Heteroaryl compounds as IRAK4 inhibitors, compositions thereof and uses thereof

Abstract

The present disclosure relates to the field of medicinal chemistry, specifically to compounds having interleukin-1 receptor associated kinase 4 (IRAK4) inhibitory activity, as well as pharmaceutical compositions and uses thereof. The present disclosure provides compounds of formula (I) as effective IRAK4 inhibitors, which can be used for the prevention and / or treatment of diseases and / or conditions associated with IRAK4.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of Chinese Patent Application No. 202111661982.5, filed on December 31, 2021, and No. 202211305127.5, filed on October 24, 2022, all of which are incorporated herein by reference in their entirety.

[0002] FIELD OF THE INVENTION The present disclosure relates to amide compounds having inhibitory activity against the MyD88 / IRAK4 pathway, compositions comprising such compounds, and methods of their use. The present disclosure further relates to pharmaceutical compositions comprising at least one compound according to the present disclosure, useful for treating conditions associated with kinase modulation, including IRAK-4, in mammals, including various diseases, including tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, metabolic diseases, and genetic diseases, and methods of inhibiting kinase activity. [Background technology]

[0003] Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine / threonine protein kinase involved in the interleukin (IL) receptor family (e.g., IL-1R, IL-18R, or IL-33R) and the Toll-like receptor (TLR) family (excluding TLR3). It plays an important role in inflammatory signaling pathways. See Henderson and Goldbach-Mansky, Clin. Immunol. 2010, 135, 210-222.

[0004] Animal studies have shown that knocking out the IRAK4 protein in mice prevents the interleukin-1 receptor (IL-1R)- and TLR-mediated signaling pathways and the release of associated cytokines. See Suzuki et al., Nature 2002, 416, 750-756. Increasing evidence indicates that IRAK4 is an attractive target for treating inflammatory diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, etc.).

[0005] As a key regulator of the Toll-like signaling pathway, IRAK4, via its death domain (DD), can form a mydosome complex with myeloid differentiation primary response 88 (MyD88) and downstream IRAK1 / 2. (See Lin et al., Nature 2010, 465, 885-890.) In this complex, IRAK4 is first activated by trans-autophosphorylation, followed by activation of IRAK1 / 2, which in turn activates the downstream nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. (See Ferrao et al., Mol. Cell 2014, 55, 891-903.) Therefore, both the kinase activity and scaffolding function of IRAK4 play important roles in the transmission of inflammatory signals. Numerous experiments have demonstrated that inhibiting IRAK4 kinase activity by gene editing or small molecule compounds can reduce the expression of inflammatory cytokines and alleviate the associated inflammatory phenotype in vitro and in vivo. See Chaudhary et al., J. Med. Chem. 2015, 58, 96-110. Furthermore, it has been reported that MyD88 has acquired functional mutations in some malignant hematologic cancers (e.g., 29% of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) and Waldenstrand macroglobulinemia (WM)), suggesting that regulation of IRAK4 may have therapeutic benefits for some hematologic cancers. See Ondrejka et al., Am. J. Clin. Pathol. 2013, 140, 387-394.

[0006] Currently, there are no commercially available drugs targeting IRAK4. Many pharmaceutical companies have been working on this target. Among them, PF-06650833, developed by Pfizer, is the first IRAK4 inhibitor to enter clinical trials. See Lee et al., J. Med. Chem. 2017, 60, 5521-5542. This IRAK4 inhibitor has entered Phase II clinical trials for the treatment of rheumatoid arthritis and hidradenitis suppurativa. Recently, Bayer has launched two IRAK4 inhibitors (BAY-1830839 and BAY-1834845), which are currently in Phase I clinical trials. Rigel's R-835 is also in Phase I clinical trials. The indications for Bayer and Rigel's IRAK4 inhibitors are primarily in the areas of autoimmune diseases, inflammation, and ABC-DLBCL. CA4948, a small molecule IRAK4 inhibitor developed by Curis Pharmaceuticals, has been reported to be effective in six patients with relapsed or refractory myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). See Gummadi et al., ACS Med. Chem. Lett., 2020, 11, 2374-2381. Therefore, the development of small molecule inhibitors of IRAK4 is a research direction with high clinical value. Summary of the Invention

[0007] The present disclosure provides compounds capable of inhibiting IRAK4, as well as compositions and uses thereof. These disclosed IRAK4 inhibitors, as well as compositions and uses thereof, can effectively prevent or treat diseases and disorders associated with IRAK4 activation.

[0008] One object of the present disclosure is to provide IRAK4 inhibitors, as well as compositions and uses thereof.

[0009] A first aspect of the present disclosure is a compound of formula (I): [ka] or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof, wherein Ring A is selected from the group consisting of: [ka] each n is independently 0, 1, 2, or 3; X 1 is O or S; X 2 is N or CH; If present, R 1 is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-2 Alkylene-C 3-6 Cycloalkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NH(C 3-6 cycloalkyl), -N(C 3-6 Cycloalkyl)2, OC 1-6 Alkyl, 3-8 membered heterocyclyl, 6-10 membered bridged biheterocyclyl, 5-12 membered spirobiheterocyclyl, 6-12 membered fused biheterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, where C 1-6 Alkyl, C 3-6 Each of the cycloalkyl, aryl, heteroaryl, heterocyclyl, bridged biheterocyclyl, spirobiheterocyclyl, and fused biheterocyclyl independently contains one, two, or three R a When present, each of the heterocyclyl, bridged biheterocyclyl, spirobiheterocyclyl, fused biheterocyclyl, and heteroaryl contains one or more heteroatoms independently selected from the group consisting of O, S, NH, N, P(=O), S(=O), and S(=O)2; R 2 is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-2 Alkylene-C 3-6 Cycloalkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NH(C 3-6 cycloalkyl), -N(C 3-6 Cycloalkyl)2, hydroxy, -OC 1-6Alkyl, -OC 3-6 cycloalkyl, O-heterocyclyl, where heterocyclyl is 3-8 membered heterocyclyl, 3-8 membered heterocyclyl, 6-10 membered bridged biheterocyclyl, 5-12 membered spirobiheterocyclyl, 6-12 membered fused biheterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, where C 1-6 Alkyl, C 3-6 Each of the cycloalkyl, aryl, heteroaryl, heterocyclyl, bridged biheterocyclyl, spirobiheterocyclyl, and fused biheterocyclyl independently contains one, two, or three R b When present, each of the heterocyclyl, bridged biheterocyclyl, spirobiheterocyclyl, fused biheterocyclyl, and heteroaryl contains one or more heteroatoms independently selected from the group consisting of O, S, NH, N, P(=O), S(=O), and S(=O)2; preferably, R 2 is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-2 Alkylene-C 3-6 Cycloalkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NH(C 3-6 cycloalkyl), -N(C 3-6 Cycloalkyl)2, OC 1-6 Alkyl, 3-8 membered heterocyclyl, 6-10 membered bridged biheterocyclyl, 5-12 membered spirobiheterocyclyl, 6-12 membered fused biheterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, where C 1-6 Alkyl, C 3-6 Each of the cycloalkyl, aryl, heteroaryl, heterocyclyl, bridged biheterocyclyl, spirobiheterocyclyl, and fused biheterocyclyl independently contains one, two, or three R bWhen present, each of the heterocyclyl, bridged biheterocyclyl, spirobiheterocyclyl, fused biheterocyclyl, and heteroaryl contains one or more heteroatoms independently selected from the group consisting of O, S, NH, N, P(=O), S(=O), and S(=O)2; If present, each R 5 and R 6 are independently hydrogen, deuterium, and C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-2 Alkylene-C 3-6 cycloalkyl, where each C 1-6 Alkyl and C 3-6 Cycloalkyl may independently be one, two, or three R c or R 5 and R 6 together with the carbon atoms to which they are attached form a saturated 5- or 6-membered spiro heterocycle containing one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, wherein the saturated 5- or 6-membered spiro heterocycle is selected from one, two, or three R c is replaced by; If present, R 7 is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-2 Alkylene-C 3-6 cycloalkyl, or a 5- or 6-membered heterocyclyl containing one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, wherein each C 1-6 Alkyl and C 3-6 Cycloalkyl may independently be one, two, or three R c is replaced by; If present, R 8 is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-2 Alkylene-C 3-6cycloalkyl, or a 5-6 membered heterocyclyl containing one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur; each R 9 , R 10 , R 11 , and R 12 However, independently, hydrogen, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-2 Alkylene-C 3-6 cycloalkyl, or a 5-6 membered heterocyclyl containing one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, wherein each C 1-6 Alkyl, C 3-6 Cycloalkyl and heterocyclyl may independently have one, two, or three R c or R 9 and R 10 combine with the carbon to which they are attached to form a carbonyl; Ring Z 1 is selected from the group consisting of: (1) a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur; (2) Phenyl (3) a 5-6 membered unsaturated or saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from the group consisting of oxygen and nitrogen; (4) a 7- to 10-membered fused bicyclic heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur; and (5) Unsaturated or saturated C 3-6 cycloalkyl; Ring Z 2 does not exist or ring Z 2 is selected from the group consisting of: (1) a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur; (2) Phenyl (3) a 5-6 membered unsaturated or saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from the group consisting of oxygen and nitrogen; and (4) Unsaturated or saturated C 3-6 cycloalkyl; Here, ring Z 2 If does not exist, R d is Ring Z 2 Replace R d is Ring Z 1 Concatenate with; If present, each R a are independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, methylamino, dimethylamino, cyano, methyl, deuterated methyl, methoxy, deuterated methoxy, ethyl, cyclopropyl, tert-butoxycarbonyl, carbamoyl, C 1-2 Alkylene-hydroxy, C 1-2 Alkylene-methoxy, or C 1-2 alkylene-deuterated methoxy; If present, each R b are independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, methylamino, dimethylamino, cyano, C 1-3 Alkyl, deuterated methyl, methoxy, deuterated methoxy, cyclopropyl, C 1-2 Alkylene-hydroxy, C 1-2 Alkylene-methoxy, or C 1-2 alkylene-deuterated methoxy; or two R on non-adjacent carbons b , together with the atoms attached to it, form a ring; or two R on the same carbon b , together with the carbon attached to it to form a carbonyl; If present, each R c are independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, methylamino, dimethylamino, cyano, methyl, deuterated methyl, methoxy, or deuterated methoxy; If present, each R d are independently hydrogen, deuterium, methyl, deuterated methyl, ethyl, cyclopropyl, C1-2 Alkylene-hydroxy, C 1-2 Alkylene-methoxy, C 1-2 alkylene-deuterated methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, or difluoromethoxy; and If present, each R 3 and R 4 is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, methylamino, dimethylamino, nitro, cyano, methyl, deuterated methyl, methoxy, deuterated methoxy, ethyl, cyclopropyl, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, or dimethylphosphinyl.

[0010] In some embodiments of the aspects provided herein, including any one of the embodiments described above, the compound is of formula (IA): [ka] where n, X 1 , Z 1 , Z 2 , R 1 , R 2 , R 3 , and R 4 is defined as above.

[0011] In some embodiments of the aspects provided herein, including any one of the embodiments described above, the compound is of Formula (I-A1): [ka] where n, Z 1 , Z 2 , R 1 , R 2 , R 3 , and R 4 is defined as above.

[0012] In some embodiments of the aspects provided herein, including any one of the embodiments described above, the compound is of formula (IC): [ka] where n, R 1 , R 2 , R 3 , R d , and Z 1 is defined as above.

[0013] In some embodiments of the aspects provided herein, including any one of the embodiments described above, the compound is of Formula (I-A2): [ka] where n, R 1 , and R 2 is defined as above.

[0014] In some embodiments of the aspects provided herein, including any one of the embodiments described above, the compound is of formula (IB): [ka] where n, Z 1 , Z 2 , R 2 , R 3 , R 4 , R 5 , and R 6 is defined as above.

[0015] In some embodiments of the aspects provided herein, including any one of the embodiments described above, the compound is of Formula (I-B1): [ka] where n, Z 1 , Z 2 , R 2 , R 3 , and R 4is defined as above.

[0016] In some embodiments, including any one of the embodiments described above, the compound is of formula (ID): [ka] where n, R 2 , R 3 , R 5 , R 6 , R d , and Z 1 is defined as above.

[0017] In some embodiments, including any one of the embodiments described above, the compound is of Formula (I-B2): [ka] where R 2 is defined as above.

[0018] In some embodiments, including any one of the previously described embodiments, including compounds of formula (I), (IA), (I-A1), (IB), (I-B1), (IC), and (ID), ring Z 1 is selected from the group consisting of: (1) a 5-6 membered heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur; (2) phenyl; and (3) a 7-10 membered fused bicyclic heterocyclyl comprising 1, 2, or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur.

[0019] In some embodiments, including any one of the embodiments described above, (1) ring Z 2 If exists, [ka] is selected from the group consisting of: [ka] Preferably, it is selected from the group consisting of: [ka] or preferably selected from the group consisting of: [ka] (2) Z 2 does not exist, [ka] is selected from the group consisting of: [ka] Preferably, it is selected from the group consisting of: [ka] More preferably, it is selected from the group consisting of: [ka]

[0020] In some embodiments, including any one of the previously described embodiments, including compounds of formula (I), (IA), (I-A1), (IB), and (I-B1): (1) Ring Z 2 If there is [ka] is selected from the group consisting of: [ka] Preferably, it is selected from the group consisting of: [ka] Also preferably, it is selected from the group consisting of: [ka] More preferably, it is selected from the group consisting of: [ka] (2) Ring Z 2 If does not exist, R d Ring Z 2 Instead of R d Ring Z 1 connected to R d is as above.

[0021] In some embodiments, including any one of the previously described embodiments, including compounds of formula (I), (IA), (I-A1), (IB), (I-B1), (IC), and (ID), R 1 is selected from the group consisting of: [ka] Preferably, it is selected from the group consisting of: [ka] More preferably, it is selected from the group consisting of: [ka] More preferably, it is selected from the group consisting of: [ka]

[0022] In some embodiments, including any one of the previously described embodiments, including compounds of formula (I), (IA), (I-A1), (IB), (I-B1), (IC), and (ID), R 2 is -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NH(C 3-6 cycloalkyl), -N(C3-6 Cycloalkyl)2, hydroxy, -OC 1-6 Alkyl, -OC 3-6 cycloalkyl, O-heterocyclyl, where heterocyclyl is 3-8 membered heterocyclyl, 3-8 membered heterocyclyl, 6-10 membered bridged biheterocyclyl, 5-12 membered spirobiheterocyclyl, 6-12 membered fused biheterocyclyl, where C 1-6 Alkyl, C 3-6 Each of the cycloalkyl, heterocyclyl, spirobiheterocyclyl, and fused biheterocyclyl independently has one, two, or three R b is substituted with R b is as defined above; preferably, R 2 is -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NH(C 3-6 cycloalkyl), -N(C 3-6 Cycloalkyl)2, -OC 1-6 alkyl, 3- to 8-membered heterocyclyl, 5- to 12-membered spirobiheterocyclyl, and 6- to 12-membered fused biheterocyclyl, wherein C 1-6 Alkyl, C 3-6 Each of the cycloalkyl, heterocyclyl, spirobiheterocyclyl, and fused biheterocyclyl independently has one, two, or three R b is substituted with R b is as above.

[0023] In some embodiments, including any one of the embodiments described above, R 2 is selected from the group consisting of: [ka] Preferably, it is selected from the group consisting of: [ka] Also preferably, it is selected from the group consisting of: [ka] More preferably, it is selected from the group consisting of: [ka]

[0024] Another aspect of the present disclosure is a compound of formula (II): [ka] or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof, wherein [ka] is a single or double bond; Y1 is O, S or CH2; Y2 is CR 1 or C(R 5 )R 6 is; Y3 is N or O; R 1 , R 2 , R 5 and R 6 is defined above with respect to formula (I).

[0025] In some embodiments, including any one of the embodiments described above, the compound of formula (II): [ka] or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof, [ka] is selected from the group consisting of: [ka] Preferably, it is selected from the group consisting of: [ka]

[0026] In some embodiments, including any one of the embodiments described above, for a compound of Formula (II): R 1 is selected from the group consisting of: [ka] Preferably, it is selected from the group consisting of: [ka]

[0027] In some embodiments, including any one of the embodiments described above, for a compound of Formula (II): R 2 is selected from the group consisting of: [ka] Preferably, it is selected from the group consisting of: [ka]

[0028] In some embodiments, including any one of the embodiments described above, for a compound of Formula (II): R 5 and R 6 Each of the 1-6 It is alkyl, preferably methyl.

[0029] A second aspect of the present disclosure provides a compound or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof, wherein the compound is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0030] A third aspect of the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the embodiments described above, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative, or isomer thereof, and a pharmaceutically acceptable carrier.

[0031] A fourth aspect of the present disclosure provides a pharmaceutical formulation comprising a compound of any one of the embodiments described hereinabove, including the first and second aspects, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof, or the pharmaceutical composition of the third aspect, wherein the pharmaceutical formulation is a tablet, capsule, injectable, granule, powder, suppository, pill, gel, dispersion, oral liquid, inhalant, suspension, or solid suspension, or a combination thereof.

[0032] A fifth aspect of the present disclosure provides a composition comprising: (i) a compound of any one of the embodiments described hereinabove, including those of the first and second aspects, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative or isomer thereof, or a pharmaceutical composition described herein according to the third aspect, or a pharmaceutical formulation according to the fourth aspect; and (ii) one or more additional therapeutic agents, wherein the one or more additional therapeutic agents are an anti-neurodegenerative agent, an anti-inflammatory agent, and / or an anti-cancer agent.

[0033] A sixth aspect of the present disclosure provides a compound of any one of the embodiments disclosed herein, including those according to the first and second aspects, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative, or isomer thereof, or a pharmaceutical composition as disclosed herein according to the third aspect, or a pharmaceutical formulation as disclosed herein according to the fourth aspect, or a composition as disclosed herein according to the fifth aspect, for use as a medicament in the treatment of a disease or disorder associated with interleukin-1 receptor-associated kinase 4 (IRAK4).

[0034] A seventh aspect of the present disclosure provides use of a compound of any one of the embodiments disclosed herein, including those according to the first and second aspects, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative, or isomer thereof, or a pharmaceutical composition disclosed herein according to the third aspect, or a pharmaceutical formulation disclosed herein according to the fourth aspect, or a composition disclosed herein according to the fifth aspect, for treating and / or preventing a disease or disorder associated with IRAK4.

[0035] An eighth aspect of the present disclosure provides a method for treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of the embodiments disclosed herein, including those according to the first and second aspects, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotopically labeled derivative, or isomer thereof, or a pharmaceutical composition disclosed herein according to the third aspect, or a pharmaceutical formulation disclosed herein according to the fourth aspect, or a composition disclosed herein according to the fifth aspect, wherein the disease or disorder is associated with IRAK4.

[0036] In some embodiments, including any one of the embodiments described hereinbefore, the disease or disorder is uveitis, dermatitis, acute lung injury, type II diabetes, arthritis, ulcerative colitis, Crohn's disease, early-onset inflammatory bowel disease, extraintestinal inflammatory bowel disease, ischemia / reperfusion injury in organ transplantation, non-alcoholic fatty liver disease, autoimmune hepatitis, asthma, endometriosis, psoriasis, systemic lupus erythematosus, sarcoid septicemia, Wegener's granulomatosis, pulmonary fibrosis, renal fibrosis, hepatic fibrosis, myocardial infarction, hypersensitivity pneumonitis, interstitial lung disease, ankylosing spondylitis, sclerosis, systemic sclerosis, polymyositis, rheumatoid arthritis, myasthenia gravis, juvenile-onset diabetes, glomerulonephritis, autoimmune thyroiditis, transplant rejection, Blau syndrome, scleroderma, stomatitis, retinitis pigmentosa, proliferative vitreoretinopathy, Best's macular degeneration, eczema, urticaria, vasculitis, eosinophils Myofasciitis, wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, diabetic macular inflammation, retinal vein occlusion, cystoid macular edema, glaucoma, Parkinson's disease, Alzheimer's disease, Huntington's disease, breast cancer, lung cancer, bladder cancer, pancreatic cancer, liver cancer, head and neck squamous cell carcinoma, thyroid carcinoma, sarcoma, osteosarcoma, desmoid, melanoma, prostate cancer, colorectal cancer, ovarian cancer, cervical cancer, esophageal cancer, The disease or disorder is selected from the group consisting of gastric cancer, myeloma, lymphoma, mantle cell lymphoma, cutaneous T-cell lymphoma, chronic and non-progressive anemia, idiopathic or essential thrombocythemia, leukemia, acute leukemia, chronic leukemia, lymphocytic leukemia, myelogenous leukemia, myelodysplastic syndrome, myeloproliferative disorder, brain tumor, astrocytoma, medulloblastoma, Schwann cell tumor, primary neuroectodermal tumor, or pituitary tumor.

[0037] In some embodiments, including any one of the embodiments described above, the disease or disorder is lymphoma, endometriosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, or rheumatoid arthritis. In some embodiments, including any one of the embodiments described above, the lymphoma is primary central nervous system lymphoma or diffuse large B-cell lymphoma with a MYD88 L265P mutation.

[0038] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in the art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the present disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive. [Brief explanation of the drawings]

[0039] [Figure 1] FIG. 1 shows the experimental results of the inhibition of IRAK4 activity by compound A4 in Example 4.

[0040] [Figure 2] FIG. 2 shows the experimental results of inhibition of IRAK4 activity by compound B5 in Example 64.

[0041] [Figure 3] FIG. 3 shows the experimental results of binding of compound A4 to IRAK4 in Example 4.

[0042] [Figure 4] FIG. 4 shows the experimental results of inhibition of binding to IRAK4 by compound B5 in Example 64.

[0043] Before proceeding with the detailed description, it is to be understood that the following detailed description is merely exemplary in nature and is not intended to limit the invention or its application and uses. Thus, while the present disclosure has been illustrated and described in terms of specific exemplary embodiments for convenience of explanation, it will be understood that it may be implemented in various other types of embodiments and equivalents, and in various other systems and environments. Furthermore, there is no intention to be bound by any theory presented in the preceding background or the following detailed description.

[0044] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0045] Detailed Description of the Invention While various embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.

[0046] Effects of the present disclosure The disclosed compounds having IRAK4 inhibitory activity of the present disclosure can be used as potent inhibitors of IRAK4 and can be used to prevent and / or treat diseases and / or disorders associated with or responsive to IRAK4.

[0047] definition Compounds are generally described herein using standard nomenclature. For compounds with asymmetric centers, it is understood that all optical isomers and mixtures thereof are included (unless otherwise specified). Furthermore, compounds with carbon-carbon double bonds can exist in Z- and E-forms, and all isomeric forms thereof are included in the present invention unless otherwise specified. When compounds exist in various tautomeric forms, the compounds described are not limited to a specific tautomer, but rather are intended to include all tautomers.

[0048] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a molecule" includes a plurality of such molecules, and the like.

[0049] As used herein, the terms "about" or "approximately" generally refer to within + / - 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a specified amount.

[0050] As used herein, the term "halogen" or "halide" generally refers to fluorine, chlorine, bromine, and iodine. As used herein, the term "haloalkyl" or "halo-alkyl" generally refers to an alkyl group substituted with one or more independently selected halogens (e.g., a "C1-C6 haloalkyl" group has 1-6 carbon atoms and at least one halogen). Examples of haloalkyl groups include, but are not limited to, mono-, di-, or tri-fluoromethyl; mono-, di-, or tri-chloromethyl; mono-, di-, tri-, tetra-, or penta-fluoroethyl; mono-, di-, tri-, tetra-, or penta-chloroethyl; and 1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl. As used herein, the term "haloalkoxy" or "halo-alkoxy" generally refers to an alkoxy group substituted with one or more independently selected halogens (e.g., a "C-C haloalkoxy" or "C-C halo-alkoxy" group has 1-6 carbon atoms and at least one halogen bonded to one of the carbon atoms). Examples of haloalkoxy groups include, but are not limited to, mono- or di-fluoromethoxy; mono- or di-chloromethoxy; mono-, di-, tri-, or tetra-fluoroethoxy; and mono-, di-, tri-, or tetra-chloroethoxy.

[0051] As used herein, the term "alkyl" generally refers to a straight or branched chain saturated aliphatic hydrocarbon. An alkyl group may contain 1-8 carbon atoms (C 1-8 alkyl), 1-6 carbon atoms (C 1-6and groups having 1-4 carbon atoms (C-C alkyl), such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl. 1-3 Alkyl refers to straight or branched chain alkyl groups of 1-3 carbon atoms, including, for example, methyl, ethyl, propyl, and isopropyl. In some cases, the substituents on the alkyl group are specified. For example, "cyanoalkyl" refers to an alkyl group substituted with at least one cyano substituent. In some embodiments, C 1-6 Alkyl is preferably methyl, ethyl, n-propyl, isopropyl or tert-butyl.

[0052] The term “alkylene” by itself or as part of another substituent means (CH) n where N can be a number from 1 to about 10. By way of example, "C alkylene" includes, but is not limited to, methylene, 1,1-ethylene, and 1,2-ethylene.

[0053] The term "alkenyl" as used herein generally refers to a straight- or branched-chain alkene group containing at least one unsaturated carbon-carbon double bond. Alkenyl groups include C alkyl groups, having 2-8, 2-6, or 2-4 carbon atoms, respectively. 2-8 Alkenyl group, C 2-6 Alkenyl groups and C 2-4Alkenyl groups include, for example, ethenyl, allyl, or isopropenyl. As used herein, the term "alkynyl" generally refers to a straight-chain or branched-chain alkyne group having one or more unsaturated carbon-carbon bonds, at least one of which is a triple bond. Alkynyl groups include C 1 -C 2 -C 3 -C 4 -C 6 -C 7 -C 8 -C 9 -C 10 -C 11 -C 12 -C 13 -C 14 -C 15 -C 16 -C 17 -C 18 -C 19 -C 20 -C 21 -C 22 -C 23 -C 24 -C 25 -C 26 -C 27 -C 28 -C 29 -C 30 -C 31 -C 32 -C 29 -C 33 -C 29 -C 34 -C 29 -C 35 -C 36 -C 37 -C 38 -C 39 -C 40 -C 41 -C 42 -C 43 -C 44 -C 45 -C 46 -C 47 -C 48 -C 49 -C 50 -C 51 -C 52 -C 53 -C 54 -C 55 -C 56 -C 57 -C 58 -C 59 -C 60 -C 61 -C 62 -C 63 -C 64 -C 65 -C 66 -C 67 -C 68 -C 69 -C 70 -C 71 -C 72 -C 73 -C 74 -C 75 -C 76 -C 77 -C 78 -C 79 -C 80 -C 81 -C 82 -C 83 -C 84 -C 85 -C 86 - 2-8 Alkynyl group, C 2-6 Alkynyl groups and C 2-4 Alkynyl groups are included.

[0054] The term "alkoxy" as used herein generally refers to an alkyl group as described above attached to another chemical moiety through an oxygen bridge. Alkoxy groups include alkyl groups of different lengths, for example, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 1-6 Alkoxy groups and C 1-4 As used herein, the term "OC" refers to an alkoxy group. 1-6 "Alkyl" generally refers to an alkoxy group containing an alkyl group (1-6 carbon atoms) attached to an oxygen atom. Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy are representative alkoxy groups.

[0055] As used herein, the term "cycloalkyl" generally refers to a group consisting of one or more saturated rings in which all ring members are carbon. For example, certain cycloalkyl groups include C 3-6 Cycloalkyl, where the cycloalkyl group contains one or more rings having 3-6 ring members that are all carbon, including, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. As used herein, the term "cycloalkenyl" generally refers to a group consisting of one or more unsaturated rings in which all the ring members are carbon.

[0056] As used herein, the term "heterocyclic" or "heterocycle" or "heterocyclyl" or "cycloheteroalkyl" generally refers to a ring structure (monocyclic or polycyclic) containing 3-12 ring atoms (3-12-membered heterocycle), 3-8 ring atoms (3-8-membered heterocycle or 3-8-membered cycloheteroalkyl), 3-6 ring atoms (3-6-membered heterocycle or 3-6-membered cycloheteroalkyl), or 5-6 ring atoms (5-6-membered heterocycle or 5-6-membered cycloheteroalkyl), in which at least one ring atom is carbon and at least one ring atom is a heteroatom selected from N, O, and S, or the heteroatom group is selected from P(=O), S(=O), and S(=O). Heterocyclic groups can be aromatic or non-aromatic. Piperidine and oxetane are non-limiting examples of non-aromatic heterocycles. Thiazole and pyridine are non-limiting examples of aromatic heterocycles. Other examples of heterocycles include aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactam, valerolactam, caprolactam, butyrolactone, valerolactone, and caprolactone.

[0057] The term "6-10-membered bridged biheterocyclyl" or "6-10-membered bridged heterobicyclyl," as used herein, generally refers to a saturated or partially unsaturated bicyclic ring structure containing 6-10 carbon atoms or heteroatoms or heteroatom groups, in which at least one ring atom is carbon and at least one ring atom is a heteroatom selected from N, O, and S, or a heteroatom group selected from P(=O), S(=O), and S(=O). Non-limiting examples include, but are not limited to, 3,6-diazabicyclo[3.1.1]hept-1-yl, 3,6-diazabicyclo[3.1.1]hept-3-yl, and 3,6-diazabicyclo[3.1.1]hept-6-yl.

[0058] The term "5-12-membered spirobiheterocyclyl" as used herein generally refers to a saturated or partially unsaturated bicyclic ring structure containing 5-12 (particularly 6-9) carbon or heteroatoms or heteroatom groups, where the two rings are joined by a carbon and at least one ring atom is a heteroatom selected from N, O and S, or a heteroatom group selected from P(=O), S(=O) and S(=O)2. Non-limiting examples include 4,7-diazaspiro[2.5]oct-7-yl, 1-oxa-6-azaspiro[3.3]hept-6-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl, 2,5-diazaspiro[3.4]oct-2-yl, 5-oxa-2-azaspiro[3.4]oct-2-yl, 6-oxa-2-azaspiro[3.4]oct-2-yl, 1-oxa-7-azundaspiro[3.5]non-7-yl, and the like.

[0059] As used herein, the term "6- to 12-membered fused biheterocyclyl" generally refers to a saturated or partially unsaturated bicyclic ring structure containing 6-12 (especially 7-10) carbon atoms or heteroatoms or heteroatom groups. The two rings share a carbon-carbon bond, a carbon-heteroatom bond, or a heteroatom-heteroatom bond (in other words, the two rings share two adjacent ring atoms). The 6- to 12-membered fused biheterocyclyl contains at least one ring atom that is a heteroatom selected from N, O, and S, or a heteroatom group selected from P(=O), S(=O), and S(=O). Non-limiting examples include, but are not limited to, 3,7-diazabicyclo[3.3.0]oct-3-yl, 3,6-diazabicyclo[3.3.0]oct-3-yl, and 2,7-diazabicyclo[3.3.0]oct-2-yl.

[0060] The term "aryl" refers to an alkyl group having 6-12 carbon atoms (C 6-12 aryl) or 6-10(C 6-10"(aryl)" refers to an all-carbon monocyclic or fused-ring polycyclic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, 2,3-indanyl, biphenyl, and anthracenyl. Aryl groups can be substituted or unsubstituted. Representative substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, sulfonyl, amino, and -NR X R Y , where R X and R Y are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, acetyl, sulfonyl, trifluoromethanesulfonyl, and in combination, 5- or 6-membered heteroalicyclic rings. Exemplary substituted alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, aminomethyl, aminoethyl, hydroxymethyl, methoxymethyl, 2-fluoroethyl, 2-methoxyethyl, and the like.

[0061] The term "heteroaryl," as used herein, generally refers to an aromatic or aryl group in which at least one ring carbon of the aromatic group (aryl) is replaced by a heteroatom selected from N, O, and S, or a heteroatom group selected from P(=O), S(=O), and S(=O). Heteroaryls include, for example, 5-12 membered heteroaryls, 5-10 membered heteroaryls, 5-7 membered monocyclic structures, or 7-12 membered bicyclic structures. The number of heteroatoms or heteroatom groups in a heteroaryl can be 1, 2, 3, 4, or more. Examples include, but are not limited to, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridazinyl, 1,2,5-oxadiazolyl, furanyl, pyridin-2(1H)-onyl, pyridin-4(1H)-onyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, naphthyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuryl, quinolinyl, isoquinolyl, and quinazolinyl. Heteroaryl groups can be substituted or unsubstituted. Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, sulfonyl, amino, and -NR X R Y R X and R Y is as defined above.

[0062] The term "7-10 membered fused bicyclic heterocyclyl" as used herein refers to a fused bicyclic ring system formed by the fusion of an aryl group with a heteroaryl group or the fusion of two heteroaryl groups, i.e., the two rings have two adjacent ring atoms in common. Non-limiting examples include, but are not limited to, benzothienyl, indolyl, benzimidazolyl, pyridiimidazolyl, pyridazinoimidazolyl, pyrazolopyrimidinyl, benzothiazolyl, benzofuryl, quinolinyl, isoquinolinyl, and quinazolinyl.

[0063] As used herein, the term "amino" generally refers to primary amino groups (-NH), secondary amino groups (-NH-), and tertiary amino groups ( [ka] ) refers to

[0064] As used herein, the term "alkylamino", "(-NH(C 1-6 alkyl), (-N(C 1-6 alkyl)2), (-NH(C 3-6 cycloalkyl)" and "(-N(C 3-6 "Cycloalkyl)2)" generally refers to a secondary or tertiary amine consisting of one or two alkyl or cycloalkyl groups, each of which may be independently selected.

[0065] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. For example, Berge et al. describe pharmaceutically acceptable salts in detail in Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Inorganic acids from which salts can be derived include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, but are not limited to, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, succinic acid, lactic acid, malic acid, and the like.

[0066] Pharmaceutically acceptable salts derived from appropriate bases include, but are not limited to, alkali metal, alkaline earth metal, ammonium, and other amine salts. Inorganic bases from which salts can be derived include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Organic bases from which salts can be derived include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc., examples of which include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, and quaternary amine N. + (C 1-6In some embodiments, pharmaceutically acceptable base addition salts include, but are not limited to, ammonium, potassium, sodium, calcium, or magnesium salts. In some embodiments, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, aryl sulfonates, and the like, where appropriate. Bis salts (i.e., two counterions) and higher salts (e.g., three or more counterions) are encompassed within the meaning of pharmaceutically acceptable salts. In some embodiments, salts are formed from reaction with LiOH, NaOH, KOH, Na2CO3, K2CO3, NaHCO3, KHCO3, MgCO3, CaCO3, NH4OH, Et3N, or tetrabutylammonium hydroxide.

[0067] As used herein, the term "ester" refers to organic compounds composed of ester linkages, including monoesters, diesters, triesters, and polyesters.

[0068] As used herein, the term "solvate" refers to a compound that further contains a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate may be a disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate." Other solvates include, but are not limited to, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, and the like. Pharmaceutically acceptable solvates and hydrates are complexes that may contain, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, 3, or 4 solvent or water molecules.

[0069] As used herein, unless otherwise specified, a "prodrug" refers to a compound that can be converted under physiological conditions or by solvolysis into a biologically active compound described herein, e.g., Formula (I), (IA), (I-A1), (IB), (I-B1), (IC), or (ID). Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. A prodrug may be inactive when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis. A discussion of prodrugs is found in Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties. The term "prodrug" is also meant to include any covalently bonded carrier that releases an active compound described herein, e.g., Formula (I), (IA), (I-A1), (IB), (I-B1), (IC), or (ID), in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the active compounds described herein can be prepared by modifying functional groups present in a compound of Formula (I), (IA), (I-A1), (IB), (I-B1), (IC), or (ID) such that the modifications are cleaved, either by routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds in which a hydroxy, amino, or mercapto group is bonded to any group that cleaves to form a free hydroxy, amino, or mercapto group, respectively, when a prodrug of a compound of Formula (I), (IA), (I-A1), (IB), (I-B1), (IC), or (ID) is administered to a mammalian subject.

[0070] The terms "isotopically labeled," "isotopically labeled," "isotopically labeled derivative," and "isotopically labeled" refer to an unnatural proportion of atomic isotopes at one or more of the atoms that constitute such a compound. For example, a compound may contain, for example, tritium ( 3 H), iodine-125( 125 I), carbon-14 ( 14 The compounds can also be radiolabeled with radioisotopes such as 2 H, 11 C. 13 C. 15 N, 17 O. 18 O. 18 F, 32 P, 35 S, 36 Certain isotopically labeled disclosed compounds (e.g., 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. Tritium isotopes (i.e., 3 H) and carbon-14 isotopes (i.e., 14 C) can facilitate preparation and detection. Furthermore, substitution with heavy isotopes such as deuterium (i.e., H) can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). Isotopically labeled disclosed compounds can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. In some embodiments, provided herein are compounds that may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. All isotopic variations of the disclosed compounds, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0071] The term "isomer" as used herein generally refers to different compounds having the same molecular formula, including all isomers, including enantiomers, diastereomers, tautomers, and geometric isomers (including cis- and trans-isomers). For example, "isomer" includes geometric double bond cis- and trans-isomers, also referred to as E- and Z-isomers; R- and S-enantiomers; diastereomers, (d)- and (l)-isomers, racemic mixtures thereof; and other mixtures thereof as falling within the scope of this disclosure, unless otherwise specified. As used herein, the term "tautomer" refers to a type of isomer that includes two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, a triple bond to a single bond, or vice versa). Therefore, all stereochemical isomers of the compounds described in this disclosure, as well as their enantiomers, diastereomers, tautomers or geometric isomers (or cis-trans isomers), or combinations thereof, are included within the scope of this disclosure.

[0072] As used herein, the term "independently" means that at least two groups (or ring systems) present in a structure having the same or similar range of values ​​may have the same or different meanings under certain circumstances. For example, if the substituents X and Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl, or aryl, then when the substituent X is hydrogen, the substituent Y can be hydrogen, halogen, hydroxy, cyano, alkyl, or aryl. Similarly, when the substituent Y is hydrogen, the substituent X can be hydrogen, halogen, hydroxy, cyano, alkyl, or aryl.

[0073] As used herein, the term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and non-occurrence of the subsequently described event or circumstance.

[0074] As used herein, the terms "substituent" and "substituted" generally refer to a molecular moiety covalently bonded to an atom within the molecule of interest. For example, a ring substituent may be a moiety such as a halogen, alkyl group, hydroxy group, haloalkyl group, or other group covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a ring member. Substituents for aromatic groups are generally covalently bonded to a ring carbon atom. Substituents for linear chains may be a moiety such as a halogen, alkyl group, haloalkyl group, or other group covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a member of a linear chain.

[0075] The term " pharmaceutically acceptable " as used herein generally refers to a form of a compound that is safe for administration to a subject. For example, the free base, salt form, solvate, hydrate, prodrug or derivative form of a compound described herein that is approved by a government or regulatory agency, such as the Food and Drug Administration (FDA) of the United States, for use in mammals by oral ingestion or other administration routes is pharmaceutically acceptable.

[0076] In some embodiments, a compound(s) of Formula (I), (IA), (I-A1), (IB), (I-B1), (IC), or (ID) is used to treat a subject by administering the compound(s) as a pharmaceutical composition. To this end, the compound(s) are, in one embodiment, combined with one or more pharmaceutically acceptable excipients, including carriers, diluents, or adjuvants, to form a suitable composition, as described in more detail herein.

[0077] As used herein, the term "excipient" generally refers to a pharmaceutically acceptable additive, carrier, adjuvant, or other suitable ingredient, other than the active pharmaceutical ingredient (API), that is normally included for formulation and / or administration purposes.

[0078] The term "diluent" as used herein generally refers to an agent used as a filler to achieve the desired volume or weight of the composition.The diluent can be present in the pharmaceutical composition in the form of a single compound or a mixture of compounds in the granule.Non-limiting examples of diluents include lactose, starch, pregelatinized starch, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose acetate, dextrose, mannitol, sodium phosphate, potassium phosphate, calcium phosphate, fructose, maltose, sorbitol, or sucrose.

[0079] The term "adjuvant" as used herein generally refers to any substance or mixture of substances that, when used in conjunction with a compound disclosed herein, increases the effectiveness or potency of the compound disclosed herein against a target. However, when an adjuvant is used alone, no pharmacological effect is observed against the same target.

[0080] As used herein, the terms "prevent" or "preventing" refer to preventing, avoiding, avoiding, obstructing, stopping, or impeding something from happening, especially by proactive action. Where reduce, inhibit, or prevent are used herein, it is understood that the use of the other two words is also expressly disclosed unless specifically indicated otherwise.

[0081] As used herein, the terms "treat," "treating," "treatment," and "therapy" generally refer to therapy, including, but not limited to, curative therapy, prophylactic therapy, and preventative therapy. Prophylactic treatment generally prevents the onset of a disorder altogether or delays the onset of a preclinically evident stage of a disorder in an individual. Treatment includes the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. The term includes active treatment, i.e., treatment dedicated to ameliorating a disease, pathological condition, or disorder, and also includes causal treatment, i.e., treatment directed at eliminating the cause of an associated disease, pathological condition, or disorder. In addition, the term includes palliative treatment, i.e., treatment aimed at alleviating symptoms rather than curing the disease, pathological condition, or disorder; prophylactic treatment, i.e., treatment aimed at minimizing or partially or completely suppressing the onset of an associated disease, pathological condition, or disorder; and supportive treatment, i.e., treatment used to complement another specific treatment aimed at ameliorating an associated disease, pathological condition, or disorder.

[0082] The term "effective amount" or "therapeutically effective amount," as used herein, refers to a sufficient amount of an administered drug or compound to relieve to some extent one or more symptoms of the disease or condition being treated; achieve the goal of improving the severity and frequency of the disorder more than treatment with each drug alone; and result in a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system; while avoiding side effects typically associated with alternative therapies. For example, an "effective amount" for therapeutic use is the amount of a composition as disclosed herein required to provide a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case can be determined using techniques such as dose escalation studies. In one embodiment, an effective amount is administered in a single dosage form or in multiple dosage forms.

[0083] Regardless of the selected route of administration, the compounds of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms or by other conventional methods known to those skilled in the art.

[0084] The actual dosage of the active ingredient in the pharmaceutical compositions of the present invention can be varied, without toxicity to the patient, to obtain an effective amount of the active ingredient to achieve the desired therapeutic response for a particular patient, composition, and mode of administration.

[0085] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound of the invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular hedgehog inhibitor employed, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and such factors as are well known in the medical arts.

[0086] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start doses of the compounds of the present invention employed in the pharmaceutical composition at levels lower than those required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0087] Generally, the appropriate daily dose of the compound of the present invention is the amount of the compound that is the lowest effective dose to produce a therapeutic effect. Such an effective amount generally depends on the above-mentioned factors. In general, the intravenous, intracerebroventricular, and subcutaneous administration dose of the compound of the present invention to a patient ranges from about 0.0001 to about 100 mg per kg of body weight per day. The mode of administration can have a significant effect on the dosage. Higher doses can be used for local administration.

[0088] If desired, the effective daily dose of active compound can be administered as 2, 3, 4, 5, 6 or more sub-doses at appropriate intervals throughout the day, and optionally can be administered in unit dosage form.Those skilled in the art will easily understand that dosage level can vary as a function of specific compound, severity of symptoms and the sensitivity of the subject to side effects.Those skilled in the art can easily determine the dosage of a given compound disclosed herein by various means.

[0089] Pharmaceutical Compositions / Formulations One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), (IA), (I-A1), (IB), (I-B1), (IC), or (ID), or a stereoisomer, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0090] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of the active compound into a pharmaceutically usable preparation. Appropriate formulations depend on the selected route of administration. Summaries of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed., Easton, Pa.: Mack Publishing Company (1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania (1975); Liberman, HA and Lachman, L, EDS., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY (1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed., Lippincott Williams & Wilkins (1999), which are incorporated herein by reference for their disclosure.

[0091] As used herein, a pharmaceutical composition refers to a mixture of a compound of Formula (I), (IA), (I-A1), (IB), (I-B1), (IC), or (ID) with other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersing agents, surfactant lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, humectants, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof. The pharmaceutical composition facilitates administration of the compound to an organism. In practicing the methods of treatment or use provided herein, a therapeutically effective amount of a compound described herein is administered in a pharmaceutical composition to a mammal having the disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. The therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds can be used alone or in combination with one or more therapeutic agents as components of mixtures.

[0092] The pharmaceutical formulations described herein are administered to a subject by any suitable route of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast-dissolve formulations, tablets, capsules, pills, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and combinations of immediate release and controlled release formulations.

[0093] All preparations for oral administration are in dosages suitable for such administration.Examples of such dosage units are tablets or capsules.In some embodiments, they contain about 1-2000mg, advantageously about 1-500mg, typically about 5-150mg of active ingredient.The daily dosage suitable for humans or other mammals varies greatly depending on patient condition and other factors, but can also be determined by routine methods and practices.

[0094] Traditional formulation techniques include, for example, one or a combination of the following methods: (1) dry blending, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) melting. Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Worcester coating), tangential coating, top spraying, tabletting, extrusion, and the like.

[0095] Synthesis method The examples and preparations provided below illustrate and exemplify the compounds described herein and methods for preparing such compounds. In general, the compounds described herein can be prepared by processes known in the general chemical arts.

[0096] The compounds of the present invention can be prepared starting from commercially available materials using various synthetic routes, including those described below. The starting materials of the present invention are known, commercially available, or can be synthesized similarly to or according to methods known in the art. Many starting materials can be prepared according to known processes, and in particular, can be prepared using the processes described in the Examples. When synthesizing starting materials, functional groups are sometimes protected with appropriate protecting groups as necessary. Functional groups can be removed according to procedures known in the art.

[0097] The protection of functional groups by protecting groups, the protecting groups themselves, and reactions for their removal (commonly called "deprotection") can be found, for example, in standard reference works such as J.F.W.M. Comie, Protective Groups in Organic Chemistry, Plenum Press, London and New York (1973), in T.W. Greene, Protective Groups in Organic Synthesis, Wiley, New York (1981), in The Peptides, Volume 3, E. Gross and J. Meienhofer editors, Academic Press, London and New York (1981).

[0098] All synthetic procedures described herein can be carried out under known reaction conditions, advantageously those described herein, either in the absence or presence (usually) of solvents or diluents.

[0099] The present invention further encompasses "intermediate" compounds, including structures produced from the described synthetic procedures, whether isolated or not, prior to ultimately obtaining the desired compound. Structures resulting from performing steps from transient starting materials, structures resulting from deviations from the described methods at any stage, and structures forming from starting materials under reaction conditions are all "intermediates" encompassed by the present invention. Additionally, structures produced by using starting materials in the form of reactive derivatives or salts, or by compounds obtained by processes according to the present invention, and structures obtained by treating compounds of the present invention in situ are also within the scope of the present invention.

[0100] Novel starting materials and / or intermediates, as well as processes for their preparation, are also the subject of this invention. In selected embodiments, such starting materials are used and reaction conditions are selected to yield the desired compound(s).

[0101] The starting materials of the present invention are known, commercially available, or can be synthesized similarly to or according to methods known in the art. Many starting materials can be prepared according to known processes, in particular, by using the processes described in the Examples. When synthesizing starting materials, functional groups are sometimes protected with appropriate protecting groups as necessary. Protecting groups, their introduction and removal have been described above.

[0102] All reagents and solvents were obtained commercially as analytically pure or chemically pure unless otherwise noted. Commercially available reagents and solvents were used without purification unless otherwise noted. When necessary, some reagents and solvents were purified by standard techniques, such as distillation. Anhydrous solvents were treated according to standard or referenced methods. For example, tetrahydrofuran can be purified by distillation from sodium. All thin-layer chromatography (TLC, GF254) analyses and column purifications (100-200 mesh) were performed on silica gel (Qingdao Haiyang Chemical Co., Ltd. or Yantai Chemical Co., Ltd.) using petroleum ether (bp 60-90°C) / ethyl acetate (v / v) as the eluent; and spots were revealed by UV visualization at 254 nm and I2 vapor or phosphomolybdic acid. All organic layers after extraction were dried over anhydrous Na2SO4 unless otherwise noted. All nuclear magnetic resonance spectra ( 1 H NMR was recorded on a Varian-400 spectrometer at 400 MHz using TMS as the internal standard. LC-MS was performed on an Agilent 1100 system equipped with an LC-MS D-trap recorder, a diode array detector (DAD) with detection wavelengths of 214 nm and 254 nm, and an ESI source. The HPLC column was an Agela Durashell C18 column (3.5 μm, 4.6 × 50 mm). A gradient of 0.1% NH4HCO3 aqueous solution and acetonitrile was run from 5 / 95 to 95 / 5 with the indicated run time (e.g., 5 min) at a flow rate of 1.8 mL / min.

[0103] The size and scale of the synthesis method vary depending on the amount of the desired final product. Specific reactants and amounts are described in the examples, but it is understood that those skilled in the art will know other alternative, equally viable, sets of reactants that will yield the same compound. Thus, when common oxidizing agents, reducing agents, and solvents of various natures (aprotic, nonpolar, polar, etc.) are utilized, equivalents are known in the art and are contemplated herein for use in the present method.

[0104] Many of the following steps illustrate various workups after the reaction is complete. Workup typically involves quenching the reaction to eliminate residual catalytic activity and starting reagents. This is typically followed by the addition of an organic solvent and separation of the aqueous and organic layers. The product is typically obtained from the organic layer, while unused reactants, spurious by-products, and unwanted chemicals are typically captured in the aqueous layer and discarded. In standard organic synthesis procedures found throughout the literature, workup typically involves drying the product by exposure to a drying agent such as anhydrous Na2SO4, removing excess water and aqueous by-products that remain partially dissolved in the organic layer, and concentrating the remaining organic layer. Concentration of the dissolved product can be achieved by known means, such as evaporation under pressure or evaporation at elevated temperature and pressure. Such concentration can be achieved using standard laboratory equipment, such as rotary evaporation. This can optionally be followed by one or more purification steps, including, but not limited to, flash column chromatography, filtration through various media, and / or other preparative methods known in the art, and / or crystallization / recrystallization. (See, for example, Addison Ault, "Techniques and Experiments for Organic Chemistry," 6th Ed., University Science Books, Sausalito, Calif., 1998, Ann B. McGuire, Ed., pp. 45-59).

[0105] Abbreviation

[0106] NBS is N-bromosuccinimide. T3P is 1-propylphosphonic acid cyclic anhydride. DMF means N,N-dimethylformamide. LDA is lithium diisopropylamide. DCE means 1,2-dichloroethane. DCM is dichloromethane. TEA is triethylamine. EtOAc or EA means ethyl acetate. THF is tetrahydrofuran. TFA is trifluoroacetic acid. TKB is potassium tert-butoxide. DAST is diethylaminosulfur trifluoride. DMEDA is 1,2-dimethylethylenediamine. EG is ethylene glycol. Xantphos is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. HATU is 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate. DIPEA is diisopropylethylamine. Pd(dppf)Cl2 is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). Pd(OAc)2 is palladium(II) acetate. DPPA is diphenylphosphoryl azide. DIAD is diisopropyl azodiformate. NMP is N-methylpyrrolidone. TLC means thin layer chromatography. HPLC means high performance liquid chromatography. LC-MS means liquid chromatography mass spectrometry. NMR stands for nuclear magnetic resonance.

[0107] General synthetic route The following methods AA-BK are embodiments of several general synthetic routes leading to compounds of formula (I), (IA), (I-A1), (IB), (I-B1), (IC), or (ID). Detailed reaction conditions for each method are described in the examples provided below.

[0108] Method AA [ka]

[0109] Nitration of the pyridine at C2 gave the corresponding nitropyridinol intermediate (step a), and reduction of the nitro group with zinc powder gave the corresponding aminopyridinol intermediate (step b). Subsequent cyclization of the aminopyridinol compound with potassium ethylxanthate gave the oxazolo[4,5-b]pyridine-2-thiol compound (step c). Methylation of the thiol group gave the desired compound (step d).

[0110] Method AB [ka]

[0111] Sulfide moiety and amine S N Ar reaction afforded the corresponding amino-substituted oxazolo[4,5-b]pyridine intermediate (Step a). Bromination of C6 of the oxazolo[4,5-b]pyridine with NBS facilitated subsequent palladium-catalyzed Heck coupling with ethyl acrylate to give the alkene intermediate (Steps b and c). Ozonation of the alkene intermediate by bubbling O3 and Pinnick oxidation afforded the carboxylic acid compound (Steps d and e). Amide coupling in the presence of T3P converted the carboxylic acid to the corresponding amine—the desired compound (Step f).

[0112] method ac [ka]

[0113] S-catalyzed coupling of the chlorine moiety on C5 of oxazolo[4,5-b]pyridine with an amine N Ar reaction gave the corresponding 5-amino substituted intermediate (step a).

[0114] Method AD [ka]

[0115] Methylation of N-(tert-butoxycarbonyl)proline was achieved by treatment with iodomethane under basic conditions (Step a). Alkylation of proline methyl ester with chloroiodomethane afforded the 2-chloromethyl-substituted proline methyl ester (Step b). This ester was reduced to the alcohol with borohydride, followed by Dess-Martin oxidation to afford the aldehyde (Step c). This aldehyde was then subjected to reductive amination with benzylamine to afford the corresponding intermediate (Step d). Intramolecular cyclization under H2 atmosphere, followed by benzyl deprotection, afforded the desired compound (Steps e and f).

[0116] Method AE [ka]

[0117] Boc-deprotection under acidic conditions gave the secondary amine, which was reacted with formaldehyde via reductive amination to give the tertiary amine (steps a and b), followed by hydrogenation to give 5-methyl-2,5-diazaspiro[3,4]octane (step c).

[0118] Method AF [ka]

[0119] The carboxylic acid was reacted with oxalyl dichloride in the presence of DMF to give the acyl chloride, which was then treated with 1,3,5-tribenzyl-1,3,5-triazinane to give the benzyl-protected lactam (step a). The amide was reduced with lithium aluminum hydride in the presence of a Lewis acid to give the tertiary amine (step b).

[0120] Method AG [ka]

[0121] The secondary amine was generated by cyclization of tert-butyl 4-oxopiperidine-1-carboxylate with trimethylsulfoxonium iodide, followed by Boc-deprotection under acidic conditions (steps a and b).

[0122] Method AH [ka]

[0123] Tertiary amine compounds were obtained by reductive amination of secondary amines and paraformaldehyde with sodium triacetoxyborohydride (step a).

[0124] Method AI [ka]

[0125] Palladium acetate-catalyzed coupling of 3-bromoaniline with dimethylphosphine oxide gave the corresponding compound (step a).

[0126] Method AJ [ka]

[0127] Suzuki coupling of aryl halides with boronic esters gave the desired products (step a).

[0128] Method AK [ka]

[0129] The 2H-tetrazole intermediate was synthesized by 1,3-dipolar cycloaddition of 3-cyanonitrobenzene with sodium azide (step a), followed by hydrogenation of the nitro group to give the aniline compound (step b).

[0130] Method AL [ka]

[0131] Palladium acetate-catalyzed coupling of oxazole with 4-bromo-2-methylpyridine gave ethyl 2-(2-methylpyridin-4-yl)oxazole-4-carboxylate. This ester was hydrolyzed under basic conditions to give 4-oxazolecarboxylic acid (Steps a and b). The carboxyl group was converted to a Boc-protected amino group by Curtius rearrangement (Step c). The Boc-protected amino group then attacked an acyl chloride prepared with another pyridinecarboxylic acid under strongly basic conditions to give the amide, which was then removed under strongly acidic conditions (Steps d and e).

[0132] method AM [ka]

[0133] The Boc on the piperazine was removed under acidic conditions to give the desired compound (step a).

[0134] method an [ka]

[0135] 2-Bromotan-1-ol and piperazine under inorganic base conditions N 2 reacted to produce the 4-(2-hydroxyethyl)-substituted piperazine (step a).

[0136] Method AO [ka]

[0137] Reductive amination reaction between piperazine and formaldehyde using sodium triacetoxyborohydride as a reducing agent gave 4-methylpiperazine (step a).

[0138] Method AP [ka]

[0139] Boc-deprotection was achieved by treatment with HCl / EA or CF3COOH to give the corresponding compounds (step a).

[0140] Method BA [ka]

[0141] The aryllithium reagent, prepared by lithium-bromine exchange of 3-bromopyridine with n-butyllithium, attacked 2,2-dimethyloxirane to give 3-(2,2,2-hydroxydimethylethyl)pyridine (Step a), which underwent intramolecular cyclization to give 6-fluoro-2,2-dimethyl-2,3-dihydrofuro[2,3-b]pyridine (Step b). Bromination of C5 of 2,3-dihydrofuro[2,3-b]pyridine with NBS gave the corresponding intermediate (Step c). Heck coupling reaction between ethyl acrylate and C5 of brominated 2,3-dihydrofuro[2,3-b]pyridine gave the alkene intermediate, which was ozonated with O3 to give the aldehyde, which was finally oxidized with sodium chlorite via Pinnick oxidation to give the carboxylic acid (Steps d, e, and f).

[0142] Method BB [ka]

[0143] The corresponding intermediate was obtained by amide coupling reaction of the acyl chloride prepared from 2,3-dihydrofuro[2,3-b]pyridine-3-carboxylic acid with the corresponding amine (step a). The fluorinated C6 of 2,3-dihydrofuro[2,3-b]pyridine and the amine were then reacted under basic conditions to give the corresponding intermediate (step a). N Reaction with Ar afforded the corresponding compound (step b).

[0144] Method B.C. [ka]

[0145] This compound can be synthesized by converting the fluorinated aromatic ring and the corresponding alcohol under basic conditions with NaH. N This was obtained by reacting with Ar (step a).

[0146] Method BD [ka]

[0147] The carboxyl group of cyclopropylcarboxylic acid was converted to a Boc-protected cyclopropylamine by Curtius rearrangement, and the Boc group was removed under acidic conditions to give the primary amine hydrochloride (Steps a and b). This amine was then subjected to a Michael addition with dimethyl-(E)-2-(3-methoxyallylidene)malonate to give the corresponding intermediate (Step c). The amino group cyclized one of the symmetrical esters via intramolecular attack, and the other ester was hydrolyzed to the carboxyl group under strong basic conditions to give the 1-substituted-2-oxopyridine-3-carboxylic acid (Step d). Another Curtius rearrangement and Boc-deprotection transformed the carboxylic acid into the 3-amino-1-substituted-2-pyridinone (Steps e and f).

[0148] How to BE [ka]

[0149] The amino group of 3-aminopyridin-2(1H)-one was protected by treatment with CbzCl under basic conditions (step a). Cham-Lam coupling of 2-pyridinone with potassium cyclopropyltrifluoroborate gave 3-benzyloxycarbonylamino-1-cyclopropyl-2-pyridinone. Cbz-deprotection under H atmosphere gave the product (steps b and c).

[0150] Method BF [ka]

[0151] S on C6 of 2,3-dihydrofuro[2,3-b]pyridine with water N Ar afforded the 2-pyridin-ol intermediate, which reacted with sodium 2-chloro-2,2-difluoroacetate to give the fluorinated compound (steps a, b).

[0152] Method BG [ka]

[0153] The BOC-protected amine was treated with EA / HCl to remove the BOC protecting group and give the corresponding secondary amine (step a).

[0154] Method BH [ka]

[0155] The Bn- or Cbz-protecting group was removed with Pd / C under an H2 atmosphere to give the corresponding alcohol or secondary amine.

[0156] Method BI [ka]

[0157] Reaction of secondary amines with formaldehyde and sodium triacetoxyborohydride as a reducing agent gave tertiary amine products (step a).

[0158] How to BJ [ka]

[0159] 3-(Benzyloxy)cyclobutan-1-one was reacted with a Grignard reagent to give the benzyl-protected tetrahedral alcohol, which was then removed by hydrogenation to give 1-methyl-cyclobutane-1,3-diol (steps a and b).

[0160] Method BK [ka]

[0161] The Mitsunobu reaction of cis-3-(benzyloxy)cyclobutan-1-ol with 4-nitrobenzoic acid afforded an ester intermediate with chiral inversion of the alcohol moiety, which was then hydrolyzed to give trans-3-(benzyloxy)cyclobutan-1-ol (steps a and b). [Example]

[0162] Example 1, Methods AA, AB, AC

[0163] Preparation of (R)-5-(3-hydroxypyrrolidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A1) [ka]

[0164] Step a. 6-Chloro-2-nitropyridin-3-ol: To a solution of 6-chloropyridin-3-ol (12 g, 96 mmol) in concentrated H2SO4 (150 mL) was added potassium nitrate (12 g, 116 mmol) in an ice bath. After stirring at room temperature for 2 h, the reaction mixture was slowly poured into ice water. The resulting precipitate was collected by filtration and washed with water. The filter cake was dried to give the desired product (15.4 g, 91%) as a yellow solid. 1 H NMR (300MHz, DMSO-d6) δ 11.94(s,1H), 7.76(d, J=8.4Hz, 1H), 7.71(d, J=8.4Hz, 1H).

[0165] Step b. 2-Amino-6-chloropyridin-3-ol: To a solution of 6-chloro-2-nitropyridin-3-ol (14 g, 83 mmol) in THF / water (300 mL / 100 mL) was added ammonium chloride (89 g, 1673 mmol) and zinc powder (44 g, 669 mmol) in portions at 50 °C. The mixture was stirred at the same temperature for 1 h. The reaction mixture was diluted with EA (200 mL) and washed with water (200 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 2 / 1) to give the desired product (11 g, 94%) as a yellow solid. 1 H NMR (300MHz, DMSO-d6) δ 9.72(s, 1H), 6.82(d, J=7.8Hz, 1H), 6.37(d, J=7.8Hz, 1H), 5.88(s, 2H).LC-MS (m / z):145.1 [M+H] + .

[0166] Step c. 5-Chlorooxazolo[4,5-b]pyridine-2-thiol: A solution of 2-amino-6-chloropyridin-3-ol (23 g, 162 mmol) and potassium ethylxanthate (39 g, 243 mmol) in pyridine (100 mL) was stirred at 120 °C for 4 h. After cooling to room temperature, the mixture was evaporated under reduced pressure. The residue was diluted with ice water (100 mL), and the mixture was adjusted to pH 1 with 3 N hydrochloric acid. The resulting precipitate was collected by filtration and washed with water. The filter cake was dried to give the desired product (29 g, 96%) as a gray solid. 1 H NMR (300MHz, DMSO-d6) δ 9.86(s, 1H), 7.87(s, 1H), 7.31(s, 1H).LC-MS (m / z):187.1 [M+H] + .

[0167] Step d. 5-Chloro-2-(methylthio)oxazolo[4,5-b]pyridine: To a solution of 5-chlorooxazolo[4,5-b]pyridine-2-thiol (29 g, 155 mmol) in EA (300 mL) was added potassium carbonate (43 g, 313 mmol) followed by methyl iodide (20 mL, 311 mmol) at room temperature. After stirring for 2 h, the mixture was diluted with water (200 mL) and extracted with EA (100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the intermediate product (28 g, 91%) as a gray solid. 1 H NMR (300MHz, DMSO-d6) δ 8.14 (d, J=8.4 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 2.79(s, 3H).

[0168] Step e. 5-Chloro-2-morpholinooxazolo[4,5-b]pyridine: To a solution of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (28 g, 140 mmol) in THF (250 mL) was added morpholine (46 mL), and the mixture was stirred at 90 °C overnight. After cooling to room temperature, the solvent was removed in vacuo, and the residue was diluted with water (100 mL). The resulting precipitate was collected by filtration and washed with water. The filter cake was dried to give the desired product (32 g, 93%) as a gray solid. 1H NMR (300 MHz, CDCl3) δ 7.37 (d, J=8.1 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 3.85-3.78 (m, 4H), 3.78-3.72 (m, 4H).LC-MS (m / z):240.0 [M+H]+.

[0169] Step f. 6-Bromo-5-chloro-2-morpholinooxazolo[4,5-b]pyridine: To a solution of 5-chloro-2-morpholinooxazolo[4,5-b]pyridine (32 g, 133 mmol) in MeCN (330 mL) was added NBS (33 g, 186 mmol) in portions at room temperature. After completion of the reaction, the mixture was diluted with EA (1000 mL) and extracted with 1N NaOH (aq). The combined organic layers were dried over NaSO, filtered, and concentrated to give the intermediate product (28 g, 66%) as a gray solid. 1 H NMR (300MHz, DMSO-d6) δ 8.25 (s, 1H), 3.80-3.69 (m, 4H), 3.70-3.61 (m, 4H).LC-MS (m / z):318.0 [M+H] + .

[0170] Step g. Ethyl (E)-3-(5-chloro-2-morpholinoxazolo[4,5-b]pyridin-6-yl)acrylate: To a solution of 6-bromo-5-chloro-2-morpholinoxazolo[4,5-b]pyridine (11 g, 36 mmol) in dry DMF (350 mL) was added tri(o-tolyl)phosphine (3.3 g, 11 mmol), palladium acetate (0.70 g, 3.6 mmol), TEA (11 g, 107 mmol), and ethyl acrylate (18.7 mL). The mixture was refluxed under N at 140 °C overnight, and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1) to give the desired product (9.1 g, 76%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.88 (d, J=15.9 Hz, 1H), 6.72 (d, J=15.9 Hz, 1H), 4.20 (q, J=6.9 Hz, 2H), 3.77-3.72 (m, 4H), 3.71-3.67 (m, 4H), 1.26 (t, J=6.9 Hz, 3H).LC-MS (m / z):338.1 [M+H] + .

[0171] Step h. 5-Chloro-2-morpholinoxazolo[4,5-b]pyridine-6-carbaldehyde: To a solution of ethyl (E)-3-(5-chloro-2-morpholinoxazolo[4,5-b]pyridin-6-yl)acrylate (4.8 g, 18 mmol) in DCM / MeOH (300 mL / 100 mL) was bubbled dry O3 at -70 °C for 3 h. The reaction was complete, as detected by TLC, and quenched by the addition of dimethyl sulfide (2 mL). The solvent was removed in vacuo to give the crude product (4.0 g, 83%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.04 (s, 1H), 3.77-3.72 (m, 8H).

[0172] Step i. 5-Chloro-2-morpholinoxazolo[4,5-b]pyridine-6-carboxylic acid: To a solution of 5-chloro-2-morpholinoxazolo[4,5-b]pyridine-6-carbaldehyde (5.0 g, 19 mmol) in t-BuOH (250 mL) was added 2-methyl-2-butene (13 g, 187 mmol), sodium chlorite (6.9 g, 187 mmol), and sodium dihydrogen phosphate dehydrate (17 g, 187 mmol) in water (200 mL). After stirring at room temperature for 2 h, the mixture was adjusted to pH 2 with 1N aqueous hydrochloric acid and extracted with DCM (300 mL × 3). The solvent was removed in vacuo to give the desired product (4.2 g, 79%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.14 (s, 1H), 3.75-3.72 (m, 4H), 3.71-3.68 (m, 4H). LC-MS (m / z):284.0 [M+H] + .

[0173] Step j. 5-Chloro-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: To a solution of 5-chloro-2-morpholinooxazolo[4,5-b]pyridine-6-carboxylic acid (1.0 g, 3.5 mmol) and 6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (615 mg, 3.5 mmol) in dry DMF (2 mL) was added TEA (1.8 g, 18 mmol) and a 50% T3P solution in DMF (2 mL). The reaction mixture was stirred at 110 °C for 2 h via microwave reactor. The mixture was poured into ice water (250 mL), and the resulting precipitate was collected by filtration and washed with water. The filter cake was dried to give the desired product (510 mg, 33%) as a gray solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 8.00-7.91 (m, 2H), 7.86-7.75 (m, 1H), 7.41 (d, J=7.5 Hz, 1H), 3.87 (s, 3H), 3.79-3.73 (m, 4H), 3.72-3.67 (m, 4H).LC-MS (m / z):440.0 [M+H] + .

[0174] Step k. (R)-5-(3-hydroxypyrrolidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: To a solution of 5-chloro-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide (60 mg, 0.14 mmol) and (R)-pyrrolidin-3-ol (18 mg, 0.21 mmol) in dry 1,4-dioxane (5 mL), KCO (22 mg, 0.16 mmol) was added, and the mixture was stirred at 100 °C for 24 h. The mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to give the desired product (15 mg, 38%) as a white solid.

[0175] Example 2, Method AC

[0176] Preparation of (R)-5-(3-hydroxypyrrolidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A2) [ka]

[0177] Step a. (R)-5-(3-hydroxypyrrolidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was followed to give the title compound (8 mg, 22%) as a white solid.

[0178] Example 3, Method AC

[0179] Preparation of N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-5-(4-methylpiperazin-1-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A3)

[0180] [ka]

[0181] Step a N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-5-(4-methylpiperazin-1-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was carried out to obtain the compound (10 mg, 29%) as a white solid.

[0182] Example 4, Method AC

[0183] Preparation of 5-(4-hydroxypiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A4) [ka]

[0184] Step a. 5-(4-hydroxypiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was carried out to provide the compound (9 mg, 26%) as a white solid.

[0185] Example 5, Method AC

[0186] Preparation of N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholino-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)oxazolo[4,5-b]pyridine-6-carboxamide: (A5) [ka]

[0187] Step a N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholino-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)oxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was carried out to obtain the compound (8 mg, 22%) as a white solid.

[0188] Example 6, Method AC

[0189] Preparation of (S)-5-(3-hydroxypyrrolidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A6) [ka]

[0190] Step a: (S)-5-(3-hydroxypyrrolidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to give the compound (10 mg, 30%) as a white solid.

[0191] Example 7, Method AC

[0192] Preparation of N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-5-(methylamino)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A7) [ka]

[0193] Step a N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-5-(methylamino)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was carried out to give the compound (5 mg, 10%) as a yellow solid.

[0194] Example 8, Methods AC, AD, AP

[0195] Preparation of N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholino-5-(2,5-diazaspiro[3.4]octan-2-yl)oxazolo[4,5-b]pyridine-6-carboxamide: (A8) [ka]

[0196] Step a. 1-(tert-Butyl) 2-methyl 2-(chloromethyl)pyrrolidine-1,2-dicarboxylate: To a solution of (tert-butoxycarbonyl)proline (22 g, 100 mmol) in DMF (120 mL) was slowly added K2CO3 (28 g, 200 mmol) and iodomethane at room temperature. The reaction mixture was stirred overnight at room temperature, diluted with ethyl acetate (500 mL), and washed with saturated aqueous NaCl (100 mL × 4). The organic layer was dried over Na2SO4, filtered, and concentrated to give the intermediate as a white solid. To a solution of LDA (150 mmol) in anhydrous THF (400 mL) was added a THF solution (30 mL) of the white solid intermediate at -78 °C and stirred for 1 hour. A THF solution (20 mL) of chloroiodomethane (21 g, 120 mmol) was added dropwise at -78 °C. The reaction was stirred overnight at room temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride (200 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the desired product (15 g, 54%) as a green oil. 1 H NMR (300 MHz, CDCl3) δ 4.55-4.14 (m, 1H), 3.99-3.84 (m, 1H), 3.84-3.56 (m, 4H), 3.55-3.36 (m, 1H), 2.50-2.26 (m, 1H), 2.22-1.81 (m, 3H), 1.51-1.33 (m, 9H).LC-MS (m / z):299.8 [M+Na] + .

[0197] Step b. tert-Butyl 2-(chloromethyl)-2-formylpyrrolidine-1-carboxylate: To a solution of 1-(tert-butyl) 2-methyl 2-(chloromethyl)pyrrolidine-1,2-dicarboxylate (1.8 g, 6.6 mmol) in EtOH (50 mL), CaCl2 (1.1 g, 9.9 mmol) was slowly added, and the mixture was stirred at room temperature for 30 minutes. NaBH4 (1.0 g, 27 mmol) was slowly added at 0 °C. The reaction was stirred overnight at room temperature and quenched with saturated aqueous ammonium chloride (40 mL). The resulting precipitate was filtered. The filtrate was extracted with dichloromethane (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a residue. To a solution of the residue in dichloromethane (50 mL), Dess-Martin periodinane (DMP) (2.8 g, 6.6 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 3 hours and quenched with saturated aqueous NaSO (10 mL) and saturated aqueous NaHCO (20 mL). The mixture was extracted with dichloromethane (20 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the desired product (1.1 g, 69%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 9.62-9.36 (m, 1H), 4.26-3.86 (m, 2H), 3.77-3.50 (m, 2H), 2.29-2.01 (m, 3H), 2.00-1.81 (m, 1H), 1.54-1.33 (m, 9H).

[0198] Step c. tert-Butyl 2-((benzylamino)methyl)-2-(chloromethyl)pyrrolidine-1-carboxylate: To a solution of tert-butyl 2-(chloromethyl)-2-formylpyrrolidine-1-carboxylate (9.7 g, 39 mmol) in toluene / methanol (80 mL / 20 mL) was added benzylamine (4.8 g, 45 mmol) and stirred at 40 °C overnight. The reaction mixture was concentrated and dissolved in MeOH (100 mL). NaBH (5.9 g, 156 mmol) was added slowly at 0 °C. The reaction was stirred at room temperature overnight and quenched with saturated aqueous ammonium chloride (150 mL). The mixture was extracted with dichloromethane (100 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated to give the crude product, which was used in the next step without further purification.

[0199] Step d. tert-Butyl 2-benzyl-2,5-diazaspiro[3.4]octane-5-carboxylate: A mixture of tert-butyl 2-((benzylamino)methyl)-2-(chloromethyl)pyrrolidine-1-carboxylate and TEA (7.9 g, 78 mmol) in DMF (50 mL) was stirred overnight at 100 °C under a N atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (300 mL) and washed with saturated aqueous NaCl (100 mL × 4). The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the desired product (10 g, 85%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.30-7.15 (m, 5H), 4.23-3.61 (m, 4H), 3.51-3.01 (m, 4H), 2.41-2.13 (m, 2H), 1.86-1.50 (m, 11H).LC-MS (m / z):303.1 [M+H] + .

[0200] Step e. tert-Butyl 2,5-diazaspiro[3.4]octane-5-carboxylate: A suspension of tert-butyl 2-benzyl-2,5-diazaspiro[3.4]octane-5-carboxylate (500 mg, 1.6 mmol) and Pd(OH) (34 mg, 0.25 mmol) in MeOH (50 mL) was stirred at room temperature under an H atmosphere for 24 h. The suspension was filtered, and the filtrate was concentrated to give the desired product (300 mg, 86%) as a yellow oil. 1 H NMR (300 MHz, CDCl3) δ 4.69-4.46 (m, 2H), 4.37 (s, 1H), 3.42-3.14 (m, 4H), 2.45-2.31 (m, 2H), 2.29-2.15 (m, 2H), 1.50 (s, 9H).

[0201] Step f. tert-Butyl 2-(6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)-2-morpholinooxazolo[4,5-b]pyridin-5-yl)-2,5-diazaspiro[3.4]octane-5-carboxylate: The procedure described in example 1 was followed to provide the compound (50 mg, 74%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.21 (s, 1H), 8.03-7.89 (m, 2H), 7.84-7.71 (m, 2H), 7.40-7.33 (m, 1H), 3.88 (s, 3H), 3.76-3.69 (m, 6H), 3.69-3.60 (m, 4H), 3.56 (s, 2H), 3.30-3.21 (m, 2H), 2.32-2.15 (m, 2H), 1.77-1.57 (m, 2H), 1.14 (s, 9H).

[0202] Step g N-(6-(1-Methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholino-5-(2,5-diazaspiro[3.4]octan-2-yl)oxazolo[4,5-b]pyridine-6-carboxamide: To a solution of tert-butyl 2-(6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)-2-morpholinooxazolo[4,5-b]pyridin-5-yl)-2,5-diazaspiro[3.4]octane-5-carboxylate (50 mg, 0.08 mmol) in dry DCM (5 mL) was added CF3COOH (0.5 mL). The mixture was stirred at room temperature overnight. The solvent of the reaction mixture was removed in vacuo, and the residue was adjusted to pH 8 with saturated aqueous NaHCO3. The aqueous phase was extracted with DCM (10 mL x 3), and the organic layer was dried over Na2SO4, filtered, and concentrated to give the product (5 mg, 12%) as a yellow solid.

[0203] Example 9, Methods AC, AE

[0204] Preparation of N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-5-(5-methyl-2,5-diazaspiro[3.4]octan-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A9) [ka]

[0205] Step a. 2-Benzyl-2,5-diazaspiro[3.4]octane: A solution of tert-butyl 2-benzyl-2,5-diazaspiro[3.4]octane-5-carboxylate (2.0 g, 6.6 mmol) in HCl / EA (15 mL, 27 mmol) was stirred at room temperature overnight. The reaction mixture was diluted with EA (100 mL) and filtered to give the intermediate as a white solid. To a solution of the white solid and paraformaldehyde (596 mg, 20 mmol) in DCE (30 mL) were added TEA (3.3 g, 33 mmol) and NaBH(OAc) (7.0 g, 33 mmol) sequentially at 0 °C. The reaction was stirred at room temperature overnight and then quenched with saturated aqueous NaHCO (30 mL). The mixture was extracted with dichloromethane (30 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by basic Al2O3 column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the desired product (680 mg, 48%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.36-7.24 (m, 5H), 3.64 (s, 2H), 3.29 (d, J=7.2 Hz, 2H), 3.11 (d, J=7.2 Hz, 2H), 2.66 (t, J=6.8 Hz, 2H), 2.45 (s, 3H), 2.12 (t, J=7.2 Hz, 2H), 1.81-1.65 (m, 2H).LC-MS (m / z):217.0 [M+H] + .

[0206] Step b. 5-Methyl-2,5-diazaspiro[3.4]octane: A suspension of 2-benzyl-2,5-diazaspiro[3.4]octane (680 mg, 3.2 mmol) and Pd(OH) (68 mg, 0.48 mmol) in MeOH (50 mL) was stirred at room temperature under an H atmosphere for 24 h. The suspension was filtered and concentrated to give the desired product (300 mg) as a yellow oil, which was used in the next step without further purification.

[0207] Step c N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-5-(5-methyl-2,5-diazaspiro[3.4]octan-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to give the compound (10 mg, 38%) as a yellow solid.

[0208] Example 10, Method AC

[0209] Preparation of 5-(3-cyclopropyl-3-hydroxyazetidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A10) [ka]

[0210] Step a. 5-(3-cyclopropyl-3-hydroxyazetidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to provide the compound (9 mg, 26%) as a yellow solid.

[0211] Example 11, Method AC

[0212] Preparation of 5-(4,4-difluoropiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A11) [ka]

[0213] Step a. 5-(4,4-Difluoropiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to give the compound (11 mg, 23%) as a yellow solid.

[0214] Example 12, Method AC

[0215] Preparation of 5-(3,3-difluoropyrrolidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A12) [ka]

[0216] Step a. 5-(3,3-Difluoropyrrolidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to obtain the compound (5 mg, 11%) as a yellow solid.

[0217] Example 13, Method AC

[0218] Preparation of N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholino-5-(piperazin-1-yl)oxazolo[4,5-b]pyridine-6-carboxamide: (A13) [ka]

[0219] Step a N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholino-5-(piperazin-1-yl)oxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was carried out to obtain the compound (10 mg, 23%) as a yellow solid.

[0220] Example 14, Method AC

[0221] Preparation of 5-(3-hydroxy-3-methylazetidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A14) [ka]

[0222] Step a. 5-(3-hydroxy-3-methylazetidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to provide the compound (6 mg, 18%) as a yellow solid.

[0223] Example 15, Method AC

[0224] Preparation of 5-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A15) [ka]

[0225] Step a. 5-(6,6-Difluoro-2-azaspiro[3.3]heptan-2-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was carried out to obtain the compound (10 mg, 27%) as a white solid.

[0226] Example 16, Method AC

[0227] Preparation of 5-(3-hydroxypiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A16) [ka]

[0228] Step a. 5-(3-hydroxypiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to give the compound (10 mg, 17%) as a white solid.

[0229] Example 17, Method AC

[0230] Preparation of N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-5-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A17) [ka]

[0231] Step a N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-5-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to obtain the compound (7 mg, 38%) as a yellow solid.

[0232] Example 18, Methods AC and AF

[0233] Preparation of N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholino-5-(6-oxa-2-azaspiro[3.4]octan-2-yl)oxazolo[4,5-b]pyridine-6-carboxamide: (A18) [ka]

[0234] Step a. 2-Benzyl-6-oxa-2-azaspiro[3.4]octan-1-one: To a solution of tetrahydrofuran-3-carboxylic acid (500 mg, 4.3 mmol) in dry DCM (10 mL) was added catalytic amounts of DMF and oxalyl chloride (1.6 g, 13 mmol). After stirring at room temperature for 1 h, the reaction mixture was concentrated in vacuo to give the crude product. Meanwhile, to a separate solution of 1,3,5-tribenzyl-1,3,5-triazinane (610 mg, 4.3 mmol) in dry DCM (10 mL) was added boron trifluoride ethyl etherate (610 mg, 4.3 mmol) and stirred for 1 h under a N atmosphere. To a solution of the acyl chloride in dry DCM (10 mL), dry TEA (1.3 g, 13 mmol) and the solution prepared above were added slowly and sequentially at -78 °C under a N atmosphere. The mixture was stirred for 10 minutes and then placed in an ice-water bath overnight. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM (30 mL x 3). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the desired product (558 mg, 85%) as a yellow oil. 1 H NMR (400 MHz, CDCl3): δ 7.33 (dd, J=14.8, 6.4 Hz, 3H), 7.23 (d, J=7.0 Hz, 2H), 4.40 (q, J=14.8 Hz, 2H), 3.99 (q, J=9.2 Hz, 2H), 3.88 (dd, LC-MS (m / z):217.9 [M+H]+ .

[0235] Step b. 2-Benzyl-6-oxa-2-azaspiro[3.4]octane: To a solution of aluminum trichloride (366 mg, 2.8 mmol) in dry THF (20 mL), lithium aluminum hydride (460 mg, 2.1 mmol) and 2-benzyl-6-oxa-2-azaspiro[3.4]octan-1-one (460 mg, 2.1 mmol) were added sequentially in an ice-water bath under an atmosphere of N. After stirring at 0 °C for 2.5 h, the mixture was quenched by the addition of water (0.32 mL), 10% aqueous NaOH (0.64 mL), and water (0.96 mL). The suspension was filtered, and the filtrate was diluted with water (10 mL) and extracted with EA (30 mL × 3). The organic layer was dried over NaSO, filtered, and concentrated to give the desired product (350 mg, 81%) as a yellow oil. 1 H NMR (400 MHz, CDCl3):δ 7.39-7.27 (m, 4H), 7.26-7.20 (m, 1H), 3.83 (s, 2H), 3.76 (t, J=6.8 Hz, 2H), 3.61 (s, 2H), 3.24 (s, 4H), 2.09 (t, J=6.8 Hz, 2H).LC-MS (m / z):204.0 [M+H] + .

[0236] Step c N-(6-(1-Methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholino-5-(6-oxa-2-azaspiro[3.4]octan-2-yl)oxazolo[4,5-b]pyridine-6-carboxamide: A suspension of 2-benzyl-6-oxa-2-azaspiro[3.4]octane (200 mg, 0.10 mmol) and 10% Pd / C (50 mg) in MeOH (50 mL) was stirred overnight at room temperature under an H atmosphere. The suspension was filtered and concentrated to give the desired product, which was used in the next step without further purification. The procedure described in Example 1 was carried out to give the compound (27 mg, 48%) as a yellow solid.

[0237] Example 19, Methods AC and AP

[0238] Preparation of 5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A19) [ka]

[0239] Step a. tert-Butyl 5-(6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)-2-morpholinooxazolo[4,5-b]pyridin-5-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: The procedure described in example 8 was followed to provide the compound (50 mg, 74%) as a yellow solid. 1 H NMR (300 MHz, CDCl3) δ 10.68 (s, 1H), 8.22-8.05 (m, 2H), 7.94-7.81 (m, 2H), 7.70 (s, 1H), 7.24-7.16 (m, 1H), 3.97 (s, 3H), 3.90-3.75 (m, 8H), 3.75-3.49 (m, 4H), 3.45-3.26 (m, 3H), 3.13-2.95 (m, 2H), 2.17 (m, 1H), 1.39 (s, 9H).

[0240] Step b. 5-(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 8 was carried out to obtain the compound (27 mg, 65%) as a yellow solid.

[0241] Example 20, Methods AC and AP

[0242] Preparation of 5-H[3,4-b]pyrrol-1(2H)-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A20) [ka]

[0243] Step a. 5-(Hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 8 was carried out to provide the compound (11 mg, 19%) as a yellow solid.

[0244] Example 21, Method AC

[0245] Preparation of (R)-5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A21) [ka]

[0246] Step a. (R)-5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to provide the compound (10 mg, 17%) as a yellow solid.

[0247] Example 22, Method AC

[0248] Preparation of 5-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A22) [ka]

[0249] Step a. 5-(6-Hydroxy-2-azaspiro[3.3]heptan-2-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to provide the compound (10 mg, 17%) as a yellow solid.

[0250] Example 23, Method AC

[0251] Preparation of 5-(4-(dimethylamino)piperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A23) [ka]

[0252] Step a. 5-(4-(dimethylamino)piperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to give the compound (27 mg, 37%) as a yellow solid.

[0253] Example 24, Method AC

[0254] Preparation of 5-(4-methoxypiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A24) [ka]

[0255] Step a. 5-(4-Methoxypiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to give the compound (16 mg, 28%) as a white solid.

[0256] Example 25, Method AC

[0257] Preparation of 5-(4-hydroxy-4-methylpiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A25) [ka]

[0258] Step a. 5-(4-hydroxy-4-methylpiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to give the compound (10 mg, 17%) as a white solid.

[0259] Example 26, Methods AC and AG

[0260] Preparation of N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholino-5-(1-oxa-7-azaspiro[3.5]nonan-7-yl)oxazolo[4,5-b]pyridine-6-carboxamide: (A26) [ka]

[0261] Step a. tert-Butyl 1-oxa-7-azaspiro[3.5]nonane-7-carboxylate: To a solution of trimethylsulfoxonium iodide (2.0 g, 10 mmol) in t-BuOH (70 mL) was added t-BuOK (2.8 g, 25 mmol). After stirring at 50 °C for 1.5 h, the mixture was added with tert-butyl 4-oxopiperidine-1-carboxylate (5.5 g, 25 mmol) and stirred at the same temperature for 48 h. After cooling to room temperature, the mixture was diluted with EA (150 mL) and washed with saturated aqueous NaCl (50 mL × 3). The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the desired product (1.5 g, 66%) as a colorless oil. 1 H NMR (300 MHz, CDCl3) δ 4.68-4.39 (m, 2H), 3.41 (s, 4H), 2.54-2.26 (m, 2H), 1.98-1.67 (m, 4H), 1.45 (s, 9H).

[0262] Step b N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholino-5-(1-oxa-7-azaspiro[3.5]nonan-7-yl)oxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to give the compound (20 mg, 27%) as a yellow solid.

[0263] Example 27, Method AC

[0264] Preparation of (S)-5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A27) [ka]

[0265] Step a. (S)-5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was followed to provide the compound (14 mg, 38%) as a white solid.

[0266] Example 28, Method AC

[0267] Preparation of 5-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A28) [ka]

[0268] Step a. 5-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was carried out to provide the compound (18 mg, 30%) as a white solid.

[0269] Example 29, Methods AC and AP

[0270] Preparation of 5-(3-aminopiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide hydrochloride: (A29) [ka]

[0271] Step a. 5-(3-aminopiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide hydrochloride: The procedure described in example 8 was carried out to provide the compound (8 mg, 13%) as a yellow solid.

[0272] Example 30, Method AC

[0273] Preparation of 5-(3,4-dimethylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide hydrochloride: (A30) [ka]

[0274] Step a. 5-(3,4-Dimethylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide hydrochloride: The compound obtained by the procedure described in Example 1 was added to a solution of 2.8 N hydrochloric acid / EA (5 mL) and stirred at room temperature overnight. The mixture was filtered and dried to give the product (15 mg, 27%) as a yellow solid.

[0275] Example 31, Method AC

[0276] Preparation of (S)-5-(3,4-dimethylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide hydrochloride: (A31) [ka]

[0277] Step a. (S)-5-(3,4-Dimethylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide hydrochloride: The compound obtained by the procedure described in Example 1 was added to a solution of 2.8 N hydrochloric acid / EA (5 mL) and stirred at room temperature overnight. The mixture was filtered and dried to give the product (19 mg, 32%) as a yellow solid.

[0278] Example 32, Method AC

[0279] Preparation of 5-(3,5-dimethylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A32) [ka]

[0280] Step a. 5-(3,5-dimethylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to give the compound (30 mg, 53%) as a white solid.

[0281] Example 33, Method AH

[0282] Preparation of N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholino-5-(3,4,5-trimethylpiperazin-1-yl)oxazolo[4,5-b]pyridine-6-carboxamide: (A33) [ka]

[0283] Step a: N-(6-(1-Methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholino-5-(3,4,5-trimethylpiperazin-1-yl)oxazolo[4,5-b]pyridine-6-carboxamide: To a solution of 5-(3,5-dimethylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide (120 mg, 0.23 mmol) and polyoxymethylene (POM) (70 mg, 2.3 mmol) in DCE (10 mL) was added NaBH(OAc) (487 mg, 2.3 mmol) at 0 °C. The reaction was stirred at room temperature overnight and quenched with saturated aqueous NH4Cl (30 mL). The mixture was extracted with dichloromethane (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the desired product (65 mg, 53%) as a yellow solid.

[0284] Example 34, Method AC

[0285] Preparation of 5-(4-(2-methoxyethyl)piperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide hydrochloride: (A34) [ka]

[0286] Step a. 5-(4-(2-Methoxyethyl)piperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide hydrochloride: The product obtained by the procedure described in Example 1 was added to a solution of 2.8 N hydrochloric acid / EA (5 mL) and stirred at room temperature overnight. The mixture was filtered and dried to give the compound (10 mg, 8%) as a yellow solid.

[0287] Example 35, Method AC

[0288] Preparation of 5-(4-cyclopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide hydrochloride: (A35) [ka]

[0289] Step a. 5-(4-Cyclopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide hydrochloride: The product obtained by the procedure described in Example 1 was added to a solution of 2.8 N hydrochloric acid / EA (5 mL) and stirred at room temperature overnight. The mixture was filtered and dried to give the compound (30 mg, 48%) as a yellow solid.

[0290] Example 36, Method AC

[0291] Preparation of 5-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide hydrochloride: (A36) [ka]

[0292] Step a. 5-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide hydrochloride: The product obtained by the procedure described in Example 1 was added to a solution of 2.8 N hydrochloric acid / EA (5 mL) and stirred at room temperature overnight. The mixture was filtered and dried to give the compound (8 mg, 7%) as a yellow solid.

[0293] Example 37, Method AC

[0294] Preparation of 5-(3-(hydroxymethyl)-4-methylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide hydrochloride: (A37) [ka]

[0295] Step a. 5-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide hydrochloride: The product obtained by the procedure described in Example 1 was added to a solution of 2.8 N hydrochloric acid / EA (5 mL) and stirred at room temperature overnight. The mixture was filtered and dried to give the compound (10 mg, 7%) as a yellow solid.

[0296] Example 38, Methods AB, AC, AK

[0297] Preparation of (R)-N-(6-(difluoromethyl)pyridin-2-yl)-5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A38) [ka]

[0298] Step a. 2-Bromo-6-(difluoromethyl)pyridine: To a solution of 6-bromopicolinaldehyde (3.7 g, 20 mmol) in dry DCM (30 mL) was added DAST (3.9 g, 24 mmol), and the mixture was stirred at room temperature overnight. The mixture was quenched with saturated aqueous NaHCO in an ice-water bath and extracted with DCM (20 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated to give the desired product as a brown oil, which was used directly in the next step.

[0299] Step b. 6-(Difluoromethyl)pyridin-2-amine: A suspension of 2-bromo-6-(difluoromethyl)pyridine (828 mg, 4.0 mmol), CuO (29 mg, 0.2 mmol), KCO (110 mg, 0.80 mmol), and N,N-dimethylethylenediamine (35 mg, 0.40 mmol) in a mixed solution (aqueous ammonia / ethylene glycol = 10 mL / 8 mL) was stirred at room temperature overnight. The mixture was diluted with DCM (20 mL) and washed with saturated aqueous NaCl (20 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the desired product (300 mg, 52%). 1 H NMR (300 MHz, CDCl3) δ 7.58-7.48 (m, 1H), 6.94 (d, J=7.2 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 6.42 (t, J=55.8 Hz, 1H), 4.58 (br s, 2H).LC-MS (m / z):145.1 [M+H] + .

[0300] Step c. 5-chloro-N-(6-(difluoromethyl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide:

[0301] The procedure described in Example 1 was carried out to give the product (25 mg, 6%) as a yellow solid. 1 H NMR (300 MHz, CDCl3) δ 9.18 (s, 1H), 8.45 (d, J=8.1 Hz, 1H), 8.04-7.81 (m, 2H), 7.42 (d, J=7.5 Hz, 1H), 6.52 (t, J=55.8 Hz, 1H), 3.83 (s, 8H).

[0302] Step d. (R)—N-(6-(difluoromethyl)pyridin-2-yl)-5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was carried out to give the product (20 mg, 63%) as a white solid.

[0303] Example 39, Methods AB, AC

[0304] Preparation of (R)-5-(3-hydroxypyrrolidin-1-yl)-2-morpholino-N-(pyrazolo[1,5-a]pyrimidin-3-yl)oxazolo[4,5-b]pyridine-6-carboxamide: (A39) [ka]

[0305] Step a. 5-Chloro-2-morpholino-N-(pyrazolo[1,5-a]pyrimidin-3-yl)oxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was followed to give the product (510 mg, 33%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.05 (d, J=6.0 Hz, 1H), 8.65 (s, 1H), 8.53 (d, J=3.9 Hz, 1H), 8.03 (s, 1H), 7.04 (dd, J= 6.9, 4.2 Hz, 1H), 3.80-3.72 (m, 4H), 3.71-3.64 (m, 4H).

[0306] Step b. (R)-5-(3-hydroxypyrrolidin-1-yl)-2-morpholino-N-(pyrazolo[1,5-a]pyrimidin-3-yl)oxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was carried out to give the compound (53 mg, 53%) as a white solid.

[0307] Example 40, Methods AB, AC

[0308] Preparation of (R)-5-(3-hydroxypyrrolidin-1-yl)-N-(1-methyl-1H-pyrazol-4-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A40) [ka]

[0309] Step a. 5-Chloro-N-(1-methyl-1H-pyrazol-4-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was carried out to give the product (240 mg, 35%) as a grey solid.

[0310] Step b. (R)-5-(3-hydroxypyrrolidin-1-yl)-N-(1-methyl-1H-pyrazol-4-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was carried out to give the compound (50 mg, 51%) as a white solid.

[0311] Example 41, Methods AB, AC

[0312] Preparation of 5-(4-hydroxypiperidin-1-yl)-N-(6-methylpyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A41) [ka]

[0313] Step a. 5-Chloro-N-(6-methylpyridin-2-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was carried out to give the product (40 mg, 28%) as a grey solid. 1H NMR (300 MHz,DMSO-d6) δ 10.98 (s, 1H), 8.08-7.94 (m, 2H), 7.79-7.66 (m, 1H), 7.04 (d, J=6.6 Hz, 1H), 3.86-3.72 (m, 4H), 3.72-3.62 (m, 4H), 2.48-2.31 (m, 3H).LC-MS (m / z):374.1 [M+H] + .

[0314] Step b. 5-(4-Hydroxypiperidin-1-yl)-N-(6-methylpyridin-2-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to give the compound (29 mg, 60%) as a white solid.

[0315] Example 42, Methods AB, AC

[0316] Preparation of N-(6-cyanopyridin-2-yl)-5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A42) [ka]

[0317] Step a. 5-Chloro-N-(6-cyanopyridin-2-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was carried out to give the product (46 mg, 63%) as a grey solid.

[0318] Step b N-(6-cyanopyridin-2-yl)-5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to give the compound (11 mg, 60%) as a white solid.

[0319] Example 43, Methods AB, AC

[0320] Preparation of 5-(4-hydroxypiperidin-1-yl)-N-(6-methoxypyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A43) [ka]

[0321] Step a. 5-Chloro-N-(6-methoxypyridin-2-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was carried out to give the product (94 mg, 32%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.08 (s, 1H), 7.85-7.68 (m, 2H), 6.65-6.53 (m, 1H), 3.83 (s, 3H), 3.79-3.74 (m, 4H), 3.74-3.68 (m, 4H).LC-MS (m / z):390.1 [M+H] + .

[0322] Step b. 5-(4-Hydroxypiperidin-1-yl)-N-(6-methoxypyridin-2-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to give the compound (28 mg, 48%) as a white solid.

[0323] Example 44, Methods AB, AC, AI

[0324] Preparation of N-(3-(dimethylphosphoryl)phenyl)-5-(4-methoxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A44) [ka]

[0325] Step a. (3-Aminophenyl)dimethylphosphine oxide: A suspension of 3-bromoaniline (200 mg, 1.2 mmol), dimethylphosphine oxide (136 mg, 1.7 mmol), Pd(OAc) (25 mg, 0.11 mmol), xantphos (63 mg, 0.11 mmol), and KPO (371 mg, 1.7 mmol) in dry 1,4-dioxane (10 mL) was stirred at 120 °C overnight. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 30 / 1) to give the desired product (80 mg, 41%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.22 (s, 1H), 7.11 (d, J=12.6 Hz, 1H), 7.02-6.90 (m, 1H), 6.80 (d, J=8.4 Hz, 1H), 3.72 (s, 2H), 1.69 (d, J=12.6 Hz, 6H).LC-MS (m / z):170.1 [M+H] + .

[0326] Step b. 5-Chloro-N-(3-(dimethylphosphoryl)phenyl)-2-morpholinoxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was carried out to give the desired product (120 mg, 26%) as a grey solid. 1 H NMR (300 MHz, CDCl3) δ 10.16-10.11 (m, 1H), 8.24 (s, 1H), 8.04 (d, J=13.3 Hz, 1H), 7.85 (s, 1H), 7.53-7.43 (m, 1H), 7.29 (s, 1H), 3.93-3.69 (m, 8H),1.61 (d, J=12.8 Hz, 6H).LC-MS (m / z):435.0 [M+H] + .

[0327] Step c N-(3-(dimethylphosphoryl)phenyl)-5-(4-methoxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was carried out to give the desired product (40 mg, 57%) as a white solid.

[0328] Example 45, Methods AB, AC

[0329] Preparation of 5-(4-hydroxypiperidin-1-yl)-N-(2-methoxypyridin-3-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A45) [ka]

[0330] Step a. 5-Chloro-N-(2-methoxypyridin-3-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was carried out to give the product (30 mg, 22%) as a yellow oil. 1 H NMR (300 MHz, CDCl3) δ 9.22 (s, 1H), 8.73 (d, J=6.6 Hz, 1H), 8.08 (s, 1H), 7.91 (d, J=3.3 Hz, 1H), 7.00-6.90 (m, 1H), 4.05 (s, 3H), 3.83 (s, 8H).LC-MS (m / z):390.1 [M+H] + .

[0331] Step b. 5-(4-hydroxypiperidin-1-yl)-N-(2-methoxypyridin-3-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to give the compound (17 mg, 58%) as a white solid.

[0332] Example 46, Method AC

[0333] Preparation of 5-(4-methoxypiperidin-1-yl)-N-(6-methoxypyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A46) [ka]

[0334] Step a. 5-(4-Methoxypiperidin-1-yl)-N-(6-methoxypyridin-2-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was carried out to provide the compound (25 mg, 48%) as a white solid.

[0335] Example 47, Methods AB, AC, AJ

[0336] Preparation of N-(2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-(4-methoxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A47) [ka]

[0337] Step a. 2-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)aniline: A suspension of 3-bromo-2-methoxyaniline (500 mg, 2.4 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (603 mg, 2.9 mmol), KCO (684 mg, 4.9 mmol), and Pd(dppf)Cl (183 mg, 0.25 mmol) in a mixed solvent (1,4-dioxane / water = 20 mL / 2 mL) was stirred overnight at 100 °C under a N atmosphere. After cooling to room temperature, the mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE / EA = 3 / 1) to give the desired product (380 mg, 70%) as a yellow solid.

[0338] Step b. 5-chloro-N-(2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to give the compound (60 mg, 73%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 9.49 (s, 1H), 8.42 (s, 1H), 8.16 (s, 1H), 7.87 (s, 1H), 7.80 (s, 1H), 7.22-7.12 (m, 2H), 3.98 (s, 3H), 3.90-3.80 (m, 8H), 3.67 (s, 3H).

[0339] Step c N-(2-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-(4-methoxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to give the compound (13 mg, 18%) as a white solid.

[0340] Example 48, Methods AB, AC, AK

[0341] Preparation of N-(3-(2H-tetrazol-5-yl)phenyl)-5-(4-methoxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A48) [ka]

[0342] Step a. 5-(3-Nitrophenyl)-2H-tetrazole: To a solution of 3-nitrobenzonitrile (1.0 g, 6.8 mmol) in DMF (15 mL) was added NaN (2.6 g, 40 mmol) and ammonium chloride (2.2 g, 40 mmol). The mixture was stirred at 120 °C overnight. After cooling to room temperature, the mixture was diluted with water (25 mL) and extracted with DCM (25 mL × 3). The combined organic layers were dried over Na SO , filtered, and concentrated to give the desired product (620 mg, 50%) as a white solid.1 H NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 7.79-7.66 (m, 2H), 7.23-7.16 (m, 1H).

[0343] Step b. 3-(2H-Tetrazol-5-yl)aniline: A suspension of 5-(3-nitrophenyl)-2H-tetrazole (620 mg, 3.2 mmol) and 10% Pd / C (300 mg) in MeOH (50 mL) was stirred overnight at room temperature under an H atmosphere. The suspension was filtered and concentrated to give the desired product (430 mg, 82%). 1 H NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.26 (s, 1H), 7.19 (d, J=7.2 Hz, 1H), 7.15-7.09 (m, 1H), 6.73 (d, J=7.2 Hz, 1H), 4.97 (s, 2H).

[0344] Step c N-(3-(2H-tetrazol-5-yl)phenyl)-5-chloro-2-morpholinoxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was followed to give the compound (51 mg, 19%) as a brown solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.55 (s, 1H), 8.14 (s, 1H), 7.82 (d, J=6.9 Hz, 1H), 7.77 (d, J=6.9 Hz, 1H), 7.68-7.54 (m, 1H), 3.85-3.71 (m, 8H).

[0345] Step d N-(3-(2H-tetrazol-5-yl)phenyl)-5-(4-methoxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 1 was carried out to give the compound (7 mg, 12%) as a white solid.

[0346] Example 49, Methods AC, AL

[0347] Preparation of (R)-5-(3-hydroxypyrrolidin-1-yl)-N-(2-(2-methylpyridin-4-yl)oxazol-4-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A49) [ka]

[0348] Step a. Ethyl 2-(2-methylpyridin-4-yl)oxazole-4-carboxylate: To a suspension of 4-bromo-2-methylpyridine (7.5 g, 44 mmol), ethyl oxazole-4-carboxylate (6.2 g, 44 mmol), and tris-o-tolylphosphane (2.6 g, 8.7 mmol) in DMF (200 mL) was added Pd(OAc) (500 mg, 4.4 mmol) and CsCO (15.6 g, 48 mmol). After stirring at 70 °C overnight, the mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product used in the next step.

[0349] Step b. 2-(2-Methylpyridin-4-yl)oxazole-4-carboxylic acid: To a solution of the above crude material in THF (50 mL) was added LiOH (2.1 g, 87 mmol) in water (10 mL). The mixture was stirred at room temperature overnight and filtered. The filter cake was dissolved in water (20 mL) and the pH was adjusted to 4 with 1 N aqueous hydrochloric acid. The resulting precipitate was collected by filtration to give the product (2.3 g, 25%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.64 (d, J=5.1 Hz, 1H), 7.81 (s, 1H), 7.72 (d, J=4.8 Hz, 1H), 2.57 (s, 3H).LC-MS (m / z):205.1 [M+H] + .

[0350] Step c. tert-Butyl (2-(2-methylpyridin-4-yl)oxazol-4-yl)carbamate: To a solution of 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (510 mg, 2.5 mmol) and TEA (505 mg, 5.0 mmol) in t-BuOH (20 mL) was added DPPA (756 mg, 2.8 mmol) under a N atmosphere. After stirring at 100 °C overnight, the mixture was cooled and concentrated in vacuo. The residue was purified on a silica gel column (PE / AE = 1 / 1) to give the desired product (230 mg, 33%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 8.60 (d, J=5.1 Hz, 1H), 7.91 (s, 1H), 7.69 (s, 1H), 7.61 (d, J=4.8 Hz, 1H), 6.94 (s, 1H), 2.63 (s, 3H), 1.52 (s, 9H).LC-MS (m / z):276.0 [M+H] + .

[0351] Step d. tert-Butyl (5-chloro-2-morpholinooxazolo[4,5-b]pyridine-6-carbonyl)(2-(2-methylpyridin-4-yl)oxazol-4-yl)carbamate: To a solution of 5-chloro-2-morpholinooxazolo[4,5-b]pyridine-6-carboxylic acid (500 mg, 4.3 mmol) in dry DCM (10 mL) was added catalytic amounts of DMF and oxalyl chloride (1.6 g, 13 mmol). After stirring at 50 °C for 1 h, the reaction mixture was concentrated in vacuo to give the crude product. 60% NaH (142 mg, 3.6 mmol) was added to dry THF (25 mL), and to the above mixture was added tert-butyl (2-(2-methylpyridin-4-yl)oxazol-4-yl)carbamate (195 mg, 0.71 mmol) and a solution of the above crude acyl chloride in THF (2 mL) under a N atmosphere at 0 °C. After stirring at room temperature for 1 h, the mixture was quenched with acetic acid (1 mL) at -10 °C and concentrated in vacuo. The residue was purified on a silica gel column (PE / AE = 1 / 1) to give the desired product (150 mg, 39%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.68-8.55 (m, 2H), 8.14 (s, 1H), 7.80 (s, 1H), 7.73-7.68 (m, 1H), 3.79-3.65 (m, 8H), 2.58 (s, 3H), 1.20 (s, 9H).

[0352] Step e. 5-Chloro-N-(2-(2-methylpyridin-4-yl)oxazol-4-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: To a solution of tert-butyl (5-chloro-2-morpholinooxazolo[4,5-b]pyridine-6-carbonyl)(2-(2-methylpyridin-4-yl)oxazol-4-yl)carbamate (150 mg, 0.28 mmol) in DCM (5 mL), TFA (0.5 mL) was added and stirred at room temperature for 5 h. The mixture was concentrated in vacuo, and the pH of the residue was adjusted to 8 with saturated aqueous NaHCO. The resulting precipitate was collected by filtration and dried to give the product (90 mg, 73%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.67 (d, J=5.1 Hz, 1H), 8.53 (s, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.77 (d, J=4.8 Hz, 1H), 3.80-3.65 (m, 8H), 2.61 (s, 3H).

[0353] Step f. (R)-5-(3-hydroxypyrrolidin-1-yl)-N-(2-(2-methylpyridin-4-yl)oxazol-4-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was followed to provide the compound (15 mg, 38%) as a white solid.

[0354] Example 50, Method AC

[0355] Preparation of 5-(4-methoxypiperidin-1-yl)-N-(2-methoxypyridin-3-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A50) [ka]

[0356] Step a. 5-(4-Methoxypiperidin-1-yl)-N-(2-methoxypyridin-3-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was carried out to provide the compound (15 mg, 38%) as a white solid.

[0357] Example 51, Methods AB, AM

[0358] Preparation of 5-(4-methoxypiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(piperazin-1-yl)oxazolo[4,5-b]pyridine-6-carboxamide hydrochloride: (A51) [ka]

[0359] Step a. tert-Butyl 4-(5-chlorooxazolo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate: The procedure described in Example 1 was followed to give the desired compound (3.0 g, 72%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.37 (d, J=8.1 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 3.77-3.67 (m, 4H), 3.64-3.51 (m, 4H), 1.48 (s, 9H).

[0360] Step b. tert-Butyl 4-(6-bromo-5-chlorooxazolo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate: The procedure described in Example 1 was followed to give the desired compound (3.0 g, 83%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.68 (s, 1H), 3.77-3.71 (m, 4H), 3.62-3.55 (m, 4H), 1.49 (s, 9H).

[0361] Step c. tert-Butyl (E)-4-(5-chloro-6-(3-ethoxy-3-oxoprop-1-en-1-yl)oxazolo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate: The procedure described in Example 1 was followed to give the desired compound (460 mg, 46%) as a yellow solid. 1 H NMR (300 MHz, CDCl3) δ 8.07 (d, J=15.9 Hz, 1H), 7.64 (s, 1H), 6.30 (d, J=15.9 Hz, 1H), 4.33-4.22 (m, 2H), 3.82-3.71 (m, 4H), 3.64-3.52 (m, 4H), 1.49 (s, 9H), 1.35 (t, J=5.7 Hz, 3H).LC-MS (m / z):437.1 [M+H] + .

[0362] Step d. tert-Butyl 4-(5-chloro-6-formyloxazolo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate: The procedure described in Example 1 was followed to give the desired compound (250 mg, 68%) as a yellow solid. 1 H NMR (300 MHz, CDCl3) δ 10.37 (s, 1H), 7.91 (s, 1H), 3.88-3.73 (m, 4H), 3.66-3.52 (m, 4H), 1.48 (s, 9H).LC-MS (m / z):367.1 [M+H] + .

[0363] Step e. 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-chlorooxazolo[4,5-b]pyridine-6-carboxylic acid: The procedure described in example 1 was carried out to give the desired compound (40 mg, 77%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.14 (s, 1H), 3.78-3.63 (m, 4H), 3.60-3.46 (m, 4H), 1.44 (s, 9H).LC-MS (m / z):383.1 [M+H] + .

[0364] Step f. tert-Butyl 4-(5-chloro-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)oxazolo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate: The procedure described in example 1 was followed to give the desired compound (10 mg, 18%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.98-7.91 (m, 2H), 7.85-7.75 (m, 1H), 7.46-7.35 (m, 1H), 3.87 (s, 3H), 3.75-3.63 (m, 4H), 3.57-3.48 (m, 4H), 1.43 (s, 9H).

[0365] Step f. tert-Butyl 4-(5-(4-methoxypiperidin-1-yl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)oxazolo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate: The procedure described in example 1 was followed to give the desired compound (45 mg, 49%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.46-13.31 (m, 1H), 8.35-8.20 (m, 2H), 8.10-7.99 (m, 2H), 7.78 (s, 1H), 7.39 (s, 1H), 3.87 (s, 3H), 3.76-3.63 (m, 9H), 3.25-3.13 (m, 5H), 3.10-2.93 (m, 2H), 2.25-1.98 (m, 4H), 1.43 (s, 9H). LC-MS (m / z):618.3 [M+H] + .

[0366] Step f. 5-(4-Methoxypiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(piperazin-1-yl)oxazolo[4,5-b]pyridine-6-carboxamide hydrochloride: A suspension of tert-butyl 4-(5-(4-methoxypiperidin-1-yl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)oxazolo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate (30 mg, 0.05 mmol) in 2.8 N HCl / EA (5 mL) was stirred overnight at room temperature. The mixture was concentrated to dryness to give the compound (25 mg, 86%) as a yellow solid.

[0367] Example 52, Method AO

[0368] Preparation of 5-(4-methoxypiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(4-methylpiperazin-1-yl)oxazolo[4,5-b]pyridine-6-carboxamide: (A52) [ka]

[0369] Step a. 5-(4-Methoxypiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(4-methylpiperazin-1-yl)oxazolo[4,5-b]pyridine-6-carboxamide: To a solution of 5-(4-methoxypiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(piperazin-1-yl)oxazolo[4,5-b]pyridine-6-carboxamide (30 mg, 0.058 mmol) and POM (18 mg, 0.58 mmol) in DCE (2 mL) was added NaBH(OAc) (124 mg, 0.58 mmol) at 0 °C. The reaction was stirred at room temperature overnight and quenched with saturated aqueous NH4Cl (30 mL). The mixture was extracted with dichloromethane (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified on a silica gel column (DCM / MeOH = 20 / 1) to give the desired product (6 mg, 20%) as a white solid.

[0370] Example 53, Method AC

[0371] Preparation of 2,5-bis((R)-3-hydroxypyrrolidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)oxazolo[4,5-b]pyridine-6-carboxamide: (A53) [ka]

[0372] Step a. 2,5-bis((R)-3-hydroxypyrrolidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)oxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was followed to obtain the by-product (20 mg, 37%) as a white solid.

[0373] Example 54, Methods AA and AB

[0374] Preparation of 5-methoxy-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinooxazolo[4,5-b]pyridine-6-carboxamide: (A54) [ka]

[0375] Step a. 6-Methoxy-2-nitropyridin-3-ol: The procedure described in Example 1 was carried out to give the product (5.0 g, 77%) as a yellow solid. 1 H NMR (300 MHz, CDCl3) δ 10.18 (s, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 3.98 (s, 3H).

[0376] Step b. 2-Amino-6-methoxypyridin-3-ol: The procedure described in Example 1 was carried out to give the product (2.7 g, 82%) as a black solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 6.95-6.70 (m, 1H), 5.87-5.66 (m, 1H), 5.35 (s, 2H), 3.65 (s, 3H).

[0377] Step c. 5-Methoxyoxazolo[4,5-b]pyridine-2-thiol: The procedure described in Example 1 was followed to give the product (1.0 g, 77%) as a yellow solid. 1 H NMR (300 MHz, CDCl3) δ 7.49 (d, J=8.8 Hz, 1H), 6.60 (d, J=9.3 Hz, 1H), 3.92 (s, 3H).LC-MS (m / z):183.1 [M+H] + .

[0378] Step d. 5-Methoxy-2-(methylthio)oxazolo[4,5-b]pyridine: The procedure described in Example 1 was followed to give the product (1.8 g, 81%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J=8.4 Hz, 1H), 6.82 (d, J=7.5 Hz, 1H), 4.19 (s, 3H), 2.98 (s, 3H).

[0379] Step e. 5-Methoxy-2-morpholinoxazolo[4,5-b]pyridine: The procedure described in Example 1 was followed to give the product (700 mg, 58%) as a brown solid. 1 H NMR (300 MHz, CDCl3) δ 7.39 (d, J=8.4 Hz, 1H), 6.37 (d, J=8.4 Hz, 1H), 3.96 (s, 3H), 3.84-3.79 (m, 4H), 3.74-3.68 (m, 4H).

[0380] Step f. 6-Bromo-5-methoxy-2-morpholinoxazolo[4,5-b]pyridine: The procedure described in Example 1 was followed to give the product (90 mg, 68%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.65 (s, 1H), 4.04 (s, 3H), 3.85-3.78 (m, 4H), 3.76-3.69 (m, 4H).LC-MS (m / z):313.9 [M+H] + .

[0381] Step g. Ethyl (E)-3-(5-methoxy-2-morpholinooxazolo[4,5-b]pyridin-6-yl)acrylate: 1 H NMR(300MHz, CDCl3)δ 7.91(d, J=15.9 Hz, 1H), 7.57 (s, 1H), 6.42 (d, J=16.2 Hz, 1H), 4.26 (q, 7.2 Hz, 2H), 4.05 (s, 3H), 3.86-3.70 (m, 8H), 1.33 (t, J=7.2 Hz, 3H).

[0382] Step h. 5-Methoxy-2-morpholinoxazolo[4,5-b]pyridine-6-carbaldehyde: The procedure described in Example 1 was followed to give the product (100 mg, 84%) as a yellow solid. 1 H NMR (300 MHz, CDCl3) δ 10.29 (s, 1H), 7.87 (s, 1H), 4.09 (s, 3H), 3.82 (s, 8H).

[0383] Step i. 5-Methoxy-2-morpholinoxazolo[4,5-b]pyridine-6-carboxylic acid: The procedure described in Example 1 was carried out to give the product (70 mg, 74%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.05 (s, 1H), 3.89 (s, 3H), 3.77-3.70 (m, 4H), 3.70-3.62 (m, 4H).

[0384] Step g. 5-Methoxy-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-morpholinoxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in Example 1 was followed to give the product (16 mg, 26%) as a white solid.

[0385] Example 55, Method AM

[0386] Preparation of N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(piperazin-1-yl)-5-(1-oxa-7-azaspiro[3.5]nonan-7-yl)oxazolo[4,5-b]pyridine-6-carboxamide: (A55) [ka]

[0387] Step a. tert-Butyl 4-(6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)-5-(1-oxa-7-azaspiro[3.5]nonan-7-yl)oxazolo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate: The procedure described in example 1 was followed to give the product (40 mg, 54%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 8.05 (d, J=7.8 Hz, 1H), 7.92 (s, 1H), 7.78 (t, J=7.8 Hz, 1H), 7.37 (d, J=7.5 Hz, 1H), 5.65-5.56 (m, 1H), 4.52-4.43 (m, 1H), 3.89 (s, 3H), 3.80-3.61 (m, 6H), 3.58-3.44 (m, 6H), 3.26-3.18 (m, 2H), 2.45-2.35 (m, 2H), 2.27-2.15 (m, 2H), 1.41 (s, 9H).LC-MS (m / z):629.9 [M+H] + .

[0388] Step b N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(piperazin-1-yl)-5-(1-oxa-7-azaspiro[3.5]nonan-7-yl)oxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 51 was followed to give the product (50 mg, 65%) as a white solid.

[0389] Example 56, Method AM

[0390] Preparation of 5-(4-hydroxy-4-methylpiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(piperazin-1-yl)oxazolo[4,5-b]pyridine-6-carboxamide: (A56) [ka]

[0391] Step a. tert-Butyl 4-(5-(4-hydroxy-4-methylpiperidin-1-yl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)oxazolo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate: The procedure described in example 1 was carried out to give the product (96 mg, 55%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.36 (s, 1H), 8.26 (s, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.01 (s, 1H), 7.79 (t, J=7.5 Hz, 1H), 7.38 (d, J=7.5 Hz, 1H), 4.60 (s, 1H), 3.87 (s, 3H), 3.75-3.66 (m, 4H), 3.57-3.47 (m, 4H), 3.28-3.20 (m, 2H), 3.07-2.94 (m, 2H), 1.89 (s, 3H), 1.44 (s, 9H), 1.33-1.17 (m, 4H).LC-MS (m / z):617.8 [M+H] + .

[0392] Step b. 5-(4-hydroxy-4-methylpiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(piperazin-1-yl)oxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 51 was carried out to give the product (38 mg, 49%) as a white solid.

[0393] Example 57, Method AN

[0394] Preparation of 2-(4-(2-hydroxyethyl)piperazin-1-yl)-5-(4-methoxypiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)oxazolo[4,5-b]pyridine-6-carboxamide: (A57) [ka]

[0395] Step a. 2-(4-(2-hydroxyethyl)piperazin-1-yl)-5-(4-methoxypiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)oxazolo[4,5-b]pyridine-6-carboxamide: To a solution of 5-(4-methoxypiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(piperazin-1-yl)oxazolo[4,5-b]pyridine-6-carboxamide (30 mg, 0.058 mmol) and 2-bromoethan-1-ol (11 mg, 0.087 mmol) in dry DMF (2 ml) was added KCO (16 mg, 0.12 mmol) and stirred at 100 °C overnight. The mixture was diluted with water (5 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated, and the residue was purified by silica gel column (DCM / MeOH = 50 / 1) to give the desired product (5 mg, 15%) as a white solid.

[0396] Example 58, Method AO

[0397] Preparation of N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(4-methylpiperazin-1-yl)-5-(1-oxa-7-azaspiro[3.5])nonan-7-yl)oxazolo[4,5-b]pyridine-6-carboxamide: (A58) [ka]

[0398] Step a N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(4-methylpiperazin-1-yl)-5-(1-oxa-7-azaspiro[3.5]nonan-7-yl)oxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 52 was followed to give the product (12 mg, 80%) as a white solid.

[0399] Example 59, Method AO

[0400] Preparation of 5-(4-hydroxy-4-methylpiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(4-methylpiperazin-1-yl)oxazolo[4,5-b]pyridine-6-carboxamide: (A59) [ka]

[0401] Step a. 5-(4-hydroxy-4-methylpiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(4-methylpiperazin-1-yl)oxazolo[4,5-b]pyridine-6-carboxamide: The procedure described in example 52 was carried out to provide the product (6 mg, 40%) as a white solid.

[0402] Example 60, Methods BA and BB

[0403] Preparation of 6-(4-methoxypiperidin-1-yl)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B1) [ka]

[0404] Step a. 1-(2,6-Difluoropyridin-3-yl)-2-methylpropan-2-ol: To a solution of 3-bromo-2,6-difluoropyridine (200 mg, 1.0 mmol) in dry THF (10 mL) was added n-BuLi (0.44 mL, 1.1 mmol), and the mixture was stirred at −78° C. for 0.5 h. Then, 2,2-dimethyloxirane (86 mg, 1.2 mmol) and boron trifluoride etherate (0.15 mL, 1.2 mmol) were slowly added, and the mixture was stirred at −78° C. for 2 h.

[0405] The reaction mixture was quenched by adding water (10 mL) and extracted with EA (20 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated, and the residue was purified by silica gel column (PE / EA = 4 / 1) to give the desired product (50 mg, 27%) as a yellow solid. 1 H NMR (300 MHz, CDCl3) δ 7.82 (dd, J=16.5, 8.1 Hz, 1H), 6.79 (d, J=8.1 Hz, 1H), 2.78 (s, 2H), 1.26 (s, 6H).

[0406] Step b. 6-Fluoro-2,2-dimethyl-2,3-dihydrofuro[2,3-b]pyridine: To a solution of 1-(2,6-difluoropyridin-3-yl)-2-methylpropan-2-ol (40 mg, 0.21 mmol) in dry THF (10 mL) was added t-BuOK (47 mg, 0.42 mmol), and the mixture was stirred at 50 °C overnight. The mixture was diluted with EA (10 mL) and washed with water (10 mL × 3). The combined organic layers were dried over Na SO , filtered, and concentrated. The residue was purified on a silica gel column (PE / EA = 5 / 1) to give the desired product (50 mg, 27%) as a colorless clay. 1 H NMR (300 MHz, CDCl3) δ 7.52-7.38 (m, 1H), 6.35 (d, J=6.9 Hz, 1H), 2.99 (s, 2H), 1.51 (s, 6H).

[0407] Step c. 5-Bromo-6-fluoro-2,2-dimethyl-2,3-dihydrofuro[2,3-b]pyridine: To a solution of 6-fluoro-2,2-dimethyl-2,3-dihydrofuro[2,3-b]pyridine (1.0 g, 6.0 mmol) in dry CH3CN (100 mL) was added NBS (1.6 g, 9.0 mmol), and the mixture was stirred at room temperature overnight. The mixture was diluted with water (50 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified on a silica gel column (PE / EA = 10 / 1) to give the desired product (300 mg, 21%) as a yellow solid.1 H NMR (300 MHz, CDCl3) δ 7.60 (d, J=8.4 Hz, 1H), 3.01 (s, 2H), 1.51 (s, 6H).

[0408] Step d. Ethyl (E)-3-(6-fluoro-2,2-dimethyl-2,3-dihydrofuro[2,3-b]pyridin-5-yl)acrylate: To a solution of 5-bromo-6-fluoro-2,2-dimethyl-2,3-dihydrofuro[2,3-b]pyridine (100 mg, 0.41 mmol) in dry DMF (2 mL) was added tri(o-tolyl)phosphine (36 mg, 0.12 mmol), palladium acetate (9.0 mg, 0.04 mmol), TEA (121 mg, 1.2 mmol), and ethyl acrylate (810 mg, 8.1 mmol). The mixture was refluxed under N at 140 °C for 2 h, and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1) to give the desired product (50 mg, 46%) as a yellow solid. 1 H NMR (300 MHz, CDCl3) δ 7.68 (d, J=16.5 Hz, 1H), 7.68 (s, 1H), 6.33 (d, J=16.2 Hz, 1H), 4.24 (q, J=7.2 Hz, 2H), 3.03 (s, 2H), 1.53 (s, 6H), 1.32 (t, J=7.2 Hz, 3H).

[0409] Step e. 6-Fluoro-2,2-dimethyl-2,3-dihydrofuro[2,3-b]pyridine-5-carbaldehyde: A solution of ethyl (E)-3-(6-fluoro-2,2-dimethyl-2,3-dihydrofuro[2,3-b]pyridin-5-yl)acrylate (50 mg, 0.18 mmol) in DCM / MeOH (30 mL / 3 mL) was bubbled with dry O for 10 min at -78 °C. The reaction was complete as detected by TLC and quenched by the addition of dimethyl sulfide (0.5 mL). The solvent was removed in vacuo to give the crude product (40 mg) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 10.14 (s, 1H), 8.01 (d, J=8.7 Hz, 1H), 3.06 (s, 2H), 1.57 (s, 6H).

[0410] Step f. 6-Fluoro-2,2-dimethyl-2,3-dihydrofuro[2,3-b]pyridine-5-carboxylic acid: To a solution of 6-fluoro-2,2-dimethyl-2,3-dihydrofuro[2,3-b]pyridine-5-carbaldehyde (50 mg, 0.25 mmol) in t-BuOH (5 mL) was added 2-methyl-2-butene (175 mg, 2.5 mmol), sodium chlorite (112 mg, 1.2 mmol), and aqueous sodium dihydrogen phosphate dehydrate (390 mg, 2.5 mmol) (5 mL). After stirring at room temperature for 2 h, the mixture was adjusted to pH 2 with 1N aqueous hydrochloric acid and extracted with DCM (30 mL × 3). The solvent was removed in vacuo to give the desired product (40 mg, 77%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.13 (d, J=9.3 Hz, 1H), 3.07 (s, 2H), 1.48 (s, 6H).

[0411] Step g. 6-Fluoro-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: To a solution of 6-fluoro-2,2-dimethyl-2,3-dihydrofuro[2,3-b]pyridine-5-carboxylic acid (477 mg, 2.3 mmol) in dry DCM (20 mL) was added catalytic amounts of DMF and oxalyl chloride (2.8 g, 23 mmol). After stirring at 30 °C for 6 h, the reaction mixture was concentrated in vacuo to give the crude product. To a separate solution of 6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (470 mg, 2.7 mmol) and DIPEA (580 mg, 4.5 mmol) in dry DCM (20 mL) was added a solution of the above crude product in DCM (1 mL). The mixture was stirred at room temperature for 3 hours and quenched with saturated aqueous NaHCO. The mixture was extracted with DCM (30 mL x 3), and the combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified on a silica gel column (DCM / MeOH = 50 / 1) to give the desired product (450 mg, 54%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 9.01 (d, J=13.8 Hz, 1H), 8.32 (d, J=9.6 Hz, 1H), 8.12 (d, J=8.1 Hz, 1H), 7.92 (d, J=3.6 Hz, 1H), 7.70 (t, J=7.8 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 3.96 (s, 3H), 3.09 (s, 2H), 1.57 (s, 6H).

[0412] Step h. 6-(4-Methoxypiperidin-1-yl)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: To a solution of 6-fluoro-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide (55 mg, 0.15 mmol) in dry 1,4-dioxane (3 mL) was added KCO (207 mg, 1.5 mmol) and 4-methoxypiperidine (172 mg, 1.5 mmol), and the mixture was stirred at 100 °C overnight. The mixture was concentrated in vacuo and the residue was purified by silica gel column (DCM / MeOH=50 / 1) to give the desired product (14 mg, 20%) as a white solid.

[0413] Example 61, Method BB

[0414] Preparation of 2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-(4-methylpiperazin-1-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B2) [ka]

[0415] Step a. 2,2-Dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-(4-methylpiperazin-1-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 60 was carried out to provide the product (22 mg, 61%) as a white solid.

[0416] Example 62, Method BB

[0417] Preparation of 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B3) [ka]

[0418] Step a. 6-(4-(2-hydroxyethyl)piperazin-1-yl)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in example 60 was carried out to provide the product (21 mg, 54%) as a white solid.

[0419] Example 63, Method BB

[0420] Preparation of 6-(4-cyclopropylpiperazin-1-yl)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B4) [ka]

[0421] Step a. 6-(4-Cyclopropylpiperazin-1-yl)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in example 60 was carried out to provide the product (24 mg, 37%) as a white solid.

[0422] Example 64, Method BB

[0423] Preparation of 6-(4-hydroxypiperidin-1-yl)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B5) [ka]

[0424] Step a. 6-(4-Hydroxypiperidin-1-yl)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 60 was carried out to provide the product (22 mg, 61%) as a white solid.

[0425] Example 65, Method BB

[0426] Preparation of 2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B6) [ka]

[0427] Step a. 2,2-Dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in example 60 was followed to provide the product (17 mg, 38%) as a white solid.

[0428] Example 66, Method BB

[0429] Preparation of 6-(4-hydroxy-4-methylpiperidin-1-yl)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B7) [ka]

[0430] Step a. 6-(4-Hydroxy-4-methylpiperidin-1-yl)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 60 was carried out to provide the product (23 mg, 52%) as a white solid.

[0431] Example 67, Method BB

[0432] Preparation of 2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-(4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B8) [ka]

[0433] Step a. 2,2-Dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-(4,7-diazaspiro[2.5]octan-7-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 60 was followed to provide the product (29 mg, 69%) as a white solid.

[0434] Example 68, Methods BB and BD

[0435] Preparation of N-(1-((1S,2R)-2-fluorocyclopropyl)-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-hydroxypiperidin-1-yl)-2,2-dimethyl-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B9) [ka]

[0436] Step a. tert-Butyl ((1S,2R)-2-fluorocyclopropyl)carbamate: To a solution of (1R,2R)-2-fluorocyclopropane-1-carboxylic acid (2.8 g, 26.9 mmol) in t-BuOH (120 mL), TEA (8.1 g, 81 mmol) and DPPA (8.1 g, 30 mmol) were added and stirred at 90 °C for 72 h under N. The mixture was diluted with saturated aqueous NaHCO (50 mL) and extracted with EA (60 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified on a silica gel column (PE / EA = 10 / 1) to give the desired product (3.4 g, 72%) as a green oil. 1 H NMR (300 MHz, CDCl3) δ 4.83 (s, 1H), 4.58 (d, J=63.6 Hz, 1H), 2.62 (s, 1H), 1.45 (s, 9H), 1.10-0.82 (m, 2H).

[0437] Step b. (1S,2R)-2-Fluorocyclopropan-1-amine hydrochloride: To a solution of tert-butyl ((1S,2R)-2-fluorocyclopropyl)carbamate (2.1 g, 12 mmol) in EA (10 mL) was added 3N hydrochloric acid / EA solution (24 mL), and the mixture was stirred at room temperature overnight. The mixture was concentrated to give the desired product (1.3 g, 98%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 2H), 4.88 (d, J=63.8 Hz, 1H), 2.69-2.54 (m, 1H), 1.27-1.01 (m, 2H).

[0438] Step c. Dimethyl 2-((E)-3-(((1S,2R)-2-fluorocyclopropyl)amino)allylidene)malonate: To a solution of (1S,2R)-2-fluorocyclopropan-1-amine hydrochloride (777 mg, 7.0 mmol) in dry methanol (12 mL), dimethyl (E)-2-(3-methoxyallylidene)malonate (2.1 g, 10 mmol) and TEA (2.1 g, 21 mmol) were added and stirred at room temperature under N atmosphere for 3 h. The mixture was concentrated in vacuo, and the residue was purified on a silica gel column (PE / EA = 1 / 1) to give the desired product (1.1 g, 65%) as a yellow solid. 1 H NMR (300 MHz, CDCl3) δ 7.64 (d, J=12.3 Hz, 1H), 7.10-6.99 (m, 1H), 6.39 (t, J=12.9 Hz, 1H), 5.09 (s, 1H), 4.72 (d, J=64.2 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 2.60 (s, 1H), 1.27-1.16 (m, 1H), 1.07-0.91 (m, 1H).

[0439] Step d. 1-((1S,2R)-2-Fluorocyclopropyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid: To a solution of dimethyl 2-((E)-3-(((1S,2R)-2-fluorocyclopropyl)amino)allylidene)malonate (960 mg, 4 mmol) in EtOH (15 mL) was added KOH (360 mg, 6.4 mmol) at room temperature. After stirring at room temperature for 1 h, the mixture was refluxed at 90 °C for 3 h. The solvent was concentrated in vacuo, and the residue was diluted with water (10 mL), and the pH was adjusted to 1 with 2 N aqueous hydrochloric acid. The resulting precipitate was filtered and dried to give the desired product (760 mg, 96%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 14.07 (s, 1H), 8.53 (d, J=7.2 Hz, 1H), 7.70 (d, J=6.9 Hz, 1H), 6.57 (t, J=6.9 Hz, 1H), 4.97 (d, J=60.0 Hz, 1H), 3.47-3.32 (m, 1H), 1.71-1.53 ​​(m, 2H).

[0440] Step e. tert-Butyl (1-((1S,2R)-2-fluorocyclopropyl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate: To a solution of 1-((1S,2R)-2-fluorocyclopropyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (760 mg, 3.9 mmol) in t-BuOH (25 mL), TEA (600 mg, 5.9 mmol) and DPPA (1.3 g, 4.6 mmol) were added and stirred at 90 °C for 4 h under N. The mixture was diluted with saturated aqueous NaCl (15 mL) and extracted with EA (20 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified on a silica gel column (PE / EA = 1 / 1) to give the desired product (480 mg, 48%) as a yellow solid. 1 H NMR (300 MHz, CDCl3) δ 8.01-7.92 (m, 1H), 7.65 (s, 1H), 6.96 (d, J=6.3 Hz, 1H), 6.21 (t, J=7.2 Hz, 1H), 4.91 (d, J=64.5 Hz, 1H), 3.34-3.23 (m, 1H), 1.39-1.20 (m, 2H), 1.50 (s, 9H).

[0441] Step f. 3-Amino-1-((1S,2R)-2-fluorocyclopropyl)pyridin-2(1H)-one: To a solution of tert-butyl (1-((1S,2R)-2-fluorocyclopropyl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate (450 mg, 1.6 mmol) in EA (2 mL) was added a 3 N hydrochloric acid / EA solution (12 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo, and the residue was adjusted to pH 8 with saturated aqueous NaHCO and extracted with EA (20 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated to give the desired product (255 mg, 95%) as a yellow oil. 1 H NMR (300 MHz, CDCl3) δ 6.77 (d, J=6.9 Hz, 1H), 6.52 (d, J=6.0 Hz, 1H), 6.06 (t, J=6.9 Hz, 1H), 4.89 (d, J=60.0 Hz, 1H), 4.21 (s, 2H), 3.34-3.21 (m, 1H), 1.50-1.35 (m, 2H).

[0442] Step g. 6-Fluoro-N-(1-((1S,2R)-2-fluorocyclopropyl)-2-oxo-1,2-dihydropyridin-3-yl)-2,2-dimethyl-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in example 60 was followed to give the desired product (100 mg, 56%) as a yellow solid. 1 H NMR (300 MHz, CDCl3) δ 9.72 (s, 1H), 8.49 (s, 1H), 8.37-8.13 (m, 1H), 7.15-7.01 (m, 1H), 6.37-6.19 (m, 1H), 4.91 (d, J=60.4 Hz, 1H), 3.40-3.21 (m, 1H), 3.06 (s, 2H), 1.46-1.35 (m, 2H), 1.23 (s, 6H).

[0443] Step hN-(1-((1S,2R)-2-Fluorocyclopropyl)-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-hydroxypiperidin-1-yl)-2,2-dimethyl-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 60 was carried out to give the desired product (69 mg, 58%) as a yellow solid.

[0444] Example 69, Methods BB and BE

[0445] Preparation of N-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-hydroxypiperidin-1-yl)-2,2-dimethyl-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B10) [ka]

[0446] Step a. Benzyl (2-oxo-1,2-dihydropyridin-3-yl)carbamate: To a solution of 3-aminopyridin-2(1H)-one (1.2 g, 11 mmol) in water (150 mL) was added NaCO (2.6 g, 24 mmol) and NaHCO (1.0 g, 12 mmol), followed by acetone (20 mL) and Cbz-Cl (2.1 g, 12 mmol) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 4 h. The reaction was diluted with EA (100 mL) and washed with water (100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated to give the desired product (2 g, 74%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.31 (s, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.47-7.25 (m, 5H), 7.07 (d, J=6.6 Hz, 1H), 6.23 (t, J=6.6 Hz, 1H), 5.15 (s, 2H).LC-MS (m / z):244.9 [M+H] + .

[0447] Step b. Benzyl (1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)carbamate: A suspension of benzyl (2-oxo-1,2-dihydropyridin-3-yl)carbamate (1.4 g, 5.7 mmol), potassium cyclopropyltrifluoroborate (1.7 g, 11.5 mmol), copper acetate (1.2 g, 6.0 mmol), 2,2'-bipyridine (0.94 g, 6.0 mmol), and NaCO (1.3 g, 13 mmol) in DCE (35 mL) was stirred at 70 °C for 15 h with air exposure. The mixture was diluted with EA (100 mL) and washed with water (80 mL) and saturated brine (80 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated, and the residue was purified by silica gel column (PE / EA=5 / 1) to give the desired product (327 mg, 20%) as a black solid. 1 H NMR (300 MHz, CDCl3) δ 7.97 (s, 1H), 7.93-7.87 (m, 1H), 7.43-7.31 (m, 4H), 7.28-7.20 (m, 1H), 7.02-6.87 (m, 1H), 6.26-6.08 (m, 1H), 5.19 (s, 2H), 3.50-3.14 (m, 1H), 1.16-1.08 (m, 2H), 0.97-0.79 (m, 2H).LC-MS (m / z):284.9 [M+H] + .

[0448] Step c. 3-Amino-1-cyclopropylpyridin-2(1H)-one: A suspension of benzyl (1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)carbamate (320 mg, 1.1 mmol) and 5% Pd / C (90 mg, 0.040 mmol) in MeOH (50 mL) and THF (15 mL) was stirred overnight at room temperature under an H atmosphere. The suspension was filtered, and the filtrate was concentrated to give the desired product (150 mg, 88%) as a gray oil. 1H NMR (300 MHz, CDCl3) δ 6.73 (d, J=6.3 Hz, 1H), 6.50 (d, J=7.5 Hz, 1H), 6.02 (t, J=6.3 Hz, 1H), 4.20 (s, 2H), 2.73-2.52 (m, 1H), 1.21-1.02 (m, 2H), 0.89-0.80 (m, 2H).LC-MS (m / z):151.0 [M+H] + .

[0449] Step d N-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)-6-fluoro-2,2-dimethyl-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in example 60 was followed to give the desired product (60 mg, 39%) as a gray solid. 1H NMR (300 MHz, CDCl3) δ 9.77 (s, 1H), 8.44 (s, 1H), 8.26 (d, J=7.5 Hz, 1H), 7.04 (d, J=10.2 Hz, 1H), 6.39-6.12 (m, 1H), 3.53-3.24 (m, 1H), 3.05 (s, 2H), 1.54 (s, 6H), 1.21-1.01 (m, 2H), 0.97-0.83 (m, 2H).LC-MS (m / z):344.1 [M+H] + .

[0450] Step e N-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-hydroxypiperidin-1-yl)-2,2-dimethyl-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in example 60 was carried out to give the desired product (16 mg, 19%) as a white solid.

[0451] Example 70, Method BC

[0452] Preparation of 6-methoxy-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B11) [ka]

[0453] Step a. 6-Methoxy-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: To a solution of dry MeOH (87 mg, 2.7 mmol) in dry THF (5 mL) was slowly added 60% NaH (108 mg, 2.7 mmol). After stirring at room temperature for 1 hour, the mixture was added with 6-fluoro-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide (50 mg, 0.14 mmol) and refluxed overnight. The reaction mixture was diluted with water (10 mL), extracted with EA (10 mL × 3), and washed with saturated brine (20 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated, and the residue was purified on a silica gel column (DCM / MeOH=50 / 1) to give the desired product (20 mg, 39%) as a white solid.

[0454] Example 71, Method BC

[0455] Preparation of 6-ethoxy-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B12) [ka]

[0456] Step a. 6-Ethoxy-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 70 was followed to give the desired product (26 mg, 48%) as a white solid.

[0457] Example 72, Method BC

[0458] Preparation of 6-isopropoxy-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B13) [ka]

[0459] Step a. 6-Isopropoxy-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 70 was followed to give the desired product (26 mg, 47%) as a white solid.

[0460] Example 73, Method BC

[0461] Preparation of 6-cyclobutoxy-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B14) [ka]

[0462] Step a. 6-Cyclobutoxy-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 70 was followed to give the desired product (28 mg, 52%) as a white solid.

[0463] Example 74, Method BC

[0464] Preparation of 6-(cyclopentyloxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B15) [ka]

[0465] Step a. 6-(Cyclopentyloxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 70 was carried out to give the desired product (16 mg, 27%) as a white solid.

[0466] Example 75, Method BC

[0467] Preparation of 2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-(oxetan-3-yloxy)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B16) [ka]

[0468] Step a. 2,2-Dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-(oxetan-3-yloxy)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 70 was carried out to give the desired product (20 mg, 35%) as a white solid.

[0469] Example 76, Method BC

[0470] Preparation of (S)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-((tetrahydrofuran-3-yl)oxy)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B17) [ka]

[0471] Step a. (S)-2,2-Dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-((tetrahydrofuran-3-yl)oxy)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in example 70 was carried out to give the desired product (12 mg, 20%) as a white solid.

[0472] Example 77, Method BC

[0473] Preparation of 6-(2-hydroxyethoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B18) [ka]

[0474] Step a. 6-(2-hydroxyethoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 70 was carried out to give the desired product (8 mg, 14%) as a white solid.

[0475] Example 78, Method BC

[0476] Preparation of 6-(2-methoxyethoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B19) [ka]

[0477] Step a. 6-(2-Methoxyethoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in example 70 was carried out to give the desired product (23 mg, 40%) as a white solid.

[0478] Example 79, Method BF

[0479] Preparation of 6-(difluoromethoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B20) [ka]

[0480] Step a. 6-Hydroxy-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: To a solution of 6-fluoro-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide (350 mg, 0.95 mmol) in a mixture of 45 mL of 1,4-dioxane and 45 mL of water, KCO (1.3 g, 9.4 mmol) was added, and the mixture was stirred at 72 °C for 4 hours. After completion of the reaction, the mixture was concentrated in vacuo, and the residue was purified on a silica gel column (DCM / MeOH = 50 / 1) to give the desired product (170 mg, 49%) as a yellow solid.

[0481] Step b. 6-(Difluoromethoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: To a solution of 6-hydroxy-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide (60 mg, 0.16 mmol) in NMP (9 mL) was added sodium 2-chloro-2,2-difluoroacetate (63 mg, 0.41 mmol) and KCO (57 mg, 0.41 mmol). After stirring at 70 °C for 15 h, the mixture was quenched with water (15 mL) and extracted with EA (20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated, and the residue was purified on a silica gel column (DCM / MeOH=50 / 1) to give the desired product (10 mg, 15%) as a white solid.

[0482] Example 80, Method BC

[0483] Preparation of 2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-((1-methylpyrrolidin-3-yl)oxy)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B21) [ka]

[0484] Step a. 2,2-Dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-((1-methylpyrrolidin-3-yl)oxy)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 70 was carried out to give the desired product (17 mg, 29%) as a white solid.

[0485] Example 81, Methods BC, BG

[0486] Preparation of 2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-(pyrrolidin-3-yloxy)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B22) [ka]

[0487] Step a. tert-Butyl 3-((2,2-dimethyl-5-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)-2,3-dihydrofuro[2,3-b]pyridin-6-yl)oxy)pyrrolidine-1-carboxylate: The procedure described in example 70 was followed to give the desired product (140 mg, 97%) as a white solid.

[0488] Step b. 2,2-Dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-(pyrrolidin-3-yloxy)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: To a solution of tert-butyl 3-((2,2-dimethyl-5-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)-2,3-dihydrofuro[2,3-b]pyridin-6-yl)oxy)pyrrolidine-1-carboxylate (140 mg, 0.27 mmol) in EA (2 mL) was added 3N hydrochloric acid / EA (0.4 mL) and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, the pH was adjusted to 8 with saturated aqueous NaHCO (5 mL), and extracted with EA (6 mL × 3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated, and the residue was purified on a silica gel column (DCM / MeOH=20 / 1) to give the desired product (37 mg, 32%) as a white solid.

[0489] Example 82, Method BC

[0490] Preparation of 2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B23) [ka]

[0491] Step a. 2,2-Dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 70 was carried out to give the desired product (24 mg, 39%) as a white solid.

[0492] Example 83, Method BC

[0493] Preparation of 6-(cyclopropylmethoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B24) [ka]

[0494] Step a. 6-(cyclopropylmethoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 70 was carried out to give the desired product (30 mg, 52%) as a white solid.

[0495] Example 84, Methods BC, BG

[0496] Preparation of 2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-(2-(methylamino)ethoxy)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B25) [ka]

[0497] Step a. tert-Butyl (2-((2,2-dimethyl-5-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)-2,3-dihydrofuro[2,3-b]pyridin-6-yl)oxy)ethyl)(methyl)carbamate: The procedure described in example 70 was followed to give the desired product (35 mg, 49%) as a white solid. 1H NMR(300 MHz, DMSO-d6)δ 10.21(s, 1H), 8.26(s, 1H), 8.21(s, 1H), 8.02-7.93(m, 2H), 7.77(t, J=8.4 Hz, 1H), 7.38(d, J=8.4 Hz, 1H), 4.67 (t, J=4.8 Hz, 2H), 3.89 (s, 3H), 3.68 (t, J=4.8 Hz, 2H), 3.06 (s, 2H), 1.99 (s, 3H), 1.48 (s, 6H), 1.17 (s, 9H).LC-MS (m / z):522.9 [M+H] + .

[0498] Step b. 2,2-Dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-(2-(methylamino)ethoxy)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 81 was carried out to give the desired product (2 mg, 7%) as a white solid.

[0499] Example 85, Method BC

[0500] Preparation of 6-(1-cyclopropylethoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B26) [ka]

[0501] Step a. 6-(1-cyclopropylethoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in example 70 was carried out to give the desired product (7 mg, 12%) as a white solid.

[0502] Example 86, Methods BC, BH

[0503] Preparation of 6-(cis-3-hydroxycyclobutoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B27) [ka]

[0504] Step a. 6-(cis-3-(benzyloxy)cyclobutoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 70 was followed to give the crude product (180 mg) as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.29-8.16 (m, 2H), 8.06-7.93 (m, 2H), 7.80 (t, J=8.1 Hz, 1H), 7.46-7.21 (m, 6H), 5.07-4.99 (m, 1H), 4.47 (s, 2H), 3.93-3.87 (m, 1H), 3.82 (s, 3H), 3.05 (s, 2H), 3.01-2.90 (m, 2H), 2.34-2.19 (m, 2H), 1.47 (s, 6H).LC-MS (m / z):525.8 [M+H] + .

[0505] Step b. 6-(cis-3-Hydroxycyclobutoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: A suspension of 6-(cis-3-(benzyloxy)cyclobutoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide (180 mg, 0.34 mmol) and 5% Pd / C (30 mg) in MeOH (50 mL) was stirred overnight at room temperature under an H atmosphere. The suspension was filtered and concentrated to give the desired product (30 mg, 25%) as a white solid.

[0506] Example 87, Methods BC, BG

[0507] Preparation of 2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-((2-oxo-1,3-oxazinan-5-yl)oxy)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B28) [ka]

[0508] Step a. 2,2-Dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-((2-oxo-1,3-oxazinan-5-yl)oxy)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 81 was followed to obtain the by-product (20 mg, 16%) as a white solid.

[0509] Example 88, Method BC

[0510] Preparation of 6-cyclopropoxy-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B29) [ka]

[0511] Step a. 6-Cyclopropoxy-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 70 was followed to give the desired product (27 mg, 39%) as a white solid.

[0512] Example 89, Methods BC, BH

[0513] Preparation of 6-(azetidin-3-yloxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B30) [ka]

[0514] Step a. Benzyl 3-((2,2-dimethyl-5-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)-2,3-dihydrofuro[2,3-b]pyridin-6-yl)oxy)azetidine-1-carboxylate: The procedure described in Example 70 was followed to give the desired product (560 mg, 31%) as a colorless oil. 1 H NMR (300 MHz, CDCl3) δ 7.37-7.31 (m, 5H), 5.08 (s, 2H), 4.66-4.55 (m, 1H), 4.27-4.18 (m, 2H), 3.94-3.83 (m, 2H), 2.78 (d, J=4.5 Hz, 1H).

[0515] Step b. 6-(Azetidin-3-yloxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 86 was followed to give the desired product (75 mg, 71%) as a white solid.

[0516] Example 90, Method BI

[0517] Preparation of 2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-((1-methylazetidin-3-yl)oxy)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B31) [ka]

[0518] Step a. 2,2-Dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-((1-methylazetidin-3-yl)oxy)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: To a solution of 6-(azetidin-3-yloxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide (55 mg, 0.13 mmol) and POM (8.0 mg, 0.26 mmol) in DCE (10 mL) was added NaBH(OAc) (41 mg, 0.20 mmol) at 0 °C. The reaction was stirred at room temperature overnight and quenched with saturated aqueous NH4Cl (30 mL). The mixture was extracted with dichloromethane (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified on a silica gel column (DCM / MeOH = 20 / 1) to give the desired product (8 mg, 14%) as a yellow solid.

[0519] Example 91, Method BC

[0520] Preparation of 6-(2-(dimethylamino)ethoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B32) [ka]

[0521] Step a. Benzyl 6-(2-(dimethylamino)ethoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in example 70 was followed to give the desired product (16 mg, 27%) as a white solid.

[0522] Example 92, Method BC

[0523] Preparation of (R)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-((tetrahydrofuran-3-yl)oxy)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B33) [ka]

[0524] Step a. Benzyl (R)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-6-((tetrahydrofuran-3-yl)oxy)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 70 was followed to give the desired product (29 mg, 49%) as a white solid.

[0525] Example 93, Methods BC, BJ

[0526] Preparation of 6-(3-hydroxy-3-methylcyclobutoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B35) [ka]

[0527] Step a. 3-(Benzyloxy)-1-methylcyclobutan-1-ol: To a solution of 3-(benzyloxy)-1-methylcyclobutan-1-ol (500 mg, 2.8 mmol) in dry THF (10 mL) was added 3N methylmagnesium chloride (2.8 mL, 8.5 mmol) at -78 °C under a N atmosphere. After stirring at room temperature for 2 h, the mixture was quenched by the addition of MeOH (5 mL) and concentrated in vacuo. The residue was purified on a silica gel column (DCM / MeOH = 20 / 1) to give the desired product (400 mg, 73%) as a yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 7.31 (s, 5H), 5.00 (s, 1H), 4.33 (s, 2H), 3.69-3.61 (m, 1H), 2.30-2.20 (m, 2H), 1.98-1.88 (m, 2H), 1.14 (s, 3H).LC-MS (m / z):214.9 [M+Na] + .

[0528] Step b. 1-Methylcyclobutane-1,3-diol: A suspension of 3-(benzyloxy)-1-methylcyclobutan-1-ol (400 mg, 2.1 mmol) and 5% Pd / C (40 mg) in MeOH (20 mL) was stirred overnight at room temperature under an H atmosphere. The suspension was filtered and concentrated to give the desired product (110 mg, 52%) as a colorless oil. 1 H NMR (300 MHz, DMSO-d6) δ 4.89 (d, J=5.4 Hz, 1H), 4.83 (s, 1H), 3.74-3.64 (m, 1H), 2.23-2.13 (m, 2H), 1.90-1.79 (m, 2H), 1.12 (s, 3H).

[0529] Step c. 6-(3-Hydroxy-3-methylcyclobutoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 70 was followed to give the desired product (84 mg, 46%) as a white solid.

[0530] Example 94, Methods BC, BH, BK

[0531] Preparation of 6-(trans-3-hydroxycyclobutoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: (B36) [ka]

[0532] Step a. trans-3-(benzyloxy)cyclobutyl 4-nitrobenzoate: To a solution of cis-3-(benzyloxy)cyclobutan-1-ol (100 mg, 0.56 mmol), 4-nitrobenzoic acid (187 mg, 1.1 mmol), and PPh3 (440 mg, 1.7 mmol) in dry THF (10 mL) was slowly added diisopropyl azodicarboxylate (DIAD) (339 mg, 1.7 mmol) at 0 °C. After stirring overnight at room temperature, the solvent was concentrated in vacuo, and the residue was purified on a silica gel column (PE / EA = 10 / 1) to give the desired product (168 mg, 91%) as a yellow solid. 1 H NMR (300 MHz, CDCl3) δ 8.29 (d, J=8.8 Hz, 2H), 8.20 (d, J=8.3 Hz, 2H), 7.43-7.29 (m, 5H), 5.57-5.35 (m, 1H), 4.46 (s, 2H), 4.40-4.29 (m, 1H), 2.68-2.56 (m, 2H), 2.54-2.44 (m, 2H).

[0533] Step b. trans-3-(benzyloxy)cyclobutan-1-ol: To a solution of trans-3-(benzyloxy)cyclobutyl 4-nitrobenzoate (168 mg, 0.51 mmol) in 1,4-dioxane (5 mL) was added 0.4 N aqueous NaOH (40 mg, 1.0 mmol). After stirring at room temperature for 1 h, the mixture was acidified with AcOH (0.3 mL) and concentrated in vacuo. The residue was diluted with EA (20 mL) and washed with saturated aqueous NaHCO (15 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated to give the desired product (80 mg, 89%) as a yellow oil. 1 H NMR (300 MHz, CDCl3) δ 7.40-7.28 (m, 5H), 4.64-4.50 (m, 1H), 4.41 (s, 2H), 4.35-4.23 (m, 1H), 2.50-2.30 (m, 2H), 2.24-2.11 (m, 2H), 1.75 (s, 1H).

[0534] Step c. 6-(trans-3-(benzyloxy)cyclobutoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: The procedure described in Example 70 was followed to give the desired product (100 mg, 44%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 10.55 (s, 1H), 8.35 (s, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.97 (s, 1H), 7.82 (s, 1H), 7.70 (t, J=8.1 Hz, 1H), 7.38-7.31 (m, 5H), 7.21 (d, J=7.5 Hz, 1H), 5.70-5.57 (m, 1H), 4.61-4.52 (m, 1H), 4.47 (s, 2H), 3.93 (s, 3H), 3.05 (s, 2H), 2.82-2.61 (m, 4H), 1.59 (s, 6H).

[0535] Step d. 6-(trans-3-Hydroxycyclobutoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide: To a suspension of 6-(trans-3-(benzyloxy)cyclobutoxy)-2,2-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carboxamide (100 mg, 0.19 mmol), 5% Pd / C (20 mg), and Pd(OH) (20 mg) in EtOH (20 mL) was added concentrated hydrochloric acid dropwise, and the mixture was stirred at room temperature under an atmosphere of H overnight. The suspension was filtered and concentrated to give the desired product (40 mg, 48%) as a colorless oil.

[0536] Table 1 details some of the compounds that were prepared according to the methods described above, as shown in the third column of the table.

[0537] Table 1. Selected compounds of the present disclosure (A1-A59 and B1-B36). [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21] [Table 1-22] [Table 1-23] [Table 1-24] [Table 1-25] [Table 1-26] [Table 1-27]

[0538] Example 95. Screening of compounds against IRAK4 with ATP.

[0539] Prepare 1x kinase base buffer and stop buffer for kinase testing: (1) base buffer: 50 mM HEPES (pH 7.5), 0.0015% Brij-35; (2) stop buffer: 100 mM HEPES (pH 7.5), 0.015% Brij-35, 0.2% coating reagent #3, 50 mM EDTA. Next, prepare the compounds for testing: Dilute the compounds in 100% DMSO to 50x the final desired highest inhibitor concentration in the reaction. Transfer 100 μL of this compound dilution to wells of a 96-well plate (source plate). Serially dilute the compounds 3-fold for a total of 10 dilutions. Transfer 10 μL of compound from the source plate to a new 96-well plate (intermediate plate) and add 90 μL of 1x kinase buffer. Shake the mixture on the intermediate plate for 10 minutes. Transfer 5 μL from each well of the 96-well intermediate plate to a 384-well plate in duplicate. Add 10 μL of 2.5x enzyme solution to each well of a 384-well assay plate and incubate at room temperature for 10 minutes. Add 10 μL of 2.5x FAM-labeled peptide and ATP solution and incubate at 28°C for a set period. Finally, add 30 μL of stop buffer to terminate the reaction. Collect data using a caliper and measure IC. 50 get

[0540] Table 2. IC of selected compounds against IRAK4 kinase. 50 Results [Table 2]

[0541] CA4948 (emabsertib): [ka]

[0542] The results of enzyme activity experiments demonstrated that the compounds of the present disclosure exhibit unexpected inhibitory effects against IRAK4 kinase. As shown, the activity of compounds A24, A26, B1, and B36 is more than 25-fold greater than that of the positive control compound CA4948 (see ACS Med. Chem. Lett. 2020, 11, 2374-2381). The activity of compounds A4, A25, A35, A51-A52, A55-A59, B4-B7, B12-B17, B23-B24, B26-B27, B29, B33, and B35 is more than 10-fold greater than that of the control compound CA4948. The activity of compounds A11, A36, A54, and B18-B19 is more than 5-fold greater than that of CA4948. Figure 1 shows the experimental results of IRAK4 kinase inhibition by compound A4. FIG. 2 shows the experimental results of IRAK4 kinase inhibition by compound B5.

[0543] Example 96. Kinase binding ability

[0544] The equilibrium dissociation constant is the kinase binding constant (K d The interaction of test compounds with specific kinases was measured using KINOMEscan, a site-specific competitive binding assay. Kinase-tagged T7 phage strains were derived from the BL21 strain of E. coli host. E. coli was infected with T7 phage and incubated until lysis occurred. The remaining kinases were produced in HEK-293 cells and tagged with DNA. To create affinity resins for kinases, streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands. The assay consisted of three components: a DNA-tagged kinase, an immobilized ligand, and a test compound. The immobilized ligand could compete with the compound for binding to the kinase active site. The affinity beads were washed with wash buffer and resuspended in elution buffer after reaction in a 384-well polypropylene plate. Kinase-DNA tag qPCR was used to evaluate the ability of test compounds to bind to selected kinases. The assay was performed according to the manufacturer's instructions (Eurofins DiscoverX Corporation).

[0545] Coupling constant (K d ) was calculated using a standard dose-response curve using the Hill equation:

number

[0546] Table 3. K between IRAK4 and selected compounds d [Table 3]

[0547] The binding assay results showed that compounds A1, A4, and B5 all have high binding affinity to IRAK4. d is less than 1 nM. Figure 3 shows the experimental results of the kinase binding assay of compound A4, and Figure 4 shows the experimental results of the kinase binding assay of compound B5.

[0548] Example 97. Evaluation of metabolic stability in microsomes.

[0549] An appropriate concentration of microsome working solution (0.56 mg / mL) was prepared in potassium phosphate buffer. Test compounds were incubated with liver microsomes from humans, SD rats, CD-1 mice, and beagle dogs at 37°C for 10 minutes with constant shaking. The reaction was initiated by the addition of nicotinamide adenine dinucleotide phosphate (NADPH) coenzyme after a 10-minute preincubation. Samples were taken at 5, 15, 30, 45, and 60 minutes and placed in stop solution (cold acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards). All sampling plates were shaken for 10 minutes and then centrifuged at 4000 rpm for 20 minutes at 4°C. Each supernatant from the bioanalysis plate was sealed and shaken for 10 minutes before LC-MS analysis.

[0550] Table 4. Metabolic stability of selected compounds using liver microsomes from four species. [Table 4]

[0551] The results of the metabolic stability experiments showed that (1) compounds A1 and A4 have good metabolic stability in human, rat, mouse, and dog liver microsomes, (2) compound A24 has good metabolic stability in human and mouse liver microsomes and moderate metabolic stability in rat and dog liver microsomes, and (3) compound B5 has good metabolic stability in human, rat, and dog liver microsomes and moderate metabolic stability in mouse liver microsomes.

[0552] Example 98. Pharmacokinetic study in ICR mice.

[0553] Working solution: 10% DMSO + 10% Solutol + 80% (20% Hp-β-CD)

[0554] Single-dose pharmacokinetic parameters of medicilone were measured in two groups of male ICR mice (3 mice per group). The groups were administered iv (2 mg / kg) or po (10 mg / kg), and blood was collected from the submandibular or saphenous vein at the following time points post-dose: 0.083 (iv only), 0.25, 0.5, 1, 2, 4, 6 (po only), 8, and 24 hours. A 50 μL aliquot of plasma was protein precipitated with 250 μL of internal standard solution (200 ng / mL tolbutamide in MeOH), vortex-mixed for 1 minute, and centrifuged at 14,000 rpm for 5 minutes. The test compound concentrations in the plasma samples were measured using LC-MS / MS, and peak areas were compared with a calibration curve determined using 5-5000 ng / mL of test compound in ICR mouse plasma. The results are shown in Table 5. The area under the curve (AUC) is the definite integral of the plasma concentration of a drug as a function of time from time zero to 24 hours. max represents the peak plasma concentration of the drug, and T max is C maxrepresents the time it takes to reach T 1 / 2 is the elimination half-life or C max represents the time it takes for the capacitance to drop to half, Cl represents the clearance, and V d represents the apparent volume of distribution, F represents the bioavailability, po represents oral administration, and iv represents intravenous injection.

[0555] Table 5. PK profiles of selected compounds in ICR mice [Table 5]

[0556] In vivo pharmacokinetic studies showed that compounds A4 and B5 were well metabolized in mice after intravenous administration, with low clearance rates and good half-lives. After oral administration, these compounds demonstrated extremely high oral exposure and bioavailability. These results indicate that compounds A4 and B5 were well absorbed orally in mice.

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, solvate, or isotopically labeled derivative thereof, wherein Ring A is selected from the group consisting of: 【Chemistry 2】 wherein each n is independently 0, 1, 2, or 3; X １ is O; X ２ is N; If present, R １ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－２ Alkylene-C ３－６ Cycloalkyl, —NH(C １－６ alkyl), -N(C １－６ alkyl) ２ , —NH(C ３－６ cycloalkyl), -N(C ３－６ cycloalkyl) ２ , O.C. １－６ Alkyl, 3-8 membered heterocyclyl, 6-10 membered bridged biheterocyclyl, 5-12 membered spirobiheterocyclyl, 6-12 membered fused biheterocyclyl, C ６－１０ aryl, or 5-10 membered heteroaryl, wherein C １－６ Alkyl, C ３－６ Each of the cycloalkyl, aryl, heteroaryl, heterocyclyl, bridged biheterocyclyl, spirobiheterocyclyl, and fused biheterocyclyl independently has one, two, or three R ａ When present, each of heterocyclyl, bridged biheterocyclyl, spirobiheterocyclyl, fused biheterocyclyl and heteroaryl is substituted with O, S, NH, N, P(=O), S(=O) and S(=O) ２ containing one or more heteroatoms independently selected from the group consisting of: R ２ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－２ Alkylene-C ３－６ Cycloalkyl, —NH(C １－６ alkyl), -N(C １－６ alkyl) ２ , —NH(C ３－６ cycloalkyl), -N(C ３－６ cycloalkyl) ２ , hydroxy, -OC １－６ Alkyl, —OC ３－６ Cycloalkyl, O-heterocyclyl wherein the heterocyclyl is a 3- to 8-membered heterocyclyl, 3- to 8-membered heterocyclyl, 6- to 10-membered bridged biheterocyclyl, 5- to 12-membered spirobiheterocyclyl, 6- to 12-membered fused biheterocyclyl, C ６－１０ aryl, or 5-10 membered heteroaryl, wherein C １－６ Alkyl, C ３－６ Each of the cycloalkyl, aryl, heteroaryl, heterocyclyl, bridged biheterocyclyl, spirobiheterocyclyl, and fused biheterocyclyl independently has one, two, or three R ｂ When present, each of heterocyclyl, bridged biheterocyclyl, spirobiheterocyclyl, fused biheterocyclyl and heteroaryl is substituted with O, S, NH, N, P(=O), S(=O) and S(=O) ２ and wherein, when present, each of heterocyclyl, bridged biheterocyclyl, spirobiheterocyclyl, fused biheterocyclyl, and heteroaryl is selected from the group consisting of O, S, NH, N, P(═O), S(═O), and S(═O). ２ containing one or more heteroatoms independently selected from the group consisting of: If present, each R ５ and R ６ are independently hydrogen, deuterium, C １－６ Alkyl, C ３－６ cycloalkyl, or C １－２ Alkylene-C ３－６ cycloalkyl, where each C １－６ Alkyl and C ３－６ Cycloalkyl is independently one, two, or three R ｃ or R ５ and R ６ together with the carbon atoms to which they are attached form a saturated 5- or 6-membered spiro heterocycle containing one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, wherein the saturated 5- or 6-membered spiro heterocycle contains one, two, or three R ｃ is replaced by; Ring Z １ is selected from the group consisting of: (1) a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur; (2) phenyl; (3) a 5-6 membered unsaturated or saturated heterocyclyl containing one or two heteroatoms independently selected from the group consisting of oxygen and nitrogen; and (4) Unsaturated or saturated C ３－６ cycloalkyl; Ring Z ２ does not exist or does not have ring Z ２ is selected from the group consisting of: (1) a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur; (2) phenyl; (3) a 5-6 membered unsaturated or saturated heterocyclyl containing one or two heteroatoms independently selected from the group consisting of oxygen and nitrogen; and (4) Unsaturated or saturated C ３－６ cycloalkyl; Here, ring Z ２ If there is no ｄ Ring Z ２ and R ｄ Ring Z １ Concatenate with; If present, each R ａ are independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, methylamino, dimethylamino, cyano, methyl, deuterated methyl, methoxy, deuterated methoxy, ethyl, cyclopropyl, tert-butoxycarbonyl, carbamoyl, C １－２ Alkylene-hydroxy, C １－２ Alkylene-methoxy, or C １－２ alkylene-deuterated methoxy; If present, each R ｂ are independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, methylamino, dimethylamino, cyano, C １－３ Alkyl, deuterated methyl, methoxy, deuterated methoxy, cyclopropyl, C １－２ Alkylene-hydroxy, C １－２ Alkylene-methoxy, or C １－２ alkylene-deuterated methoxy; or two R on non-adjacent carbons ｂ forms a ring together with the atoms attached thereto; or two R ｂ combines with the carbon attached to it to form a carbonyl; If present, each R ｃ are independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, methylamino, dimethylamino, cyano, methyl, deuterated methyl, methoxy, or deuterated methoxy; If present, each R ｄ are independently hydrogen, deuterium, methyl, deuterated methyl, ethyl, cyclopropyl, C １－２ Alkylene-hydroxy, C １－２ Alkylene-methoxy, C １－２ alkylene-deuterated methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, or difluoromethoxy; and If present, each R ３ and R ４ is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, methylamino, dimethylamino, nitro, cyano, methyl, deuterated methyl, methoxy, deuterated methoxy, ethyl, cyclopropyl, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, or dimethylphosphinyl.

2. 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or isotopically labeled derivative thereof, wherein the compound is of formula (IA): 【Transformation 3】 Here, n, X １ , Z １ , Z ２ , R １ , R ２ , R ３ , and R ４ is defined according to claim 1.

3. 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or isotopically labeled derivative thereof, wherein the compound is of formula (IB): 【Chemistry 4】 Here, n and Z １ , Z ２ , R ２ , R ３ , R ４ , R ５ , and R ６ is defined according to claim 1.

4. 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or isotopically labeled derivative thereof, wherein the compound is of formula (IC): 【Transformation 5】 Here, n, R １ , R ２ , R ３ , R ｄ , and Z １ is defined according to claim 1.

5. 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or isotopically labeled derivative thereof, wherein the compound is of formula (ID): 【Transformation 6】 Here, n, R ２ , R ３ , R ５ , R ６ , R ｄ , and Z １ is defined according to claim 1.

6. 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or isotopically labeled derivative thereof, wherein ring Z １ is selected from the group consisting of: (1) a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur; and (2) Phenyl.

7. 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or isotopically labeled derivative thereof, wherein: (1) Ring Z ２ If exists, 【Transformation 7】 is selected from the group consisting of: 【Transformation 8】 (2) Z ２ does not exist, 【Chemistry 9】 is selected from the group consisting of: 【Chemistry 10】 。

8. 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or isotopically labeled derivative thereof, wherein R １ is selected from the group consisting of: 【Chemistry 11】 。

9. 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or isotopically labeled derivative thereof, wherein: (1) Ring Z ２ If exists, 【Chemistry 12】 is selected from the group consisting of: 【Chemistry 13】 (2) Ring Z ２ If there is no ｄ Ring Z ２ and R ｄ Ring Z １ Connect with R ｄ is according to claim 1.

10. 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or isotopically labeled derivative thereof, wherein: R ２ is -NH(C １－６ alkyl), -N(C １－６ alkyl) ２ , —NH(C ３－６ cycloalkyl), -N(C ３－６ cycloalkyl) ２ , hydroxy, -OC １－６ Alkyl, —OC ３－６ cycloalkyl, O-heterocyclyl wherein the heterocyclyl is a 3- to 8-membered heterocyclyl, a 3- to 8-membered heterocyclyl, a 6- to 10-membered bridged biheterocyclyl, a 5- to 12-membered spirobiheterocyclyl, a 6- to 12-membered fused biheterocyclyl, wherein C １－６ Alkyl, C ３－６ Each of the cycloalkyl, heterocyclyl, spirobiheterocyclyl, and fused biheterocyclyl independently has one, two, or three R ｂ and R ｂ is according to claim 1.

11. 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or isotopically labeled derivative thereof, wherein R ２ is selected from the group consisting of: 【Chemistry 14】 。

12. Compound of formula (II): 【Chemistry 15】 or a pharmaceutically acceptable salt, solvate, or isotopically labeled derivative thereof, wherein 【Chemistry 16】 is selected from the group consisting of: 【Chemistry 17】 R １ is selected from the group consisting of: [Chemistry 18] R ２ is selected from the group consisting of: 【Chemistry 19】 R ５ , R ６ are each independently C １－６ It is alkyl.

13. A compound or a pharmaceutically acceptable salt, solvate, or isotopically labeled derivative thereof, wherein the compound is selected from the group consisting of: 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 。

14. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt, solvate, or isotopically labeled derivative thereof, and a pharmaceutically acceptable carrier.

15. (i) a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, or isotopically labeled derivative thereof; and (ii) one or more additional therapeutic agents, wherein the one or more additional therapeutic agents are anti-neurodegenerative agents, anti-inflammatory agents, and / or anti-cancer agents; A composition comprising:

16. 14. A composition comprising a compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, or isotopically labeled derivative thereof, for use in a method of treating a disease or disorder in a subject, the method comprising administering a therapeutically effective amount of the composition to the subject, wherein the disease or disorder is associated with interleukin-1 receptor-associated kinase 4 (IRAK4).

17. The disease or disorder may be uveitis, dermatitis, acute lung injury, type II diabetes, arthritis, ulcerative colitis, Crohn's disease, early-onset inflammatory bowel disease, extraintestinal inflammatory bowel disease, ischemia / reperfusion injury in organ transplantation, non-alcoholic fatty liver disease, autoimmune hepatitis, asthma, endometriosis, psoriasis, systemic lupus erythematosus, sarcoidosis, Wegener's granulomatosis, pulmonary fibrosis, renal fibrosis, hepatic fibrosis, or urinary tract infection. fibrosis, myocardial infarction, hypersensitivity pneumonitis, interstitial lung disease, ankylosing spondylitis, sclerosis, systemic sclerosis, polymyositis, rheumatoid arthritis, myasthenia gravis, juvenile-onset diabetes, glomerulonephritis, autoimmune thyroiditis, transplant rejection, Blau syndrome, scleroderma, stomatitis, retinitis pigmentosa, proliferative vitreoretinopathy, Best's macular degeneration, eczema, urticaria, vasculitis, eosinophilic fasciitis, wet and dry age-related yellowing 17. The composition of claim 16, wherein the tumor is selected from the group consisting of macular degeneration, diabetic retinopathy, retinopathy of prematurity, diabetic macular inflammation, retinal vein occlusion, cystoid macular edema, glaucoma, Parkinson's disease, Alzheimer's disease, Huntington's disease, breast cancer, lung cancer, bladder cancer, pancreatic cancer, liver cancer, squamous cell carcinoma of the head and neck, thyroid carcinoma, sarcoma, osteosarcoma, desmoid, melanoma, prostate cancer, colorectal cancer, ovarian cancer, cervical cancer, esophageal cancer, gastric cancer, myeloma, lymphoma, mantle cell lymphoma, cutaneous T-cell lymphoma, chronic and non-progressive anemia, idiopathic or essential thrombocythemia, leukemia, acute leukemia, chronic leukemia, lymphocytic leukemia, myelogenous leukemia, myelodysplastic syndrome, myeloproliferative disorder, brain tumor, astrocytoma, medulloblastoma, Schwann cell tumor, primary neuroectodermal tumor, and pituitary tumor.

18. 17. The composition of claim 16, wherein the disease or disorder is lymphoma, endometriosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, or rheumatoid arthritis.

19. 19. The composition of claim 18, wherein the lymphoma is primary central nervous system lymphoma or diffuse large B-cell lymphoma with MYD88 L265P mutation.

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