo, CR, O, or N, where R is hydrogen, OR 11 , N(R 11 )2, optionally substituted with halogen atoms, aryl groups or aralkyl groups 1-10 alkyl or cycloalkyl, wherein R 11 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; preferably, U is independently and at each occurrence selected from C-halo, CR or N; preferably, R is hydrogen or C 1-4 alkyl, more preferably U is independently and at each occurrence selected from CR or N, more preferably R is hydrogen; -D is each independently and at each occurrence selected from C, CR, or N, where R is hydrogen, C 1-5alkyl or cycloalkyl); preferably, D is independently and at each occurrence selected from C, CR or N, and preferably, R is hydrogen; - m is an integer equal to 1 or 2; - n is an integer equal to 0 or 1; -R a1 are each, independently of one another, a hydrogen, a C 1-5 Alkyl, C 2-15 Alkenyl, and C 2-15 alkynyl, wherein C 1-5 Alkyl, C 2-15 Alkenyl, and C 2-15 The alkynyl is optionally substituted with a halogen atom, an aryl group, or an aralkyl group; each n1 is an integer ranging from 0 to 5, preferably R a1 is hydrogen or C 1-5 is alkyl; -R a2 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, NO2, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, CON(R 11 )2, and SO2N(R 11 )2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl substituent optionally being selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, aryl, N(R 11 )2, CF3, CN, COOR 11 , CO(R 11)2, CON(R 11 )2, SO2N(R 11 )2 OR 11 and further substituted with {wherein R 11 are each, independently of one another, a hydrogen, a C 1-6 selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; more preferably, R a2 are respectively, halo, OR 11 , C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, SR 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, and CON(R 11 )2, wherein R 11 are each, independently of one another, a hydrogen, a C 1-4 alkyl, cycloalkyl, and heterocyclyl); even more preferably, R a2 are respectively, Haro and OC 1-4 Alkyl, C 1-4 Alkyl 、 Cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, OCH2O, OCH2CH2O, COOH, COO(C 1-4 alkyl), CO(heterocyclyl), CO(C 1-4 alkyl), CONH(C1-4 n2 are each independently selected from the group consisting of CONH(cycloalkyl), CONH(alkyl), and CONH(cycloalkyl); n2 are each an integer ranging from 0 to 4; preferably, n2 are each an integer ranging from 0 to 2; - B is each, independently of one another, and at each occurrence, CR, O, N, S and NR 7´ wherein R is hydrogen or C optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-10 alkyl, and R 7´ is hydrogen, C 1-6 Alkyl, C 1-6 selected from the group consisting of alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF3; preferably, B is each, independently of one another and at each occurrence, selected from the group consisting of CR, O, and NR 7´ where R 7´ is hydrogen or C 1-4 alkyl, and R is hydrogen or C 1-4 (It is alkyl). -E is each, independently of one another, and at each occurrence, CR, O, N, S and NR 7´ wherein R is hydrogen or C optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-10 alkyl, and R 7´ is hydrogen, C 1-6 Alkyl, C 1-6 selected from the group consisting of alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF3; preferably, E is each, independently of the others, and at each occurrence, selected from the group consisting of CR, O, and NR 7´ wherein R 7´ is hydrogen or C 1-4 alkyl, and R is hydrogen or C 1-4 (It is alkyl). -R a4 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, NO2, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, and CON(R 11 )2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent optionally being selected from the group consisting of halo, alkyl, cycloalkyl, aryl, N(R 11 )2, CN, or OR 11 and further substituted with {wherein R 11 are each, independently of one another, a hydrogen, a C 1-6 and selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; more preferably, R a4 are respectively, halo, OR 11 , C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, SR 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, and CON(R 11 )2, wherein R11 are each, independently of one another and at each occurrence, hydrogen, and C 1-4 alkyl); even more preferably, R a4 are respectively, Haro and OC 1-4 Alkyl, C 1-4 Alkyl 、 n4 is independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, OCHO, and OCH2CH2O; each n4 is an integer ranging from 0 to 4; preferably, each n4 is an integer ranging from 0 to 2; -R a3 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, aralkyl, halo, CF3, OR 11 , S.R. 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, and CON(R 11 )2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent optionally being selected from the group consisting of halo, alkyl, cycloalkyl, aryl, N(R 11 )2, CN, or OR 11 Further selected by {wherein R 11 are each, independently of one another, a hydrogen, a C 1-6 and selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4alkyl)}; more preferably, R a3 are respectively, C 1-6 are independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; even more preferably, R a3 is C 1-4 alkyl, and each n3 is an integer ranging from 0 to 2. The cycloalkyl is a monocyclic, bicyclic, or tricyclic ring system of 3 to 7 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 and 1 or 2 heteroatoms independently selected from O or N; the aryl is a phenyl, naphthyl, or anthracenyl optionally carbocyclically fused to a cycloalkyl or heterocyclyl of 5 to 7 ring members; and the heteroaryl is a monocyclic ring structure containing 5 or 6 ring atoms, including 1 to 3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

[0060] In a preferred embodiment of the present invention, compound (C), or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof, for use as a kinase inhibitor is a compound of formula (IIa)-(IXa):

[0061] During the ceremony, R1 and R2 are each, independently of each other and at each occurrence, hydrogen, halo, C 1-6 Alkyl, C 2-5 Alkenyl, C 2-5 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, CF3, COR 21 , N(R 21 )2, CN, CONR 21 , C(O)OR 21 , and OR 21 and each optional alkyl substituent is optionally substituted with one or more substituents selected from heterocyclyl, N(R 11 )2 OR 11 wherein R 21 and R 22 are each, independently of one another, a hydrogen, a C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 and selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, and aralkyl substituents are optionally selected from halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, phenyl, OR 31 or N(R 32 )2, wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; each p is an integer ranging from 0 to 4; each q is an integer ranging from 0 to 2; - R3 each independently of the other and at each occurrence is hydrogen, halo, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, 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 )O and OC(R 21 )2C(R 22 )2O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally selected from the group consisting of halo, C 1-15 Alkyl, CF3, N(R 21 )2, CN, or OR 21 and is substituted with one or more substituents selected from the group consisting of 21 and R 22 are each, independently of one another, a hydrogen, a C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 and selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, aryl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; each r is an integer ranging from 0 to 3; provided that R3 = NR 21 , when R7=H, then R3 and NR7 together may form a saturated or unsaturated cyclic moiety; -R4 and R ´ Each 4, independently of one another and at each occurrence, is hydrogen, C 1-6 Alkyl, and C 2-6 alkenyl, wherein C 1-6Alkyl, and C 2-6 alkenyl is optionally substituted with a halogen atom; x is an integer ranging from 0 to 7, provided that when x=0, A and R7 together may form a saturated or unsaturated cyclic moiety; -T is selected from CH, NR, O or S, where R is hydrogen, optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-10 alkyl or cycloalkyl); preferably, T is selected from CH2 or O; -U is each independently and at each occurrence selected from C-halo, CR, O, or N, where R is hydrogen, OR 11 , N(R 11 )2, optionally substituted with halogen atoms, aryl groups or aralkyl groups 1-10 alkyl or cycloalkyl, wherein R 11 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; preferably, U is independently and at each occurrence selected from C-halo, CR or N; preferably, R is hydrogen or C 1-4 alkyl, more preferably U is independently and at each occurrence selected from CR or N, more preferably R is hydrogen; -D is each independently and at each occurrence selected from C, CR, or N, where R is hydrogen, C 1-5 alkyl or cycloalkyl); preferably, D is independently and at each occurrence selected from C, CR or N, and preferably, R is hydrogen; - m is an integer equal to 1 or 2; - n is an integer equal to 0 or 1; -R a1 are each, independently of one another, a hydrogen, a C 1-5 Alkyl, C 2-15Alkenyl, and C 2-15 alkynyl, wherein C 1-5 Alkyl, C 2-15 Alkenyl, and C 2-15 The alkynyl is optionally substituted with a halogen atom, an aryl group, or an aralkyl group; each n1 is an integer ranging from 0 to 5, preferably R a1 is hydrogen or C 1-5 is alkyl; -R a2 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, NO2, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, CON(R 11 )2, SO2N(R 11 )2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl substituent optionally being selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, aryl, N(R 11 )2, CF3, CN, COOR 11 , CO(R 11 )2, CON(R 11 )2, SO2N(R 11 )2 OR 11 wherein R 11 are each, independently of one another, a hydrogen, a C 1-6 selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, C 1-6Alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; more preferably, R a2 are respectively, halo, OR 11 , C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, SR 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, and CON(R 11 )2, wherein R 11 are each, independently of one another, a hydrogen, a C 1-4 alkyl, cycloalkyl, and heterocyclyl); even more preferably, R a2 are respectively, Haro and OC 1-4 Alkyl, C 1-4 Alkyl 、 Cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, OCH2O, OCH2CH2O, COOH, COO(C 1-4 alkyl), CO(heterocyclyl), CO(C 1-4 alkyl), CONH(C 1-4 n2 are each independently selected from the group consisting of CONH(cycloalkyl), CONH(alkyl), and CONH(cycloalkyl); n2 are each an integer ranging from 0 to 4; preferably, n2 are each an integer ranging from 0 to 2; - B is each, independently of one another, and at each occurrence, CR, O, N, S and NR 7´ wherein R is hydrogen or C optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-10 alkyl, and R 7´ is hydrogen, C1-6 Alkyl, C 1-6 selected from the group consisting of alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF3; preferably, B is each, independently of one another and at each occurrence, selected from the group consisting of CR, O, and NR 7´ where R 7´ is hydrogen or C 1-4 alkyl, and R is hydrogen or C 1-4 (It is alkyl). -E is, independently of one another and at each occurrence, CR, O, N, S and NR 7´ wherein R is hydrogen or C optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-10 alkyl, and R 7´ is hydrogen, C 1-6 Alkyl, C 1-6 selected from the group consisting of alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF3; preferably, E is each, independently of the others, and at each occurrence, selected from the group consisting of CR, O, and NR 7´ wherein R 7´ is hydrogen or C 1-4 alkyl, and R is hydrogen or C 1-4 (It is alkyl). -R a4 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, NO2, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, and CON(R 11)2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent optionally being selected from the group consisting of halo, alkyl, cycloalkyl, aryl, N(R 11 )2, CN, or OR 11 wherein R 11 are each, independently of one another, a hydrogen, a C 1-6 and selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; more preferably, R a4 are respectively, halo, OR 11 , C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, SR 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, and CON(R 11 )2, wherein R 11 are each, independently of one another and at each occurrence, hydrogen, and C 1-4 alkyl); even more preferably, R a4 are respectively, Haro and OC 1-4 Alkyl, C 1-4 Alkyl 、n4 is independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, OCHO, and OCH2CH2O; each n4 is an integer ranging from 0 to 4; preferably, each n4 is an integer ranging from 0 to 2; -R a3 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, aralkyl, halo, CF3, OR 11 , S.R. 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, and CON(R 11 )2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent optionally being selected from the group consisting of halo, alkyl, cycloalkyl, aryl, N(R 11 )2, CN, or OR 11 Further selected by {wherein R 11 are each, independently of one another, a hydrogen, a C 1-6 and selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; more preferably, R a3 are respectively, C 1-6 are independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; even more preferably, R a3 is C 1-4alkyl, and each n3 is an integer ranging from 0 to 2. The cycloalkyl is a monocyclic, bicyclic, or tricyclic ring system of 3 to 7 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 and 1 or 2 heteroatoms independently selected from O or N; the aryl is a phenyl, naphthyl, or anthracenyl optionally carbocyclically fused to a cycloalkyl or heterocyclyl of 5 to 7 ring members; and the heteroaryl is a monocyclic ring structure containing 5 or 6 ring atoms, including 1 to 3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

[0062] According to one embodiment of the present invention, compound (C) for use as a kinase inhibitor, or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof, is preferably a compound selected from formulae (IIa-a) to (IXa-a) [hereinafter referred to as compounds (C) of class (I)]: [ka] TIFF0007633702000008.tif34170

[0063] During the ceremony, R1, R2, R3, R4, R´4, R a1 , R a2 , R a3 , R a4 , T, U, B, E, D, p, q, r, x, n1, n2, n3, n4, m, and n have the same meanings as above for formulae (IIa) to (IXa), and the dashed bond represents an optional double bond; -p1 is an integer in the range of 0 to 3 -R'1 is selected from the group consisting of (R'1-a) to (R'1-d): [ka] During the ceremony, - X, Y and Z are each, independently of one another, CR, O, N, S and NR 7´ wherein R is hydrogen or C optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-6 alkyl, and R 7´ is hydrogen, C 1-6 Alkyl, C 1-6 alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF3; preferably, X, Y, and Z are each, independently of one another and at each occurrence, selected from the group consisting of CR, O, and NR 7´ where R 7´ is hydrogen or C 1-4 alkyl, and R is hydrogen or C 1-4 (It is alkyl). R b1 each independently and at each occurrence is hydrogen, halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, CN, COR 11 , CON(R 11 )2, and OR 11 wherein the alkyl, cycloalkyl, and heterocyclyl are optionally selected from the group consisting of heterocyclyl, OR 11 , N.R. 11 wherein R 11 are each, independently of one another and at each occurrence, hydrogen, halo, and C 1-6 alkyl); each p1 is an integer ranging from 0 to 3. The cycloalkyl is a monocyclic, bicyclic, or tricyclic ring system of 3 to 7 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 and 1 or 2 heteroatoms independently selected from O or N; the aryl is a phenyl, naphthyl, or anthracenyl optionally carbocyclically fused to a cycloalkyl or heterocyclyl of 5 to 7 ring members; and the heteroaryl is a monocyclic ring structure containing 5 or 6 ring atoms, including 1 to 3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

[0064] In a preferred embodiment of the present invention, compound (C), or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof, for use as a kinase inhibitor is a compound of formula (IIa-a) to (IXa-a):

[0065] During the ceremony, R1 and R2 are each, independently of each other and at each occurrence, hydrogen, halo, C 1-6 Alkyl, C 2-5 Alkenyl, C 2-5 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, CF3, COR21 , N(R 21 )2, CN, CONR 21 , C(O)OR 21 , and OR 21 and each optional alkyl substituent is optionally substituted with one or more substituents selected from heterocyclyl, N(R 11 )2 OR 11 wherein R 21 and R 22 are each, independently of one another, a hydrogen, a C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 and selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, and aralkyl substituents are optionally selected from halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, phenyl, OR 31 or N(R 32 )2, wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; each q is an integer ranging from 0 to 2; - R3 each independently of the other and at each occurrence is hydrogen, halo, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, 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 )O and OC(R 21 )2C(R22 )2O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally selected from the group consisting of halo, C 1-15 Alkyl, CF3, N(R 21 )2, CN, or OR 21 and is substituted with one or more substituents selected from the group consisting of 21 and R 22 are each, independently of one another, a hydrogen, a C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 and selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, aryl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; each r is an integer ranging from 0 to 3; provided that R3 = NR 21 , when R7=H, then R3 and NR7 together may form a saturated or unsaturated cyclic moiety; -R4 and R ´ Each 4, independently of one another and at each occurrence, is hydrogen, C 1-6 Alkyl, and C 2-6 alkenyl, wherein C 1-6 Alkyl, and C 2-6 alkenyl is optionally substituted with a halogen atom; x is an integer ranging from 0 to 7, provided that when x=0, A and R7 together may form a saturated or unsaturated cyclic moiety; -T is selected from CH, NR, O or S, where R is hydrogen, optionally substituted with a halogen atom, an aryl group or an aralkyl group;1-10 alkyl or cycloalkyl); preferably, T is selected from CH2 or O; -U is each independently and at each occurrence selected from C-halo, CR, O, or N, where R is hydrogen, OR 11 , N(R 11 )2, optionally substituted with halogen atoms, aryl groups or aralkyl groups 1-10 alkyl or cycloalkyl, wherein R 11 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; preferably, U is independently and at each occurrence selected from C-halo, CR or N; preferably, R is hydrogen or C 1-4 alkyl, more preferably U is independently and at each occurrence selected from CR or N, more preferably R is hydrogen; -D is each independently and at each occurrence selected from C, CR, or N, where R is hydrogen, C 1-5 alkyl or cycloalkyl); preferably, D is independently and at each occurrence selected from C, CR or N, and preferably, R is hydrogen; - m is an integer equal to 1 or 2; - n is an integer equal to 0 or 1; -R a1 are each, independently of one another, a hydrogen, a C 1-5 Alkyl, C 2-15 Alkenyl, and C 2-15 alkynyl, wherein C 1-5 Alkyl, C 2-15 Alkenyl, and C 2-15 The alkynyl is optionally substituted with a halogen atom, an aryl group, or an aralkyl group; each n1 is an integer ranging from 0 to 5, preferably R a1 is hydrogen or C 1-5 is alkyl; -R a2 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, NO2, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, CON(R 11 )2, and SO2N(R 11 )2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl substituent optionally being selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, aryl, N(R 11 )2, CF3, CN, COOR 11 , CO(R 11 )2, CON(R 11 )2, SO2N(R 11 )2 OR 11 wherein R 11 are each, independently of one another, a hydrogen, a C 1-6 selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; more preferably, R a2 are respectively, halo, OR 11 , C1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, SR 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, and CON(R 11 )2, wherein R 11 are each, independently of one another, a hydrogen, a C 1-4 alkyl, cycloalkyl, and heterocyclyl); even more preferably, R a2 are respectively, Haro and OC 1-4 Alkyl, C 1-4 Alkyl 、 Cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, OCH2O, OCH2CH2O, COOH, COO(C 1-4 alkyl), CO(heterocyclyl), CO(C 1-4 alkyl), CONH(C 1-4 n2 are each independently selected from the group consisting of CONH(cycloalkyl), CONH(alkyl), and CONH(cycloalkyl); n2 are each an integer ranging from 0 to 4; preferably, n2 are each an integer ranging from 0 to 2; - B is each, independently of one another, and at each occurrence, CR, O, N, S and NR 7´ wherein R is hydrogen or C optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-10 alkyl, and R 7´ is hydrogen, C 1-6 Alkyl, C 1-6 selected from the group consisting of alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF3; preferably, B is each, independently of one another and at each occurrence, selected from the group consisting of CR, O, and NR 7´ where R 7´ is hydrogen or C 1-4 alkyl, and R is hydrogen or C1-4 (It is alkyl). -E is, independently of one another and at each occurrence, CR, O, N, S and NR 7´ wherein R is hydrogen or C optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-10 alkyl, and R 7´ is hydrogen, C 1-6 Alkyl, C 1-6 selected from the group consisting of alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF3; preferably, E is each, independently of the others, and at each occurrence, selected from the group consisting of CR, O, and NR 7´ wherein R 7´ is hydrogen or C 1-4 alkyl, and R is hydrogen or C 1-4 (It is alkyl). -R a4 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, NO2, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, and CON(R 11 )2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent optionally being selected from the group consisting of halo, alkyl, cycloalkyl, aryl, N(R 11 )2, CN, or OR 11 and further substituted with {wherein R 11 are each, independently of one another, a hydrogen, a C 1-6and selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; more preferably, R a4 are respectively, halo, OR 11 , C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, SR 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, and CON(R 11 )2, wherein R 11 are each, independently of one another and at each occurrence, hydrogen, and C 1-4 alkyl); even more preferably, R a4 are respectively, Haro and OC 1-4 Alkyl, C 1-4 Alkyl 、 n4 is independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, OCHO, and OCH2CH2O; each n4 is an integer ranging from 0 to 4; preferably, each n4 is an integer ranging from 0 to 2; -R a3 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, aralkyl, halo, CF3, OR 11, S.R. 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, and CON(R 11 )2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent optionally being selected from the group consisting of halo, alkyl, cycloalkyl, aryl, N(R 11 )2, CN, or OR 11 Further selected by {wherein R 11 are each, independently of one another, a hydrogen, a C 1-6 and selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; more preferably, R a3 are respectively, C 1-6 are independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; even more preferably, R a3 is C 1-4 alkyl, and each n3 is an integer ranging from 0 to 2. - A dash bond represents an optional double bond -R'1 is selected from the group consisting of (R'1-a) to (R'1-d), [ka] During the ceremony, - X, Y and Z are each, independently of one another, CR, O, N, S and NR 7´wherein R is hydrogen or C optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-6 alkyl, and R 7´ is hydrogen, C 1-6 Alkyl, C 1-6 alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF3; preferably, X, Y, and Z are each, independently of one another and at each occurrence, selected from the group consisting of CR, O, and NR 7´ where R 7´ is hydrogen or C 1-4 alkyl, and R is hydrogen or C 1-4 (It is alkyl). -R b1 each independently and at each occurrence is hydrogen, halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, CN, COR 11 , CON(R 11 )2, and OR 11 wherein the alkyl, cycloalkyl, and heterocyclyl are optionally selected from the group consisting of heterocyclyl, OR 11 , N.R. 11 wherein R 11 are each, independently of one another and at each occurrence, hydrogen, halo, and C 1-6 alkyl); each p1 is an integer ranging from 0 to 3; The cycloalkyl is a monocyclic, bicyclic, or tricyclic ring system of 3 to 7 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 and 1 or 2 heteroatoms independently selected from O or N; the aryl is a phenyl, naphthyl, or anthracenyl optionally carbocyclically fused to a cycloalkyl or heterocyclyl of 5 to 7 ring members; and the heteroaryl is a monocyclic ring structure containing 5 or 6 ring atoms, including 1 to 3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

[0066] According to one embodiment of the present invention, compound (C), or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof, for use as a kinase inhibitor is preferably a compound selected from among formulae (IIb) to (IXb) [hereinafter referred to as compounds (C) of class (II)]: [ka] TIFF0007633702000012.tif34170 (In the formula, R1, R2, R3, R4, R´4, R a1 , R a2 , R a3 , R a4 , T, U, B, E, D, p, q, r, x, n1, n2, n3, n4, m, and n have the same meanings as above for formulae (IIa) to (IXa), and a dashed bond represents an optional double bond).

[0067] According to one embodiment of the present invention, compound (C), or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof, for use as a kinase inhibitor is preferably a compound selected from among formulae (IIc) to (IXc) [hereinafter referred to as compounds (C) of class (III)]: [ka] TIFF0007633702000014.tif34170 (In the formula, R1, R2, R3, R4, R´4, R a1 , R a2 , R a3 , R a4 , T, U, B, E, D, p, q, r, x, n1, n2, n3, n4, m, and n have the same meanings as above for formulae (IIa) to (IXa), and a dashed bond represents an optional double bond).

[0068] Preferred compounds of class (I) are herein selected from the compounds of formulae (IIa-1) to (IXa-1): [ka] TIFF0007633702000016.tif39170

[0069] During the ceremony, R1, R a1 , R a2 , R a3 , R a4 , T, U, B, E, D, p, n1, n2, n3, n4, m, and n have the same meanings as above for formulae (IIa) to (IXa), and the dashed bond represents an optional double bond; -R4, independently of each other and at each occurrence, is hydrogen, CF3, C 1-4 alkyl or cycloalkyl; preferably selected from hydrogen, methyl, ethyl, propyl, butyl, tert-butyl or isobutyl; -R3, each independently of the other and at each occurrence, is hydrogen, halo, CF3, C 1-4 Alkyl, cycloalkyl, OR 21 , and N(R 21 )2, wherein R 21 are each, independently of one another, a hydrogen, a C 1-4Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, or C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; more preferably, R3 is hydrogen, Cl, Br, F, OMe, N(R 21 )2 and C 1-4 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl or C 3-6 Cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl).

[0070] In a preferred embodiment of the present invention, compound (C), or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof, for use as a kinase inhibitor is a compound of formula (IIa-1) to (IXa-1):

[0071] During the ceremony, - R1 each independently and at each occurrence is hydrogen, halo, C 1-6 Alkyl, C 2-5 Alkenyl, C 2-5 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, CF3, COR 21 , N(R 21 )2, CN, CONR 21 , C(O)OR 21 , and OR 21 and each optional alkyl substituent is optionally substituted with one or more substituents selected from heterocyclyl, N(R 11 )2 OR 11 and further substituted with {wherein R 21 and R 22 are each, independently of one another, a hydrogen, a C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 and selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, and aralkyl substituents are optionally selected from halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, phenyl, OR 31 or N(R 32 )2, wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; each p is an integer ranging from 0 to 4; -R4, independently of each other and at each occurrence, is hydrogen, CF3, C 1-4 alkyl or cycloalkyl; preferably selected from hydrogen, methyl, ethyl, propyl, butyl, tert-butyl or isobutyl; -R3, each independently of the other and at each occurrence, is hydrogen, halo, CF3, C 1-4 Alkyl, cycloalkyl, OR 21 , and N(R 21)2, wherein R 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, or C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; more preferably, R3 is hydrogen, Cl, Br, F, OMe, N(R 21 )2 and C 1-4 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl or C 3-6 Cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). -T is selected from CH, NR, O or S, where R is hydrogen, optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-10 alkyl or cycloalkyl); preferably, T is selected from CH2 or O; -U is each independently and at each occurrence selected from C-halo, CR, O, or N, where R is hydrogen, OR 11 , N(R 11 )2, optionally substituted with halogen atoms, aryl groups or aralkyl groups 1-10 alkyl or cycloalkyl, wherein R 11 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; preferably, U is independently and at each occurrence selected from C-halo, CR or N; preferably, R is hydrogen or C 1-4alkyl, more preferably U is independently and at each occurrence selected from CR or N, more preferably R is hydrogen; -D is each independently and at each occurrence selected from C, CR, or N, where R is hydrogen, C 1-5 alkyl or cycloalkyl); preferably, D is independently and at each occurrence selected from C, CR or N, and preferably, R is hydrogen; - m is an integer equal to 1 or 2; - n is an integer equal to 0 or 1; -R a1 are each, independently of one another, a hydrogen, a C 1-5 Alkyl, C 2-15 Alkenyl, and C 2-15 alkynyl, wherein C 1-5 Alkyl, C 2-15 Alkenyl, and C 2-15 The alkynyl is optionally substituted with a halogen atom, an aryl group, or an aralkyl group; each n1 is an integer ranging from 0 to 5, preferably R a1 is hydrogen or C 1-5 is alkyl; -R a2 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, NO2, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, CON(R 11 )2, and SO2N(R 11)2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl substituent optionally being selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, aryl, N(R 11 )2, CF3, CN, COOR 11 , CO(R 11 )2, CON(R 11 )2, SO2N(R 11 )2 OR 11 wherein R 11 are each, independently of one another, a hydrogen, a C 1-6 selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; more preferably, R a2 are respectively, halo, OR 11 , C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, SR 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, and CON(R 11 )2, wherein R 11 are each, independently of one another, a hydrogen, a C 1-4 alkyl, cycloalkyl, and heterocyclyl); even more preferably, R a2 are respectively, Haro and OC1-4 Alkyl, C 1-4 Alkyl 、 Cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, OCH2O, OCH2CH2O, COOH, COO(C 1-4 alkyl), CO(heterocyclyl), CO(C 1-4 alkyl), CONH(C 1-4 n2 are each independently selected from the group consisting of CONH(cycloalkyl), CONH(alkyl), and CONH(cycloalkyl); n2 are each an integer ranging from 0 to 4; preferably, n2 are each an integer ranging from 0 to 2; - B is each, independently of one another, and at each occurrence, CR, O, N, S and NR 7´ wherein R is hydrogen or C optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-10 alkyl, and R 7´ is hydrogen, C 1-6 Alkyl, C 1-6 selected from the group consisting of alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF3; preferably, B is each, independently of one another and at each occurrence, selected from the group consisting of CR, O, and NR 7´ where R 7´ is hydrogen or C 1-4 alkyl, and R is hydrogen or C 1-4 (It is alkyl). -E is each, independently of one another, and at each occurrence, CR, O, N, S and NR 7´ wherein R is hydrogen or C optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-10 alkyl, and R 7´ is hydrogen, C 1-6 Alkyl, C 1-6 selected from the group consisting of alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF3; preferably, E is each, independently of the others, and at each occurrence, selected from the group consisting of CR, O, and NR 7´ wherein R 7´is hydrogen or C 1-4 alkyl, and R is hydrogen or C 1-4 (It is alkyl). -R a4 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, NO2, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, and CON(R 11 )2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent optionally being selected from the group consisting of halo, alkyl, cycloalkyl, aryl, N(R 11 )2, CN, or OR 11 wherein R 11 are each, independently of one another, a hydrogen, a C 1-6 and selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; more preferably, R a4 are respectively, halo, OR 11 , C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, SR11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, and CON(R 11 )2, wherein R 11 are each, independently of one another and at each occurrence, hydrogen, and C 1-4 alkyl); even more preferably, R a4 are respectively, Haro and OC 1-4 Alkyl, C 1-4 Alkyl 、 n4 is independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, OCHO, and OCH2CH2O; each n4 is an integer ranging from 0 to 4; preferably, each n4 is an integer ranging from 0 to 2; -R a3 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, aralkyl, halo, CF3, OR 11 , S.R. 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, and CON(R 11 )2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent optionally being selected from the group consisting of halo, alkyl, cycloalkyl, aryl, N(R 11 )2, CN, or OR 11 Further selected by {wherein R 11 are each, independently of one another, a hydrogen, a C 1-6and selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; more preferably, R a3 are respectively, C 1-6 are independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; even more preferably, R a3 is C 1-4 alkyl, and each n3 is an integer ranging from 0 to 2. The cycloalkyl is a monocyclic, bicyclic, or tricyclic ring system of 3 to 7 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 and 1 or 2 heteroatoms independently selected from O or N; the aryl is a phenyl, naphthyl, or anthracenyl optionally carbocyclically fused to a cycloalkyl or heterocyclyl of 5 to 7 ring members; and the heteroaryl is a monocyclic ring structure containing 5 or 6 ring atoms, including 1 to 3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

[0072] In one embodiment of the present invention, the compounds (C) of class (I) are selected from the compounds of formula (II-a) and (IX-a).

[0073] In a preferred embodiment of the present invention, the compound (C) according to the present invention for use as a kinase inhibitor according to the general formula (IIa-1) is a compound selected from the group of the following formula (IIa-1-1) herein: [ka]

[0074] During the ceremony, -R´´1 and R´´´1 are hydrogen and OR 21 wherein R 21 are each independently 1-4 alkyl); -R'3 is each hydrogen, halo and C 1-4 selected from the group consisting of alkyl; -R´´4 are each hydrogen and C 1-4 alkyl.

[0075] In a preferred embodiment of the present invention, the compound (C) according to the present invention for use as a kinase inhibitor according to the general formula (IIIa-1) is a compound selected from among the compounds of the following formulae (IIIa-1-1) and (IIIa-1-2) herein: [ka]

[0076] During the ceremony, Each of R'''1 and R'''1 is independently hydrogen, halo, C 1-4 alkyl, heterocyclyl selected from the group consisting of azetidinyl and pyrrolidinyl, heteroaryl selected from the group consisting of imidazolyl, pyrazolyl, triazolyl and pyrimidinyl, CN, N(R 21 )2 and OR 21 wherein R 21 are each independently hydrogen, C 1-4 alkyl or cyclopropyl); -R'3 is each hydrogen, halo and C 1-4 Alkyl, or OR 21 wherein R 21 is C 1-4 alkyl); -R´´4 are each hydrogen and C 1-4 selected from the group consisting of alkyl; -R5 is a C group such as hydrogen, halo, cyclopropyl, etc. 3-6 cycloalkyl, heterocyclyl selected from the group consisting of morpholinyl and azetidinyl, heteroaryl such as furanyl, CF3, CN, COR 21 , CON(R 21 )2, C(O)OR 21 , OR 21 and OCH2CH2O, wherein R 21 are each independently a C such as hydrogen, methyl, ethyl, isobutyl, etc. 1-4 is a heterocyclyl selected from the group consisting of alkyl, azetidinyl, and morpholinyl; -n´4 is an integer equal to 0, 1 or 2].

[0077] [ka]

[0078] During the ceremony, - R´´1 and R´´´1 are each hydrogen, halo, C 1-4 heteroaryl selected from the group consisting of alkyl, azetidinyl, furanyl, oxazolyl, oxazidiazolyl, isoxazolyl, pyrazinyl, pyridinyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, and pyrimidinyl; CF, CN, N(R 21 )2, CON(R 21 )2 and OR 21 wherein R 21 are each independently hydrogen, optionally substituted with halo, 1-4 alkyl or cyclopropyl); -R´´3 are each hydrogen, halo and C 1-4 selected from the group consisting of alkyl; -R´´4 are each hydrogen and C 1-4 selected from the group consisting of alkyl; -R5 each represents a heteroaryl selected from the group consisting of hydrogen, halo, cycloalkyl such as cyclopropyl, and furanyl, CN, COR 21 , CON(R 21 )2, COOR 21 , and OR 21 wherein R 21 are each independently selected from hydrogen, C such as methyl, ethyl, iso-butyl, optionally substituted with cycloalkyl selected from the group consisting of halo, cyclopropyl, and cyclobutyl. 1-4 alkyl); n'4 is an integer equal to 0, 1, 2, or 3].

[0079] In a preferred embodiment of the present invention, the compound (C) according to the present invention for use as a kinase inhibitor according to the general formula (IVa-1) is a compound selected from among the compounds of the following formula (IVa-1-1) herein: [ka]

[0080] During the ceremony, - R''1 and R''1 are each hydrogen, halo and OR 21 wherein R 21 is C 1-4 alkyl); -R'3 are each C 1-4 It is alkyl.

[0081] In a preferred embodiment of the present invention, the compound (C) according to the present invention for use as a kinase inhibitor according to the general formula (IVa-1) is a compound selected from among the compounds of the following formula (Va-1-1) herein: [ka]

[0082] During the ceremony, -R´´1 and R´´´1 are hydrogen and OR 21 wherein R 21 is C 1-4 alkyl); -R'3 are each C 1-4 It is alkyl.

[0083] In a preferred embodiment of the present invention, the compound (C) according to the present invention for use as a kinase inhibitor according to the general formula (VIIa-1) is a compound selected from among the compounds of the following formula (VIIa-1-1) herein: [ka]

[0084] During the ceremony, - R''1 and R''1 are each hydrogen, halo and OR 21 wherein R 21 is C 1-4 alkyl); -E is selected from the group consisting of N-R5 and O, wherein R5 is hydrogen or C 1-4 selected from the group consisting of alkyl; -R´3 is C 1-4 is alkyl; - R4 is hydrogen; -R6 is hydrogen and C 1-4 alkyl].

[0085] Preferred compounds of class (I) are herein selected from the compounds of formulae (IIa-a1) to (IXa-a1): [ka] TIFF0007633702000024.tif34170

[0086] During the ceremony, R1, R´1, R a1 , R a2 , R a3 , R a4 , T, U, B, E, D, p1, n1, n2, n3, n4, m, and n have the same meanings as above for formulae (IIa-a) to (IXa-a), and the dashed bond represents an optional double bond; -R4, independently of each other and at each occurrence, is hydrogen, CF3, C 1-4 alkyl or cycloalkyl; preferably selected from hydrogen, methyl, ethyl, propyl, butyl, tert-butyl or isobutyl; -R3, independently of each other and at each occurrence, is hydrogen, CF3, halo, C 1-4 Alkyl, cycloalkyl, OR 21 , and N(R 21 )2, wherein R 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, or C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; more preferably, R3 is hydrogen, Cl, Br, F, OMe, N(R 21 )2 and C 1-4 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl or C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). The cycloalkyl is a monocyclic, bicyclic, or tricyclic ring system of 3 to 7 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 and 1 or 2 heteroatoms independently selected from O or N; the aryl is a phenyl, naphthyl, or anthracenyl optionally carbocyclically fused to a cycloalkyl or heterocyclyl of 5 to 7 ring members; and the heteroaryl is a monocyclic ring structure containing 5 or 6 ring atoms, including 1 to 3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

[0087] In a preferred embodiment of the present invention, compound (C), or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof, for use as a kinase inhibitor is a compound of formula (IIa-a1) to (IXa-a1):

[0088] During the ceremony, - R1, independently of each other and at each occurrence, is hydrogen, halo, C 1-6 Alkyl, C 2-5 Alkenyl, C 2-5 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, CF3, COR21 , N(R 21 )2, CN, CONR 21 , C(O)OR 21 , and OR 21 and each optional alkyl substituent is optionally substituted with one or more substituents selected from heterocyclyl, N(R 11 )2 OR 11 wherein R 21 and R 22 are each, independently of one another, a hydrogen, a C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 and selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, and aralkyl substituents are optionally selected from halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, phenyl, OR 31 or N(R 32 )2, wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; each p1 is an integer ranging from 0 to 3; R'1 is selected from the group consisting of (R'1-a) to (R'1-d): [ka] During the ceremony, X, Y and Z are each, independently of one another and for each occurrence, CR, O, N, S and NR 7´ wherein R is hydrogen or C optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-6 alkyl, and R 7´ is hydrogen, C 1-6 Alkyl, C 1-6is selected from the group consisting of alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF3, and each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or aralkyl substituent is optionally selected from the group consisting of heterocyclyl, N(R 11 )2, or OR 11 Preferably, X, Y and Z are each, independently of one another and at each occurrence, selected from the group consisting of CR, O and NR 7´ where R 7´ is hydrogen or C 1-4 alkyl, and R is hydrogen or C 1-4 (It is alkyl). R b1 each independently and at each occurrence is hydrogen, halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, CN, CF3, COR 11 , CON(R 11 )2, NR 11 , and OR 11 wherein the alkyl, cycloalkyl, and heterocyclyl are optionally selected from the group consisting of heterocyclyl, OR 11 , N.R. 11 wherein R 11 are each, independently of one another and at each occurrence, hydrogen, halo, and C 1-6 alkyl); each p1 is an integer ranging from 0 to 3; · Dash bonds represent optional double bonds; -R3, each independently of the other and at each occurrence, is hydrogen, halo, CF3, C 1-4 Alkyl, cycloalkyl, OR 21 , and N(R 21 )2, wherein R 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, or C 3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; more preferably, R3 is hydrogen, Cl, Br, F, OMe, N(R 21 )2 and C 1-4 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl or C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; -R4, independently of each other and at each occurrence, is hydrogen, CF3, C 1-4 alkyl or cycloalkyl; preferably selected from hydrogen, methyl, ethyl, propyl, butyl, tert-butyl or isobutyl; -T is selected from CH, NR, O or S, where R is hydrogen, optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-10 alkyl or cycloalkyl); preferably, T is selected from CH2 or O; -U is each independently and at each occurrence selected from C-halo, CR, O, or N, where R is hydrogen, OR 11 , N(R 11 )2, optionally substituted with halogen atoms, aryl groups or aralkyl groups 1-10 alkyl or cycloalkyl, wherein R 11 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; preferably, U is independently and at each occurrence selected from C-halo, CR or N; preferably, R is hydrogen or C 1-4alkyl, more preferably U is independently and at each occurrence selected from CR or N, more preferably R is hydrogen; -D is each independently and at each occurrence selected from C, CR, or N, where R is hydrogen, C 1-5 alkyl or cycloalkyl); preferably, D is independently and at each occurrence selected from C, CR or N, and preferably, R is hydrogen; - m is an integer equal to 1 or 2; - n is an integer equal to 0 or 1; -R a1 are each, independently of one another, a hydrogen, a C 1-5 Alkyl, C 2-15 Alkenyl, and C 2-15 alkynyl, wherein C 1-5 Alkyl, C 2-15 Alkenyl, and C 2-15 The alkynyl is optionally substituted with a halogen atom, an aryl group, or an aralkyl group; each n1 is an integer ranging from 0 to 5, preferably R a1 is hydrogen or C 1-5 is alkyl; -R a2 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, NO2, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, CON(R 11 )2, and SO2N(R 11)2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl substituent optionally being selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, aryl, N(R 11 )2, CF3, CN, COOR 11 , CO(R 11 )2, CON(R 11 )2, SO2N(R 11 )2 OR 11 and further substituted with {wherein R 11 are each, independently of one another, a hydrogen, a C 1-6 selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; more preferably, R a2 are respectively, halo, OR 11 , C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, SR 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, and CON(R 11 )2, wherein R 11 are each, independently of one another, a hydrogen, a C 1-4 alkyl, cycloalkyl, and heterocyclyl); even more preferably, R a2 are respectively, Haro and OC1-4 Alkyl, C 1-4 Alkyl 、 Cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, OCH2O, OCH2CH2O, COOH, COO(C 1-4 alkyl), CO(heterocyclyl), CO(C 1-4 alkyl), CONH(C 1-4 n2 are each independently selected from the group consisting of CONH(cycloalkyl), CONH(alkyl), and CONH(cycloalkyl); n2 are each an integer ranging from 0 to 4; preferably, n2 are each an integer ranging from 0 to 2; - B is each, independently of one another, and at each occurrence, CR, O, N, S and NR 7´ wherein R is hydrogen or C optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-10 alkyl, and R 7´ is hydrogen, C 1-6 Alkyl, C 1-6 selected from the group consisting of alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF3; preferably, B is each, independently of one another and at each occurrence, selected from the group consisting of CR, O, and NR 7´ where R 7´ is hydrogen or C 1-4 alkyl, and R is hydrogen or C 1-4 (It is alkyl). -E is each, independently of one another, and at each occurrence, CR, O, N, S and NR 7´ wherein R is hydrogen or C optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-10 alkyl, and R 7´ is hydrogen, C 1-6 Alkyl, C 1-6 selected from the group consisting of alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF3; preferably, E is each, independently of the others, and at each occurrence, selected from the group consisting of CR, O, and NR 7´ wherein R 7´is hydrogen or C 1-4 alkyl, and R is hydrogen or C 1-4 (It is alkyl). -R a4 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, NO2, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, and CON(R 11 )2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent optionally being selected from the group consisting of halo, alkyl, cycloalkyl, aryl, N(R 11 )2, CN, or OR 11 wherein R 11 are each, independently of one another, a hydrogen, a C 1-6 and selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; more preferably, R a4 are respectively, halo, OR 11 , C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, SR11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, and CON(R 11 )2, wherein R 11 are each, independently of one another and at each occurrence, hydrogen, and C 1-4 alkyl); even more preferably, R a4 are respectively, Haro and OC 1-4 Alkyl, C 1-4 Alkyl 、 n4 is independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, OCHO, and OCH2CH2O; each n4 is an integer ranging from 0 to 4; preferably, each n4 is an integer ranging from 0 to 2; -R a3 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, aralkyl, halo, CF3, OR 11 , S.R. 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, and CON(R 11 )2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent optionally being selected from the group consisting of halo, alkyl, cycloalkyl, aryl, N(R 11 )2, CN, or OR 11 Further selected by {wherein R 11 are each, independently of one another, a hydrogen, a C 1-6and selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; more preferably, R a3 are respectively, C 1-6 are independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; even more preferably, R a3 is C 1-4 alkyl, and each n3 is an integer ranging from 0 to 2. The cycloalkyl is a monocyclic, bicyclic, or tricyclic ring system of 3 to 7 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 and 1 or 2 heteroatoms independently selected from O or N; the aryl is a phenyl, naphthyl, or anthracenyl optionally carbocyclically fused to a cycloalkyl or heterocyclyl of 5 to 7 ring members; and the heteroaryl is a monocyclic ring structure containing 5 or 6 ring atoms, including 1 to 3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

[0089] Preferred compounds of class (I) are herein selected from the compounds of formulae (Xa-1) to (XVIIa-1): [ka] TIFF0007633702000027.tif34170

[0090] During the ceremony, R1, R a1 , R a2 , R a3 , R a4 , T, U, B, E, D, p, n1, n2, n3, n4, m, and n have the same meanings as above for formulae (IIa) to (IXa), and the dashed bond represents an optional double bond; -R3, independently of each other and at each occurrence, is hydrogen, CF3, halo, C 1-4 Alkyl, cycloalkyl, OR 21 , and N(R 21 )2, wherein R 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, or C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; more preferably, R3 is hydrogen, Cl, Br, F, OMe, N(R 21 )2 and C 1-4 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl or C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl).

[0091] In a preferred embodiment of the present invention, compound (C), or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof, for use as a kinase inhibitor is a compound of formula (Xa-1) to (XVIIa-1):

[0092] During the ceremony, - R1 each independently and at each occurrence is hydrogen, halo, C 1-6 Alkyl, C 2-5 Alkenyl, C 2-5Alkynyl, 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, CF3, COR 21 , N(R 21 )2, CN, CONR 21 , C(O)OR 21 , and OR 21 and each optional alkyl substituent is optionally substituted with one or more substituents selected from heterocyclyl, N(R 11 )2 OR 11 wherein R 21 and R 22 are each, independently of one another, a hydrogen, a C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 and selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, and aralkyl substituents are optionally selected from halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, phenyl, OR 31 or N(R 32 )2, wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4alkyl)}; each p is an integer ranging from 0 to 4; -R3, each independently of the other and at each occurrence, is hydrogen, halo, CF3, C 1-4 Alkyl, cycloalkyl, OR 21 , and N(R 21 )2, wherein R 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, or C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; more preferably, R3 is hydrogen, Cl, Br, F, OMe, N(R 21 )2 and C 1-4 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, where R 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl or C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). -T is selected from CH, NR, O or S, where R is hydrogen, optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-10 alkyl or cycloalkyl); preferably, T is selected from CH2 or O; -U is each independently and at each occurrence selected from C-halo, CR, O, or N, where R is hydrogen, OR 11 , N(R 11 )2, optionally substituted with halogen atoms, aryl groups or aralkyl groups 1-10 alkyl or cycloalkyl, wherein R 11 are each, independently of one another and at each occurrence, hydrogen and C1-4 alkyl)}; preferably, U is independently and at each occurrence selected from C-halo, CR or N; preferably, R is hydrogen or C 1-4 alkyl, more preferably U is independently and at each occurrence selected from CR or N, more preferably R is hydrogen; -D is each independently and at each occurrence selected from C, CR, or N, where R is hydrogen, C 1-5 alkyl or cycloalkyl); preferably, D is independently and at each occurrence selected from C, CR or N, and preferably R is hydrogen; - m is an integer equal to 1 or 2; - n is an integer equal to 0 or 1; -R a1 are each, independently of one another, a hydrogen, a C 1-5 Alkyl, C 2-15 Alkenyl, and C 2-15 alkynyl, wherein C 1-5 Alkyl, C 2-15 Alkenyl, and C 2-15 The alkynyl is optionally substituted with a halogen atom, an aryl group, or an aralkyl group; each n1 is an integer ranging from 0 to 5, preferably R a1 is hydrogen or C 1-5 is alkyl; -R a2 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, NO2, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR11 , CO(R 11 )2, CON(R 11 )2, and SO2N(R 11 )2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl substituent optionally being selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, aryl, N(R 11 )2, CF3, CN, COOR 11 , CO(R 11 )2, CON(R 11 )2, SO2N(R 11 )2 OR 11 wherein R 11 are each, independently of one another, a hydrogen, a C 1-6 selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; more preferably, R a2 are respectively, halo, OR 11 , C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, SR 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, and CON(R 11 )2, wherein R 11 are each, independently of one another, a hydrogen, a C 1-4alkyl, cycloalkyl, and heterocyclyl); even more preferably, R a2 are respectively, Haro and OC 1-4 Alkyl, C 1-4 Alkyl 、 Cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, OCH2O, OCH2CH2O, COOH, COO(C 1-4 alkyl), CO(heterocyclyl), CO(C 1-4 alkyl), CONH(C 1-4 n2 are each independently selected from the group consisting of CONH(cycloalkyl), CONH(alkyl), and CONH(cycloalkyl); n2 are each an integer ranging from 0 to 4; preferably, n2 are each an integer ranging from 0 to 2; - B is each, independently of one another, and at each occurrence, CR, O, N, S and NR 7´ wherein R is hydrogen or C optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-10 alkyl, and R 7´ is hydrogen, C 1-6 Alkyl, C 1-6 selected from the group consisting of alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF3; preferably, B is each, independently of one another and at each occurrence, selected from the group consisting of CR, O, and NR 7´ where R 7´ is hydrogen or C 1-4 alkyl, and R is hydrogen or C 1-4 alkyl). -E is each, independently of one another, and at each occurrence, CR, O, N, S and NR 7´ wherein R is hydrogen or C optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-10 alkyl, and R 7´ is hydrogen, C 1-6 Alkyl, C 1-6selected from the group consisting of alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF3; preferably, E is each, independently of the others, and at each occurrence, selected from the group consisting of CR, O, and NR 7´ wherein R 7´ is hydrogen or C 1-4 alkyl, and R is hydrogen or C 1-4 alkyl). -R a4 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, NO2, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, and CON(R 11 )2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent optionally being selected from the group consisting of halo, alkyl, cycloalkyl, aryl, N(R 11 )2, CN, or OR 11 wherein R 11 are each, independently of one another, a hydrogen, a C 1-6 and selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4alkyl)}; more preferably, R a4 are respectively, halo, OR 11 , C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, SR 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, and CON(R 11 )2, wherein R 11 are each, independently of one another and at each occurrence, hydrogen, and C 1-4 alkyl); even more preferably, R a4 are respectively, Haro and OC 1-4 Alkyl, C 1-4 Alkyl 、 n4 is independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, OCHO, and OCH2CH2O; each n4 is an integer ranging from 0 to 4; preferably, each n4 is an integer ranging from 0 to 2; -R a3 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, aralkyl, halo, CF3, OR 11 , S.R. 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, and CON(R 11 )2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent optionally being selected from the group consisting of halo, alkyl, cycloalkyl, aryl, N(R 11 )2, CN, or OR 11 Further selected by {wherein R11 are each, independently of one another, a hydrogen, a C 1-6 and selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; more preferably, R a3 are respectively, C 1-6 are independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; even more preferably, R a3 is C 1-4 alkyl, and each n3 is an integer ranging from 0 to 2. The cycloalkyl is a monocyclic, bicyclic, or tricyclic ring system of 3 to 7 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 and 1 or 2 heteroatoms independently selected from O or N; the aryl is a phenyl, naphthyl, or anthracenyl optionally carbocyclically fused to a cycloalkyl or heterocyclyl of 5 to 7 ring members; and the heteroaryl is a monocyclic ring structure containing 5 or 6 ring atoms, including 1 to 3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

[0093] Preferred compounds of class (I) are herein selected from the compounds of formulae (XVIIIa-1) to (XXVa-1): [ka] TIFF0007633702000029.tif34170

[0094] During the ceremony, R1, R a1 , R a2 , R a3 , R a4 , T, U, B, E, D, p, n1, n2, n3, n4, m, and n have the same meanings as above for formulae (IIa) to (IXa), and the dashed bond represents an optional double bond; -R3, independently of each other and at each occurrence, is hydrogen, CF3, halo, C 1-4 Alkyl, cycloalkyl, OR 21 , N(R 21 )2, wherein R 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, or C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; more preferably, R3 is hydrogen, Cl, Br, F, OMe, N(R 21 )2 and C 1-4 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, where R 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl or C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl).

[0095] In a preferred embodiment of the present invention, compound (C), or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof, for use as a kinase inhibitor is a compound of formula (XVIIIa-1) to (XXVa-1):

[0096] During the ceremony, - R1 each independently and at each occurrence is hydrogen, halo, C 1-6 Alkyl, C 2-5 Alkenyl, C 2-5 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, CF3, COR 21 , N(R 21 )2, CN, CONR 21 , C(O)OR 21 , and OR 21 and each optional alkyl substituent is optionally substituted with one or more substituents selected from heterocyclyl, N(R 11 )2 OR 11 wherein R 21 and R 22 are each, independently of one another, a hydrogen, a C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 and selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, and aralkyl substituents are optionally selected from halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, phenyl, OR 31 or N(R 32)2, wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; each p is an integer ranging from 0 to 4; -R3, each independently of the other and at each occurrence, is hydrogen, halo, CF3, C 1-4 Alkyl, cycloalkyl, OR 21 , and N(R 21 )2, wherein R 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, or C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; more preferably, R3 is hydrogen, Cl, Br, F, OMe, N(R 21 )2 and C 1-4 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, where R 21 are each, independently of one another, a hydrogen, a C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl or C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). -T is selected from CH, NR, O or S, where R is hydrogen, optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-10 alkyl or cycloalkyl); preferably, T is selected from CH2 or O; -U is each independently and at each occurrence selected from C-halo, CR, O, or N, where R is hydrogen, OR 11 , N(R 11)2, optionally substituted with halogen atoms, aryl groups or aralkyl groups 1-10 alkyl or cycloalkyl, wherein R 11 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; preferably, U is independently and at each occurrence selected from C-halo, CR or N; preferably, R is hydrogen or C 1-4 alkyl, more preferably U is independently and at each occurrence selected from CR or N, more preferably R is hydrogen; -D is each independently and at each occurrence selected from C, CR, or N, where R is hydrogen, C 1-5 alkyl or cycloalkyl); preferably, D is independently and at each occurrence selected from C, CR or N, and preferably R is hydrogen; - m is an integer equal to 1 or 2; - n is an integer equal to 0 or 1; -R a1 are each, independently of one another, a hydrogen, a C 1-5 Alkyl, C 2-15 Alkenyl, and C 2-15 alkynyl, wherein C 1-5 Alkyl, C 2-15 Alkenyl, and C 2-15 The alkynyl is optionally substituted with a halogen atom, an aryl group, or an aralkyl group; each n1 is an integer ranging from 0 to 5, preferably R a1 is hydrogen or C 1-5 is alkyl; -R a2 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, NO2, CF3, CN, OR11 , S.R. 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, CON(R 11 )2, and SO2N(R 11 )2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl substituent optionally being selected from the group consisting of halo, C 1-6 Alkyl, cycloalkyl, aryl, N(R 11 )2, CF3, CN, COOR 11 , CO(R 11 )2, CON(R 11 )2, SO2N(R 11 )2 OR 11 wherein R 11 are each, independently of one another, a hydrogen, a C 1-6 selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; more preferably, R a2 are respectively, halo, OR 11 , C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, SR 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R11 )2, and CON(R 11 )2, wherein R 11 are each, independently of one another, a hydrogen, a C 1-4 alkyl, cycloalkyl, and heterocyclyl); even more preferably, R a2 are respectively, Haro and OC 1-4 Alkyl, C 1-4 Alkyl 、 Cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, OCH2O, OCH2CH2O, COOH, COO(C 1-4 alkyl), CO(heterocyclyl), CO(C 1-4 alkyl), CONH(C 1-4 n2 are each independently selected from the group consisting of CONH(cycloalkyl), CONH(alkyl), and CONH(cycloalkyl); n2 are each an integer ranging from 0 to 4; preferably, n2 are each an integer ranging from 0 to 2; - B is each, independently of one another, and at each occurrence, CR, O, N, S and NR 7´ wherein R is hydrogen or C optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-10 alkyl, and R 7´ is hydrogen, C 1-6 Alkyl, C 1-6 selected from the group consisting of alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF3; preferably, B is each, independently of one another and at each occurrence, selected from the group consisting of CR, O, and NR 7´ where R 7´ is hydrogen or C 1-4 alkyl, and R is hydrogen or C 1-4 alkyl). -E is each, independently of one another, and at each occurrence, CR, O, N, S and NR 7´ wherein R is hydrogen or C optionally substituted with a halogen atom, an aryl group or an aralkyl group; 1-10 alkyl, and R7´ is hydrogen, C 1-6 Alkyl, C 1-6 selected from the group consisting of alkenyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and CF3; preferably, E is each, independently of the others, and at each occurrence, selected from the group consisting of CR, O, and NR 7´ wherein R 7´ is hydrogen or C 1-4 alkyl, and R is hydrogen or C 1-4 alkyl). -R a4 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, halo, NO2, CF3, CN, OR 11 , S.R. 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, and CON(R 11 )2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent optionally being selected from the group consisting of halo, alkyl, cycloalkyl, aryl, N(R 11 )2, CN, or OR 11 wherein R 11 are each, independently of one another, a hydrogen, a C 1-6 and selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; more preferably, R a4 are respectively, halo, OR 11 , C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, SR 11 , N(R 11 )2, OC(R 11 )2O, OC(R 11 )2C(R 11 )2O, COOR 11 , CO(R 11 )2, and CON(R 11 )2, wherein R 11 are each, independently of one another and at each occurrence, hydrogen, and C 1-4 alkyl); even more preferably, R a4 are respectively, Haro and OC 1-4 Alkyl, C 1-4 Alkyl 、 n4 is independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, OCHO, and OCH2CH2O; each n4 is an integer ranging from 0 to 4; preferably, each n4 is an integer ranging from 0 to 2; -R a3 are each independently of each other and for each occurrence, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, aralkyl, halo, CF3, OR 11 , S.R. 11 , N(R 11 )2, COOR 11 , CO(R 11 )2, and CON(R 11 )2, each optional alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl substituent optionally being selected from the group consisting of halo, alkyl, cycloalkyl, aryl, N(R11 )2, CN, or OR 11 Further selected by {wherein R 11 are each, independently of one another, a hydrogen, a C 1-6 and selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; more preferably, R a3 are respectively, C 1-6 are independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; even more preferably, R a3 is C 1-4 alkyl, and each n3 is an integer ranging from 0 to 2. The cycloalkyl is a monocyclic, bicyclic, or tricyclic ring system of 3 to 7 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 and 1 or 2 heteroatoms independently selected from O or N; the aryl is a phenyl, naphthyl, or anthracenyl optionally carbocyclically fused to a cycloalkyl or heterocyclyl of 5 to 7 ring members; and the heteroaryl is a monocyclic ring structure containing 5 or 6 ring atoms, including 1 to 3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

[0097] Preferred compounds of class (I) are herein selected from the compounds of formulae (XXVIa-1) to (XXXIIIa-1): [ka] TIFF0007633702000031.tif40170

[0098] In the formula, R1, R a1 , R a2 , R a3 , R a4 , T, U, B, E, D, p, n1, n2, n3, n4, m, and n have the same meanings as above for formulas (IIa) to (IXa), and the dashed bond represents an optional double bond.

[0099] In a preferred embodiment of the present invention, the compound (C) of the general formula (IIa-1) of the present invention for use as a kinase inhibitor is a compound selected from the following formulas (XXXIV) to (XLII) herein: [ka] TIFF0007633702000033.tif106170

[0100] In a preferred embodiment of the present invention, the compound (C) of general formula (IIIa-1) according to the present invention for use as a kinase inhibitor is a compound selected from among the following formulae (XLIII) to (CXCVIII-39) herein: [ka] TIFF0007633702000035.tif238170TIFF0007633702000036.tif225170TIFF0007633702000037.tif246170TIFF0007633702000038.tif250170TIFF0007633702000039.tif221170TIFF0007633702000040.tif251170TIFF0007633702000041.tif217170TIFF0007633702000042.tif242170TIFF0007633702000043.tif254170TIFF0007633702000044.tif250170TIFF0007633702000045.tif246170TIFF0007633702000046.tif238170TIFF0007633702000047.tif229170TIFF0007633702000048.tif221170TIFF0007633702000049.tif250170TIFF0007633702000050.tif246170TIFF0007633702000051.tif246170TIFF0007633702000052.tif254170TIFF0007633702000053.tif233170TIFF0007633702000054.tif242170TIFF0007633702000055.tif246170TIFF0007633702000056.tif225170TIFF0007633702000057.tif116170TIFF0007633702000058.tif136170TIFF0007633702000059.tif242170TIFF0007633702000060.tif238170TIFF0007633702000061.tif242170TIFF0007633702000062.tif236170TIFF0007633702000063.tif119170

[0101] In a more preferred embodiment of the present invention, compound (C) according to the present invention, or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof, for use as a kinase inhibitor according to the general formula (IIIa-1), as used herein, is a compound of the following formulae (LXI), (LXIII), (LXXII), (LXXIV) to (LXXXV), (LXXXVI), (CXIII), (CLXXXVI), (CLXXXVIII), (CXC) to (CXCVI), (CXCVII-6) to (CXCVII-7), (CXCVII-16) to (CXCVII-17), (CXCVII-19) to (CXCVII-20), (CXCVII-27), (CXCVII-33) to (CXCVII-35), or (CXCVII-37) to (CXCVII-38): [ka] TIFF0007633702000065.tif246170TIFF0007633702000066.tif246170TIFF0007633702000067.tif238170

[0102] In a preferred embodiment of the present invention, the compound (C) according to the present invention for use as a kinase inhibitor according to the general formula (IIIa-a1) is a compound selected from among the compounds of the following formulae (CXCVIII-1) to (CXCVIII-90) herein: [ka] TIFF0007633702000069.tif242170TIFF0007633702000070.tif242170TIFF0007633702000071.t if242170TIFF0007633702000072.tif242170TIFF0007633702000073.tif242170TIFF0007633702 000074.tif242170TIFF0007633702000075.tif242170TIFF0007633702000076.tif242170TIFF00 07633702000077.tif242170TIFF0007633702000078.tif242170TIFF0007633702000079.tif56170

[0103] In a more preferred embodiment of the present invention, compound (C) according to the present invention for use as a kinase inhibitor according to the general formula (IIIa-a1), or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof, is represented herein by the following formulae (CXCVIII-3), (CXCVIII-7), (CXCVIII-11), (CXCVIII-16), (CXCVIII-19) to (CXCVIII-21), (CXCVIII-23) to (CXCVIII-26), (CXCVIII-28) to (CXCVIII-31), (CXCVIII-3 3) to (CXCVIII-39), (CXCVIII-42) to (CXCVIII-47), (CXCVIII-49), (CXCVIII-51) to (CXCVIII-53), (CXCVIII-56), (CXCVIII-59), (CXCVIII-62), (CXCVIII-66), (CXCVIII-67), (CXCVIII-70), (CXCVIII-71), (CXCVIII-73) to (CXCVIII-75), (CXCVIII-81) to (CXCVIII-86), or (CXCVIII-88) to (CXCVIII-90): [ka] TIFF0007633702000081.tif233170TIFF0007633702000082.tif242170TIFF0007633702000083.tif24217 0TIFF0007633702000084.tif242170TIFF0007633702000085.tif242170TIFF0007633702000086.tif89170

[0104] In a preferred embodiment of the present invention, the compound (C) of general formula (IVa-1) according to the present invention for use as a kinase inhibitor is a compound selected from the group consisting of the following formulae (CXCIX) to (CCI) herein: [ka]

[0105] In a preferred embodiment of the present invention, the compound (C) of general formula (Va-1) according to the present invention for use as a kinase inhibitor is a compound selected from among the compounds of formula (CCII) or (CCIII) herein below: [ka]

[0106] In a preferred embodiment of the present invention, the compound (C) of general formula (VIa-1) according to the present invention for use as a kinase inhibitor is a compound of formula (CCIV) herein below: [ka]

[0107] In a preferred embodiment of the present invention, the compound (C) of general formula (VIIa-1) according to the present invention for use as a kinase inhibitor is a compound of the following formulae (CCIV-1) to (CCIV-6) herein: [ka]

[0108] In a preferred embodiment of the present invention, the compound (C) of general formula (VIIIa-1) according to the present invention for use as a kinase inhibitor is a compound of the following formula (CCV) herein: [ka]

[0109] In a preferred embodiment of the present invention, the compound (C) according to the present invention for use as a kinase inhibitor according to general formula (IXa-1) is a compound selected from among the compounds of formulae (CCVI) to (CCXIV) herein below: [ka] TIFF0007633702000093.tif58170

[0110] In a preferred embodiment of the present invention, the compound (C) of general formula (XIa-1) according to the present invention for use as a kinase inhibitor is a compound selected from the following formulae (CCXV) to (CCXIX) herein: [ka]

[0111] In a preferred embodiment of the present invention, the compound (C) according to the present invention for use as a kinase inhibitor according to the general formula (XVIIIa-1) is herein a compound of the following formula (CCXX): [ka]

[0112] In a preferred embodiment of the present invention, the compound (C) according to the present invention for use as a kinase inhibitor according to the general formula (XXIIIa-1) is a compound selected from among the compounds of the following formulae (CCXXI) to (CCXXIV) herein: [ka]

[0113] In a preferred embodiment of the present invention, the compound (C) according to the present invention for use as a kinase inhibitor according to the general formula (XXIVa-1) is a compound selected from among the compounds of the following formulae (CCXXV) to (CCXXXII) herein: [ka] TIFF0007633702000098.tif73170

[0114] In a preferred embodiment of the present invention, the compound (C) of general formula (XXVIIa-1) according to the present invention for use as a kinase inhibitor is a compound of the following formula (CCXXXIII) herein: [ka]

[0115] In a preferred embodiment of the present invention, the compound (C) according to the present invention for use as a kinase inhibitor according to general formula (Ia) is a compound selected from among the compounds of formulae (CCXXXIV) to (CCXXXVII) herein below: [ka]

[0116] The present invention further relates to an in vitro method for inhibiting protein kinase activity, comprising contacting the protein kinase with a compound of formula (I'a) as defined above [hereinafter referred to as compound (C)], or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof. [ka]

[0117] During the ceremony, -A is hydrogen, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Independently selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl are optionally selected from halo, NO, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF, 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, SO2NR 11 COR 12 , SO2NR 11 CO2R 12 , SO2NR 11 CON(R 11 )2, NR 11 COR 12 , N.R. 11 CO2R 12 , N.R. 11 CON(R 11 )2, NR 11 C(NR 11 )NHR 11, C.O.R. 11 , C(O)OR 11 , CON(R 11 )2, CONR 11 SO2R 12 , N.R. 11 SO2R 12 , SO2NR 11 CO2R 12 , OCONR 11 SO2R 12 ,OC(O)R 11 , C(O)OCH2OC(O)R 11 , and OCON(R 11 )2, each optional alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, heteroaryl substituent optionally being substituted with one or more substituents independently selected from the group consisting of halo, NO2, alkyl, cycloalkyl, aryl, CF3, N(R 11 ) 2, alkyl or aryl or heteroaryl amide, NR 11 COR 12 , N.R. 11 SO2R 12 , C.O.R. 11 , CON(R 11 )2, NR 11 CON(R 11 )2, OC(O)R 11 , OC(O)N(R 11 )2, S(O)3R 11 , P(O)(OR 11 )2, SR 11 , S(O)R 12 , SO2R 12 , SO2N(R 11 )2, CN, or OR 11 wherein R 11 and R 12 are each, independently of one another, a hydrogen, a C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15and CF3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF3 substituents are optionally selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2 (wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; -R7 is hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl; 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are optionally substituted with halogen atoms, aryl groups, aralkyl groups, CF, N(R 11 )2, CN or OR 11 and is substituted by 11 are each, independently of one another, a hydrogen, a C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 and CF3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF3 substituents are optionally selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, alkyl or aryl or heteroaryl amide, OR 31 or N(R 32 )2 (wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C1-4 alkyl)}; s and t are each equal to 0 or 1; R1 and R2 are each, independently of each other and at each occurrence, hydrogen, halo, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 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 )O and OC(R 21 )2C(R 22 )2O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of halo, C 1-15 Alkyl, CF3, N(R 21 )2, CN, or OR 21 and is substituted with one or more substituents selected from the group consisting of 21 and R 22 are each, independently of one another, a hydrogen, a C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 and selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, aryl, OR 31 or N(R 32 )2, wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4alkyl)}; each p is an integer ranging from 0 to 4; each q is an integer ranging from 0 to 2; - R3 each independently of the other and at each occurrence is hydrogen, halo, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, CF3, CN, NO2, 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 )O and OC(R 21 )2C(R 22 )2O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of halo, C 1-15 Alkyl, CF3, N(R 21 )2, CN, or OR 21 and is substituted with one or more substituents selected from the group consisting of 21 and R 22 are each, independently of one another, a hydrogen, a C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 and selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, aryl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4alkyl)}; each r is an integer ranging from 0 to 3; provided that R3 = NR 21 and when R7 = H, then R3 and NR7 together may form a saturated or unsaturated cyclic moiety; -R4 and R ´ Each 4, independently of one another and at each occurrence, is hydrogen, CF3, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 alkynyl, cycloalkyl, and heterocyclyl; 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl and heterocyclyl are optionally substituted with halogen atoms, aryl groups, aralkyl groups, OR 13 , S.R. 13 , N(R 13 )2, CF3 or CN, where each R 13 are each, independently of one another and at each occurrence, a hydrogen atom, optionally a halogen atom, an aryl group, an aralkyl group, OR 31 or N(R 32 )2 is substituted with C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or aralkyl, wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; x is an integer ranging from 0 to 7, provided that when x=0, A and R7 together may form a saturated or unsaturated cyclic moiety.

[0118] In a further aspect, the present invention relates to an in vitro method of inhibiting protein kinase activity, comprising contacting the protein kinase with a compound of formula (Ia) as defined above [hereinafter compound (C)], or an N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or stereoisomer thereof. [ka]

[0119] During the ceremony, -A is C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Independently selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl are optionally selected from halo, NO, C 1-6 Alkyl, C 2-5 Alkenyl, 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, SO2NR 11 COR 12 , SO2NR 11 CO2R 12 , SO2NR 11 CON(R 11 )2, NR 11 COR 12 , N.R. 11 CO2R 12 , N.R. 11 CON(R 11 )2, NR 11 C(NR 11 )NHR 11 , C.O.R. 11, C(O)OR 11 , CON(R 11 )2, CONR 11 SO2R 12 , N.R. 11 SO2R 12 , SO2NR 11 CO2R 12 , OCONR 11 SO2R 12 ,OC(O)R 11 , C(O)OCH2OC(O)R 11 , and OCON(R 11 and each optional alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, heteroaryl substituent is optionally substituted with one or more substituents independently selected from the group consisting of halo, NO, C 1-6 Alkyl, cycloalkyl, aryl, CF3, N(R 11 ) 2, alkyl or aryl or heteroaryl amide, NR 11 COR 12 , N.R. 11 SO2R 12 , C.O.R. 11 , CON(R 11 )2, NR 11 CON(R 11 )2, OC(O)R 11 , OC(O)N(R 11 )2, S(O)R 12 , SO2R 12 , SO2N(R 11 )2, CN, or OR 11 wherein R 11 and R 12 are each, independently of one another, a hydrogen, a C 1-6 Alkyl, C 2-5 Alkenyl, C 2-5 and CF3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and CF3 substituents are optionally selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, alkyl or aryl or heteroaryl amide, OR31 or N(R 32 )2 (wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; -R7 is each hydrogen or C 1-6 is alkyl; R1 and R2 are each, independently of each other and at each occurrence, hydrogen, halo, C 1-6 Alkyl, C 2-5 Alkenyl, C 2-5 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 )O and OC(R 21 )2C(R 22 )2O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of halo, C 1-6 Alkyl, C 2-5 Alkenyl, C 2-5 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 is optionally substituted with one or more substituents selected from heterocyclyl, N(R 11 )2 OR 11wherein R 21 and R 22 are each, independently of one another, a hydrogen, a C 1-6 Alkyl, C 2-5 Alkenyl, C 2-5 selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl substituents are optionally selected from halo, C 1-6 Alkyl, cycloalkyl, heterocyclyl, aryl, OR 31 or N(R 32 )2, wherein R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; each p is an integer ranging from 0 to 4; each q is an integer ranging from 0 to 2; - R3 each independently of the other and at each occurrence is hydrogen, halo, C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 Alkynyl, cycloalkyl, heterocyclyl, 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 )O and OC(R 21 )2C(R 22 )2O, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally selected from the group consisting of halo, C 1-15 Alkyl, CF3, N(R 21 )2, CN, or OR 21 and is substituted with one or more substituents selected from the group consisting of21 and R 22 are each, independently of one another, a hydrogen, a C 1-15 Alkyl, C 2-15 Alkenyl, C 2-15 and selected from the group consisting of alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl substituents are optionally selected from halo, alkyl, cycloalkyl, heterocyclyl, aryl, OR 31 or N(R 32 )2, where R 31 and R 32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; each r is an integer ranging from 0 to 3; provided that R3 = NR 21 and when R7 = H, then R3 and NR7 together may form a saturated or unsaturated cyclic moiety; -R4 and R ´ Each 4, independently of one another and at each occurrence, is hydrogen, CF3, C 1-6 Alkyl, C 2-5 Alkenyl, C 2-5 and selected from the group consisting of alkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally substituted with halogen atoms, aryl groups, aralkyl groups, OR 13 , S.R. 13 , N(R 13 )2, CF3 or CN, where R 13 are each independently a hydrogen atom, optionally a halogen atom, an aryl group, an aralkyl group, OR 31 or N(R 32 )2 is substituted with C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or aralkyl, wherein R 31 and R32 are each, independently of one another and at each occurrence, hydrogen and C 1-4 alkyl)}; x is an integer ranging from 0 to 7, provided that when x=0, A and R7 together may form a saturated or unsaturated cyclic moiety; The cycloalkyl is a monocyclic, bicyclic, or tricyclic ring system of 3 to 7 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 and 1 or 2 heteroatoms independently selected from O or N; the aryl is a phenyl, naphthyl, or anthracenyl optionally carbocyclically fused to a cycloalkyl or heterocyclyl of 5 to 7 ring members; and the heteroaryl is a monocyclic ring structure containing 5 or 6 ring atoms, including 1 to 3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

[0120] It will be further understood that all definitions and preferences set forth for compound (C) above apply equally to this and all further embodiments, as described below.

[0121] As used above and below, the following definitions apply unless otherwise stated:

[0122] The term halo, alone or in combination, means all halogens, ie, chloro (Cl), bromo (Br), fluoro (F), iodo (I).

[0123] 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 is defined as a straight or branched chain alkyl group having F to G carbon atoms, e.g., C 1-4Alkyl is defined as a straight-chain or branched alkyl group 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, it is a straight-chain or branched alkyl group containing 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, even more preferably 1 to 6 carbon atoms, 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.

[0124] The term alkenyl, alone or in combination, unless otherwise specified, refers to 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 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. Alkyl also includes straight or branched chain alkoxy 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 or branched chain moiety, with the exception of cyclopropyl.

[0125] The term alkynyl, alone or in combination, unless otherwise specified, 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.

[0126] The term aryl, alone or in combination, refers to phenyl, naphthyl, or anthracenyl optionally carbocyclically fused to 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 may be optionally substituted, with the substituents attached to the aryl at one point or the substituents attached to the aryl at two points to form a bicyclic ring system, e.g., benzodioxole, benzodioxane, benzimidazole.

[0127] The term heteroaryl, alone or in combination, means a monocyclic aromatic ring system containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing 1 to 3 heteroatoms independently selected from the group 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 system such that a stable aromatic ring is maintained. More specifically, the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzisoxazolyl, benzothiophenyl, dibenzofuran, benzodiazepin-2-one-5-yl, and the like.

[0128] 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 benzo-fused or fused with a 5- or 6-ring-membered heteroaryl, and / or optionally substituted as in the case of a 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 either case, a heterocyclyl can be fused with an aryl to form a bicyclic ring system.

[0129] 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 having from 3 to 6 ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like.

[0130] The term aralkyl refers to an organic compound containing an aromatic nucleus to which an alkyl group is attached. These alkyl groups include groups such as methyl, ethyl, propyl, butyl, and octyl. Thus, the term aralkyl is considered to include aralkyl hydrocarbons such as alkylbenzenes and various alkylnaphthalenes. From this definition of the term aralkyl compound, it can be seen that the term includes compounds such as benzyl, the three isomers of xylyl, the two isomers of trimethylbenzene, ethylbenzene, p-methylbiphenyl, and α-methylnaphthalene.

[0131] The present invention further relates to a pharmaceutical composition comprising a carrier and, as an active ingredient, an effective amount of a compound (C) of formula (Ia) or (I'a) as specified herein or a compound of any subgroup of compounds of formulae (IIa) to (IXa), (IIa-a) to (IXa-a), (IIb) to (IXb), (IIc) to (IXc), (IIa-1) to (XXXIIIa-1) and (IIa-a1) to (IXa-a1) as specified herein and defined in any one of the embodiments presented herein.

[0132] The present invention relates to a compound (C) of formula (Ia) or (I'a) as specified herein or any subgroup of compounds of formulae (IIa) to (IXa), (IIa-a) to (IXa-a), (IIb) to (IXb), (IIc) to (IXc), (IIa-1) to (XXXIIIa-1) and (IIa-a1) to (IXa-a1) as specified herein and defined in any one of the embodiments presented herein, for use as a medicament.

[0133] The present invention relates to the treatment of cancer, metabolic disorders (such as diabetes), inflammatory and autoimmune disorders (e.g., inflammatory bowel diseases, e.g., Crohn's disease and ulcerative colitis, inflammatory lung diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, and psoriasis and psoriatic arthritis), neurological disorders (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth neuropathy, amyotrophic lateral sclerosis, and epilepsy), atherosclerosis and cardiovascular disease, Sjogren's syndrome, renal allograft rejection, virally induced diseases, circulatory disorders, osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, pediatric disorders, and rheumatoid arthritis. The present invention relates to a compound (C) of formula (Ia) or (I'a) as specified herein, or a compound of any subgroup of compounds of formulae (IIa) to (IXa), (IIa-a) to (IXa-a), (IIb) to (IXb), (IIc) to (IXc), (IIa-1) to (XXXIIIa-1) and (IIa-a1) to (IXa-a1) as specified herein and defined in any one of the embodiments presented herein, for use in the treatment of a disease selected from endometriosis, asthma and allergic asthma, ocular diseases (such as retinopathy, age-related macular degeneration and uveitis), chronic and neuropathic pain, and fibroproliferative diseases.

[0134] The present invention further relates to a method of inhibiting protein kinase activity in a warm-blooded animal, comprising administering to an animal in need thereof a kinase-inhibiting effective amount of compound (C) of formula (Ia) or (I'a) as specified herein, or a compound of any subgroup of compounds of formulae (IIa)-(IXa), (IIa-a)-(IXa-a), (IIb)-(IXb), (IIc)-(IXc), (IIa-1)-(XXXIIIa-1) and (IIa-a1)-(IXa-a1) as specified herein and defined in any one of the embodiments presented herein.

[0135] The present invention further provides a method for inhibiting protein kinase activity in a warm-blooded animal, comprising administering to an animal in need thereof a kinase-inhibiting effective amount of compound (C) of formula (Ia) or (I'a) as specified herein, or a compound of any subgroup of compounds of formulae (IIa)-(IXa), (IIa-a)-(IXa-a), (IIb)-(IXb), (IIc)-(IXc), (IIa-1)-(XXXIIIa-1) and (IIa-a1)-(IXa-a1) as specified herein and according to any one of the embodiments presented herein, wherein the protein kinase is selected from the group consisting of 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 D1, ... 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), M The method is directed to a method in which the protein kinase is selected from the group consisting of APK1 (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). Preferably, the protein kinase is selected from the group consisting of CSF1R, FLT3, Kit, PDGFRB (PDGFR beta), and PDGFRA (PDGFR alpha).

[0136] The present invention further provides a method for the treatment of cancer, metabolic disorders (such as diabetes), inflammatory and autoimmune disorders (e.g., inflammatory bowel disease, e.g., Crohn's disease and ulcerative colitis, inflammatory lung disease, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, and psoriasis and psoriatic arthritis), neurological disorders (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth neuropathy, amyotrophic lateral sclerosis, and epilepsy), atherosclerosis and cardiovascular disease, Sjogren's syndrome, renal allograft rejection, virally induced diseases, circulatory disorders, osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, and asthma in warm-blooded animals. and a method of treating a disease selected from allergic asthma, eye diseases (such as retinopathy, age-related macular degeneration and uveitis), chronic and neuropathic pain, and fibroproliferative diseases, comprising administering to an animal in need thereof an effective amount of compound (C) of formula (Ia) or (I'a) as specified herein, or a compound of any subgroup of compounds of formulae (IIa)-(IXa), (IIa-a)-(IXa-a), (IIb)-(IXb), (IIc)-(IXc), (IIa-1)-(XXXIIIa-1) and (IIa-a1)-(IXa-a1) as specified herein and according to any one of the embodiments presented herein.

[0137] It should be noted that the radical positions on any molecular moiety used in these definitions may be anywhere on such moiety as long as it is chemically stable.

[0138] 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.

[0139] When any variable occurs more than once in any constituent, each definition is independent. Whenever used hereinafter, the term "compound (C) of formula (Ia)" or "the compound" or similar terms is meant to include all compounds (C) of formula (Ia), N-oxides, addition salts and stereochemical isomers. An embodiment includes compound (C) of formula (Ia), (I'a), or any subgroup of compounds of formulas (IIa) to (IXa), (IIa-a) to (IXa-a), (IIb) to (IXb), (IIc) to (IXc), (IIa-1) to (XXXIIIa-1) and (IIa-a1) to (IXa-a1), as specified herein, and N-oxides, salts, possible stereoisomeric forms thereof. Another embodiment includes compound (C) of formula (Ia), (I'a), or any subgroup of compounds of formulae (IIa) to (IXa), (IIa-a) to (IXa-a), (IIb) to (IXb), (IIc) to (IXc), (IIa-1) to (XXXIIIa-1) and (IIa-a1) to (IXa-a1), as specified herein, and salts, possible stereoisomeric forms thereof.

[0140] Compound (C) of formula (Ia) or (I'a) as specified herein, or any subgroup of compounds of formulae (IIa) to (IXa), (IIa-a) to (IXa-a), (IIb) to (IXb), (IIc) to (IXc), (IIa-1) to (XXXIIIa-1) and (IIa-a1) to (IXa-a1) as specified herein, possesses several chiral centers and exists as stereochemically isomeric forms. The term "stereochemically isomeric forms" as used herein defines all possible compounds composed of the same atoms bonded by the same bond sequence but having different, non-interchangeable three-dimensional structures that compound (C) of formula (Ia) as specified herein, or any subgroup of compounds of formulas (IIa) to (IXa), (IIa-a) to (IXa-a), (IIb) to (IXb), (IIc) to (IXc), (IIa-1) to (XXXIIIa-1) and (IIa-a1) to (IXa-a1) as specified herein, may have.

[0141] Unless otherwise stated or indicated, the chemical names of compounds (C) of formula (Ia) or (I'a) as specified herein, or of any subgroup of compounds of formulas (IIa)-(IXa), (IIa-a)-(IXa-a), (IIb)-(IXb), (IIc)-(IXc), (IIa-1)-(XXXIIIa-1), and (IIa-a1)-(IXa-a1) as specified herein, encompass mixtures of all possible stereochemically isomeric forms that the compounds may possess. Such mixtures may include all diastereomers and / or enantiomers of the basic molecular structure of the compounds. All stereochemically isomeric forms of the compounds of the present invention, either in pure form or mixed with one another, are intended to be embraced within the scope of the present invention.

[0142] Pure stereoisomeric forms of compound (C) of formula (Ia) or (I'a) as specified herein, or of any subgroup of compounds of formulae (IIa) to (IXa), (IIa-a) to (IXa-a), (IIb) to (IXb), (IIc) to (IXc), (IIa-1) to (XXXIIIa-1) and (IIa-a1) to (IXa-a1) as specified herein, and of intermediates referred to herein, are defined as isomers that are substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of the compound or intermediate. In particular, the term "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 isomer) and up to 100% (i.e., 100% of one isomer and none of the other), more particularly to compounds or intermediates having a stereoisomeric excess of 90% to 100%, even more particularly to compounds or intermediates having a stereoisomeric excess of 94% to 100%, and most particularly to compounds or intermediates having a stereoisomeric excess of 97% to 100%. The terms "enantiomerically pure" and "diastereomerically pure" should be understood in a similar manner, but taking into account the enantiomeric and diastereomeric excess, respectively, of the mixture in question.

[0143] The 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 their diastereomeric salts with optically active acids or bases.Examples include tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic 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 use enantiomerically pure starting materials.

[0144] The diastereomeric racemates of compound (C) of formula (Ia) or (I'a) as specified herein, or of any subgroup of compounds of formulae (IIa) to (IXa), (IIa-a) to (IXa-a), (IIb) to (IXb), (IIc) to (IXc), (IIa-1) to (XXXIIIa-1) and (IIa-a1) to (IXa-a1) as specified herein, can be obtained separately by conventional methods. Suitable physical separation methods which may be advantageously used are, for example, selective crystallization and chromatography, e.g., column chromatography.

[0145] The absolute stereochemical configuration of compounds (C) of formula (Ia) or (I'a) as specified herein, or of any subgroup of compounds of formulae (IIa) to (IXa), (IIa-a) to (IXa-a), (IIb) to (IXb), (IIc) to (IXc), (IIa-1) to (XXXIIIa-1) and (IIa-a1) to (IXa-a1) as specified herein, N-oxides, salts, solvates and intermediates used in the preparation thereof have not been experimentally determined.

[0146] 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 diffraction.

[0147] The present invention is further intended to include all isotopes of atoms occurring in compound (C) of formula (Ia) or (I'a) as specified herein, or in any subgroup of compounds of formulas (IIa)-(IXa), (IIa-a)-(IXa-a), (IIb)-(IXb), (IIc)-(IXc), (IIa-1)-(XXXIIIa-1), and (IIa-a1)-(IXa-a1) as specified herein. Isotopes include atoms having the same atomic number but different mass numbers. By way of general, non-limiting example, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0148] For therapeutic use, salts of compounds (C) of formula (Ia) or (I'a) as specified herein, or of any subgroup of compounds of formulas (IIa)-(IXa), (IIa-a)-(IXa-a), (IIb)-(IXb), (IIc)-(IXc), (IIa-1)-(XXXIIIa-1), and (IIa-a1)-(IXa-a1) as specified herein, 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 may also find use, 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.

[0149] The above-mentioned pharmaceutically acceptable acid and base addition salts are meant to include the therapeutically active non-toxic acid and base addition salts that can be formed by compound (C) of formula (Ia) or (I'a) as specified herein, or by compounds of any subgroup of compounds of formulas (IIa) to (IXa), (IIa-a) to (IXa-a), (IIb) to (IXb), (IIc) to (IXc), (IIa-1) to (XXXIIIa-1) and (IIa-a1) to (IXa-a1) as specified herein. Pharmaceutically acceptable acid addition salts can be conveniently obtained by treating the base form with a suitable acid in the anionic form of such. Suitable anions include, for example, trifluoroacetate, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsyiate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxyl Examples of counter ions include naphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, triethiodide, etc. The selected counter ion 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.

[0150] Compound (C) of formula (Ia) or (I'a) as specified herein, or any subgroup of compounds of formulas (IIa)-(IXa), (IIa-a)-(IXa-a), (IIb)-(IXb), (IIc)-(IXc), (IIa-1)-(XXXIIIa-1), and (IIa-a1)-(IXa-a1) as specified herein, containing an acidic proton, can also be converted to their non-toxic metal or amine addition salt forms by treatment with appropriate cationic organic and inorganic bases. Suitable base salts include those formed with organic cations such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, and the like, and those formed with metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Conversely, the salt forms can be converted to the free form by treatment with an appropriate acid.

[0151] The term addition salt as used herein above also includes solvates which the compound (C) of formula (Ia) or (I'a) as specified herein or any subgroup of compounds of formulae (IIa) to (IXa), (IIa-a) to (IXa-a), (IIb) to (IXb), (IIc) to (IXc), (IIa-1) to (XXXIIIa-1) and (IIa-a1) to (IXa-a1) as specified herein, and salts thereof, may form. Such solvates are, for example, hydrates, alcoholates, etc.

[0152] The N-oxide form of a compound (C) of formula (Ia) or (I'a) as specified herein or of any subgroup of compounds of formulae (IIa) to (IXa), (IIa-a) to (IXa-a), (IIb) to (IXb), (IIc) to (IXc), (IIa-1) to (XXXIIIa-1) and (IIa-a1) to (IXa-a1) as specified herein is meant to include compounds of formula (I) in which one or several nitrogen atoms are oxidized to the so-called N-oxide.

[0153] It will be appreciated that compound (C) of formula (Ia) or (I'a) as specified herein, or any subgroup of compounds of formulae (IIa) to (IXa), (IIa-a) to (IXa-a), (IIb) to (IXb), (IIc) to (IXc), (IIa-1) to (XXXIIIa-1) and (IIa-a1) to (IXa-a1) as specified herein, may have metal binding, chelating, complex-forming properties and may therefore exist as a metal complex or metal chelate. Such metallated derivatives of compound (C) of formula (Ia) or (I'a) as specified herein, or of any subgroup of compounds of formula (IIa)-(IXa), (IIa-a)-(IXa-a), (IIb)-(IXb), (IIc)-(IXc), (IIa-1)-(XXXIIIa-1) and (IIa-a1)-(IXa-a1) as specified herein, are intended to be included within the scope of the present invention.

[0154] Some of the compounds (C) of formula (Ia) or (I'a) as specified herein, or of any subgroup of compounds of formulae (IIa) to (IXa), (IIa-a) to (IXa-a), (IIb) to (IXb), (IIc) to (IXc), (IIa-1) to (XXXIIIa-1) and (IIa-a1) to (IXa-a1) as specified herein, may also exist in their tautomeric forms. Such forms, even if not explicitly shown in the above formula, are intended to be included within the scope of the present invention.

[0155] In a further aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of compound (C) of formula (Ia) or (I'a) as specified herein, or a compound of any subgroup of compounds of formulae (IIa) to (IXa), (IIa-a) to (IXa-a), (IIb) to (IXb), (IIc) to (IXc), (IIa-1) to (XXXIIIa-1), and (IIa-a1) to (IXa-a1) as specified herein, and a pharmaceutically acceptable carrier. A therapeutically effective amount in the context of the present invention is an amount effective to inhibit the activity of protein kinases, in particular 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 D1, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-39, IL-41, IL-42, IL-43, IL-44, IL-45, IL-46, IL-47, IL-48, 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) The amount of the compound is sufficient to prevent, stabilize, or reduce disease mediated by a protein kinase selected from the group consisting of: CSF1R, FLT3, Kit, PDGFRB (PDGFR beta), and PDGFRA (PDGFR alpha).

[0156] Examples of diseases mediated by protein kinases include, among others, cancer, metabolic disorders (such as diabetes), inflammatory and autoimmune disorders (e.g., inflammatory bowel diseases, e.g., Crohn's disease and ulcerative colitis, inflammatory lung diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, and psoriasis and psoriatic arthritis), neurological disorders (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth neuropathy, amyotrophic lateral sclerosis, and epilepsy), atherosclerosis and cardiovascular disease, Sjogren's syndrome, renal allograft rejection, virally induced diseases, circulatory disorders, osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, ocular diseases (such as retinopathy, age-related macular degeneration, and uveitis), chronic and neuropathic pain, and fibroproliferative diseases.

[0157] In a further aspect, the present invention relates to a process for preparing a pharmaceutical composition as specified herein, comprising intimately admixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound (C) of formula (Ia) or (I'a) as specified herein, or a compound of any subgroup of compounds of formulas (IIa) to (IXa), (IIa-a) to (IXa-a), (IIb) to (IXb), (IIc) to (IXc), (IIa-1) to (XXXIIIa-1) and (IIa-a1) to (IXa-a1) as specified herein.

[0158] Thus, compound (C) of formula (Ia) or (I'a) as specified herein, or any subgroup of compounds of formulas (IIa)-(IXa), (IIa-a)-(IXa-a), (IIb)-(IXb), (IIc)-(IXc), (IIa-1)-(XXXIIIa-1), and (IIa-a1)-(IXa-a1) as specified herein, can be formulated into various pharmaceutical forms for administration purposes. Suitable compositions include all compositions typically used for systemic drug administration. To prepare the pharmaceutical compositions of the present invention, an effective amount of the specific compound as the active ingredient, optionally in addition salt form or metal complex form, is combined in intimate admixture with a pharmaceutically acceptable carrier, which can take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are preferably in unitary dosage forms suitable for oral, rectal, transdermal administration, or parenteral injection. For example, in preparing compositions in oral dosage form, any of the usual pharmaceutical media can be used, such as water, glycols, oils, alcohols, and the like 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.

[0159] Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously used. For parenteral compositions, the carrier usually comprises, at least in large part, sterile water, although other ingredients, for example, to aid solubility, may be included. For example, injection solutions can be prepared in which the carrier comprises saline, glucose solution, or a mixture of saline and glucose solution. Injection suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents, etc. can be used. Solid-form preparations intended to be converted into liquid-form preparations immediately before use are also included. In compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and / or a suitable wetting agent, optionally combined with minor amounts of suitable additives of any nature that do not introduce significant adverse effects on the skin.

[0160] Compound (C) of formula (Ia) or (I'a) as specified herein, or any subgroup of compounds of formula (IIa) to (IXa), (IIa-a) to (IXa-a), (IIb) to (IXb), (IIc) to (IXc), (IIa-1) to (XXXIIIa-1) and (IIa-a1) to (IXa-a1) as specified herein, of the present invention may also be administered via oral inhalation or insufflation methods using methods and formulations used in the art for administration via this method. Thus, in general, compound (C) of formula (Ia) or (I'a) as specified herein, or any subgroup of compounds of formulae (IIa)-(IXa), (IIa-a)-(IXa-a), (IIb)-(IXb), (IIc)-(IXc), (IIa-1)-(XXXIIIa-1) and (IIa-a1)-(IXa-a1) as specified herein, can be administered to the lung in the form of a solution, suspension or dry powder, preferably a solution. Any system developed for the delivery of solutions, suspensions or dry powders via oral inhalation or insufflation is suitable for administering the present compounds.

[0161] Accordingly, the present invention further provides a pharmaceutical composition adapted for administration by inhalation or insufflation via the mouth, comprising a compound (C) of formula (Ia) or (I'a) as specified herein, or a compound of any subgroup of compounds of formulae (IIa) to (IXa), (IIa-a) to (IXa-a), (IIb) to (IXb), (IIc) to (IXc), (IIa-1) to (XXXIIIa-1) and (IIa-a1) to (IXa-a1) as specified herein, and a pharmaceutically acceptable carrier. Preferably, the compounds of the invention are administered in a nebulized or aerosolized dose via inhalation of a solution.

[0162] For ease of administration and uniformity of dosage, it is particularly advantageous to prepare the above-mentioned pharmaceutical composition in unit dosage form.Unit dosage form as used herein refers to a physically separate unit that is suitable as unit dosage, and each unit contains a predetermined amount of active ingredient that is calculated to produce desired therapeutic effect, combined with necessary pharmaceutical carrier.The example of such unit dosage form is tablet (including scored tablet or coated tablet), capsule, pill, suppository, powder packet, wafer, injection solution or suspension etc., and their multiple portions (segregated multiple).

[0163] Compounds (C) of formula (Ia) or (I'a) as specified herein, or compounds of any subgroup of compounds of formulae (IIa) to (IXa), (IIa-a) to (IXa-a), (IIb) to (IXb), (IIc) to (IXc), (IIa-1) to (XXXIIIa-1) and (IIa-a1) to (IXa-a1) as specified herein, exhibit kinase inhibitory properties. Diseases and disorders treatable using the compounds and methods of the invention include diseases mediated by protein kinases, such as cancer, metabolic disorders (such as diabetes), inflammatory and autoimmune disorders (e.g., inflammatory bowel disease, e.g., Crohn's disease and ulcerative colitis, inflammatory lung disease, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, and psoriasis and psoriatic arthritis), neurological disorders (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth neuropathy, amyotrophic lateral sclerosis, and epilepsy), atherosclerosis and cardiovascular disease, Sjogren's syndrome, renal allograft rejection, virally induced diseases, circulatory disorders, osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, ocular diseases (such as retinopathy, age-related macular degeneration, and uveitis), chronic 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 are free of unfavorable phenomena such as insufficient rapid onset and tissue retention.

[0164] The combination of the present invention can be used as a medicine. Such use as a medicine or method of treatment includes systemic administration to a diseased subject of an amount effective to combat the conditions associated with the disease. In conclusion, the combination of the present invention can be used to treat cancer, metabolic disorders (such as diabetes), inflammatory and autoimmune disorders (e.g., inflammatory bowel disease, e.g., Crohn's disease and ulcerative colitis, inflammatory lung disease, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, and psoriasis and psoriatic arthritis), neurological disorders (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot-Marie-Tooth neuropathy, amyotrophic lateral sclerosis, and epilepsy), atherosclerosis, and cardiovascular diseases. The present invention can be used in the manufacture of a medicament useful for the treatment, prevention, or combating of diseases or conditions associated with protein kinases, including diseases, Sjogren's syndrome, renal allograft rejection, virally induced diseases, circulatory diseases, osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, eye diseases (such as retinopathy, age-related macular degeneration, and uveitis), chronic and neuropathic pain, and fibroproliferative diseases.

[0165] As used herein, the term "therapeutically effective amount" means an amount of an active compound or 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.

[0166] In general, an effective antiviral daily dose is contemplated to be between 0.01 mg and 1500 mg per day, more preferably between 0.1 mg and 50 mg per day. It may be appropriate to administer the required dose as one, two, three, four or more (sub)doses at appropriate intervals throughout the day. The (sub)doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, particularly 5 to 200 mg, of active ingredient per unit dosage form.

[0167] The exact dosage and frequency of administration depend on the specific compound (C) of formula (Ia) or (I'a) specified herein, or any subgroup of compounds of formulas (IIa)-(IXa), (IIa-a)-(IXa-a), (IIb)-(IXb), (IIc)-(IXc), (IIa-1)-(XXXIIIa-1), and (IIa-a1)-(IXa-a1) specified herein, the specific condition being treated, the severity of the condition being treated, the age, weight, sex, degree of disability, and general physical condition of the particular patient, and other medications the individual may be taking, which are well known to those skilled in the art. Furthermore, it is clear that the effective daily dose may be reduced or increased depending on the response of the treated subject and / or the evaluation of the physician prescribing the compound of the present invention. Therefore, the effective daily dose ranges described above are only guidelines. [Example]

[0168] Example 1: General synthetic procedure for analogs 3-76, 205-210 and 247-265

[0169] The following procedures exemplify the preparation of analogs 3-76, 205-210, and 247-265. The synthetic schemes are outlined below. In Method A, the synthesis begins with the coupling of a 4-chloroquinoline derivative with the appropriate ethyl or methyl 3-hydroxybenzoate derivative. In Method B, the carboxylic acid is prepared by deesterification of the ethyl or methyl 3-hydroxybenzoate derivative. In Methods C, D, or E, the 3-(4-quinolyloxy)benzamide is prepared from the corresponding benzoic acid by activation with either DMAP (Method C, compounds 3-67 and 205-210), HOBt (Method D, compounds 68-75), or 2-chloro-1-methyl-pyridinium iodide (Method E, compound 76), followed by reaction with the appropriate amine R8NH2. Examples of the structures of the final compounds can be found in Table 1.

[0170] [ka]

[0171] Method A: To a solution of ethyl or methyl 3-hydroxybenzoate (1 equiv.) in DMF (5 mL / mmol) under nitrogen, solid cesium carbonate (2.5 equiv.) was added, followed by 4-chloroquinoline (1 equiv.). The reaction mixture was stirred at 110 °C until completion (2 h to overnight). A saturated solution of NH4Cl was added, and the aqueous layer was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on a Biotage (cyclohexane / EtOAc: 0-50%) to afford the expected intermediate 1.

[0172] The following compound 1a is an example illustrating Method A.

[0173] Preparation of ethyl 3-(4-quinolyloxy)benzoate (1a): [ka]

[0174] Intermediate 1a was synthesized according to general method A from ethyl-3-hydroxybenzoate (6.02 mmol) and 4-chloroquinoline (6.02 mmol) in 77% yield as a colorless oil.

[0175] The following table shows intermediate 1 prepared by Method A:

number

[0176] Method B: To a solution of the appropriate intermediate 1 (1 equiv.) in EtOH or MeOH (2.5 mL / mmol) was added a solution of NaOH 2N (2.9 mL / mmol). The reaction mixture was stirred at 50 °C or rt until completion. The EtOH or MeOH was removed and the crude product was acidified with HCl 1N until pH = 2-3. The precipitate was filtered off, washed with water, and dried over PO in a vacuum desiccator to give the expected intermediate 2.

[0177] The following compound 2a is an example illustrating Method B.

[0178] Preparation of 3-(4-quinolyloxy)benzoic acid (2a): [ka]

[0179] Intermediate 2a was synthesized according to general method B from intermediate 1a (5.28 mmol) in 89% yield as a white powder.

[0180] The following table shows intermediate 2 prepared by method B:

number

[0181] Method C: To a suspension of the appropriate intermediate 2 (1 equiv.) in DCM (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 product was purified by flash column chromatography (DCM / MeOH: 0–10%) and reverse-phase chromatography (HO / MeOH: 0–100%) on a Biotage to give the expected compound.

[0182] The following compound 32 is an example illustrating Method C:

[0183] Preparation of 3-[(7-methoxy-4-quinolyl)oxy]-2-methyl-N-(4-pyridylmethyl)benzamide (32): [ka]

[0184] Compound 32 was synthesized according to general procedure C from intermediate 2e (0.30 mmol) and 4-(aminomethyl)pyridine (0.33 mmol) in 81% yield (97 mg) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.05(t,J=5.86Hz,1H),8.61(d,J=5.14Hz,1H),8.54-8.52(m,2H),8.27(d,J=9.07Hz,1H), 7.45-7.43(m,3H),7.36-7.31(m,4H),6.32(d,J=5.15Hz,1H),4.49(d,J=6.07Hz,2H),3.95(s,3H),2.15(s,3H);MS(ESI,EI + ): m / z=400.20(MH + ).

[0185] Method D: To a suspension of the appropriate intermediate 2 (1 equiv.) in DMF (5 mL / mmol) under nitrogen, EDC.HCl (1.2 equiv.) and HOBt (1.2 equiv.) were added, and the reaction mixture was stirred at room temperature for 5 min. The appropriate amine (1.3 equiv.) was added, and the reaction mixture was stirred at room temperature overnight (or over the weekend). The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH: 0-5%) and reverse-phase chromatography (HO / MeOH: 0-100%) on a Biotage to give the expected compound.

[0186] The following compound 68 is an example illustrating Method D: Preparation of 3-methoxy-N-[(2-methoxyphenyl)methyl]-5-(4-quinolyloxy)benzamide (68): [ka]

[0187] Compound 68 was synthesized according to general method D from intermediate 2c (0.237 mmol) and 2-methoxybenzylamine (0.308 mmol) in 56% yield (55 mg) as a white powder.1 H NMR(400MHz,CDCl3)δ(ppm):8.70(d,J=5.13Hz,1H),8.31(dd,J=0.95Hz and J=8.40Hz,1H),8.11( d,J=8.44Hz,1H),7.79-7.75(m,1H),7.60-7.56(m,1H),7.34(dd,J=1.55Hz and J=7.38Hz,1H),7.3 0-7.26(m,2H),7.11-7.10(m,1H),6.95-6.91(m,1H),6.89-6.87(m,1H),6.85-6.84(m,1H),6.6 4(brs,1H),6.61(d,J=5.18Hz,1H),4.62(d,J=5.74Hz,2H),3.85(s,3H),3.84(s,3H);MS(ESI,EI + ): m / z=415.4(MH + ).

[0188] Method E: To a suspension of the appropriate intermediate 2 (1 equiv.) in DMF (10 mL / mmol) under nitrogen, triethylamine (2.4 equiv.), the appropriate amine (1.2 equiv.), and then 2-chloro-1-methylpyridinium iodide (1.5 equiv.) were added. The reaction mixture was stirred at room temperature for 5 min. The appropriate amine (1.3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM, and the organic layer was washed with brine. The aqueous layer was extracted once with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH: 0-5%) and reverse-phase chromatography (HO / MeOH: 0-100%) on a Biotage to give the expected compound.

[0189] The following compound 76 is an example illustrating Method E:

[0190] Preparation of N-(1-methylindazol-3-yl)-3-(4-quinolyloxy)benzamide (76): [ka]

[0191] Compound 76 was synthesized according to general method E from intermediate 2a (0.186 mmol) and 1-methyl-1,1-indazol-3-amine (0.226 mmol) in 65% yield (48 mg) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.9(s,1H),8.74(d,J=5.12Hz,1H),8.34(dd,J=8.22Hz and J=0.8Hz,1H),8.07-7.97(m,3H),7.87-7.8 3(m,1H),7.74-7.67(m,3H),7.60-7.55(m,2H),7.42-7.37(m,1H),7.11-7.07(m,2H),6.75(d,J=5.23Hz,1H),4.00(s,3H);MS(ESI,EI + ): m / z = 395.10 (MH + ).

[0192] Example 2: General procedure for the preparation of analogs 84-110 and 211

[0193] The following procedures illustrate the preparation of analogs 84-110 and 211, and the synthetic schemes are outlined below. The synthesis begins with the amidation of the appropriate 3-hydroxybenzoic acid by the appropriate amine step (hereinafter referred to as Methods F, G, or H) via activation with either HOBt, EDC.HCl, and TEA (Method F), PyBOP and DIEA (Method G), or EDC.HCl (Method H). In the final step of Method I, the preparation of 3-(4-quinolyloxy)benzamide analogs 84-110 and 211 was achieved from the corresponding 4-chloroquinoline derivatives. Example structures of the final compounds can be found in Table 1.

[0194] [ka]

[0195] Method F: To a solution of the appropriate carboxylic acid (1 equiv.) in DMF (5-6 mL / mmol) under nitrogen, the appropriate amine (1.3 equiv.), triethylamine (1.2 equiv.), HOBt (1.1 equiv.), and then EDC.HCl (1.1 equiv.) were added. The reaction mixture was stirred at room temperature overnight (or until completion). The mixture was diluted with ethyl acetate and washed three times with water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was either purified by flash chromatography on silica gel (DCM / MeOH: 0-2.5%) or triturated in Et2O to give the expected intermediate.

[0196] The following compound 77a is an example illustrating Method F.

[0197] Preparation of 4-fluoro-3-hydroxy-N-[(2-methoxyphenyl)methyl]benzamide (77a): [ka]

[0198] Intermediate 77a was synthesized according to general procedure F from 4-fluoro-3-hydroxy-benzoic acid (0.641 mmol) and 2-methoxybenzylamine (0.833 mmol) in 94% yield as a yellow oil.

[0199] Method G: To a stirred solution of the appropriate carboxylic acid (1 equiv.) in DMF (6 mL / mmol) under nitrogen was added DIEA (1.1 equiv.), PyBOP (1 equiv.), and the appropriate amine (1.5 equiv.). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed and the crude product was co-evaporated with toluene under reduced pressure. The oil was purified by reverse-phase chromatography (HO / MeOH: 0-100%) to give the expected intermediate.

[0200] The following compound 77g is an example illustrating Method G.

[0201] Preparation of 4-fluoro-3-hydroxy-N-(4-pyridylmethyl)benzamide (77 g): [ka]

[0202] Intermediate 77g was synthesized as a white powder in 35% yield from 4-fluoro-3-hydroxy-benzoic acid (3.0 mmol) and 4-(aminomethyl)pyridine (4.50 mmol) following general method G.

[0203] Method H: To a stirred solution of the appropriate carboxylic acid (1 equiv.) in DMF (4-5 mL / mmol) under nitrogen was added the appropriate amine (1.2 equiv.) and EDC.HCl (1.5 equiv.). The reaction mixture was stirred at room temperature overnight. The solvent was removed and water was added. The mixture was extracted with ethyl acetate, and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (DCM / MeOH: 0-5%) to give the expected intermediate.

[0204] The following compound 81e is an example illustrating Method H:

[0205] Preparation of 3-hydroxy-2-methyl-N-(4-pyridylmethyl)benzamide (81e): [ka]

[0206] Intermediate 81e was synthesized in 80% yield as a white powder from 2-methyl-3-hydroxybenzoic acid (2.00 mmol) and 4-(aminomethyl)pyridine (2.00 mmol) according to general procedure H. MS (ESI, EI + ): m / z=243.3(MH + ).

[0207] The following table shows intermediates 77-83 prepared by Methods F, G or H:

number

[0208] Method I: In an oven-dried screw-cap test tube, the appropriate quinoline (1 equiv.) and cesium carbonate (2.5 equiv.) were added to a solution of the appropriate hydroxylbenzamide (1 equiv. or 1.1 equiv.) in DMF (5 mL / mmol). The reaction mixture was stirred at 90-100 °C until completion (1 h to overnight) and concentrated under reduced pressure. The crude product was purified by flash chromatography (DCM / MeOH: 0-5%) and reverse-phase chromatography (HO / MeOH: 0-100%) to give the expected compound.

[0209] The following compound 108 is an example illustrating Method I:

[0210] Preparation of 3-[(7-chloro-4-quinolyl)oxy]-2-methyl-N-(4-pyridylmethyl)benzamide (108): [ka]

[0211] Compound 108 was synthesized according to general method H from intermediate 81e (0.20 mmol) and 4,7-dichloroquinoline (0.20 mmol) in 41% yield (33 mg) as a white solid. 1 H NMR(400MHz,CDCl3)δ(ppm):9.05(t,J=6.03Hz,1H),8.73(d,J=5.15Hz,1H),8.54-8.53(m,2H),8.41(d,J=9.03Hz,1H),8.11(d,J=2.08Hz,1H) ,7.73(dd,J=8.85 and 1.97Hz,1H),7.47-7.44(m,2H),7.40-7.35(m,3H),6.49(d,J=5.13Hz,1H),4.50(d,J=5.90Hz,2H),2.15(s,3H);MS(ESI,EI + ): m / z = 402.2 (MH + ).

[0212] Example 3: General procedure for the preparation of analogs 113-114

[0213] The following procedures illustrate the preparation of analogs 113-114, and the synthetic schemes are outlined below. Examples of structures of the final compounds can be found in Table 1.

[0214] [ka]

[0215] Compound 113 below is an example illustrating these procedures.

[0216] Preparation of benzofuran-3-one oxime (111): [ka]

[0217] To a solution of 2,3-dihydrobenzofuran-3-one (1.86 mmol) in MeOH (2.5 mL / mmol) were added TEA (3.73 mmol) and hydroxylamine hydrochloride (3.73 mmol). The reaction mixture was stirred overnight at room temperature. Since starting material was always present, TEA (1.86 mmol) and hydroxylamine hydrochloride (1.86 mmol) were added, and the reaction mixture was stirred again for 16 h. The solvent was removed, and the mixture was diluted with ethyl acetate and washed three times with water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the expected intermediate 111 as a yellow solid in 93% yield. MS (ESI, EI) + ): m / z=150(MH + ).

[0218] Preparation of 2,3-dihydrobenzofuran-3-amine (112): [ka]

[0219] To a solution of intermediate 111 (1.74 mmol) in EtOH (7 mL / mmol) was added 50% Raney Ni in water (500 mg). The reaction mixture was hydrogenated at room temperature overnight. The crude product was filtered through a pad of Celite and washed with ethanol. The filtrate was concentrated under reduced pressure, and the solid was dried under vacuum to give the expected intermediate 112 as a dark orange gum in 90% yield.

[0220] Preparation of N-(2,3-dihydrobenzofuran-3-yl)-3-(4-quinolyloxy)benzamide (113): [ka]

[0221] To a solution of intermediate 2a (0.226 mmol) and intermediate 112 (0.34 mmol) in DCM (2.5 mL) was added solid DMAP (0.497 mmol), followed by EDC.HCl (0.452 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen. The crude product was diluted with DCM and washed with water. The aqueous phase was extracted, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on a Biotage (DCM / MeOH: 0-10%) to give the expected compound 113 as a white solid in 27% yield (23 mg). 1 H NMR(400MHz,CDCl3)δ(ppm):8.68(d,J=5.30Hz,1H),8.35(d,J=8.39Hz,1H),8.21(d,J=8.39Hz,1H),7.85-7.79(m,1H),7.72-7.53(m,4H),7. 40-7.34(m,2H),7.30-7.25(m,1H),6.97-6.88(m,2H),6.59-6.56(m,2 H),5.82-5.76(m,1H),4.82-4.76(m,1H),4.50-4.46(m,1H);MS(ESI,EI + ): m / z=383(MH + ).

[0222] Example 4: Procedure for the preparation of N-(1-tert-butylpyrazol-4-yl)-3-(4-quinolyloxy)benzamide 117

[0223] The following procedure illustrates the preparation of N-(1-tert-butylpyrazol-4-yl)-3-(4-quinolyloxy)benzamide 117, and the synthetic scheme is outlined below.

[0224] [ka]

[0225] Preparation of 1-tert-butyl-4-nitro-pyrazole (115): [ka]

[0226] To a stirred solution of 4-nitropyrrole (8.84 mmol) and tert-butyl bromide (115 mmol) in DMF (44 mL) under nitrogen, potassium carbonate (141.5 mmol) was added. The reaction mixture was warmed to 80 °C overnight. DMF was removed, and the crude mixture was dissolved in DCM and washed twice with brine. The aqueous phase was extracted once, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on a Biotage (cyclohexane / EtOAc: 0-30%) to give the expected compound 115 as a white solid in 49% yield (730 mg). MS (ESI, EI) + ): m / z=170(MH + ).

[0227] Preparation of 1-tert-butylpyrazol-4-amine (116): [ka]

[0228] To a solution of intermediate 115 (4.30 mmol) in EtOH (7 mL / mmol) was added 10% Pd / C (80 mg). The reaction mixture was hydrogenated at room temperature overnight. The crude product was filtered through a pad of Celite and washed with ethanol. The filtrate was concentrated under reduced pressure and the solid was dried under vacuum to give the expected intermediate 116 as a dark gum in quantitative yield. MS (ESI, EI + ): m / z=140(MH + ).

[0229] Preparation of N-(1-tert-butylpyrazol-4-yl)-3-(4-quinolyloxy)benzamide (117): [ka]

[0230] To a solution of intermediate 2a (0.188 mmol) and intermediate 116 (0.282 mmol) in DMF (2 mL) was added solid DMAP (0.415 mmol), followed by EDC.HCl (0.376 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen. The crude product was diluted with DCM and washed with water. The aqueous phase was extracted, and the combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH: 0-5%) and reverse-phase chromatography (HO / MeOH: 0-100%) on a Biotage to give the expected compound 117 as a white solid in 54% yield (39 mg). 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.51(s,1H),8.80(d,J=5.09Hz,1H),8.35(dd,J=8.30Hz and J=0.91Hz,1H),8.14-8. 12(m,2H),8.01-7.98(m,1H),7.94-7.90(m,2H),7.77-7.58(m,4H),6.77(d,J=5.01Hz,1H),1.57(s,9H);MS(ESI,EI + ): m / z=385(MH + ).

[0231] Example 5: General procedure for the preparation of analogs 122-124

[0232] The following procedures illustrate the preparation of analogs 122-124, and the synthetic schemes are outlined below. Example structures of the final compounds can be found in Table 1.

[0233] [ka]

[0234] Compound 122 below is an example illustrating these procedures.

[0235] Preparation of 3-nitro-1H-indole (118): [ka]

[0236] To a stirred solution of NBS (21.34 mmol) in CHCN (43 mL) under nitrogen, AgNO (21.34 mmol) was added as a solid. The reaction mixture was heated to reflux for 5 min, and indole (21.34 mmol) was added. The reaction mixture was stirred at 70 °C for 3 h, then diluted with DCM and washed with a saturated solution of sodium bicarbonate. The aqueous phase was extracted once, and the combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on a Biotage (DCM / MeOH: 0-3%) to give the expected compound 118 as a brown solid in 24% yield. MS (ESI, EI) + ): m / z=163(MH + ).

[0237] Preparation of 1-methyl-3-nitro-indole (119): [ka]

[0238] To a solution of intermediate 118 (2.46 mmol) in DMF (12 mL) was added 60% sodium hydride in mineral oil (3.70 mmol). The reaction mixture was stirred at 50 °C for 1 h. Methyl indole (9.86 mmol) was then added at room temperature, and the reaction mixture was stirred for 1 h. The reaction mixture was then diluted with EtOAc and washed with a saturated solution of ammonium chloride. The aqueous phase was extracted once, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on a Biotage (DCM / MeOH: 0-2%) to give the expected compound 119 as a beige solid in quantitative yield. MS (ESI, EI) + ): m / z=177(MH + ).

[0239] Preparation of 1H-indol-3-amine (120): [ka]

[0240] To a solution of intermediate 118 (1.31 mmol) in EtOH (10 mL) was added 10% Pd / C (25 mg). The reaction mixture was hydrogenated at room temperature overnight. The crude product was filtered through a pad of Celite and washed with ethanol. The filtrate was concentrated under reduced pressure, and the solid was dried under vacuum to give the expected intermediate 120 as a dark solid in quantitative yield. MS (ESI, EI + ): m / z=133(MH + ).

[0241] Preparation of 1-methylindole-3-amine (121): [ka]

[0242] The previous procedure was used with intermediate 120 (2.48 mmol) and 10% Pd / C (50 mg) to give intermediate 121 in 75% yield as a red gum. MS (ESI, EI) + ): m / z=147(MH + ).

[0243] Preparation of N-(1H-indol-3-yl)-3-(4-quinolyloxy)benzamide (122): [ka]

[0244] To a solution of intermediate 2a (0.188 mmol) and intermediate 120 (0.282 mmol) in DMF (2 mL) was added solid DMAP (0.415 mmol), followed by EDC.HCl (0.376 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen. The crude product was diluted with DCM and washed with water. The aqueous phase was extracted, and the combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH: 0-9%) and reverse-phase chromatography (HO / MeOH: 0-100%) on a Biotage to give the expected compound 122 as a beige solid in 13% yield (9 mg). 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.92(s,1H),10.23(s,1H),8.74(d,J=5.19Hz,1H ),8.35(dd,J=8.16Hz and J=0.86Hz,1H),8.08-8.05(m,1H),8.01-7.99(m,1H),7.95 -7.94(m,1H),7.88-7.77(m,3H),7.72-7.67(m,2H),7.54-7.51(m,1H),7.36-7.3 5(m,1H),7.11-7.08(m,1H),7.00-6.96(m,1H),6.73(d,J=5.09Hz,1H);MS(ESI,EI + ): m / z=380.10(MH + ).

[0245] Example 6: Procedure for the preparation of 3-[(2-amino-4-quinolyl)oxy]-N-benzyl-benzamide 127

[0246] The following procedure illustrates the preparation of 3-[(2-amino-4-quinolyl)oxy]-N-benzyl-benzamide analog 127, and the synthetic scheme is outlined below.

[0247] [ka]

[0248] Preparation of N-(4-chloro-2-quinolyl)-1,1-diphenyl-methanimine (125): [ka]

[0249] To a solution of 2,4-dichloroquinoline (1.51 mmol) in dry toluene (15 mL), NaOtBu (2.27 mmol), BINAP (0.15 mmol), and Pd(dba) (0.076 mmol) were added, and the reaction mixture was stirred at room temperature for 5 min. Finally, diphenylmethanamine (1.51 mmol) was added, and the reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was concentrated, and the crude product was partitioned with ethyl acetate and water. The organic layer was washed with water, brine, dried over NaSO, and concentrated to give the expected intermediate 125 as a brown solid, which was used in the next step without purification.

[0250] Preparation of 4-chloroquinolin-2-amine (126): [ka]

[0251] To a solution of intermediate 125 (1.514 mmol) in THF (5 mL) was added an aqueous solution of HCl (1N) (1.5 mL), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized with aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography (DCM / MeOH: 0-3%) and reverse-phase chromatography (HO / MeOH: 0-100%) to give the expected compound 126 as a white solid in 57% yield (over two steps). MS (ESI, EI) + ): m / z=179.1(MH + ).

[0252] Preparation of 3-[(2-amino-4-quinolyl)oxy]-N-benzyl-benzamide (127): [ka]

[0253] Compound 127 was synthesized according to general method I from intermediate 83a (0.308 mmol) and intermediate 126 (0.280 mmol) in 19% yield (20 mg) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.00(d,J=8.22Hz,1H),7.63-7.60(m,1H),7.57-7.49(m,3H),7.44-7.41(m,1H) ),7.27-7.26(m,4H),7.24-7.20(m,3H),6.46-6.43(m,1H),5.72(s,1H),4.56(s,2H),4.55(s,2H);MS(ESI,EI + ): m / z = 370.1 (MH + ).

[0254] Example 7: Procedure for the preparation of 7-aminoquinoline analogs 134-153 and 266-272

[0255] The following procedures illustrate the preparation of 7-aminoquinoline analogs 134-153 and 266-272, and the synthetic schemes are outlined below.

[0256] The synthesis begins with the coupling of 7-bromo-4-chloroquinoline with intermediates 83a, 83e, 77g, 77d, 81e, or 81b according to Method I described in Example 2. Method J achieved the preparation of analogs 134-153 and 266-272 by amination at the bromo position. Examples of the structures of the final compounds can be found in Table 1.

[0257] [ka]

[0258] Method J: The appropriate intermediate (1 equiv.), tris(dibenzylideneacetone)dipalladium (0.05–0.075 equiv.), JohnPhos (0.10–0.15 equiv.), and sodium tert-butoxide (2 equiv.) were placed in an oven-dried screw-cap test tube. The tube was then evacuated under vacuum and backfilled with nitrogen (this sequence was repeated three times). Toluene (10 mL / mmol) and the appropriate amine (5 equiv.) were added. The reaction mixture was stirred and heated at 100 °C overnight. The mixture was then concentrated and purified by flash column chromatography (DCM / MeOH: 0–10%) and reverse-phase chromatography (HO / MeOH: 0–100%) on a Biotage™ to afford the expected compounds.

[0259] The following compound 134 is an example illustrating Method J:

[0260] Preparation of N-benzyl-3-[[7-(methylamino)-4-quinolyl]oxy]benzamide (134): [ka]

[0261] Compound 134 was synthesized according to general method J from intermediate 128 (0.20 mmol) and methylamine (2 M in THF, 1.00 mmol) in 50% yield (35 mg) as a yellow powder. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.12(t,J=5.65Hz,1H),8.46(d,J=5.21Hz,1H),7.95(d,J=9.04Hz ,1H),7.86-7.84(m,1H),7.73(t,J=1.88Hz,1H),7.61(t,J=7.91Hz,1H),7.43-7.40(m,1H),7.35- 7.30(m,4H),7.26-7.22(m,1H),7.04(dd,J=9.08 and 2.23Hz,1H),6.78(d,J=2.24Hz,1H),6.46(q, J=4.83Hz,1H),6.30(d,J=5.26Hz,1H),4.47(d,J=5.91Hz,2H),2.81(d,J=5.18Hz,3H) + ): m / z=429.2(MH + ).

[0262] Example 8: Procedure for the preparation of 7-aminoquinoline analogs 154 and 273

[0263] The following procedures illustrate the preparation of 7-aminoquinoline analogs 154 and 273, and the synthetic schemes are outlined below. Example structures of the final compounds can be found in Table 1.

[0264] [ka]

[0265] Compound 154 below is an example illustrating this procedure.

[0266] Intermediate 128 (1 equiv.), CuI (0.2 equiv.), L-proline (0.40 equiv.), and potassium carbonate (3 equiv.) were placed in an oven-dried screw-cap test tube. The tube was then evacuated under vacuum and backfilled with nitrogen (this sequence was repeated three times). DMSO (10 mL / mmol) and ammonium hydroxide (0.6 mL / mmol) were added. The reaction mixture was stirred and heated at 80 °C for 40 h. The mixture was then partitioned between DCM and a saturated solution of ammonium chloride. The aqueous phase was extracted twice with DCM, and the combined organic layers were dried over NaSO, filtered, and concentrated. The crude product was purified by flash column chromatography on a Biotage™ (HO / MeOH: 0-100%) to give the expected compound 154 as a yellow powder in 11% yield (8 mg). MS (ESI, EI+): m / z = 370.1 (MH+).

[0267] Example 9: Procedures for the preparation of alkyl and aryl quinoline analogs 155 and 344-387

[0268] The following procedures illustrate the preparation of alkyl and aryl quinoline analogs 155 and 344-387 by Suzuki-Miyaura cross-coupling according to Method K1 (compounds 155, 344-372) or Method K2 (compounds 373-387), and the synthetic schemes are outlined below. When the reaction is carried out with ester derivatives, saponification according to General Method B described in Example 1 and peptide coupling according to General Method C are necessary to obtain the final compounds. Examples of the structures of the final compounds can be found in Table 1.

[0269] [ka]

[0270] Method K1: The appropriate intermediate (1 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), DCM (0.10 equiv.), alkyl or aryl boronic acid or pinacol ester (1.2 equiv.), and cesium carbonate (2.4 equiv.) were placed in an oven-dried screw-cap test tube. The tube was then evacuated under vacuum and backfilled with nitrogen (this sequence was repeated three times). Dioxane (10 mL / mmol) was added. The reaction mixture was stirred and heated at 100 °C until completion (1 h to overnight). The mixture was then concentrated and purified by flash column chromatography (DCM / MeOH: 0-10%) and reverse-phase chromatography (HO / MeOH: 0-100%) on a Biotage to give the expected compound.

[0271] The following compound 155 is an example illustrating method k1:

[0272] Preparation of N-benzyl-3-[(7-methyl-4-quinolyl)oxy]benzamide (155): [ka]

[0273] Compound 155 was synthesized as a white powder in 77% yield (56 mg) from intermediate 128 (0.20 mmol) and methylboronic acid (0.24 mmol) according to general method k1. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.13(t,J=5.92Hz,1H),8.67(d,J=5.15Hz,1H),8.20(d,J=8.44Hz,1H),7.89-7.84(m,2H),7.78-7.77(m,1H),7.63( t,J=7.98Hz,1H),7.53-7.46(m,2H),7.32-7.30(m,4H),7.26-7.21(m,1H) ),6.61(d,J=5.20Hz,1H),4.47(d,J=5.93Hz,2H),2.55(s,3H);MS(ESI,EI + ): m / z=369.2(MH + ).

[0274] Method K2: The appropriate intermediate (1 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), DCM (0.10 equiv.), and an arylboronic acid or pinacol ester (1.2 equiv.) were placed in an oven-dried screw-cap test tube. The tube was then evacuated under vacuum and backfilled with nitrogen (this sequence was repeated three times). Dioxane (10 mL / mmol) and cesium carbonate (1 M aqueous solution, 3 equiv.) were added under a nitrogen atmosphere. The reaction mixture was stirred and heated at 100 °C until completion (1 h to overnight). The mixture was then concentrated and purified by flash column chromatography (DCM / MeOH: 0-10%) and reverse-phase chromatography (HO / MeOH: 0-100%) on a Biotage™ to afford the expected compound.

[0275] The following compound 373 is an example illustrating method k2:

[0276] Preparation of 2-methyl-3-[[7-(1H-pyrazol-4-yl)-4-quinolyl]oxy]-N-(4-pyridylmethyl)benzamide (373): [ka]

[0277] Compound 373 was synthesized as a white powder in 28% yield (10 mg) from intermediate 132 (0.09 mmol) and 1H-pyrazole-4-boronic acid pinacol ester (0.13 mmol) according to general method k2. 1 H NMR(400MHz,DMSO-d6)δ(ppm):13.0(bs,1H),9.07(t,J=5.93Hz,1H),8.66(d,J=5.14Hz,1H),8.54-8.53(m,2H),8.35-8.27(m,4H),7.98 (dd,J=8.68 and 1.64Hz,1H),7.46-7.44(m,2H),7.38-7.35(m,3H),6.37(d,J=4.97Hz,1H),4.50(d,J=5.97Hz,2H),2.17(s,3H);MS(ESI,EI + ): m / z=436.30(MH + ).

[0278] Example 10: Procedure for the preparation of analogs 160-169

[0279] The following procedures illustrate the preparation of analogs 160-169. The synthetic scheme is outlined below. Preparation of the appropriate amine is achieved by reductive hydrogenation of the corresponding commercially available nitrile (Method L). Final peptide coupling according to general method C described in Example 1 affords analogs 160-169. Example structures of the final compounds can be found in Table 1.

[0280] [ka]

[0281] Compound 160 below is an example illustrating these procedures.

[0282] Method L: The appropriate nitrile derivative (1 equiv.) was dissolved in 7N methanolic ammonia (5 mL / mmol) or a mixture of THF / NH4OH (1 / 1, 5 mL / mmol) under a nitrogen atmosphere. Ni / Raney (50% in water, 500 mg / mmol) was added, and the reaction mixture was hydrogenated at room temperature until completion. The crude product was filtered through a pad of Celite and washed with methanol. The filtrate was concentrated under reduced pressure, and the solid was dried under vacuum to give the expected amine, which was used without further purification.

[0283] The following compound 156 is an example illustrating Method L:

[0284] Preparation of 3,5-dichloro-4-pyridyl)methanamine (156): [ka]

[0285] Amine 156 was synthesized in quantitative yield as a dark green solid from 3,5-dichloroisonicotinonitrile (2.00 mmol) according to general procedure L. MS (ESI, EI +): m / z=177.20(MH + ).

[0286] The following table shows intermediates 156-159 prepared by Method L:

number

[0287] Preparation of 3-[(7-chloro-4-quinolyl)oxy]-N-[(3,5-dichloro-4-pyridyl)methyl]-2-methyl-benzamide (160): [ka]

[0288] Compound 160 was synthesized according to general procedure C from intermediate 2g (0.10 mmol) and amine 156 (0.25 mmol) in 40% yield (19 mg) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.92(t,J=4.74Hz,1H),8.78(d,J=8.77Hz,1H),8.71(s,2H),8.47(d,J=8.93Hz,1H),8.17(d,J=1.99Hz,1H),7 .78(dd,J=2.28 and 9.02Hz,1H),7.50-7.46(m,1H),7.41-7.39(m,2H),6.50(d,J=5.06Hz,1H),4.74(d,J=4.80Hz,2H),2.18(s,3H);MS(ESI,EI + ): m / z=474.15(MH + ).

[0289] Example 11: Procedure for the preparation of 2-arylpyridine quinoline analogs 170 and 388-394

[0290] The following procedures illustrate the preparation of 2-alkyl and aryl pyridine quinoline analogs 170 and 388-394 by Suzuki-Miyaura cross-coupling according to Method M (compound 170) or Method K1 described in Example 9 (compounds 388-394); the synthetic schemes are outlined below. Examples of structures of the final compounds can be found in Table 1.

[0291] [ka]

[0292] Method M: The appropriate intermediate (1 equiv.) was dissolved in a mixture of dioxane / water (4 / 1, 10 mL / mmol) in an oven-dried screw-cap test tube under nitrogen. Arylboronic acid (1.2 equiv.) and potassium phosphate (2.0 equiv.) were then added, and the tube was evacuated under vacuum and backfilled with nitrogen (this sequence was repeated three times). After this, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).DCM (0.08 equiv.) was added. The reaction mixture was stirred and heated at 80 °C overnight. The mixture was then concentrated and purified by flash column chromatography (DCM / MeOH: 0-10%) and reverse-phase chromatography (HO / MeOH: 0-100%) on a Biotage™ to give the expected compound.

[0293] The following compound 170 is an example illustrating Method M:

[0294] Preparation of N-[[2-(3-furyl)-4-pyridyl]methyl]-3-[(7-methoxy-4-quinolyl)oxy]-2-methyl-benzamide (170): [ka]

[0295] Compound 170 was synthesized according to general method M from compound 40 (0.115 mmol) and furan-3-boronic acid (0.138 mmol) in 52% yield (28 mg) as an orange powder. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.06(t,J=6.11Hz,1H),8.61(d,J=5.70Hz,1H),8 .52(d,J=5.10Hz,1H),8.31-8.26(m,2H),7.78(t,J=1.66Hz,1H),7.67(bs,1H), 7.47-7.42(m,3H),7.35-7.31(m,2H),7.25-7.23(m,1H),7.02-7.01(m,1H),6.3 2(d,J=5.20Hz,1H),4.52(d,J=5.94Hz,2H),3.95(s,3H),2.15(s,3H);MS(ESI,EI + ): m / z=466.25(MH + ).

[0296] Example 12: Procedures for the preparation of 2-cyanopyridine and 2-ketone quinoline analogs 171-179 and 317

[0297] The following procedures illustrate the preparation of 2-cyanopyridine and 2-ketone analogs 171-179 and 317. The synthetic scheme is outlined below.

[0298] The synthesis begins with the preparation of 2-cyanopyridinequinoline analogs 171-175 and 317 from the appropriate chloroquinoline derivatives described in Example 1, according to Method N. In Method O, the synthesis of 2-ketone pyridine analogs 176-179 was achieved by the addition of alkylmagnesium halides. Example structures of the final compounds can be found in Table 1.

[0299] [ka]

[0300] Method N: The appropriate compound (1 equiv.) and zinc cyanide (1.2 equiv.) were dissolved in DMF (10 mL / mmol) in an oven-dried screw-cap test tube under a nitrogen atmosphere. The tube was degassed under vacuum and backfilled with nitrogen (this sequence was repeated three times), after which [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.3 equiv.) was added. The reaction mixture was stirred and heated at 150 °C under microwave irradiation for 1 h. The mixture was diluted with DCM and washed with water. The aqueous phase was extracted three times with DCM, and the combined organic layers were washed with cold water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was then purified by flash column chromatography (DCM / MeOH: 0-10%) and reverse-phase chromatography (HO / MeOH: 0-100%) on a Biotage™ to afford the expected nitrile compound and carboxamide by-product.

[0301] The following compounds 171-172 are examples illustrating Method N:

[0302] Preparation of 3-[(7-methoxy-4-quinolyl)oxy]-2-methyl-N-[(2-cyano-4-pyridyl)methyl]benzamide (171) and 4-[[[3-[(7-methoxy-4-quinolyl)oxy]-2-methyl-benzoyl]amino]methyl]pyridine-2-carboxamide (172): [ka]

[0303] Compound 171 was synthesized according to general method N from compound 40 (0.37 mmol) in 55% yield (86 mg) as a beige powder along with the carboxamide by-product 172 (11 mg).

[0304] Compound 171: 1H NMR(400MHz,DMSO-d6)δ(ppm):9.12(t,J=5.82Hz,1H),8.73(d,J=5.13Hz,1H),8.62(d,J=5.14Hz,1H),8.27(d,J=9.14Hz,1H),8.01-8.00(m,1H ),7.71-7.70(m,1H),7.51-7.43(m,3H),7.36-7.31(m,2H),6.31(d,J=5.10Hz,1H),4.57(d,J=5.83Hz,2H),3.95(s,3H),2.15(s,3H);MS(ESI,EI + ):m / z=425.35(MH + ).

[0305] Compound 172: 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.15(t,J=5.94Hz,1H),8.62-8.59(m,2H),8.27(d,J=9.08Hz,1H),8.12(bs,1H),8.05(bs,1H),7.64(bs,1H),7.55(d d,J=1.79andび5.10Hz,1H),7.48-7.42(m,3H),7.35-7.31(m,2H),6.32(d,J= 5.21Hz,1H),4.57(d,J=6.10Hz,2H),3.95(s,3H),2.14(s,3H);MS(ESI,EI + ):m / z=443.35(MH + ).

[0306] Method O: The appropriate nitrile (1 equiv.) was dissolved in THF (10 mL / mmol) under a nitrogen atmosphere. The mixture was cooled to 0°C, and the appropriate alkylmagnesium halide (5 equiv.) was added dropwise. The reaction mixture was warmed to room temperature (for alkylmagnesium bromides) or 60°C (for alkylmagnesium chlorides) and stirred overnight. The mixture was diluted with ethyl acetate and washed with cold water. The aqueous phase was extracted once with ethyl acetate, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was then purified by flash column chromatography (DCM / MeOH: 0-10%) and reverse-phase chromatography (HO / MeOH: 0-100%) on a Biotage to give the expected compound.

[0307] The following compound 176 is an example illustrating Method O:

[0308] Preparation of N-[(2-acetyl-4-pyridyl)methyl]-3-[(7-methoxy-4-quinolyl)oxy]-2-methyl-benzamide (176): [ka]

[0309] Compound 176 was synthesized according to general procedure O from compound 171 (0.15 mmol) and methylmagnesium bromide (3N in ether, 0.76 mmol) in 27% yield (18 mg) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.15(t,J=6.19Hz,1H),8.69(d,J=5.05Hz,1H) ,8.62(d,J=5.30Hz,1H),8.27(d,J=9.16Hz,1H),7.96-7.95(m,1H),7.63(dd,J =1.80 and 5.05Hz,1H),7.48-7.41(m,3H),7.36-7.31(m,2H),6.32(d,J=5.02Hz, 1H),4.57(d,J=6.09Hz,2H),3.95(s,3H),2.64(s,3H),2.15(s,3H);MS(ESI,EI + ): m / z=442.35(MH + ).

[0310] Example 13: Procedures for the preparation of 3-aryl and 3-aminoaryl quinoline analogs

[0311] The following procedures illustrate the preparation of 3-aryl and 3-aminoaryl quinoline analogs. The synthetic schemes are outlined below. Example structures of the final compounds can be found in Table 1.

[0312] [ka]

[0313] Method P: Iodo compound 43 (1 equiv.), arylboronic acid (1.2 equiv.), and cesium carbonate (1 M aqueous solution, 2 equiv.) were dissolved in dioxane (10 mL / mmol) in an oven-dried screw-cap test tube under a nitrogen atmosphere. The tube was evacuated under reduced pressure and backfilled with nitrogen (this sequence was repeated three times), after which palladium tetrakistriphenylphosphine (0.1 equiv.) was added. The reaction mixture was stirred and heated at 100 °C overnight. The reaction mixture was then concentrated under reduced pressure, and the crude product was purified by flash column chromatography (DCM / MeOH: 0-10%) and reverse-phase chromatography (HO / MeOH: 0-100%) on a Biotage™ to give the expected compound.

[0314] The following compound 180 is an example illustrating Method P:

[0315] Preparation of N-[[3-(3-furyl)phenyl]methyl]-3-[(7-methoxy-4-quinolyl)oxy]-2-methyl-benzamide (180): [ka]

[0316] Compound 180 was synthesized according to general procedure P from compound 43 (0.08 mmol) and furan-3-boronic acid (0.096 mmol) in 68% yield (25 mg) as a white powder. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.03(t,J=6.16Hz,1H),8.66(d,J=5.15Hz,1H),8.33(d,J=9.17Hz,1H),8.21(bs,1H),7.80(t,J=1.54,1H) MS(ESI,EI + ): m / z=465.25(MH + ).

[0317] Method Q: Iodo compound 43 (1 equiv.), tris(dibenzylideneacetone)dipalladium (0.1 equiv.), Binap (0.20 equiv.), and sodium tert-butoxide (5 equiv.) were placed in an oven-dried screw-cap test tube. The tube was then evacuated under vacuum and backfilled with nitrogen (this sequence was repeated three times). Toluene (10 mL / mmol) and the appropriate amine (10 equiv.) were added. The reaction mixture was stirred and heated at 90 °C overnight. The mixture was then concentrated and purified by flash column chromatography (DCM / MeOH: 0-10%) and reverse-phase chromatography (HO / MeOH: 0-100%) on a Biotage™ to give the expected compound.

[0318] The following compound 181 is an example illustrating Method Q:

[0319] Preparation of 3-[(7-methoxy-4-quinolyl)oxy]-2-methyl-N-[(3-morpholinophenyl)methyl]benzamide (181): [ka]

[0320] Compound 181 was synthesized as a white powder in 69% yield (33 mg) from compound 43 (0.10 mmol) and morpholine (1.00 mmol) according to general method Q. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.95(t,J=5.88Hz,1H),8.66(d,J=5.14Hz,1H),8.32(d,J=9.31Hz,1H),7.49-7.34(m,5H),7.26(t,J=7.85Hz,1H),6.98 (bs,1H),6.91-6.85(m,2H),6.37(d,J=5.28Hz,1H),4.48(d,J=6.08Hz,2H) ,4.00(s,3H),3.80-3.78(m,4H),3.16-3.14(m,4H),2.19(s,3H);MS(ESI,EI + ): m / z=484.35(MH + ).

[0321] Example 14: Procedure for the preparation of 7-cyanoquinoline analog 182

[0322] The following procedure illustrates the preparation of analog 182. The synthetic scheme is outlined below. [ka]

[0323] Preparation of 3-[(7-cyano-4-quinolyl)oxy]-2-methyl-N-(4-pyridylmethyl)benzamide (182): [ka]

[0324] Compound 182 was synthesized from compound 108 (0.18 mmol) according to general procedure N described in Example 12 in 66% yield (46 mg) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.07(t,J=6.11Hz,1H),8.85(d,J=5.17Hz,1H),8.43(d,J=1.12Hz,1H),8.57(bs,1H),8.55-8.53( MS(ESI,EI+ ): m / z=395.40(MH + ).

[0325] Example 15: Procedure for the preparation of analog 186

[0326] The following procedure illustrates the preparation of analog 186. The synthetic scheme is outlined below. [ka]

[0327] Preparation of ethyl 4-(methylsulfonyloxymethyl)pyridine-2-carboxylate (183): [ka]

[0328] To a stirred solution of methyl 4-(hydroxymethyl)pyridine-2-carboxylate (2.99 mmol) in DCM (15 mL) under nitrogen at 0 °C, DIEA (8.97 mmol) and methanesulfonyl chloride (3.58 mmol) were added dropwise. The reaction mixture was allowed to reach room temperature and stirred for 45 minutes. The mixture was then diluted with DCM and washed with water and brine. The organic layer was dried over Na SO , filtered, and concentrated under reduced pressure to give the expected compound 183, which was used without purification.

[0329] Preparation of methyl 4-(azidomethyl)pyridine-2-carboxylate (184): [ka]

[0330] To a solution of intermediate 183 (2.99 mmol) in DMF (9 mL) was added sodium azide (3.59 mmol). The reaction mixture was stirred at 60 °C for 3 h, then diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on a Biotage (DCM / MeOH: 0-5%) to give the expected compound 184 as a tan oil in 87% yield. MS (ESI, EI) + ): m / z=193.20(MH + ).

[0331] Preparation of methyl 4-(aminomethyl)pyridine-2-carboxylate (185): [ka]

[0332] To a solution of intermediate 184 (2.60 mmol) in THF (15 mL) was added 10% Pd / C (100 mg) under nitrogen. The reaction mixture was hydrogenated at room temperature for 4 hours. The crude product was filtered through a pad of Celite and washed with THF. The filtrate was concentrated under reduced pressure to give the expected intermediate 185 as a yellow oil in quantitative yield. MS (ESI, EI) + ): m / z=167.25(MH + ).

[0333] Preparation of methyl 4-[[[3-[(7-methoxy-4-quinolyl)oxy]-2-methyl-benzoyl]amino]methyl]pyridine-2-carboxylate (186): [ka]

[0334] Compound 186 was synthesized according to general procedure C from intermediate 2f (1.61 mmol) and amine 185 (1.78 mmol) in 82% yield (604 mg) as a white powder. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.14(t,J=6.05Hz,1H),8.69-8.60(m,2H),8.27(d,J=9.35Hz,1H),8.06(bs,1H),7.62-7.6 0(m,1H),7.47-7.31(m,5H),6.31(d,J=5.34Hz,1H),4.59-4.57(m,2H),3.95(s,3H),3.87(s,3H),2.15(s,3H);MS(ESI,EI + ): m / z=458.25(MH + ).

[0335] Example 16: Procedure for the preparation of analogue 191

[0336] The following procedure illustrates the preparation of analog 191. The synthetic scheme is outlined below. [ka]

[0337] Preparation of imidazo[1,2-a]pyridin-7-ylmethanol (187): [ka]

[0338] To a stirred solution of ethyl imidazo[1,2-a]pyridine-7-carboxylate (2.00 mmol) in THF (20 mL) under nitrogen at 0°C, lithium aluminum hydride (1 M in THF, 3 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was then cooled to 0°C, quenched with aqueous sodium hydroxide (3%), and stirred for 10 minutes. The resulting mixture was filtered through a pad of Celite, washed with ethyl acetate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on a Biotage (DCM / MeOH: 0-20%) to give the expected compound 187 as a white powder in 68% yield. MS (ESI, EI) + ): m / z=149.25(MH + ).

[0339] Preparation of imidazo[1,2-a]pyridin-7-ylmethyl methanesulfonate (188): [ka]

[0340] To a stirred solution of intermediate 187 (1.36 mmol) in DCM (8 mL) under nitrogen at 0 °C, DIEA (4.08 mmol) and methanesulfonyl chloride (1.63 mmol) were added dropwise. The reaction mixture was allowed to reach room temperature and stirred for 1 h. The mixture was diluted with DCM and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the expected compound 188, which was used without purification.

[0341] Preparation of 7-(azidomethyl)imidazo[1,2-a]pyridine (189): [ka]

[0342] To a solution of intermediate 188 (1.36 mmol) in DMF (4 mL) was added sodium azide (1.63 mmol). The reaction mixture was stirred at 60 °C overnight, then diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on a Biotage (DCM / MeOH: 0-5%) to give the expected compound 189 as a brown oil in 42% yield. MS (ESI, EI) + ): m / z=174.25(MH + ).

[0343] Preparation of imidazo[1,2-a]pyridin-7-ylmethanamine (190): [ka]

[0344] To a solution of intermediate 189 (0.58 mmol) in ethyl acetate (6 mL) was added 10% Pd / C (30 mg) under nitrogen. The reaction mixture was hydrogenated at room temperature for 48 hours. The crude product was filtered through a pad of Celite and washed with THF. The filtrate was concentrated under reduced pressure to give the expected intermediate 190 as a yellow oil in 87% yield. MS (ESI, EI) + ): m / z=148.25(MH + ).

[0345] Preparation of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-[(7-methoxy-4-quinolyl)oxy]-2-methyl-benzamide (191): [ka]

[0346] Compound 191 was synthesized according to general procedure C from intermediate 2f (1.61 mmol) and amine 190 (1.78 mmol) in 52% yield (23 mg) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.03(t,J=5.82Hz,1H),8.61(d,J=5.23Hz,1H), 8.51(d,J=7.00Hz,1H),8.27(d,J=9.26Hz,1H),7.90(bs,1H),7.54-7.52(m,1H ),7.47-7.41(m,4H),7.35-7.30(m,2H),6.89(dd,J=1.49 and 6.81Hz,1H),6.31( d,J=5.06Hz,1H),4.51(d,J=5.99Hz,2H),3.96(s,3H),2.14(s,3H);MS(ESI,EI + ): m / z = 439.30 (MH + ).

[0347] Example 17: Procedures for the preparation of 2-amidopyridine and 4-amidoarylquinoline analogs 195-204

[0348] The following procedures illustrate the preparation of 2-amidopyridine and 4-amidoarylquinoline analogs 195-204. The synthetic scheme is outlined below. The synthesis begins with saponification of the appropriate methyl ester analogs (Method R, compounds 192-194). Preparation of the amidopyridine or aryl derivatives 195-204 was achieved by peptide coupling reactions according to general method C described in Example 1. Example structures of the final compounds can be found in Table 1 below.

[0349] [ka]

[0350] The following compound 195 is an example illustrating these procedures.

[0351] Method R: To a solution of the appropriate ester compound (1 equiv.) in methanol (5 mL / mmol) was added sodium hydroxide (2N, 5 mL / mmol). The reaction mixture was stirred and heated at 50°C for 6 hours. MeOH was removed under reduced pressure. The mixture was then acidified to pH 2-3 with 1N aqueous HCl and concentrated. The crude product was purified by reverse-phase chromatography (HO / MeOH: 0-100%) to give the expected compound.

[0352] The following compound 192 is an example illustrating Method R:

[0353] Preparation of 3-[[[3-[(7-methoxy-4-quinolyl)oxy]-2-methyl-benzoyl]amino]methyl]benzoic acid (192): [ka]

[0354] Compound 192 was synthesized from compound 55 (0.10 mmol) according to general procedure R in 64% yield (28 mg) as a white powder. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.04(t,J=6.53Hz,1H),8.61(d,J=5.12Hz,1H),8.27(d,J=9.21Hz,1H),7.96(bs,1H),7.85-7.82( m, 1H),7.61-7.58(m,1H),7.50-7.30(m,6H),6.31(d,J=5.29Hz,1H),4.52(d,J=6.12Hz,2H),3.95(s,3H),2.14(s,3H) + ): m / z=443.25(MH + ).

[0355] Preparation of 3-[(7-methoxy-4-quinolyl)oxy]-2-methyl-N-[[4-(methylcarbamoyl)phenyl]methyl]benzamide (195): [ka]

[0356] Compound 195 was synthesized according to general procedure C from compound 193 (0.10 mmol) and methylamine (2 M in THF, 0.11 mmol) in 44% yield (20 mg) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.00(t,J=6.52Hz,1H),8.60(d,J=5.14Hz,1H),8.41-8.38(m,1H),8.26(d,J=9.16Hz,1H),7.81(d,J=8.35Hz,2H), 7.45-7.38(m,5H),7.33-7.30(m,2H),6.31(d,J=5.22Hz,1H),4.51(d,J= 6.02Hz,2H),3.95(s,3H),2.78(d,J=4.58Hz,3H),2.14(s,3H);MS(ESI,EI + ): m / z=456.40(MH + ).

[0357] Example 18: Procedures for the preparation of polysubstituted halo-4-pyridinequinoline analogs 224-231

[0358] The following procedures illustrate the preparation of polysubstituted halo-4-pyridinequinoline analogs 224-231. The synthetic scheme is outlined below. The synthesis begins with the conversion of a substituted halopyridine-4-carboxylic acid to the corresponding carboxamide derivative (Method S). The resulting substituted halopyridine-4-carboxamide analog was dehydrated in the presence of trifluoroacetic anhydride to give the nitrile compound (Method T). Reductive hydrogenation afforded the corresponding substituted halo-4-pyridylmethanamine (Method U). The final peptide coupling reaction with the quinoline derivative (Method V) was accomplished. Example structures of the final compounds can be found in Table 1.

[0359] [ka]

[0360] Method S: To a solution of the appropriate pyridine-4-carboxylic acid compound (1 equiv.) in DMF (1.5 mL / mmol) under a nitrogen atmosphere, diisopropylethylamine (3 equiv.), HATU (1.3 equiv.), and ammonium chloride (1.3 equiv.) were added. The reaction mixture was stirred at room temperature for 2 h. DMF was removed under reduced pressure, and the crude product was purified by flash column chromatography on a Biotage (cyclohexane / EtOAc: 0-100%) to give the expected compound.

[0361] The following compound 214 is an example illustrating Method S:

[0362] Preparation of 2,6-difluoropyridine-4-carboxamide (214): [ka]

[0363] Intermediate 214 was synthesized according to general procedure S from 2,6-difluoropyridine-4-carboxylic acid (1.61 mmol) and ammonium chloride (2.09 mmol) in quantitative yield (274 mg) as a yellow solid. MS (ESI, EI + ): m / z=159.25(MH+ ).

[0364] The following table shows intermediates 212-215 prepared by Method S:

number

[0365] Method T: To a solution of the appropriate pyridine-4-carboxylic acid compound (1 equiv.) in DCM (5 mL / mmol) at 0° C. under a nitrogen atmosphere, diisopropylethylamine (3 equiv.) and TFAA (2 equiv.) were added. The reaction mixture was stirred at 0° C. until completion (30 min-2 h), then diluted with DCM and washed with brine. The resulting organic layer was dried over Na2SO4, filtered, and carefully concentrated (bath temperature = 30° C., final pressure = 550 mbar) to give the nitrile compound, which was used without further purification.

[0366] The following compound 218 is an example illustrating Method T:

[0367] Preparation of 2,6-difluoropyridine-4-carbonitrile (218): [ka]

[0368] Compound 218 was synthesized according to general method T from intermediate 214 (1.73 mmol) and TFAA (3.46 mmol) in quantitative yield (243 mg, crude) as a yellow oil.

[0369] The following table shows intermediates 216-219 prepared by Method T:

number

[0370] Method U: To a solution of the appropriate pyridine-4-carbonitrile compound (1 equiv.) in THF (5 mL / mmol) under a nitrogen atmosphere, concentrated hydrochloric acid (37%, 0.5 mL / mmol) was added, followed by 10% Pd / C (100% by mass). The reaction mixture was hydrogenated at room temperature for 4 to 6.5 hours. The crude product was filtered through a pad of Celite and washed with THF. The filtrate was concentrated under reduced pressure to give the expected intermediate as the hydrochloride salt.

[0371] The following compound 222 is an example illustrating Method U:

[0372] Preparation of 2,6-difluoro-4-pyridyl)methanamine (222): [ka]

[0373] Compound 222 was synthesized as a yellow gum (493 mg, crude) from intermediate 218 (1.73 mmol) and 10% Pd / C (243 mg) according to general method U. MS (ESI, EI + ): m / z=145.30(MH + ).

[0374] The following table shows intermediates 216-219 prepared by Method U:

number

[0375] Method V: To a suspension of the appropriate intermediate 2 (1 equiv.) in DCM (10 mL / mmol) under nitrogen, DMAP (2.2 equiv.), EDC.HCl (2 equiv.), triethanolamine (5 equiv.), and the appropriate amine (excess) were added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM and washed with a saturated solution of NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC-MS (column: Shim-pack GIS C18, 5 μm, 100 × 30 mm) using a linear gradient of 30% to 100% CH3CN + 0.1% HCOOH in HO + 0.1% HCOOH to give the expected compound.

[0376] The following compound 228 is an example illustrating Method V:

[0377] Preparation of N-[(2,6-difluoro-4-pyridyl)methyl]-3-[(7-methoxy-4-quinolyl)oxy]-2-methyl-benzamide (228): [ka]

[0378] Compound 228 was synthesized according to general method V from intermediate 2f (0.15 mmol) and crude intermediate 222 (218 mmol) in 56% yield (36 mg) as a gray powder. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.12(t,J=5.88Hz,1H),8.64(d,J=5.33Hz,1H),8.29(d,J=9.09Hz,1H),7.51-7.44( m,3H),7.37-7.33(m,2H),7.14(bs,2H),6.34(d,J=5.32Hz,1H),4.59(d,J=6.01Hz,2H),3.96(s,3H),2.15(s,3H); 19 FNMR(400MHz,DMSO-d6)δ(ppm):-71.22;MS(ESI,EI + ): m / z=436.25(MH + ).

[0379] Example 19: Procedure for the preparation of polysubstituted quinoline analogs 279-285

[0380] The following procedures illustrate the preparation of analogs 279-285. The synthetic scheme is outlined below. The synthesis begins with the condensation of Meldrum's acid, triethyl orthoformate, and a substituted aniline (Method W), followed by pyrolysis in a Dowtherm (Method X). Chlorination in the presence of thionyl chloride and a catalytic amount of DMF afforded the 4-chloroquinoline analogs (Method Y). Finally, the preparation of 3-(4-quinolyloxy)benzamide derivatives 279-285 is achieved according to general method I described in Example 2. Examples of final compounds can be found in Table 1.

[0381] [ka]

[0382] Method W: A solution of Meldrum's acid (1 equiv.) in triethyl orthoformate (10 equiv.) was heated under nitrogen to 105°C for 1 h. The appropriately substituted aniline (1 equiv.) was then added, and the reaction mixture was stirred at 105°C for an additional 1 h. After cooling to room temperature, a solid appeared, and pentane was added. The solid was filtered, washed with pentane, and dried under vacuum to give the expected intermediate, which was used without further purification.

[0383] The following compound 276 is an example illustrating Method W:

[0384] Preparation of 5-[(3,5-difluoroanilino)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (276): [ka]

[0385] Compound 276 was synthesized in 96% yield as a white solid from 3,5-difluoroanilino (7.74 mmol) according to general method W. MS (ESI, EI+): m / z = 284.3 (MH+).

[0386] Method X: A solution of the appropriate intermediate (1 equiv.) in diphenyl ether (2.5 mL / mmol) was heated at 230° C. for 1 h. After cooling to room temperature, a solid appeared and pentane was added. The solid was filtered, washed with pentane, and dried under vacuum to give the expected intermediate, which was used without further purification.

[0387] The following compound 277 is an example illustrating Method X:

[0388] Preparation of 5,7-difluoroquinolin-4-ol (277): [ka]

[0389] Intermediate 277 was synthesized from compound 276 (7.45 mmol) according to general method X in 65% yield as a beige powder. MS (ESI, EI+): m / z=182.2 (MH+).

[0390] Method Y: To a stirred solution of the appropriate intermediate (1 equiv.) in dichloromethane under nitrogen was added thionyl chloride (10 equiv.) and 2 drops of DMF. The reaction mixture was heated at 80° C. for 1 h. The reaction mixture was concentrated under reduced pressure and then slowly quenched with a 7N solution of ammonia in methanol until pH=10. The mixture was concentrated and coevaporated twice with toluene. The crude product was purified by flash column chromatography on a Biotage (DCM / MeOH: 0-5%) to give the expected intermediate.

[0391] The following compound 278 is an example illustrating Method Y:

[0392] Preparation of 4-chloro-5,7-difluoro-quinoline (278): [ka]

[0393] Intermediate 278 was synthesized in 67% yield from compound 277 (1.10 mmol) according to general method Y as a white powder. MS (ESI, EI+): m / z=280.3 (MH+).

[0394] Preparation of 3-[(5,7-difluoro-4-quinolyl)oxy]-2-methyl-N-(4-pyridylmethyl)benzamide (279): [ka]

[0395] Compound 279 was synthesized according to general method I from intermediate 278 (0.15 mmol) and intermediate 81e (0.15 mmol) in 20% yield (12 mg) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.05(t,J=5.80Hz,1H),8.73(d,J=5.33Hz,1H),8.54-8.53(m,2H),7.70-7.67(m,1H),7.64-7.58(m,1H) ),7.46-7.44(m,2H),7.36-7.34(m,3H),6.51(d,J=5.30Hz,1H),4.50(d,J=6.02Hz,2H),2.16(s,3H);MS(ESI,EI+):m / z=406.20(MH+).

[0396] Example 20: Procedure for the preparation of 7-substituted quinoline analogs 288-291

[0397] The following procedures illustrate the preparation of analogs 288-291. The synthetic scheme is outlined below. The synthesis begins with a peptide coupling reaction between 4-chloroquinoline-7-carboxylic acid and the appropriate amine (Method Z). For the synthesis of 4-chloroquinoline-7-carboxamide, Method S described in Example 18 was used. The preparation of 7-substituted 3-(4-quinolyloxy)benzamide derivatives 288-291 is achieved according to General Method I described in Example 2. Examples of final compounds can be found in Table 1.

[0398] [ka]

[0399] Method Z: To a stirred solution of 4-chloroquinoline-7-carboxylic acid (1 equiv.) in DMF (10 mL / mmol) under nitrogen, carbonyldiimidazole (1.2 equiv.) was added. The reaction mixture was stirred at room temperature for 30 minutes. The appropriate amine (1.2 equiv.) was then added and stirred overnight. The reaction mixture was concentrated and co-evaporated twice with toluene under reduced pressure to give the expected intermediate, which was used without further purification.

[0400] The following compounds 286-287 are examples illustrating Method Z.

[0401] Preparation of 4-chloro-N-prop-2-ynyl-quinoline-7-carboxamide (286) [ka]

[0402] Intermediate 286 was synthesized according to general method Z from 4-chloroquinoline-7-carboxylic acid (0.15 mmol) and propargylamine (0.17 mmol) as a colorless gum in quantitative yield.

[0403] Preparation of 4-chloroquinoline-7-carboxamide (287) [ka]

[0404] Intermediate 287 was synthesized according to general procedure S from 4-chloroquinoline-7-carboxylic acid (0.50 mmol) and ammonium chloride (0.65 mmol) as a beige solid in quantitative yield.

[0405] Preparation of 4-[2-methyl-3-(4-pyridylmethylcarbamoyl)phenoxy]quinoline-7-carboxamide (288) [ka]

[0406] Compound 288 was synthesized according to general method I from intermediate 287 (0.50 mmol) and intermediate 81e (0.50 mmol) in 25% yield (50 mg) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.06(t,J=6.11Hz,1H),8.77(d,J=5.10Hz,1H),8.60 -8.59(m,1H),8.55-8.53(m,2H),8.44(d,J=8.74Hz,1H),8.33(bs,1H),8.13(dd,J= 8.74 and 1.64Hz, 1H), 7.63 (bs, 1H), 7.47-7.46 (m, 2H), 7.40-7.36 (m, 3H), 6.52 (d, J= 5.22Hz,1H),4.50(d,J=6.10Hz,2H),2.16(s,3H);MS(ESI,EI+):m / z=413.15(MH+).

[0407] Preparation of 2-methyl-3-[[7-(5-methyloxazol-2-yl)-4-quinolyl]oxy]-N-(4-pyridylmethyl)benzamide (291) [ka]

[0408] Compound 291 was synthesized according to general method I from intermediate 286 (0.15 mmol) and intermediate 81e (0.15 mmol) in 14% yield (9 mg) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.07(t,J=6.05Hz,1H),8.77(d,J=5.15Hz,1H),8.55-8.51(m,4H),8.23(dd,J=8.75 and 1.44Hz,1H),7.47-7.44(m,2H), 7.41-7.36(m,3H),7.14(d,J=1.25Hz,1H),6.50(d,J=5.17Hz,1H),4.50(d, J=5.96Hz,2H),2.48(s,3H),2.18(s,3H);MS(ESI,EI+):m / z=451.15(MH+).

[0409] Example 21: Procedure for the preparation of 7-heteroarylquinoline analogs 293-294

[0410] The following procedures illustrate the preparation of analogs 293-294, and the synthetic scheme is outlined below. [ka]

[0411] Preparation of 3-[[7-(N-hydroxycarbamimidoyl)-4-quinolyl]oxy]-2-methyl-N-(4-pyridylmethyl)benzamide (292) [ka]

[0412] To a stirred solution of compound 182 (0.38 mmol) in ethanol (4 mL) under a nitrogen atmosphere was added hydroxylamine hydrochloride (1.14 mmol) and triethylamine (1.14 mmol). The reaction mixture was heated at 50° C. for 1 hour and 30 minutes, then concentrated under reduced pressure and dried under vacuum to give the expected intermediate 292 as a white powder in quantitative yield, which was used without further purification. MS (ESI, EI+): m / z = 428.15 (MH+).

[0413] Preparation of 2-methyl-3-[[7-(1,2,4-oxadiazol-3-yl)-4-quinolyl]oxy]-N-(4-pyridylmethyl)benzamide (293) [ka]

[0414] To a stirred solution of compound 292 (0.12 mmol) in triethyl orthoformate (1 mL) under a nitrogen atmosphere, trifluoroacetic acid (2 drops) was added. The reaction mixture was heated at 60°C for 2 hours and at 80°C for 2 hours. The reaction mixture was then diluted with DCM, and the organic layer was washed with a saturated solution of ammonium chloride. The aqueous layer was extracted once with DCM. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH: 0-10%) and reverse-phase chromatography (HO / MeOH: 0-100%) on a Biotage™ to give the expected compound 293 as a white powder in 18% yield (9 mg). 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.85(bs,1H),9.08(t,J=6.02Hz,1H),8.81(d, J=5.15Hz,1H),8.69(bs,1H),8.59(d,J=8.83Hz,1H),8.54(d,J=4.34Hz,2H), 8.30(d,J=8.56Hz,1H),7.48-7.45(m,2H),7.42-7.36(m,3H),6.56(d,J=5.08 Hz,1H),4.50(d,J=5.59Hz,2H),2.18(s,3H);MS(ESI,EI+):m / z=438.05(MH+).

[0415] Preparation of 2-methyl-3-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)-4-quinolyl]oxy]-N-(4-pyridylmethyl)benzamide (294) [ka]

[0416] To a stirred solution of compound 292 (0.16 mmol) in DMF (2 mL) under a nitrogen atmosphere, Meldrum's acid (0.24 mmol) was added. The reaction mixture was heated at 100 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by flash column chromatography on a Biotage (DCM / MeOH: 0-10%) and preparative HPLC-MS (column: Shim-pack GIS C18, 5 μm, 100 × 30 mm) using a linear gradient of 5% to 60% CHCN + 0.1% HCOOH in HO + 0.1% HCOOH to give the expected compound 294 as a white powder in 18% yield (13 mg). 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.07(t,J=5.96Hz,1H),8.80(d,J=5.18Hz,1H),8.64(d,J=1.28Hz,1H),8.58-8.53(m,3H),8.26(dd,J=8.64 and 1.56Hz, 1H),7.48-7.45(m,2H),7.42-7.35(m,3H),6.56(d,J=5.15Hz,1H),4.50(d, J=6.00Hz,2H),2.75(s,3H),2.18(s,3H);MS(ESI,EI+):m / z=452.10(MH+).

[0417] Example 22: Procedure for the preparation of 7-heteroarylquinoline analogue 297

[0418] The following procedure illustrates the preparation of analog 297, and the synthetic scheme is outlined below. [ka]

[0419] Preparation of 4-chloroquinoline-7-carbohydrazide (295) [ka]

[0420] To a stirred solution of 4-chloroquinoline-7-carboxylic acid (0.19 mmol) in acetonitrile (2 mL) under a nitrogen atmosphere, EDC.HCl (0.23 mmol) and HOBt (0.23 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour and 30 minutes. After cooling to 0 °C, hydrazine (1 M in THF, 0.39 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The acetonitrile was removed under reduced pressure, and the crude product was dissolved in water to give a solid, which was filtered, washed with water, and dried over PO in a vacuum desiccator to give the expected intermediate 295 as a white powder in 86% yield, which was used without further purification.

[0421] Preparation of 2-(4-chloro-7-quinolyl)-1,3,4-oxadiazole (296) [ka]

[0422] A stirred solution of intermediate 295 (0.16 mmol) in triethyl orthoformate (1.5 mL) was heated at 100° C. for 1 h 30 min. The reaction mixture was concentrated under reduced pressure to give the expected intermediate 296 as a white powder in quantitative yield, which was used without further purification. MS (ESI, EI): m / z = 232.05 (MH).

[0423] Preparation of 2-methyl-3-[[7-(1,3,4-oxadiazol-2-yl)-4-quinolyl]oxy]-N-(4-pyridylmethyl)benzamide (297) [ka]

[0424] To a stirred solution of compound 296 (0.09 mmol) in DMF (2 mL) under a nitrogen atmosphere was added intermediate 81e (0.09 mmol) and cesium carbonate (0.13 mmol). The reaction mixture was heated at 80° C. for 1 h 30 min. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (DCM / MeOH: 0-10%) and reverse-phase chromatography (HO / MeOH: 0-100%) on a Biotage to give the expected compound 297 as a white powder in 8% yield (3 mg).1 H NMR(400MHz,DMSO-d6)δ(ppm):9.48(s,1H),9.08(t,J=5.83Hz,1H),8.82(d,J=5.12Hz,1H),8.64-8.61(m,2H),8.54-8.53(m,2H),8.31(dd,J=8.78 and 1.63Hz,1H),7.49-7.46(m,2H),7.43-7.36(m,3H),6.58(d,J=5.12Hz,1 H),4.50(d,J=6.02Hz,2H),2.18(s,3H);MS(ESI,EI+):m / z=438.10(MH+).

[0425] Example 23: Procedure for the preparation of 7-heteroarylquinoline analogue 301

[0426] The following procedure illustrates the preparation of analog 301, and the synthetic scheme is outlined below. [ka]

[0427] Preparation of 4-chloroquinoline-7-carbonyl chloride (298) [ka]

[0428] To a stirred solution of 4-chloroquinoline-7-carboxylic acid (0.24 mmol) in DCM (2.5 mL) was added oxalyl chloride (0.48 mmol) and DMF (2 drops) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the expected intermediate 298 as a white powder in quantitative yield, which was used without further purification.

[0429] Preparation of N'-acetyl-4-chloroquinoline-7-carbohydrazide (299) [ka]

[0430] To a stirred solution of acetylhydrazine (0.24 mmol) and sodium carbonate (0.24) in water (2 mL) under a nitrogen atmosphere was added intermediate 298 (0.24 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography on a Biotage (DCM / MeOH: 0-15%) to give the expected intermediate 299 as a white powder in 89% yield. MS (ESI, EI+): m / z = 264.05 (MH+).

[0431] Preparation of 2-(4-chloro-7-quinolyl)-5-methyl-1,3,4-oxadiazole (300) [ka]

[0432] To a stirred solution of intermediate 299 (0.15 mmol) in acetonitrile (4 mL) under a nitrogen atmosphere was added POCl (0.30 mmol). The reaction mixture was heated at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography on a Biotage (DCM / MeOH: 0-10%) to give the expected intermediate 300 as a white powder in 60% yield. MS (ESI, EI): m / z = 246.05 (MH).

[0433] Preparation of 2-methyl-3-[[7-(5-methyl-1,3,4-oxadiazol-2-yl)-4-quinolyl]oxy]-N-(4-pyridylmethyl)benzamide (301) [ka]

[0434] Compound 301 was synthesized according to general method I from intermediate 300 (0.09 mmol) and intermediate 81e (0.09 mmol) in 33% yield (13 mg) as a white powder. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.08(t,J=6.00Hz,1H),8.82(d,J=5.19Hz,1H),8.61-8.53(m,4H),8.26(dd,J=8.70 and 1.69Hz,1H),7.49-7 .45(m,2H),7.42-7.36(m,3H),6.57(d,J=5.11Hz,1H),4.50(d,J=6.05Hz,2H),2.67(s,3H),2.18(s,3H);MS(ESI,EI+):m / z=452.15(MH+).

[0435] Example 24: Procedure for the preparation of 7-heteroarylquinoline analogs 303-316

[0436] The following procedures illustrate the preparation of analogs 303-316, and the synthetic scheme is outlined below. The synthesis begins with the preparation of 7-boronic acid quinoline pinacol ester derivative 302, followed by Suzuki-Miyaura cross-coupling reactions to give analogs 303-316, following general procedure K2 described in Example 9. Examples of final compounds can be found in Table 1.

[0437] [ka]

[0438] Compound 303 below is an example illustrating these procedures.

[0439] Preparation of 2-methyl-N-(4-pyridylmethyl)-3-[[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-quinolyl]oxy]benzamide (302) [ka]

[0440] To a stirred solution of intermediate 132 (0.10 mmol) in dioxane (1 mL) under a nitrogen atmosphere was added bis(pinacolato)diboron (0.15 mmol), potassium acetate (0.30 mmol), and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).DCM (0.10 equiv.). The reaction mixture was heated at 100 °C for 1 h. The reaction mixture was then diluted with DCM, and the organic layer was washed with brine. The aqueous layer was extracted three times with DCM, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the expected intermediate 302 in quantitative yield as a brown gum, which was used without further purification.

[0441] Preparation of 2-methyl-3-[[7-(3-methylimidazol-4-yl)-4-quinolyl]oxy]-N-(4-pyridylmethyl)benzamide (303) [ka]

[0442] Compound 303 was synthesized as a green powder in 42% yield (19 mg) from intermediate 302 (0.10 mmol) and 5-bromo-1-methyl-1H-imidazole (0.10 mmol) according to general method K2. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.07(t,J=6.31Hz,1H),8.73(d,J=4.98Hz,1H),8.54(d,J=5.76Hz,2H),8.43(d,J=8.67Hz,1H),8.15(bs,1H),7. 87-7.83(m,2H),7.47-7.33(m,6H),6.47(d,J=5.20Hz,1H),4.50(d,J=6.02Hz,2H),3.85(s,3H),2.18(s,3H);MS(ESI,EI+):m / z=450.15(MH+).

[0443] Example 25: Procedure for the preparation of 7-heteroarylquinoline analogs 318-334

[0444] The following procedures illustrate the preparation of analogs 318-334, and the synthetic schemes are outlined below. Copper cross-coupling reactions with the appropriate 7-bromoquinoline derivative and (substituted) pyrrole or pyrazole are achieved to yield the expected 7-pyrrole or pyrazole analogs. When the reaction is performed with an ester derivative, saponification according to General Method B described in Example 1 and peptide coupling according to General Method C are required to obtain the final compounds. Examples of final compounds can be found in Table 1.

[0445] [ka]

[0446] Method AA: The appropriate 7-bromoquinoline derivative (1 equiv.), copper iodide (2.2 equiv.), and cesium carbonate (4 equiv.) were placed in an oven-dried screw-cap test tube. The tube was then evacuated under reduced pressure and backfilled with nitrogen (this sequence was repeated three times). Acetonitrile (10 mL / mmol), DMEDA (3.5 equiv.), and the appropriate (substituted) pyrrole or pyrazole (2.1 equiv.) were added. The reaction mixture was heated at 80°C overnight or at 150°C under microwave irradiation for 1 hour and 30 minutes. The reaction mixture was then concentrated under reduced pressure and purified by flash column chromatography on a Biotage™ (DCM / MeOH: 0-10%) or, in the case of amide derivatives, by reverse-phase chromatography (HO / MeOH: 0-100%) to give the expected compounds.

[0447] The following compound 318 is an example illustrating Method AA:

[0448] Preparation of 2-methyl-3-[(7-pyrazol-1-yl-4-quinolyl)oxy]-N-(4-pyridylmethyl)benzamide (318) [ka]

[0449] Compound 318 was synthesized as a white powder in 47% yield (45 mg) from intermediate 132 (0.22 mmol) and 1H-pyrazole (0.47 mmol) following general method AA. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.07(t,J=6.09Hz,1H),8.82(d,J=2.57Hz,1H) ,8.73(d,J=5.16Hz,1H),8.55-8.47(m,4H),8.30(dd,J=9.10 and 2.29Hz,1H),7 .88(d,J=1.63Hz,1H),7.47-7.35(m,5H),6.66-6.65(m,1H),6.44(d,J=5.15H) z,1H),4.50(d,J=5.98Hz,2H),2.18(s,3H);MS(ESI,EI+):m / z=436.10(MH+).

[0450] Example 26: Procedure for the preparation of 7-triazolequinoline analogs 336-338

[0451] The following procedures illustrate the preparation of analogs 336-338, and the synthetic scheme is outlined below. The synthesis begins with the preparation of the 7-azidoquinoline derivative (Method AB). Copper-catalyzed azide-alkyne cycloaddition leads to the expected triazole derivative (Method AC). When the reaction is carried out with an ester derivative, saponification according to General Method B described in Example 1 and peptide coupling according to General Method C are necessary to obtain the final compound. Examples of final compounds can be found in Table 1.

[0452] [ka]

[0453] Method AB: The appropriate 7-bromoquinoline derivative (1 equiv.), sodium azide (2.5 equiv.), and copper iodide (0.3 equiv.) were placed in an oven-dried screw-cap test tube. The tube was then degassed under vacuum and backfilled with nitrogen (this sequence was repeated three times). EtOH / HO (7 / 3, 4 mL / mmol) and DMEDA (0.6 equiv.) were added. The reaction mixture was heated at 100 °C for 15 min under microwave irradiation. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography on a Biotage™ (DCM / MeOH: 0-10%) to give the expected compound.

[0454] The following compound 335 is an example illustrating Method AB:

[0455] Preparation of 3-[(7-azido-4-quinolyl)oxy]-N-[(4-pyridyl)methyl]-2-methyl-benzamide (335) [ka]

[0456] Compound 335 was synthesized from intermediate 132 (0.07 mmol) according to general method AB in 77% yield as a yellow oil. MS (ESI, EI+): m / z = 447.15 (MH+).

[0457] Method AC: To a stirred solution of the appropriate 7-azidoquinoline derivative (1 equiv.) in DMF (10 mL / mmol) under a nitrogen atmosphere, copper iodide (0.2 equiv.), sodium ascorbate (0.4 equiv.), propiolic acid (2 equiv.), and DBU (0.5–1 equiv.) were added under nitrogen. The reaction mixture was either stirred overnight at room temperature or heated at 60 °C for 1 h. The reaction mixture was then concentrated under reduced pressure, coevaporated twice with toluene, and purified by flash column chromatography on a Biotage (DCM / MeOH: 0–10%) and, in the case of amide derivatives, reverse-phase chromatography (HO / MeOH: 0–100%) to give the expected compounds.

[0458] The following compound 336 is an example illustrating Method AC:

[0459] Preparation of 2-methyl-N-(4-pyridylmethyl)-3-[[7-(triazol-1-yl)-4-quinolyl]oxy]benzamide (336) [ka]

[0460] Compound 336 was synthesized as a white powder in 63% yield (13 mg) from intermediate 335 (0.05 mmol) and propiolic acid (0.10 mmol) following general method AC. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.16(d,J=1.19Hz,1H),9.07(t,J=5.89Hz,1H),8. 80(d,J=5.12Hz,1H),8.63(bs,1H),8.61-8.60(m,1H),8.54-8.53(m,2H),8.35(d d,J=8.99 and 2.26Hz,1H),8.09(d,J=1.15Hz,1H),7.49-7.36(m,5H),6.52(d,J=5. 30Hz,1H),4.50(d,J=5.94Hz,2H),2.18(s,3H);MS(ESI,EI+):m / z=437.10(MH+).

[0461] Example 27: Procedure for the preparation of 7-triazolequinoline analogs 339-340

[0462] The following procedures illustrate the preparation of analogs 339-340, and the synthetic schemes are outlined below. Examples of final compounds can be found in Table 1.

[0463] [ka]

[0464] Method AD: To a stirred solution of 7-azidoquinoline derivative (1 equiv.) in toluene (20 mol / mmol) under nitrogen, the appropriate alkyne (20 equiv.) was added in an oven-dried screw-cap test tube. The reaction mixture was heated at 100 °C for 24 h, then concentrated under reduced pressure and purified by flash column chromatography (DCM / MeOH: 0-10%) and reverse-phase chromatography (HO / MeOH: 0-100%) on a Biotage™ to give the expected compound. In the case of compound 340, a trimethylsilyl-protected alkyne was used, requiring an additional synthetic step to deprotect the trimethylsilyl group with TBAF (1.1 equiv.) in THF.

[0465] The following compound 339 is an example illustrating Method AD:

[0466] Preparation of 3-[[7-(4,5-dimethyltriazol-1-yl)-4-quinolyl]oxy]-2-methyl-N-(4-pyridylmethyl)benzamide (339) [ka]

[0467] Compound 339 was synthesized as a white powder in 18% yield (7 mg) from intermediate 335 (0.08 mmol) and 2-butyne (1.66 mmol) following general method AD. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.08(t,J=6.17Hz,1H),8.82(d,J=5.21Hz,1H), 8.61(d,J=8.83Hz,1H),8.55-8.53(m,2H),8.24(d,J=2.09Hz,1H),7.93(dd,J=8 .88 and 2.03Hz,1H),7.49-7.36(m,5H),6.56(d,J=5.28Hz,1H),4.50(d,J=5.95H z,2H),2.40(s,3H),2.32(s,3H),2.19(s,3H);MS(ESI,EI+):m / z=465.15(MH+).

[0468] Example 28: Procedure for the preparation of 7-triazolequinoline analogs 341-343

[0469] The following procedures illustrate the preparation of analogs 341-343, and the synthetic schemes are outlined below. Examples of final compounds can be found in Table 1. [ka]

[0470] Method AE: The 7-bromoquinoline derivative (1 equiv.), sodium azide (2.5 equiv.), the appropriate alkynecarboxylic acid (1.5 equiv.), copper iodide (0.3 equiv.), and potassium carbonate (1.5 equiv.) were placed in an oven-dried screw-cap test tube. The tube was then evacuated under vacuum and backfilled with nitrogen (this sequence was repeated three times). DMSO / HO (7 / 3, 4 mL / mmol) and DMEDA (0.6 equiv.) were added. The reaction mixture was heated at 100 °C under microwave irradiation for 45 min. Water was then added, and the resulting precipitate was filtered and dried over PO in a vacuum desiccator. The solid was purified by flash column chromatography (DCM / MeOH: 0-10%) and reverse-phase chromatography (HO / MeOH: 0-100%) on a Biotage™ to give the expected compound.

[0471] The following compound 341 is an example illustrating Method AE: Preparation of 3-[[7-(4-ethyltriazol-1-yl)-4-quinolyl]oxy]-2-methyl-N-(4-pyridylmethyl)benzamide (341) [ka]

[0472] Compound 341 was synthesized as a white powder in 61% yield (28 mg) from intermediate 132 (0.10 mmol) and 2-pentynoic acid (0.15 mmol) following general method AE. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 9.07 (t, J = 6.13 Hz, 1H), 8.91 (bs, 1H), 8.80 (d, J = 5.14 Hz, 1H), 8.60 (d, J = 9.10 Hz, 1H), 8.55 - 8.53 (m, 3H), 8.32 (dd, J = 9.08 and 2.13 Hz, 1H), 7.48 (d, J = 4.47 Hz, 2H), 7.41 (q, J = 4.90 Hz, 1H), 7.37 - 7.36 (m, 2H), 6.51 (d, J = 5.14 Hz, 1H), 4.51 (d, J = 6.04 Hz, 2H), 2.80 (q, J = 7.66 Hz, 2H), 2.18 (s, 3H), 1.33 (t, J = 7.70 Hz, 3H); MS (ESI, EI+): m / z = 465.15 (MH+).

[0473]

Table 1

[0474] Example 29: Cell-based assay: Biological assay measuring cell proliferation in leukemia cell lines

[0475] The compounds were evaluated in various leukemia cell lines (Molm-13, MV4-11, HL-60, and M-NFS-60). Cell proliferation was measured for each. The protocols for these assays are described below.

[0476] MV4.11: Exponentially growing MV4.11 cells (DSMZ, ACC-102) were seeded at 2.10^4 per 200 μl of complete medium. 20 μL of test compound dilutions were added to each well, and the plates were incubated at 37°C and 5% CO2 for 72 hours. Untreated cells and a positive control (0.5% Triton X-100 for the last 15 minutes) served as maximum and minimum viability standards. At the end of the incubation, 100 μl of supernatant was removed and replaced with 10 μl of WST-1 solution (Cell Proliferation Reagent WST-1, Roche Applied Science). After 3 hours of incubation at 37°C and 5% CO2, optical density was measured at 450 nm and 620 nm against background using a microplate reader (Envision2105, Perkinelmer).

[0477] MOLM-13: Exponentially growing MOLM-13 cells (DSMZ, ACC-554) were seeded at 2.10^4 per 200 μl of complete medium. 20 μL of test compound dilutions were added to each well, and the plates were incubated at 37°C and 5% CO2 for 72 hours. Untreated cells and a positive control (0.5% Triton X-100 for the last 15 minutes) served as maximum and minimum viability standards. At the end of the incubation, 100 μl of supernatant was removed and replaced with 10 μl of WST-1 solution (Cell Proliferation Reagent WST-1, Roche Applied Science). After 3 hours of incubation at 37°C and 5% CO2, optical density was measured at 450 nm and 620 nm against background using a microplate reader (Envision2105, Perkinelmer).

[0478] M-NFS-60: Exponentially growing M-NFS-60 cells (ATCC, CRL-1838) were seeded at 10^4 per 200 μl of complete medium containing β-mercaptoethanol and M-CSF (62 ng / mL) or IL-34 (500 ng / mL). 20 μL of test compound dilutions were added to each well, and the plates were incubated at 37°C and 5% CO2 for 72 hours. Untreated cells and a positive control (0.5% Triton X-100 for the last 15 minutes) served as reference for maximum and minimum viability. At the end of the incubation, 100 μl of supernatant was removed and replaced with 10 μl of WST-1 solution (Cell Proliferation Reagent WST-1, Roche Applied Science). After 3 hours of incubation at 37°C, 5% CO2, the optical density was measured at 450 nm and 620 nm against background in a microplate reader (Envision2105, Perkinelmer).

[0479] HL-60: Exponentially growing HL-60 cells (DSMZ, ACC-3) were seeded at 2.10^4 per 200 μl of complete RPMI medium. 20 μL of test compound dilutions were added to each well, and the plates were incubated at 37°C and 5% CO2 for 72 hours. Untreated cells and a positive control (0.5% Triton X-100 for the last 15 minutes) served as maximum and minimum viability standards. At the end of the incubation, 100 μl of supernatant was removed and replaced with 10 μl of WST-1 solution (Cell Proliferation Reagent WST-1, Roche Applied Science). After 3 hours of incubation at 37°C and 5% CO2, optical density was measured at 450 nm and 620 nm against background using a microplate reader (Envision2105, Perkinelmer).

[0480] IC50s were determined and experiments were performed at least in duplicate. The biological results of some of these assays are presented in the table below.

[0481] NB Report IC50 as

number

[0482] [Table 2] JPEG0007633702000253.jpg250170JPEG0007633702000254.jpg250170JPEG0007633702000255.jpg250170 JPEG0007633702000256.jpg250170JPEG0007633702000257.jpg250170JPEG0007633702000258.jpg161170

[0483] Example 30: Cell-based assay: Biological assay measuring cell proliferation in non-cancer cell lines

[0484] The CSF1R receptor has been expressed in the HEK cell line according to the following protocol.

[0485] HEK-CSF1R-STAT5-Luc: Exponentially growing HEK293T cells (ATCC® CRL-3216™) ectopically expressing the human CSF1R receptor (Origene) and five copies of the STAT5 response element (STAT5 RE, Promega) driving transcription of a luciferase reporter were seeded at 5.10^3 per 20 μl of complete DMEM medium. The following day, 2.25 μL of test compound dilutions were added to each well and stimulated with 600 ng / ml M-CSF. Plates were incubated at 37°C and 5% CO2 for 24 hours. Unstimulated and stimulated cells served as references for maximum and minimum induction. At the end of the incubation, 25 μl of Steady-Glo® Luciferase Assay System (Promega) was added 5 minutes after lysis, and luminescence was measured in a microplate reader (Envision2105, Perkinelmer).

[0486] HEK-CSF1R-SRE-Luc: Exponentially growing HEK293T cells (ATCC® CRL-3216™) ectopically expressing the human CSF1R receptor (Origene) and a serum response element (SRE, Promega) driving transcription of a luciferase reporter were seeded at 5.10^3 per 20 μl of complete DMEM medium. The following day, 2.25 μL of test compound dilutions were added to each well and stimulated with 600 ng / ml M-CSF. Plates were incubated at 37°C and 5% CO2 for 24 hours. Unstimulated and stimulated cells served as references for maximum and minimum induction. At the end of the incubation, 25 μl of Steady-Glo® Luciferase Assay System (Promega) was added 5 minutes after lysis, and luminescence was measured in a microplate reader (Envision 2105, Perkinelmer).

[0487] HEK-CSF1R-WST-1: Exponentially growing HEK293T cells (ATCC® CRL-3216™) were seeded at 5.10^3 per 200 μl of complete DMEM medium. The next day, 20 μL of test compound dilutions were added to each well, and the plates were incubated at 37°C, 5% CO2 for 72 hours. Untreated cells and a positive control (0.5% Triton X-100 for the last 15 minutes) served as maximum and minimum viability standards. At the end of the incubation, 100 μL of supernatant was removed and replaced with 10 μL of WST-1 solution (Cell Proliferation Reagent WST-1, Roche Applied Science). After 3 hours of incubation at 37°C, 5% CO2, optical density was measured at 450 nm and 620 nm against background using a microplate reader (Envision2105, Perkinelmer).

[0488] IC50s were determined and experiments were performed at least in duplicate. The biological results of some of these assays are presented in the table below.

[0489] NB Report IC50 as

number

[0490] [Table 3] JPEG0007633702000261.jpg250170JPEG0007633702000262.jpg250170JPEG0007633702 000263.jpg250170JPEG0007633702000264.jpg250170JPEG0007633702000265.jpg34170

[0491] Example 31: Target-based assays: Biological assays measuring protein kinase inhibition

[0492] Biochemical assays were performed to measure protein kinase inhibition. Kinase binding assays were performed for different kinases using the SelectScreen Biochemical Kinase Profiling Service® platform (ThermoFisher Scientific). For all kinases, Z'-Lyte® biochemical kinase assay technology was used. Inhibition was measured in duplicate at 50 nM for each compound and is reported as a percentage. Some data are presented in the table below.

[0493] [Table 4]

[0494] Example 32: Efficacy of Compound 32 in a streptozotocin-induced diabetic neuropathic pain model

[0495] Experiments were performed on 8-week-old male C57B16J mice (Charles River). Six mice were used per group in this study.

[0496] Diabetes is induced by a single IP injection (100 μL / 10 g) of 200 μg / mL streptozotocin solution. Blood glucose is tested before injection, on D+3 and D+7 after injection. All injected mice showed a blood glucose concentration of less than 350 mg / dL on D+7 and were then used for compound analgesic testing.

[0497] Compound 32 was administered orally at 6 mg / mL in Capryol 90 solution (50 μL / 10 g), and pregabalin was administered subcutaneously at 0.5 mg / mL in phosphate buffer (100 μL / 10 g) on ​​D+14 and D+16. Time course measurements were taken at +1, +2, +4, and +6 hours after compound administration.

[0498] Mechanical response thresholds in mice were measured with calibrated Von Frey filaments using an up / down method blinded to the operator. Measurements were performed before and 14 days after streptozotocin injection.

[0499] Statistical analysis was performed using SigmaPlot 12.5 software. The percentage of the maximum possible effect was calculated as follows: MPE%=[(Test value - Pre-test value) / (Cutoff - Pre-test value)]*100

[0500] The cutoff, test and pre-test values ​​correspond to the baseline measurement, the post-dose measurement and the pre-dose measurement, respectively.

[0501] [Table 5]

[0502] [Table 6]

[0503] Example 33: Efficacy of Compound 108 in a streptozotocin-induced diabetic neuropathic pain model

[0504] Experiments were performed on 8-week-old male C57B16J mice (Charles River). Ten mice were used per group in this study.

[0505] Diabetes is induced by a single IP injection (100 μL / 10 g) of 200 μg / mL streptozotocin solution. Blood glucose is tested before injection, on D+3 and D+7 after injection. All injected mice showed a blood glucose concentration of less than 350 mg / dL on D+7 and were then used for compound analgesic testing.

[0506] Compound 108 was administered orally at 2, 5, and 10 mg / mL in 0.9% NaCl solution (50 μL / 10 g), and pregabalin was administered subcutaneously at 0.5 mg / mL in phosphate buffer (100 μL / 10 g) on ​​D+14 and D+17. Time course measurements were taken at +1, +2, +4, and +6 hours after compound administration.

[0507] Mechanical response thresholds in mice were measured with calibrated Von Frey filaments using an up / down method blinded to the operator. Measurements were performed before and 14 days after streptozotocin injection.

[0508] Statistical analysis was performed using SigmaPlot 12.5 software. The percentage of the maximum possible effect was calculated as follows: MPE%=[(Test value - Pre-test value) / (Cutoff - Pre-test value)]*100

[0509] The cutoff, test and pre-test values ​​correspond to the baseline measurement, the post-dose measurement and the pre-dose measurement, respectively.

[0510] [Table 7]

[0511] [Table 8]

[0512] Comparative Example 34: Preparation Procedures for Quinazoline Analogues 395-397 (i.e., Comparative Compounds 395-397, i.e., CC395, CC396, and CC397)

[0513] The following procedures illustrate the preparation of quinazoline-based comparative compounds according to Method I described in Example 2. The synthetic scheme is outlined below. [ka]

[0514] Preparation of 3-[(7-methoxyquinazolin-4-yl)oxy]-2-methyl-N-(4-pyridylmethyl)benzamide (CC395): [ka]

[0515] Compound CC395 was synthesized according to general method I from intermediate 81e (0.20 mmol) and 4-chloro-7-methoxyquinazoline (0.20 mmol) in 65% yield (52 mg) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.08(t,J=5.93Hz,1H),8.63(bs,1H),8.54-8.52(m,2H),8.34 -8.32(m,1H),7.42-7.34(m,7H),4.49(d,J=5.94Hz,2H),3.99(s,3H),2.11(s,3H);MS(ESI,EI + ): m / z=401.35(MH + ).

[0516] Preparation of N-[(3-fluoro-4-pyridyl)methyl]-3-(7-methoxyquinazolin-4-yl)oxy-2-methyl-benzamide (CC396): [ka]

[0517] Compound CC396 was synthesized according to general method I from intermediate 81f (0.20 mmol) and 4-chloro-7-methoxyquinazoline (0.20 mmol) in 44% yield (37 mg) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.10(t,J=5.73Hz,1H),8.63(bs,1H),8.54(d,J=1.68Hz,1H),8.43-8.42( m,1H),8.34-8.32(m,1H),7.47-7.36(m,6H),4.55(d,J=5.92Hz,2H),3.99(s,3H),2.10(s,3H);MS(ESI,EI + ): m / z=419.35(MH + ).

[0518] Preparation of 3-[(7-chloroquinazolin-4-yl)oxy]-2-methyl-N-(4-pyridylmethyl)benzamide (CC397): [ka]

[0519] Compound CC397 was synthesized according to general method I from intermediate 81e (0.30 mmol) and 4,7-dichloroquinazoline (0.30 mmol) in 57% yield (69 mg) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.10(t,J=6.13Hz,1H),8.75(bs,1H),8.55-8.53(m,2H),8.47(d,J=8.72Hz,1H),8.13(d,J=1.9 MS(ESI,EI) + ): m / z=405.25(MH + ).

[0520] Comparative Example 35: Cell-based assay comparison between compounds 32, 44, and 108 and quinazoline comparison compounds CC395 to CC397

[0521] Cell-based assays of the above compounds CC395 to CC397 against M-NFS-60 and HEK-CSF1R were carried out according to the procedures described in Examples 29 and 30 and compared with their quinoline analogues 32, 44 and 108. The IC50s are presented in Table 9 below:

[0522] [Table 9]

[0523] Quinoline analogs 32, 44, and 108 were found to exhibit 19-fold, 22-fold, and 22-fold reduced IC50 values ​​against M-NFS-60 and 36-fold, 86-fold, and 145-fold reduced IC50 values ​​against HEK-CSF1R-STAT5 compared to the comparative quinazoline compounds CC395, CC396, and CC397, respectively, thus demonstrating the superior inhibitory effects of the compounds of the present invention against the cancerous M-NFS-60 cell line and the non-cancerous HEK-CSF1R-STAT5 cell line.

[0524] Comparative Example 36: Analogs 398-401 (i.e., Compound 398 and Comparative Compounds 399-401, i.e., CC399, CC400, and CC401)

[0525] To account for the non-equivalence of the bridging group CONH, analogs 398-401 were prepared. The biological results are reported in the table below.

[0526] [Table 10]

[0527] Carboxamide 398 was found to exhibit 26-fold, 21-fold, and 38-fold reduced IC50 against M-NFS-60 and 61-fold, 39-fold, and 67-fold reduced IC50 against HEK-CSF1R-STAT5 compared to comparative compounds CC399, CC400, and CC401, respectively, thus demonstrating the superior inhibitory effects of the compounds of the present invention against the cancer M-NFS-60 cell line and the non-cancerous HEK-CSF1R-STAT5 cell line.

Claims

1. Compounds of formula (IIa) to (IXa) [hereinafter, compounds (C) of class (I)], or an N-oxide, a pharma- ceutically acceptable salt, a pharma- ceutically acceptable solvate or a stereoisomer thereof: 【Chemistry 1】 【change】 where the dashed bond represents an optional double bond: -R １ and R ２ are each independently of each other and at each occurrence hydrogen, halo, C １－６ Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF ３ , C.N., O.R. ２１ , S.R. ２１ , N(R ２１ ) ２ , C(O)OR ２１ , and CON(R ２１ ) ２ wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from the group consisting of halo, C １－６ Alkyl, 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, cycloalkyl, or heterocyclyl substituent is optionally further substituted with heterocyclyl, ２１ are each independently of one another and at each occurrence hydrogen, C １－６ each p is an integer ranging from 0 to 4; each q is an integer ranging from 0 to 2; -R ３ are each independently of each other and at each occurrence hydrogen, halo, C １－１５ Alkyl, OR ２１ , and N(R ２１ ) ２ wherein R ２１ are each, independently of one another, a hydrogen atom or a C １－１５ alkyl}; each r is an integer ranging from 0 to 3; -R ４ and R ´ ４ are each, independently of one another, a hydrogen atom or a C １－６ alkyl; x is an integer ranging from 0 to 2; -T is CH2; -U is, each occurrence independently, selected from C-halo, C-R, or N, where R is hydrogen, OR １１ , N(R １１ ) ２ , C １－１０ alkyl or cycloalkyl, １１ are each independently, and at each occurrence, hydrogen and C １－４ alkyl); -D is each independently and at each occurrence selected from C, C-R or N, where R is hydrogen; - m is an integer equal to 1 or 2; - n is an integer equal to 0 or 1; -R ａ１ each, independently of the others and at each occurrence, is hydrogen; each n1 is an integer ranging from 0 to 5; -R ａ２ Each, independently of the others, and for each occurrence, １－１５ Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, CF ３ , C.N., O.R. １１ , S.R. １１ , N(R １１ ) ２ , COOR １１ , CO(R １１ ) ２ , and CON(R １１ ) ２ and each optional alkyl, cycloalkyl, heterocyclyl, and heteroaryl substituent is optionally selected from the group consisting of halo, C １－６ Alkyl, cycloalkyl, N(R １１ ) ２ , C.F. ３ , C.N., C.O.R. １１ , CO(R １１ ) ２ , CON(R １１ ) ２ OR １１ wherein R １１ are each independently of one another and at each occurrence hydrogen, C １－６ n2 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl substituents are optionally substituted with halo; each n2 is an integer ranging from 0 to 4; -B is each independently, and at each occurrence, C-R, O, N, S and NR ７´ wherein R is selected from hydrogen or C optionally substituted with a halogen atom; １－１０ alkyl; R ７´ is hydrogen and C １－６ alkyl); -E is, independently of each other and at each occurrence, C-R, O, N, S and NR ７´ wherein R is selected from hydrogen or C optionally substituted with a halogen atom; １－１０ alkyl; R ７´ is hydrogen and C １－６ alkyl); -R ａ４ Each, independently of the others, and for each occurrence, １－１５ alkyl; each n4 is an integer ranging from 0 to 4; -R ａ３ Each, independently of the others, and for each occurrence, １－１５ Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, CF ３ , OR １１ , S.R. １１ , N(R １１ ) ２ , COOR １１ , CO(R １１ ) ２ , and CON(R １１ ) ２ and each optional alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl substituent is optionally selected from the group consisting of halo, alkyl, cycloalkyl, N(R １１ ) ２ , CN, or OR １１ wherein R １１ are each independently of one another and at each occurrence hydrogen, C １－６ n3 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, wherein said alkyl, cycloalkyl, and heterocyclyl substituents are optionally substituted with halo; each n3 is an integer ranging from 0 to 2; said cycloalkyl is a monocyclic, bicyclic or tricyclic ring system of 3 to 7 ring members per ring; said heterocyclyl is a saturated, partially saturated or fully saturated monocyclic, bicyclic or tricyclic ring containing from 3 to 12 carbon atoms and 1 or 2 heteroatoms independently selected from O or N; said aryl is a phenyl, naphthyl or anthracenyl optionally carbocyclically fused with a cycloalkyl or heterocyclyl of 5 to 7 ring members; said heteroaryl is a monocyclic ring structure containing 5 or 6 ring atoms, including 1 to 3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

2. 2. The compound of claim 1, or an N-oxide, pharma- ceutically acceptable salt, pharma- ceutically acceptable solvate, or stereoisomer thereof: During the ceremony, -T is CH2; -U is each independently and at each occurrence selected from C-halo, C-R, or N, and R is hydrogen or C 1-4 alkyl; -D is independently, and at each occurrence, selected from C, C-R or N, and R is hydrogen; -R ａ１ is hydrogen; -R ａ２ are respectively halo, OR １１ , C １－６ Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF ３ , C.N., S.R. １１ , N(R １１ ) ２ , COOR １１ , CO(R １１ ) ２ , and CON(R １１ ) ２ wherein R １１ are each independently of one another and at each occurrence hydrogen, C １－４ each n2 is an integer ranging from 0 to 2; -B is each independently, and at each occurrence, C-R, O and NR ７´ wherein R ７´ is hydrogen or C １－４ alkyl, R is hydrogen or C １－４ alkyl); -R ａ４ are respectively C １－６ alkyl; each n4 is an integer ranging from 0 to 2; -R ａ３ are respectively C １－６ each n3 is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

3. 3. The compound (C) according to claim 1 or 2, or an N-oxide, a pharma- ceutically acceptable salt, a pharma- ceutically acceptable solvate or a stereoisomer thereof: During the ceremony, -R １ and R ２ are each independently of each other and at each occurrence hydrogen, halo, C １－６ Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF ３ , C.N., O.R. ２１ , S.R. ２１ , N(R ２１ ) ２ , C(O)OR ２１ , and CON(R ２１ ) ２ wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from the group consisting of halo, C １－６ Alkyl, cycloalkyl, heterocyclyl, CF ３ , C.O.R. ２１ , N(R ２１ ) ２ , C.N., C.O.R. ２１ , C(O)OR ２１ OR ２１ and each optional alkyl substituent is optionally further substituted with heterocyclyl, ２１ are each independently of one another and at each occurrence hydrogen, C １－６ each p is an integer ranging from 0 to 4; each q is an integer ranging from 0 to 2; -R ３ are each independently of each other and at each occurrence hydrogen, halo, C １－１５ Alkyl, OR ２１ , and N(R ２１ ) ２ wherein R ２１ are each, independently of one another, a hydrogen atom or a C １－１５ alkyl}; each r is an integer ranging from 0 to 3; -R ４ and R ´ ４ are each, independently of one another, a hydrogen atom or a C １－６ alkyl; and x is an integer ranging from 0 to 2.

4. The compound according to claim 1 or 2, which is of formula (IIa-a) to (IXa-a) [hereinafter, compound (C) of class (I)], or an N-oxide, a pharma- ceutically acceptable salt, a pharma- ceutically acceptable solvate or a stereoisomer thereof: 【Chemistry 2】 【change】 In the formula, R １ , R ２ , R ３ , R ４ , R ４ ', R ａ１ , R ａ２ , R ａ３ , R ａ４ , T, U, B, E, D, q, r, x, n1, n2, n3, n4, m, and n are as defined in claim 1; -R' １ is (R' １ -a) to (R' １ -d) is selected from the group consisting of 【Chemistry 3】 During the ceremony, X, Y and Z are each, independently of one another and at each occurrence, C-R, O, N, S and NR ７´ wherein R is selected from hydrogen or C optionally substituted with a halogen atom; １－６ alkyl; R ７´ is hydrogen, C １－６ Alkyl, cycloalkyl, heterocyclyl, and CF ３ wherein each alkyl, cycloalkyl, or heterocyclyl substituent is optionally further substituted with heterocyclyl; ・R ｂ１ Each independently and at each occurrence is hydrogen, halo, C １－６ Alkyl, cycloalkyl, heterocyclyl, CN, CF ３ , C.O.R. １１ , CON(R １１ ) ２ , N.R. １１ and OR １１ wherein the alkyl, cycloalkyl, and heterocyclyl are optionally substituted with heterocyclyl, １１ are each independently selected from hydrogen, halo, and C １－６ alkyl); each p1 is an integer ranging from 0 to 3; - a dashed bond represents an optional double bond}; The cycloalkyl is a monocyclic, bicyclic or tricyclic ring system of 3 to 7 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 and 1 or 2 heteroatoms independently selected from O or N; the aryl is a phenyl, naphthyl or anthracenyl optionally carbocyclically fused with a cycloalkyl or heterocyclyl of 5 to 7 ring members; the heteroaryl is a monocyclic ring structure containing 5 or 6 ring atoms, including 1 to 3 heteroatoms independently selected from O or N, or a bicyclic aromatic group having 8 to 10 atoms.

5. In the formula, R １ , R ２ , R ３ , R ４ , R ４ ', p, q, r, x, R ａ１ , R ａ２ , R ａ３ , R ａ４ 5. The compound (C) of claim 4, wherein n1, n2, n3, n4, m, and n are as defined in claim 3, or an N-oxide, a pharma- ceutically acceptable salt, a pharma- ceutically acceptable solvate, or a stereoisomer thereof.

6. The compound according to claim 1 or 2, which is represented by the formula (IIa-1) to (IXa-1) [hereinafter referred to as compound (C) of class (I)] or an N-oxide, a pharma- ceutically acceptable salt, a pharma- ceutically acceptable solvate or a stereoisomer thereof: 【Chemistry 4】 【change】 In the formula, R １ , R ａ１ , R ａ２ , R ａ３ , R ａ４ , T, U, B, E, D, p, n1, n2, n3, n4, m, n are as defined in claim 1, and the dashed bond represents an optional double bond: -R ４ are each, independently of one another, a hydrogen atom or a C １－４ alkyl; -R ３ are each independently of each other and at each occurrence hydrogen, halo, C １－４ Alkyl, OR ２１ , and N(R ２１ ) ２ Independently selected from the group consisting of: ２１ are each, independently of one another, a hydrogen atom or a C １－４ (alkyl).

7. R １ , p, R ａ１ , R ａ２ , R ａ３ , R ａ４ , T, U, B, E, D, n1, n2, n3, n4, m, and n are as defined in claim 3. Compound (C) of general formula (IIa-1) to (IXa-1) according to claim 6, or an N-oxide, a pharma- ceutically acceptable salt, a pharma- ceutically acceptable solvate or a stereoisomer thereof.

8. The compound according to claim 1 or 2, which is of formula (IIa-a1) to (IXa-a1) [hereinafter, compound (C) of class (I)], or an N-oxide, a pharma- ceutically acceptable salt, a pharma- ceutically acceptable solvate or a stereoisomer thereof: 【Chemistry 5】 【change】 In the formula, R １ , R' １ , R ａ１ , R ａ２ , R ａ３ , R ａ４ , T, U, B, E, D, p1, n1, n2, n3, n4, m, n are as described in claim 4, and the dashed bond represents an optional double bond: -R ４ are each, independently of one another, a hydrogen atom or a C １－４ alkyl; -R ３ are each independently of each other and at each occurrence hydrogen, halo, C １－４ Alkyl, OR ２１ , and N(R ２１ ) ２ wherein R ２１ are each, independently of one another, a hydrogen atom or a C １－４ (alkyl).

9. R １ , R ａ１ , R ａ２ , R ａ３ , R ａ４ 9. The compound (C) of claim 8, wherein n1, n2, n3, n4, m, and n are as defined in claim 3, or an N-oxide, a pharma- ceutically acceptable salt, a pharma- ceutically acceptable solvate, or a stereoisomer thereof.

10. The compound according to claim 1 or 2, which is represented by the formula (Xa-1) to (XVIIa-1) [hereinafter referred to as compound (C) of class (I)], or an N-oxide, a pharma- ceutically acceptable salt, a pharma- ceutically acceptable solvate or a stereoisomer thereof: 【Chemistry 6】 In the formula, R １ , R ａ１ , R ａ２ , R ａ３ , R ａ４ , T, U, B, E, D, p, n1, n2, n3, n4, m, n are as described in claim 1, and the dashed bond represents an optional double bond: -R ３ are each independently of each other and at each occurrence hydrogen, halo, C １－４ Alkyl, OR ２１ , and N(R ２１ ) ２ wherein R ２１ are each, independently of one another, a hydrogen atom or a C １－４ (alkyl).

11. R １ , p, R ａ１ , R ａ２ , R ａ３ , R ａ４ 11. The compound (C) of claim 10, or an N-oxide, pharma- ceutically acceptable salt, pharma- ceutically acceptable solvate or stereoisomer thereof, wherein n, T, U, B, E, D, n1, n2, n3, n4, m, and n are as defined in claim 3.

12. The compound according to claim 1 or 2, which is represented by the formula (XVIIIa-1) to (XXVa-1) [hereinafter referred to as compound (C) of class (I)], or an N-oxide, a pharma- ceutically acceptable salt, a pharma- ceutically acceptable solvate or a stereoisomer thereof: 【Chemistry 7】 【change】 In the formula, R １ , R ａ１ , R ａ２ , R ａ３ , R ａ４ , T, U, B, E, D, p, n1, n2, n3, n4, m, n are as defined in claim 1, and the dashed bond represents an optional double bond; -R ３ are each independently of each other and at each occurrence hydrogen, halo, C １－４ Alkyl, OR ２１ , and N(R ２１ ) ２ wherein R ２１ are each, independently of one another, a hydrogen atom or a C １－４ (alkyl).

13. R １ , p, R ａ１ , R ａ２ , R ａ３ , R ａ４ 13. The compound (C) of claim 12, or an N-oxide, pharma- ceutically acceptable salt, pharma- ceutically acceptable solvate or stereoisomer thereof, wherein n, T, U, B, E, D, n1, n2, n3, n4, m, and n are as defined in claim 3.

14. The compound (C) according to claim 6, wherein the compound of formula (IIIa-1) is a compound of the following formula (LXI), (LXIII), (LXXII), (LXXIV) to (LXXXV), (LXXXVI), (CXIII), (CLXXXVI), (CLXXXVIII), (CXC) to (CXCVI), (CXCVII-6) to (CXCVII-7), (CXCVII-16) to (CXCVII-17), (CXCVII-19) to (CXCVII-20), (CXCVII-27), (CXCVII-33) to (CXCVII-35), or (CXCVII-37) to (CXCVII-38), or an N-oxide, pharma-ceutically acceptable salt, pharma-ceutically acceptable solvate, or stereoisomer thereof: 【Chemistry 8】 【change】 【change】 【change】

15. The compound of formula (IIIa-a1) is represented by the following formulae (CXCVIII-3), (CXCVIII-7), (CXCVIII-11), (CXCVIII-16), (CXCVIII-19) to (CXCVIII-21), (CXCVIII-23) to (CXCVIII-26), (CXCVIII-28) to (CXCVIII-31), (CXCVIII-33) to (CXCVIII-39), (CXCVIII-42) to (CXCVIII-47), (CXCVIII-49), (CXCVIII-51) to (CXCVIII-53), 9. The compound (C) according to claim 8, which is a compound of formula (CXCVIII-56), (CXCVIII-59), (CXCVIII-62), (CXCVIII-66), (CXCVIII-67), (CXCVIII-70), (CXCVIII-71), (CXCVIII-73) to (CXCVIII-75), (CXCVIII-81) to (CXCVIII-86), or (CXCVIII-88) to (CXCVIII-90), or an N-oxide, pharma-ceutically acceptable salt, pharma-ceutically acceptable solvate, or stereoisomer thereof: 【Chemistry 9】 【change】 【change】 【change】 【change】 【change】 【change】

16. 16. A pharmaceutical composition comprising a carrier and, as an active ingredient, a compound (C) according to any one of claims 1 to 15.

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

18. A compound according to any one of claims 1 to 15 for use in the treatment of a disease selected from cancer, metabolic disorders, inflammatory and autoimmune disorders, neurological disorders, atherosclerosis and cardiovascular diseases, Sjogren's syndrome, renal allograft rejection, virally induced diseases, circulatory diseases, osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, eye diseases, chronic and neuropathic pain, and fibroproliferative diseases.

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