Compounds active against bromodomains

Abstract

Compounds of formula (I) that modulate bromodomains, pharmaceutical compositions containing said compounds, and uses of said compounds in therapy are disclosed. TIFF2025514712000144.tif26170

Description

[Technical field]

[0001] The present application relates to compounds active against bromodomains, pharmaceutical compositions containing the compounds, and methods of treating diseases or disorders with the compounds. [Background technology]

[0002] Bromodomains are protein domains of biological and pharmaceutical interest, for example as components of transcription factor complexes and determinants of epigenetic memory. The human genome encodes 61 bromodomains that are present in 46 human proteins and can be classified into eight different bromodomain families based on primary sequence conservation (Nat Rev Drug Discov. 2014 May; 13(5): 337-56). One such family, the BET family, or bromodomain and extra-terminal domain family, includes BRD2, BRD3, BRD4 and BRDT, all of which are found in humans. Bromodomains can recognize acetylated lysine residues in histones and other proteins. The BET family has a common domain structure characterized by two amino-terminal bromodomains that show a high level of sequence conservation and a more divergent carboxy-terminal recruitment domain (Filippakopoulos, P. et al., Nature 2010, 468, 1067-1073). The two bromodomains of BET proteins are typically referred to as BD1 and BD2, where BD1 refers to the most N-terminal bromodomain of the two bromodomains. BRD2 and BRD3 have been reported to associate with histones along with actively transcribed genes and may be involved in promoting transcriptional elongation (Leroy et al, Mol. Cell. 2008, 30, 51-60). It has also been reported that BRD4 or BRD3 can fuse with NUT (nuclear protein in testis) to form a new fusion oncogene in highly malignant intraepithelial neoplasia called NUT midline carcinoma. It has been suggested that the BRD-NUT fusion protein contributes to carcinogenesis (Oncogene 2008, 27, 2237-2242). BRDT is uniquely expressed in the testis and ovary.

[0003] All BET family members have been reported to have some involvement in the cell cycle. In addition, some viruses utilize these proteins to anchor their genomes to host cell chromatin as part of the process of viral replication (You et al. Cell 2004 117, 349-60). BRD4 appears to be involved in the recruitment of the pTEF-P complex to inducible genes, which leads to phosphorylation of RNA polymerase and increased transcriptional output (Hargreaves et al, Cell 2009 138, 129-145). WO 2009 / 084693, WO 2012 / 075383, WO 2011 / 054553, WO 2011 / 054841, WO 2011 / 054844, WO 2011 / 054845, WO 2011 / 054846, WO 201 WO 1 / 054848, WO 2011 / 143669, WO 2011 / 161031, WO 2013 / 027168, WO 2014 / 095774, WO 2014 / 095775 and WO 2016 / 016316 relate to bromodomains and modulators thereof.

[0004] Despite the progress in the field of molecules that modulate the function of bromodomains, there is a need for additional bromodomain inhibitors with improved tolerability and reduced side effects. A particularly concerning side effect of some known bromodomain modulators is phosphodiesterase 3 (PDE3) inhibitory activity. The PDE3 family in mammals consists of two members, PDE3A and PDE3B. PDE3A is primarily involved in cardiovascular function, and it is well known that chronic treatment with PDE3 inhibitors increases mortality in patients with heart failure. The most common and severe side effect of PDE3 inhibitors is ventricular arrhythmias, which can be life-threatening. PDE3 inhibitors are generally not recommended for long-term use in patients with heart failure due to their strong cardiac stimulant effects. There is a clear need for bromodomain inhibitors that are well tolerated and do not have the cardiovascular side effects of inhibition of phosphodiesterase 3. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2009 / 084693 Brochure [Patent Document 2] International Publication No. 2012 / 075383 Brochure [Patent Document 3] International Publication No. 2011 / 054553 Brochure [Patent Document 4] International Publication No. 2011 / 054841 Brochure [Patent Document 5] International Publication No. 2011 / 054844 Brochure [Patent Document 6] International Publication No. 2011 / 054845 Brochure [Patent Document 7] International Publication No. 2011 / 054846 Brochure [Patent Document 8] International Publication No. 2011 / 054848 Brochure [Patent Document 9] International Publication No. 2011 / 143669 Brochure [Patent Document 10] International Publication No. 2011 / 161031 Brochure [Patent Document 11] International Publication No. 2013 / 027168 Brochure [Patent Document 12] International Publication No. 2014 / 095774 Brochure [Patent Document 13] International Publication No. 2014 / 095775 Brochure [Patent Document 14] International Publication No. 2016 / 016316 Brochure [Non-patent literature]

[0006] [Non-Patent Document 1] Nat Rev Drug Discov.2014 May;13(5):337-56 [Non-Patent Document 2] Filippakopoulos P. et al.,Nature 2010,468,1067-1073 [Non-Patent Document 3] Leroy et al,Mol.Cell.2008,30,51-60 [Non-Patent Document 4] Oncogene 2008,27,2237-2242 [Non-Patent Document 5] You et al.Cell 2004 117,349-60 [Non-Patent Document 6] Hargreaves et al,Cell 2009 138,129-145 Summary of the Invention [Means for solving the problem]

[0007] Embodiments disclosed herein include a compound of formula (I) [ka] or pharma- ceutically acceptable salts, polymorphs, stereoisomers, and tautomers thereof, wherein X is selected from the group consisting of -C(R4R5)-, -S-, -O-, and N(R6)-; Y is -N- or C(R7)-, wherein R7 is hydrogen, and 1~4 alkyl; A is selected from the group consisting of an unsubstituted or substituted 5- or 6-membered alicyclic ring system; an unsubstituted or substituted 5- to 10-membered heteroalicyclic ring system; and NR8R9; R1 is hydrogen, hydroxy, halogen, unsubstituted or substituted C 1~4 Alkyl, unsubstituted or substituted C 1~4 Alkoxy, and unsubstituted or substituted -OR 10 (wherein R 10 is C 3~6 Cycloalkyl, 4-6 membered heteroalicyclyl, and C 1~4 hydroxyalkyl; R2 is selected from the group consisting of hydrogen, hydroxy, halogen, unsubstituted or substituted C 1~4 Alkyl, and unsubstituted or substituted C 1~4 alkoxy; provided that R1 and R2 cannot simultaneously be selected from hydrogen; or R1, R2 and the carbon atoms to which they are attached together form a ring; R3 may be absent or may be present in one or two occurrences, and if present, is selected from the group consisting of C 1~4 alkyl; R and R are independently hydrogen, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted C 1~6 Alkenyl, unsubstituted or substituted C 1~6 Alkynyl, unsubstituted or substituted C 1~6 R is selected from the group consisting of hydrogen, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted C 3~6 Cycloalkyl, and unsubstituted or substituted C 2~6 heteroalicyclyl; R and R are independently selected from the group consisting of hydrogen, unsubstituted or substituted C 1~4 Alkyl, and unsubstituted or substituted C 3~4 cycloalkyl, provided that at least one of R and R is unsubstituted or substituted C 1~4Alkyl, and unsubstituted or substituted C 3~4 cycloalkyl.

[0008] In another aspect, the compounds of Formula (I), (II) and (III), and their pharma- ceutically acceptable salts, polymorphs, stereoisomers and tautomers, are active bromodomain inhibitors and do not inhibit the activity of phosphodiesterase enzyme 3 (PDE3).

[0009] In another aspect, the compounds of Formula (I), (II) and (III), as well as pharma- ceutically acceptable salts, polymorphs, stereoisomers and tautomers thereof, and at least one pharma- ceutically acceptable excipient, are comprised in a pharmaceutical composition.

[0010] In another aspect, the compounds of Formula (I), (II) and (III) disclosed herein, as well as pharmaceutically acceptable salts, polymorphs, stereoisomers and tautomers thereof, are used to treat diseases or conditions associated with systemic or tissue inflammation, inflammatory responses to infection or products of infectious organisms, or hypoxia, autoimmune and allergic processes, cell activation and proliferation, cancer, metabolism, fibrosis, and in the prevention and treatment of viral infections.

[0011] In another aspect, disclosed herein are compounds of Formula (I), (II) and (III), and pharma- ceutically acceptable salts, polymorphs, stereoisomers and tautomers thereof, in compositions for use in the treatment of diseases or conditions associated with systemic or tissue inflammation, inflammatory responses to infection or products of infectious organisms, or hypoxia, autoimmune and allergic processes, cell activation and proliferation, cancer, metabolism, fibrosis, and in the prophylaxis and treatment of viral infections.

[0012] In one aspect, the disease or condition is selected from the group consisting of rheumatoid arthritis, osteoarthritis, gout, psoriasis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, inflammatory bowel syndrome, Crohn's disease, ulcerative colitis, colitis, asthma, chronic obstructive airway disease, pneumonia, myocarditis, pericarditis, myositis, eczema, dermatitis, atopic dermatitis, allergy, ankylosing spondylitis, lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune eye disease, Sjogren's disease, optic neuritis, neuromyelitis optica, myasthenia gravis, Guillain-Barre syndrome, grey's disease, and the like. vascular disease, alopecia, vitiligo, bullous skin disease, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, hypophysitis, thyroiditis, Addison's disease, diabetes mellitus type I, acute rejection of transplanted organs, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ dysfunction such as glomerulonephritis, vasculitis including giant cell arteritis, polyarteritis nodosa, Behçet's disease, Wegener's granulomatosis, Kawasaki disease, Takayasu's arteritis, etc.; or For the treatment of sepsis, septic syndrome, septic shock, endotoxemia, multisystem inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, post-operative syndrome, sarcoidosis, Herxheimer reaction, encephalitis, myelitis, meningitis, malaria, and SIRS associated with viral infections such as influenza, shingles, herpes simplex, and coronavirus; or Treatment of ischemia-reperfusion injury, myocardial infarction, cerebrovascular ischemia (stroke), acute coronary syndrome, renal reperfusion injury, organ transplantation, coronary artery bypass surgery, cardiac bypass surgery, pulmonary, renal, hepatic, gastrointestinal, or peripheral limb embolism; or Treatment of diseases or conditions such as hypercholesterolemia, arteriosclerosis, and Alzheimer's disease; or Treatment of diseases or conditions such as idiopathic pulmonary fibrosis, pulmonary fibrosis, intestinal fibrosis, hepatic fibrosis, nonalcoholic steatohepatitis, liver cirrhosis, renal fibrosis, postoperative stenosis, bone marrow fibrosis, keloid formation, skin fibrosis, hand fibrosis, systemic sclerosis, scleroderma, and cardiac fibrosis; or Treatment or prevention of viral infections, such as herpes viruses, human papilloma viruses, human immunodeficiency viruses (HIV), adenoviruses, and pox viruses; or Colon cancer, midline carcinoma, sarcoma, mesenchymal, liver, kidney and neurological tumors; acute lymphoblastic leukemia, acute myeloid leukemia, adult T-cell leukemia / lymphoma, bladder cancer, blastoma, osteosarcoma, breast cancer, brain cancer, Burkitt's lymphoma, epithelial carcinoma, myeloid sarcoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colorectal cancer, diffuse large B-cell lymphoma, endometrial cancer, esophageal cancer, follicular lymphoma, gastrointestinal cancer, glioblastoma multiforme, glioma, gallbladder cancer, gastric cancer, head and neck cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, intestinal cancer, kidney cancer, laryngeal cancer, leukemia, lung cancer, lymph for the treatment of pancreatic cancer, liver cancer, small cell lung cancer, non-small cell lung cancer, melanoma, mesothelioma, lymphoma, non-small cell lung cancer, melanoma, mesothelioma, multiple myeloma, eye cancer, optic nerve tumors, oral cancer, ovarian cancer, pituitary tumors, primary central nervous system lymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, rectal cancer, skin cancer, spinal cord tumors, small intestine cancer, gastric cancer, T cell lymphoma, testicular cancer, thyroid cancer, thyroid cancer, pharyngeal cancer, genitourinary cancer, urothelial carcinoma, uterine cancer, vaginal cancer, or Wilms' tumor; or for the treatment of obesity, such as obesity associated with the treatment of cancer, or obesity associated with diabetes and cardiac hypertrophy. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All patents, applications, published applications and other documents referenced herein are incorporated by reference in their entirety. In the event that there are multiple definitions for a term herein, the definition in this section shall prevail unless otherwise stated.

[0014] As used herein, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10Any "R" group, such as, but not limited to, represents a substituent that may be attached to the specified atom. A non-limiting list of R groups includes, but is not limited to, hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and heteroalicyclyl. When two "R" groups are covalently bonded to the same atom or adjacent atoms, they are "taken together" or "combined" as defined herein to form a cycloalkyl, aryl, heteroaryl, or heteroalicyclyl group. For example, but not limited to, NR a R b R in the group a and R b When are referred to as "together" or "combined," it is meant that they are covalently linked to each other at their terminal atoms to form a ring that includes the nitrogen. [ka]

[0015] Whenever a group is described as being "unsubstituted or substituted" or "substituted or unsubstituted", when substituted, the substituents (which may be one or more, such as 1, 2, 3 or 4) are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. 1~4 Whenever not defined as alkyl, the group is unsubstituted.

[0016] When a substituent is considered to be "substituted", the substituent itself is substituted. When a referenced substituent is substituted, it means that one or more hydrogen atoms on the referenced substituent can be substituted with a group individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. The protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and can be found in Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety.

[0017] As used herein, "C m ~C n (C m to C n )," "C m ~C n (C m -C n )" or "C m~n (C m-n)" (where "m" and "n" are integers) refers to the number of carbon atoms in the group in question; that is, a group may contain from "m" to "n" carbon atoms. Thus, for example, a "C1-C4 alkyl" group refers to all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, CH3CH(CH3)CH2-, and (CH3)3C-. When "m" and "n" are not specified for a group, the broadest range described in these definitions is to be assumed.

[0018] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain group that is fully saturated (no double or triple bonds). An alkyl group can have 1 to 20 carbon atoms (wherever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; for example, "1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although this definition also encompasses the occurrence of the term "alkyl" where no numerical range is specified). An alkyl group can also be defined as "C 1~6 The alkyl group may be a medium size alkyl having 1-10 carbon atoms, such as "C1-C4 alkyl," "C 1~4 By way of example only, "C1-C4 alkyl" or "C 1~4"Alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like. When substituted, the substituents are one or more groups individually and independently selected from alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof.

[0019] As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. When two or more double bonds are present, the double bonds may or may not be conjugated. An alkenyl group may have 2 to 20 carbon atoms (wherever it appears herein, a numerical range such as "2 to 20" refers to each integer in the given range; for example, "2 to 20 carbon atoms" means that an alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 20 carbon atoms, but this definition also encompasses the occurrence of the term "alkenyl" where no numerical range is specified). When substituted, the substituents are one or more groups individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof.

[0020] As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in a straight or branched hydrocarbon chain. An alkynyl group may have 2 to 20 carbon atoms (wherever it appears herein, a numerical range such as "2 to 20" refers to each integer in the given range; for example, "2 to 20 carbon atoms" means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 20 carbon atoms, but this definition also encompasses the occurrence of the term "alkynyl" where no numerical range is specified). An alkynyl group may be unsubstituted or substituted. If substituted, the substituents may be selected from the same groups disclosed above for alkenyl group substitution.

[0021] As used herein, "hetero" refers to one or more carbon atoms that may be attached to a group, and associated hydrogen atoms in the attached group are independently replaced with the same or different heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur.

[0022] As used herein, "heteroalkyl," alone or in combination with another term, refers to a linear or branched alkyl group of a specified number of carbon atoms, in which one or more carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms and associated hydrogen atoms, are independently replaced with the same or different heteroatoms selected from nitrogen, oxygen, and sulfur. The replaced carbon atoms may be located in the middle or at the end of the alkyl group. Examples of heteroalkyl include, but are not limited to, -S-alkyl, -O-alkyl, -NH-alkyl, alkyl-O-alkyl, and the like.

[0023] As used herein, "aryl" refers to a carbocyclic (all carbon) ring or two or more fused rings (rings that share two adjacent carbon atoms) having a completely delocalized pi-electron system. Aryl groups can range from 6 to 10 carbon atoms (C 6~10aryl). In some embodiments, the aryl group comprises six carbon atoms (C6 aryl). Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted. When substituted, a hydrogen atom is replaced by one or more groups independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. When substituted, the substituents on an aryl group may form a non-aromatic ring fused to the aryl group, such as a cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.

[0024] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system having a fully delocalized pi-electron system) in which at least one of the atoms in the ring system is a heteroatom, i.e., an element other than carbon, such as, but not limited to, nitrogen, oxygen, and sulfur. Heteroaryl groups can range from 5 to 10 atoms, with one or more atoms, such as 1, 2, 3, or 4 atoms, being independently selected from oxygen, sulfur, and nitrogen. In some embodiments, heteroaryl groups contain 5 to 7 atoms. Examples of "heteroaryl" include, but are not limited to, furan, thiophene, phthalazine, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrazole, and triazine. Heteroaryl may be substituted. When substituted, a hydrogen atom is replaced by a substituent that is one or more groups independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. When substituted, the substituents on the heteroaryl group may form a non-aromatic ring fused to the aryl group, such as cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.

[0025] An "aralkyl" or "arylalkyl" is an aryl group linked via an alkylene group as a substituent. The alkylene and aryl groups of the aralkyl may be substituted. Examples include, but are not limited to, benzyl, substituted benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group. In some cases, the aryl group is a C6 aryl.

[0026] A "heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group linked via an alkylene group as a substituent. The alkylene and heteroaryl groups of a heteroaralkyl may be substituted. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, pyrazolylalkyl, and imidazolylalkyl, as well as substituted and benzo-fused analogs thereof. In some cases, the alkylene group is a lower alkylene group, and in some cases, the alkylene group is -CH2- or -CH2CH2-.

[0027] An "alkylene" is a tethering group that forms a bond linking molecular fragments through their terminal carbon atoms. Alkylene can have 1 to 20 carbon atoms. Alkylene is also referred to as "C 1~6 Alkylene can be a medium size alkylene having 1 to 10 carbon atoms, such as "C1-C4 alkylene," "C1-C2 alkylene," "C1-C3 alkylene," "C1-C4 ... 1~4 A lower alkylene group may be designated as "alkylene" or a similar designation. Non-limiting examples include methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-) and butylene (-(CH)-) groups. In the case of methylene, the two linked fragments are attached to the same carbon atom. Lower alkylene groups may be substituted, for example with lower alkyl.

[0028] As used herein, "heteroalkylene", alone or in combination with another term, refers to an alkylene group of a specified number of carbon atoms, in which one or more carbon atoms, for example 1, 2, 3 or 4 carbon atoms, are independently replaced with the same or different heteroatoms selected from oxygen, sulfur and nitrogen. Examples of heteroalkylene include, but are not limited to, -CH2-O-, -CH2-CH2-O-, -CH2-CH2-CH2-O-, -CH2-NH-, -CH2-CH2-NH-, -CH2-CH2-CH2-NH-CH2-, -O-CH2-CH2-O-CH2-CH2-O-, -O-CH2-CH2-O-CH2-CH2-CH2- and the like.

[0029] As used herein, "alkylidene" refers to a divalent group such as =CR'R'', which is attached to a carbon of another group forming a double bond. Alkylidene groups include, but are not limited to, methylidene (=CH2) and ethylidene (=CHCH3). As used herein, "arylalkylidene" refers to an alkylidene group where R' or R'' is an aryl group. Alkylidene groups may be optionally substituted.

[0030] As used herein, "alkoxy" refers to the group -OR where R is alkyl, e.g., methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), cyclopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, amoxy, tert-amoxy, etc. Alkoxy may be optionally substituted.

[0031] As used herein, "alkylthio" refers to a group of the formula -SR, where R is alkyl as defined above, e.g., methylmercapto, ethylmercapto, n-propylmercapto, 1-methylethylmercapto (isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec-butylmercapto, tert-butylmercapto, etc. Alkylthio may be optionally substituted.

[0032] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, where R is aryl as defined above, e.g., phenoxy, naphthalenyloxy, azulenyloxy, anthracenyloxy, naphthalenylthio, phenylthio, etc. Both aryloxy and arylthio may be optionally substituted.

[0033] As used herein, "alkenyloxy" refers to the formula -OR where R is alkenyl as defined above, e.g., vinyloxy, propenyloxy, n-butenyloxy, iso-butenyloxy, sec-pentenyloxy, tert-pentenyloxy, etc. Alkenyloxy may be optionally substituted.

[0034] As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, or aryl linked through a carbonyl group as a substituent. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. Acyl may be substituted.

[0035] As used herein, "cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon ring system that is fully saturated (no double bonds). When composed of two or more rings, the rings may be joined in a fused, bridged or spiro-connected manner. Cycloalkyl groups include those having C3 to C6. 10 and in other embodiments, from C3 to C6. The cycloalkyl group may be unsubstituted or substituted. Exemplary cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. If substituted, the substituents may be selected from alkyl, or, unless otherwise indicated, those set forth above for substitution of alkyl groups. If substituted, the substituents on the cycloalkyl group may form an aromatic ring fused to the cycloalkyl group, such as aryl and heteroaryl.

[0036] As used herein, "cycloalkenyl" refers to a cycloalkyl group that contains one or more double bonds in the ring, provided that if there are more than one, they cannot form a completely delocalized pi-electron system in the ring (otherwise the group would be "aryl" as defined herein). When composed of more than one ring, the rings can be linked in a fused, bridged or spiro-bonded manner. Cycloalkenyl groups can be unsubstituted or substituted. If substituted, the substituents can be selected from alkyl or, unless otherwise indicated, the groups disclosed above for alkyl group substitution. If substituted, the substituents on the cycloalkenyl group can form an aromatic ring fused to the cycloalkenyl group, such as aryl and heteroaryl.

[0037] As used herein, "cycloalkynyl" refers to a cycloalkyl group containing one or more triple bonds in the ring. When composed of two or more rings, the rings may be joined in a fused, bridged or spiro-bonded manner. Cycloalkynyl groups include those having C3 to C6 10 Cycloalkynyl groups can be unsubstituted or substituted. When substituted, the substituents can be selected from alkyl or, unless otherwise indicated, the groups disclosed above for alkyl group substitution. When substituted, the substituents on the cycloalkynyl group can form an aromatic ring fused to the cycloalkynyl group, such as aryl and heteroaryl.

[0038] As used herein, "heteroalicyclyl" or "heteroalicyclyl" refers to a 3- to 18-membered ring consisting of carbon atoms and 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. A heteroalicyclyl or heteroalicyclyl group is a C2-C 10and in other embodiments, from C2 to C9, and in other embodiments, from C2 to C8. A "heteroalicyclyl" or "heteroalicyclyl" can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can be linked in a fused, bridged, or spiro-bonded fashion; the nitrogen, carbon, and sulfur atoms in a "heteroalicyclyl" or "heteroalicyclyl" can be oxidized; the nitrogen can be quaternized; the rings can also contain one or more double bonds, so long as they do not form a fully delocalized pi-electron system throughout the entire ring. Heteroalicyclyl groups can be unsubstituted or substituted. If substituted, the substituents may be one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, alkylthio, arylthio, cyano, halogen, C-amido, N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. Examples of such "heteroalicyclic" or "heteroalicyclyl" include, but are not limited to, azepinyl, azetidinyl, dioxolanyl, imidazolinyl, imidazolinolyl, morpholinyl, oxetanyl, oxiranyl, piperidinyl N-oxide, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), piperazinyl, pyranyl, 4-piperidinonyl, tetrahydrofuranyl, tetrahydropyranyl, pyrazolidinyl, 2-oxopyrrolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone.When substituted, the substitutions on the cycloalkyl group may form an aromatic ring fused to the cycloalkyl group, such as aryl and heteroaryl.

[0039] "(Cycloalkyl)alkyl" is a cycloalkyl group linked via an alkylene group as a substituent. The alkylene and cycloalkyl of (cycloalkyl)alkyl may be substituted. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. In some cases, the alkylene group may be a lower alkylene group (C 1~4 alkylene).

[0040] A "(cycloalkenyl)alkyl" is a cycloalkenyl group linked as a substituent via an alkylene group. The alkylene and cycloalkenyl of a (cycloalkenyl)alkyl may be optionally substituted. In some cases, the alkylene group is a lower alkylene group.

[0041] A "(cycloalkynyl)alkyl" is a cycloalkynyl group linked as a substituent via an alkylene group. The alkylene and cycloalkynyl of a (cycloalkynyl)alkyl may be optionally substituted. In some cases, the alkylene group is a lower alkylene group.

[0042] As used herein, "halo" or "halogen" refers to F (fluoro), Cl (chloro), Br (bromo) or I (iodo).

[0043] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen. An example of a haloalkyl is a C 11 alkyl group in which one or more of the hydrogen atoms are replaced by halogen, e.g., fluoro. 1~3Alkyl. Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1-chloro-2-fluoromethyl, 2-fluoroisobutyl. Haloalkyl may be optionally substituted.

[0044] As used herein, "haloalkoxy" refers to the RO- group, where R is a haloalkyl group. Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. Haloalkoxy may be optionally substituted.

[0045] An "O-carboxy" group refers to an "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein. O-carboxy is optionally substituted.

[0046] A "C-carboxy" group refers to a "-C(=O)OR" group where R can be the same as defined for O-carboxy. C-carboxy can be optionally substituted.

[0047] A "trihalomethanesulfonyl" group refers to an "X3CSO2-" group, where X is a halogen.

[0048] The dashed lines --- represent optional unsaturation between the atoms forming the bond. The bond may be unsaturated (e.g., C=C, C=N, C=O) or saturated (e.g., CC, CN, CO). The dashed bonds are present in ring systems that may form part of an aromatic ring system.

[0049] A "nitro" group refers to a "-NO2" group.

[0050] A "cyano" group refers to a "-CN" group.

[0051] A "cyanato" group refers to a "-OCN" group.

[0052] An "isocyanato" group refers to a "-NCO" group.

[0053] A "thiocyanato" group refers to a "-SCN" group.

[0054] A "carbonyl" group refers to a "-C(=O)-" group.

[0055] A "thiocarbonyl" group refers to a "-C(=S)-" group.

[0056] An "oxo" group refers to a "=O" group.

[0057] An "isothiocyanato" group refers to a "-NCS" group.

[0058] A "sulfinyl" group refers to a "-S(=O)-R" group, where R can be the same as defined for O-carboxy. Sulfinyl may be optionally substituted.

[0059] A "sulfonyl" group refers to a "SO2R" group, where R can be the same as defined for O-carboxy. Sulfonyl may be optionally substituted.

[0060] An "S-sulfonamide" group is R A and R B are independently the same as defined for the R group defined for O-carboxy, or substituted or unsubstituted C 3~8 Cycloalkyl, substituted or unsubstituted C 3~8 Cycloalkenyl, substituted or unsubstituted C 3~8 Cycloalkyl, substituted or unsubstituted C 3~8 "-SONR" which may be combined to form a ring system selected from the group consisting of cycloalkenyl, substituted or unsubstituted heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. A R B" group. The S-sulfonamide may be optionally substituted.

[0061] An "N-sulfonamide" group is one selected from R and R A may be the same as defined for the R group defined for O-carboxy. A )-". N-Sulfonamides may be optionally substituted.

[0062] A "trihalomethanesulfonamido" group refers to an "X3CSON(R)-" group with X as the halogen and R can be the same as defined for O-carboxy. Trihalomethanesulfonamido may be optionally substituted.

[0063] An "amide" group is a "C-amide" group, i.e., -C(=O)NR A R B ” group (wherein, R A and R B are independently the same as defined for the R group defined for O-carboxy, or substituted or unsubstituted C 3~8 Cycloalkyl, substituted or unsubstituted C 3~8 Cycloalkenyl, substituted or unsubstituted C 3~8 Cycloalkyl, substituted or unsubstituted C 3~8 A "C-amido" group may be optionally substituted; alternatively, an "amido" group may refer to an "N-amido" group, i.e., "RC(=O)NR A - group (wherein R and R A may independently be the same as defined for the R group as defined for O-carboxy). N-amido may be optionally substituted.

[0064] "Ester" refers to the group "-C(=O)OR" where R can be the same as defined for O-carboxy. Esters may be optionally substituted.

[0065] A lower alkoxyalkyl refers to an alkoxy group linked via a lower alkylene group. A lower alkoxyalkyl may be optionally substituted.

[0066] "Amino" refers to "RNH2" (primary amine), "R2NH" (secondary amine), and "RN" (tertiary amine), where each R may be independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl. The amino group may be optionally substituted.

[0067] Aminoalkyl refers to an amino group linked via an alkylene group. Aminoalkyl may be optionally substituted.

[0068] The terms "ring" and "ring system" are used interchangeably throughout this disclosure.

[0069] Unsubstituted or monosubstituted amine groups in the compounds herein can be converted to amides, hydroxyl groups can be converted to esters, and carboxyl groups can be converted to amides or esters using techniques well known to those of skill in the art (see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 314-315, 1999). rd Ed., John Wiley & Sons, New York, NY, 1999).

[0070] As used herein, abbreviations for protecting groups, amino acids and other compounds follow their common usage, accepted abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 11:942-944 (1972)), unless otherwise indicated.

[0071] As used herein, the following terms have the meanings accepted in the chemical literature.

[0072] [Table 1]

[0073] [Table 2]

[0074] [Table 3]

[0075] In any compound having one or more chiral centers disclosed herein, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may be independently of the R or S configuration, or a mixture thereof. The terms "R" and "S" as used herein are configurations defined in the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45:13-30. The present disclosure contemplates various stereoisomers and mixtures thereof, which are specifically included within the scope of the present disclosure. Stereoisomers include enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds of the present disclosure can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers, or by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods include (1) binding the mixture of enantiomers to a chiral auxiliary and separating the resulting mixture of diastereomers by recrystallization or chromatography, and optionally isolating the optically pure product from the auxiliary, as described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2) directly separating the mixture of optical enantiomers in a chiral chromatography column, or (3) partial recrystallization. Furthermore, the compounds provided herein may be scalomic mixtures. In addition, in any compound having one or more double bonds that produce geometric isomers that can be defined as E or Z, it is understood that each double bond may be independently E or Z or a mixture thereof. Similarly, all tautomeric forms are also intended to be included.

[0076] The compounds disclosed herein can exist as cis or trans isomers, and the substituents on the rings can be attached so that they are on the same side of the ring (cis) or on opposite sides of the ring (trans). For example, cyclobutane can exist in a cis or trans configuration and can exist as a single isomer or a mixture of cis and trans isomers. Individual cis or trans isomers of the compounds disclosed herein can be prepared synthetically from commercially available starting materials using selective organic transformations, or in single isomeric form by purifying a mixture of cis and trans isomers. Such methods are well known to those skilled in the art and can include separation of isomers by recrystallization or chromatography.

[0077] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure in which the displacement of hydrogen atoms and electrons is altered; typical examples are the "enol"-"keto" forms. [ka]

[0078] "Enol"-"keto" tautomerism can be illustrated by formula I and its tautomeric forms: [ka]

[0079] Further non-limiting examples of tautomers include imine-enamine tautomers (-CH-CH=NH and -CH=CH-NH), or tautomeric forms of heteroaryl groups that contain ring atoms bonded to both the -NH- and =N- ring moieties, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0080] It is understood that isotopes may exist in the compounds described herein.Each chemical element as represented in the compound structure may include any isotope of said element.For example, in the compounds described herein, hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium).Therefore, in this specification, reference to a compound includes all possible isotopic forms, unless the context clearly indicates otherwise.

[0081] As used herein, "pharmaceutical acceptable salt" refers to a salt of a compound that does not impair the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reacting the compounds disclosed herein with an acid or base. Salts formed with bases include ammonium salts (NH4 + ); alkali metal salts such as, but not limited to, sodium or potassium; alkaline earth salts such as, but not limited to, calcium or magnesium; salts of organic bases such as, but not limited to, dicyclohexylamine, piperidine, piperazine, methylpiperazine, N-methyl-D-glucamine, diethylamine, ethylenediamine, tris(hydroxymethyl)methylamine; and salts with the amino group of amino acids such as, but not limited to, arginine and lysine. Useful acid-based salts include, but are not limited to, acetate, hydrobromide, acetate, adipate, aspartate, ascorbate, benzoate, butyrate, caprate, caproate, caprylate, camsylate, citrate, decanoate, formate, fumarate, gluconate, glutarate, glycolate, hexanoate, laurate, lactate, maleate, nitrate, oleate, oxalate, octanoate, propanoate, palmitate, phosphate, sebacate, succinate, stearate, sulfate, sulfonate such as methanesulfonate, ethanesulfonate, p-toluenesulfonate, salicylate, tartrate, and tosylate salts.

[0082] Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or from 1 to about 100, or from 1 to about 10, or from 1 to about 2, 3 or 4 solvent or water molecules.

[0083] As used herein, a "prodrug" refers to a compound that may not be pharmacologic active, but is converted to an active drug upon in vivo administration. Prodrugs may be designed to alter the metabolic stability or transport properties of a drug, mask side effects or toxicity, improve the flavor of a drug, or change other properties or characteristics of a drug. Prodrugs are often useful because they can be administered more easily than the parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug is not. Prodrugs may also have better solubility than the active parent drug in pharmaceutical compositions. A non-limiting example of a prodrug is a compound disclosed herein, which is administered as an ester ("prodrug") to facilitate absorption through cell membranes where water solubility is detrimental to mobility, but is then metabolically hydrolyzed to a carboxylic acid (the active entity) once inside the cell, where water solubility is advantageous. A further example of a prodrug may be a short peptide (polyamino acid) attached to an acid group, which is metabolized in vivo to release the active parent compound. Knowledge of pharmacodynamic processes and in vivo drug metabolism allows one of skill in the art to design prodrugs of a pharmacologic active compound once that compound is known (see, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).

[0084] As used herein, "modulating" the function of a bromodomain or bromodomain-containing protein means increasing that cellular function above the basal level measured in the particular environment in which it is found, or decreasing that cellular function below the basal level measured in the environment in which it is found, and / or preventing that cellular function from occurring altogether.

[0085] An "agonist" is defined as a compound that increases the basal activity of a receptor (ie, signal transduction mediated by the receptor).

[0086] As used herein, a "partial agonist" refers to a compound that has affinity for a receptor, but, unlike an agonist, binds to the receptor and elicits only a portion of the pharmacological response normally associated with that receptor, even when multiple receptors are occupied by the compound.

[0087] An "inverse agonist" is defined as a compound that reduces or inhibits the basal activity of a receptor such that the compound is not technically an antagonist, but rather an agonist that has negative intrinsic activity.

[0088] As used herein, "antagonist" refers to a compound that binds to a receptor and forms a complex that does not elicit any response as if the receptor were not occupied. Antagonists attenuate the action of agonists on the receptor. Antagonists may bind reversibly or irreversibly, effectively eliminating the activity of the receptor, either permanently or at least until the antagonist is metabolized or dissociated, or removed by physical or biological processes.

[0089] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animals" include cold-blooded and warm-blooded vertebrates and invertebrates, such as birds, fish, crustaceans, reptiles, and especially mammals. "Mammals" include, but are not limited to, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; cows; horses; primates, such as monkeys, chimpanzees, and apes, and especially humans.

[0090] As used herein, a "patient" refers to a subject being treated by a medical professional, such as an MD or DVM, to cure or at least ameliorate the effects of a particular disease or disorder, or to prevent the disease or disorder from occurring in the first place.

[0091] "Receptor" is intended to include any molecule present inside or on the surface of a cell that can affect the physiology of the cell when it is inhibited or stimulated by a ligand. Generally, a receptor contains an extracellular domain with ligand-binding properties, a transmembrane domain that anchors the receptor to the cell membrane, and a cytoplasmic domain that generates a cellular signal in response to ligand binding ("signal transduction"). Receptors also include any intracellular molecule that generates a signal in response to binding. Receptors also include any molecule that has the characteristic structure of a receptor but does not have an identifiable ligand. In addition, receptors include truncated, modified, mutated receptors, or any molecule that contains part or all of the sequence of a receptor. "Ligand" is intended to include any substance that binds to or interacts with a bromodomain or a bromodomain-containing protein.

[0092] "Selective" or "selectivity" is defined as the ability of a compound to preferentially bind to or inhibit a particular protein or a particular domain of a protein over other proteins or other domains. "Selective" or "selectivity" of a bromodomain binding compound or inhibitor can refer to a compound that can preferentially bind to a BET family bromodomain over a non-BET family bromodomain-containing protein. It can also refer to a compound that can preferentially bind to the N-terminal bromodomain of a BET family protein over the C-terminal bromodomain, or a compound that can preferentially bind to the C-terminal bromodomain over the N-terminal domain.

[0093] As used herein, "co-administration" of pharmacologically active compounds refers to the delivery of two or more separate chemical entities, whether in vitro or in vivo. Co-administration refers to the simultaneous delivery of separate agents; the simultaneous delivery of a mixture of agents; and the delivery of one agent followed by a second or additional agent. Co-administered agents are generally intended to work in combination with each other.

[0094] As used herein, the term "effective amount" means the amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal or human that is desired by a researcher, veterinarian, medical doctor or other clinician, including reduction or alleviation of the symptoms of the disease being treated.

[0095] compound Embodiments disclosed herein include compounds of formula (I) [ka] or pharma- ceutically acceptable salts, polymorphs, stereoisomers, and tautomers thereof, wherein X is selected from the group consisting of -C(R4R5)-, -S-, -O-, and N(R6)-; Y is -N- or C(R7)-, wherein R7 is hydrogen, and 1~4 alkyl; A is selected from the group consisting of an unsubstituted or substituted 5- or 6-membered alicyclic ring system; an unsubstituted or substituted 5- to 10-membered heteroalicyclic ring system; and NR8R9; R1 is hydrogen, hydroxy, halogen, unsubstituted or substituted C 1~4 Alkyl, unsubstituted or substituted C 1~4 Alkoxy, and unsubstituted or substituted -OR 10 (wherein R 10 is C 3~6 Cycloalkyl, 4-6 membered heteroalicyclyl, and C 1~4 hydroxyalkyl; R2 is selected from the group consisting of hydrogen, hydroxy, halogen, unsubstituted or substituted C 1~4 Alkyl, and unsubstituted or substituted C 1~4alkoxy; provided that R1 and R2 cannot simultaneously be selected from hydrogen; or R1, R2 and the carbon atoms to which they are attached together form a ring; R3 may be absent or may be present in one or two occurrences, and if present, is selected from the group consisting of C 1~4 alkyl; R and R are independently hydrogen, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted C 1~6 Alkenyl, unsubstituted or substituted C 1~6 Alkynyl, unsubstituted or substituted C 1~6 R is selected from the group consisting of hydrogen, unsubstituted or substituted C 1~6 Alkyl, unsubstituted or substituted C 3~6 Cycloalkyl, and unsubstituted or substituted C 2~6 heteroalicyclyl; R 8、 and R9 are independently hydrogen, unsubstituted or substituted C 1~4 Alkyl, and unsubstituted or substituted C 3~4 cycloalkyl; provided that at least one of R and R is unsubstituted or substituted C 1~4 Alkyl, and unsubstituted or substituted C 3~4 cycloalkyl.

[0096] In some embodiments, the compounds of formula (I) or pharma- ceutically acceptable salts, polymorphs, stereoisomers, and tautomers relate to X being selected from the group consisting of -C(R4R5)-, -O-, and N(R6)-. In other embodiments, X is -C(R4R5)-, where R4 and R5 are hydrogen, hydroxy, C 1~4 Alkyl, C 1~4 In some embodiments, R4 and R5 are both hydrogen, in other embodiments, R4 is hydrogen and R5 is methyl, and in other embodiments, R4 and R5 are both methyl. In other embodiments, X is -O-. In other embodiments, X is -N(R6)-, where R6 is hydrogen, C 1~4 Alkyl, C 1~4haloalkyl, and 4- or 5-membered heteroalicyclyl, for example selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, and tetrahydrofuranyl, for example hydrogen, methyl or ethyl.

[0097] In some embodiments of Formula (I), Y is -N- or -C(R7)-, where R7 is hydrogen or C 1~4 Alkyl, for example hydrogen.

[0098] In some embodiments of Formula (I), Y is -N- and X is -CH2-.

[0099] In some embodiments of Formula (I), Y is -N- and X is -O-.

[0100] In some embodiments of formula (I), Y is -N- and X is -N(R6)-, where R6 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, and tetrahydrofuranyl, e.g., hydrogen, methyl, or ethyl.

[0101] In some embodiments of Formula (I), A is selected from the group consisting of a 5- or 6-membered alicyclic ring system; a 5- to 10-membered heteroalicyclic ring system; and NR8R9, where each ring system is unsubstituted or substituted. In some embodiments, the ring system, e.g., a 5- to 10-membered heteroalicyclic ring system, is unsubstituted, where R8 and R9 are independently hydrogen, unsubstituted or substituted C. 1~4 Alkyl, and unsubstituted or substituted C 3~4 cycloalkyl, provided that at least one of R and R is a substituted C 1~4 Alkyl, or unsubstituted or substituted C 3~4 cycloalkyl.

[0102] In some embodiments of Formula (I), the ring system, e.g., a 5-10 membered heteroalicyclic ring system, may be selected from the group consisting of hydrogen, hydroxy, halogen, unsubstituted or substituted C 1~4 Alkyl, and unsubstituted or substituted C 1~4Substituted with a substituent selected from the group consisting of alkoxy.

[0103] In some embodiments of Formula (I), A is an unsubstituted or substituted 5-10 membered heteroalicyclic ring system selected from the group consisting of a 5-membered heteroalicyclic ring system containing at least one nitrogen atom, a 6-membered heteroalicyclic ring system containing at least one nitrogen or oxygen atom, a 7-membered heteroalicyclic ring system containing at least one nitrogen atom, an 8-membered heteroalicyclic ring system containing at least one nitrogen atom, all of which may be unsubstituted or substituted, and the substituents, if present, may be present in the amount of one, two or three and may be independently selected from the group consisting of methyl, ethyl, propyl, and halogen.

[0104] In some embodiments of Formula (I), A is unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative.

[0105] In some embodiments of Formula (I), A is an unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative, Y is -N- or -CH-, and X is -C(R4R5)-, where R4 and R5 are independently hydrogen or C. 1~4 alkyl, such as hydrogen or methyl), or X is -N(R6)-, where R6 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, and tetrahydrofuranyl, such as hydrogen, methyl, or ethyl, or X is -O-.

[0106] In some embodiments of formula (I), A is unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative, Y is -N- and X is -CH-, or X is -N(R)- (wherein R is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, and tetrahydrofuranyl, e.g., hydrogen, methyl, or ethyl), or X is -O-.

[0107] In some embodiments of formula (I), A is unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative, Y is -N-, X is -CH2-, or X is -N(R6)- (wherein R6 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, and tetrahydrofuranyl, e.g., hydrogen, methyl, or ethyl).

[0108] In some embodiments of Formula (I), Y is -N- and X is -C(R4R5)-, where R4 and R5 are independently hydrogen or C 1~4 alkyl, e.g., hydrogen or methyl), or X is -N(R6)-, where R6 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, and tetrahydrofuranyl, e.g., hydrogen, methyl, or ethyl, or X is -O- and A is [ka] wherein R is an unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative selected from the group consisting of 11 , R 13 , R 16 , and R 17 is absent, or is present one or two times, and if present, is independently selected from the group consisting of hydroxy, fluoro, methyl, ethyl, and propyl. 11 , R 13 , R 16 , and R 17 is absent. In other embodiments, A is an unsubstituted morpholine.

[0109] In some embodiments of Formula (I), A is an unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative, Y is -N-, X is -O-, and the unsubstituted or substituted morpholine or unsubstituted or substituted morpholine derivative is [ka] (wherein R 11 , R 13 , R 16 , and R 17 is absent, or is present one or two times, and if present, is independently selected from the group consisting of hydroxy, fluoro, methyl, ethyl, and propyl. 11 , R 13 , R 16 , and R 17 is absent. In other embodiments, A is unsubstituted morpholine.

[0110] In some embodiments of Formula (I), A is an unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative, Y is -N-, X is -O-, and the unsubstituted or substituted morpholine or unsubstituted or substituted morpholine derivative is [ka] (wherein R 11 is absent, or is present one or two times, and if present, is independently selected from the group consisting of hydroxy, fluoro, methyl, ethyl, and propyl. 11 does not exist.

[0111] In some embodiments of Formula (I), A is an unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative, Y is -N-, X is -O-, and the unsubstituted or substituted morpholine or unsubstituted or substituted morpholine derivative is [ka] (wherein R 13 , R 16 , and R 17 is absent, or is present one or two times, and if present, is independently selected from the group consisting of hydroxy, fluoro, methyl, ethyl, and propyl. 13 , R 16, and R 17 does not exist.

[0112] In some embodiments of Formula (I), Y is -N- and X is -C(R4R5)-, where R4 and R5 are independently hydrogen, hydroxyl, C 1~4 Alkyl, C 1~4 or X is -N(R6)-, where R6 is selected from the group consisting of hydrogen, methyl, n-propyl, isopropyl, and tetrahydrofuranyl, for example hydrogen, methyl, or ethyl; or X is -O-, and A is an unsubstituted or substituted 5-10 membered heteroalicyclic ring system other than unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative; non-limiting examples of such groups are: [ka] (where R 12 , R 14 , R 15 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 is independently absent or present in the amount of 1, 2 or 3, and when present, is selected from halogen, hydroxy, C 1~4 Alkyl 、 and C 1~4 In another embodiment, A is selected from the group consisting of: [ka] (wherein R 18 , R 19 , R 20 , R 21 , R 22、 R 23 and R 24is independently absent, or present at one or two occurrences, and when present, is independently selected from the group consisting of hydroxy, fluoro, methyl, ethyl, and propyl). 18 , R 19 , R 20 , R 21 , R 22、 R 23 and R 24 is present and is selected from the group consisting of hydroxy, fluoro, and methyl. 18 , R 19 , R 20 , R 21 , R 22、 R 23 and R 24 is present twice and is selected from the group consisting of fluoro and methyl.

[0113] In another embodiment of formula (I), A is [ka] (wherein R 18 is absent, present one or present two and is selected from the group consisting of fluoro and methyl. 18 There exists one.

[0114] In some embodiments, A is an unsubstituted or substituted 5-10 membered heteroalicyclic ring system other than unsubstituted or substituted morpholine or unsubstituted or substituted morpholine derivatives (including bridged morpholine derivatives), which refers to a heteroalicyclic ring other than (i.e., not) unsubstituted or substituted morpholine or unsubstituted or substituted morpholine derivatives. Unsubstituted or substituted morpholine derivatives are understood to include the morpholine scaffold, examples of which include: [ka] It is.

[0115] In some embodiments, unsubstituted or substituted 5-10 membered heteroalicyclic ring system other than unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative means a heteroalicyclic ring other than the following: [ka]

[0116] In some embodiments of formula (I), Y is -N-, X is -CH-, or X is -N(R)- (wherein R is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, and tetrahydrofuranyl, e.g., hydrogen, methyl, or ethyl), or X is -O-, and A is a 5- or 6-membered alicyclic ring system.

[0117] In some embodiments of formula (I), R3 may be absent (which indicates that the carbon atom adjacent to X is unsubstituted), or R3 may be present 1 or 2 and linked to the same or different carbon atoms; R3 may be C 1~4 In some embodiments, R3 is methyl.

[0118] In some embodiments of formula (I), R3 is methyl, A is unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative, Y is -N- or -C(R7)- (wherein R7 is hydrogen), X is -CH2)-, or X is N(R6)- (wherein R6 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, and tetrahydrofuranyl, e.g., hydrogen, methyl, or ethyl), or X is -O-.

[0119] In some embodiments of formula (I), R3 is absent, A is unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative, Y is -N- or -C(R7)- (wherein R7 is hydrogen), X is -CH2)-, or X is N(R6)- (wherein R6 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, and tetrahydrofuranyl, e.g., hydrogen, methyl, or ethyl), or X is -O-.

[0120] In some embodiments of Formula (I), A is selected from -NR8R9, where R8 and R9 are independently selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, and cyclopropylmethyl. In some embodiments, R8 and R9 are independently methyl or cyclopropylmethyl.

[0121] In some embodiments of formula (I), A is selected from -NR8R9 (wherein R8 and R9 are independently selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, and cyclopropylmethyl, provided that at least one of R8 and R9 is selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, and cyclopropylmethyl), X is -O-, and Y is -N-.

[0122] In some embodiments, the compounds of formula (I), or pharma- ceutically acceptable salts, polymorphs, stereoisomers, and tautomers thereof, include those in which R is hydrogen, hydroxy, halogen, unsubstituted or substituted C 1~4 Alkyl, and unsubstituted or substituted C 1~4 Alkoxy, and unsubstituted or substituted -OR 10 (where R 10 is C 3~6 Cycloalkyl, 4-6 membered heteroalicyclyl, and C 1~4 hydroxyalkyl).

[0123] In some embodiments of formula (I), R2 is hydrogen, hydroxy, halogen, unsubstituted or substituted C1~4 Alkyl, and unsubstituted or substituted C 1~4 alkoxy, with the proviso that R1 and R2 cannot simultaneously be selected from hydrogen.

[0124] In some embodiments, the compounds of formula (I), or pharma- ceutically acceptable salts, polymorphs, stereoisomers, and tautomers, are such that R1, R2, and the carbon atom to which they are attached are taken together to form a ring. Particular examples of rings are heteroalicyclic rings, such as 5- and 6-membered rings containing one or more heteroatoms (e.g., one or more triatoms). Some examples are: [ka] It is.

[0125] In some embodiments of formula (I), R1 is hydrogen, hydroxy, fluoro, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxypropoxy, butoxy, -O-azetidinyl, -O-CH2CH2OH 、 -O-CH2CH2NHCH3.

[0126] In some embodiments of Formula (I), R1 is selected from the group consisting of methyl, methoxy, and ethoxy. In some embodiments, R1 is methoxy.

[0127] In some embodiments of formula (I), R2 is selected from the group consisting of hydrogen, fluoro, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, and butoxy. In some embodiments, R2 is hydrogen.

[0128] In some embodiments of Formula (I), R 1 is methoxy and R 2 is hydrogen.

[0129] In some embodiments, the compound has the following formula (II): or a pharma- ceutically acceptable salt, polymorph, stereoisomer, or tautomer: [ka] (Wherein, R1 is C 1~4 alkoxy, where X, Y, A and R3 are as described above.

[0130] In some embodiments of Formula (II), A is selected from the group consisting of: [ka] (In the formula, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 is independently absent or present in the amount of 1, 2 or 3, and when present, is selected from halogen, hydroxy, C 1~4 Alkyl 、 and C 1~4 alkoxy).

[0131] In some embodiments of Formula (II), A is selected from the group consisting of: [ka] (In the formula, R 11 , R 13 , R 16 , and R 17 is absent, or is present one or two times, and if present, is independently selected from the group consisting of hydroxy, fluoro, methyl, ethyl, and propyl. In some embodiments of Formula (II), R 11 , R 13 , R 16 , and R 17 does not exist.

[0132] In some embodiments of Formula (II), A is selected from the group consisting of: [ka] (In the formula, R 18 , R 19 , R 20 , R 21 , R 22、 R 23 and R 24 is independently absent, or present at one or two occurrences, and when present, is independently selected from the group consisting of hydroxy, fluoro, methyl, ethyl, and propyl). In some embodiments of Formula (II), R 18 , R 19 , R 20 , R 21 , R 22、 R 23 and R 24 is present and is selected from the group consisting of hydroxy, fluoro, and methyl.

[0133] In some embodiments of Formula (II), X is -C(R4R5)-, where R4 and R5 are independently hydrogen or C 1~4 or X is -N(R6)-, where R6 is hydrogen, C 1~4 Alkyl, C 1~4 haloalkyl, and 4- or 5-membered heteroalicyclyl; or X is -O-.

[0134] In some embodiments of Formula (II), R3 is absent or methyl.

[0135] In some embodiments of Formula (II), R 1 is methoxy, R 2 is hydrogen, and R 3 is absent or methyl.

[0136] In some embodiments, the compound has the following formula (III): or a pharma- ceutically acceptable salt, polymorph, stereoisomer, or tautomer: [ka] (Wherein, R1 is C 1~4 R2 is hydrogen; R3 is absent or present and, if present, is selected from methyl; R 11 is absent; Y is -N- or -CH-; and X is -O- or N(R6), where R6 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, and oxetanyl.

[0137] In some embodiments of Formula (III), R1 is methoxy; R3 is absent; Y is -N-; and X is -O-.

[0138] In some embodiments of Formula (III), R1 is methoxy; R3 is absent; Y is -CH-; and X is -O-.

[0139] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt, polymorph, stereoisomer, or tautomer thereof, is N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide; N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide, (5R)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-(4,8-dimethyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-(6-methyl-8-oxo-3,9-dihydro-2H-furo[3,2-h]quinolin-4-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-[8-(2-hydroxyethoxy)-4-methyl-2-oxo-1H-quinolin-6-yl]-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-[8-(azetidin-3-yloxy)-4-methyl-2-oxo-1H-quinolin-6-yl]-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-(7-fluoro-8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-(7-methyl-9-oxo-3,10-dihydro-2H-[1,4]dioxino[2,3-h]quinolin-5-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-(4,7-dimethyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-(8-ethoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-[4-methyl-8-[2-(methylamino)ethoxy]-2-oxo-1H-quinolin-6-yl]-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 2-morpholino-N-(4,7,8-trimethyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-(7-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-6-methyl-2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-6-(oxetan-3-yl)-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxamide, 6-ethyl-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxamide, 6-isopropyl-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxamide, 2-(dimethylamino)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 2-[cyclopropylmethyl(methyl)amino]-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 2-(diethylamino)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 2-[ethyl(isopropyl)amino]-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 2-(3,6-dihydro-2H-pyran-4-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 2-(cyclopentan-1-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 2-(3,3-difluoropyrrolidin-1-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(2R)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 2-(2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-(1-methyl-2-azabicyclo[2.1.1]hexan-2-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 2-(8-azabicyclo[3.2.1]octan-8-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[rac-(3aR,6aR)-2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(2S)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 2-[(3R)-3-fluoropyrrolidin-1-yl]-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 2-[(3S)-3-fluoropyrrolidin-1-yl]-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[rac-(3R,4S)-3,4-difluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[rac-(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, and 2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide.

[0140] In another aspect, the compounds of formula (I) and their pharma- ceutically acceptable salts, polymorphs, stereoisomers, and tautomers are active bromodomain inhibitors and do not inhibit the activity of phosphodiesterase enzyme 3 (PDE3).

[0141] In another aspect, the compounds of formula (I), as well as pharma- ceutically acceptable salts, polymorphs, stereoisomers, and tautomers thereof, and at least one pharma- ceutically acceptable excipient, are comprised in a pharmaceutical composition.

[0142] In another aspect, compounds of formula (I) and pharma- ceutically acceptable salts, polymorphs, stereoisomers, and tautomers thereof for use in the treatment of diseases or conditions associated with systemic or tissue inflammation, inflammatory responses to infection, or hypoxia, cell activation and proliferation, metabolism, fibrosis, and in the prophylaxis and treatment of viral infections.

[0143] In another aspect, the compounds of Formula (I), (II) and (III), and pharma- ceutically acceptable salts, polymorphs, stereoisomers and tautomers thereof, are useful for the treatment of rheumatoid arthritis, osteoarthritis, gout, psoriasis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, inflammatory bowel syndrome, Crohn's disease, ulcerative colitis, colitis, asthma, chronic obstructive airway disease, pneumonia, myocarditis, pericarditis, myositis, eczema, dermatitis, atopic dermatitis, allergies, ankylosing inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis ... spondylitis, lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune eye disease, Sjogren's disease, optic neuritis, neuromyelitis optica, myasthenia gravis, Guillain-Barre syndrome, Graves' disease, alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, hypophysitis, thyroiditis, Addison's disease, type I diabetes mellitus, acute rejection of a transplanted organ; or For the treatment of diseases or conditions such as acute gout, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ damage such as glomerulonephritis, vasculitis including giant cell arteritis, polyarteritis nodosa, Behcet's disease, Wegener's granulomatosis, Kawasaki disease, Takayasu's arteritis, vasculitis with organ damage, and acute rejection of transplanted organs; or For the treatment of sepsis, septic syndrome, septic shock, endotoxemia, multisystem inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, post-operative syndrome, sarcoidosis, Herxheimer reaction, encephalitis, myelitis, meningitis, malaria, and SIRS associated with viral infections such as influenza, shingles, herpes simplex, and coronavirus; or Treatment of ischemia-reperfusion injury, myocardial infarction, cerebrovascular ischemia (stroke), acute coronary syndrome, renal reperfusion injury, organ transplantation, coronary artery bypass surgery, cardiac bypass surgery, pulmonary, renal, hepatic, gastrointestinal, or peripheral limb embolism; or For the treatment of diseases or conditions such as hypercholesterolemia, arteriosclerosis, and Alzheimer's disease; or For the treatment of diseases or conditions such as idiopathic pulmonary fibrosis, pulmonary fibrosis, intestinal fibrosis, hepatic fibrosis, nonalcoholic steatohepatitis, liver cirrhosis, renal fibrosis, postoperative stenosis, bone marrow fibrosis, keloid formation, skin fibrosis, hand fibrosis, systemic sclerosis, scleroderma, and cardiac fibrosis; or For the treatment or prevention of viral infections, such as herpes viruses, human papilloma viruses, human immunodeficiency viruses (HIV), adenoviruses, and pox viruses; or Colon cancer, midline carcinoma, sarcoma, mesenchymal, liver, kidney and neurological tumors; acute lymphoblastic leukemia, acute myeloid leukemia, adult T-cell leukemia / lymphoma, bladder cancer, blastoma, osteosarcoma, breast cancer, brain cancer, Burkitt's lymphoma, epithelial carcinoma, myeloid sarcoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colorectal cancer, diffuse large B-cell lymphoma, endometrial cancer, esophageal cancer, follicular lymphoma, gastrointestinal cancer, glioblastoma multiforme, glioma, gallbladder cancer, gastric cancer, head and neck cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, for the treatment of intestinal cancer, renal cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, liver cancer, small cell lung cancer, non-small cell lung cancer, melanoma, mesothelioma, lymphoma, non-small cell lung cancer, melanoma, mesothelioma, multiple myeloma, eye cancer, optic nerve tumors, oral cancer, ovarian cancer, pituitary tumors, primary central nervous system lymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, rectal cancer, skin cancer, spinal cord tumors, small intestine cancer, gastric cancer, T-cell lymphoma, testicular cancer, thyroid cancer, thyroid cancer, pharyngeal cancer, genitourinary cancer, urothelial carcinoma, uterine cancer, vaginal cancer, or Wilms' tumor; or Treatment of obesity, such as obesity associated with the treatment of cancer, or obesity associated with diabetes and cardiac hypertrophy The composition is included for use in

[0144] Further examples of diseases, disorders or conditions include obesity, such as obesity associated with the treatment of cancer, or obesity associated with diabetes and cardiac hypertrophy.

[0145] Method of administration The compound or pharmaceutical composition may be administered to a patient by any suitable means. Non-limiting examples of methods of administration include, among others, those deemed appropriate by the skilled artisan to contact the compounds disclosed herein with living tissues: (a) via oral route, including administration in capsules, tablets, granules, sprays, syrups, or other such forms; (b) via parenteral route, such as rectal, vaginal, intraurethral, ​​intraocular, intranasal, or intraauricular, including administration as aqueous suspensions, oily preparations, or as drops, sprays, suppositories, liniments, ointments, and the like; (c) via subcutaneous, intraperitoneal, intravenous, intramuscular, intradermal, intraorbital, intraarticular, intraspinal, intrasternal injection, and the like (including infusion pump delivery); (d) local administration, such as direct injection in the kidney or cardiac region, e.g., depot placement, intratumoral injection, or intralymph node injection; and (e) local administration.

[0146] Pharmaceutical compositions suitable for administration include compositions in which the active ingredient is contained in an amount effective to achieve its intended purpose. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal (including humans) being treated, and the physical characteristics of the particular animal under consideration. Dosages can be adjusted to achieve the desired effect, but will depend on factors such as body weight, diet, concurrent medications, and other factors recognized by those skilled in the medical arts. More specifically, a therapeutically effective amount refers to an amount of compound effective to treat, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0147] As is readily apparent to those skilled in the art, the useful in vivo dosage and the specific mode of administration to be administered will vary depending on the age, weight and mammalian species being treated, the specific compound being utilized, and the specific application for which these compounds are utilized. The determination of effective dosage levels, i.e., the dosage levels required to achieve the desired result, can be achieved by those skilled in the art using routine pharmacological methods. Usually, human clinical application of a product begins at a relatively low dosage level, and the dosage level is increased until the desired effect is achieved. Alternatively, acceptable in vitro tests can be used to establish the useful dose and route of administration of the composition identified by the methods herein using established pharmacological methods.

[0148] In non-human animal testing, application of a promising product is initiated at a relatively high dosage level, and the dosage is reduced until the desired effect is not obtained or adverse side effects disappear. The dosage administered to a human or non-human subject can range over a wide range, depending on the desired effect and therapeutic indication. Typically, the dosage can be about 10 micrograms / kg body weight to 1000 mg / kg body weight, preferably about 100 micrograms / kg body weight to 10 mg / kg body weight. Alternatively, the dosage can be based on and calculated by the patient's body surface area, as will be understood by those skilled in the art.

[0149] The exact formulation, route of administration and dosage of the pharmaceutical compositions disclosed herein may be selected by the individual physician in consideration of the patient's condition (see, for example, Fingl et al. 1975, "The Pharmacological Basis of Therapeutics", especially Ch. 1, p. 1, which is incorporated herein by reference in its entirety). Typically, the dosage range of the composition administered to a patient may be about 0.5 to 1000 mg per kg of the patient's body weight. The dosage may be a single dose or a series of two or more doses administered over one or more days, as required by the patient. In cases where human dosages of the compounds have been established for at least some conditions, those same dosages, or dosages that are about 0.1% to about 500%, more preferably about 25% to about 250%, of the established human dosages, may be used. In cases where human dosages have not been established, such as in the case of newly discovered pharmaceutical compounds, a dosage that is less than or equal to 100 mg / kg of the ED, as qualified by toxicity and efficacy tests in animals, may be used. 50 Value or ID 50 Suitable dosages for humans can be extrapolated from these values, or other appropriate values ​​obtained from in vitro or in vivo tests.

[0150] It should be noted that the attending physician would know how and when to discontinue, interrupt or adjust dosing due to toxicity or organ damage. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response is not adequate (excluding toxicity). The magnitude of the dose administered in the management of the disorder of interest will vary with the severity of the condition being treated and with the route of administration. The severity of the condition may be assessed, for example, in part, by standard prognostic evaluation methods. Furthermore, the dose and perhaps frequency of administration will also vary with the age, weight, and response of the individual patient. A program equivalent to that described above may be used in veterinary medicine.

[0151] While the exact dosage will be determined on a drug-by-drug basis, in most cases some generalizations can be made regarding dosage. A daily dosage regimen for an adult human patient may be, for example, an oral dose of 0.1 mg to 2000 mg, preferably 1 mg to 500 mg, e.g., 5 to 200 mg, of each active ingredient. Eye drops may range in concentration from 0.005 to 5 percent. In one embodiment, eye drops may range from 0.01 to 1 percent, or in another embodiment, 0.01 to 0.3 percent. In other embodiments, intravenous, subcutaneous, or intramuscular doses of between 0.01 mg to 100 mg, preferably between 0.1 mg to 60 mg, e.g., 1 to 40 mg, of each active ingredient are used. When administering a pharma-ceutically acceptable salt, the dosage may be calculated as the free base. In some embodiments, the composition is administered 1 to 4 times per day. Alternatively, the compositions disclosed herein may be administered by continuous intravenous infusion, preferably at a dose of up to 1000 mg of each active ingredient per day. As will be appreciated by those skilled in the art, in certain circumstances, it may be necessary to administer the compounds disclosed herein in amounts that exceed or far exceed the preferred dosage ranges or frequencies set forth above to effectively and aggressively treat, particularly aggressive diseases or infections. In some embodiments, the compounds are administered for a period of continuous therapy, for example, for a week or more, or for months or years.

[0152] Dosage and interval can be adjusted individually to provide plasma or tissue levels of the active moiety sufficient to maintain the modulating effect, or minimum effective concentration (MEC). MEC will vary for each compound, but can be estimated from in vitro data. The dosage required to achieve MEC will depend on individual characteristics and route of administration. However, HPLC assay or bioassay can be used to determine plasma concentration.

[0153] Dosage intervals can also be determined using the MEC value. Compositions should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.

[0154] In cases of local administration or selective uptake, the effective local concentration of a drug may not be related to plasma concentration.

[0155] The amount of composition administered will be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.

[0156] The compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicity of a particular compound, or a subset of compounds, sharing certain chemical moieties can be established by determining the toxicity in vitro on cell lines, such as mammalian, preferably human cell lines. The results of such tests are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of a particular compound in an animal model, such as a mouse, rat, rabbit, or monkey, can be determined using known methods. The efficacy of a particular compound can be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in vitro models exist for almost every class of pathology, including but not limited to cancer, cardiovascular disease, and various immune dysfunctions. Similarly, acceptable animal models can be used to establish the efficacy of chemicals to treat such pathologies. When selecting a model to determine efficacy, one skilled in the art can be guided by the state of the art to select the appropriate model, dose, and route of administration, and regime. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans.

[0157] The composition may be provided in a pack or dispenser device, if necessary, which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the approval by the agency of the drug form for human or veterinary administration. Such notice may, for example, be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. Compositions containing the compounds disclosed herein formulated with a compatible pharmaceutical carrier may also be prepared, placed in a suitable container, and labeled for the treatment of a designated condition.

[0158] Overview As described above with respect to certain illustrative embodiments, it is not intended to be limited to the specific forms described herein. Any combination of the above embodiments should be understood to be within the scope of the present disclosure. Rather, the present disclosure is limited only by the scope of the appended claims, and other embodiments other than the above specific embodiments are equally possible within the scope of these appended claims.

[0159] In the claims, the term "comprises / comprising" does not exclude the presence of other species or steps. Furthermore, although individual features may be included in different claims, these may in some cases be advantageously combined, and the inclusion in different claims does not imply that a combination of features is not feasible and / or advantageous. In addition, references in the singular do not exclude a plural. The terms "a", "an", "first", "second", etc. do not exclude a plural.

[0160] The phrases "at least one" and "one or more" refer to one or a number greater than one, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. EXAMPLES

[0161] experiment The following examples are merely illustrative and should not be construed as limiting the scope of the present disclosure in any way. Rather, the present disclosure is limited only by the scope of the appended claims.

[0162] The compounds described below are prepared using commercially available starting materials unless otherwise specified. The following is a non-exhaustive list of starting materials used in the synthesis of the compounds prepared herein.

[0163] As can be seen from the table below, the compounds were found to have beneficial activity. All reagents were of commercial grade and were used as is without further purification unless otherwise indicated. Commercially available anhydrous solvents were used for reactions carried out under an inert atmosphere. Reagent grade solvents were used in all other cases unless otherwise specified.

[0164] IUPAC name supplier Acetaldehyde Sigma-Aldrich Diazomethyl(trimethyl)silane Sigma-Aldrich Morpholine Sigma-Aldrich Formaldehyde Sigma-Aldrich N-Ethylethanamine Sigma-Aldrich 2-(Benzotriazol-1-yl)acetic acid Enamine-BB 1-Cyclopropyl-N-methyl-methanamine Enamine-BB N-Methylmethanamine Sigma-Aldrich N-Ethylpropan-2-amine Enamine-BB 8-Azabicyclo[3.2.1]octane Fluorochem Acetone Sigma-Aldrich 3-Oxa-8-azabicyclo[3.2.1]octane Combi-Blocks 6-Amino-4,7-dimethyl-1H-quinolin-2-one Enamine-BB 3,3-Difluoropyrrolidine Enamine-BB Oxetan-3-one Combi-Blocks 3,3a,4,5,6,6a-Hexahydro-1H-furo[3,4-c]pyrrole Combi-Blocks 7-Azabicyclo[2.2.1]heptane Combi-Blocks 6,6-Difluoro-3-azabicyclo[3.1.0]hexane Enamine-BB (2R)-2-Methylpyrrolidine Sigma-Aldrich 2-(3,6-Dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Sigma-Aldrich 2-Bromoethanol Sigma-Aldrich 4-Amino-6-methyl-3,9-dihydro-2H-furo[3,2-h]quinolin-8-one Sundia 3-Bromoazetidine-1-carboxylate tert-Butyl Combi-Blocks 3-Bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine Astatech 2-Chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid Chembridge 5-Bromo-2-(bromomethyl)pyrimidine Fluorochem 2-(Cyclopentan-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Fluorochem 2-(2-Aminophenyl)ethanol Fluorochem 3,3a,4,5,6,6a-Hexahydro-2H-furo[2,3-c]pyrrole Fluorochem 1-Methyl-2-azabicyclo[2.1.1]hexane Enamine-BB rac-(3aR,6aR)-3,3a,4,5,6,6a-Hexahydro-2H-furo[2,3-c]pyrrole Enamine-BB (1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptane Enamine-BB (1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptane Combi-Blocks (2S)-2-Methylpyrrolidine Combi-Blocks N-(2-Chloroethyl)-N-methyl-tert-butyl carbamate Combi-Blocks (3S)-3-Fluoropyrrolidine Combi-Blocks (3R)-3-Fluoropyrrolidine Combi-Blocks (3R,4S)-3,4-Difluoropyrrolidine Advanced ChemBlocks (3R,4R)-3,4-Difluoropyrrolidine Advanced ChemBlocks

[0165] Detailed descriptions of the preparation of individual compounds of formula (I) are provided below.

[0166] Compound names were generated using Accelrys Draw 4.2.

[0167] The compounds were characterized by LC-MS analysis and / or 1H-nuclear magnetic resonance (NMR) and were consistent with the proposed structures in all cases.

[0168] Unless otherwise indicated, compounds are analyzed and purified using the following systems.

[0169] analysis: A Waters Acquity system equipped with an Acquity BEH C18 (1.7 μm, 2.1 × 50 mm) using a linear gradient of a binary solvent system (water / acetonitrile / formic acid (A: 100 / 0 / 0.1% and B: 0 / 100 / 0.1%)) at a flow rate of 0.5 mL / min and a DAD at ambient temperature, coupled with MS detection SQD I.

[0170] Preparative separation: Preparative HPLC was performed on a Waters Acquity system using a C18 reversed-phase column (Supelco DISCOVERY C18, 25 cm × 21.2 mm) with a linear gradient of a binary solvent system (water / acetonitrile / formic acid (A: 100 / 0 / 0.1% and B: 0 / 100 / 0.1%)) at a flow rate of 45 mL / min with UV detection at 254 nm coupled with MS detection on a Waters Micromass ZQ quadrupole MS.

[0171] Chemical shifts associated with NMR are reported in parts per million (ppm) and are referenced to non-deuterated solvent residues. Conventional abbreviations were used to designate major peaks, e.g., s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad line. Common solvent abbreviations are chloroform-d or CDCl3, deuterated chloroform; DMSO-d6, hexadeuterated dimethylsulfoxide; CD3COOD, deuterated acetic acid; and CD3OD, deuterated methanol.

[0172] General synthesis Compounds of general formula (I) and compounds described herein, including specific examples, may be prepared, for example, by the reaction routes depicted in Schemes 1 to 7. By way of example, the variables R1, R2, R3, R4, X, A, etc. used in the following schemes have the meanings described in the claims, summary, and detailed description unless otherwise indicated.

[0173] The abbreviations used in this disclosure have the following meanings:

[0174] [Table 4]

[0175] [Table 5]

[0176] [Table 6]

[0177] Synthesis of the final compound: Scheme 1 [ka] Compounds of formula (I) can be prepared using the general synthetic route depicted in Scheme 1 and the specific example disclosed as Example 2 for the preparation of 2-(3,6-dihydro-2H-pyran-4-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide.

[0178] A compound of formula (1), where halo is (CI, Br, or I), and a compound of formula A-R102, where R102 is a boronic acid or a derivative thereof (e.g., a pinacol ester), are treated under Suzuki coupling conditions (N. Miyama and A. Suzuki, Chem. Rev. 1995, 95:2457-2483, J. Organomet. Chem. 1999, 576:147-148). For example, the coupling reaction can be carried out in the presence of a palladium catalyst and a base, optionally in the presence of a ligand, and in a suitable solvent at elevated temperature (about 60° C. to about 150° C.). The reaction can be accelerated by microwave irradiation. Examples of palladium catalysts include, but are not limited to, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(triphenylphosphine)palladium(II) dichloride, and palladium(II) acetate. Examples of suitable bases that may be used include, but are not limited to, sodium, potassium, and cesium carbonates or phosphates, and cesium fluoride. Examples of suitable ligands include, but are not limited to, 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamant, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), and 1,1'bis(diphenylphosphanyl)ferrocene. Examples of suitable solvents include, but are not limited to, methanol, ethanol, dimethoxyethane, N,N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran, toluene, and water, or mixtures thereof.

[0179] Compounds of formula (2) can also be prepared by replacing the halogen atom (F, Cl, or Br) of formula (1) with an appropriate amine as defined under the general structure of A. Replacement of the halogen atom can be accomplished in a solvent such as, but not limited to, dimethylsulfoxide, dimethylformamide, dioxane, or tetrahydrofuran, in the presence of a base such as, but not limited to, cesium, potassium, or sodium carbonate, or sodium hydride, at a temperature of about 20° C. to about 160° C. The reaction can be facilitated by microwave irradiation.

[0180] Hydrolysis of ester (2) provides an acid of formula (3), which can be reacted with 1,1'-carbonyldiimidazole (CDI), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl), 1,3-dicyclohexylcarbodiimide (DCC), polymeric amines, etc., in a solvent such as, but not limited to, tetrahydrofuran, N,N-dimethylformamide, or dichloromethane at a temperature from about room temperature to about 70° C., optionally in the presence of a base such as, but not limited to, triethylamine, N,N-diisopropylethylamine, or potassium carbonate, and optionally in the presence of a catalyst such as 4-dimethylaminopyridine. with an amine of formula (4) in the presence of a coupling reagent such as supported 1,3-dicyclohexylcarbodiimide (PS-DCC), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), or O-benzotriazol-1-yl N,N,N',N'-tetramethyluronium hexafluoroborate (TBTU) in the presence or absence of a coupling auxiliary such as, but not limited to, l-hydroxy-7-azabenzotriazole (HOAT), or 1-hydroxybenzotriazole hydrate (HOBT) to provide a compound of formula (I).

[0181] A specific example is N-(4,8-dimethyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 7).

[0182] Scheme 2 [ka] Alternatively, compounds of general formula (I) can be prepared as described in Scheme 2. Acid (3a) can be reacted with amine (4) to give compound (5), which can then be treated with compound A-R102 of formula 5) (wherein halo is F, Cl, or Br) using reaction conditions as described in Scheme 1.

[0183] Scheme 3 [ka] Compounds of general formula (I), where X is -N(R6), can be prepared from compounds of formula (6) by reductive amination using an appropriate aldehyde or ketone (7) in the presence of a reducing agent, such as, but not limited to, sodium cyanoborohydride, sodium borohydride, or sodium triacetoxyborohydride, in a solvent, such as, but not limited to, tetrahydrofuran, 1,2-dichloroethane, as depicted in Scheme 3. Acetic acid can be used as a catalyst.

[0184] A specific example is N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-6-methyl-2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxamide (Example 32).

[0185] Scheme 4 [ka] Compounds of general formula (I), where R1 is -OR10, can be prepared from compounds of formula (8) by alkylating the -OH group using compounds of formula (9), where halo is Br or Cl, in a solvent such as, but not limited to, N,N-dimethylformamide or dimethylsulfoxide, in the presence of a base such as, but not limited to, sodium hydride, cesium carbonate, or potassium carbonate, at a temperature between about room temperature and about 120°C, as depicted in Scheme 4.

[0186] A specific example is N-[8-(2-hydroxyethoxy)-4-methyl-2-oxo-1H-quinolin-6-yl]-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 36).

[0187] Synthesis of intermediates Scheme 5 [ka] Compounds of formula (4) can be prepared using a general synthetic route as shown in Scheme 5. Depending on R1 and R2, compounds of formula (12) can be prepared by treating compounds of formula (11) with, for example, methyl acetoacetate or 2,2,6-trimethyl-1,3-dioxin-4-one at elevated temperatures (e.g., about 60°C to about 140°C) in the presence of a base such as pyridine in a solvent such as, but not limited to, toluene. Compounds of formula (13) can be obtained by treating (12) with, for example, but not limited to, triflic acid, or polyphosphoric acid in the presence or absence of a solvent such as, but not limited to, dichloromethane at about room temperature to about 100°C. Compounds of formula (14) can be prepared by nitration with nitric acid in acetic anhydride at temperatures of about 0°C to 50°C. Reduction of the nitro group of compounds of formula (14) using reagents known to those skilled in the art, such as, but not limited to, platinum on carbon, platinum(IV) oxide, Raney nickel, iron metal or zinc in acidic medium, provides amines of formula (4).

[0188] A specific example is 6-amino-8-ethoxy-4-methyl-1H-quinolin-2-one.

[0189] Scheme 6 [ka] Alternatively, depending on R1 and R2, compounds of formula (4) can be prepared using a general synthetic route as shown in Scheme 6, where the amino group of compound (11) is first protected with a suitable protecting group using a reagent such as, but not limited to, acetic anhydride or Boc anhydride. The protecting group is removed after the nitration step described in Scheme 5 using an acid such as, but not limited to, hydrochloric acid or trifluoroacetic acid in the presence or absence of a solvent such as, but not limited to, dichloromethane.

[0190] Scheme 7 [ka] Compounds of formula (1) in which R3 is present can be prepared as outlined in Scheme 7. Compounds of formula (19) in which R103 is -OH are treated with alkynyl derivative (25) in which R104 is Br in the presence of a base such as, but not limited to, NaH in a solvent such as N,N-dimethylformamide or tetrahydrofuran at a temperature between about -20°C and room temperature to give compounds of formula (20). Treatment of (20) with nitrobenzene at a temperature between about 100°C and about 180°C gives compounds of formula (21). Insertion of a carbonyl group into (21) gives compounds of formula (22). This can be accomplished by adding CO to the reaction, and generally the conversion can be promoted by a palladium catalyst, such as, but not limited to, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), or palladium(II) acetate, an optional ligand, such as, but not limited to, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), and a base, such as, but not limited to, triethylamine, N,N-diisopropylethylamine, or potassium carbonate. Examples of suitable solvents include, but are not limited to, methanol, N,N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran, or mixtures thereof. CO can be added directly to the reaction in the form of CO gas or can be prepared in situ from reagents such as, but not limited to, formic acid and mesyl chloride. Compound (23) can be obtained from (22) by treatment with urea / hydrogen peroxide complex and trifluoroacetic anhydride in a solvent such as, but not limited to, dichloromethane, acetonitrile, or mixtures thereof at temperatures between about 0° C. and about room temperature.

[0191] A specific example is methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate.

[0192] Alternatively, compound (20) can be obtained from compound of formula (19) (wherein R103 is -Br) and compound (25) (wherein R104 is -OH) under the same conditions, and then compound (22) can be obtained from compound (21) by base-mediated carboxylation using CO2 and a strong base such as, but not limited to, n-BuLi in a solvent such as, but not limited to, tetrahydrofuran at a temperature of about -78°C to about -50°C. A specific example is methyl (5R)-2-chloro-5-methyl-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate.

[0193] It can be understood that the synthetic schemes and specific examples described in this disclosure are examples and should not be construed as limiting the scope of the present disclosure.

[0194] Optimum reaction conditions and reaction times for each individual step may vary depending on the particular reactants used and the substituents contained in the reactants used. Unless otherwise specified, solvents, temperatures and other reaction conditions can be readily selected by one skilled in the art. Specific procedures are provided in the experimental section. The reactants can be worked up in conventional manner, for example by removing the solvent from the residue and further purifying according to methods commonly known in the art, including but not limited to crystallization, distillation, extraction, trituration and chromatography. Unless otherwise specified, starting materials and reagents are commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.

[0195] Routine experimentation, including proper manipulation of reaction conditions, reagents and sequences of synthetic routes, protection of any chemical functional groups that may not be compatible with the reaction conditions, and deprotection at appropriate points in the reaction sequence of the method, is within the scope of the present invention. Suitable protecting groups and methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art, and examples can be found in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety. The synthesis of the compounds of the present invention can be achieved by methods similar to those described in the above synthetic schemes and specific examples.

[0196] If the starting materials are not commercially available, they can be prepared by procedures selected from standard organic chemistry techniques, techniques analogous to the synthesis of known structurally similar compounds, or techniques analogous to those described in the Schemes or Synthetic Examples sections above.

[0197] If an optically active form of a compound is required, it may be obtained by carrying out one of the procedures described herein using optically active starting materials (prepared, for example, by asymmetric induction of an appropriate reaction step) or by resolving a stereoisomeric mixture of the compound or intermediate using standard procedures (for example, chromatographic separation, recrystallization or enzymatic resolution).

[0198] Similarly, if a pure geometric isomer of a compound is required, it can be prepared by carrying out one of the procedures described above using a pure geometric isomer as a starting material, or by resolving a mixture of geometric isomers of the compound or intermediates using standard procedures such as chromatographic separation.

[0199] Working Example: Synthesis of intermediates Preparation of 6-amino-8-ethoxy-4-methyl-1H-quinolin-2-one (Intermediate 1) [ka]

[0200] Preparation of N-(2-ethoxyphenyl)-3-oxo-butanamide: [ka] To a stirred solution of 2-ethoxyaniline (5.0 g, 36.49 mmol) in toluene (500 mL) was added methyl acetoacetate (4.23 g, 36.5 mmol) followed by pyridine (15 mL, 3 vol) and the reaction mixture was stirred at 120° C. for 40 hours. After completion, the reaction mixture was warmed to room temperature and the solvent was evaporated. The residue was taken up in diethyl ether, stirred for 15 minutes and the precipitated solid was filtered to give N-(2-ethoxyphenyl)-3-oxo-butanamide as a brown solid (4.0 g, 50%).

[0201] Preparation of 8-ethoxy-4-methyl-1H-quinolin-2-one: [ka] To a stirred solution of N-(2-ethoxyphenyl)-3-oxo-butanamide (3.5 g, 15.83 mmol) in DCM (350 mL) was added triflic acid (3.4 ml, 39.59 mmol) and the reaction mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was poured into ice water, basified with solid NaHCO3, and the solid was filtered. The solid was washed with diethyl ether and dried under vacuum to give 8-ethoxy-4-methyl-1H-quinolin-2-one as a brown solid (2.0 g, 62%).

[0202] Preparation of 8-ethoxy-4-methyl-6-nitro-1H-quinolin-2-one: [ka] Nitric acid (0.57 ml, 13.79 mmol) was added to a solution of 8-ethoxy-4-methyl-1H-quinolin-2-one (1.4 g, 6.9 mmol) in acetic anhydride (42 ml, 30 vol) at 0° C., and the reaction mixture was stirred at the same temperature for 45 minutes. After completion, the reaction mixture was quenched with ice water and the solid was collected by filtration. The solid was washed with water and n-pentane (3×50 mL) to give 8-ethoxy-4-methyl-6-nitro-1H-quinolin-2-one (compound 4) (750 mg, 44%) as a yellow solid.

[0203] Preparation of 6-amino-8-ethoxy-4-methyl-1H-quinolin-2-one (Intermediate 1): [ka] A suspension of 8-ethoxy-4-methyl-6-nitro-1H-quinolin-2-one (750 mg, 3.024 mmol) in methanol (7.5 mL) was degassed with nitrogen for 10 min. After addition of Pd / C (10%) (75 mg), the reaction mixture was stirred in a Parr shaker under hydrogen atmosphere (40 psi) at room temperature for 16 h. After completion, the reaction mixture was filtered through a celite bed. The filtrate was evaporated to give 6-amino-8-ethoxy-4-methyl-1H-quinolin-2-one (500 mg, 75%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):δ 9.99(brs,1H),6.52(d,J=1.6Hz,1H),6.39(d,J=1.6Hz,1H),6.13(brs,1H),4.99(s,2H),4.04(dd,J =14,7.2Hz,2H),2.29(d,J=0.8Hz,3H),1.40(t,J=6.8Hz,3H);LCMS[M+H]+:219.24m / z,HPLC:95.14%.

[0204] Preparation of 6-amino-4,7,8-trimethyl-1H-quinolin-2-one (Intermediate 2): [ka]

[0205] Preparation of N-(2,3-dimethylphenyl)-3-oxobutanamide: [ka] To a stirred solution of 2,3-dimethylaniline (25 g, 206.6 mmol) in toluene (25 mL, 10 vol) was added methyl 3-oxobutanoate (35 g, 309.9 mmol 1.0 eq) and pyridine (75 ml, 3 vol) and stirred at 120° C. for 16 h. After completion, the reaction mixture was warmed to room temperature and the solvent was evaporated in vacuo. The residue was purified by 100-200 mesh column chromatography eluting with 50% EtOAc in petroleum ether to give N-(2,3-dimethylphenyl)-3-oxobutanamide as a brown solid (18 g, 46%).

[0206] Preparation of 4,7,8-trimethyl-1H-quinolin-2-one: [ka] Triflic acid (21.5 ml, 243.0 mmol, 10 eq) was added to a stirred solution of N-(2,3-dimethylphenyl)-3-oxobutanamide (5.0 g, 24.3 mmol, 1.0 equiv) in DCM (50 mL, 10 vol) at 0° C. and stirred at room temperature for 16 h. After completion, the reaction mixture was poured into ice water, basified with solid NaHCO3, and extracted with EtOAc (2×300 mL). The crude product was purified by 100-200 mesh column chromatography eluting with 5% methanol in dichloromethane to give 4,7,8-trimethyl-1H-quinolin-2-one as a brown solid (4.0 g, 87%).

[0207] Preparation of 4,7,8-trimethyl-6-nitro-1H-quinolin-2-one: [ka] Nitric acid (0.14 ml, 3.42 mmol, 2 eq) was added to a solution of 4,7,8-trimethyl-1H-quinolin-2-one (320 mg, 1.71 mmol) in acetic anhydride (9.6 ml, 30 vol) at 0° C. and the reaction mixture was stirred at 0° C. for 45 min. After completion, the reaction mixture was quenched with ice water, basified with aqueous NaHCO3 and extracted with ethyl acetate (2×50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by 100-200 mesh column chromatography eluting with 30% EtOAc in petroleum ether to give 4,7,8-trimethyl-6-nitro-1H-quinolin-2-one (100 mg, 25%) as a yellow solid.

[0208] Preparation of 6-amino-4,7,8-trimethyl-1H-quinolin-2-one (Intermediate 2): [ka] A suspension of 4,7,8-trimethyl-6-nitro-1H-quinolin-2-one (100 mg, 0.43 mmol) in methanol (1 mL, 10 vol) was degassed with nitrogen for 10 min. After addition of Pd / C (10%) (10 mg), the reaction mixture was stirred at room temperature under hydrogen atmosphere (40 psi) for 16 h. After completion, the reaction mixture was filtered through a celite bed and the filtrate was evaporated to give 6-amino-4,7,8-trimethyl-1H-quinolin-2-one (80 mg, 97%) as a brown solid. LCMS [M+H] + 203.17m / z;1H NMR(400MHz,DMSO-d6):δ 10.22(br s,1H),6.83(s,1H),6.26(s,1H),4.74(brs,2H),2.34(s,3H),2.31(s,3H),2.13(s,3H).

[0209] Preparation of 6-amino-7-fluoro-8-methoxy-4-methyl-1H-quinolin-2-one (Intermediate 3): [ka]

[0210] Preparation of N-(3-fluoro-2-methoxy-phenyl)-3-oxo-butanamide: [ka] 3-Fluoro-2-methoxy-aniline (2.8 g, 20 mmol, 1 eq) was dissolved in toluene (5 ml), heated to 70° C., and 2,2,6-trimethyl-1,3-dioxin-4-one (3.3 g, 23 mmol, 1.15 eq) was added. The reaction mixture was heated at 110° C. and stirred for 1.5 h. The reaction mixture was cooled to room temperature. The reaction mixture was dissolved in a minimum of DCM and purified with Biotage Isolera (heptane / EtOAc 95 / 5, then 95 / 5->40 / 60, and again heptane / EtOAc 90 / 10, then 95 / 5->40 / 60). The fractions containing the product were evaporated to give 2.5 g (55%) of N-(3-fluoro-2-methoxy-phenyl)-3-oxo-butanamide as a yellow oil. LCMS [M+H] + 226m / z.

[0211] Preparation of 7-fluoro-8-methoxy-4-methyl-1H-quinolin-2-one: [ka] N-(3-fluoro-2-methoxy-phenyl)-3-oxo-butanamide (2.5 g, 11 mmol, 1 eq.) was dissolved in DCM (20 ml). Trifluoromethanesulfonic acid (8 ml, 90.6 mmol, 8.23 ​​eq.) was added dropwise at room temperature over 15 min, then stirred at room temperature for 2 h, followed by the addition of more trifluoromethanesulfonic acid (2 ml, 22.5 mmol, 2.5 eq.).

[0212] After 3 hours, the reaction mixture was poured into 70 ml of ice water and stirred for 10 minutes, then filtered. The product was washed with water (3×20 ml) and then dried overnight at room temperature under 1 mbar vacuum to give 1.5 g (66%) of 7-fluoro-8-methoxy-4-methyl-1H-quinolin-2-one as a white powder. LCMS [M+H]+ 208 m / z. 1H NMR(300MHz,DMSO-d6)δ 11.17(s,1H),7.46(dd,J=9.0,5.3Hz,1H),7.12(dd,J=11.1,9.0Hz,1H),6.38(d,J=1.3Hz,1H),2.39(d,J=1.2Hz,3H).

[0213] Preparation of 7-fluoro-8-methoxy-4-methyl-6-nitro-1H-quinolin-2-one: [ka] 7-Fluoro-8-methoxy-4-methyl-1H-quinolin-2-one (1.5 g, 7.2 mmol, 1 eq.) was suspended in Ac2O and cooled to 0° C. HNO3 65% aqueous solution (0.6 ml, 8.6 mmol, 1.19 eq.) was added dropwise and stirred at 0° C. for 1.5 h, then poured into 150 ml of ice-cold water and stirred until solidified. The product was filtered, washed with water (3×25 ml), then dried at room temperature under a vacuum of 1 mbar, then triturated with DCM / MeOH / EtOAc (5+0.5+5 ml). The product was filtered, washed with EtOAc (2×10 ml) and dried under 5 mbar vacuum at 45° C. to give 7-fluoro-8-methoxy-4-methyl-6-nitro-1H-quinolin-2-one (860 mg) as an off-white powder (approximately 70% of the desired product plus 20% of the other regioisomer). 1 H NMR(300MHz,DMSO-d6)δ 11.79(s,1H),8.22(d,J=7.4Hz,1H),6.56(s,1H),3.97(d,J=1.4Hz,3H),2.47(d,J=1.2Hz,3H).

[0214] Preparation of 6-amino-7-fluoro-8-methoxy-4-methyl-1H-quinolin-2-one (Intermediate 3): [ka] 7-Fluoro-8-methoxy-4-methyl-6-nitro-1H-quinolin-2-one (860 mg) was dissolved in MeOH (35 ml) and 10% Pd / C (55 mg) was added. The mixture was stirred at room temperature for 2 hours with a H2 balloon. The reaction mixture was diluted with acetone (15 ml) and filtered through Celite. The filtrate was evaporated and the residue was triturated with boiling acetone (30 ml).

[0215] The product was filtered, washed with acetone (5 ml) and dried overnight at room temperature under 1 mbar vacuum to give 440 mg (58%) of 6-amino-7-fluoro-8-methoxy-4-methyl-1H-quinolin-2-one as a yellow powder. LCMS [M+H]+ 223 m / z. 1 H NMR(300MHz,DMSO-d6)δ 10.73(s,1H),6.78(d,J=8.8Hz,1H),6.30(d,J=1.3Hz,1H),5.12(s,2H),3.86(d,J=1.3Hz,3H).

[0216] Preparation of 6-amino-7-methoxy-4-methyl-1H-quinolin-2-one (Intermediate 4): [ka]

[0217] Preparation of N-(3-methoxyphenyl)acetamide: [ka] 3-Methoxyaniline (10.0 g, 81.3 mmol) was added to acetic anhydride (24.8 g, 243.9 mmol) at 0° C. The reaction mixture was then warmed to room temperature and stirred for 2 h. After completion, the reaction mixture was basified with NaHCO3 and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and the residue was washed with n-pentane to give N-(3-methoxyphenyl)acetamide as a light brown solid (10 g, 76%).

[0218] Preparation of N-(3-methoxy-4-nitro-phenyl)acetamide: [ka] To a solution of N-(3-methoxyphenyl)acetamide (9.5 g, 57.5 mmol, 1.0 equiv) in acetic anhydride (150 mL, 15 vol) was added nitric acid (4.8 mL, 115.1 mmol, 2.0 equiv) at 0° C. and the reaction mixture was stirred at the same temperature for 30 min. After completion, the reaction mixture was quenched in ice water, basified with aqueous NaHCO3, and extracted with ethyl acetate (2×500 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by 100-200 mesh silica gel column chromatography eluted with 30% EtOAc in petroleum ether to give N-(3-methoxy-4-nitrophenyl)acetamide (2.4 g, 20%) as a yellow solid.

[0219] Preparation of 3-methoxy-4-nitroaniline: [ka] N-(3-Methoxy-4-nitrophenyl)acetamide (2.4 g, 11.42 mmol) was added at room temperature while stirring 1N HCl (24 mL, 10 vol) and the reaction mixture was stirred at 100° C. for 2 h. After completion, the reaction mixture was poured into ice water, basified with aqueous NaHCO3 and extracted with ethyl acetate (2×50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was washed with n-pentane to give 3-methoxy-4-nitroaniline as a brown solid (1.8 g, 94%).

[0220] Preparation of N-(3-methoxy-4-nitrophenyl)-3-oxobutanamide: [ka] To a stirred solution of 3-methoxy-4-nitroaniline (1.8 g, 10.71 mmol, 1 equiv) in toluene (1.8 mL, 10 vol), methyl 3-oxobutanoate (1.2 g, 10.71 mmol) was added followed by pyridine (15 ml, 3 vol) at room temperature and the reaction mixture was stirred at 100° C. for 16 hours. After completion, the reaction mixture was warmed to room temperature and the solvent was evaporated. The crude product was purified by silica gel column chromatography (100-200 mesh) using 50% EtOAc in petroleum ether to give N-(3-methoxy-4-nitrophenyl)-3-oxobutanamide as a brown solid (1.7 g, 63%).

[0221] Preparation of 7-Methoxy-4-methyl-6-nitro-1H-quinolin-2-one: [ka] Triflic acid (2.02 ml, 7.93 mmol) was added to a stirred solution of N-(3-methoxy-4-nitrophenyl)-3-oxobutanamide (600 mg, 2.38 mmol) in DCM (6 mL) at 0° C. and stirred at room temperature for 16 h. After completion, the reaction mixture was poured into ice water, basified with solid NaHCO3, and extracted with EtOAc (2×50 mL). The crude product was purified by column chromatography (100-200 mesh silica gel) eluted with 5% methanol in dichloromethane to give 7-methoxy-4-methyl-6-nitro-1H-quinolin-2-one as a brown solid (50 mg, 9%).

[0222] Preparation of 6-amino-7-methoxy-4-methyl-1H-quinolin-2-one (Intermediate 4): [ka] A suspension of 7-methoxy-4-methyl-6-nitro-1H-quinolin-2-one (50 mg, 0.21 mmol) in methanol (0.5 mL, 10 vol) was degassed under argon for 10 minutes. To this suspension was added 10% Pd / C (5 mg) and the reaction was stirred under hydrogen atmosphere (40 psi) at room temperature for 12 hours. Upon completion, the reaction mixture was filtered through a celite bed. The filtrate was evaporated to give 6-amino-7-methoxy-4-methyl-1H-quinolin-2-one (30 mg, 70%) as a brown solid. 1 H NMR(400MHz,DMSO-d6):δ 11.14(brs,1H),6.87(s,1H),6.75(s,1H),6.14(s,1H),4.68(brs,2H),3.81(s,3H),2.33(s,3H);LCMS[M+H]+:205.20m / z

[0223] Preparation of 5-amino-7-methyl-3,10-dihydro-2H-[1,4]dioxino[2,3-h]quinolin-9-one (Intermediate 5): [ka]

[0224] Preparation of N-(2,3-dihydro-1,4-benzodioxin-5-yl)-3-oxo-butanamide: [ka] 2,3-Dihydro-1,4-benzodioxin-5-amine (3 g, 20 mmol, 1 eq) was dissolved in toluene (10 ml), warmed to 110° C., and 2,2,6-trimethyl-1,3-dioxin-4-one (3 ml, 22.7 mmol, 1.1 eq) was added. The reaction mixture was stirred for 0.75 h and then cooled to room temperature. The solvent was evaporated and the crude mixture was purified on a Biotage Isolera (heptane / EtOAc 93 / 7, then 93 / 7->30 / 70). Evaporation of fractions containing the product gave 2.8 g (60%) of N-(2,3-dihydro-1,4-benzodioxin-5-yl)-3-oxo-butanamide as a yellow oil. 1H NMR (300 MHz, chloroform-d) δ 9.18 (s, 1H), 7.88 (dd, J = 8.2, 1.5 Hz, 1H), 6.83 (t, J = 8.2 Hz, 1H), 6.66 (dd, J = 8.3, 1.5 Hz, 1H), 4.38 (ddd, J = 5.3, 3.1, 1.1 Hz, 2H), 4.34-4.24 (m, 2H), 3.62 (s, 2H), 2.35 (s, 3H).

[0225] Preparation of 7-methyl-3,10-dihydro-2H-[1,4]dioxino[2,3-h]quinolin-9-one: [ka] N-(2,3-dihydro-1,4-benzodioxin-5-yl)-3-oxo-butanamide (2.8 g, 11.9 mmol, 1 eq.) was dissolved in DCM (20 ml). Trifluoromethanesulfonic acid (10.5 ml, 119 mmol, 10 eq.) and DCM (5 ml) were added dropwise at room temperature over 20 min. The reaction mixture was stirred at room temperature for 1 h, then poured into 100 ml of ice water and stirred for 20 min. The reaction mixture was filtered and washed with water (2×15 ml) and Et2O (10 ml). The product was dissolved in EtOAc / DCM / MeOH=1 / 10.2 (150 ml), dried over Na2SO4 and evaporated. The product was dried under 1 mbar vacuum at room temperature for 1 h to give 2.5 g (97%) of 7-methyl-3,10-dihydro-2H-[1,4]dioxino[2,3-h]quinolin-9-one as a pale yellow powder. 1 H NMR (300 MHz, chloroform-d) δ 9.00 (s, 1H), 7.18 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H), 6.42 (d, J = 1.2 Hz, 1H), 4.52-4.33 (m, 4H), 2.45 (d, J = 1.2 Hz, 3H).

[0226] Preparation of 7-methyl-5-nitro-3,10-dihydro-2H-[1,4]dioxino[2,3-h]quinolin-9-one: [ka] 7-Methyl-3,10-dihydro-2H-[1,4]dioxino[2,3-h]quinolin-9-one (2.5 g, 11.5 mmol, 1 equiv.) was suspended in Ac2O (40 ml) and cooled to 0° C. HNO3 65% aqueous solution (1.1 ml, 17.3 mmol, 1.5 equiv.) was added dropwise and stirred at 0° C. for 40 min, then poured into 400 ml of ice water and stirred at room temperature for 10 min. The product was filtered and washed with water (2×30 ml). The product was triturated with ultrasound in DCM / EtOAc 1 / 1 (10 ml), filtered and washed with EtoAc / heptane 1 / 1 (10 ml), heptane (10 ml), DCM / EtOAc 1 / 1 (10 ml) and heptane (2×10 ml). The product was air-dried, triturated by ultrasound in 1:1 DCM / MeOH (20 ml) and filtered. The product was purified by Biotage Isolera (ACN (0.1% FA) / H2O (0.1% FA) 1:99, then 1:99->40:60). Relevant fractions were evaporated. The earlier fractions were repurified by Biotage Isolera (ACN (0.1% FA) / H2O (0.1% FA) 0:100, then 0:100->80:20). The product, 7-methyl-5-nitro-3,10-dihydro-2H-[1,4]dioxino[2,3-h]quinolin-9-one (150 mg) was obtained as a mixture with the other regioisomer in a 4:6 ratio. 1 H NMR(300MHz,DMSO-d6)δ 11.21(s,1H),7.95(s,1H),6.42(s,1H),4.52-4.45(m,4H),2.42(d,J=1.2Hz,3H).

[0227] Preparation of 5-amino-7-methyl-3,10-dihydro-2H-[1,4]dioxino[2,3-h]quinolin-9-one (Intermediate 5): [ka] 7-Methyl-5-nitro-3,10-dihydro-2H-[1,4]dioxino[2,3-h]quinolin-9-one (150 mg) was dissolved in MeOH (10 ml), 10% Pd / C (15 mg) was added and the mixture was subjected to three vacuum / H2 cycles. The reaction was stirred with a H2 balloon at room temperature for 4 h. The reaction mixture was filtered through Celite and evaporated to give 5-amino-7-methyl-3,10-dihydro-2H-[1,4]dioxino[2,3-h]quinolin-9-one (120 mg, 90%) as a brown oil. LCMS [M+H] + 233 m / z, mixture of positional isomers.

[0228] Preparation of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (intermediate 6): [ka]

[0229] Preparation of 5-bromo-2-(prop-2-ynoxymethyl)pyrimidine: [ka] To a stirred solution of (5-bromopyrimidin-2-yl)methanol (20 g, 105.82 mmol) in dry DMF (100 mL), NaH (3.8 g, 246 mmol) was added portionwise at 0° C. and the reaction mixture was stirred at the same temperature for 15 min. To this, propargyl bromide (9.6 mL, 1.2 eq) was added dropwise over 20 min and the reaction mixture was stirred at 0° C. for 30 min. After 30 min, the reaction mixture was warmed to room temperature and to this, 0.12 eq. of propargyl bromide (0.96 mL, 0.12 eq.) was added dropwise. Again the reaction mixture was stirred at the same temperature for 45 min. After completion, the reaction mixture was quenched with 15% Na2SO3 solution (100 mL), 5% LiCl solution (100 mL), diluted with water (100 mL) and extracted with EtOAc (2×500 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel (100-200 mesh) column chromatography eluted with 5% EtOAc in petroleum ether to give 5-bromo-2-(prop-2-ynoxymethyl)pyrimidine (18 g, 75% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3):δ 8.80(s,2H),4.82(s,2H),4.39(d,J=2.4Hz,2H),2.48(t,J=2.4Hz,1H):LCMS[M+H] + :227.01m / z.

[0230] Preparation of 3-bromo-5,7-dihydrofuro[3,4-b]pyridine: [ka] A solution of 5-bromo-2-(prop-2-ynoxymethyl)pyrimidine (25 g, 110 mmol) in nitrobenzene (75 mL) was heated with stirring at 180 °C for 4 h while flushing with argon into a flask containing the reaction mixture and chilled hypochlorite to quench the HCN produced in the reaction. Upon completion, the reaction mixture was cooled to room temperature and directly purified by silica gel (100-200 mesh) column chromatography eluting with 25% EtOAc in petroleum ether to give 3-bromo-5,7-dihydrofuro[3,4-b]pyridine (18 g, 81% yield) as an off-white solid. 1 H NMR(300MHz,DMSO-d6):δ 8.57(t,J=0.6Hz,1H),8.03(d,J=0.6Hz,1H),5.06(s,2H),4.90(t,J=1.8Hz,2H):LCMS[M+H] + :202.00m / z.

[0231] Preparation of methyl 5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: [ka] A 1 L autoclave was charged with 3-bromo-5,7-dihydrofuro[3,4-b]pyridine (30 g, 150 mmol), DMF (90 mL), MeOH (90 mL), 4A° MS sieves, followed by Et3N (61 mL, 450 mmol) at room temperature and the reaction mixture was degassed with argon for 10 min. To this was added Pd(OAc)2 (5.04 g, 7.5 mmol), Xantphos (4.34 g, 7.5 mmol) and charged with CO gas (100 psi). The reaction mixture was heated at 90° C. for 4 h. After completion, the reaction mixture was concentrated under reduced pressure to give the crude compound which was purified by silica gel (100-200 mesh) column chromatography eluted with 15% EtOAc in petroleum ether to give 5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate methyl (21.6 g, 81% yield) as an off-white solid. 1H NMR(400MHz,CDCl3):δ 9.11(s,1H),8.15(s,1H),5.20(t,J=0.8Hz,2H),5.11(t,J=1.6Hz,2H),3.96(s,3H);LCMS[M+H] + :180.08m / z

[0232] Preparation of methyl 1-oxido-5,7-dihydrofuro[3,4-b]pyridin-1-ium-3-carboxylate: [ka] To a stirred solution of 5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate methyl (30 g, 167.59 mmol) in DCM (250 mL) and ACN (250 mL) was added urea / hydrogen peroxide complex (29.4 g, 313.4 mmol) and the reaction mixture was cooled to 0° C. To this was added TFAA (41 mL, 293.29) dropwise over 25 min. The reaction mixture was then allowed to warm to room temperature and stirred at the same temperature for 30 h. Further TFAA (3 mL, 21.78 mmol) was added and stirred for 10 min. After completion, the reaction mixture was diluted with DCM (300 mL), quenched with NaHCO3 solution (800 mL) and the pH was adjusted to 7.5 with 5M NaOH solution (12 mL). The layers were separated and the aqueous layer was extracted with DCM (2×500). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography eluted with 5% MeOH in DCM to give methyl 1-oxido-5,7-dihydrofuro[3,4-b]pyridin-1-ium-3-carboxylate (29.8 g, 94% yield) as an off-white solid. 1 H NMR(400MHz,CDCl3):δ 8.69(s,1H),7.72(s,1H),5.20(dd,J=8.4,2Hz,4H),3.97(s,3H);LCMS[M+H] + :195.97m / z.

[0233] Preparation of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (intermediate 6): [ka] POCl3 (70.4 mL, 753.84 mmol, freshly distilled) was added to 1-oxido-5,7-dihydrofuro[3,4-b]pyridin-1-ium-3-methylcarboxylate (20 g, 102.56 mmol) at 0° C. The reaction mixture was heated at 100° C. for 1 h under argon. After completion, the reaction mixture was diluted with DCM (100 mL) and quenched with an ice-cold mixture of DCM (400 mL) / saturated aqueous NaHCO3 (800 mL) with stirring for 15 min and shaken until gas evolution ceased. Brine solution (200 mL) was added and the layers were separated. The aqueous layer was extracted with DCM (2×800 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude compound, which was purified by silica gel (100-200 mesh) column chromatography eluting with 15% EtOAc in petroleum ether to give methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (13.2 g, 61% yield) as an off-white solid. 1 H NMR(400MHz,CDCl3):δ 8.03(t,J=0.8,1H),5.17-5.16(m,2H),5.06(t,J=2Hz,2H),3.96(s,3H);LCMS[M+H] + :214.09m / z.

[0234] Preparation of (5R)-2-chloro-5-methyl-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (intermediate 7): [ka]

[0235] Preparation of 5-bromo-2-[[(1R)-1-methylprop-2-ynoxy]methyl]pyrimidine [ka] To a stirred solution of 5-bromo-2-(bromomethyl)pyrimidine (470 mg, 1.87 mmol) in dry THF (4 mL) under argon at -10°C, NaH (60% in mineral oil, 97 mg, 2.3 mmol) was added in small portions and the reaction mixture was stirred at the same temperature for 10 min. To this was added (2R)-but-3-yn-2-ol (153 mg, 2.2 mmol) and the reaction mixture was stirred for 1 h. After completion, the reaction mixture was quenched with saturated aqueous NH4Cl (6 mL) and extracted with EtOAc (3 x 6 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel (100-200 mesh) column chromatography eluted with 2-30% EtOAc in heptane to give 5-bromo-2-[[(1R)-1-methylprop-2-ynoxy]methyl]pyrimidine (254 mg, 56% yield). LCMS [M+H] + :241.06 / 243 m / z. 1 H NMR (300 MHz, chloroform-d) δ 8.82 (s, 2H), 4.98 (d, J = 14.0 Hz, 1H), 4.78 (d, J = 14.0 Hz, 1H), 4.47 (qd, J = 6.6, 2.1 Hz, 1H), 2.49 (d, J = 2.1 Hz, 1H), 1.60 (s, 3H).

[0236] Preparation of (5R)-3-bromo-5-methyl-5,7-dihydrofuro[3,4-b]pyridine: [ka] A solution of 5-bromo-2-[[(1R)-1-methylprop-2-ynoxy]methyl]pyrimidine (254 mg, 1.05 mmol) in nitrobenzene (2 mL) was heated with stirring under an argon atmosphere at 180° C. for 2 h. Upon completion, the reaction mixture was cooled to room temperature and directly purified by silica gel flash column chromatography, eluting with 1-30% EtOAc in heptane to give (5R)-3-bromo-5-methyl-5,7-dihydrofuro[3,4-b]pyridine (203 mg, 90% yield). LCMS [M+H] + :214 / 216.7m / z. 1H NMR (300 MHz, chloroform-d) δ 8.55 (dd, J = 2.1, 0.8 Hz, 1H), 7.62 (dd, J = 2.1, 1.0 Hz, 1H), 5.41-5.31 (m, 1H), 5.08-4.91 (m, 2H), 1.54 (d, J = 6.4 Hz, 3H).

[0237] Preparation of methyl (5R)-5-methyl-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: [ka] In a two-chamber reaction vial, one chamber was charged with methyl 3-bromo-5,7-dihydrofuro[3,4-b]pyridine (202 g, 0.94 mmol), DMF (1.6 mL), MeOH (0.8 mL) and Et3N (393 μL, 2.82 mmol) and flushed with argon at room temperature for 10 min. To this was added Pd(OAc)2 (11 mg, 0.05 mmol) and xanphos (27 mg, 0.05 mmol). The second chamber was charged with HCOOH (142 μL, 3.76 mmol) and MsCl (289 μL, 3.76 mmol) in toluene (7 mL) and flushed with argon. Et3N (800 μL, 5.64 mmol) was immediately added to the second chamber to initiate CO generation. The reaction mixture was heated at 85° C. for 45 min. After completion, the reaction mixture was poured into water and extracted with EtOAc. The combined extracts were washed with water, 5% LiCl and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude compound was purified by flash chromatography using EtOAc / heptane (10-70% EtOAc) to give methyl (5R)-5-methyl-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (373.5 mg, 73% yield). LCMS [M+H] + :194.16m / z. 1H NMR (300 MHz, chloroform-d) δ 9.13 (dd, J = 1.9, 0.8 Hz, 1H), 8.10 (dd, J = 1.8, 1.0 Hz, 1H), 5.49-5.31 (m, 1H), 5.24-4.97 (m, 2H), 3.99 (s, 3H), 1.58 (d, J = 6.4 Hz, 3H).

[0238] Preparation of methyl (5R)-5-methyl-1-oxide-5,7-dihydrofuro[3,4-b]pyridin-1-ium-3-carboxylate: [ka] To a stirred solution of (5R)-5-methyl-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (130 mg, 0.673 mmol) in DCM (3 mL) and ACN (6 mL) cooled to 0 °C was added urea-hydrogen peroxide complex (165 mg, 1.75 mmol) and TFAA (41 mL, 293.29 mmol). The reaction mixture was then stirred at room temperature for 30 h. An additional urea-hydrogen peroxide complex (16 mg) and TFAA (24.4 μL) were added and stirred for 30 min. After completion, TEA (1 mL) was added to the reaction mixture at 0 °C, stirred for 10 min, and evaporated under vacuum to give methyl (5R)-5-methyl-1-oxide-5,7-dihydrofuro[3,4-b]pyridin-1-ium-3-carboxylate (131 mg, 93% yield). LCMS [M+H] + :210.17m / z. 1 H NMR (300 MHz, chloroform-d) δ 8.73 (s, 1H), 7.70 (d, J = 1.2 Hz, 1H), 5.54-5.38 (m, 1H), 5.38-5.06 (m, 2H), 4.00 (s, 3H), 1.58 (d, J = 6.4 Hz, 3H).

[0239] Preparation of (5R)-2-chloro-5-methyl-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (Intermediate 7): [ka] To (5R)-5-methyl-1-oxide-5,7-dihydrofuro[3,4-b]pyridin-1-ium-3-carboxylate (130 mg, 0.62 mmol) was added POCl3 (400 μL, 4.4 mmol, freshly distilled). The reaction mixture was heated at 100° C. under argon for 3 h. Upon completion, excess reagent was removed under vacuum to give methyl (5R)-2-chloro-5-methyl-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (90% yield). LCMS [M+H] +: 228.13m / z.

[0240] Preparation of methyl 5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (intermediate 8) [ka]

[0241] Preparation of 5-bromo-2-(1-methylprop-2-ynoxymethyl)pyrimidine: [ka] To a solution of but-3-yn-2-ol (140 mg, 2 mmol, 1.17 equiv) in dry THF (4 mL) under argon at -10°C, NaH 60% by weight (84 mg, 2.1 mmol, 1.235 equiv) was added in one portion and stirred at -10°C for 10 min. 5-Bromo-2-(bromomethyl)pyrimidine (430 mg, 1.7 mmol, 1 equiv) was then added and stirred in an ice-acetone bath for 1 h. Saturated aqueous NH4Cl (6 ml) was then added followed by EtOAc (6 ml). The layers were separated and the aqueous layer was washed with EtOAc (6 ml). The combined organic extracts were washed with brine and evaporated. The crude product was purified with Biotage Isolera: (heptane / EtOAc 98 / 2->70 / 30). Fractions containing the product were evaporated to give 251 mg (62%) of 5-bromo-2-(1-methylprop-2-ynoxymethyl)pyrimidine as a colorless oil. 1H NMR(300MHz,CDCl3)δ 8.82(s,2H),4.97(d,J=14.0Hz,1H),4.78(d,J=13.9Hz,1H),4.47(dd,J=6.6,2.1Hz,1H),2.49(d,J=2.1Hz,1H),1.58(d,J=6.6Hz,3H).

[0242] Preparation of 3-bromo-5-methyl-5,7-dihydrofuro[3,4-b]pyridine: [ka] A solution of 5-bromo-2-(1-methylprop-2-ynoxymethyl)pyrimidine (251 mg, 1.05 mmol, 1 equiv.) in PhNO2 (4 mL) was stirred at 180° C. for 2 h. It was then purified on a Biotage Isolera (heptane / EtOAc 99 / 1, then heptane / EtOAc 99 / 1->70 / 30). Evaporation of the product-containing fractions gave 180 mg (81%) of 3-bromo-5-methyl-5,7-dihydrofuro[3,4-b]pyridine as a colorless oil. 1 H NMR(300MHz,CDCl3)δ 8.55(dd,J=2.1,0.9Hz,1H),7.62(dd,J=2.1,1.0Hz,1H),5.43-5.29(m,1H),5.12-4.90(m,2H),1.54(d,J=6.4Hz,3H).

[0243] Preparation of methyl 5-methyl-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: [ka] 3-Bromo-5-methyl-5,7-dihydrofuro[3,4-b]pyridine (180 mg, 0.84 mmol, 1 equiv) was dissolved in dry THF (4 ml) under argon and cooled to -78°C. n-BuLi 1.6M / Hexane (0.55 ml, 0.88 mmol, 1.05 equiv) was added dropwise over 3 min, then stirred for 5 min. Two solid chunks of CO2 were added, the bath was removed, and stirred for 20 min. The reaction mixture was evaporated to give 250 mg of crude (5-methyl-5,7-dihydrofuro[3,4-b]pyridine-3-carbonyl)oxylithium as a yellow foam. LCMS [M+H] + 180 m / z. This was dissolved in DCM / MeOH / DMF (4+2+1 ml) and to this solution was added TEA (0.3 ml, 2.19 mmol, 2.6 eq) followed by HATU (350 mg, 0.92 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated. The residue was partitioned between EtOAc (8 ml) and 5% aqueous LiCl (5 ml). The layers were separated and the aqueous layer was washed with EtOAc (5 ml). The combined organic extracts were washed with brine, evaporated in vacuo and purified on a Biotage Isolera (heptane / EtOAc 99 / 1->60 / 40). Evaporation of fractions containing the product gave 75 mg (42% over two steps) of methyl 5-methyl-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate as a colourless oil. LCMS [M+H] + 194m / z.

[0244] Preparation of methyl 5-methyl-1-oxo-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: [ka] Methyl 5-methyl-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (75 mg, 0.386 mmol, 1 equiv) was dissolved in ACN / DCM (4+2 ml) and cooled to 0 °C. H2O2·urea complex (94 mg, 1 mmol, 2.6 equiv) was added followed by TFAA (0.14 ml, 1 mmol, 2.6 equiv). The bath was removed. Stirred at room temperature for 30 min. H2O2·urea complex (94 mg, 1 mmol, 2.6 equiv) was added followed by TFAA (0.14 ml, 1 mmol, 2.6 equiv). Stirred at room temperature for 30 min. Cooled to 0 °C. TEA (0.6 ml, 4.39 mmol, 11.4 equiv) was added. Stirred for 10 min. The reaction mixture was evaporated. Purification on Biotage Isolera (EtOAc / MeOH 100 / 0, then EtOAc / MeOH 100 / 0->85 / 15). Evaporation of fractions containing the product gave 81 mg (100%) of methyl 5-methyl-1-oxo-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate as a white material. LCMS [M+H] + 210m / z. 1 H NMR(300MHz,DMSO-d6)δ 8.50(t,J=1.0Hz,1H),7.79(t,J=1.1Hz,1H),5.42(dtt,J=6.4,1.7,0.9Hz,1H),5.06(dd,J=11.8,2.3Hz,2H),3.90(s,3H),1.48(d,J=6.4Hz,3H).

[0245] Preparation of methyl 5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (intermediate 8): [ka] Methyl 5-methyl-1-oxo-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (81 mg, 0.387 mmol, 1 equiv.) was mixed with POCl3 (0.2 ml, 2.14 mmol, 5.5 equiv.) in a 7 ml vial. The mixture was shaken at 80° C. for 30 min and then at 100° C. for 1 h. The reaction mixture was concentrated and morpholine (1 ml, 11 mmol, 35 equiv.) was added while the mixture was cooled, followed by DMF (1 ml). The reaction mixture was shaken at 80° C. for 30 min and then at 100° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (7 ml) and washed with 5% aqueous LiCl (7 ml). The layers were separated and the aqueous layer was washed with EtOAc (7 ml). The combined organic extracts were washed with brine and evaporated. The crude product was dissolved in a minimum of DCM and purified on a Biotage Isolera (heptane / EtOAc 99 / 1->50 / 50). Evaporation of fractions containing the product gave 50 mg (46% over two steps) of methyl 5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate as a brown oil. LCMS [M+H] + 279m / z. 1 H NMR(300MHz,chloroform-d)δ 7.74(d,J=0.9Hz,1H),5.22(m,1H),4.95-4.76(m,2H),3.82(s,3H),3.79-3.70(m,4H),3.38-3.28(m,4H),1.41(d,J=6.3Hz,3H).

[0246] Working Example: N-(8-Methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide (Example 1) [ka]

[0247] Preparation of benzyl 3-bromo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate: [ka] To a suspension of 3-bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride (300 mg, 1.87 mmol) in dry DCM (25 mL) was added DIPEA (812 μL, 4.67 mmol) and the mixture was stirred at room temperature for 15 min, followed by the dropwise addition of benzyl chloroformate (295 μL, 2.06 mmol). The reaction mixture was then stirred at room temperature for an additional 60 min. The reaction was then diluted with EtOAc (125 mL), washed with 0.1 M aqueous NaOH (2×50 mL) and saturated aqueous NaHCO3 (100 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (Isolera One, Biotage) using a heptane / EtOAc mixture (100 / 0 to 0 / 100) as eluent to give the title product 3-bromo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate benzyl as a white solid (400 mg, 65%). 1 H NMR (300 MHz, chloroform-d) δ 8.48 (s, 1H), 7.77-7.51 (m, 1H), 7.37-7.22 (m, 6H), 5.16 (d, J = 2.3 Hz, 2H), 4.72-4.63 (m, 4H).

[0248] Preparation of 5,7-dihydropyrrolo[3,4-b]pyridine-3,6-dicarboxylate O6-benzyl O3-methyl [ka] In a two-chamber reaction vial, one chamber was charged with benzyl 3-bromo-5,7-dihydrofuro[3,4-b]pyridine-6-carboxylate (1.0 g, 3.0 mmol), DMF (8 mL), MeOH (4 mL), and Et3N (1.25 mL, 9.0 mmol) and flushed with argon at room temperature for 10 min. To this was added Pd(OAc)2 (100 mg, 0.45 mmol) and Xantphos (260 mg, 0.45 mmol). The second chamber was charged with HCOOH (300 μL, 7.9 mmol) and MsCl (612 μL, 7.9 mmol) in toluene (5 mL) and flushed with argon. Et3N (1.6 mL, 11.9 mmol) was immediately added to the second chamber to initiate CO generation. The reaction mixture was heated at 100 °C for 2 h. After completion, the reaction mixture was diluted with EtOAc (150 mL), washed with saturated aqueous NaHCO3 (2 x 75 mL), 5% LiCl (2 x 25 mL) and brine (75 mL), dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (Isolera One, Biotage) using DCM / MeOH mixture (100 / 0 to 95 / 5) as eluent to give 5,7-dihydropyrrolo[3,4-b]pyridine-3,6-dicarboxylate O6-benzyl O3-methyl as a white solid (410 mg, 43%). 1 H NMR(300MHz,chloroform-d)δ 9.14(d,J=1.9Hz,1H),8.20(dd,J=18.0,2.1Hz,1H),7.47-7.34(m,6H),5.26(d,J=1.9Hz,2H),4.89-4.82(m,4H),3.98(s,3H).

[0249] Preparation of 1-oxido-5,7-dihydropyrrolo[3,4-b]pyridin-1-ium-3,6-dicarboxylate O6-benzyl O3-methyl: [ka] A solution of 5,7-dihydropyrrolo[3,4-b]pyridine-3,6-dicarboxylate O6-benzyl O3-methyl (410 mg, 1.3 mmol) in dry DCM (25 mL) was treated with m-CPBA (321 mg, 77% purity, 1.6 mmol) at 0° C. The reaction mixture was then allowed to warm to room temperature and stirred for 16 h. The reaction was diluted with EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (2×75 mL) and brine (100 mL). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (Isolera One, Biotage) using DCM / MeOH mixture (100 / 0 to 90 / 10) as eluent to give the title product 1-oxido-5,7-dihydropyrrolo[3,4-b]pyridin-1-ium-3,6-dicarboxylate O6-benzyl O3-methyl as a white solid (360 mg, 85%). LCMS [M+H] + :329.2m / z

[0250] Preparation of 2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-3,6-dicarboxylate O6-benzyl O3-methyl [ka] A solution of 1-oxido-5,7-dihydropyrrolo[3,4-b]pyridin-1-ium-3,6-dicarboxylate O6-benzyl O3-methyl (360 mg, 1.1 mmol) in POCl3 (3.0 mL) was stirred at 80° C. for 1.5 h. The crude reaction mixture was concentrated under vacuum and evaporated twice with toluene to remove all volatiles. The residue was then redissolved in dry DMF (4.0 mL) and morpholine was added. The mixture was stirred at 120° C. for 1 h and subsequently concentrated in vacuo. The residue was purified by silica gel column chromatography (Isolera One, Biotage) using DCM / MeOH mixture (100 / 0 to 90 / 10) as eluent to give the title product 2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-3,6-dicarboxylate O6-benzyl O3-methyl as a solid with UV purity of about 70% by UPLC-MS (400 mg, 70% purity, 63% yield for two steps).

[0251] Preparation of benzyl 3-[(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)carbonyl]-2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate: [ka] A solution of 2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-3,6-dicarboxylate O6-benzyl O3-methyl (400 mg, 70% purity, 1.0 mmol) in MeOH (10 mL) was treated with 0.7 M aqueous NaOH (4.5 mL) and the mixture was stirred at room temperature for 16 h, then quenched with saturated aqueous NaHCO3 until the pH was about 9. The aqueous solution was concentrated in vacuo and the residue was used in the next step without further purification.

[0252] The above residue was suspended in dry DMF (4.0 mL) and treated with EDC·HCl (183 mg, 0.93 mmol) and HOAt (126 mg, 0.96 mmol), followed by DIPEA (472 μL, 2.7 mmol) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (191 mg, 0.93 mmol). The reaction mixture was stirred at 65° C. for 4 h and then poured into ice-cold water with vigorous stirring. The formed precipitate was filtered and washed with cold water. The precipitate was purified by silica gel column chromatography (Isolera One, Biotage) using DCM / MeOH mixture (100 / 0 to 80 / 20) as eluent to give the title product benzyl 3-[(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)carbonyl]-2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate as a white solid (150 mg, 46% yield for two steps).

[0253] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide (Example 1): [ka] A solution of benzyl 3-[(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)carbonyl]-2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (50 mg, 0.087 mmol) in MeOH (5.0 mL) was treated with 10% w / w Pd / C (10 mg) and the reaction mixture was stirred under an atmosphere of H for 30 min. The reaction mixture was then filtered through a pad of Celite® and concentrated in vacuo. The residue was purified by silica gel column chromatography (Isolera One, Biotage) using DCM / MeOH mixture (100 / 0 to 90 / 10) as eluent to give the title product N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide as a pale yellow / white solid (19 mg, 50%). 1H NMR(300MHz,DMSO-d6)δ 10.62(s,2H),7.79(s,1H),7.76(d,J=2.0Hz,1H),7.59(d,J=1.9Hz,1H),6.46(d,J=1.3Hz,1H),4.12-4.05(m, 2H),4.00(d,J=1.8Hz,2H),3.90(s,3H),3.71-3.61(m,4H),3.25-3.19(t,J=4.6Hz,4H),2.39(d,J=1.2Hz,3H).

[0254] Preparation of 2-chloro-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide: [ka] Methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (600 mg, 2.8 mmol, 1 equiv) was dissolved in THF (15 ml) and 5M aqueous NaOH (1.4 ml, 6 mmol, 2.5 equiv) and water (3 ml) were added. The mixture was shaken at 45° C. overnight, then cooled to 0° C. and acidified to pH 7 with 5M aqueous HCl. The layers were separated and the aqueous layer was extracted with EtOAc (2×15 ml). The combined organic extracts were dried over Na2SO4 and evaporated to give 600 mg of crude 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid as an orange powder. The crude product was dissolved in DMF (6 ml) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (613 mg, 3 mmol, 1.07 equiv), DIPEA (1.57 ml, 9 mmol, 3.21 equiv), EDC·HCl (573 mg, 3 mmol, 1.07 equiv) and HOAt (408 mg, 3 mmol, 1.07 equiv) were added. The reaction mixture was shaken at 60° C. for 2 h. After cooling to room temperature, water (10 ml) and 5% aqueous LiCl (10 ml) were added to the mixture and stirred at room temperature for 10 min. The mixture was filtered, washed with water (2×10 ml), air-dried, triturated with ACN (10 ml) and filtered. The filtrate was washed with ACN (2 x 5 ml) and dried under 1 mbar vacuum at room temperature for 3 h to give 780 mg of 2-chloro-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide as a yellow powder. LCMS [M+H] + 386m / z. 1 H NMR(300MHz,DMSO-d6)δ 10.73(s,1H),10.69(s,1H),8.06(d,J=1.0Hz,1H),7.71(d,J=1.9Hz,1H),7.52(d,J=2.0Hz,1H),6.4 6(d,J=1.3Hz,1H),5.12(d,J=2.1Hz,2H),5.00(d,J=2.0Hz,2H),3.89(s,3H),2.39(d,J=1.2Hz,3H).

[0255] Preparation of 2-(3,6-dihydro-2H-pyran-4-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 2) [ka]

[0256] Preparation of methyl 2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (66 mg, 0.31 mmol, 1 eq) in dioxane (1.8 mL) and water (0.6 mL) was added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (78 mg, 0.37 mmol, 1.2 eq), Pd(dppf)Cl2 (6 mg, 0.02 eq) and Cs2CO3 (202 mg, 2 eq) under argon and the reaction mixture was stirred at 130° C. for 45 min. After completion, the solvent was evaporated under vacuum and the product was extracted from DCM / water. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography using DCM / MeOH (0-5% MeOH) to give methyl 2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (54 mg, 67% yield). LCMS [M+H] + 262.20m / z. 1 H NMR(300MHz,chloroform-d)δ 7.92(s,1H),5.85(s,1H),5.21(s,2H),5.11(s,2H),4.32(q,J=2.7Hz,2H),3.97(t,J=5.3Hz,2H),3.90(s,3H),2.56(tq,J=5.2,2.5Hz,2H)

[0257] Preparation of 2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid: To a solution of methyl 2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (112 mg, 0.43 mmol, 1 eq) in methanol (0.6 mL) and THF (0.6 mL), 2M LiOH was added (430 μL) and the reaction mixture was stirred at 35° C. for 3 h. After completion, 2N HCl was added to neutralize (430 μL). The solvent was evaporated under vacuum with acetonitrile and toluene to remove excess HCl to give crude 2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid as a white solid. LCMS [M+H] + 248.18m / z.

[0258] Preparation of 2-(3,6-dihydro-2H-pyran-4-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 2): To a solution of 2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.43 mmol, 1.0 eq.) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (96 mg, 0.47 mmol, 1.1 eq.) in DMF (3 mL), DIPEA (150 μL, 0.85 mmol, 2 eq.) and HATU (79 mg, 0.47 mmol, 1.2 eq.) were added and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was extracted from EtOAc and 5% LiCl. The combined organic extracts were washed with water and brine. After evaporation of the solvent, the crude product was purified by silica gel flash chromatography using DCM / MeOH (0-10% MeOH) to give 82 mg (44% yield) of 2-(3,6-dihydro-2H-pyran-4-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide. LCMS [M+H] +434.19m / z. 1 H NMR(300MHz,DMSO-d6)δ 10.65(s,1H),10.48(s,1H),7.88(s,1H),7.62(d,J=1.9Hz,1H),7.46(d,J=1.9Hz,1H),6.46(d,J=1.3Hz,1H),6.14-6.10(m,1H) ,5.13(s,2H),5.02-4.93(m,2H),4.11-4.06(m,2H),3.88(s,3H),3.76(t,J=5.4Hz,2H),2.62-2.53(m,2H),2.38(d,J=1.2Hz,3H)

[0259] Preparation of 2-(cyclopentan-1-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 3) [ka]

[0260] Preparation of 2-(cyclopentan-1-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 3): To a solution of 2-chloro-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (77 mg, 0.2 mmol, 1 equiv.) in dioxane (1.6 mL) and water (0.5 mL), 2-(cyclopentan-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (117 mg, 0.6 mmol, 3 equiv.), Pd(dppf)Cl2 (3.4 mg, 0.02 equiv.) and Cs2CO3 (130 mg, 2 equiv.) were added under argon and the reaction mixture was stirred at 130° C. for 45 min. After completion, the solvent was evaporated under vacuum and the product was extracted from EtOAc / water. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography using DCM / MeOH (0-10% MeOH) to give methyl 2-(cyclopentan-1-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (29 mg, 35% yield). LCMS [M+H] + 418.21 m / z. 1 H NMR(300MHz,chloroform-d)δ 7.92(s,1H),5.85(s,1H),5.21(s,2H),5.11(s,2H),4.32(q,J=2.7Hz,2H),3.97(t,J=5.3Hz,2H),3.90(s,3H),2.56(tq,J=5.2,2.5Hz,2H)

[0261] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-(1-methyl-2-azabicyclo[2.1.1]hexan-2-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 4): [ka] 2-Chloro-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (50 mg, 0.13 mmol, 1 eq.) and 4-methyl-3-azabicyclo[2.1.1]hexane (30 mg, 0.31 mmol, 2.38 eq.) were dissolved in DMSO (2.4 ml) and DIPEA (0.1 ml, 0.57 mmol, 4.38 eq.) was added. The reaction mixture was heated in a microwave reactor at 135° C. for 1 hour. 4-Methyl-3-azabicyclo[2.1.1]hexane (30 mg, 0.31 mmol, 2.38 eq.) was added and then heated at 135° C. for 2 hours and then at 145° C. for 45 minutes. Purification was performed with Biotage Isolera (ACN (0.1% FA) / H2O (0.1% FA) 0 / 100, then 0 / 100->80 / 20). Fractions containing the product were evaporated, triturated with Et2O (0.7 ml), decanted and dried under vacuum at 1 mbar for 3 h at room temperature to give the title product N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-(1-methyl-2-azabicyclo[2.1.1]hexan-2-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 9 mg (15% yield). LCMS [M+H] + 447m / z. 1 H NMR(300MHz,DMSO-d6)δ 11.23(s,1H),10.65(s,1H),8.00(s,1H),7.70(d,J=1.9Hz,1H),7.57(d,J=2.0Hz,1H),6.46(s,1H),5.06(s,2H),4.89( d,J=2.0Hz,2H),3.90(s,3H),3.38(s,2H),2.73(d,J=2.7Hz,1H),2.39(d,J=1.2Hz,3H),1.78-1.68(m,4H),1.63(s,3H).

[0262] 2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 5): [ka] A 100 μl Chromacol 01-CVG vial was charged with 6,6-difluoro-3-azabicyclo[3.1.0]hexane (2.4 μmol), 2-chloro-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (2.4 μmol), dry DMSO (48 μl) and DIPEA (9.6 μmol, 1.7 μl). The mixture was heated at 140°C overnight, cooled and spun down. The reaction mixture was transferred to a Twin.Tec plate and evaporated using a SpeedVac (45°C, 1-2 hours). The crude product was purified by HPLC-CLND to give the pure title compound 2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 161 μg. LCMS [M+H] + 469.17m / z

[0263] Preparation of 2-(dimethylamino)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 6): [ka] To a solution of 2-chloro-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (200 mg, 1 eq.) in dry DMF was added NHMe2 (2M in THF, 1.0 mL) and the reaction mixture was stirred for 1 h at 120° C. The crude reaction mixture was filtered through a Celite® pad and purified directly by reverse phase preparative HPLC to give the title product 2-(dimethylamino)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide as a pale pink solid (55 mg). 1H NMR(300MHz,DMSO-d6)δ 10.63(s,1H),10.45(s,1H),7.73(d,J=2.0Hz,1H),7.70(s,1H),7.56(d,J=2.0Hz,1H),6.44(d,J=1.3 Hz,1H),5.00(t,J=2.1Hz,2H),4.84(t,J=2.1Hz,2H),3.88(s,3H),2.97(s,6H),2.37(d,J=1.1Hz,3H).

[0264] Preparation of N-(4,8-dimethyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 7): [ka]

[0265] Preparation of methyl 2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: [ka] To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (213.6 mg, 1 mmol, 1 equiv.) in dry DMSO (5 mL), morpholine (175 μL, 2 mmol, 2 equiv.) and DIPEA (522 μL, 3 mmol, 3 equiv.) were added and stirred at 125° C. for 3 h. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The extracts were combined, washed with water, 5% LiCl, and brine, dried over anhydrous Na2SO4, filtered, and evaporated. The crude compound was purified by flash chromatography using EtOAc / heptane (20-70% EtOAc) to give methyl 2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (177.7 mg, 67% yield) as a white solid.

[0266] Preparation of 2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid: [ka] To a solution of methyl 2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (40 mg, 0.15 mmol, 1 eq) in methanol (2 mL) and THF (2 mL) was added 2M LiOH (350 μL, 0.35 mmol, 2 eq) and the reaction mixture was stirred at 30° C. for 3 h. After completion, 2N HCl was added to neutralize (350 μL, 0.35 mmol, 2 eq). The solvent was evaporated under vacuum with acetone and toluene to remove the acid, giving crude 2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid as a yellow solid. LCMS [M+H] + 251.17m / z.

[0267] Preparation of N-(4,8-dimethyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 7): [ka] To a solution of 2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.15 mmol, 1 equiv.) and 6-amino-4,8-dimethyl-1H-quinolin-2-one (31 mg, 0.15 mmol, 1 equiv.) in DMF (5 mL) was added DIPEA (80 μL, 0.45 mmol, 3 equiv.) and HATU (63.3 mg, 0.16 mmol, 1.1 equiv.) and the reaction mixture was stirred at 60° C. overnight.

[0268] After completion, the reaction mixture was poured into water and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with water, 5% LiCl and brine. The precipitate was filtered off, washed with water and dried to give 31.3 mg of the title compound N-(4,8-dimethyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide as a white solid (49% yield for two steps). LCMS [M+H] + 421.22m / z. 1H NMR(300MHz,DMSO-d6)δ 10.73(s,1H),10.52(s,1H),8.02(d,J=2.2Hz,1H),7.83(s,1H),7.72-7.65(m,1H),6.46(d,J=1.3Hz,1H),5.04( d,J=2.2Hz,2H),4.89(t,J=2.1Hz,2H),3.70-3.57(m,4H),3.28-3.22(m,4H),2.44(s,3H),2.40(d,J=1.2Hz,3H).

[0269] Preparation of N-(6-methyl-8-oxo-3,9-dihydro-2H-furo[3,2-h]quinolin-4-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 8): [ka] N-(6-methyl-8-oxo-3,9-dihydro-2H-furo[3,2-h]quinolin-4-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide was prepared from 2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid and 4-amino-6-methyl-3,9-dihydro-2H-furo[3,2-h]quinolin-8-one according to the procedure described in Example 7 (N-(4,8-dimethyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide). Obtained 22.5 mg (33% yield over two steps) of N-(6-methyl-8-oxo-3,9-dihydro-2H-furo[3,2-h]quinolin-4-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide. LCMS [M+H] + 449.19m / z. 1 H NMR(300MHz,DMSO-d6)δ 11.06(s,1H),10.21(s,1H),7.87(s,1H),7.62(s,1H),6.37(s,1H),5.05(s,2H),4. 89(s,2H),4.78-4.68(m,2H),3.68(t,J=4.5Hz,4H),3.00-3.50(m,4H),2.37(s,3H).

[0270] Preparation of N-(7-fluoro-8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 9): [ka] N-(7-fluoro-8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide was prepared from 2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid and 6-amino-7-fluoro-8-methoxy-4-methyl-1H-quinolin-2-one according to the procedure described in Example 7 (N-(4,8-dimethyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide). Obtained 9.4 mg (14% yield) of N-(7-fluoro-8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide. LCMS [M+H] + 455.16m / z. 1 H NMR(300MHz,DMSO-d6)δ 11.25(s,1H),10.87(s,1H),8.07-7.98(m,2H),6.45(s,1H),5.07(s,2H),4.92( d,J=2.1Hz,2H),3.93(s,3H),3.78-3.67(m,4H),3.30-3.20(m,4H),2.40(s,3H).

[0271] Preparation of N-(7-methyl-9-oxo-3,10-dihydro-2H-[1,4]dioxino[2,3-h]quinolin-5-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 10): [ka] N-(7-methyl-9-oxo-3,10-dihydro-2H-[1,4]dioxino[2,3-h]quinolin-5-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide was prepared from 2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid and 5-amino-7-methyl-3,10-dihydro-2H-[1,4]dioxino[2,3-h]quinolin-9-one according to the procedure described in Example 7 (N-(4,8-dimethyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide). The precipitate was further washed with DMF and 25% water in acetonitrile to give the desired product. Obtained 21.7 (25% yield) mg of N-(7-methyl-9-oxo-3,10-dihydro-2H-[1,4]dioxino[2,3-h]quinolin-5-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide. LCMS [M+H] + 465.1m / z. 1 H NMR(300MHz,DMSO-d6)δ 11.01(s,1H),10.76(s,1H),8.33(s,1H),8.21(s,1H),6.32(s,1H),5.09(s,2H),4.94(t,J=2.0H z,2H),4.54-4.38(m,4H),3.78(dd,J=6.5,3.0Hz,4H),3.18(dd,J=6.0,3.3Hz,4H),2.38(s,3H).

[0272] Preparation of N-(4,7-dimethyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 11): [ka] N-(4,7-dimethyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide was prepared from 2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid and 6-amino-4,7-dimethyl-1H-quinolin-2-one according to the procedure described in Example 7 (N-(4,8-dimethyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide). The precipitate was further washed with DMF and 25% water in acetonitrile to give the product.

[0273] Obtained 26.9 mg (38% yield) of N-(4,7-dimethyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide. LCMS [M+H]+ 421.17 m / z. 1 H NMR(300MHz,)δ 11.57(s,1H),10.08(s,1H),7.91(s,1H),7.85(s,1H)7.18(s,1H),6.37(s,1H),5.06(s,2H),4 .89(t,J=2.1Hz,2H),3.71(dd,J=5.3,3.8Hz,4H),3.003.50(m,4H),2.39(s,3H),2.35(s,3H).

[0274] Preparation of N-(8-ethoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 12): [ka] N-(8-ethoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide was prepared from 2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid and 6-amino-8-ethoxy-4-methyl-1H-quinolin-2-one according to the procedure described in Example 7 (N-(4,8-dimethyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide). The precipitate was further washed with DMF and 25% water in acetonitrile to give the product. Obtained 31.2 mg (41% yield) of N-(8-ethoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide. LCMS [M+H] + 451.7m / z. 1 H NMR(300MHz,DMSO-d6)δ 10.63-10.50(m,2H),7.84(s,1H),7.76(d,J=1.9Hz,1H),7.55(d,J=1.9Hz,1H),6.46(s,1H),5.04(s,2H),4 .89(s,2H),4.14(q,J=6.9Hz,2H),3.70-3.60(m,4H),3.30-3.18(m,4H),2.39(s,3H),1.45(t,J=6.9Hz,3H).

[0275] Preparation of 2-morpholino-N-(4,7,8-trimethyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 13): [ka] 2-Morpholino-N-(4,7,8-trimethyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide was prepared from 2-Morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid and 6-amino-4,7,8-trimethyl-1H-quinolin-2-one according to the procedure described in Example 7 (N-(4,8-dimethyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide). The precipitate was further washed with water and EtOAc to give the product. Obtained 22.0 mg (33% yield) of 2-morpholino-N-(4,7,8-trimethyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide. LCMS [M+H] + 435.2m / z. 1 H NMR(300MHz,DMSO-d6)δ 10.63(s,1H),10.16(s,1H),7.91(s,1H),7.64(s,1H),6.41(s,1H),5.06(s,2H),4.9 5-4.85(m,2H),3.75-3.68(m,4H),3.00-3.5(m,4H),2.42-2.36(m,3H),2.28(s,3H).

[0276] Preparation of N-(7-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 14): [ka] N-(7-Methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide was prepared from 2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid and 6-amino-7-methoxy-4-methyl-1H-quinolin-2-one according to the procedure described in Example 7 (N-(4,8-dimethyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide). The precipitate was further washed with 5% acetonitrile in water to obtain the product. Obtained 34.5 mg (46% yield) of N-(7-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide. LCMS [M+H] + 437.62m / z. 1 H NMR(300MHz,DMSO-d6)δ 10.84(s,1H),8.75(s,1H),8.55(s 1H),8.18(s,1H),7.00(s,1H),6.30(s,1H),5.09(s,2H),4.94(s,2H),3.98(s,3H),3.79-3.72(m,4H),3.44-3.37(m,4H),2.39(s,3H).

[0277] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 15): [ka] To a solution of 2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (2.6 g, 10.4 mmol) in DMF (30 mL) were added 6-amino-8-methoxy-4-methylquinolin-2(1H)-one (2.12 g, 10.4 mmol), EDC·HCl (3.97 g, 20.8 mmol), HOAt (2.82 mg, 20.8 mmol) and DIPEA (7.5 mL, 41.6 mmol) successively at 0° C. The reaction mixture was then stirred at room temperature for 16 h. After completion, the reaction mixture was quenched with water (100 mL) and the precipitated solid was filtered, washed with cold water and dried under vacuum to give N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (2.26 g, 50%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ 10.64(br s,1H),10.56(br s,1H),7.83(s,1H),7.74(d,J=1.2Hz,1H),7.56(d,J=1.6Hz,1H),6.45(s,1H), 5.04(s,2H),4.88(s,2H),3.89(s,3H),3.65(t,J=3.6Hz,4H),3.26(t,J=3.6Hz 4H),2.38(s,3H),LCMS[M+H] + :437.17m / z.

[0278] Preparation of 2-(3,3-difluoropyrrolidin-1-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 16) [ka]

[0279] Preparation of methyl 2-(3,3-difluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (42.7 mg, 0.2 mmol, 1 equiv.) in dry DMSO (1 mL) was added 3,3-difluoropyrrolidine (57.4 mg, 0.4 mmol, 2 equiv.) and DIPEA (140 μL, 0.8 mmol, 4 equiv.) and the reaction mixture was stirred at 125° C. for 1 h. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography using EtOAc / heptane, (10-50% EtOAc) to give methyl 2-(3,3-difluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (128 mg, 56.6% yield) as a yellow solid. LCMS [M+H] + 285.19m / z. 1 H NMR(300MHz,DMSO-d6)δ 7.92(s,1H),4.99(s,2H),4.84(s,2H),3.83(s,3H),3.72(t,J=13.2Hz,2H),3.57(t,J=7.3Hz,2H),2.47-2.36(m,2H).

[0280] Preparation of 2-(3,3-difluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid: To a solution of methyl 2-(3,3-difluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (30 mg, 0.125 mmol, 1 eq.) in methanol (1 mL) and THF (1 mL), 2M LiOH was added (125 μL, 0.250 mmol, 2 eq.) and the reaction mixture was stirred at 35° C. for 3 h. After completion, 2N HCl was added to neutralize (125 μL, 0.250 mmol, 2 eq.). The solvent was evaporated under vacuum with acetonitrile and toluene to remove excess HCl to give 2-(3,3-difluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid as a yellow solid. LCMS [M+H] + 285.19m / z.

[0281] Preparation of 2-(3,3-difluoropyrrolidin-1-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 16): To a solution of 2-(3,3-difluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.125 mmol, 1 equiv.) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (25.3 mg, 0.125 mmol, 1 equiv.) in DMF (4 mL) was added DIPEA (60 μL, 0.35 mmol, 3 equiv.) and HATU (47 mg, 0.125 mmol, 1 equiv.) and the reaction mixture was stirred at 35° C. for 3 h and then at room temperature overnight.

[0282] After completion, the reaction mixture was poured into water and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with water, 5% LiCl and brine. After evaporation of the solvent, the crude product was further washed with 25% water in acetonitrile and then dried to give 34 mg of 2-(3,3-difluoropyrrolidin-1-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide as an off-white solid (17% yield over two steps). LCMS [M+H] + 455.4m / z. 1 H NMR(300MHz,DMSO-d6)δ 10.66(s,1H),10.59(s,1H),7.77(s,1H),7.73(d,J=1.9Hz,1H),7.56(d,J=1.9Hz,1H),6.46(s,1H) ,5.02(s,2H),4.87(s,2H),3.89(s,3H),3.80(t,J=13.2Hz,2H),3.65(t,J=7.2Hz,2H),2.38(s,3H).

[0283] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 17): [ka]

[0284] Preparation of methyl 2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (42.7 mg, 0.2 mmol, 1 equiv.) in dry DMSO (1 mL) was added 3-oxa-8-azabicyclo[3.2.1]octane (60 mg, 0.4 mmol, 2 equiv.) and DIPEA (140 μL, 0.8 mmol, 4 equiv.) and the reaction mixture was stirred at 125° C. for 1 h. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography using EtOAc / heptane (10-50% EtOAc) to give 48 mg of methyl 2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (33% yield) as a white solid. LCMS [M+H] + 291.16 m / z.

[0285] Preparation of 2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid: To a solution of methyl 2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (41 mg, 0.14 mmol, 1 eq.) in methanol (1 mL) and THF (1 mL), 2M LiOH was added (400 μL, 0.80 mmol) and the reaction mixture was stirred at 35° C. for 3 h. After completion, 2N HCl was added (400 μL, 0.80 mmol). The solvent was evaporated under vacuum with acetonitrile and toluene to remove excess HCl to give 2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid as a white solid. LCMS [M+H] + 277.14m / z.

[0286] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 17): To a solution of 2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.14 mmol, 1 equiv.) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (31.7 mg, 0.155 mmol, 1.1 equiv.) in DMF (4 mL) was added DIPEA (74 μL, 0.42 mmol, 3 equiv.) and HATU (59 mg, 0.155 mmol, 1.1 equiv.) and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl, and brine. After evaporation of the solvent, the crude product was purified by flash chromatography on a silica gel column using DCM / MeOH (0-10% MeOH) to give 39 mg of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide as an off-white solid (Example 17) (51% yield for two steps). LCMS [M+H] + 463.18m / z. 1 H NMR(300MHz,DMSO-d6)δ 10.65(s,1H),10.48(s,1H),7.77-7.71(m,2H),7.56(d,J=1.9Hz,1H),6.45(s,1H),5.02(s,2H),4.86(s ,2H),4.23-4.14(m,2H),3.88(s,3H),3.68(d,J=10.5Hz,2H),3.54-3.44(m,2H),2.38(d,J=1.2Hz,3H).

[0287] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(2R)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 18): [ka]

[0288] Preparation of methyl 2-[(2R)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (42.7 mg, 0.2 mmol, 1 equiv.) in dry DMSO (1 mL) was added (2R)-2-methylpyrrolidine (60 mg, 0.4 mmol, 2 equiv.) and DIPEA (140 μL, 0.8 mmol, 4 equiv.) and the reaction mixture was stirred at 125° C. for 1 h. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography using EtOAc / heptane (10-50% EtOAc) to give methyl 2-[(2R)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (43 mg, 83% yield) as a white solid. LCMS [M+H] + 263.19m / z. 1 H NMR(300MHz,DMSO-d6)δ 7.81(s,1H),4.96(s,2H),4.88-4.72(m,2H),4.32-4.17(m,1H),3.80(s,3H),3.58-3.42(m,1H),2 .86-2.75(m,1H),2.18-2.05(m,1H),1.95-1.82(m,1H),1.80-1.43(m,2H),1.20(d,J=6.0Hz,3H).

[0289] Preparation of 2-[(2R)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid: To a solution of methyl 2-[(2R)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (42 mg, 0.16 mmol, 1 eq) in methanol (1 mL) and THF (1 mL) was added 2M LiOH (160 μL, 0.32 mmol) and the reaction mixture was stirred at 35° C. for 3 h. After completion, 2N HCl was added to neutralize (160 μL, 0.32 mmol). The solvent was evaporated under vacuum with acetonitrile and toluene to remove excess HCl to give 2-[(2R)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid as a white solid. LCMS [M+H] + 249.16m / z.

[0290] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(2R)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 18): To a solution of 2-[(2R)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.18 mmol, 1.1 equiv.) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (36 mg, 0.18 mmol, 1.1 equiv.) in DMF (4 mL), DIPEA (84 μL, 0.48 mmol, 3 equiv.) and HATU (67 mg, 0.18 mmol, 1.1 equiv.) were added and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl, and brine. After evaporation of the solvent, the crude product was purified by preparative chromatography to give 16 mg of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(2R)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 18) as an off-white solid (23% yield over two steps). LCMS [M+H] + 435.23m / z. 1H NMR (300MHz, DMSO-d6) δ 10.62(s,1H),10.46(s,1H),7.74(d,J=2.0Hz,1H),7.66(s,1H),7.56(d,J=2.0 Hz,1H),6.45(d,J=1.4Hz,1H),4.99(s,2H),4.90-4.75(m,2H),4.35-4.21(m,1 H),3.88(s,3H),3.20-3.11(m,1H),2.38(d,J=1.2Hz,3H),2.15-1.97(m,1H),1 .95-1.83(m,1H),1.80-1.62(m,1H),1.60-1.47(m,1H),1.20(d,J=6.0Hz,3H).

[0291] Preparation of 2-(2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 19): [ka]

[0292] Preparation of methyl 2-(2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (42.7 mg, 0.2 mmol, 1 equiv.) in dry DMSO (1 mL) was added 3,3a,4,5,6,6a-hexahydro-2H-furo[2,3-c]pyrrole (60 mg, 0.4 mmol, 2 equiv.) and DIPEA (140 μL, 0.8 mmol, 4 equiv.) and the reaction mixture was stirred at 125° C. for 1.5 h. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography using EtOAc / heptane (2-50% EtOAc) to give methyl 2-(2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (39.8 mg, 68% yield) as a white solid. LCMS [M+H] + 291.17m / z. 1 H NMR(300MHz,DMSO-d6)δ 7.81(s,1H),4.96(s,2H),4.88-4.73(m,2H),4.48-4.40(m,1H),3.85(dd,J=8.3,7.3Hz,1H),3.81(s,3H),3.78-3.67(m ,1H),3.63-3.54(m,1H),3.50-3.38(m,1H),3.38-3.25(m,2H),2.99-2.86(m,1H),2.12-1.97(m,1H),1.88-1.77(m,1H).

[0293] Preparation of 2-(2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid: To a solution of methyl 2-(2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (39 mg, 0.13 mmol, 1 equiv.) in methanol (1 mL) and THF (1 mL), 2M LiOH was added (134 μL, 0.26 mmol, 2 equiv.) and the reaction mixture was stirred at 35° C. for 2 days. Upon completion, 2N HCl was added to neutralize (134 μL, 0.26 mmol). The solvent was evaporated under vacuum with acetonitrile and toluene to remove excess HCl to give 2-(2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid as a white solid. LCMS[M+H] + ; 277.14m / z.

[0294] Preparation of 2-(2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 19): To a solution of 2-(2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.13 mmol, 1.0 equiv.) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (30 mg, 0.15 mmol, 1.1 equiv.) in DMF (3 mL) was added DIPEA (70 μL, 0.4 mmol, 3 equiv.) and HATU (56 mg, 0.15 mmol, 1.1 equiv.) and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl, and brine. After evaporation of the solvent, the crude product was purified by preparative chromatography to give 26 mg of 2-(2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 19) as an off-white solid (42% yield over two steps). LCMS [M+H] + 463.18m / z. 1 H NMR (300MHz, DMSO-d6) δ 10.65(s,1H),10.49(s,1H),7.73(d,J=1.9Hz,1H),7.67(s,1H),7.55(d,J=1 .9Hz,1H),6.45(s,1H),4.99(s,2H),4.89-4.77(m,2H),4.47-4.40(m,1H),3 .88(s,3H),3.86-3.77(m,1H),3.73-3.65(m,1H),3.62-3.45(m,3H),3.45(s ,1H),2.96-2.84(m,1H),2.38(s,3H),2.09-1.95(m,1H),1.80-1.69(m,1H).

[0295] Preparation of 2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 20): [ka]

[0296] Preparation of methyl 2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (42 mg, 0.2 mmol, 1 equiv.) in dry DMSO (1 mL) was added 3,3a,4,5,6,6a-hexahydro-1H-furo[3,4-c]pyrrole (45 mg, 0.4 mmol, 2 equiv.) and DIPEA (140 μL, 0.8 mmol, 4 equiv.) and the reaction mixture was stirred at 125° C. for 1 h. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography using EtOAc / heptane (10-70% EtOAc) to give methyl 2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (45.5 mg, 78% yield) as a white solid. LCMS [M+H] + 291.17m / z. 1 H NMR(300MHz,DMSO-d6)δ 7.80(s,1H),4.96(s,2H),4.80(s,2H),3.81(s,3H),3.80-3.75(m,2H),3.60-3.44(m,4H),3.28-3.20(m,2H),2.99-2.87(m,2H).

[0297] Preparation of 2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid: To a solution of methyl 2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (45 mg, 0.16 mmol, 1 eq.) in methanol (1 mL) and THF (1 mL), 2M LiOH was added (200 μL, 3 eq.) and the reaction mixture was stirred at 35° C. overnight. 2N HCl was added (200 μL). The solvent was evaporated in vacuum with acetonitrile and toluene to remove excess HCl to give crude 2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid as a white solid (42 mg). LCMS [M+H] + 277.14m / z.

[0298] Preparation of 2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 20): To a solution of 2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.16 mmol, 1.0 equiv.) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (36 mg, 0.17 mmol, 1.1 equiv.) in DMF (4 mL) was added DIPEA (84 μL, 0.48 mmol, 3 equiv.) and HATU (65 mg, 0.17 mmol, 1.1 equiv.) and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl, and brine. After evaporation of the solvent, the crude product was further washed with 25% water in acetonitrile and then dried to give 23.4 mg of 2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 20) as an off-white solid (32.6% yield over two steps). LCMS [M+H] + 463.24m / z. 1 H NMR(300MHz,DMSO-d6)δ 10.64(s,1H),10.48(s,1H),7.74(d,J=1.9Hz,1H),7.68(s,1H),7.55(d,J=1.9Hz,1H),6.45(s,1H),5.00(s,2H),4.90-4.78(s,2H),3.88 (s,3H),3.79(dd,J=8.7,6.6Hz,2H),3.58(dd,J=10.6,7.4Hz,2H),3.51-3.43(m,2H),3.41-3.36(m,2H),2.96-2.90(m,2H),2.38(s,3H).

[0299] Preparation of 2-(8-azabicyclo[3.2.1]octan-8-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 21): [ka]

[0300] Preparation of methyl 2-(8-azabicyclo[3.2.1]octan-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (42 mg, 0.2 mmol, 1 equiv.) in dry DMSO (1 mL), 8-azabicyclo[3.2.1]octane hydrochloride (60 mg, 0.4 mmol, 2 equiv.) and DIPEA (140 μL, 0.8 mmol, 4 equiv.) were added and the reaction mixture was stirred at 125° C. for 1 h. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography using EtOAc / heptane (10-50% EtOAc) to give methyl 2-(8-azabicyclo[3.2.1]octan-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (45.5 mg, 47.5% yield) as a white solid. LCMS [M+H] + 289.18m / z.1H NMR(300MHz,DMSO-d6)δ 7.80(s,1H),4.95(s,2H),4.79(t,J=2.0Hz,2H),4.23(s,2H),3.80(s,3H),3.08(s,1H),1.85-1.62(m,6H),1.51-1.35(m,3H).

[0301] Preparation of 2-(8-azabicyclo[3.2.1]octan-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid: To a solution of methyl 2-(8-azabicyclo[3.2.1]octan-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (45 mg, 0.16 mmol, 1 eq.) in methanol (1 mL) and THF (1 mL), 2M LiOH was added (200 μL, 3 eq.) and the reaction mixture was stirred at 37° C. overnight. 2N HCl (200 μL) was added to the mixture. The solvent was evaporated under vacuum with acetonitrile and toluene to remove excess HCl to give crude 2-(8-azabicyclo[3.2.1]octan-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid as a white solid. LCMS [M+H]+ 275.19 m / z.

[0302] Preparation of 2-(8-azabicyclo[3.2.1]octan-8-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 21): To a solution of 2-(8-azabicyclo[3.2.1]octan-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (26 mg, 0.095 mmol, 1.0 equiv.) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (21 mg, 0.105 mmol, 1.1 equiv.) in DMF (4 mL), DIPEA (50 μL, 0.28 mmol, 3 equiv.) and HATU (40 mg, 0.105 mmol, 1.1 equiv.) were added and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl, and brine. After evaporation of the solvent, the crude product was further washed with 25% water in acetonitrile and 2% MeOH in DCM, then dried to give 18.1 mg of 2-(8-azabicyclo[3.2.1]octan-8-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 21) as an off-white solid (41.4% yield over two steps). LCMS [M+H] + 461.26m / z. 1H NMR(300MHz,DMSO-d6)δ 10.63(s,1H),10.45(s,1H),7.73(d,J=1.9Hz,1H),7.67(s,1H),7.54(d,J=1.9Hz,1H),6.45(s,1H),5.00(t,J =1.9Hz,2H),4.84(t,J=2.1Hz,2H),4.33(s,2H),3.87(s,3H),2.37(s,3H),1.891.58(m,7H),1.511.28(m,3H).

[0303] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[rac-(3aR,6aR)-2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 22): [ka]

[0304] Preparation of methyl 2-[rac-(3aR,6aR)-2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (42 mg, 0.2 mmol, 1 equiv.) in dry DMSO (1 mL) was added rac-(3aR,6aR)-hexahydro-2H-furo[2,3-c]pyrrole hydrochloride (45 mg, 0.4 mmol, 2 equiv.) and DIPEA (140 μL, 0.8 mmol, 4 equiv.) and the reaction mixture was stirred at 125° C. for 1 h. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography using EtOAc / heptane (20-70% EtOAc) to give methyl 2-[rac-(3aR,6aR)-2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (43.3 mg, 74% yield) as a white solid. LCMS [M+H] + 291.17m / z. 1 H NMR(300MHz,DMSO-d6)δ 7.81(s,1H),4.96(s,2H),4.88-4.70(m,2H),4.44(t,J=5.0Hz,1H),3.81(s,3H),3.77-3.68(m,1H),3.58(dd,J= 12.5,4.7Hz,1H),3.50-3.38(m,2H),3.38-3.24(m,2H),2.99-2.85(m,1H),2.15-1.96(m,1H),1.88-1.77(m,1H).

[0305] Preparation of 2-[rac-(3aR,6aR)-2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid: To a solution of methyl 2-[rac-(3aR,6aR)-2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (41 mg, 0.145 mmol, 1 equiv.) in methanol (1 mL) and THF (1 mL) was added 2M LiOH (250 μL, 4 equiv.) and the reaction mixture was stirred overnight at 35° C. Upon completion, 2N HCl was added to neutralize (250 μL). The solvent was evaporated under vacuum with acetonitrile and toluene to remove excess HCl to give crude 2-[rac-(3aR,6aR)-2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid as a white solid. LCMS [M+H] + 277.14m / z.

[0306] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[rac-(3aR,6aR)-2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 22): To a solution of 2-[rac-(3aR,6aR)-2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.145 mmol, 1.0 equiv.) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (33 mg, 0.16 mmol, 1.1 equiv.) in DMF (3 mL), DIPEA (76 μL, 0.43 mmol, 3 equiv.) and HATU (61 mg, 0.16 mmol, 1.1 equiv.) were added and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl, and brine. After evaporation of the solvent, the crude product was purified by preparative chromatography to give 28 mg of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[rac-(3aR,6aR)-2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide as an off-white solid (Example 22) (41.8% yield over two steps). LCMS [M+H] + 463.24m / z. 1 H NMR(300MHz,DMSO-d6)δ 10.63(s,1H),10.49(s,1H),7.73(d,J=1.9Hz,1H),7.67(s,1H),7.55(d,J=1.9Hz,1H), 6.45(s,1H),5.00(t,J=1.9Hz,2H),4.90-4.76(m,2H),4.47-4.40(m,1H),3.88(s,3H), 3.85-3.78(m,1H),3.69(td,J=8.2,4.7Hz,1H),3.62-3.45(m,3H),3.40(dd,J=6.2,5.0 Hz,1H),2.97-2.85(m,1H),2.38(d,J=1.2Hz,3H),2.08-1.95(m,1H),1.80-1.70(m,1H).

[0307] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 23): [ka]

[0308] Preparation of methyl 2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (42 mg, 0.2 mmol, 1 equiv.) in dry DMSO (1 mL) was added (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (45 mg, 0.4 mmol, 2 equiv.) and DIPEA (140 μL, 0.8 mmol, 4 equiv.) and the reaction mixture was stirred at 125° C. for 1 h. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography using EtOAc / heptane (20-70% EtOAc) to give methyl 2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (33 mg, 59.8% yield) as a white solid. LCMS [M+H] + 277.17m / z. 1 H NMR(300MHz,DMSO-d6)δ 7.85(s,1H),4.97(s,2H),4.89-4.73(m,3H),4.58(s,1H),3.80(s,3H),3.78-3.70(m,2H),3.54 (dd,J=10.2,1.6Hz,1H),2.68(dd,J=10.3,1.4Hz,1H),1.90-1.77(m,2H),1.24(d,J=3.4Hz,1H).

[0309] Preparation of 2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid: To a solution of methyl 2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (33 mg, 0.12 mmol, 1 eq.) in methanol (1 mL) and THF (1 mL), 2M LiOH was added (200 μL) and the reaction mixture was stirred at 35° C. for 2 days. 2N HCl was added to neutralize (200 μL). The solvent was evaporated under vacuum with acetonitrile and toluene to remove excess HCl to give crude 2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid as a white solid. LCMS [M+H] + 263.13m / z.

[0310] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 23): To a solution of 2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.12 mmol, 1.0 equiv.) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (33 mg, 0.16 mmol, 1.1 equiv.) in DMF (3 mL), DIPEA (76 μL, 0.43 mmol, 3 equiv.) and HATU (61 mg, 0.16 mmol, 1.1 equiv.) were added and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl, and brine. After evaporation of the solvent, the crude product was purified by preparative chromatography to give 11.6 mg of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 23) as an off-white solid (21.6% for two steps). LCMS [M+H] + 449.22m / z. 1 H NMR(300MHz,DMSO-d6)δ 10.63(s,1H),10.49(s,1H),7.72(d,J=1.9Hz,1H),7.68(s,1H),7.54(d,J=1.9Hz,1H),6.45(s,1H),5.00(s,2H),4.92-4.76(m,3H) ,4.57(s,1H),3.88(s,3H),3.76(s,2H),3.54(dd,J=10.0,1.6Hz,1H),2.91-3.07(m,1H),2.37(d,J=1.2Hz,3H),1.90-1.75(m,2H).

[0311] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 24) [ka]

[0312] Preparation of methyl 2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (64 mg, 0.3 mmol, 1 equiv.) in dry DMSO (2 mL), (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (81 mg, 0.6 mmol, 2 equiv.) and DIPEA (209 μL, 0.8 mmol, 4 equiv.) were added and the reaction mixture was stirred at 125° C. for 1 h. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography using EtOAc / heptane (30-70% EtOAc) to give methyl 2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (47.5 mg, 60% yield) as a white solid. LCMS [M+H] + 277.14m / z. 1 H NMR(300MHz,DMSO-d6)δ 7.85(s,1H),4.97(s,2H),4.87-4.73(m,3H),4.58(s,1H),3.80(s,3H),3.77-3.7 0(m,2H),3.54(dd,J=10.2,1.6Hz,1H),2.68(d,J=10.2Hz,1H),1.91-1.78(m,2H).

[0313] Preparation of 2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid: To a solution of methyl 2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (47 mg, 0.17 mmol, 1 eq.) in methanol (1 mL) and THF (1 mL), 2M LiOH was added (350 μL) and the reaction mixture was stirred at 35° C. for 2 days. 2N HCl was added (350 μL). The solvent was evaporated under vacuum with acetonitrile and toluene to remove excess HCl to give crude 2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid as a white solid. LCMS [M+H] + 263.12 m / z.

[0314] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 24) To a solution of 2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.17 mmol, 1.0 equiv.) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (39 mg, 0.19 mmol, 1.1 equiv.) in DMF (3 mL), DIPEA (90 μL, 0.5 mmol, 3 equiv.) and HATU (71 mg, 0.19 mmol, 1.1 equiv.) were added and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl, and brine. After evaporation of the solvent, the crude product was purified by preparative chromatography to give N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 24) as an off-white solid (22.8 mg, 29.6% yield over two steps). LCMS [M+H]+ 449.16m / z. 1 H NMR(300MHz,DMSO-d6)δ 10.64(s,1H),10.50(s,1H),7.72(d,J=1.9Hz,1H),7.69(s,1H),7.54(d,J=1.9Hz,1H),6.45(s,1H),5.01(s,2H),4.94-4.75(m,3H),4.56 (d,J=2.2Hz,1H),3.88(s,3H),3.76(s,2H),3.54(dd,J=9.9,1.6Hz,1H),2.99(d,J=9.9Hz,1H),2.37(d,J=1.2Hz,3H),1.87-1.77(m,2H).

[0315] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(2S)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 25): [ka]

[0316] Preparation of methyl 2-[(2S)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (64 mg, 0.3 mmol, 1 equiv.) in dry DMSO (2 mL), (2S)-2-methylpyrrolidine (51 mg, 0.6 mmol, 2 equiv.) and DIPEA (209 μL, 0.8 mmol, 4 equiv.) were added and the reaction mixture was stirred at 125° C. for 1 h. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography using EtOAc / heptane (10-90% EtOAc) to give methyl 2-[(2S)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (57 mg, 72% yield) as a white solid. LCMS [M+H]+ 263.12 m / z. 1 H NMR(300MHz,DMSO-d6)δ 7.81(d,J=0.9Hz,1H),4.96(s,2H),4.80(qt,J=13.6,1.9Hz,2H),4.1-4.19(m,1H),3.80(s,3H),3.50-3.42 (m,1H),2.85-2.75(m,1H),2.20-2.06(m,1H),1.99-1.80(m,1H),1.73-1.47(m,2H),1.20(d,J=6.0Hz,3H).

[0317] Preparation of 2-[(2S)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid: To a solution of methyl 2-[(2S)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (56 mg, 0.21 mmol, 1 eq) in methanol (1 mL) and THF (1 mL), 2M LiOH was added (350 μL) and the reaction mixture was stirred at 35° C. for 2 days. After completion, 2N HCl was added to neutralize (350 μL). The solvent was evaporated under vacuum with acetonitrile and toluene to remove excess HCl to give crude 2-[(2S)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid as a white solid. LCMS [M+H] + 249.15m / z.

[0318] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(2S)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 25): To a solution of 2-[(2S)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.21 mmol, 1.0 equiv.) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (48 mg, 0.23 mmol, 1.1 equiv.) in DMF (3 mL), DIPEA (149 μL, 0.85 mmol, 4 equiv.) and HATU (97 mg, 0.25 mmol, 1.2 equiv.) were added and the reaction mixture was stirred at 35° C. overnight. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl, and brine. After evaporation of the solvent, the crude product was purified by preparative chromatography to give N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(2S)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide as an off-white solid (16.7 mg, 18% yield over two steps). LCMS [M+H] + 435.17m / z. 1 H NMR(300MHz,DMSO-d6)δ 10.63(s,1H),10.46(s,1H),7.74(d,J=1.9Hz,1H),7.66(s,1H),7.56(d,J=1.9Hz, 1H),6.45(s,1H),5.04-4.97(m,2H),4.92-4.75(m,2H),4.35-4.22(m,1H),3.88(s ,3H),3.56-3.45(m,1H),3.20-3.11(m,2H),2.38(d,J=1.2Hz,3H),2.12-2.00(m,1 H),1.95-1.83(m,1H),1.77-1.62(m,1H),1.61-1.48(m,1H),1.20(d,J=6.0Hz,3H).

[0319] Preparation of 2-[cyclopropylmethyl(methyl)amino]-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 26) [ka]

[0320] Preparation of 2-[cyclopropylmethyl(methyl)amino]-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 26): Methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (60 mg, 0.28 mmol, 1 eq), 1-cyclopropyl-N-methyl-methanamine HCl salt (76 mg 0.63 mmol, 2.25 ml) and DIPEA (0.2 ml, 1.15 mmol, 4.1 eq) were dissolved in DMSO (0.5 ml) and shaken at 100° C. for 3 h, then at 60° C. overnight, at 100° C. for 1 h and cooled to room temperature. 5% aqueous LiCl was added (3.5 ml) and extracted with DCM (3×1.5 ml). The combined organic extracts were directly purified on Biotage Isolera (heptane / EtOAc 98 / 2, then 98 / 2->35 / 65). After completion, the reaction mixture was warmed to room temperature and the solvent was evaporated under vacuum. Fractions containing the product were evaporated to give 40 mg of methyl 2-[cyclopropylmethyl(methyl)amino]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate as a yellow oil. LCMS [M+H] + 263 m / z. The oil was dissolved in MeOH (0.5 ml) and 2M aqueous LiOH was added (0.2 ml, 0.4 mmol, 2.66 equiv). The reaction mixture was shaken at 60° C. for 4 h, cooled to room temperature and 5M HCl (0.085 ml, 0.425 mmol, 2.83 equiv) was added. The reaction mixture was evaporated, acetonitrile (4 ml) was added and evaporated. 60 mg of crude 2-[cyclopropylmethyl(methyl)amino]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid was obtained as a pale yellow oil. LC-MS [M+H] +249 m / z. The crude product was dissolved in DMF (0.4 ml) and DIPEA (0.1 ml, 0.57 mmol), 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (33 mg, 0.162 mmol) and HATU (76 mg, 0.2 mmol) were added. The reaction mixture was heated at 60° C. for 1.5 h and then cooled to room temperature. 5% aqueous LiCl (3 ml) was added and the product was extracted with EtOAc (2×1.5 ml). The extracts were combined and directly purified on a Biotage Isolera (SiO2NH) (heptane / EtOAc 100 / 0, then 100 / 0->18 / 82, then 18 / 82). The relevant fractions containing the product were evaporated, triturated with Et2O (solvent decanted) and dried at 1 mbar / room temperature for 2 h to give 2-[cyclopropylmethyl(methyl)amino]-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 17 mg, as a pale yellow powder. LCMS [M+H] + 435m / z, UV(254nm)>95%. 1 H NMR(300MHz,DMSO-d6)δ 10.63(s,1H),10.54(s,1H),7.87-7.62(m,2H),7.54(d,J=1.9Hz,1H),6.45(d,J=1.4Hz,1H),5.00(s,2H),4.84(t,J=2.0Hz,2H), 3.88(s,3H),3.29(d,J=6.6Hz,2H),2.98(s,3H),2.37(d,J=1.2Hz,3H),1.09-0.94(m,1H),0.50-0.33(m,2H),0.25-0.10(m,2H).

[0321] Preparation of 2-(diethylamino)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 27): [ka]

[0322] Preparation of methyl 2-(diethylamino)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (128 mg, 0.6 mmol, 1 equiv.) in DMSO (5 mL), N-ethylethanamine (125 mg, 1.2 mmol, 2 equiv.) and DIPEA (418 μL, 2.4 mmol, 4 equiv.) were added and the reaction mixture was stirred at 125° C. for 10 h. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl, and brine, dried over anhydrous Na2SO4, filtered, and evaporated. The crude product was purified by flash chromatography using EtOAc / heptane (10-90% EtOAc) to give methyl 2-(diethylamino)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (65 mg, 43%) as a white solid. LCMS [M+H] + 251.3m / z. 1 H NMR(300MHz,DMSO-d6)δ 7.75(s,1H),4.95(s,2H),4.79(t,J=2.0Hz,2H),3.80(s,3H),1.08(t,J=7.0Hz,6H).

[0323] Preparation of 2-(diethylamino)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid: To a solution of methyl 2-(diethylamino)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (65 mg, 0.26 mmol, 1 eq) in methanol (1 mL) and THF (1 mL) was added 2M LiOH (350 μL) and the reaction mixture was stirred at 35° C. for 2 days. 2N HCl was added (350 μL). The solvent was evaporated in vacuum with acetonitrile and toluene to remove excess HCl to give crude 2-(diethylamino)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid as a white solid. LCMS [M+H] + 237.51m / z.

[0324] Preparation of 2-(diethylamino)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 27): To a solution of 2-(diethylamino)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.26 mmol, 1.0 equiv) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (58 mg, 0.29 mmol, 1.1 equiv) in DMF (3 mL) was added DIPEA (181 μL, 1.09 mmol, 4 equiv), HOAt (71 mg, 0.29 mmol, 1.1 equiv) and EDC HCl (100 mg, 0.52 mmol, 2 equiv) and the reaction mixture was stirred at 35° C. overnight. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl and brine. After evaporation in vacuo, the crude product was further washed with 25% water in acetonitrile and DMF, then dried to give 42 mg of 2-(diethylamino)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide as an off-white solid (38% yield). LCMS [M+H] + 426.63m / z. 1 H NMR(300MHz,DMSO-d6)δ 10.72(s,1H),10.66(s,1H),7.73(s,1H),7.71(d,J=1.9Hz,1H),7.54(d,J=1.9Hz,1H),6.45(d,J=1.3Hz,1H),5.01( t,J=2.0Hz,2H),4.85(t,J=1.9Hz,2H),3.88(s,3H),3.39(q,J=7.0Hz,4H),2.38(d,J=1.2Hz,3H),1.15-1.03(m,6H).

[0325] Preparation of 2-[ethyl(isopropyl)amino]-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 28) [ka]

[0326] Preparation of methyl 2-[ethyl(isopropyl)amino]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (128 mg, 0.6 mmol, 1 equiv.) in dry DMSO (5 mL), N-ethylpropan-2-amine (125 mg, 1.2 mmol, 2 equiv.) and DIPEA (418 μL, 2.4 mmol, 4 equiv.) were added and the reaction mixture was stirred at 125° C. for 7 h and then at 80° C. for an additional 8 h. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography using EtOAc / heptane (10-90% EtOAc) to give methyl 2-[ethyl(isopropyl)amino]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (19 mg, 12% yield) as a white solid. LCMS [M+H] + 265.52m / z. 1 H NMR(300MHz,DMSO-d6)δ 7.77(s,1H),5.01-4.92(m,2H),4.80(t,J=2.0Hz,2H),3.79(s,3H),1.12(d,J=6.6Hz,6H),0.99(t,J=6.9Hz,3H).

[0327] Preparation of 2-[ethyl(isopropyl)amino]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid: To a solution of methyl 2-[ethyl(isopropyl)amino]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (18 mg, 0.07 mmol, 1 equiv.) in methanol (0.3 mL) and THF (0.3 mL) was added 2M LiOH (100 μL) and the reaction mixture was stirred at 35° C. overnight. Then 2N HCl (100 μL) was added. The solvent was evaporated in vacuum with acetonitrile and toluene to give crude 2-[ethyl(isopropyl)amino]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid as a white solid. LCMS [M+H] + 251.50 m / z.

[0328] Preparation of 2-[ethyl(isopropyl)amino]-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 28): To a solution of 2-[ethyl(isopropyl)amino]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.07 mmol, 1.0 equiv) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (15 mg, 0.075 mmol, 1.1 equiv) in DMF (1 mL) was added DIPEA (48 μL, 0.28 mmol, 4 equiv), HOAt (19 mg, 0.075 mmol, 1.1 equiv) and EDC·HCl (26 mg, 0.14 mmol, 2 equiv) and the reaction mixture was stirred at 35° C. overnight. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl and brine. After evaporation of the solvent, the crude product was purified by preparative chromatography to give 2-[ethyl(isopropyl)amino]-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide as an off-white solid (15 mg, 51% yield). LCMS [M+H] + 437.64m / z. 1H NMR(300MHz,DMSO-d6)δ 11.11(s,1H),10.68(s,1H),7.88(s,1H),7.68(d,J=1.9Hz,1H),7.53(d,J=1.9Hz,1H),6.46(s,1H),5.04(s,2H),4 .89(s,2H),3.97(q,J=6.6Hz,1H),3.89(s,3H),2.38(d,J=1.2Hz,3H),1.11(d,J=6.5Hz,6H),1.02(t,J=7.0Hz,3H).

[0329] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (Example 29): [ka]

[0330] Preparation of methyl 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate: 2-Chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (150 mg, 0.7 mmol, 1 equiv.) was dissolved in MeOH (2 mL) and DCM (4 mL) and cooled in an ice bath to which was added 2M diazomethyl(trimethyl)silane in hexanes (400 μL) and the reaction mixture was stirred at room temperature for 1 h. An additional 300 μL of diazomethyl(trimethyl)silane was added (total 700 μL, 1.4 mmol, 2 equiv.) and stirred for 30 min. After completion, the solvent was evaporated under vacuum to give methyl 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (145 mg, 98% yield). LCMS [M+H] + 212.12 m / z. 1 H NMR(300MHz,DMSO-d6)δ 7.93(t,J=1.1Hz,1H),3.74(s,3H),2.81(dd,J=8.2,7.1Hz,4H),2.04-1.92(m,2H).

[0331] Preparation of methyl 2-morpholino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate: To a solution of methyl 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (143 mg, 0.68 mmol, 1 equiv.) in dry DMSO (6 mL), morpholine (118 μL, 1.35 mmol, 2 equiv.) and DIPEA (354 μL, 2.03 mmol, 3 equiv.) were added and the reaction mixture was stirred at 120° C. overnight. The reaction mixture was then poured into 5% LiCl and extracted with EtOAc (2×30 mL). The combined extracts were washed with water, 5% LiCl, and brine. After evaporation of the solvent, the crude product was purified by silica flash chromatography in heptane / EtOAc (20-50% EtOAc) to give 111 mg of methyl 2-morpholino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (52% yield). LCMS [M+H]+ 263.2 m / z. 1 H NMR(300MHz,DMSO-d6)δ 7.80(s,1H),3.79(s,3H),3.71-3.60(m,4H),3.24-3.16(m,4H),2.85-2.75(m,4H),2.10-1.96(m,2H).

[0332] Preparation of 2-morpholino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid: To a solution of methyl 2-morpholino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (109 mg, 0.42 mmol, 1 equiv) in methanol (3 mL) and THF (4 mL) was added 2M LiOH (1.5 mL) and the reaction mixture was stirred at room temperature overnight. The organic solvent was evaporated under vacuum and the mixture was neutralized with 10% KHSO4. It was then extracted with EtOAc, washed with brine, dried and evaporated to give 77 mg of crude 2-morpholino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (75% yield). LCMS [M+H]+ 249.21 m / z. 1H NMR(300MHz,DMSO-d6)δ 13.55(s,1H),7.88(s,1H),3.74-3.61(m,4H),3.24-3.15(m,4H),2.90-2.79(m,4H),2.13-2.00(m,2H).

[0333] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (Example 29): To a solution of 2-morpholino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (77 mg, 0.31 mmol, 1.0 equiv) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (75 mg, 0.37 mmol, 1.2 equiv) in DMF (3 mL) was added DIPEA (267 μL, 1.53 mmol, 5 equiv), HOAt (50 mg, 0.37 mmol, 1.2 equiv) and EDC·HCl (70 mg, 0.37 mmol, 1.2 equiv) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under vacuum and the crude product was purified by silica gel flash chromatography with DCM / MeOH (0-10% MeOH) to give 80 mg of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (59% yield). LCMS [M+H] + 435.20 m / z. 1 H NMR(300MHz,DMSO-d6)δ 10.67(s,1H),10.64(s,1H),7.76(2H),7.59(d,J=1.9Hz,1H),6.45(s,1H),3.89(s,3H),3.67(t,J= 4.6Hz,4H),3.20(t,J=4.6Hz,4H),2.93-2.82(m,4H),2.39(d,J=1.2Hz,3H),2.09(q,J=7.7Hz,2H).

[0334] Preparation of (5R)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 30): [ka]

[0335] Preparation of methyl (5R)-5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: To a solution of (5R)-2-chloro-5-methyl-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (172 mg, 1 eq.) in dry DMF (2 mL) was added morpholine (2 mL) and the reaction was stirred at 100° C. for 1 h. After completion, the reaction mixture was poured into water and extracted with EtOAc. The combined extracts were washed with water, 5% LiCl, and brine, dried over anhydrous 2SO4, filtered, and evaporated. The crude compound was purified by flash chromatography using EtOAc / heptane (1-50% EtOAc) to give (5R)-5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (54.6 mg, 31% yield). LCMS [M+H]+: 279.21 m / z. 1 H NMR(300MHz,CDCl3)δ 7.86(d,J=0.9Hz,1H),5.34-5.24(m,1H),5.05-4.87(m,2H),3.92(s,3H),3.87-3.81(m,4H),3.47-3.38(m,4H),1.50(d,3H).

[0336] Preparation of (5R)-5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid: To a solution of methyl (5R)-5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (52 mg, 0.19 mmol, 1 equiv.) in methanol (0.5 mL) and THF (0.5 mL), 2M LiOH was added (200 μL) and the reaction mixture was stirred at room temperature overnight. 2N HCl (200 μL) was added. The solvent was evaporated in vacuum with acetonitrile and toluene to remove excess HCl to give crude (5R)-5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (90% yield). LCMS [M+H] + 279.2m / z.

[0337] Preparation of (5R)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 30): To a solution of (5R)-5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.19 mmol, 1.0 equiv) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (42 mg, 0.20 mmol, 1.1 equiv) in DMF (1 mL) was added DIPEA (65 μL, 0.37 mmol, 2 equiv) and HATU (78 mg, 0.20 mmol, 1.1 equiv) and the reaction mixture was stirred at 45° C. for 1.5 h. The solvent was evaporated under vacuum and the crude product was purified by reverse phase column chromatography to give 32 mg of (5R)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (38% yield). LCMS [M+H]+M / z+1451.28. 1H NMR(300MHz,DMSO-d6)δ 10.69-10.60(s,1H),10.56(s,1H),7.81(d,J=0.9Hz,1H),7.75(d,J=1.9Hz,1H),7.57(d,J=1.9Hz,1H),6.46(s,1H),5.33-5. 23(m,1H),4.95-4.80(m,2H),3.89(s,3H),3.69-3.61(m,4H),3.29-3.24(m,4H),2.39(d,J=1.2Hz,3H),1.43(d,J=6.3Hz,3H).

[0338] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 31) [ka] To a solution of ethyl 5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (50 mg, 0.18 mmol, 1 equiv.) in MeOH (0.5 ml), 2M aqueous LiOH (0.18 ml, 0.36 mmol, 2 equiv.) was added and shaken at 45° C. for 30 min. 2M aqueous LiOH (0.09 ml, 0.18 mmol, 1 equiv.) was added and shaken at 45° C. After 2 h, the reaction mixture was evaporated and 5M aqueous HCl (0.108 ml, 0.540, 3 equiv.) was added, followed by ACN (1 ml) and then evaporated. The residue was evaporated from toluene (2×1 ml). Crude 5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid was dissolved in DMF (0.7 ml) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (40 mg, 0.2 mmol, 1.1 equiv.) was added followed by DIPEA (0.062 ml, 0.36 mmol, 2 equiv.). HATU (76 mg, 0.2 mmol, 1.1 equiv.) was then added, sonicated and shaken at 45° C. After 1.5 h, HATU (15 mg, 0.039 mmol, 0.2 equiv.) was added and shaken at 45° C. for 15 min. The reaction mixture was directly purified on a Biotage Isolera (ACN (0.1% FA) / H2O (0.1% FA) 2 / 98, then 2 / 98->70 / 30). Fractions containing the product were evaporated, triturated with ACN (0.5 ml), filtered and washed with ACN (0.7 ml) to give N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 31), 26 mg (32% over two steps) as a brown oil. LCMS [M+H] + 451m / z. 1H NMR(300MHz,DMSO-d6)δ 10.63(s,1H),10.56(s,1H),7.81(d,J=0.9Hz,1H),7.75(d,J=2.0Hz,1H),7.57(d,J=1.9Hz,1H),6.46(s,1H),5.28(q,J=6.0 Hz,1H),5.00-4.71(m,2H),3.89(s,3H),3.69-3.62(m,4H),3.31-3.22(m,4H),2.39(d,J=1.2Hz,3H),1.43(d,J=6.3Hz,3H).

[0339] General method 1 [ka]

[0340] Protocol: A 100 mM solution of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide in dry THF (24 μl, 1 eq.) was mixed with a 300 mM solution of aldehyde in dry THF (24 μl, 3 eq.). This solution was then added to 6.0 μmol of SiliaBond cyanoborohydride in a filter plate. The plate was washed with 12 μl of 300 mM acetic acid in dry THF and shaken overnight at room temperature. THF (100 μl) was then added to the wells and the mixture was drained, collected and washed with 100 μl of acetonitrile. The solvent was removed by SpeedVac and the compounds were analyzed and purified by HPLC-CLND.

[0341] Analysis system: Agilent Infinity I / II -TOF6230B / CLND Antek 8060 equipped with an Acquity BEH C18 (1.7 μm, 2.1 × 50 mm) with a flow rate of 0.75 mL / min and a linear gradient of the binary solvent system water / methanol / formic acid (A: 100 / 0 / 0.1% and B: 0 / 100 / 0.1%) using a DAD.

[0342] Purification System: A Shimadzu Nexera X2 system using a C18 reversed-phase column (Merck Chromolith Speedrod RP-18E, 10 x 100 mm) with a linear gradient of the binary solvent system water / methanol / formic acid (A: 100 / 0 / 0.1% and B: 0 / 100 / 0.1%) with a flow rate of 7.0 mL / min and UV detection at 254 nm, coupled with MS detection by a Shimadzu LCMS [M+H]+-2020.

[0343] After purification, the solvent was removed by SpeedVac (45°C, 2-3 hours).

[0344] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-6-methyl-2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxamide (Example 32) [ka] This compound was prepared according to general method 1 by reacting (N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide) (Example 1) with formaldehyde. Isolated yield after purification: 14.8 μg. LCMS [M+H] + 450.22m / z.

[0345] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-6-(oxetan-3-yl)-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxamide (Example 33): [ka] This compound was prepared according to general method 1 by reacting (N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide) (Example 1) with oxetan-3-one. Isolated yield after purification: 150 μg. LCMS [M+H]+ 492.23 m / z.

[0346] Preparation of 6-ethyl-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxamide (Example 34): [ka] This compound was prepared according to general method 1 by reacting (N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide) (Example 1) with acetaldehyde. Isolated yield after purification: 105 μg. LCMS [M+H]+ 464.24 m / z.

[0347] Preparation of 6-isopropyl-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxamide (Example 35): [ka] This compound was prepared according to general method 1 by reacting (N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide) (Example 1) with acetone. Isolated yield after purification: 71 μg. LCMS [M+H] + 478.25m / z.

[0348] General method 2 [ka]

[0349] Preparation of N-(8-hydroxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide: [ka] To a suspension of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (800 mg, 1.83 mmol, 1.0 equiv.) in dry NMP (3.0 mL) was added Na2S (715 mg, 9.2 mmol, 5.0 equiv.) and the mixture was stirred at 140° C. for 48 h. The crude reaction mixture was then poured into ice-cold water (100 mL) and the aqueous solution was acidified to pH ∼4. The resulting precipitate was filtered and washed with HO to afford the title compound as a light brown solid (500 mg, 66%), which was used in the next step without further purification.

[0350] General Protocol for Alkylation A solution of N-(8-hydroxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (1 equiv.) and alkylating agent (2.0 equiv.) in DMF was treated with K2CO3 (3.0 equiv.) and the reaction mixture was stirred for 2-16 h at 100° C. The crude reaction mixture was then filtered through a cotton pad and directly purified by reverse phase preparative HPLC.

[0351] General protocol for deprotection The isolated intermediate was dissolved in a mixture of DMSO and 4M HCl in dioxane (1:1) and stirred for 2 h at 60° C. The reaction mixture was then concentrated in vacuo and the residue was purified by reverse phase preparative HPLC to give the final product.

[0352] Preparation of N-[8-(2-hydroxyethoxy)-4-methyl-2-oxo-1H-quinolin-6-yl]-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 36): [ka] Following the general protocol for alkylation, 0.23 mmol of N-(8-hydroxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 0.46 mmol of 2-bromoethanol and 0.39 mmol of K2CO3 was used to obtain the title compound N-[8-(2-hydroxyethoxy)-4-methyl-2-oxo-1H-quinolin-6-yl]-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide as a solid (30 mg, 27%). 1 H NMR(300MHz,DMSO-d6)δ 10.97(s,1H),10.56(s,1H),7.84(s,1H),7.76(d,J=1.9Hz,1H),7.53(d,J=1.9Hz,1H),6.48(t,J=1.6Hz,1H),5.35(t,J=6.9Hz,1H), 5.04(s,2H),4.88(s,2H),4.03(t,J=4.3Hz,2H),3.83(d,J=7.7Hz,2H),3.67-3.61(m,4H),3.28-3.23(m,4H),2.40(d,J=1.2Hz,3H).

[0353] Preparation of N-[8-(azetidin-3-yloxy)-4-methyl-2-oxo-1H-quinolin-6-yl]-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 37): [ka] Following the general protocol for alkylation, 0.34 mmol of N-(8-hydroxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 0.68 mmol of tert-butyl 3-bromoazetidine-1-carboxylate and 1.02 mmol of K2CO3 were used to give the intermediate compound tert-butyl 3-[[4-methyl-6-[(2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carbonyl)amino]-2-oxo-1H-quinolin-8-yl]oxy]azetidine-1-carboxylate as a solid (75 mg, 37%). Following the general protocol for deprotection using 0.1 mmol of tert-butyl 3-[[4-methyl-6-[(2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carbonyl)amino]-2-oxo-1H-quinolin-8-yl]oxy]azetidine-1-carboxylate, the title product N-[8-(azetidin-3-yloxy)-4-methyl-2-oxo-1H-quinolin-6-yl]-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide was obtained as a solid (42 mg, 86%). 1 H NMR(300MHz,DMSO-d6)δ 11.11(s,1H),10.55(s,1H),9.24(d,J=29.9Hz,2H),7.87(d,J=1.8Hz,1H),7.84(s,1H),7.30(d,J=1.9Hz,1H),6.50(s,1H), 5.23-5.10(m,1H),5.04(s,2H),4.89(s,2H),4.46-4.19(m,4H),3.71-3.58(m,4H),3.30-3.23(m,4H),2.40(d,J=1.2Hz,3H).

[0354] Preparation of N-[4-methyl-8-[2-(methylamino)ethoxy]-2-oxo-1H-quinolin-6-yl]-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 38): [ka] Following the general protocol for alkylation, 0.34 mmol of N-(8-hydroxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 0.68 mmol of tert-butyl N-(2-bromoethyl)carbamate and 1.02 mmol of K2CO3 were used to give the intermediate compound tert-butyl N-methyl-N-[2-[[4-methyl-6-[(2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carbonyl)amino]-2-oxo-1H-quinolin-8-yl]oxy]ethyl]carbamate as a solid (19 mg, 9%). Following the general protocol for deprotection, 0.04 mmol of tert-butyl N-methyl-N-[2-[[4-methyl-6-[(2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carbonyl)amino]-2-oxo-1H-quinolin-8-yl]oxy]ethyl]carbamate was used to give the title product N-[4-methyl-8-[2-(methylamino)ethoxy]-2-oxo-1H-quinolin-6-yl]-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide as a solid (11 mg, 70%). 1 H NMR(300MHz, methanol-d4)δ 8.11(s,1H),7.87(d,J=1.9Hz,1H),7.81(d,J=1.9Hz,1H),6.69(s,1H),5.18-5.14(m,2H),5.07-5.02(m,2 H),4.57-4.51(m,2H),3.86-3.79(m,4H),3.68-3.62(m,2H),3.50-3.43(m,4H),2.91(s,3H),2.57(s,3H).

[0355] Preparation of 2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 39) [ka] Step 1: Preparation of methyl 2-(7-azabicyclo[2.2.1]heptan-7-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate A solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (0.7 mmol, 1.0 equiv.), 7-azabicyclo[2.2.1]heptane hydrochloride (1.5 mmol, 2.0 equiv.) and DIPEA (1.5 mmol, 2.0 equiv.) in dry DMF (3 mL) was stirred at 120° C. for 6 h. The reaction mixture was then diluted with EtOAc (75 mL) and washed with saturated aqueous NaHCO3 (2×25 mL) and 5% aqueous LiCl (25 mL). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (Isolera One, Biotage) using heptane / EtOAc (100 / 0 to 60 / 40) to give methyl 2-(7-azabicyclo[2.2.1]heptan-7-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate as a white solid (20 mg, 10%). 1H NMR (300 MHz, methanol-d4) δ 7.89 (d, J = 1.7 Hz, 1H), 5.07-5.02 (m, 2H), 4.30-4.23 (m, 2H), 3.90 (s, 3H), 1.87-1.83 (m, 4H), 1.54-1.40 (m, 4H).

[0356] Step 2: Preparation of 2-(7-azabicyclo[2.2.1]heptan-7-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid Methyl 2-(7-azabicyclo[2.2.1]heptan-7-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (20 mg, 1 equiv.) was dissolved in 20 mL of a mixture of MeOH / 0.4M aqueous NaOH (1 / 1) and the reaction mixture was stirred for 16 h at 60° C. The crude reaction was neutralized with 2M aqueous HCl and concentrated in vacuo to give 2-(7-azabicyclo[2.2.1]heptan-7-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid as crude product, which was used in the next step without further purification.

[0357] Step 3: Preparation of 2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 39): The crude product 2-(7-azabicyclo[2.2.1]heptan-7-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.07 mmol, 1.0 equiv.) was suspended in DMF (2.0 mL) and treated with 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (1.1 equiv.), EDC·HCl (1.1 equiv.), HOAt (1.1 equiv.) and DIPEA (2.5 equiv.). The reaction mixture was stirred at 60 °C for 16 h. The crude reaction was filtered through a cotton pad and purified directly by reverse-phase preparative HPLC to give 2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide as a solid (30 mg, 88% over two steps). 1 H NMR(300MHz,DMSO-d6)δ 10.65(s,1H),10.43(s,1H),7.78(d,J=1.9Hz,1H),7.71(s,1H),7.57(d,J=1.9Hz,1H),6.46(s,1H),5.01(s,2H) ),4.85(s,2H),4.28(s,2H),3.88(s,3H),2.38(d,J=1.2Hz,3H),1.73-1.62(m,4H),1.44-1.36(d,J=6.8Hz,4H).

[0358] Preparation of 2-[(3R)-3-fluoropyrrolidin-1-yl]-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 40): [ka]

[0359] Preparation of methyl 2-[(3R)-3-fluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate Following the procedure described in step 1 of the preparation of 2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide in Example 39, using 0.7 mmol of 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate and 1.5 mmol of (3R)-3-fluoropyrrolidine hydrochloride, the intermediate product 2-[(3R)-3-fluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate was obtained as a solid (140 mg, 75%).

[0360] Preparation of 2-[(3R)-3-fluoropyrrolidin-1-yl]-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 40): According to the procedure described in steps 2 and 3 of the preparation of 2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide in Example 39, 0.52 mmol of the intermediate compound 2-[(3R)-3-fluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate was used, followed by amide coupling with 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (1.1 equivalents) and silica gel column chromatography (Isolera After purification by HPLC (Cat. No. 13, Biotage) using a mixture of DCM / MeOH (100 / 0 to 80 / 20) followed by recrystallization with MeOH instead of purification by preparative HPLC, the final product 2-[(3R)-3-fluoropyrrolidin-1-yl]-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide was obtained as a solid (35 mg, 20% for two steps).1 H NMR(300MHz,DMSO-d6)δ 10.65(s,1H),10.54(s,1H),7.74(d,J=1.9Hz,1H),7.70(s,1H),7.56(d,J=1.9Hz,1H),6.45(s,1H),5.37(d,J=53. 8Hz,1H),5.01(s,2H),4.93-4.77(m,2H),3.88(s,3H),3.86-3.45(m,4H),2.38(d,J=1.2Hz,3H),2.31-2.09(m,2H).

[0361] Preparation of 2-[(3S)-3-fluoropyrrolidin-1-yl]-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 41): [ka]

[0362] Preparation of methyl 2-[(3R)-3-fluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: Following the procedure described in step 1 of the preparation of 2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide in Example 39, using 0.7 mmol of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate and 1.5 mmol of (3S)-3-fluoropyrrolidine hydrochloride, intermediate product 2-[(3R)-3-fluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate was obtained as a solid (140 mg, 75%).

[0363] Preparation of 2-[(3S)-3-fluoropyrrolidin-1-yl]-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 41): Following a procedure similar to that described in steps 2 and 3 of the preparation of 2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide in Example 39, 0.52 mmol of the intermediate compound 2-[(3S)-3-fluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate was used, followed by amide coupling with 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (1.1 eq.) and purified by silica gel column chromatography (Isolera After purification by HPLC (Cat. No. 13, Biotage) using a mixture of DCM / MeOH (100 / 0 to 80 / 20) followed by recrystallization with MeOH instead of purification by preparative HPLC, the final product 2-[(3S)-3-fluoropyrrolidin-1-yl]-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide was obtained as a solid (15 mg, 20% for two steps). 1 H NMR(300MHz,DMSO-d6)δ 10.65(s,1H),10.54(s,1H),7.78-7.65(m,2H),7.70(s,1H),7.56(d,J=1.9Hz,1H),6.45(s,1H),5.36(d,J=5 3.8Hz,1H),5.01(s,2H),4.93-4.76(m,2H),3.88(s,3H),3.85-3.58(m,4H),2.37(s,3H),2.31-2.08(m,2H).

[0364] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[rac-(3R,4S)-3,4-difluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 42): [ka]

[0365] Preparation of methyl 2-[rac-(3R,4S)-3,4-difluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: Following the procedure described in step 1 of 2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide in Example 39, 0.7 mmol of 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate and 1.5 mmol of (3R,4S)-3,4-difluoropyrrolidine hydrochloride were used, and a DCM / MeOH (100 / 0 to 85 / 15) eluent system was used for purification to obtain intermediate product 2-[rac-(3R,4S)-3,4-difluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate methyl ester as a solid (140 mg, 70%). 1 H NMR (300 MHz, chloroform-d) δ 7.84 (s, 1H), 5.33-5.22 (m, 1H), 5.15-5.04 (m, 3H), 4.93 (t, J = 1.9 Hz, 2H), 3.92 (s, 3H), 3.90-3.60 (m, 4H).

[0366] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[rac-(3R,4S)-3,4-difluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 42): According to the procedure described in steps 2 and 3 of 2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide in Example 39, 0.49 mmol of the intermediate compound 2-[rac-(3R,4S)-3,4-difluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide was obtained. Amide coupling with methyl benzoate followed by 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (1.1 equiv.) afforded the final product N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[rac-(3R,4S)-3,4-difluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide as a solid (98 mg, 74% for two steps).

[0367] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[rac-(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 43): [ka]

[0368] Preparation of methyl 2-[rac-(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate: Following the procedure described in step 1 of 2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide in Example 39, 0.7 mmol of 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate and 1.5 mmol of (3S,4S)-3,4-difluoropyrrolidine hydrochloride were used, and a DCM / MeOH (100 / 0 to 85 / 15) eluent system was used for purification to obtain intermediate product 2-[rac-(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate methyl ester as a solid (160 mg, 80%). 1 H NMR (300 MHz, chloroform-d) δ 7.86 (s, 1H), 5.33-5.29 (m, 1H), 5.20-5.11 (m, 1H), 5.10 (s, 2H) 5.03-4.88 (m, 2H), 4.23-4.10 (m, 1H), 4.09-3.99 (m, 1H), 3.92 (s, 3H), 3.65-3.48 (m, 2H).

[0369] N-(8-Methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[rac-(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 43): According to the procedure described in steps 2 and 3 of Example 39, 2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 0.56 mmol of the intermediate compound 2-[rac-(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide was obtained. Amide coupling with methyl carboxylate followed by 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (1.1 equiv.) afforded the final product N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[rac-(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide as a solid (118 mg, 78%).

[0370] The binding affinity of the compounds was measured using the bromoscan assay and the phosphodiesterase 3 assay.

[0371] Bromoscan assays were performed by DiscoveRx Corporation. The relevant assay names are BRD4(1) for the first bromodomain of BRD4 and BRD4(2) for the second bromodomain of BRD4. Additional Bromoscan assays covering other bromodomains may be used to establish the selectivity profile of the compound of interest. To perform the Bromoscan assays, T7 phage strains displaying the relevant bromodomains were grown in parallel in 24-well blocks in E. coli hosts derived from the BL21 strain. E. coli were grown to logarithmic phase, infected with cryopreserved T7 phage (multiplicity of infection = 0.4) and incubated with shaking at 32 °C until lysis (90-150 min). The lysates were centrifuged (5,000 × g) and filtered (0.2 μm) to remove cellular debris. Streptavidin-coated magnetic beads were treated with biotinylated small molecule or acetylated peptide ligands for 30 min at room temperature to generate affinity resins for bromodomain assays. Ligand-bound beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA (bovine serum albumin), 0.05% Tween 20, 1 mM DTT (dithiothreitol)) to remove unbound ligand and reduce nonspecific phage binding. Binding reactions were assembled by combining bromodomains, ligand-bound affinity beads, and test compounds in 1× binding buffer (17% SeaBlock, 0.33× PBS, 0.04% Tween 20, 0.02% BSA, 0.004% sodium azide, 7.4 mM DTT). Test compounds were prepared as 1000x stocks in 100% DMSO and then diluted 1:10 in monoethylene glycol (MEG) to create stocks at 100x the screening concentration (resulting stock solutions are 10% DMSO / 90% MEG). Compounds were then diluted directly into the assay such that the final concentrations of DMSO and MEG were 0.1% and 0.9%, respectively. All reactions were performed in polystyrene 96-well plates in a final volume of 0.135 ml.The assay plate was incubated at room temperature with shaking for 1 h and the affinity beads were washed with wash buffer (1x PBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (1x PBS, 0.05% Tween 20, 2 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 min. Bromodomain concentrations in the eluates were measured by qPCR (quantitative real-time polymerase chain reaction). Binding constants (Kd) were calculated using the Hill equation with a standard dose-response curve, i.e., response = background + ((signal - background) / (1 + Kd). ヒルスロープ / dose ヒルスロープ )). The Hill slope was set to -1. Curves were fitted using a nonlinear least-squares fit with the Levenberg-Marquardt algorithm.

[0372] Radioactive PDE3A assay Partially purified human recombinant phosphodiesterase (PDE3A) was obtained by cloning the cDNA and expressing it in S. frugiperda insect cells using a baculovirus expression system. The culture was centrifuged at 400 x g for 5 min to harvest the cells. The cell pellet was resuspended in 20 ml of RIPA buffer (150 mM NaCl, 10 mM Tris, 0.1% NP-40, pH 8.3) (4 ml per 200 ml of culture) and protease inhibitors (100 μl / 10 ml) and incubated on ice for 10-20 min, followed by centrifugation at 3500 x g for 10 min at 4 °C. The supernatant was saved and the pellet was discarded. Tritium-labeled cyclic AMP was hydrolyzed to 5'-AMP by PDE3A. The 5'-AMP was then further hydrolyzed to adenosine by nucleotidase in snake venom. Anion exchange resins bind all charged nucleotides and 3This leaves [3H] adenosine as the only labeled compound counted by liquid scintillation. The radioassay method is a modification of the two-stage method of Thompson and Appleman [Biochemistry 10;311-316;1971] adapted to a 96-well plate format. 50 μl of diluted PDE3A was added to 50 μl of [ 3 [H]-cAMP (non-radioactive 25 Ci / mmol) and 11 μl of 50% DMSO (or compound dilution) were incubated for 20 min at 30° C. Enzyme was diluted in 20 mM Tris HCl pH 7.4 (×2.2 final concentration) and [3H]-cAMP was diluted in 10 mM MgCl2, 40 mM Tris HCl pH 7.4 (×2.2 final concentration). Reactions were performed in a Greiner 96 deep well 1 ml master block. Plates were centrifuged for 9 s followed by a 20 min incubation. Reactions were stopped by denaturing the PDE enzyme (2 min at 70° C., plates were cooled on ice for 10 min) followed by the addition of 25 μl of snake venom nucleotidase (225 μg / ml final concentration) and incubation for 10 min (at 30° C.) and plates were centrifuged for 9 s followed by incubation. After incubation, 200 μl of Dowex resin (1×8, 200-400 mesh) was added, the plate was shaken for 20 min, then centrifuged at 1000×g for 3 min, 50 μl of the supernatant was removed and added to 200 μl of MicroScint-20 in a white plate (Greiner 96-well Optiplate), shaken for 30 min, and read on a Perkin Elmer TopCount scintillation counter. IC50 values ​​were calculated using GraphPad Prism™ with a sigmoidal dose response (variable slope). The analysis measures four parameters including best fit values ​​for the lower and upper fits of the curve, Hill slope values, and IC50 values.

[0373] A preferred range of PDE3A inhibitory activity is a PDE3A IC50 > 6 μM, and a most preferred range is a PDE3A IC50 > 10 μM.

[0374] Result table:

[0375] [Table 7]

[0376] [Table 8]

[0377] As can be seen from the results table, the compounds disclosed herein generally show selectivity for binding to BRD4(1), the first bromodomain of BRD4, compared to PDE3A inhibition.Comparing the compounds disclosed herein in formula (I), the pharmaceutical profile is significantly improved over the compounds disclosed in WO2016 / 016316, which are considered to be related prior art.For example, comparing the compounds disclosed herein with Example 128 of WO2016 / 016316, which the inventors consider to be the best compound disclosed in the prior art, it is recognized that the compounds disclosed herein in formula (I) have substantially improved selectivity for PDE3A inhibition, which is a favorable cardiovascular risk profile.

[0378] In some embodiments, the compounds and pharma- ceutically acceptable salts disclosed herein have a binding constant for the first bromodomain of BRD4 of less than 500 nM, e.g., less than 100 nM. In some embodiments, the compounds disclosed herein are considered selective, i.e., have a selectivity for the first bromodomain of BRD4 compared to the second bromodomain of BRD4 of at least 10-fold, e.g., at least 30-fold, calculated as BRD4(2)Kd / BRD4(1)Kd. In further embodiments, the compounds disclosed herein have a binding constant for the first bromodomain of BRD4 of less than 500 nM, e.g., less than 100 nM, and a selectivity for the first bromodomain of BRD4 of at least 10-fold, e.g., at least 30-fold.

[0379] In some embodiments, the compounds and pharma- ceutically acceptable salts disclosed herein have a PDE3A IC50 of at least 6 μM, such as at least 10 μM (>10 μM).

[0380] In some embodiments, the compounds and pharma- ceutically acceptable salts disclosed herein have a PDE3A IC50 of at least 6 μM, e.g., at least 10 μM (>10 μM), and a binding constant for the first bromodomain of BRD4 of less than 500 nM, e.g., less than 100 nM, and a selectivity for the first bromodomain of BRD4 over the second bromodomain of BRD4 of at least 10-fold, e.g., at least 30-fold.

[0381] In vivo PD testing The compounds described herein can be administered (e.g., orally) to animal (e.g., mouse) models of various diseases, such as cancer or atopic dermatitis (AD), and then their in vivo efficacy can be evaluated (e.g., Li et al, 2006, PNAS, 103(31), 11736-11741). For example, the MC903 mouse model of atopic dermatitis can be used, where mice (e.g., BALB / c mice) are treated with topical administration of the vitamin D3 analog MC903 (calcipotriol) for a set number of days (e.g., 10-12 days) to induce allergic skin inflammation resembling AD. Compounds described herein are appropriately formulated and administered to see if amelioration of ear inflammation can be observed. For each compound administered, measurements are taken of ear thickness, end-phase plasma exposure, and proinflammatory markers (e.g., Th1 / Th2 cytokine levels, chemokine CCL2 levels, etc.) in mouse ear homogenates.

Claims

1. Compounds according to formula (I) 【Chemistry 1】 or its pharmaceutically acceptable salts, polymorphs, stereoisomers and tautomers [In the formula, X is -C(R ４ R ５ )-, -S-, -O-, and -N(R ６ Selected from the group consisting of: Y is -N- or -C(R ７ ) - and R ７ is hydrogen, and C １～４ Selected from the group consisting of alkyl groups; A is an unsubstituted or substituted / unsubstituted or substituted 5 or 6-membered alicyclic ring system; an unsubstituted or substituted / unsubstituted or substituted 5 to 10-membered heteroalicyclic ring system; and -NR ８ R ９ Selected from the group consisting of; R １ is selected from the group consisting of hydrogen, hydroxy, halogen, unsubstituted or substituted C １～４ alkyl, unsubstituted or substituted C １～４ alkoxy, and unsubstituted or substituted -O-R １０ , and R １０ is selected from the group consisting of C ３～６ cycloalkyl, 4- to 6-membered heteroarysilyl, and C １～４ hydroxyalkyl; R ２ C is hydrogen, hydroxyl, halogen, unsubstituted or substituted C １～４ Alkyl and unsubstituted or substituted C １～４ Selected from the group consisting of alkoxys; However, R １ and R ２ It is not possible to select hydrogen simultaneously, or, R １ , R ２ And the carbon atoms to which they are bonded together form a ring; R ３ It does not exist, or there may be one or two, if it exists, C １～４ It is alkyl; R ４ and R ５ These are, independently, hydrogen, unsubstituted or substituted C １～６ Alkyl, unsubstituted, or substituted C １～６ Alkenyl, unsubstituted, or substituted C １～６ Alkynyl, unsubstituted, or substituted C １～６ Selected from the group consisting of alkoxy, -OH, and -CN; R ６ C is hydrogen, unsubstituted or substituted. １～６ Alkyl, unsubstituted, or substituted C ３～６ Cycloalkyl and unsubstituted or substituted C ２～６ Selected from a group consisting of heteroalicyryls; R ８ and R ９ These are, independently, hydrogen, unsubstituted or substituted C １～４ Alkyl and unsubstituted or substituted C ３～４ Selected from the group consisting of cycloalkyl, however, R ８ and R ９ At least one of them is non-substituted or substituted C １～４ Alkyl and unsubstituted or substituted C ３～４ [Selected from the group consisting of cycloalkyl groups.]

2. X is -C(R4R5)-, -N(R6), or -O-, When X is -C(R4 R5)-, R4 and R5 are independently hydrogen or C1-C4 alkyl groups. If X is -N(R6), then R6 is selected from the group consisting of hydrogen, C1-4 alkyl groups, C1-4 haloalkyl groups, and 4 or 5-membered heteroallicyryls. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer, and tautomer described in claim 1.

3. R ６ The compound, pharmaceutically acceptable salt, polymorph, stereoisomer, and tautomer of the compound, pharmaceutically acceptable salt, polymorph, stereoisomer, and tautomer of claim 2, selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, and tetrahydrofuranyl.

4. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer, and tautomer according to claim 1, wherein Y is -N-.

5. R １ Hydrogen, hydroxy, fluoro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, butoxy, -O-azetidinyl, -O-CH ２ CH ２ OH, and -O-CH ２ CH ２ NHCH ３ A compound, pharmaceutically acceptable salt, polymorph, stereoisomer, and tautomer selected from the group consisting of the above.

6. R １ The compound, pharmaceutically acceptable salt, polymorph, stereoisomer, and tautomer of claim 1, wherein is methyl, methoxy, or ethoxy.

7. R ２ The compound, pharmaceutically acceptable salt, polymorph, stereoisomer, and tautomer of the compound, pharmaceutically acceptable salt, polymorph, stereoisomer, and tautomer of the compound, pharmaceutically acceptable salt, polymorph, stereoisomer, and tautomer of the compound, pharmaceutically acceptable salt, polymorph, stereoisomer, and polymorph, selected from the group consisting of hydrogen, fluoro, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, and butoxy.

8. R ２ The compound, pharmaceutically acceptable salt, polymorph, stereoisomer, and tautomer described in claim 1, wherein is hydrogen.

9. R １ , R ２ The compound, pharmaceutically acceptable salt, polymorph, stereoisomer, and tautomer according to claim 1, wherein the carbon atoms to which they are bonded together form a five- or six-membered ring system containing one or more oxygen atoms.

10. R １ , R ２ The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer of the claim 1, wherein the carbon atoms to which they are bonded together form 2,3-dihydro-1,4-dioxin or 2,3-dihydrofuran.

11. A is a compound, pharmaceutically acceptable salt, polymorph, stereoisomer, and tautomer according to claim 1, selected from the group consisting of unsubstituted or substituted morpholines, unsubstituted or substituted morpholine derivatives, and unsubstituted or substituted 5- to 10-membered heteroalicyclic ring systems other than unsubstituted or substituted morpholines or unsubstituted or substituted morpholine derivatives.

12. A is, 【Chemistry 2】 (In the formula, R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , R ２２ , R ２３ and R ２４ These are either independent, nonexistent, or one, two, or three present, and if present, halogen, hydroxyl, C １～４ Alkyl and C １～４ A compound, pharmaceutically acceptable salt, polymorph, stereoisomer, and tautomer according to claim 1, selected from the group consisting of (independently selected from the group consisting of alkoxys).

13. The aforementioned unsubstituted or substituted morpholines or unsubstituted or substituted morpholine derivatives are 【Transformation 3】 Selected from the group consisting of, R11, R13, R16, and R17 are either absent or present in groups of one or two, and if present, are independently selected from the group consisting of hydroxy, fluoro, methyl, ethyl, and propyl. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer, and tautomer described in claim 11.

14. The 5-10 member heteroalicyclic ring systems other than unsubstituted or substituted morpholines or unsubstituted or substituted morpholine derivatives are: 【Chemistry 4】 Selected from the group consisting of, R18, R19, R20, R21, R22, R23, and R24 are independently either absent or present in groups of one or two, and if present, independently selected from the group consisting of hydroxy, fluoro, methyl, ethyl, and propyl, or The aforementioned 5-10 membered heteroalicyclic ring systems other than unsubstituted or substituted morpholines or unsubstituted or substituted morpholine derivatives are: 【Transformation 5】 Selected from the group consisting of, R12, R14, and R15 are independently either absent or present in groups of one or two, and if present, independently selected from the group consisting of hydroxy, fluoro, methyl, ethyl, and propyl. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer, and tautomer described in claim 1.

15. The following equation (III) 【Transformation 6】 [In the formula, R １ C １－４ It is an alkoxy; R ２ is hydrogen; R ３ R is either absent or present as one, and if present, it is methyl; １１ is not present; Y is -N- or -CH-; X is -O- or N(R ６ ) and R ６ The compound, pharmaceutically acceptable salt, polymorph, stereoisomer, and tautomer of claim 1, comprising [selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, and oxetanyl].

16. R １ is methoxy, R ３ The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to claim 15, wherein there is no , Y is -N- or -CH-, and X is -O-.

17. The aforementioned compound, N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-2-morpholino-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-2-morpholino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-5-methyl-2-morpholino-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-2-morpholino-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide, (5R)-N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-5-methyl-2-morpholino-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, N-(4,8-dimethyl-2-oxo-1H-quinoline-6-yl)-2-morpholino-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, N-(6-methyl-8-oxo-3,9-dihydro-2H-fl[3,2-h]quinoline-4-yl)-2-morpholino-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, N-[8-(2-hydroxyethoxy)-4-methyl-2-oxo-1H-quinoline-6-yl]-2-morpholino-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, N-[8-(azetidine-3-yloxy)-4-methyl-2-oxo-1H-quinoline-6-yl]-2-morpholino-5,7-dihydrofloxacin[3,4-b]pyridine-3-carboxamide, N-(7-fluoro-8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-2-morpholino-5,7-dihydrofluoro[3,4-b]pyridine-3-carboxamide, N-(7-methyl-9-oxo-3,10-dihydro-2H-[1,4]dioxyno[2,3-h]quinoline-5-yl)-2-morpholino-5,7-dihydrofloxacin[3,4-b]pyridine-3-carboxamide, N-(4,7-dimethyl-2-oxo-1H-quinoline-6-yl)-2-morpholino-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, N-(8-ethoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-2-morpholino-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, N-[4-methyl-8-[2-(methylamino)ethoxy]-2-oxo-1H-quinoline-6-yl]-2-morpholino-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, 2-Morpholino-N-(4,7,8-trimethyl-2-oxo-1H-quinoline-6-yl)-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, N-(7-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-2-morpholino-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-6-methyl-2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-2-morpholino-6-(oxetan-3-yl)-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxamide, 6-Ethyl-N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxamide, 6-Isopropyl-N-(8-Methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxamide, 2-(dimethylamino)-N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, 2-[cyclopropylmethyl(methyl)amino]-N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, 2-(diethylamino)-N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, 2-[ethyl(isopropyl)amino]-N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, 2-(3,6-dihydro-2H-pyran-4-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, 2-(cyclopentan-1-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, 2-(3,3-difluoropyrrolidine-1-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-2-[(2R)-2-methylpyrrolidine-1-yl]-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, 2-(2,3,3a,4,6,6a-hexahydrofl[2,3-c]pyrrole-5-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-2-(1-methyl-2-azabicyclo[2.1.1]hexane-2-yl)-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, 2-(1,3,3a,4,6,6a-hexahydrofl[3,4-c]pyrrole-5-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, 2-(8-azabicyclo[3.2.1]octan-8-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-2-[rac-(3aR,6aR)-2,3,3a,4,6,6a-hexahydrofloxacin[2,3-c]pyrrole-5-yl]-5,7-dihydrofloxacin[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-2-[(2S)-2-methylpyrrolidine-1-yl]-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, 2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-5,7-dihydrofl[3,4-b]pyridine-3-carboxamide, 2-[(3R)-3-fluoropyrrolidine-1-yl]-N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-5,7-dihydrofluoro[3,4-b]pyridine-3-carboxamide, 2-[(3S)-3-fluoropyrrolidine-1-yl]-N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-5,7-dihydrofluoro[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-2-[rac-(3R,4S)-3,4-difluoropyrrolidine-1-yl]-5,7-dihydrofluoro[3,4-b]pyridine-3-carboxamide, N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-2-[rac-(3S,4S)-3,4-difluoropyrrolidine-1-yl]-5,7-dihydrofluoro[3,4-b]pyridine-3-carboxamide, and 2-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-6-yl)-5,7-dihydrofluoro[3,4-b]pyridine-3-carboxamide A compound according to claim 1, selected from the group consisting of the following.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer thereof, and at least one pharmaceutically acceptable excipient.

19. The composition according to claim 18 for the treatment of systemic or tissue inflammation, infection or inflammatory response to the products of infectious organisms, or diseases or conditions selected from the group consisting of hypoxia, autoimmune and allergic processes, cell activation and proliferation, cancer, metabolism, and fibrosis, and for the prevention and treatment of viral infections.

20. Rheumatoid arthritis, osteoarthritis, gout, psoriasis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, inflammatory bowel syndrome, Crohn's disease, ulcerative colitis, colitis, asthma, chronic obstructive airway disease, pneumonia, myocarditis, pericarditis, myositis, eczema, dermatitis, atopic dermatitis, allergy, ankylosing spondylitis, lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune eye disease, Sjögren's disease, optic neuritis, neuromyelitis optica, myasthenia gravis, Guillain-Barré syndrome, Graves' disease, alopecia, vitiligo, bullous skin disease, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, Retinitis, uveitis, scleritis, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, hypophysitis, thyroiditis, Addison's disease, type 1 diabetes, acute rejection of transplanted organs, acute gout, giant cell arteritis, lupus nephritis, glomerulonephritis, vasculitis with organ damage, polyarteritis nodosa, Behçet's disease, Wegener's granulomatosis, Kawasaki disease, Takayasu's arteritis, sepsis, septic syndrome, septic shock, endotoxemia, multiorgan inflammatory response syndrome (SIRS), multiple organ failure syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, postoperative complications Symptoms, sarcoidosis, Herxheimer's reaction, encephalitis, myelitis, meningitis, malaria, SIRS associated with viral infection, ischemia-reperfusion injury, myocardial infarction, cerebral ischemia (stroke), acute coronary syndrome, renal reperfusion injury, organ transplantation, coronary artery bypass surgery, cardiac bypass surgery, embolism of the lungs, kidneys, liver, gastrointestinal tract or peripheral limbs, hypercholesterolemia, idiopathic pulmonary fibrosis, pulmonary fibrosis, intestinal fibrosis, hepatic fibrosis, non-alcoholic steatohepatitis, cirrhosis, renal fibrosis, postoperative stenosis, myelofibrosis, keloid formation, dermatofibrosis, hand fibrosis, systemic sclerosis, scleroderma, cardiac fibrosis, herpesvirus infection, Topapillomavirus infection, human immunodeficiency virus (HIV) infection, adenovirus infection, poxvirus infection, colon cancer, midline cancer, sarcoma, mesenchymal, liver, kidney and neurological tumors, acute lymphoblastic leukemia, acute myeloid leukemia, adult T-cell leukemia / lymphoma, bladder cancer, blastoma, osteosarcoma, breast cancer, brain cancer, Burkitt lymphoma, epithelial cancer, myeloid sarcoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colorectal cancer, diffuse large B-cell lymphoma, endometrial cancer, esophageal cancer, follicular lymphoma, gastrointestinal cancer, glioblastoma multiforme, glioma, gallbladder cancer, gastric cancer, head and neck cancer,The composition according to claim 18 for treating a disease or condition selected from the group consisting of Hodgkin lymphoma, non-Hodgkin lymphoma, intestinal cancer, kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, liver cancer, small cell lung cancer, non-small cell lung cancer, melanoma, mesothelioma, lymphoma, non-small cell lung cancer, melanoma, mesothelioma, multiple myeloma, eye cancer, optic nerve tumor, oral cancer, ovarian cancer, pituitary tumor, primary central nervous system lymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, rectal cancer, skin cancer, spinal cord tumor, small intestine cancer, gastric cancer, T-cell lymphoma, testicular cancer, thyroid cancer, thyroid cancer, pharyngeal cancer, genitourinary cancer, urothelial carcinoma, uterine cancer, vaginal cancer, Wilms' tumor, and obesity.

21. The composition according to claim 18, which inhibits the activity of the bromodomain without inhibiting the activity of phosphodiesterase enzyme 3 (PDE3).

22. The compound has the following structure: 【Transformation 7】 A compound according to claim 1, or a pharmaceutically acceptable salt, polymorph, stereoisomer, and tautomer thereof.

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