Compounds active against bromodomains

Abstract

Compounds of formula (I) that modulate bromodomains, pharmaceutical compositions containing said compounds and the use of said compounds in therapy are disclosed. # imgabs0 #

Description

Technical Field

[0001] The present application relates to compounds active against bromodomains, pharmaceutical compositions comprising these compounds, and methods of using these compounds to treat diseases or disorders. Background Art

[0002] Bromodomains are protein domains of biological and pharmaceutical interest, such as components of transcription factor complexes and determinants of epigenetic memory. The human genome encodes 61 bromodomains present in 46 human proteins, and can be divided into 8 different bromodomain families based on primary sequence conservation (Nat Rev Drug Discov [Natural Review Drug Discovery]. May 2014; 13 (5): 337-56). One such family, the BET family, or bromodomain and ultra-terminal domain family, includes BRD2, BRD3, BRD4 and BRDT, all of which are present in humans. Bromodomains can recognize acetylated lysine residues in histones and other proteins. The BET family has a common domain architecture, characterized by two amino-terminal bromodomains that exhibit a high level of sequence conservation, and a more divergent carboxyl-terminal recruitment domain (Filippakopoulos, P. et al., Nature [Natural] 2010, 468, 1067-1073). The two bromodomains of BET proteins are typically referred to as BD1 and BD2, wherein BD1 refers to the last N-terminal of the two bromodomains. It is reported that BRD2 and BRD3 are associated with histones along active transcriptional genes, and can participate in promoting transcriptional elongation (Leroy et al., Mol.Cell [molecular cells]. 2008, 30, 51-60). It has also been reported that BRD4 or BRD3 can be fused with NUT (nucleoprotein in testis) to form a new fusion oncogene in a highly malignant form of epithelial tumor formation, referred to as NUT- midline cancer. It has been proposed that BRD-NUT fusion protein contributes to carcinogenesis (Oncogene [oncogene] 2008, 27, 2237-2242). BRDT is uniquely expressed in testis and ovary.

[0003] It is reported that all BET family members have some involvement in the cell cycle. In addition, some viruses use these proteins to tether their genomes to host cell chromatin as part of the viral replication process (You et al. Cell 2004 117, 349-60). BRD4 appears to be involved in the recruitment of pTEF-P complexes to inducible genes, leading to phosphorylation of RNA polymerase and increased transcriptional output (Hargreaves et al. Cell 2009 138, 129-145). WO 2009084693, WO 2012075383, WO 2011054553, WO 2011054841, WO 2011054844, WO2011054845, WO 2011054846, WO 2011054848, WO 2011143669, WO 2011161031, WO2013027168, WO 2014095774, WO 2014095775 and WO 2016016316 relate to bromodomains and modulators thereof.

[0004] Despite progress in the molecular field of regulating the function of bromodomains, there is still a need for additional bromodomain inhibitors with improved tolerability and reduced side effects. A particularly concerning side effect of some known bromodomain modulators is the inhibitory activity of phosphodiesterase inhibitor 3 (PDE3). 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 the mortality rate of patients with heart failure. The most common and serious side effect of PDE3 inhibitors is ventricular arrhythmia, which may 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. It is clear that there is a need for bromodomain inhibitors with improved tolerability and no potential cardiovascular side effects by inhibiting phosphodiesterase 3. Summary of the invention

[0005] Aspects disclosed herein relate to compounds of formula (I)

[0006]

[0007] or a pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer thereof, wherein X is selected from -C(R 4 R 5 )-, -S-, -O- and -N(R 6 )-; Y is -N- or -C(R 7 )-, where R 7 Selected from hydrogen and C1-4 alkyl; A is selected from the group consisting of: an unsubstituted or substituted 5- or 6-membered alicyclic ring system; an unsubstituted or substituted 5-10-membered heteroalicyclic ring system; and -NR 8 R 9 ; R 1 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 -OR 10 , where R 10 Selected from C 3-6 Cycloalkyl, 4-6 membered heteroalicyclic and C 1-4 Hydroxyalkyl; R 2 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 R 1 and R 2 cannot be selected from hydrogen; or R 1 , R 2 Together with the carbon atoms to which they are attached, they form a ring; R 3 Can be absent or present 1 or 2 times, and when present is C 1-4 Alkyl; R 4 and R 5 are independently selected from the group consisting of 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 Alkoxy, -OH and -CN; R 6 Selected from the group consisting of: hydrogen and unsubstituted or substituted C 1-6 Alkyl, unsubstituted or substituted C 3-6 Cycloalkyl, unsubstituted or substituted C 2-6 heteroalicyclic group; and R 8 and R 9 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 R 8 and R 9 At least one of them is unsubstituted or substituted C 1-4 Alkyl and unsubstituted or substituted C 3-4 Cycloalkyl.

[0008] In another aspect, the compounds of Formula (I), (II) and (III) and pharmaceutically acceptable salts, polymorphs, stereoisomers and tautomers thereof are active bromodomain inhibitors without inhibiting the activity of phosphodiesterase enzyme 3 (PDE3).

[0009] In another aspect, the compounds of formula (I), (II) and (III) and pharmaceutically acceptable salts, polymorphs, stereoisomers and tautomers thereof and at least one pharmaceutically acceptable excipient are contained in a pharmaceutical composition.

[0010] In another aspect, the compounds of Formula (I), (II) and (III) disclosed herein and 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, cellular activation and proliferation, cancer, metabolism, fibrosis, and for the prevention and treatment of viral infections.

[0011] In another aspect, disclosed herein are compounds of Formula (I), (II) and (III) and pharmaceutically acceptable salts, polymorphs, stereoisomers and tautomers thereof, contained in compositions for treating 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 for preventing and treating viral infections.

[0012] In one aspect, the disease or disorder is 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 syndrome ( disease), optic neuritis, neuromyelitis optica, myasthenia gravis, Guillain-Barré syndrome, Graves' disease, alopecia, vitiligo, bullous dermatoses, 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, and acute rejection of a transplanted organ, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including giant cell arteritis, polyarteritis nodosa, Behcet's disease, Wegener's granulomatosis, Kawasaki disease, Takayasu's arteritis, vasculitis with organ involvement, and acute rejection of a transplanted organ; or

[0013] Treatment of sepsis, septic syndrome, septic shock, endotoxemia, systemic 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, postoperative syndrome, sarcoidosis, Herksheimer's reaction, encephalitis, myelitis, meningitis, malaria, and SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex, and coronavirus; or

[0014] Treatment of ischemia-reperfusion injury, myocardial infarction, cerebrovascular ischemia (stroke), acute coronary syndrome, renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardiopulmonary bypass surgery, pulmonary, renal, hepatic, gastrointestinal, or peripheral limb embolism; or

[0015] Treating disorders or conditions such as hypercholesterolemia, atherosclerosis, and Alzheimer's disease; or

[0016] Treating disorders or conditions such as idiopathic pulmonary fibrosis, pulmonary fibrosis, intestinal fibrosis, liver fibrosis, nonalcoholic steatohepatitis, liver cirrhosis, renal fibrosis, post-operative stenosis, myelofibrosis, keloid formation, skin fibrosis, hand fibrosis, systemic sclerosis, scleroderma, and cardiac fibrosis; or

[0017] Treat or prevent viral infections such as herpes virus, human papillomavirus, human immunodeficiency virus (HIV), adenovirus, and poxvirus; or

[0018] Treats colon cancer, midline cancer, sarcoma, mesenchymal, liver, kidney and neural tumors; acute lymphocytic leukemia, acute myeloid leukemia, adult T-cell leukemia / lymphoma, bladder cancer, blastoma, bone cancer, breast cancer, brain cancer, Burkitt's lymphoma, 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, colorectal cancer, kidney cancer , laryngeal cancer, leukemia, lung cancer, lymphoma, liver cancer, small cell lung cancer, 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, sarcoma, skin cancer, spinal cord tumors, small intestine cancer, stomach cancer, T-cell lymphoma, testicular cancer, thyroid cancer, laryngeal cancer, genitourinary cancer, urothelial carcinoma, uterine cancer, vaginal cancer, or Wilms' tumor; or to treat obesity, such as obesity associated with cancer treatment or obesity associated with diabetes and cardiac hypertrophy. DETAILED DESCRIPTION

[0019] definition

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. All patents, applications, published applications, and other publications cited herein are incorporated by reference in their entirety. If a term herein has multiple definitions, the definitions in this section shall prevail unless otherwise stated.

[0021] As used herein, any one or more "R" groups, such as but not limited to R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 , indicating substituents that may be attached to the indicated 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 heteroalicyclic. If two "R" groups are covalently bonded to the same atom or adjacent atoms, they may "take together" or "combine" as defined herein to form a cycloalkyl, aryl, heteroaryl, or heteroalicyclic group. For example, and without limitation, if NR a R b R a and R b are indicated as "taken together" or "combined", it means that they are covalently bonded to each other at their terminal atoms to form a ring including the nitrogen:

[0022]

[0023] Whenever a group is described as "unsubstituted or substituted" or "substituted or unsubstituted", if substituted, one or more substituents (which may be present one or more times, such as 1, 2, 3 or 4 times) are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxylic acid, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonylamino, N-sulfonylamino, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonylamino and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. Whenever a group is not defined as "unsubstituted or substituted", such as C 1-4When alkyl is alkyl, the group is unsubstituted.

[0024] When a substituent is considered "substituted", the substituent itself is substituted. When a referenced substituent is substituted, it means that one or more hydrogen atoms on the referenced group can be replaced by one or more groups individually and independently selected from the following: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxylic acid, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonylamino, N-sulfonylamino, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonylamino and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. Protecting groups that can form protected derivatives of the above-mentioned substituents are known to those skilled in the art and can be found in the following reference: Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York, NY, 1999, which is hereby incorporated by reference in its entirety.

[0025] As used herein, “C m To C n ”, “C m -C n ” or “C m-n ” (where “m” and “n” are integers) refers to the number of carbon atoms in the associated group. That is, the group may contain from “m” to “n” (inclusive) carbon atoms. Thus, for example, “C 1 To C 4 "Alkyl" groups refer to all alkyl groups having from 1 to 4 carbons, i.e., CH 3 -、CH 3 CH 2 -、CH 3 CH 2 CH 2 -、(CH 3 ) 2 CH-、CH 3 CH 2 CH 2 CH 2 -、CH 3 CH 2 CH(CH 3 )-、CH 3 CH(CH 3 )CH 2- and (CH 3 ) 3 C-. If "m" and "n" are not specified for a group, the broadest range described in these definitions should be assumed.

[0026] As used herein, "alkyl" refers to a fully saturated (no double or triple bonds) straight or branched hydrocarbon chain group. An alkyl group can have 1 to 20 carbon atoms (whenever 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 covers the occurrence of the term "alkyl" in which no numerical range is specified). An alkyl group can also be a medium-sized alkyl group having 1 to 10 carbon atoms, such as "C 1-6 The alkyl group may also be a lower alkyl group having 1 to 4 carbon atoms. The alkyl group of a compound may be designated as "C 1 -C 4 Alkyl", "C 1-4 Alkyl" or similar designation. By way of example only, "C 1 -C 4 Alkyl" or "C 1-4 "Alkyl" means that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like. When substituted, one or more substituent groups are individually and independently selected from one or more of the following groups: alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, cyclohexyl ... The invention also includes but is not limited to alkyl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxylic acid, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-acylamino, N-acylamino, S-sulfonylamino, N-sulfonylamino, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonylamino and amino groups, including mono- and di-substituted amino groups, and protected derivatives thereof.

[0027] As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. If there is more than one double bond, these double bonds may be conjugated or unconjugated. The alkenyl group may have 2 to 20 carbon atoms (whenever it occurs in this article, a numerical range such as "2 to 20" refers to each integer in a given range; for example, "2 to 20 carbon atoms" means that the alkenyl group may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 20 carbon atoms, although this definition also encompasses the occurrence of the term "alkenyl" in which a numerical range is not specified). When substituted, the one or more substituent groups are individually and independently selected from one or more of the following groups: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxylic acid, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonylamino, N-sulfonylamino, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonylamino and amino, including mono- and di-substituted amino groups, and protected derivatives thereof.

[0028] 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 can have 2 to 20 carbon atoms (whenever it occurs in this article, a numerical range such as "2 to 20" refers to each integer in a given range; for example, "2 to 20 carbon atoms" means that the alkynyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 20 carbon atoms, although the definition also encompasses the occurrence of the term "alkynyl" in which no numerical range is specified). An alkynyl group can be unsubstituted or substituted. When substituted, one or more substituents can be selected from the same groups disclosed above for substitution of an alkenyl group.

[0029] As used herein, "hetero" may be attached to a group and refers to one or more carbon atoms and one or more associated hydrogen atoms in the attached group have been independently replaced by the same or different heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur.

[0030] As used herein, "heteroalkyl" by itself or in combination with another term refers to a straight or branched chain alkyl group consisting of a specified number of carbon atoms, wherein one or more carbon atoms, such as 1, 2, 3 or 4 carbon atoms and one or more associated hydrogen atoms have been independently replaced by the same or different heteroatoms selected from nitrogen, oxygen and sulfur. The replaced one or more carbon atoms may be 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, etc.

[0031] As used herein, "aryl" refers to a carbocyclic (all carbon) ring or two or more fused rings (rings that share two adjacent carbon atoms) with a completely delocalized π electron system. Aryl groups can range from 6 to 10 carbon atoms (C 6-10 In some embodiments, the aryl group contains 6 carbon atoms (C 6 The aryl group may be substituted. When substituted, the hydrogen atom is replaced by one or more substituent groups, which are independently selected from one or more groups: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic) alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxylic acid, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonylamino, N-sulfonylamino, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonylamino and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. When substituted, the substituents on the aryl group may form a non-aromatic ring fused to the aryl group and include cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.

[0032] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system with a completely nonlocalized π electron system), wherein at least one atom in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to nitrogen, oxygen and sulfur. The scope of the heteroaryl group can be from 5 to 10 atoms, wherein one or more of these atoms, such as 1, 2, 3 or 4 atoms, are independently selected from oxygen, sulfur and nitrogen. In certain embodiments, the heteroaryl group comprises 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 can be substituted. When substituted, the hydrogen atom is replaced by one or more substituent groups, which are independently selected from one or more groups of the following: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic) alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxylic acid, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-acylamino, N-acylamino, S-sulfonylamino, N-sulfonylamino, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonylamino and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. When substituted, the substituents on the heteroaryl group can form a non-aromatic ring fused to the aryl group, including cycloalkyl, cycloalkenyl, cycloalkynyl and heterocyclyl.

[0033] "Aralkyl" or "arylalkyl" is an aryl group attached as a substituent via an alkylene group. The alkylene and aryl groups of the aralkyl can 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 C 6 Aryl.

[0034] "Heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group attached as a substituent via an alkylene group. The alkylene and heteroaryl groups of the heteroaralkyl can be substituted. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furanylmethyl, thienylethyl, pyrrolidinyl, pyridylalkyl, isoxazolylalkyl, pyrazolylalkyl, and imidazolylalkyl, and their substituted and benzo-fused analogs. In some cases, the alkylene group is a lower alkylene group, and in some cases, the alkylene group is -CH 2 -or-CH 2 CH 2 -.

[0035] "Alkylene" is a tethering group that forms a bond to connect molecular fragments through the terminal carbon atoms of the molecule. Alkylene can have 1 to 20 carbon atoms. Alkylene can also be a medium-sized alkylene having 1 to 10 carbon atoms, such as "C 1-6 "". The alkylene group may also be a lower alkylene group having 1 to 4 carbon atoms. The alkylene group may be designated as "C 1 -C 4 Alkylene", "C 1-4 "alkylene" or similar designations. Non-limiting examples include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -) and butylene (-(CH 2 ) 4 -) groups. In the case of methylene, the two linked fragments are attached to the same carbon atom. The lower alkylene group may be substituted, for example by a lower alkyl group.

[0036] As used herein, "heteroalkylene" by itself or in combination with another term refers to an alkylene group consisting of the specified number of carbon atoms, wherein one or more carbon atoms, such as 1, 2, 3 or 4 carbon atoms, are independently replaced by the same or different heteroatoms selected from oxygen, sulfur and nitrogen. Examples of heteroalkylene include, but are not limited to, -CH 2 -O-, -CH 2 -CH 2 -O-, -CH 2 -CH 2 -CH 2 -O-, -CH 2 -NH-, -CH 2 -CH 2 -NH-, -CH 2 -CH 2 -CH 2 -NH-, -CH 2 -CH 2 -NH-CH 2 -、-O-CH 2 -CH 2 -O-CH 2 -CH 2 -O-, -O-CH 2 -CH 2 -O-CH 2 -CH 2 -wait.

[0037] As used herein, "alkylidene" refers to a divalent group, such as =CR'R", which is attached to one carbon of another group to form a double bond. Alkylidene groups include, but are not limited to, methylene (=CH 2 ) and ethylidene (=CHCH 3 As used herein, "arylalkylidene" refers to an alkylidene group in which R' or R" is an aryl group. The alkylidene group may be substituted.

[0038] As used herein, "alkoxy" refers to a group -OR, where R is an alkyl group, such as methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), cyclopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, tert-pentoxy, etc. The alkoxy group can be substituted.

[0039] As used herein, "alkylthio" refers to the formula -SR, wherein R is an alkyl group as defined above, for example, methylthio, ethylthio, n-propylthio, 1-methylethylthio (isopropylthio), n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, etc. The alkylthio group may be substituted.

[0040] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, wherein R is aryl as defined above, for example, phenoxy, naphthyloxy, azulenyloxy, anthracenyloxy, naphthylthio, phenylthio, etc. Both aryloxy and arylthio may be substituted.

[0041] As used herein, "alkenyloxy" refers to the formula -OR, wherein R is alkenyl as defined above, for example, vinyloxy, propenyloxy, n-butenyloxy, iso-butenyloxy, sec-pentenyloxy, tert-pentenyloxy, etc. The alkenyloxy group may be substituted.

[0042] As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, or aryl attached as a substituent via a carbonyl group. Examples include formyl, acetyl, propionyl chloride, benzoyl, and acryl. Acyl groups may be substituted.

[0043] As used herein, "cycloalkyl" refers to a fully saturated (no double bonds) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, the rings may be connected together in a fused, bridged or spiro-connected manner. The cycloalkyl group can range from C 3 To C 10 In other embodiments, the range may be from C 3 To C 6The cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. If substituted, one or more substituents may be alkyl or selected from those indicated above for substitution of alkyl groups, unless otherwise indicated. When substituted, the substituents on the cycloalkyl group may form an aromatic ring fused to the cycloalkyl group, including aryl and heteroaryl.

[0044] As used herein, "cycloalkenyl" refers to a cycloalkyl group containing one or more double bonds in the ring, although if there is more than one, they cannot form a completely non-localized π electron system in the ring (otherwise the group is an "aryl" as defined herein). When composed of two or more rings, these rings can be connected together in a fused, bridged or spiro-connected manner. The cycloalkenyl group can be unsubstituted or substituted. When substituted, the one or more substituents can be alkyl or selected from the groups disclosed above for alkyl group substitution, unless otherwise stated. When substituted, the substituents on the cycloalkenyl group can form an aromatic ring fused to the cycloalkenyl group, including aryl and heteroaryl.

[0045] 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 connected together in a fused, bridged or spiro-connected manner. The cycloalkynyl group can range from C 3 To C 10 The cycloalkynyl group may be unsubstituted or substituted. When substituted, one or more substituents may be alkyl or selected from the groups disclosed above for substitution of alkyl groups, unless otherwise indicated. When substituted, the substituents on the cycloalkynyl group may form an aromatic ring fused to the cycloalkynyl group, including aryl and heteroaryl groups.

[0046] As used herein, "heteroalicyclic" or "heteroalicyclic group" refers to a 3- to 18-membered ring consisting of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The heteroalicyclic or heteroalicyclic group can range from C 2 To C 10 In other embodiments, the range may be from C 2 To C 9 , and in other embodiments, it can range from C 2 To C 8"Heteroalicyclic" or "heteroalicyclic radical" may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be linked together in a fused, bridged, or spiro manner; and the nitrogen, carbon, and sulfur atoms in the "heteroalicyclic" or "heteroalicyclic radical" may be oxidized; the nitrogen may be quaternized; and the rings may also contain one or more double bonds, provided that they do not form a completely delocalized π-electron system in all rings. Heteroalicyclic radicals may be unsubstituted or substituted. When substituted, one or more substituents may be independently selected from one or more groups of the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxylic acid, alkylthio, arylthio, cyano, halogen, C-amido, N-amido, S-sulfonylamino, N-sulfonylamino, isocyanato, thiocyanato, isothiocyanato, nitro, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonylamino and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. Examples of such "heteroalicyclic" or "heteroalicyclic" include, but are not limited to, aza The heteroalicyclic radicals include alkyl, alkyl, alkyl, alkylene ...

[0047] "(Cycloalkyl)alkyl" is a cycloalkyl group attached as a substituent via an alkylene group. The alkylene and cycloalkyl of the (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 is a lower alkylene group (C 1-4 alkylene).

[0048] "(Cycloalkenyl)alkyl" is a cycloalkenyl group attached as a substituent via an alkylene group. The alkylene and cycloalkenyl groups of the (cycloalkenyl)alkyl may be substituted. In some cases, the alkylene group is a lower alkylene group.

[0049] "(Cycloalkynyl)alkyl" is a cycloalkynyl group attached as a substituent via an alkylene group. The alkylene and cycloalkynyl groups of the (cycloalkynyl)alkyl may be substituted. In some cases, the alkylene group is a lower alkylene group.

[0050] As used herein, "halo" or "halogen" refers to F (fluorine), Cl (chlorine), Br (bromine), or I (iodine).

[0051] As used herein, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen. Examples of haloalkyl groups are C 1-3 Alkyl. Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and 1-chloro-2-fluoromethyl, 2-fluoroisobutyl. The haloalkyl group may be substituted.

[0052] As used herein, "haloalkoxy" refers to a RO-group in which R is a haloalkyl group. Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 1-chloro-2-fluoromethoxy, 2-fluoroisobutoxy. The haloalkoxy group may be substituted.

[0053] An "O-carboxylic acid" group refers to a "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, or (heteroalicyclic)alkyl, as defined herein. The O-carboxylic acid can be substituted.

[0054] A "C-carboxy" group refers to a "-C(=O)OR" group, where R may be the same as defined for O-carboxy. The C-carboxylic acid may be substituted.

[0055] A "trihalomethanesulfonyl" group refers to a "X 3 CSO 2 -" group, wherein X is a halogen.

[0056] Virtual Key represents the 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). When a virtual bond is present in a ring system, it may form part of an aromatic ring system.

[0057] The "nitro" group refers to the "-NO 2 "Group

[0058] A "cyano" group refers to a "-CN" group.

[0059] A "cyanato" group refers to a "-OCN" group.

[0060] An "isocyanato" group refers to a "-NCO" group.

[0061] A "thiocyanato" group refers to a "-SCN" group.

[0062] A "carbonyl" group refers to a "-C(=O)-" group.

[0063] A "thiocarbonyl" group refers to a "-C(=S)-" group.

[0064] An "oxo" group refers to a "=0" group.

[0065] An "isothiocyanato" group refers to a "-NCS" group.

[0066] A "sulfinyl" group refers to a "-S(=O)-R" group, wherein R may be the same as defined for O-carboxyl. The sulfinyl group may be substituted.

[0067] A "sulfonyl" group refers to an "SO 2 R" group, wherein R may be the same as defined for the O-carboxyl group. The sulfonyl group may be substituted.

[0068] The "S-sulfonylamino" group refers to the "-SO 2 NR A R B " group, where R A and R B independently of one another may be the same as defined for the R groups as defined for O-carboxyl, or combined to form a ring system selected from the group consisting of: 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 The S-sulfonylamino group may be substituted.

[0069] The "N-sulfonylamino" group refers to the "RSO 2 N(R A )-" group, where R and R A independently of one another may be the same as defined for the R groups as defined for O-carboxyl. The N-sulfonylamino group may be substituted.

[0070] "Trihalomethanesulfonylamino" group refers to "X 3 CSO 2 N(R)-" group, wherein X (as halogen) and R may be the same as defined for O-carboxy. The trihalomethanesulfonylamino group may be substituted.

[0071] The term "acylamino" refers to a "C-acylamino" group, i.e., "-C(=O)NR A R B " group, where R A and R B independently of one another may be the same as defined for the R groups as defined for O-carboxyl, or combined to form a ring system selected from the group consisting of: 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 substituted or unsubstituted heteroalicyclic group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group. C-amido group may be substituted; or "amido" group refers to "N-amido" group, i.e., refers to "RC(=O)NR A -" group, where R and R A independently of one another may be the same as defined for the R groups as defined for O-carboxyl. The N-acylamino group may be substituted.

[0072] "Ester" refers to a "-C(=O)OR" group, where R may be the same as defined for O-carboxyl. Esters may be substituted.

[0073] Lower alkoxyalkyl refers to an alkoxy group connected via a lower alkylene group. Lower alkoxyalkyl may be substituted.

[0074] "Amino" refers to "RNH 2 ” (primary amine), “R 2 NH” (secondary amine) and “R 3 N" (tertiary amine), wherein each R can be independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, or (heteroalicyclic)alkyl. The amino group can be substituted.

[0075] Aminoalkyl refers to an amino group attached via an alkylene group. The aminoalkyl group may be substituted.

[0076] The terms "ring" and "ring system" are used interchangeably in this disclosure.

[0077] Any unsubstituted or monosubstituted amine group on the compounds herein can be converted to an amide, any hydroxy group to an ester, and any carboxyl group to an amide or ester using techniques well known to those skilled in the art (see, e.g., Greene and Wuts, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons, New York, NY, 1999).

[0078] As used herein, unless otherwise indicated, any abbreviations for protecting groups, amino acids, and other compounds shall be consistent with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 11: 942-944 (1972)).

[0079] As used herein, the following terms have their generally accepted meanings in the chemical literature.

[0080]

[0081]

[0082]

[0083] It should be understood that in any compound disclosed herein with one or more chiral centers, if absolute stereochemistry is not explicitly indicated, each center can independently have R-configuration or S-configuration or a mixture thereof. The terms "R" and "S" used herein are configurations defined in the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry in Pure Appl. Chem., 1976, 45: 13-30. Various stereoisomers and mixtures thereof are contemplated by the present disclosure, and these 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 compounds disclosed herein can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers, or by preparing a racemic mixture, followed by a resolution method well known to those of ordinary skill in the art. These resolution methods are exemplified by (1) attaching a mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography, and optionally liberating 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, or (2) separating the mixture of optical enantiomers directly on a chiral chromatographic column, or (3) fractional recrystallization methods. In addition, the compounds provided herein may be partially racemic mixtures. In addition, it should be understood that in any compound having one or more double bonds that can produce geometric isomers that can be defined as E or Z, each double bond can independently be E or Z or a mixture thereof. Likewise, all tautomeric forms are also intended to be included.

[0084] Compounds disclosed herein can exist as cis or trans isomers, wherein the substituents on the ring can be attached in such a way that they are on the same side of the ring (cis) relative to each other, or on the opposite side of the ring (trans) relative to each other. For example, cyclobutane can exist in cis or trans configuration, and can exist as a single isomer or a mixture of cis and trans isomers. The single cis or trans isomer of the compound disclosed herein can be prepared synthetically by commercially available starting materials using selective organic conversion, or prepared in a single isomeric form by purifying a mixture of cis and trans isomers. Such methods are well known to those of ordinary skill in the art, and can include separation of isomers by recrystallization or chromatography.

[0085] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure that differ in the displacement of hydrogen atoms and electrons, a typical example being the "enol"-"keto" forms:

[0086]

[0087] "Enol"-"keto" tautomerism can be exemplified by Formula I and its tautomeric forms:

[0088]

[0089] Additional non-limiting examples of tautomers include imine-enamine tautomers (-CH 2 -CH=NH and -CH=CH-NH 2 ), or a tautomeric form of a heteroaryl group containing ring atoms attached to both the ring-NH- portion and the ring=N- portion, such as pyrazole, imidazole, benzimidazole, triazole and tetrazole.

[0090] It should be understood that isotopes may be present in the compounds described herein. Each chemical element represented by a compound structure may include any isotope of the element. For example, in the compounds described herein, the hydrogen atoms may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, references to compounds herein encompass all potential isotopic forms unless the context clearly indicates otherwise.

[0091] As used herein, "pharmaceutically acceptable salts" refer to salts of compounds that do not abrogate the biological activity and properties of the compound. Pharmaceutically acceptable salts can be obtained by reacting the compounds disclosed herein with acids or bases. Base-formed salts include, but are not limited to, ammonium salts (NH 4 +); alkali metal salts, such as but not limited to sodium or potassium salts; alkaline earth metal salts, such as but not limited to calcium or magnesium salts; 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 amino groups of amino acids, such as but not limited to arginine and lysine. Useful acid-based salts include, but are not limited to, hydrochloride, hydrobromide, acetate, adipate, aspartate, ascorbate, benzoate, butyrate, caprate, caproate, caprylate, camphorsulfonate, citrate, caprate, formate, fumarate, gluconate, glutarate, glycolate, caproate, laurate, lactate, maleate, nitrate, oleate, oxalate, caprylate, propionate, palmitate, phosphate, sebacate, succinate, stearate, sulfate, sulfonate (e.g., methanesulfonate, ethanesulfonate, p-toluenesulfonate), salicylate, tartrate, toluenesulfonate.

[0092] Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or 1 to about 2, 3 or 4 solvent or water molecules.

[0093] As used herein, "prodrug" refers to a compound that may not have pharmaceutical activity but is converted into an active drug when administered in vivo. Prodrugs can be designed to change the metabolic stability or transport characteristics of a drug to mask side effects or toxicity, to improve the flavor of a drug, or to change other characteristics or properties of a drug. Prodrugs are generally useful because they may be easier to administer than the parent drug. For example, they may be bioavailable by oral administration, while the parent drug is not. In a pharmaceutical composition, a prodrug may also have better solubility than the active parent drug. Non-limitingly, an example of a prodrug is a compound disclosed herein, which is administered in the form of an ester ("prodrug") to promote absorption through a cell membrane, where water solubility is not conducive to fluidity, but is subsequently metabolically hydrolyzed to a carboxylic acid (active entity), and once inside the cell, water solubility is very favorable. Another example of a prodrug may be a short peptide (polyamino acid) bonded to an acidic group, where the peptide is metabolized in vivo to release the active parent compound. With the knowledge of in vivo pharmacodynamic processes and drug metabolism, one skilled in the art, once knowing a pharmaceutically active compound, can design a prodrug of the compound (see, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pp. 388-392).

[0094] As used herein, "modulating" the function of a bromodomain or bromodomain-containing protein means increasing its cellular function above basal levels measured in the specific environment in which it exists, or decreasing its cellular function below basal levels measured in the environment in which it exists, and / or rendering it unable to perform its cellular function at all.

[0095] An "agonist" is defined as a compound that increases the basal activity of a receptor (ie, signal transduction mediated by the receptor).

[0096] As used herein, "partial agonist" refers to a compound that has affinity for a receptor, but unlike an agonist, when bound to the receptor, it only elicits a fraction of the magnitude of the pharmacological response normally associated with that receptor, even if the compound occupies many receptors.

[0097] 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 with negative intrinsic activity.

[0098] As used herein, "antagonist" refers to a compound that binds to a receptor to form a complex that does not elicit any response, as if the receptor were unoccupied. Antagonists reduce the effect of agonists on a receptor. Antagonists may bind reversibly or irreversibly, effectively eliminating the activity of the receptor permanently, or at least until the antagonist is metabolized or dissociated or otherwise removed by physical or biological processes.

[0099] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates, such as birds, fish, shellfish, 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, in particular, humans.

[0100] As used herein, "patient" refers to a subject who is being treated by a medical professional, such as an MD or DVM, in an attempt to cure or at least alleviate the effects of a particular disease or disorder, or to treat the disease or disorder from its inception.

[0101] "Receptor" is intended to include any molecule present inside or on the surface of a cell that may affect the physiology of the cell when inhibited or stimulated by a ligand. Typically, a receptor includes an extracellular domain that has ligand binding properties, a transmembrane domain that anchors the receptor in the cell membrane, and a cytoplasmic domain that generates a cell signal ("signal transduction") in response to ligand binding. Receptors also include any intracellular molecule that generates a signal in response to ligation. Receptors also include any molecule that has a characteristic structure of a receptor but does not have a recognizable ligand. In addition, receptors include truncated, modified, mutated receptors, or any molecule that contains part or all of a receptor sequence. "Ligand" is intended to include any substance that binds to or interacts with a bromodomain or a protein containing a bromodomain.

[0102] "Selective" or "selectivity" is defined as the ability of a compound to bind to or preferentially inhibit a specific protein or specific 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 is able to preferentially bind to a bromodomain of a BET family protein over a protein containing a non-BET family bromodomain. It can also refer to a compound that is able to preferentially bind to the N-terminal bromodomain of a BET family protein over the C-terminal bromodomain or a compound that is able to preferentially bind to the C-terminal bromodomain over the N-terminal domain.

[0103] 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 act in combination with each other.

[0104] As used herein, the term "effective amount" means that amount of active compound or pharmaceutical agent that elicits in a tissue, system, animal or human the biological or medical response that the researcher, veterinarian, physician or other clinician is seeking, including reduction or alleviation of the symptoms of the disease being treated.

[0105] Compound

[0106] The embodiments disclosed herein relate to compounds of formula (I)

[0107]

[0108] or a pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer thereof, wherein X is selected from -C(R 4 R 5 )-, -S-, -O- and -N(R6 )-; Y is -N- or -C(R 7 )-, where R 7 Selected from hydrogen and C 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 5-10-membered heteroalicyclic ring system; and -NR 8 R 9 ; R 1 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 -OR 10 , where R 10 Selected from C 3-6 Cycloalkyl, 4-6 membered heteroalicyclic and C 1-4 Hydroxyalkyl; R 2 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 R 1 and R 2 cannot be selected from hydrogen; or R 1 , R 2 Together with the carbon atoms to which they are attached, they form a ring; R 3 Can be absent or present 1 or 2 times, and when present is C 1-4 Alkyl (selected from C 1-4 alkyl group); R 4 and R 5 are independently selected from the group consisting of 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 Alkoxy, -OH and -CN; R 6 Selected from the group consisting of: hydrogen and unsubstituted or substituted C 1-6 Alkyl, unsubstituted or substituted C 3-6 Cycloalkyl, unsubstituted or substituted C 2-6 heteroalicyclic group; and R 8 and R 9 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 R 8 and R 9 At least one of which is selected from the group consisting of: unsubstituted or substituted C 1-4Alkyl and unsubstituted or substituted C 3-4 Cycloalkyl.

[0109] In some embodiments, the compound of formula (I) or pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer relates to X, which is selected from -C(R 4 R 5 )-, -O- and -N(R 6 In other embodiments, X is -C(R 4 R 5 )-, where R 4 and R 5 are independently selected from the group consisting of: hydrogen, hydroxyl, C 1-4 Alkyl, C 1-4 In some embodiments, R 4 and R 5 Both are hydrogen. In other embodiments, R 4 is hydrogen and R 5 is methyl, and in another embodiment, R 4 and R 5 Both are methyl. In other embodiments, X is -O-. In other embodiments, X is -N(R 6 )-, where R 6 Selected from the group consisting of: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl and 4 or 5 membered heteroalicyclic groups, for example hydrogen, methyl, ethyl, n-propyl, isopropyl and tetrahydrofuranyl, such as hydrogen, methyl, or ethyl.

[0110] In some embodiments of Formula (I), Y is -N- or -C(R 7 )-, where R 7 is hydrogen or C 1-4 Alkyl groups, such as hydrogen.

[0111] In some embodiments of Formula (I), Y is -N-, and X is -CH 2 -.

[0112] In some embodiments of Formula (I), Y is -N-, and X is -O-.

[0113] In some embodiments of Formula (I), Y is -N-, and X is -N(R 6 )-, where R 6 Selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl and tetrahydrofuranyl, such as hydrogen, methyl or ethyl.

[0114] In some embodiments of Formula (I), A is selected from the group consisting of: a 5- or 6-membered alicyclic ring system; a 5-10-membered heteroalicyclic ring system; and -NR 8 R 9 , wherein each ring system is unsubstituted or substituted. In some embodiments, the ring system, such as a 5-10 membered heteroalicyclic ring system, is unsubstituted, wherein R 8 and R 9 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 R 8 and R 9 At least one of which is selected from the group consisting of: substituted C 1-4 Alkyl, or unsubstituted or substituted C 3-4 Cycloalkyl.

[0115] In some embodiments of formula (I), the ring system, for example, a 5-10 membered heteroalicyclic ring system, is substituted with a substituent selected from the group consisting of hydrogen, hydroxy, halogen, unsubstituted or substituted C 1-4 Alkyl and unsubstituted or substituted C 1-4 Alkoxy.

[0116] 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 comprising at least one nitrogen atom, a 6 membered heteroalicyclic ring system comprising at least one nitrogen atom or oxygen atom, a 7 membered heteroalicyclic ring system comprising at least one nitrogen atom, an 8 membered heteroalicyclic ring system comprising at least one nitrogen atom, all of which may be unsubstituted or substituted, and whenever substituted, the substituent may be present 1, 2 or 3 times and is independently selected from the group consisting of methyl, ethyl, propyl and halogen.

[0117] In some embodiments of Formula (I), A is unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative.

[0118] In some embodiments of Formula (I), A is unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative, Y is -N- or -CH-, X is -C(R 4 R 5 )-, where R 4 and R 5 are independently hydrogen or C 1-4 alkyl, such as hydrogen or methyl, or X is -N(R 6 )-, where R 6 Selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl and tetrahydrofuranyl, such as hydrogen, methyl or ethyl, or X is -O-.

[0119] 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 2 -, or X is -N(R 6 )-, where R 6 Selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl and tetrahydrofuranyl, such as hydrogen, methyl or ethyl, or X is -O-.

[0120] 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 2 -, or X is -N(R 6 )-, where R 6 Selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl and tetrahydrofuranyl, such as hydrogen, methyl or ethyl.

[0121] In some embodiments of Formula (I), Y is -N-, X is -C(R 4 R 5 )-, where R 4 and R 5 are independently hydrogen or C 1-4 alkyl, such as hydrogen or methyl, or X is -N(R 6 )-, where R 6 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-, and A is unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative selected from the group consisting of: Where R 11 , R 13 , R 16 and R 17 is absent or present 1 or 2 times, and when present is independently selected from the group consisting of hydroxy, fluoro, methyl, ethyl and propyl. In other embodiments, R 11 , R 13 , R 16 and R 17 In other embodiments, A is an unsubstituted morpholine

[0122] 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 -O-, wherein the unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative is selected from the group consisting of: Where R 11 , R 13 , R 16 and R 17is absent or present 1 or 2 times, and when present is independently selected from the group consisting of hydroxy, fluoro, methyl, ethyl and propyl. In other embodiments, R 11 , R 13 , R 16 and R 17 In other embodiments, A is unsubstituted morpholine.

[0123] 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 -O-, wherein the unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative is selected from the group consisting of: Where R 11 is absent or present 1 or 2 times, and when present is independently selected from the group consisting of hydroxy, fluoro, methyl, ethyl and propyl. In other embodiments, R 11 Does not exist.

[0124] 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 -O-, wherein the unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative is selected from the group consisting of: Where R 13 , R 16 and R 17 is absent or present 1 or 2 times, and when present is independently selected from the group consisting of hydroxy, fluoro, methyl, ethyl and propyl. In other embodiments, R 13 , R 16 and R 17 Does not exist.

[0125] In some embodiments of Formula (I), Y is -N-, X is -C(R 4 R 5 )-, where R 4 and R 5 are independently selected from the group consisting of: hydrogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, for example both are hydrogen, or X is -N(R 6 )-, where R 6 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-, 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

[0126] Where R 12 , R14 , R 15 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 is independently absent or present 1, 2 or 3 times, and when present is selected from halogen, hydroxyl, C 1-4 Alkyl and C 1-4 In other embodiments, A is selected from the group consisting of:

[0127] Where R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 R is independently absent or present one or two times, 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 1 time 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 Present twice and selected from the group consisting of fluoro and methyl.

[0128] In other embodiments of formula (I), A is selected from the group consisting of: Where R 18 is absent or is present 1 or 2 times and is selected from the group consisting of fluorine and methyl. 18 Exists 1 time.

[0129] In some embodiments, 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 (including bridged morpholine derivatives), which means a heteroalicyclic ring other than (or if it is not) unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative. Unsubstituted or substituted morpholine derivatives are understood to contain a morpholine backbone, examples being:

[0130] In some embodiments, the 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 system other than:

[0131] In some embodiments of Formula (I), Y is -N-, X is -CH 2 -, or X is -N(R 6 )-, where R 6 Selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl and tetrahydrofuranyl, such as hydrogen, methyl, or ethyl, or X is -O-, and A is a 5- or 6-membered alicyclic ring system.

[0132] In some embodiments of Formula (I), R 3 may be absent, indicating that the carbon atom adjacent to X is unsubstituted, or R 3 is present once or twice, attached to the same or different carbon atoms, and R 3 It is C 1-4 In some embodiments, R 3 It's methyl.

[0133] In some embodiments of Formula (I), R 3 is methyl, and A is unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative, and Y is -N- or -C(R 7 )-, where R 7 is hydrogen, X is -CH 2 -, or X is -N(R 6 )-, where R 6 Selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl and tetrahydrofuranyl, such as hydrogen, methyl, or ethyl, or X is -O-.

[0134] In some embodiments of Formula (I), R 3 is absent, and A is unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative, and Y is -N- or -C(R 7 )-, where R 7 is hydrogen, X is -CH 2 -, or X is -N(R 6 )-, where R 6 Selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl and tetrahydrofuranyl, such as hydrogen, methyl, or ethyl, or X is -O-.

[0135] In some embodiments of Formula (I), A is selected from -NR 8 R 9 , where R8 and R 9 is independently selected from the group consisting of methyl, ethyl, propyl, cyclopropyl and cyclopropylmethyl. 8 and R 9 is independently methyl or cyclopropylmethyl.

[0136] In some embodiments of Formula (I), A is selected from -NR 8 R 9 , where R 8 and R 9 are independently selected from the group consisting of methyl, ethyl, propyl, cyclopropyl and cyclopropylmethyl, provided that R 8 and R 9 At least one of is selected from the group consisting of methyl, ethyl, propyl, cyclopropyl and cyclopropylmethyl, and X is -O-, and Y is -N-.

[0137] In some embodiments, the compounds of Formula (I) or pharmaceutically acceptable salts, polymorphs, stereoisomers and tautomers relate to R 1 , which 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 -OR 10 , where R 10 Selected from C 3-6 Cycloalkyl, 4-6 membered heteroalicyclic and C 1-4 Hydroxyalkyl;

[0138] In some embodiments of Formula (I), R 2 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 R 1 and R 2 Cannot be selected from hydrogen at the same time;

[0139] In some embodiments, the compounds of Formula (I) or pharmaceutically acceptable salts, polymorphs, stereoisomers and tautomers relate to R 1 , R 2 , and the carbon atoms to which they are attached are taken together to form a ring. Specific examples of rings are heteroalicyclic rings, such as 5-membered and 6-membered rings containing one or more heteroatoms (such as one or more oxygen atoms).

[0140] Some examples are:

[0141]

[0142] In some embodiments of Formula (I), R 1 is selected from the group consisting of hydrogen, hydroxy, fluorine, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, butoxy, -O-azetidinyl, -O-CH 2 CH 2 OH, -O-CH 2 CH 2 NHCH 3 .

[0143] In some embodiments of Formula (I), R 1 is selected from the group consisting of methyl, methoxy and ethoxy. 1 It's a methoxy group.

[0144] In some embodiments of Formula (I), R 2 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy and butoxy. 2 It's hydrogen.

[0145] In some embodiments of Formula (I), R 1 is methoxy and R 2 It's hydrogen.

[0146] In some embodiments, the compound or pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to the following formula (II):

[0147]

[0148] Where R 1 It is C 1-4 alkoxy, and X, Y, A and R 3 is as described above.

[0149] In some embodiments of Formula (II), A is selected from the group consisting of:

[0150]

[0151] Where 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 R24 is independently absent or present 1, 2 or 3 times, and when present is selected from halogen, hydroxyl, C 1-4 Alkyl and C 1-4 A group consisting of alkoxy groups.

[0152] In some embodiments of Formula (II), A is selected from the group consisting of: Where R 11 , R 13 , R 16 and R 17 is absent or present 1 or 2 times, and when 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.

[0153] In some embodiments of Formula (II), A is selected from the group consisting of: Where R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 is independently absent or present one or two times, 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 once and is selected from the group consisting of hydroxy, fluoro, and methyl.

[0154] In some embodiments of Formula (II), X is -C(R 4 R 5 )-, where R 4 and R 5 are independently hydrogen or C 1-4 alkyl; or X is -N(R 6 )-, where R 6 Selected from hydrogen, C 1-4 Alkyl, C 1-4 The group consisting of haloalkyl and 4- or 5-membered heteroalicyclic group; or X is -O-.

[0155] In some embodiments of Formula (II), R 3 Absent or methyl.

[0156] In some embodiments of Formula (II), R 1 is methoxy and R 2 is hydrogen, and R 3 Absent or methyl.

[0157] In some embodiments, the compound or pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to the following formula (III):

[0158]

[0159] Where R 1 It is C 1-4 Alkoxy; R 2 is hydrogen; R 3 is absent or present once, and when present is selected from methyl; R 11 Not present; Y is -N- or -CH-; X is -O- or N(R 6 ), where R 6 Selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl and oxetanyl.

[0160] In some embodiments of Formula (III), R 1 is methoxy; R 3 Not present; Y is -N- and X is -O-.

[0161] In other embodiments of formula (III), R 1 is methoxy; R 3 Not present; Y is -CH- and X is -O-.

[0162] In some embodiments, the compound according to formula (I) or a pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer is selected from: N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide,

[0163] N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide,

[0164] N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide,

[0165] N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide,

[0166] (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,

[0167] 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,

[0168] N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide,

[0169] N-(4,8-dimethyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide,

[0170] 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,

[0171] N-[8-(2-hydroxyethoxy)-4-methyl-2-oxo-1H-quinolin-6-yl]-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide,

[0172] N-[8-(azetidin-3-yloxy)-4-methyl-2-oxo-1H-quinolin-6-yl]-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide,

[0173] N-(7-fluoro-8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide,

[0174] 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,

[0175] N-(4,7-dimethyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide,

[0176] N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide,

[0177] N-(8-ethoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide,

[0178] N-[4-methyl-8-[2-(methylamino)ethoxy]-2-oxo-1H-quinolin-6-yl]-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide,

[0179] 2-morpholino-N-(4,7,8-trimethyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide,

[0180] N-(7-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide,

[0181] N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-6-methyl-2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxamide,

[0182] 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,

[0183] 6-ethyl-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxamide,

[0184] 6-isopropyl-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxamide,

[0185] 2-(dimethylamino)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide,

[0186] 2-[Cyclopropylmethyl(methyl)amino]-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide,

[0187] 2-(Diethylamino)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide,

[0188] 2-[Ethyl(isopropyl)amino]-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide,

[0189] 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,

[0190] 2-(Cyclopenten-1-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide,

[0191] 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,

[0192] 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,

[0193] 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,

[0194] N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-(1-methyl-2-azabicyclo[2.1.1]hex-2-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide,

[0195] 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,

[0196] 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,

[0197] 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,

[0198] 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,

[0199] 2-(7-azabicyclo[2.2.1]hept-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide,

[0200] 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,

[0201] 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,

[0202] 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,

[0203] 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

[0204] 2-(6,6-Difluoro-3-azabicyclo[3.1.0]hex-3-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide.

[0205] In another aspect, the compounds of formula (I) and pharmaceutically acceptable salts, polymorphs, stereoisomers and tautomers thereof are active bromodomain inhibitors without inhibiting the activity of phosphodiesterase enzyme 3 (PDE3).

[0206] In one aspect, the compound of formula (I) and pharmaceutically acceptable salts, polymorphs, stereoisomers and tautomers thereof and at least one pharmaceutically acceptable excipient are contained in a pharmaceutical composition.

[0207] In another aspect, the compounds of formula (I) and pharmaceutically acceptable salts, polymorphs, stereoisomers and tautomers thereof are used to treat the following diseases or conditions: systemic or tissue inflammation, inflammatory response to infection or hypoxia, cell activation and proliferation, metabolism, fibrosis, and for the prevention and treatment of viral infections.

[0208] In another aspect, the compounds of formula (I), (II), (III) and their pharmaceutically acceptable salts, polymorphs, stereoisomers and tautomers are contained in a composition for treating the following diseases or conditions: such as 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 syndrome ( disease), optic neuritis, neuromyelitis optica, myasthenia gravis, Guillain-Barré syndrome, Graves' disease, alopecia, vitiligo, bullous dermatoses, 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, and acute rejection of a transplanted organ; or

[0209] Treatment of diseases or conditions such as acute gout, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including giant cell arteritis, polyarteritis nodosa, Behcet's disease, Wegener's granulomatosis, Kawasaki disease, Takayasu's arteritis, vasculitis with organ involvement, and acute rejection of a transplanted organ; or

[0210] Treatment of sepsis, septic syndrome, septic shock, endotoxemia, systemic 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, postoperative syndrome, sarcoidosis, Herksheimer's reaction, encephalitis, myelitis, meningitis, malaria, and SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex, and coronavirus; or

[0211] Treatment of ischemia-reperfusion injury, myocardial infarction, cerebrovascular ischemia (stroke), acute coronary syndrome, renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardiopulmonary bypass surgery, pulmonary, renal, hepatic, gastrointestinal, or peripheral limb embolism; or

[0212] Treating disorders or conditions such as hypercholesterolemia, atherosclerosis, and Alzheimer's disease; or

[0213] Treating disorders or conditions such as idiopathic pulmonary fibrosis, pulmonary fibrosis, intestinal fibrosis, liver fibrosis, nonalcoholic steatohepatitis, liver cirrhosis, renal fibrosis, post-operative stenosis, myelofibrosis, keloid formation, skin fibrosis, hand fibrosis, systemic sclerosis, scleroderma, and cardiac fibrosis; or

[0214] Treat or prevent viral infections such as herpes virus, human papillomavirus, human immunodeficiency virus (HIV), adenovirus, and poxvirus; or

[0215] Treats colon cancer, midline cancer, sarcoma, mesenchymal, liver, kidney and neural tumors; acute lymphocytic leukemia, acute myeloid leukemia, adult T-cell leukemia / lymphoma, bladder cancer, blastoma, bone cancer, breast cancer, brain cancer, Burkitt's lymphoma, 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 tumour, non-Hodgkin's lymphoma, intestinal cancer, kidney cancer, laryngeal cancer, leukaemia, lung cancer, lymphoma, liver cancer, small cell lung cancer, non-small cell lung cancer, melanoma, mesothelioma, multiple myeloma, eye cancer, optic nerve tumour, oral cancer, ovarian cancer, pituitary tumour, primary central nervous system lymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, rectal cancer, sarcoma, skin cancer, spinal cord tumour, small intestine cancer, stomach cancer, T-cell lymphoma, testicular cancer, thyroid cancer, laryngeal cancer, genitourinary cancer, urothelial carcinoma, uterine cancer, vaginal cancer, or Wilms' tumour; or

[0216] Treating obesity such as that associated with cancer treatment or that associated with diabetes and cardiac hypertrophy.

[0217] Additional examples of diseases, disorders or conditions include obesity, such as obesity associated with cancer treatment or obesity associated with diabetes and cardiac hypertrophy.

[0218] Application method

[0219] Compounds or pharmaceutical compositions can be administered to patients in any suitable manner. Non-limiting examples of methods of administration include, in particular: (a) administration by oral routes, including administration in the form of capsules, tablets, granules, sprays, syrups or other such forms; (b) administration by non-oral routes, such as rectal, vaginal, intraurethral, ​​intraocular, intranasal or intraaural administration, including administration in the form of aqueous suspensions, oily preparations, etc. or in the form of drops, sprays, suppositories, ointments, ointments, etc.; (c) administration by subcutaneous, intraperitoneal, intravenous, intramuscular, intradermal, intraorbital, intracapsular, intraspinal, intrasternal injection, including infusion pump delivery; (d) local administration, such as by direct injection in the kidney or heart area, for example, by long-acting implants, by intratumoral injections, or by intralymph node injections; and (e) local administration; as those skilled in the art consider it appropriate to contact the compounds disclosed herein with living tissue.

[0220] Pharmaceutical compositions suitable for administration include compositions in which the content of the active ingredient is effective to achieve its intended purpose. The therapeutically effective amount of the compounds disclosed herein that are required as a dosage will depend on the route of administration, the type of animal (including humans) being treated, and the physiological characteristics of the particular animal being considered. The dosage can be adjusted as required to obtain the desired effect, but will depend on a variety of factors, such as body weight, diet, simultaneous medication, and other factors that will be recognized by those skilled in the art of medicine. More specifically, a therapeutically effective amount means the amount of a compound that effectively treats, alleviates or improves the symptoms of a disease, or prolongs the survival rate of a treated subject. In particular, the determination of a therapeutically effective amount is fully within the capabilities of those skilled in the art, based on the detailed disclosure provided herein.

[0221] It will be apparent to those skilled in the art that the useful in vivo dose to be administered and the specific mode of administration will vary according to age, body weight and species of mammals being treated, the specific compounds used, and the specific uses of these compounds used. One skilled in the art can determine the effective dose level, i.e., the dose level required to achieve the desired result, using conventional pharmacological methods. Typically, human clinical use of the product begins with a lower dose level, with the increase in dose level until the desired effect is achieved. Alternatively, acceptable in vitro studies can be used to determine the useful dose and route of administration of the composition identified by the method of the present invention using established pharmacological methods.

[0222] In non-human animal studies, the use of potential products begins at higher dose levels, with the dose reduced until the desired effect is no longer achieved or the adverse side effects disappear. The dose applied to a human or non-human subject can be in a wide range, depending on the desired effect and the therapeutic indication. Typically, the dose can be between about 10 micrograms / kg and 1000 mg / kg body weight, preferably between about 100 micrograms / kg and 10 mg / kg body weight. Alternatively, as will be appreciated by those skilled in the art, the dose can be based on the surface area of ​​the patient and calculated based thereon.

[0223] The exact formulation, route of administration, and dosage of the pharmaceutical compositions disclosed herein can be selected by the individual physician based on the patient's condition. (See, e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics," which is hereby incorporated by reference in its entirety, with particular reference to Chapter 1, page 1). Typically, the dosage range of the composition administered to the patient can be from about 0.5 to 1000 mg / kg of the patient's body weight. The dosage can be a single dose over the course of one or more days, or a series of two or more doses, depending on the patient's needs. In cases where human doses for compounds have been determined for at least certain conditions, those same doses may be used, or doses between about 0.1% and 500%, more preferably between about 25% and 250%, of the determined human doses. If a human dose has not been determined (as in the case of a newly discovered drug compound), the ED may be administered. 50 or ID 50 The appropriate human dose may be extrapolated from values ​​derived from in vitro or in vivo studies, as defined by animal toxicity studies and efficacy studies.

[0224] It should be noted that due to toxicity or organ dysfunction, the attending physician will know how and when to terminate, interrupt or adjust the administration. On the contrary, if the clinical response is insufficient (excluding toxicity), the attending physician will also know to adjust the treatment to a higher level. In the management of the obstacles concerned, the size of the administered dose will vary with the severity of the desired treatment condition and the route of administration. The severity of the condition can be assessed, for example, in part by standard prognostic assessment methods. In addition, the dosage and possible dosage frequency will also vary according to the age, body weight and response of the individual patient. A program comparable to the program discussed above can be used in veterinary medicine.

[0225] Although the exact dosage will be determined according to each drug, in most cases, some generalizations can be made about the dosage. The daily dosage regimen for adult human patients can be, for example, an oral dose of each active ingredient between 0.1 mg and 2000 mg, preferably between 1 mg and 500 mg, such as 5 to 200 mg. The concentration range of eye drops can be between 0.005% and 5%. In one embodiment, the range of eye drops can be between 0.01% and 1%, or in another embodiment, between 0.01% and 0.3%. In other embodiments, the intravenous, subcutaneous or intramuscular dose of each active ingredient used is 0.01 mg to 100 mg, preferably 0.1 mg to 60 mg, such as 1 to 40 mg. In the case of administering a pharmaceutically acceptable salt, the dose can be calculated as a free base. In some embodiments, the composition is administered 1 to 4 times a day. Alternatively, the composition disclosed herein can be administered by continuous intravenous infusion, preferably administered at a dose of up to 1000 mg / day for each active ingredient. As will be appreciated by those skilled in the art, in some cases, it may be necessary to administer the compounds disclosed herein in amounts exceeding or even far exceeding the above preferred dosage ranges or frequencies to effectively and actively treat particularly aggressive diseases or infections. In some embodiments, the compounds are administered for continuous treatment over a period of time, for example, for a week or more, or for several months or years.

[0226] Dosage and interval can be adjusted individually to provide plasma or tissue levels of the active moiety sufficient to maintain the modulatory effect or minimum effective concentration (MEC). The MEC will vary for each compound but can be estimated based on in vitro data. The dose required to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.

[0227] Dosage intervals can also be determined using the MEC. Compositions should be administered using a regimen that maintains plasma levels above the MEC for 10%-90% of the time, preferably 30%-90%, and most preferably 50%-90% of the time.

[0228] In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0229] The amount of the composition administered may depend on the subject being treated, the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.

[0230] The efficacy and toxicity of the compounds disclosed herein can be evaluated using known methods. For example, the toxicology of a specific compound or a subset of compounds sharing certain chemical parts can be established by determining the in vitro toxicity to a cell line such as a mammal, preferably a human cell line. The results of such studies can generally predict the toxicity of an animal (such as a mammal, or more specifically, a human). Alternatively, the toxicity of a specific compound in an animal model such as a mouse, rat, rabbit or monkey can be determined using known methods. The efficacy of a specific compound can be established using several recognized methods, such as in vitro methods, animal models or human clinical trials. There are recognized in vitro models for almost all categories of disorders, including but not limited to cancer, cardiovascular disease and various immune dysfunctions. Similarly, acceptable animal models can be used to confirm the efficacy of chemical drugs for treating such disorders. When selecting a model to determine the efficacy, those skilled in the art can select a suitable model, dosage, and route of administration and regimen by guidance of the current status of the art. Of course, human clinical trials can also be used to determine the efficacy of compounds in humans.

[0231] If desired, these compositions can be provided in a package or dispenser device, which may contain one or more unit dosage forms containing an active ingredient. The package may, for example, include a metal or plastic foil, such as a blister package. The package or dispenser device may be accompanied by instructions for use. The package or dispenser may also be accompanied by a notice associated with the container, which is in the form specified by a government agency regulating the production, use or sale of drugs, indicating that the agency has approved the drug form for human or veterinary management. For example, such a notice may be a prescription drug label approved by the U.S. Food and Drug Administration, or it may be an approved product insert. Compositions of compounds disclosed herein formulated in compatible pharmaceutical carriers may also be prepared, placed in appropriate containers, and labeled for treatment of specified conditions.

[0232] General Description

[0233] As described above with reference to specific illustrative embodiments, it is not intended to be limited to the specific forms set forth herein. Any combination of the above embodiments should be understood to be within the scope of the present disclosure. To be precise, the present disclosure is limited only by the appended claims, and within the scope of the appended claims, other embodiments than those specifically described above are equally possible.

[0234] In the claims, the term "comprises / comprising" does not exclude the presence of other species or steps. In addition, although individual features may be included in different claims, these may be advantageously combined, and the inclusion in different claims does not mean that a combination of features is not feasible and / or disadvantageous. In addition, a singular reference does not exclude a plurality. The terms "a or an", "first", "second" etc. do not exclude a plurality.

[0235] The phrases "at least one" and "one or more" refer to a number that is 1 or greater than 1, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0236] experiment

[0237] The following examples are merely examples and should in no way be construed as limiting the scope of the present disclosure. Specifically, the present disclosure is limited only by the appended claims.

[0238] Unless explicitly stated, the compounds described below have been prepared using commercially available starting materials. The following is a non-comprehensive list of starting materials used to synthesize the compounds prepared herein.

[0239] As can be seen in the following table, these compounds were found to have beneficial activity. Unless otherwise specified, all reagents were commercial grade and used as received without further purification. Commercially available anhydrous solvents were used for reactions carried out under an inert atmosphere. Unless otherwise specified, reagent grade solvents were used in all other cases.

[0240]

[0241]

[0242]

[0243] Detailed descriptions of the preparation of individual compounds according to formula (I) are described herein below.

[0244] Compound names were generated using Accelrys Draw 4.2

[0245] The compounds were characterized using LC-MS analysis and / or 1H-nuclear magnetic resonance (NMR) and in all cases were consistent with the proposed structures.

[0246] Unless otherwise stated, compounds were analyzed and purified using the following system:

[0247] Analytical:

[0248] A Waters Acquity system equipped with Acquity BEH C18 (1.7 μm, 2.1 x 50 mm) was used with a linear gradient of the binary solvent system water / acetonitrile / formic acid (A: 100 / 0.1% and B: 0 / 100 / 0.1%) at a flow rate of 0.5 mL / min and DAD at ambient temperature, combined with MS detection SQD I.

[0249] Preparation type:

[0250] Preparative HPLC was performed on a Waters Acquity system using a C18 reverse phase column (Supelco DISCOVERY C18, 25 cm x 21.2 mm) with a linear gradient of the 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 and UV detection at 254 nm combined with MS detection on a Waters Micromass ZQ Uadrupole MS.

[0251] Chemical shifts associated with NMR are reported in parts per million (ppm) and are referenced to the non-deuterated solvent residue. Conventional abbreviations are used to designate major peaks, such as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Abbreviations used for common solvents are: chloroform-d or CDCl3, deuterated chloroform; DMSO-d6, hexadeuterated dimethyl sulfoxide; CD3COOD, deuterated acetic acid; and CD3OD, deuterated methanol.

[0252] General Synthesis

[0253] The compounds described herein, including compounds of Formula (I) and specific examples, can be prepared, for example, by the reaction pathways depicted in Schemes 1-7. For example, unless otherwise indicated, the variables R1, R2, R3, R4, X, A, etc. used in the following schemes have the meanings as described in the claims, Summary of the Invention, and Detailed Description.

[0254] The abbreviations used in this disclosure have the following meanings:

[0255]

[0256]

[0257]

[0258] Synthesis of the final compound:

[0259] Solution 1

[0260]

[0261] Compounds of formula (I) can be prepared using the general synthetic route as shown 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.

[0262] A compound of formula (1) wherein halo is (Cl, Br, or I) and a compound of formula A-R102 wherein R102 is 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, and optionally in the presence of a ligand and in a suitable solvent at elevated temperatures (about 60° C. to about 150° C.). The reaction can be promoted by microwave radiation. 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. The example of suitable alkali that can be adopted includes but is not limited to carbonate or phosphate of sodium, potassium and cesium, and cesium fluoride.The example of suitable ligand includes but is not limited to 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos) and 1,1'-bis(diphenylphosphino)ferrocene.The non-limiting examples of suitable solvent include methanol, ethanol, dimethoxyethane, N,N-dimethylformamide, dimethyl sulfoxide, dioxane, tetrahydrofuran, toluene and water or its mixture.

[0263] 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. The replacement of the halogen atom can be accomplished in a solvent (such as but not limited to dimethyl sulfoxide, dimethylformamide, dioxane, or tetrahydrofuran) and in the presence of a base (such as but not limited to cesium, potassium, or sodium carbonate, or sodium hydride) and at a temperature of from about 20° C. to about 160° C. The reaction can be promoted by microwave radiation.

[0264] Hydrolysis of the ester (2) provides an acid of formula (3), which is reacted in a solvent (such as, but not limited to, tetrahydrofuran or 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) and in the presence of a coupling reagent (such as 1,1′-carbonyldiimidazole (CDI), bis(2-oxo-3-oxazolidinyl)phosphonic chloride (BOPCl), 1,3-dicyclohexylcarbodiimide (DCC), poly(4-dimethylaminopyridine) or poly(4-dimethylaminopyridine) to obtain an acid of formula (3). The amine of formula (4) is treated in the presence of a supporting 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 tetrafluoroborate (TBTU) in the presence or absence of a coupling aid such as, but not limited to, 1-hydroxy-7-azabenzotriazole (HOAT) or 1-hydroxybenzotriazole hydrate (HOBT) to provide a compound of formula (I).

[0265] 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).

[0266] Solution 2

[0267]

[0268] Alternatively, compounds of general formula (I) can be prepared as described in Scheme 2. Reaction of acid (3a) with amine (4) to provide compound (5), followed by treatment of (5) with compound A-R102 (wherein halide is F, Cl or Br) can be achieved using reaction conditions as described in Scheme 1.

[0269] Solution 3

[0270]

[0271] The compound of formula (I) (wherein X is -N(R 6 )) can be prepared by reductive amination of a compound of formula (6) 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 described in Scheme 3. Acetic acid can be used as a catalyst.

[0272] 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)

[0273] Solution 4

[0274]

[0275] Compounds of general formula (I) (wherein R1 is -OR10) can be prepared from compounds of formula (8) by alkylating the -OH group using compounds of formula (9) (wherein the halide is Br or Cl) in the presence of a base (such as but not limited to sodium hydride, cesium carbonate, or potassium carbonate) and in a solvent (such as but not limited to N,N-dimethylformamide or dimethyl sulfoxide) at a temperature of about room temperature to about 120°C as described in Scheme 4.

[0276] 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)

[0277] Synthesis of intermediates

[0278] Solution 5

[0279]

[0280] Compounds of formula (4) can be prepared using the general synthetic pathways 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 in the presence of a base such as pyridine at elevated temperatures (e.g., at about 60°C to about 140°C) and in a solvent such as, but not limited to, toluene. Treatment of (12) with an acid such as, but not limited to, trifluoromethanesulfonic acid or polyphosphoric acid and in the presence or absence of a solvent such as, but not limited to, dichloromethane at about room temperature to about 100°C provides compounds of formula (13). Preparation of compounds of formula (13) can be achieved by nitration with nitric acid in acetic anhydride at a temperature 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).

[0281] A specific example is 6-amino-8-ethoxy-4-methyl-1H-quinolin-2-one

[0282] Solution 6

[0283]

[0284] Alternatively, depending on R1 and R2, compounds of formula (4) can be prepared using the general synthetic route as shown in Scheme 6, wherein the amino group of compound (11) is first protected by an appropriate protecting group using a reagent such as, but not limited to, acetic anhydride or Boc anhydride. After the nitration step described in Scheme 5, the protecting group is removed 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.

[0285] Solution 7

[0286]

[0287] Compounds of formula (1) (wherein R3 is present) can be prepared as outlined in Scheme 7. Compounds of formula (19) (wherein R103 is -OH) are treated with an alkynyl derivative (25) (wherein R104 is Br) in the presence of a base (such as, but not limited to, NaH) and in a solvent (such as, but not limited to, N,N-dimethylformamide or tetrahydrofuran) at a temperature from about -20°C to room temperature to provide compounds of formula (20). Treatment of (20) with nitrobenzene at a temperature from about 100°C to about 180°C provides compounds (21). Insertion of a carbonyl group into (21) provides compounds of formula (22). It can be achieved by adding CO to the reaction, and generally, the conversion can be catalyzed 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). The reaction mixture may be reacted with 1% ethylamine, ...

[0288] A specific example is methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate.

[0289] Alternatively, compound (20) can be obtained from a 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 from about -78°C to about -50°C. A specific example is (5R)-2-chloro-5-methyl-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester.

[0290] It will be understood that the synthetic schemes and specific examples as described in the present disclosure are examples and should not be taken as limiting the scope of the present disclosure.

[0291] The optimum reaction conditions and reaction times of each individual step can vary depending on the substituents present in the particular reactants employed and the reactants used. Unless otherwise specified, those of ordinary skill in the art can easily select solvents, temperature and other reaction conditions. Specific procedures are provided in the experimental section. Reaction can be post-processed in a conventional manner, for example, by removing solvent from residue and further purified according to methods generally known in the art (such as but not limited to crystallization, distillation, extraction, grinding and chromatography). Unless otherwise noted, starting materials and reagents are commercially available or can be prepared by commercially available materials using the method described in the chemical literature by those skilled in the art.

[0292] Routine experimentation, including appropriately manipulating the order of reaction conditions, reagents and synthetic pathways, protecting any chemical functional groups that are incompatible with the reaction conditions, and deprotecting at appropriate points in the reaction sequence of the method, is included 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; examples thereof can be found in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis [Protective Groups in Organic Synthesis] (3rd Edition), 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 accomplished by methods similar to those described in the synthetic schemes described above and in the specific examples.

[0293] If not commercially available, the starting materials can be prepared by procedures selected from standard organic chemistry techniques, techniques analogous to the syntheses of known structurally similar compounds, or techniques analogous to the schemes described above or the procedures described in the Synthetic Examples section.

[0294] When an optically active form of a compound is required, it can be obtained by carrying out one of the procedures described herein using optically active starting materials (e.g., by asymmetric induced preparation by appropriate reaction steps), or by resolving a mixture of stereoisomers of the compounds or intermediates using standard procedures such as chromatographic separation, recrystallization or enzymatic resolution.

[0295] Similarly, when pure geometric isomers of compounds are required, they may be prepared by carrying out one of the above procedures using the pure geometric isomers as starting materials, or by resolving a mixture of geometric isomers of compounds or intermediates using standard procedures such as chromatographic separation.

[0296] Examples:

[0297] Synthesis of intermediates

[0298] Preparation of 6-amino-8-ethoxy-4-methyl-1H-quinolin-2-one (Intermediate 1)

[0299]

[0300] Preparation of N-(2-ethoxyphenyl)-3-oxo-butyramide:

[0301]

[0302] To a stirred solution of 2-ethoxyaniline (5.0 g, 36.49 mmol) in toluene (500 mL), methyl acetoacetate (4.23 g, 36.5 mmol) was added, followed by pyridine (15 mL, 3 volumes), and the reaction mixture was stirred at 120 ° C for 40 h. After completion, the reaction mixture was allowed to warm to room temperature and the solvent was evaporated. The residue was absorbed in ether and stirred for 15 min, and the precipitated solid was filtered to obtain N- (2-ethoxyphenyl) -3- oxo-butyramide (4.0 g, 50%) as a brown solid.

[0303] Preparation of 8-ethoxy-4-methyl-1H-quinolin-2-one:

[0304]

[0305] To a stirred solution of N-(2-ethoxyphenyl)-3-oxo-butyramide (3.5 g, 15.83 mmol) in DCM (350 mL) was added trifluoromethanesulfonic acid (3.4 ml, 39.59 mmol) and the reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was poured into ice water and washed with solid NaHCO 3Alkalize and filter the solid. Wash the solid with ether and dry under vacuum to give 8-ethoxy-4-methyl-1H-quinolin-2-one (2.0 g, 62%) as a brown solid

[0306] Preparation of 8-ethoxy-4-methyl-6-nitro-1H-quinolin-2-one:

[0307]

[0308] At 0 DEG C, nitric acid (0.57ml, 13.79mmol) is added to the solution of 8-ethoxy-4-methyl-1H-quinoline-2-one (1.4g, 6.9mmol) in acetic anhydride (42ml, 30 volumes), and the reaction mixture is stirred at the same temperature for 45 minutes.After completion, the reaction mixture is quenched in ice water and solid is collected by filtration.Solid is washed with water and n-pentane (3 × 50mL) to obtain 8-ethoxy-4-methyl-6-nitro-1H-quinoline-2-one (compound -4) (750mg, 44%) as yellow solid.

[0309] Preparation of 6-amino-8-ethoxy-4-methyl-1H-quinolin-2-one (Intermediate 1):

[0310]

[0311] By 8-ethoxy-4-methyl-6-nitro-1H-quinoline-2-one (750mg, 3.024mmol) suspension in methanol (7.5mL) nitrogen degassed 10 minutes.Thereafter, add Pd / C (10%) (75mg), and react in par shaker under hydrogen atmosphere (40psi) and stir at room temperature for 16h.After completion, reaction mixture is filtered by diatomite bed.Filtrate is evaporated to obtain 6-amino-8-ethoxy-4-methyl-1H-quinoline-2-one (500mg, 75%) in yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ9.99(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%.

[0312] Preparation of 6-amino-4,7,8-trimethyl-1H-quinolin-2-one (Intermediate 2):

[0313]

[0314] Preparation of N-(2,3-dimethylphenyl)-3-oxobutyramide:

[0315]

[0316] Methyl-3-oxobutyrate (35g, 309.9mmol, 1.0 equivalent) and pyridine (75ml, 3 volumes) are added to a stirred solution of 2,3-dimethylaniline (25g, 206.6mmol) in toluene (25mL, 10 volumes), and stirred for 16h at 120°C. After completion, the reaction mixture is allowed to warm to room temperature and the solvent is evaporated in vacuo. The residue is purified by column chromatography using 100-200 meshes, eluted with 50% EtOAc in petroleum ether to obtain N-(2,3-dimethylphenyl)-3-oxobutyramide (18g, 46%) as a brown solid.

[0317] Preparation of 4,7,8-trimethyl-1H-quinolin-2-one:

[0318]

[0319] To a stirred solution of N-(2,3-dimethylphenyl)-3-oxobutanamide (5.0 g, 24.3 mmol, 1.0 eq) in DCM (50 mL, 10 vol) at 0°C was added trifluoromethanesulfonic acid (21.5 ml, 243.0 mmol, 10 eq) and allowed to stir at room temperature for 16 h. After completion, the reaction mixture was poured into ice water and washed with solid NaHCO 3 Alkalize and extract with EtOAc (2 x 300 mL). The crude product was purified by column chromatography using 100-200 mesh, eluting with 5% methanol in dichloromethane to give 4,7,8-trimethyl-1H-quinolin-2-one (4.0 g, 87%) as a brown solid

[0320] Preparation of 4,7,8-trimethyl-6-nitro-1H-quinolin-2-one:

[0321]

[0322] 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 was added nitric acid (0.14 ml, 3.42 mmol, 2 eq) and the reaction mixture was stirred at 0°C for 45 min. After completion, the reaction mixture was quenched with ice water and washed with NaHCO3 The aqueous solution was basified and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with Na 2 SO 4 Dried and concentrated under reduced pressure.The crude was purified by column chromatography using 100-200 mesh, eluting with 30% EtOAc in petroleum ether to afford 4,7,8-trimethyl-6-nitro-1H-quinolin-2-one (100 mg, 25%) as a yellow solid.

[0323] Preparation of 6-amino-4,7,8-trimethyl-1H-quinolin-2-one (Intermediate 2):

[0324]

[0325] A suspension of 4,7,8-trimethyl-6-nitro-1H-quinoline-2-one (100 mg, 0.43 mmol) in methanol (1 mL, 10 volumes) was degassed under nitrogen for 10 minutes. Thereafter, Pd / C (10%) (10 mg) was added, and the reaction was stirred at room temperature for 16 h under a hydrogen atmosphere (40 psi). After completion, the reaction mixture was filtered through a diatomaceous earth bed, and the filtrate was evaporated to obtain 6-amino-4,7,8-trimethyl-1H-quinoline-2-one (80 mg, 97%) as a brown solid. LCMS [M + H] + 203.17m / z; 1H NMR (400MHz, DMSO-d6): δ10.22(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).

[0326] Preparation of 6-amino-7-fluoro-8-methoxy-4-methyl-1H-quinolin-2-one (Intermediate 3):

[0327]

[0328] Preparation of N-(3-fluoro-2-methoxy-phenyl)-3-oxo-butyramide:

[0329]

[0330] 3-Fluoro-2-methoxy-aniline (2.8 g, 20 mmol, 1 eq) was dissolved in toluene (5 ml) and 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 amount of DCM and purified on Biotage Isolera: heptane / EtOAc 95 / 5, then 95 / 5->40 / 60 and heptane / EtOAc 90 / 10 again, then 95 / 5->40 / 60. The fraction with the product was evaporated to give N-(3-fluoro-2-methoxy-phenyl)-3-oxo-butyramide 2.5 g (55%) LCMS [M+H] as a yellow oil + 226m / z

[0331] Preparation of 7-fluoro-8-methoxy-4-methyl-1H-quinolin-2-one:

[0332]

[0333] N-(3-Fluoro-2-methoxy-phenyl)-3-oxo-butyramide (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 over 15 min at room temperature, then stirred at room temperature for 2 h before adding another portion of trifluoromethanesulfonic acid (2 ml, 22.5 mmol, 2.5 eq).

[0334] After 3h, the reaction mixture was poured onto 70ml of ice and stirred for 10min., and then filtered. The product was washed with water (3×20ml), and then dried overnight at room temperature under 1 mbar vacuum to obtain 7-fluoro-8-methoxy-4-methyl-1H-quinoline-2-one 1.5g (66%) as a white powder. LCMS [M+H] + 208m / z. 1 H NMR (300MHz, DMSO-d6) δ11.17(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).

[0335] Preparation of 7-fluoro-8-methoxy-4-methyl-6-nitro-1H-quinolin-2-one:

[0336]

[0337] 7-Fluoro-8-methoxy-4-methyl-1H-quinolin-2-one (1.5 g, 7.2 mmol, 1 eq.) was suspended in Ac 2 O and cooled to 0 °C. HNO was added dropwise 3 65% aqueous solution (0.6ml, 8.6mmol, 1.19 equivalents), stirred at 0 ° C for 1.5h, and then poured into the ice-cold water of 150ml and stirred until solidified. The product is filtered and washed with water (3×25ml), and then dried at room temperature under 1 mbar vacuum, and then ground with DCM / MeOH / EtOAc (5+0.5+5ml). The product is filtered, washed with EtOAc (2×10ml) and dried at 45 ° C under 5 mbar vacuum to obtain 7-fluoro-8-methoxy-4-methyl-6-nitro-1H-quinoline-2-one, 860mg (~70% desired product+20% other regional isomers) as off-white powder. 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).

[0338] Preparation of 6-amino-7-fluoro-8-methoxy-4-methyl-1H-quinolin-2-one (Intermediate 3):

[0339]

[0340] 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. 2 The mixture was stirred for 2 h under a 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).

[0341] The filtered product was washed with acetone (5 ml) and dried under 1 mbar vacuum at room temperature overnight 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) δ10.73(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).

[0342] Preparation of 6-amino-7-methoxy-4-methyl-1H-quinolin-2-one (Intermediate 4):

[0343]

[0344] Preparation of N-(3-methoxyphenyl)acetamide:

[0345]

[0346] 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 allowed to warm to room temperature and stirred for 2 h. After completion, the reaction mixture was treated with NaHCO 3 The mixture was basified and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were purified by Na 2 SO 4 Dried and concentrated under reduced pressure, and the residue was washed with n-pentane to give N-(3-methoxyphenyl)acetamide (10 g, 76%) as a light brown solid.

[0347] Preparation of N-(3-methoxy-4-nitro-phenyl)acetamide:

[0348]

[0349] To a solution of N-(3-methoxyphenyl)acetamide (9.5 g, 57.5 mmol, 1.0 eq.) in acetic anhydride (150 mL, 15 vol.) was added nitric acid (4.8 mL, 115.1 mmol, 2.0 eq.) 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 and washed with NaHCO 3 The aqueous solution was basified and extracted with ethyl acetate (2 x 500 mL). The combined organic layers were purified by Na 2 SO 4 Dried and concentrated under reduced pressure.The crude was purified by column chromatography using 100-200 mesh silica gel, eluting with 30% EtOAc in petroleum ether to give N-(3-methoxy-4-nitrophenyl)acetamide (2.4 g, 20%) as a yellow solid.

[0350] Preparation of 3-methoxy-4-nitroaniline:

[0351]

[0352] To a stirred solution of 1N HCl (24 mL, 10 volumes) at room temperature was added N-(3-methoxy-4-nitrophenyl)acetamide (2.4 g, 11.42 mmol) and the reaction mixture was allowed to stir at 100 °C for 2 h. After completion, the reaction mixture was poured into ice water and washed with NaHCO 3 The aqueous solution was basified and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with Na 2 SO 4 Dried and concentrated under reduced pressure.The residue was washed with n-pentane to give 3-methoxy-4-nitroaniline (1.8 g, 94%) as a brown solid.

[0353] Preparation of N-(3-methoxy-4-nitrophenyl)-3-oxobutyramide:

[0354]

[0355] At room temperature, methyl-3-oxobutyrate (1.2g, 10.71mmol) is added to a stirred solution of 3-methoxy-4-nitroaniline (1.8g, 10.71mmol, 1 equivalent) in toluene (1.8mL, 10 volumes), pyridine (15ml, 3 volumes) is subsequently added, and the reaction mixture is stirred for 16h at 100°C. After completion, the reaction mixture is allowed to warm up to room temperature and the solvent is evaporated. The crude product is purified by silica gel column chromatography using 50% EtOAc of (100-200 mesh) in petroleum ether to obtain N-(3-methoxy-4-nitrophenyl)-3-oxobutyramide (1.7g, 63%) as a brown solid.

[0356] Preparation of 7-methoxy-4-methyl-6-nitro-1H-quinolin-2-one:

[0357]

[0358] To a stirred solution of N-(3-methoxy-4-nitrophenyl)-3-oxobutanamide (600 mg, 2.38 mmol) in DCM (6 mL) at 0°C was added trifluoromethanesulfonic acid (2.02 ml, 7.93 mmol) and allowed to stir at room temperature for 16 h. After completion, the reaction mixture was poured into ice water and washed with solid NaHCO 3 Basified and extracted with EtOAc (2 x 50 mL).The crude product was purified by column chromatography using (100-200 mesh silica gel) eluting with 5% methanol in dichloromethane to give 7-methoxy-4-methyl-6-nitro-1H-quinolin-2-one (50 mg, 9%) as a brown solid.

[0359] Preparation of 6-amino-7-methoxy-4-methyl-1H-quinolin-2-one (Intermediate 4):

[0360]

[0361] By 7- methoxy -4- methyl -6- nitro -1H- quinoline -2- one (50mg, 0.21mmol) suspension in methanol (0.5mL, 10 volumes) degassed 10min under argon.10% Pd / C (5mg) is added thereto, and the reaction is stirred at room temperature for 12h under hydrogen atmosphere (40psi).After completion, reaction mixture is filtered through diatomite bed.Filtrate is evaporated to obtain 6- amino -7- methoxy -4- methyl -1H- quinoline -2- one (30mg, 70%) in brown solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ11.14(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

[0362] Preparation of 5-amino-7-methyl-3,10-dihydro-2H-[1,4]dioxino[2,3-h]quinolin-9-one (Intermediate 5):

[0363]

[0364] Preparation of N-(2,3-dihydro-1,4-benzodioxin-5-yl)-3-oxo-butyramide:

[0365]

[0366] 2,3-dihydro-1,4-benzodioxin-5-amine (3g, 20mmol, 1 equivalent) was dissolved in toluene (10ml) and heated to 110 ° C, and 2,2,6-trimethyl-1,3-dioxin-4-one (3ml, 22.7mmol, 1.1 equivalent) was added. The reaction mixture was stirred for 0.75h and then cooled to room temperature. The solvent was evaporated and the crude mixture was purified on Biotage Isolera: heptane / EtOAc 93 / 7, then 93 / 7->30 / 70. The fraction with product was evaporated to give N-(2,3-dihydro-1,4-benzodioxin-5-yl)-3-oxo-butyramide 2.8g (60%) 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).

[0367] Preparation of 7-methyl-3,10-dihydro-2H-[1,4]dioxino[2,3-h]quinolin-9-one:

[0368]

[0369] N-(2,3-dihydro-1,4-benzodioxin-5-yl)-3-oxo-butyramide (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 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 in vacuo at room temperature at 1 mbar 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 light yellow powder. 1 HNMR (300MHz, chloroform-d) δ9.00 (s, 1H), 7.18 (d, J = 8.9Hz, 1H), 6.80 (d, J = 8.9Hz, 1H), 6.42 (d, J = 1.2Hz, 1H), 4.52-4.33 (m, 4H), 2.45 (d, J = 1.2Hz, 3H).

[0370] Preparation of 7-methyl-5-nitro-3,10-dihydro-2H-[1,4]dioxino[2,3-h]quinolin-9-one:

[0371]

[0372] 7-Methyl-3,10-dihydro-2H-[1,4]dioxino[2,3-h]quinolin-9-one (2.5 g, 11.5 mmol, 1 equivalent) was suspended in Ac 2 O (40 ml) and cooled to 0° C. HNO 365% aqueous solution (1.1 ml, 17.3 mmol, 1.5 eq.), and stirred at 0°C for 40 min, then poured into 400 ml of ice and stirred at room temperature for 10 min. The product was filtered and washed with water (2×30 ml). The product was ground 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 dried in air, ground with ultrasound in DCM / MeOH=1 / 1 (20 ml) and filtered. The product was purified on Biotage Isolera: ACN (0.1% FA) / H2O (0.1% FA) 1 / 99, then 1 / 99->40 / 60. The relevant fractions were evaporated. The purified top fractions were repurified on 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 other regioisomers in a ratio of 4:6. 1 H NMR (300MHz, DMSO-d6) δ11.21(s,1H),7.95(s,1H),6.42(s,1H),4.52-4.45(m,4H),2.42(d,J=1.2Hz,3H).

[0373] Preparation of 5-amino-7-methyl-3,10-dihydro-2H-[1,4]dioxino[2,3-h]quinolin-9-one (Intermediate 5):

[0374]

[0375] 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) and 10% Pd / C (15 mg) was added and the mixture was subjected to 3 vacuum / H cycles. The reaction was stirred at room temperature under H 2 The mixture was stirred for 4 h under a balloon. 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, as a mixture of regioisomers.

[0376] Preparation of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (Intermediate 6):

[0377]

[0378] Preparation of 5-bromo-2-(prop-2-ynyloxymethyl)pyrimidine:

[0379]

[0380] At 0 ° C, NaH (3.8 g, 246 mmol) was added portionwise to a stirred solution of (5-bromopyrimidin-2-yl)methanol (20 g, 105.82 mmol) in dry DMF (100 mL), and the reaction mixture was stirred at the same temperature for 15 minutes. Over 20 minutes, bromopropyne (9.6 mL, 1.2 eq.) was added dropwise thereto, and the reaction mixture was stirred at 0 ° C for 30 minutes. After 30 minutes, the reaction mixture was allowed to warm to room temperature, and 0.12 eq. of bromopropyne (0.96 mL, 0.12 eq.) was added dropwise thereto. The reaction mixture was stirred at the same temperature for 45 minutes again. After completion, the reaction mixture was washed with 15% Na 2 SO 3 solution (100 mL), quenched with 5% LiCl solution (100 mL), diluted with water (100 mL) and extracted with EtOAc (2×500 mL). The combined organic layers were washed with Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel (100-200 mesh) column chromatography eluting with 5% EtOAc in petroleum ether to afford 5-bromo-2-(prop-2-ynyloxymethyl)pyrimidine (18 g, 75% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ8.80(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.

[0381] Preparation of 3-bromo-5,7-dihydrofuro[3,4-b]pyridine:

[0382]

[0383] A stirred solution of 5-bromo-2-(prop-2-ynyloxymethyl)pyrimidine (25 g, 110 mmol) in nitrobenzene (75 mL) was heated at 180° C. for 4 h with argon flowing over the reaction mixture and through an outlet into a flask filled with a cooled hypochlorite solution to quench the HCN formed 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 afford 3-bromo-5,7-dihydrofuro[3,4-b]pyridine (18 g, 81% yield) as an off-white solid. 1 H NMR (300 MHz, DMSO-d 6 ): δ8.57(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.

[0384] Preparation of 5,7-dihydrofurano[3,4-b]pyridine-3-carboxylic acid methyl ester:

[0385]

[0386] In a 1 L autoclave, 3-bromo-5,7-dihydrofuro[3,4-b]pyridine (30 g, 150 mmol), DMF (90 mL), MeOH (90 mL), 4A° MS sieves, and then Et 3 N (61 mL, 450 mmol), and the reaction mixture was degassed with argon for 10 min. Pd(OAc) was added 2 (5.04g, 7.5mmol), Xantphos (4.34g, 7.5mmol) and filled with CO gas (100psi). The reaction mixture was heated at 90°C for 4h. After completion, the reaction mixture was concentrated under reduced pressure to obtain a crude compound, which was purified by silica gel (100-200 mesh) column chromatography eluting with 15% EtOAc in petroleum ether to obtain 5,7-dihydrofuran [3,4-b] pyridine -3- carboxylic acid methyl esters (21.6g, 81% yield) as off-white solids. 1 H NMR (400 MHz, CDCl 3 ): δ9.11(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

[0387] Preparation of 1-oxoanion-5,7-dihydrofuran[3,4-b]pyridin-1-ium-3-carboxylic acid methyl ester:

[0388]

[0389] To a stirred solution of 5,7-dihydrofurano[3,4-b]pyridine-3-carboxylic acid methyl ester (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. Over 25 minutes, TFAA (41 mL, 293.29) was added dropwise thereto. The reaction mixture was then allowed to warm to room temperature and stirred at the same temperature for 30 minutes. Additional TFAA (3 mL, 21.78 mmol) was added and stirred for 10 minutes. After completion, the reaction mixture was diluted with DCM (300 mL) and washed with NaHCO 3 The solution was quenched with 5M NaOH solution (800 mL) and 12 mL to adjust the pH to 7.5. The layers were separated and the aqueous layer was extracted with DCM (2 x 500 mL). The combined organic layers were washed with water and lysate. 2 SO 4 The crude product was purified by column chromatography on silica gel (100-200 mesh) eluting with 5% MeOH in DCM to afford methyl 1-oxo-5,7-dihydrofuro[3,4-b]pyridin-1-ium-3-carboxylate (29.8 g, 94% yield) as an off-white solid. 1 H NMR (400 MHz, CDCl 3 ): δ8.69(s,1H),7.72(s,1H),5.20(dd,J=8.4,2Hz,4H),3.97(s,3H); LCMS[M+H] + :195.97m / z.

[0390] Preparation of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (Intermediate 6):

[0391]

[0392] To 1-oxoanionyl-5,7-dihydrofuro[3,4-b]pyridin-1-ium-3-carboxylic acid methyl ester (20 g, 102.56 mmol) was added POCl at 0 °C. 3(70.4 mL, 753.84 mmol, freshly distilled). The reaction mixture was heated at 100 °C under argon for 1 h. After completion, the reaction mixture was diluted with DCM (100 mL) and stirred with DCM (400 mL) / saturated NaHCO over 15 min. 3 The mixture was quenched with an ice-cold aqueous solution (800 mL) 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 washed with Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give the crude compound, which was purified by silica gel (100-200 mesh) column chromatography and eluted with 15% EtOAc in petroleum ether to afford 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 (400 MHz, CDCl 3 ): δ8.03(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.

[0393] Preparation of (5R)-2-chloro-5-methyl-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester (Intermediate 7):

[0394]

[0395] Preparation of 5-bromo-2-[[(1R)-1-methylprop-2-ynyloxy]methyl]pyrimidine

[0396]

[0397] At -10 ° C, under argon, to a stirred solution of 5-bromo-2-(bromomethyl)pyrimidine (470 mg, 1.87 mmol) in dry THF (4 mL) was added portionwise NaH (60% in mineral oil, 97 mg, 2.3 mmol), and the reaction mixture was stirred at the same temperature for 10 minutes. (2R)-but-3-yn-2-ol (153 mg, 2.2 mmol) was added thereto, and the reaction mixture was stirred for 1 h. After completion, the reaction mixture was washed with saturated NH 4 The quench was quenched with aqueous Cl (6 mL) and extracted with EtOAc (3×6 mL). The combined organic layers were washed with Na 2 SO 4Dry, filter and concentrate under reduced pressure to give the crude product, which was purified by silica gel (100-200 mesh) column chromatography and eluted with 2%-30% EtOAc in heptane to give 5-bromo-2-[[(1R)-1-methylprop-2-ynyloxy]methyl]pyrimidine (254 mg, 56% yield). LCMS [M+H] + :241.06 / 243m / 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).

[0398] Preparation of (5R)-3-bromo-5-methyl-5,7-dihydrofuro[3,4-b]pyridine:

[0399]

[0400] A stirred solution of 5-bromo-2-[[(1R)-1-methylprop-2-ynyloxy]methyl]pyrimidine (254 mg, 1.05 mmol) in nitrobenzene (2 mL) was heated at 180 °C under argon atmosphere for 2 h. After 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. 1 H 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).

[0401] Preparation of (5R)-5-methyl-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester:

[0402]

[0403] In a dual chamber reaction vial, one chamber was charged with 3-bromo-5,7-dihydrofuro[3,4-b]pyridine (202 g, 0.94 mmol), DMF (1.6 mL), MeOH (0.8 mL) and Et 3N (393 uL, 2.82 mmol) and purged with argon at room temperature for 10 minutes. Pd(OAc) was added 2 (11 mg, 0.05 mmol) and Xantphos (27 mg, 0.05 mmol). The second chamber was charged with CHOOH (142 uL, 3.76 mmol) and MsCl (289 uL, 3.76 mmol) in toluene (7 mL) and flushed with argon. To initiate CO formation, Et 3 N (800 uL, 5.64 mmol) was quickly added to the second chamber. 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, and the mixture was purified by anhydrous Na 2 SO 4 Dry, filter and evaporate. The crude compound was purified by flash chromatography using EtOAc / heptane (10%-70% EtOAc) to give (5R)-5-methyl-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester (373.5 mg, 73% yield). LCMS [M+H] + :194.16m / z. 1 H 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).

[0404] Preparation of (5R)-5-methyl-1-oxo-5,7-dihydrofuro[3,4-b]pyridin-1-ium-3-carboxylic acid methyl ester:

[0405]

[0406] A stirred solution of (5R)-5-methyl-5,7-dihydrofurano[3,4-b]pyridine-3-carboxylate (130 mg, 0.673 mmol) in DCM (3 mL) and ACN (6 mL) was cooled to 0 ° C, and urea peroxide complex (165 mg, 1.75 mmol) and TFAA (41 mL, 293.29) were added thereto. The reaction mixture was then stirred at room temperature for 30 minutes. Another portion of urea peroxide complex (16 mg) and TFAA (24.4 uL) were added and stirred for 30 minutes. After completion, TEA (1 mL) was added to the reaction mixture at 0 ° C, stirred for 10 min and evaporated in vacuo to give (5R)-5-methyl-1-oxo-5,7-dihydrofurano[3,4-b]pyridine-1-ium-3-carboxylic acid methyl ester (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).

[0407] Preparation of (5R)-2-chloro-5-methyl-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester (Intermediate 7):

[0408]

[0409] To (5R)-5-methyl-1-oxo-5,7-dihydrofuro[3,4-b]pyridin-1-ium-3-carboxylate (130 mg, 0.62 mmol) was added POCl 3 (400 uL, 4.4 mmol, freshly distilled). The reaction mixture was heated at 100 °C for 3 h under argon. After completion, the excess reagent was removed in vacuo to give (5R)-2-chloro-5-methyl-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester (90% yield). LCMS [M+H] + :228.13m / z.

[0410] Preparation of 5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester (Intermediate 8)

[0411]

[0412] Preparation of 5-bromo-2-(1-methylprop-2-ynyloxymethyl)pyrimidine:

[0413]

[0414] To a solution of but-3-yn-2-ol (140 mg, 2 mmol, 1.17 eq) in dry THF (4 mL) was added NaH 60% wt (84 mg, 2.1 mmol, 1.235 eq) in one portion at -10°C under argon and stirred at -10°C for 10 min. Then 5-bromo-2-(bromomethyl)pyrimidine (430 mg, 1.7 mmol, 1 eq) was added and stirred in an ice-acetone bath for 1 h. Then NH 4 Cl saturated aqueous solution (6 ml), followed by EtOAc (6 ml). The layers were separated and the aqueous layer was washed with EtOAc (6 ml). The organic extracts were combined, washed with brine and evaporated. The crude product was purified on Biotage Isolera: heptane / EtOAc 98 / 2->70 / 30. The fractions with the product were evaporated to give 5-bromo-2-(1-methylprop-2-ynyloxymethyl)pyrimidine 251 mg (62%) as a colorless oil. 1 H NMR (300 MHz, CDCl 3 )δ8.82(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).

[0415] Preparation of 3-bromo-5-methyl-5,7-dihydrofuro[3,4-b]pyridine:

[0416]

[0417] 5-Bromo-2-(1-methylprop-2-ynyloxymethyl)pyrimidine (251 mg, 1.05 mmol, 1 eq.) was dissolved in PhNO 2 The solution in (4 mL) was stirred at 180 ° C for 2 h. It was then directly purified on Biotage Isolera: heptane / EtOAc 99 / 1, then heptane / EtOAc 99 / 1->70 / 30. The fractions with product were evaporated to give 3-bromo-5-methyl-5,7-dihydrofuro[3,4-b]pyridine 180 mg (81%) as a colorless oil. 1 H NMR (300 MHz, CDCl 3)δ8.55(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).

[0418] Preparation of 5-methyl-5,7-dihydrofuran[3,4-b]pyridine-3-carboxylic acid methyl ester:

[0419]

[0420] Under argon, 3-bromo-5-methyl-5,7-dihydrofuro[3,4-b]pyridine (180 mg, 0.84 mmol, 1 eq) was dissolved in dry THF (4 ml) and cooled to -78°C. n-BuLi 1.6 M / hexane (0.55 ml, 0.88 mmol, 1.05 eq) was added dropwise during 3 min, and then stirred for 5 min. Two pieces of solid CO were added. 2 , 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 yellow foam. LCMS [M+H] + 180m / z. It was dissolved in DCM / MeOH / DMF (4+2+1ml), and TEA (0.3ml, 2.19mmol, 2.6 equiv) was added to the solution, followed by HATU (350mg, 0.92mmol, 1.1 equiv). The reaction mixture was stirred at room temperature for 1.5h, and then concentrated. The residue was distributed between EtOAc (8ml) and 5% LiCl aqueous solution (5ml). The layers were separated, and the aqueous layer was washed with EtOAc (5ml). The organic extracts were combined, evaporated in vacuo and purified on Biotage Isolera: heptane / EtOAc 99 / 1->60 / 40. The fractions with the product were evaporated to give 5-methyl-5,7-dihydrofuran [3,4-b] pyridine-3-carboxylic acid methyl ester 75mg (42% over two steps) as a colorless oil. LCMS [M+H] + 194m / z.

[0421] Preparation of 5-methyl-1-oxo-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester:

[0422]

[0423] Methyl 5-methyl-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (75 mg, 0.386 mmol, 1 eq.) was dissolved in ACN / DCM (4+2 ml) and cooled to 0°C. H 2 O 2 × urea complex (94 mg, 1 mmol, 2.6 eq.) was added, followed by TFAA (0.14 ml, 1 mmol, 2.6 eq.). The bath was removed. Stirred at room temperature for 30 min. H 2 O 2 × urea complex (94 mg, 1 mmol, 2.6 eq.), followed by TFAA (0.14 ml, 1 mmol, 2.6 eq.). Stir at room temperature for 30 min. Cool to 0 ° C. Add TEA (0.6 ml, 4.39 mmol, 11.4 eq.). Stir for 10 min. RM evaporated. Purified on Biotage Isolera: EtOAc / MeOH 100 / 0, then EtOAc / MeOH 100 / 0->85 / 15. The fractions with product were evaporated to give 5-methyl-1-oxo-5,7-dihydrofurano[3,4-b]pyridine-3-carboxylic acid methyl ester 81 mg (100%) as a white substance. LCMS [M+H] + 210m / z. 1 H NMR (300MHz, DMSO-d6) δ8.50(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).

[0424] Preparation of 5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester (Intermediate 8):

[0425]

[0426] 5-Methyl-1-oxo-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester (81 mg, 0.387 mmol, 1 equivalent) was mixed with POCl 3The mixture was stirred for 30 min at 80 °C and then for 1 h at 100 °C. The reaction mixture was concentrated and morpholine (1 ml, 11 mmol, 35 eq.) was added to the mixture under cooling conditions, followed by DMF (1 ml). The reaction mixture was shaken for 30 min at 80 °C and then for 1 h at 100 °C. The reaction mixture was cooled to room temperature, diluted with EtOAc (7 ml) and washed with 5% LiCl aqueous solution (7 ml). The layers were separated and the aqueous layer was washed with EtOAc (7 ml). The organic extracts were combined, washed with brine and evaporated. The crude product was dissolved in a minimum amount of DCM and purified on Biotage Isolera: heptane / EtOAc 99 / 1->50 / 50. The fractions with product were evaporated to give methyl 5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate 50 mg (46% over two steps) as a brown oil. LCMS [M+H] + 279m / z. 1 H NMR (300MHz, chloroform-d) δ7.74 (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).

[0427] Examples:

[0428] 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)

[0429]

[0430] Preparation of 3-bromo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylic acid benzyl ester:

[0431]

[0432] 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 dropwise addition of benzyl chloroformate (295 μL, 2.06 mmol). The reaction mixture was then stirred at room temperature for another 60 minutes. The reaction was then diluted with EtOAc (125 mL), quenched with 0.1 M NaOH aqueous solution (2 × 50 mL) and saturated NaHCO 3 The mixture was washed with aqueous solution (100 mL) and then with MgSO 4 Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Isolera One, Biotage) using a mixture of heptane / EtOAc (from 100 / 0 to 0 / 100) as eluent to give the title product benzyl 3-bromo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (400 mg, 65%) as a white solid. 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).

[0433] Preparation of 5,7-dihydropyrrolo[3,4-b]pyridine-3,6-dicarboxylic acid O6-benzyl O3-methyl ester

[0434]

[0435] In a dual chamber reaction vial, one chamber was charged with benzyl 3-bromo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (1.0 g, 3.0 mmol), DMF (8 mL), MeOH (4 mL) and Et 3 N (1.25 mL, 9.0 mmol) and purged with argon at room temperature for 10 min. Pd(OAc) was added 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. To initiate CO formation, Et 3 N (1.6 mL, 11.9 mmol) was quickly added to the second chamber. The reaction mixture was heated at 100 °C for 2 h. Upon completion, the reaction mixture was diluted with EtOAc (150 mL) and washed with saturated NaHCO3 The mixture was washed with aqueous solution (2×75 mL), 5% LiCl (2×25 mL) and brine (75 mL), and then filtered through MgSO 4 Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Isolera One, Biotage) using a mixture of DCM / MeOH (from 100 / 0 to 95 / 5) as eluent to give 06-benzyl 03-methyl 5,7-dihydropyrrolo[3,4-b]pyridine-3,6-dicarboxylate (410 mg, 43%) as a white solid. 1 H NMR (300MHz, chloroform-d) δ9.14 (d, J = 1.9 Hz, 1H), 8.20 (dd, J = 18.0, 2.1 Hz, 1H), 7.47-7.34 (m, 6H), 5.26 (d, J = 1.9 Hz, 2H), 4.89-4.82 (m, 4H), 3.98 (s, 3H).

[0436] Preparation of 1-oxoanion-5,7-dihydropyrrolo[3,4-b]pyridin-1-ium-3,6-dicarboxylic acid O6-benzyl O3-methyl ester:

[0437]

[0438] A solution of 5,7-dihydropyrrolo[3,4-b]pyridine-3,6-dicarboxylic acid O6-benzyl O3-methyl ester (410 mg, 1.3 mmol) in dry DCM (25 mL) was treated with m-CPBA (321 mg, 77% pure, 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 NaHCO 3 The organic phase was washed with aqueous solution (2×75 mL) and brine (100 mL). 4 The residue was purified by column chromatography on silica gel (Isolera One, Biotage) using a mixture of DCM / MeOH (from 100 / 0 to 90 / 10) as eluent to give the title product 1-oxoanionyl-5,7-dihydropyrrolo[3,4-b]pyridin-1-ium-3,6-dicarboxylic acid O6-benzyl O3-methyl ester (360 mg, 85%) as a white solid. LCMS [M+H] + :329.2m / z

[0439] Preparation of 2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-3,6-dicarboxylic acid O6-benzyl O3-methyl ester

[0440]

[0441] A solution of 1-oxoanion-5,7-dihydropyrrolo[3,4-b]pyridin-1-ium-3,6-dicarboxylic acid O6-benzyl O3-methyl ester (360 mg, 1.1 mmol) in POCl (3.0 mL) was stirred at 80 ° C for 1.5 h. The crude reaction mixture was concentrated in vacuo and co-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 subsequently stirred at 120 ° C for 1 h, but concentrated in vacuo. The residue was purified by column chromatography on silica gel (Isolera One, Biotage) using a mixture of DCM / MeOH (from 100 / 0 to 90 / 10) as eluent to give the title product 2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-3,6-dicarboxylic acid 06-benzyl 03-methyl ester as a solid with about 70% UV purity confirmed by UPLC-MS (400 mg, 70% pure, 63% yield over two steps).

[0442] Preparation of 3-[(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)carbamoyl]-2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylic acid benzyl ester:

[0443]

[0444] A solution of 2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-3,6-dicarboxylic acid O6-benzyl O3-methyl ester (400 mg, 70% pure, 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, followed by heating with saturated NaHCO 3 The aqueous solution was quenched until pH ~ 9. The aqueous solution was concentrated in vacuo and the residue was used in the next step without further purification.

[0445] The above residue is suspended in dry DMF (4.0mL) and treated with EDC·HCl (183mg, 0.93mmol) and HOAt (126mg, 0.96mmol), then treated with DIPEA (472μL, 2.7mmol) and 6-amino-8-methoxy-4-methyl-1H-quinoline-2-one (191mg, 0.93mmol). The reaction mixture is stirred at 65°C for 4h, and then poured into ice-cold water under strong stirring. The formed precipitate is filtered and washed with cold water. The precipitate was purified by column chromatography on silica gel (Isolera One, Biotage) using a mixture of DCM / MeOH (from 100 / 0 to 80 / 20) as eluent to give the title product, 3-[(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)carbamoyl]-2-morpholino-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylic acid benzyl ester (150 mg, 46% yield over two steps) as a white solid.

[0446] 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):

[0447]

[0448] A solution of benzyl 3-[(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)carbamoyl]-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 heated under H 2 The reaction mixture was then stirred for 30 min under a 4% CO atmosphere. The residue was filtered and concentrated in vacuo by column chromatography on silica gel (Isolera One, Biotage) using a mixture of DCM / MeOH (from 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 (19 mg, 50%) as a pale yellow / white solid.

[0449] 1H NMR (300MHz, DMSO-d6) δ10.62(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).

[0450] Preparation of 2-chloro-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide:

[0451]

[0452] 2-Chloro-5,7-dihydrofurano[3,4-b]pyridine-3-carboxylic acid methyl ester (600mg, 2.8mmol, 1 equivalent) was dissolved in THF (15ml), 5M NaOH aqueous solution (1.4ml, 6mmol, 2.5 equivalent) and water (3ml) were added. The mixture was shaken at 45°C overnight, and then cooled to 0°C and acidified to pH-7 with 5M HCl aqueous solution. The layers were separated, and the aqueous layer was extracted with EtOAc (2×15ml). The organic extracts were combined, dried over Na2SO4 and evaporated to give 600mg of crude 2-chloro-5,7-dihydrofurano[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 eq.), DIPEA (1.57 ml, 9 mmol, 3.21 eq.), EDC·HCl (573 mg, 3 mmol, 1.07 eq.) and HOAt (408 mg, 3 mmol, 1.07 eq.) 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 solution (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), dried in air, triturated with ACN (10 ml) and filtered. The filtrate was washed with ACN (2×5 ml) and dried in vacuo at 1 mbar for 3 h at room temperature 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) δ10.73(s,1H),10.69(s,1H),8.06(d,J=1.0Hz,1H),7.71(d,J=1.9Hz,1H),7.52(d,J=2.0 Hz, 1H), 6.46 (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).

[0453] 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)

[0454]

[0455] Preparation of methyl 2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate:

[0456] 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)Cl 2 (6 mg, 0.02 eq) and Cs 2 CO 3 To the mixture was added 4-(3,6-dihydro-2H-pyrans-4-yl)-5,7-dihydrofurano[3,4-b]pyridine-3-carboxylic acid methyl ester (54 mg, 67% yield) (202 mg, 2 equivalents), and the reaction mixture was stirred at 130 ° C for 45 min. After completion, the solvent was evaporated in vacuo, 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 obtain 2-(3,6-dihydro-2H-pyrans-4-yl)-5,7-dihydrofurano[3,4-b]pyridine-3-carboxylic acid methyl ester (54 mg, 67% yield). LCMS[M+H] + 262.20m / z. 1H NMR (300 MHz, chloroform-d) δ7.92 (s, 1H), 5.85 (s, 1H), 5.21 (s, 2H), 5.11 (s, 2H), 4.32 (q, J = 2.7 Hz, 2H), 3.97 (t, J = 5.3 Hz, 2H), 3.90 (s, 3H), 2.56 (tq, J = 5.2, 2.5 Hz, 2H)

[0457] Preparation of 2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid:

[0458] 2M LiOH (430 μL) was added to a solution of 2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydrofuran [3,4-b] pyridine-3-carboxylic acid methyl ester (112 mg, 0.43 mmol, 1 equivalent) in methanol (0.6 mL) and THF (0.6 mL), and the reaction mixture was stirred at 35 ° C for 3 hours. After completion, 2N HCl (430 μL) was added to neutralize. The solvent was evaporated in vacuo with acetonitrile and toluene to remove excess HCl to obtain crude 2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydrofuran [3,4-b] pyridine-3-carboxylic acid as a white solid. LCMS [M + H] + 248.18m / z.

[0459] 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):

[0460] To a solution of 2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.43mmol, 1.0 eq) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (96mg, 0.47mmol, 1.1 eq) in DMF (3mL) was added DIPEA (150uL, 0.85mmol, 2 eq) and HATU (79mg, 0.47mmol, 1.2 eq) 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 flash chromatography on silica gel 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) δ10.65(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)

[0461] Preparation of 2-(cyclopenten-1-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 3)

[0462]

[0463] Preparation of 2-(cyclopenten-1-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 3):

[0464] 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 eq) in dioxane (1.6 mL) and water (0.5 mL) under argon was added 2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (117 mg, 0.6 mmol, 3 eq), Pd(dppf)Cl 2 (3.4 mg, 0.02 eq) and Cs 2 CO 3 (130 mg, 2 eq.) and the reaction mixture was stirred at 130 °C for 45 min. After completion, the solvent was evaporated in vacuo and the product was extracted from EtOAc / water. The combined organic extracts were washed with brine and purified by anhydrous Na 2 SO 4 Dried, filtered and evaporated. The crude product was purified by flash chromatography using DCM / MeOH (0-10% MeOH) to give 2-(cyclopenten-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] + 418.21m / z. 1 HNMR (300 MHz, chloroform-d) δ7.92 (s, 1H), 5.85 (s, 1H), 5.21 (s, 2H), 5.11 (s, 2H), 4.32 (q, J = 2.7 Hz, 2H), 3.97 (t, J = 5.3 Hz, 2H), 3.90 (s, 3H), 2.56 (tq, J = 5.2, 2.5 Hz, 2H)

[0465] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-(1-methyl-2-azabicyclo[2.1.1]hex-2-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 4):

[0466]

[0467] 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 at 135° C. for 1 h in a microwave reactor. 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 h and then at 145° C. for 45 minutes. Purification on Biotage Isolera: ACN (0.1% FA) / H2O (0.1% FA) 0 / 100, then 0 / 100->80 / 20. Fractions with product were evaporated and washed with Et 2 O (0.7 ml), the solvent was decanted and dried under vacuum at room temperature at 1 mbar for 3 h to give the title product N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-(1-methyl-2-azabicyclo[2.1.1]hex-2-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 9 mg (yield 15%). LCMS [M+H] + 447m / z. 1 H NMR (300MHz, DMSO-d6) δ11.23(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).

[0468] Preparation of 2-(6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 5):

[0469]

[0470] 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 SpeedVac (45°C, 1-2h). The crude product was purified by HPLC-CLND to give the pure title compound 2-(6,6-difluoro-3-azabicyclo[3.1.0]hex-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

[0471] 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):

[0472]

[0473] 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 NHMe 2 (2M in THF, 1.0 mL), and the reaction mixture was stirred at 120° C. for 1 h. The crude reaction mixture was purified by The organic layer was filtered and directly purified 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 light pink solid (55 mg). 1H NMR (300MHz, DMSO-d6) δ10.63(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=1.3Hz,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).

[0474] 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):

[0475]

[0476] Preparation of methyl 2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate:

[0477]

[0478] To a solution of 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester (213.6 mg, 1 mmol, 1 eq) in dry DMSO (5 mL) was added morpholine (175 μL, 2 mmol, 2 eq) and DIPEA (522 μL, 3 mmol, 3 eq) 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 combined extracts were washed with water, 5% LiCl and brine and purified by anhydrous Na 2 SO 4 Dried, 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.

[0479] Preparation of 2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid:

[0480]

[0481] 2M LiOH (350 μL, 0.35mmol, 2 equivalents) was added to a solution of 2-morpholino-5,7-dihydrofurano[3,4-b]pyridine-3-carboxylic acid methyl ester (40 mg, 0.15mmol, 1 equivalent) in methanol (2mL) and THF (2mL), and the reaction mixture was stirred at 30°C for 3h. After completion, 2N HCl (350 μL, 0.35mmol, 2 equivalents) was added to neutralize. The solvent was evaporated in vacuo with acetonitrile and toluene to remove the acid to obtain a crude 2-morpholino-5,7-dihydrofurano[3,4-b]pyridine-3-carboxylic acid as a yellow solid. LCMS[M+H] + 251.17m / z.

[0482] 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):

[0483]

[0484] To a solution of 2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.15 mmol, 1 eq) and 6-amino-4,8-dimethyl-1H-quinolin-2-one (31 mg, 0.15 mmol, 1 eq) in DMF (5 mL) was added DIPEA (80 uL, 0.45 mmol, 3 eq) and HATU (63.3 mg, 0.16 mmol, 1.1 eq) and the reaction mixture was stirred at 60 °C overnight.

[0485] 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. The precipitated material was filtered off, washed with water and dried to give 31.3 mg of the title compound N-(4,8-dimethyl-2-oxo-1H-quinoline-6-yl)-2-morpholino-5,7-dihydrofurano[3,4-b]pyridine-3-carboxamide as a white solid. (49% yield over two steps), LCMS[M+H] + 421.22m / z. 1 H NMR (300 MHz, DMSO-d 6)δ10.73(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).

[0486] 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):

[0487]

[0488] 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 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) 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. 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 HNMR(300MHz,DMSO-d6)δ11.06(s,1H),10.21(s,1H),7.87(s,1H),7.62(s,1H),6.37(s,1H),5.0 5(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).

[0489] 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):

[0490]

[0491] 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 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) 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. 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)δ11.25(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).

[0492] 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):

[0493]

[0494] 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-carboxamide 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) 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. The precipitate was additionally 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)δ11.01(s,1H),10.76(s,1H),8.33(s,1H),8.21(s,1H),6.32(s,1H),5.09(s,2H),4.9 4(t,J=2.0Hz,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).

[0495] 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):

[0496]

[0497] 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-carboxamide 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) from 2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid and 6-amino-4,7-dimethyl-1H-quinolin-2-one. The precipitate was additionally washed with DMF and 25% water in acetonitrile to give the product.

[0498] 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,)δ11.57(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),3.00-3.50(m,4H),2.39(s,3H),2.35(s,3H).

[0499] 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):

[0500]

[0501] 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-carboxamide 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) from 2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid and 6-amino-8-ethoxy-4-methyl-1H-quinolin-2-one. The precipitate was additionally 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) δ10.63-10.50(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).

[0502] 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):

[0503]

[0504] 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-carboxamide 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) from 2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid and 6-amino-4,7,8-trimethyl-1H-quinolin-2-one. The precipitate was additionally 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)δ10.63(s,1H),10.16(s,1H),7.91(s,1H),7.64(s,1H),6.41(s,1H),5.06 (s,2H),4.95-4.85(m,2H),3.75-3.68(m,4H),3.00-3.5(m,4H),2.42-2.36(m,3H),2.28(s,3H).

[0505] 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):

[0506]

[0507] 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-carboxamide 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) from 2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid and 6-amino-7-methoxy-4-methyl-1H-quinolin-2-one. The precipitate was additionally washed with 5% acetonitrile in water to give 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 HNMR(300MHz,DMSO-d6)δ10.84(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).

[0508] 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):

[0509]

[0510] 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) in sequence 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. 1H NMR (400MHz, DMSO-d6): δ10.64(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.

[0511] 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)

[0512]

[0513] Preparation of methyl 2-(3,3-difluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate:

[0514] To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (42.7 mg, 0.2 mmol, 1 eq) in dry DMSO (1 mL) was added 3,3-difluoropyrrolidine (57.4 mg, 0.4 mmol, 2 eq) and DIPEA (140 μL, 0.8 mmol, 4 eq) 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 and purified by anhydrous Na 2 SO 4 Dried, 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) δ7.92 (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).

[0515] Preparation of 2-(3,3-difluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid:

[0516] 2M LiOH (125 μL, 0.250 mmol, 2 equivalents) was added to a solution of 2-(3,3-difluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester (30 mg, 0.125 mmol, 1 equivalent) in methanol (1 mL) and THF (1 mL), and the reaction mixture was stirred at 35 ° C for 3 h. After completion, 2N HCl (125 μL, 0.250 mmol, 2 equivalents) was added to neutralize. The solvent was evaporated in vacuo with acetonitrile and toluene to remove excess HCl to obtain 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.

[0517] 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):

[0518] To a solution of 2-(3,3-difluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.125 mmol, 1 eq) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (25.3 mg, 0.125 mmol, 1 eq) in DMF (4 mL) were added DIPEA (60 uL, 0.35 mmol, 3 eq) and HATU (47 mg, 0.125 mmol, 1 eq), and the reaction mixture was stirred at 35 °C for 3 h, and then stirred at room temperature overnight.

[0519] 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 solvent evaporation, the crude product was additionally 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-quinoline-6-yl)-5,7-dihydrofurano[3,4-b]pyridine-3-carboxamide (17% yield over two steps) as an off-white solid. LCMS[M+H] + 455.4m / z. 1H NMR (300MHz, DMSO-d6) δ10.66(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).

[0520] 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):

[0521]

[0522] Preparation of methyl 2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate:

[0523] To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (42.7 mg, 0.2 mmol, 1 eq) in dry DMSO (1 mL) was added 3-oxa-8-azabicyclo[3.2.1]octane (60 mg, 0.4 mmol, 2 eq) and DIPEA (140 μL, 0.8 mmol, 4 eq) 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 and purified by anhydrous Na 2 SO 4 Dried, 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] + 291.16m / z.

[0524] Preparation of 2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid:

[0525] To a solution of methyl 2-(3-oxa-8-azabicyclo[3.2.1]oct-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) was added 2M LiOH (400 μL, 0.80 mmol), and the reaction mixture was stirred at 35 ° C for 3 h. After completion, 2N HCl (400 μL, 0.80 mmol) was added. The solvent was evaporated in vacuo with acetonitrile and toluene to remove excess HCl to give 2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid as a white solid. LCMS [M+H] + 277.14m / z.

[0526] 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):

[0527] 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 (0.14mmol, 1 eq) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (31.7mg, 0.155mmol, 1.1 eq) in DMF (4mL) was added DIPEA (74uL, 0.42mmol, 3 eq) and HATU (59mg, 0.155mmol, 1.1 eq) and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30mL). 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 in 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 (Example 17) as an off-white solid (51% yield over two steps). LCMS [M+H] + 463.18m / z. 1HNMR (300MHz, DMSO-d6) δ10.65(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).

[0528] 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):

[0529]

[0530] Preparation of methyl 2-[(2R)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate:

[0531] To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (42.7 mg, 0.2 mmol, 1 eq) in dry DMSO (1 mL) was added (2R)-2-methylpyrrolidine (60 mg, 0.4 mmol, 2 eq) and DIPEA (140 μL, 0.8 mmol, 4 eq) 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 and purified by anhydrous Na 2 SO 4 Dried, 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. 1H NMR (300MHz, DMSO-d6) δ7.81(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).

[0532] Preparation of 2-[(2R)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid:

[0533] 2-[(2R)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester (42 mg, 0.16 mmol, 1 eq) was added to a solution of methanol (1 mL) and THF (1 mL) with 2M LiOH (160 μL, 0.32 mmol), and the reaction mixture was stirred at 35 ° C for 3 h. After completion, 2N HCl (160 μL, 0.32 mmol) was added to neutralize. The solvent was evaporated in vacuo 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.

[0534] 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):

[0535] 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 eq) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (36 mg, 0.18 mmol, 1.1 eq) in DMF (4 mL) was added DIPEA (84 uL, 0.48 mmol, 3 eq) and HATU (67 mg, 0.18 mmol, 1.1 eq) 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. 1 H NMR (300MHz, DMSO-d6) δ10.62(s,1H),10.46(s,1H),7.74(d,J=2.0Hz,1H),7.66(s,1 H),7.56(d,J=2.0Hz,1H),6.45(d,J=1.4Hz,1H),4.99(s,2H),4.90-4.75(m,2H),4.3 5-4.21(m,1H),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).

[0536] 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):

[0537]

[0538] 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:

[0539] To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (42.7 mg, 0.2 mmol, 1 eq) 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 eq) and DIPEA (140 μL, 0.8 mmol, 4 eq) 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, and purified by anhydrous Na 2 SO 4 Dried, 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)δ7.81(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).

[0540] 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:

[0541] 2MLiOH (134 μL, 0.26mmol, 2 equivalents) was added to a solution of 2-(2,3,3a,4,6,6a-hexahydrofuran [2,3-c] pyrrole-5-yl)-5,7-dihydrofuran [3,4-b] pyridine-3-carboxylic acid methyl ester (39 mg, 0.13mmol, 1 equivalent) in methanol (1mL) and THF (1mL), and the reaction mixture was stirred at 35°C for 2 days. After completion, 2NHCl (134 μL, 0.26mmol) was added to neutralize. The solvent was evaporated in vacuo with acetonitrile and toluene to remove excess HCl to obtain 2-(2,3,3a,4,6,6a-hexahydrofuran [2,3-c] pyrrole-5-yl)-5,7-dihydrofuran [3,4-b] pyridine-3-carboxylic acid as a white solid. LCMS [M+H] + :277.14m / z.

[0542] 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):

[0543] 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 (0.13mmol, 1.0 eq) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (30mg, 0.15mmol, 1.1 eq) in DMF (3mL) was added DIPEA (70uL, 0.4mmol, 3 eq) and HATU (56mg, 0.15mmol, 1.1 eq) and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30mL). 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. 1H NMR (300MHz, DMSO-d6) δ10.65(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).

[0544] 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):

[0545]

[0546] 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:

[0547] To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (42 mg, 0.2 mmol, 1 eq) 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 eq) and DIPEA (140 μL, 0.8 mmol, 4 eq) 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, and purified by anhydrous Na 2 SO 4 Dried, 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. 1H NMR(300MHz,DMSO-d6)δ7.80(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).

[0548] 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:

[0549] 2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester (45 mg, 0.16 mmol, 1 eq) in methanol (1 mL) and THF (1 mL) was added 2M LiOH (200 μL, 3 eq) and the reaction mixture was stirred overnight at 35 ° C. 2N HCl (200 μL) was added. The solvent was evaporated in vacuo 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 (42 mg) LCMS [M+H] as a white solid. + 277.14m / z.

[0550] 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):

[0551] 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 (0.16mmol, 1.0 eq) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (36mg, 0.17mmol, 1.1 eq) in DMF (4mL) was added DIPEA (84uL, 0.48mmol, 3 eq) and HATU (65mg, 0.17mmol, 1.1 eq) and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30mL). The combined extracts were washed with water, 5% LiCl and brine. After evaporation of the solvent, the crude product was additionally 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)δ10.64(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).

[0552] Preparation of 2-(8-azabicyclo[3.2.1]oct-8-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 21):

[0553]

[0554] Preparation of methyl 2-(8-azabicyclo[3.2.1]oct-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate:

[0555] To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (42 mg, 0.2 mmol, 1 eq) in dry DMSO (1 mL) was added 8-azabicyclo[3.2.1]octane hydrochloride (60 mg, 0.4 mmol, 2 eq) and DIPEA (140 μL, 0.8 mmol, 4 eq) 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 and purified by anhydrous Na 2 SO 4 Dried, 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) δ7.80 (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).

[0556] Preparation of 2-(8-azabicyclo[3.2.1]oct-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid:

[0557] 2-(8-azabicyclo[3.2.1]oct-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester (45 mg, 0.16 mmol, 1 eq) in methanol (1 mL) and THF (1 mL) was added 2M LiOH (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 in vacuo with acetonitrile and toluene to remove excess HCl to give crude 2-(8-azabicyclo[3.2.1]oct-8-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid as a white solid. LCMS [M+H] + 275.19 m / z.

[0558] Preparation of 2-(8-azabicyclo[3.2.1]oct-8-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 21):

[0559] 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 eq) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (21 mg, 0.105 mmol, 1.1 eq) in DMF (4 mL) was added DIPEA (50 uL, 0.28 mmol, 3 eq) and HATU (40 mg, 0.105 mmol, 1.1 eq) 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 additionally washed with 25% water in acetonitrile and 2% MeOH in DCM, and 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. 1 H NMR (300MHz, DMSO-d6) δ10.63(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),1.89-1.58(m,7H),1.51-1.28(m,3H).

[0560] 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):

[0561]

[0562] Preparation of methyl 2-[racemic-(3aR,6aR)-2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate:

[0563] To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (42 mg, 0.2 mmol, 1 eq) in dry DMSO (1 mL) was added rac-(3aR,6aR)-hexahydro-2H-furo[2,3-c]pyrrole hydrochloride (45 mg, 0.4 mmol, 2 eq) and DIPEA (140 μL, 0.8 mmol, 4 eq) 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 x 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) δ7.81 (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).

[0564] Preparation of 2-[racemic-(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:

[0565] 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 eq) in methanol (1 mL) and THF (1 mL) was added 2M LiOH (250 μL, 4 eq) and the reaction mixture was stirred overnight at 35° C. After completion, 2N HCl (250 μL) was added to neutralize. The solvent was evaporated with acetonitrile and toluene in vacuo 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.

[0566] 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):

[0567] 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 (0.145mmol, 1.0 eq) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (33mg, 0.16mmol, 1.1 eq) in DMF (3mL) was added DIPEA (76uL, 0.43mmol, 3 eq) and HATU (61mg, 0.16mmol, 1.1 eq) and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30mL). 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 (Example 22) as an off-white solid (41.8% yield over two steps). LCMS [M+H] + 463.24m / z. 1H NMR (300MHz, DMSO-d6) δ10.63(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. 2,5.0Hz,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).

[0568] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 23):

[0569]

[0570] Preparation of methyl 2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate:

[0571] To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (42 mg, 0.2 mmol, 1 eq) in dry DMSO (1 mL) was added (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (45 mg, 0.4 mmol, 2 eq) and DIPEA (140 μL, 0.8 mmol, 4 eq) 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]hept-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. 1H NMR(300MHz,DMSO-d6)δ7.85(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).

[0572] Preparation of 2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid:

[0573] 2-[(1S, 4S)-2-oxa-5-azabicyclo [2.2.1] hept-5-yl] -5,7- dihydrofuran [3,4-b] pyridine-3-carboxylic acid methyl ester (33 mg, 0.12 mmol, 1 eq) in methanol (1 mL) and THF (1 mL) was added 2M LiOH (200 μL), and the reaction mixture was stirred at 35 ° C for two days. 2N HCl (200 μL) was added to neutralize. The solvent was evaporated in vacuo with acetonitrile and toluene to remove excess HCl to give crude 2-[(1S, 4S)-2-oxa-5-azabicyclo [2.2.1] hept-5-yl] -5,7- dihydrofuran [3,4-b] pyridine-3-carboxylic acid as a white solid. LCMS [M + H] + 263.13m / z.

[0574] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 23):

[0575] To a solution of 2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.12mmol, 1.0 eq) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (33mg, 0.16mmol, 1.1 eq) in DMF (3mL) was added DIPEA (76uL, 0.43mmol, 3 eq) and HATU (61mg, 0.16mmol, 1.1 eq) and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30mL). 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]hept-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 23) as an off-white solid (21.6% over two steps). LCMS [M+H] + 449.22m / z. 1 H NMR (300MHz, DMSO-d6) δ10.63(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).

[0576] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 24):

[0577]

[0578] Preparation of methyl 2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate:

[0579] To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (64 mg, 0.3 mmol, 1 eq) in dry DMSO (2 mL) was added (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (81 mg, 0.6 mmol, 2 eq) and DIPEA (209 μL, 0.8 mmol, 4 eq) 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]hept-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)δ7.85(s,1H),4.97(s,2H),4.87-4.73(m,3H),4.58(s,1H),3.80(s,3H ),3.77-3.70(m,2H),3.54(dd,J=10.2,1.6Hz,1H),2.68(d,J=10.2Hz,1H),1.91-1.78(m,2H).

[0580] Preparation of 2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid:

[0581] To a solution of methyl 2-[(1R, 4R)-2-oxa-5-azabicyclo[2.2.1]hept-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) was added 2M LiOH (350 μL), and the reaction mixture was stirred at 35 °C for two days. 2N HCl (350 μL) was added. The solvent was evaporated in vacuo with acetonitrile and toluene to remove excess HCl to give crude 2-[(1R, 4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid as a white solid. LCMS [M+H] + 263.12m / z.

[0582] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 24):

[0583] To a solution of 2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.17mmol, 1.0 eq) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (39mg, 0.19mmol, 1.1 eq) in DMF (3mL) was added DIPEA (90uL, 0.5mmol, 3 eq) and HATU (71mg, 0.19mmol, 1.1 eq) and the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30mL). 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]hept-5-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 24) (22.8 mg, 29.6% yield over two steps) as an off-white solid. LCMS [M+H] + 449.16m / z. 1 H NMR(300MHz,DMSO-d6)δ10.64(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).

[0584] 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):

[0585]

[0586] Preparation of methyl 2-[(2S)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate:

[0587] To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (64 mg, 0.3 mmol, 1 eq) in dry DMSO (2 mL) was added (2S)-2-methylpyrrolidine (51 mg, 0.6 mmol, 2 eq) and DIPEA (209 μL, 0.8 mmol, 4 eq) 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 and purified by anhydrous Na 2 SO 4 Dried, 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] + 263.12m / z. 1 H NMR(300MHz,DMSO-d6)δ7.81(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).

[0588] Preparation of 2-[(2S)-2-methylpyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid:

[0589] 2M LiOH (350 μL) was added 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), and the reaction mixture was stirred at 35 ° C for two days. After completion, 2N HCl (350 μL) was added to neutralize. The solvent was evaporated in vacuo 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.

[0590] 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):

[0591] 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 eq) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (48 mg, 0.23 mmol, 1.1 eq) in DMF (3 mL) was added DIPEA (149 uL, 0.85 mmol, 4 eq) and HATU (97 mg, 0.25 mmol, 1.2 eq) 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 (16.7 mg, 18% yield over two steps) as an off-white solid. LCMS [M+H] + 435.17m / z. 1H NMR(300MHz,DMSO-d6)δ10.63(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),2.12-2.0 0(m,1H),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).

[0592] 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)

[0593]

[0594] 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):

[0595] 2-Chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester (60 mg, 0.28 mmol, 1 eq.), 1-cyclopropyl-N-methyl-methylamine 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 shaken at 60 ° C overnight and shaken at 100 ° C for 1 h, and cooled to room temperature. 5% LiCl aqueous solution (3.5 ml) was added and extracted with DCM (3×1.5 ml). The organic extracts were combined and purified directly on Biotage Isolera: heptane / EtOAc 98 / 2, then 98 / 2->35 / 65. After completion, the reaction mixture was allowed to warm to room temperature and the solvent was evaporated in vacuo. The fractions with the product were evaporated to give methyl 2-[cyclopropylmethyl(methyl)amino]-5,7-dihydrofuran[3,4-b]pyridine-3-carboxylate 40 mg as a yellow oil, LCMS[M+H]+263 m / z. The oil was dissolved in MeOH (0.5 ml) and 2M aqueous LiOH solution (0.2 ml, 0.4 mmol, 2.66 equiv) was added. 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. Crude 2-[cyclopropylmethyl(methyl)amino]-5,7-dihydrofuran[3,4-b]pyridine-3-carboxylic acid 60 mg was obtained as a light 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 shaken at 60°C for 1.5 h and then cooled to room temperature. 5% aqueous LiCl solution (3 ml) was added and the product was extracted with EtOAc (2×1.5 ml). The combined extracts were directly purified on Biotage Isolera (SiO2 NH): heptane / EtOAc 100 / 0, then 100 / 0->18 / 82, then 18 / 82. The relevant fractions with the product were evaporated and purified with Et 2 O (decanted solvent) 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 as a light yellow powder, 17 mg. LCMS [M+H]+ 435m / z, UV(254nm)>95%. 1 H NMR (300MHz, DMSO-d6) δ10.63(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).

[0596] 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):

[0597]

[0598] Preparation of methyl 2-(diethylamino)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate:

[0599] To a solution of 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester (128 mg, 0.6 mmol, 1 eq) in dry DMSO (5 mL) was added N-ethylethylamine (125 mg, 1.2 mmol, 2 eq) and DIPEA (418 μL, 2.4 mmol, 4 eq), 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, and the mixture was purified by anhydrous Na 2 SO 4 Dry, filter and evaporate. 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 HNMR (300MHz, DMSO-d6) δ7.75 (s, 1H), 4.95 (s, 2H), 4.79 (t, J = 2.0Hz, 2H), 3.80 (s, 3H), 1.08 (t, J = 7.0Hz, 6H).

[0600] Preparation of 2-(diethylamino)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid:

[0601] 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 two days. 2N HCl (350 μL) was added. The solvent was evaporated in vacuo 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.

[0602] 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):

[0603] To a solution of 2-(diethylamino)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.26mmol, 1.0 eq) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (58mg, 0.29mmol, 1.1 eq) in DMF (3mL) was added DIPEA (181uL, 1.09mmol, 4 eq), HOAt (71mg, 0.29mmol, 1.1 eq) and EDC·HCl (100mg, 0.52mmol, 2 eq) and the reaction mixture was stirred at 35°C overnight. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30mL). The combined extracts were washed with water, 5% LiCl and brine. After evaporation in vacuo, the crude product was additionally 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 (38% yield) as an off-white solid. LCMS [M+H] + 426.63m / z. 1H NMR (300MHz, DMSO-d6) δ10.72(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).

[0604] 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)

[0605]

[0606] Preparation of methyl 2-[ethyl(isopropyl)amino]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate:

[0607] To a solution of methyl 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (6) (128 mg, 0.6 mmol, 1 eq) in dry DMSO (5 mL) was added N-ethylpropan-2-amine (125 mg, 1.2 mmol, 2 eq) and DIPEA (418 μL, 2.4 mmol, 4 eq) and the reaction mixture was stirred at 125 °C for 7 h and then at 80 °C for another 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 and purified by anhydrous Na 2 SO 4 Dried, 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) δ7.77 (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).

[0608] Preparation of 2-[ethyl(isopropyl)amino]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid:

[0609] 2-[ethyl(isopropyl)amino]-5,7-dihydrofurano[3,4-b]pyridine-3-carboxylic acid methyl ester (18 mg, 0.07 mmol, 1 eq) was added to a solution of methanol (0.3 mL) and THF (0.3 mL) with 2M LiOH (100 μL), and the reaction mixture was stirred overnight at 35 °C. 2N HCl (100 μL) was then added. The solvent was evaporated in vacuo with acetonitrile and toluene to give crude 2-[ethyl(isopropyl)amino]-5,7-dihydrofurano[3,4-b]pyridine-3-carboxylic acid as a white solid. LCMS [M+H] + 251.50m / z.

[0610] 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):

[0611] To a solution of 2-[ethyl(isopropyl)amino]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.07mmol, 1.0 eq) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (15mg, 0.075mmol, 1.1 eq) in DMF (1 mL) was added DIPEA (48uL, 0.28mmol, 4 eq), HOAt (19mg, 0.075mmol, 1.1 eq) and EDC·HCl (26mg, 0.14mmol, 2 eq) and the reaction mixture was stirred at 35°C overnight. After completion, the reaction mixture was poured into water and extracted with EtOAc (2×30mL). 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 (15 mg, 51% yield) as an off-white solid. LCMS [M+H] + 437.64m / z. 1H NMR (300MHz, DMSO-d6) δ11.11(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).

[0612] 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):

[0613]

[0614] Preparation of 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid methyl ester:

[0615] To a solution of 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (150mg, 0.7mmol, 1 equivalent) in MeOH (2mL) and DCM (4mL) cooled on an ice bath, 2M of diazomethyl(trimethyl)silane in hexane (400uL) was added, and the reaction mixture was stirred at room temperature for 1h. An additional 300uL of diazomethyl(trimethyl)silane (700uL in total, 1.4mmol, 2 equivalents) was added and stirred for 30min. After completion, the solvent was evaporated in vacuo to give 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid methyl ester (145mg, 98% yield). LCMS[M+H] + 212.12m / z. 1 H NMR (300MHz, DMSO-d6) δ7.93 (t, J = 1.1 Hz, 1H), 3.74 (s, 3H), 2.81 (dd, J = 8.2, 7.1 Hz, 4H), 2.04-1.92 (m, 2H).

[0616] Preparation of methyl 2-morpholino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate:

[0617] To a solution of 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid methyl ester (143mg, 0.68mmol, 1 equivalent) in dry DMSO (6mL), morpholine (118uL, 1.35mmol, 2 equivalents) and DIPEA (354uL, 2.03mmol, 3 equivalents) were added, and the reaction mixture was stirred overnight at 120°C. The reaction mixture was then poured into 5% LiCl and extracted with EtOAc (2×30mL). The combined extracts were washed with water, 5% LiCl and brine. After solvent evaporation, the crude product was purified by silica flash chromatography in heptane / EtOAc (20%-50% EtOAc) to obtain 111mg of 2-morpholino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid methyl ester (52% yield). LCMS [M+H]+ 263.2 m / z. 1 H NMR (300MHz, DMSO-d6) δ7.80(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).

[0618] Preparation of 2-morpholino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid:

[0619] To a solution of methyl 2-morpholino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (109 mg, 0.42 mmol, 1 eq) in methanol (3 mL) and THF (4 mL) was added 2 M LiOH (1.5 mL) and the reaction mixture was stirred at room temperature overnight. The organic solvent was evaporated in vacuo and the mixture was washed with 10% KHSO 4 Neutralized. 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. 1 H NMR (300MHz, DMSO-d6) δ13.55(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).

[0620] 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):

[0621] To a solution of 2-morpholino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (77 mg, 0.31 mmol, 1.0 eq) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (75 mg, 0.37 mmol, 1.2 eq) in DMF (3 mL) were added DIPEA (267 uL, 1.53 mmol, 5 eq) and HOAt (50 mg, 0.37 mmol, 1.2 eq) and EDC·HCl (70 mg, 0.37 mmol, 1.2 eq) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the crude product was purified by flash chromatography on silica gel in 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] + 435.20m / z. 1 H NMR (300MHz, DMSO-d6) δ10.67(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).

[0622] 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):

[0623]

[0624] Preparation of (5R)-5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester:

[0625] To a solution of (5R)-2-chloro-5-methyl-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester (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 and purified by anhydrous Na 2 SO 4Dry, filter and evaporate. 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-carboxylic acid methyl ester (54.6 mg, 31% yield). LCMS [M+H] +: 279.21 m / z. 1 H NMR (300 MHz, CDCl 3 )δ7.86(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).

[0626] Preparation of (5R)-5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid:

[0627] To a solution of (5R)-5-methyl-2-morpholino-5,7-dihydrofurano[3,4-b]pyridine-3-carboxylic acid methyl ester (52 mg, 0.19 mmol, 1 eq) in methanol (0.5 mL) and THF (0.5 mL) was added 2M LiOH (200 uL), and the reaction mixture was stirred at room temperature overnight. 2N HCl (200 μL) was added. The solvent was evaporated in vacuo with acetonitrile and toluene to remove excess HCl to give crude (5R)-5-methyl-2-morpholino-5,7-dihydrofurano[3,4-b]pyridine-3-carboxylic acid. (Yield 90%) LCMS [M+H] + 279.2m / z.

[0628] 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):

[0629] To a solution of (5R)-5-methyl-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.19 mmol, 1.0 eq) and 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (42 mg, 0.20 mmol, 1.1 eq) in DMF (1 mL) was added DIPEA (65 uL, 0.37 mmol, 2 eq) and HATU (78 mg, 0.20 mmol, 1.1 eq), and the reaction mixture was stirred at 45 °C for 1.5 h. The solvent was evaporated in vacuo 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+1 451.28. 1 H NMR (300MHz, DMSO-d6) δ10.69-10.60(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,1 H),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).

[0630] 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)

[0631]

[0632] To a solution of 5-methyl-2-morpholino-5,7-dihydrofurano[3,4-b]pyridine-3-carboxylic acid ethyl ester (50 mg, 0.18 mmol, 1 eq) in MeOH (0.5 ml) was added LiOH 2M aqueous solution (0.18 ml, 0.36 mmol, 2 eq) and shaken at 45° C. for 30 min. LiOH 2M aqueous solution (0.09 ml, 0.18 mmol, 1 eq) was added and shaken at 45° C. After 2 h, the reaction mixture was evaporated and 5M HCl aqueous solution (0.108 ml, 0.540, 3 eq) was added, followed by ACN (1 ml) and then evaporated. The residue was evaporated from toluene (2×1 ml). The 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 eq) was added, followed by DIPEA (0.062 ml, 0.36 mmol, 2 eq). HATU (76 mg, 0.2 mmol, 1.1 eq) was then added, subjected to ultrasound and shaken at 45 °C. After 1.5 h, HATU (15 mg, 0.039 mmol, 0.2 eq) was then added and shaken at 45 °C for 15 min. The reaction mixture was directly purified on Biotage Isolera: ACN (0.1% FA) / H2O (0.1% FA) 2 / 98, then 2 / 98->70 / 30. The fractions with 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) as a brown oil, 26 mg (32% over two steps). LCMS [M+H] + 451m / z. 1 H NMR (300MHz, DMSO-d6) δ10.63(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=6.0Hz,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).

[0633] General method 1

[0634]

[0635] Protocol: A 100 mM solution of N-(8-methoxy-4-methyl-2-oxo-1H-quinoline-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). The solution was then added to 6.0 μmol 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 acetonitrile. The solvent was removed by SpeedVac, and the compound was analyzed and purified by HPLC-CLND.

[0636] Analysis system:

[0637] Agilent Infinity I / II-TOF6230B / CLND Antek 8060 equipped with Acquity BEH C18 (1.7 μm, 2.1 x 50 mm) with a linear gradient of binary solvent system water / methanol / formic acid (A: 100 / 0 / 0.1% and B: 0 / 100 / 0.1%) at a flow rate of 0.75 mL / min and DAD.

[0638] Purification system:

[0639] A Shimadzu Nexera X2 system was used with a C18 reverse phase column (Merck Chromolith Speedrod RP-18E, 10 x 100 mm), a linear gradient of a binary solvent system water / methanol / formic acid (A: 100 / 0 / 0.1% and B: 0 / 100 / 0.1%), a flow rate of 7.0 mL / min, and UV detection at 254 nm, combined with MS detection on a Shimadzu LCMS [M+H]+-2020.

[0640] After purification, the solvent was removed by SpeedVac (45 °C, 2-3 hours).

[0641] 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)

[0642]

[0643] The compound was prepared 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) and formaldehyde according to General Method 1. The amount isolated after purification was 14.8 μg. LCMS [M+H] + 450.22m / z.

[0644] Preparation of N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-6-(oxetane-3-yl)-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxamide (Example 33):

[0645]

[0646] The compound was prepared 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) and oxetan-3-one according to General Method 1. The amount isolated after purification was 150 μg. LCMS [M+H] + 492.23 m / z.

[0647] 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):

[0648]

[0649] The compound was prepared 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) and acetaldehyde according to General Method 1. The amount isolated after purification was 105 μg. LCMS [M+H] + 464.24 m / z.

[0650] 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):

[0651]

[0652] The compound was prepared 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) and acetone according to General Method 1. The amount isolated after purification was 71 μg. LCMS [M+H] + 478.25m / z.

[0653] General Method 2

[0654]

[0655] Preparation of N-(8-hydroxy-4-methyl-2-oxo-1H-quinolin-6-yl)-2-morpholino-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide:

[0656]

[0657] 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 Na 2 S (715 mg, 9.2 mmol, 5.0 equiv) was added and the mixture was stirred at 140 °C for 48 h. The crude reaction mixture was then poured onto ice-cold water (100 mL) and the aqueous solution was acidified until pH ∼4. The formed precipitate was filtered and washed with H 2 O to give the title compound (500 mg, 66%) as a light brown solid, which was used in the next step without further purification.

[0658] General protocol for alkylation

[0659] 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 eq.) and an alkylating agent (2.0 eq.) in DMF was stirred at 4 °C for 2 h. 2 CO 3 (3.0 equiv.) and the reaction mixture was stirred at 100° C. for 2-16 h. The crude reaction mixture was then filtered through a cotton path and directly purified by reverse phase preparative HPLC.

[0660] General protocol for deprotection

[0661] 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 prep-HPLC to give the final product.

[0662] 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):

[0663]

[0664] 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 K 2 CO 3 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 (30 mg, 27%) was obtained as a solid. 1 H NMR (300MHz, DMSO-d6) δ10.97(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).

[0665] 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):

[0666]

[0667] 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 K 2 CO 3 , 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 (75 mg, 37%) as a solid. Following the general procedure 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 (42 mg, 86%) was obtained as a solid. 1 H NMR (300MHz, DMSO-d6) δ11.11(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).

[0668] 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):

[0669]

[0670] 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 K 2 CO3 To obtain 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 (19 mg, 9%) as a solid. Following the general procedure for deprotection using 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, 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 (11 mg, 70%) was obtained as a solid. 1 H NMR (300MHz, methanol-d4) δ8.11(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,2H),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).

[0671] Preparation of 2-(7-azabicyclo[2.2.1]hept-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 39)

[0672]

[0673] Step 1: Preparation of 2-(7-azabicyclo[2.2.1]hept-7-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate

[0674] 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 NaHCO 3The product was stirred for 2-4h at 40 ℃ for 1 h.Then the mixture was stirred for 2 h.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 2 h.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 2 h.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 2 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 2 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 2 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 2 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 2 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 3 hours.Then the mixture was stirred for 3 hours. 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).

[0675] Step 2: Preparation of 2-(7-azabicyclo[2.2.1]hept-7-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid

[0676] Methyl 2-(7-azabicyclo[2.2.1]hept-7-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate (20 mg, 1 eq) was dissolved in 20 mL of a mixture of MeOH / 0.4 M aqueous NaOH (1 / 1), and the reaction mixture was stirred for 16 h at 60° C. The crude reaction was neutralized with 2 M aqueous HCl and concentrated in vacuo to give 2-(7-azabicyclo[2.2.1]hept-7-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid as a crude product, which was used directly in the next step without further purification.

[0677] Step 3: Preparation of 2-(7-azabicyclo[2.2.1]hept-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide (Example 39):

[0678] Crude 2-(7-azabicyclo[2.2.1]hept-7-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid (0.07 mmol, 1.0 eq) was suspended in DMF (2.0 mL) and treated with 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (1.1 eq), EDC·HCl (1.1 eq), HOAt (1.1 eq) and DIPEA (2.5 eq). 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 prep-HPLC to give 2-(7-azabicyclo[2.2.1]hept-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 HNMR (300MHz, DMSO-d6) δ10.65(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).

[0679] 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):

[0680]

[0681] Preparation of 2-[(3R)-3-fluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester

[0682] Following the procedure described in step 1 for the preparation of Example 39 2-(7-azabicyclo[2.2.1]hept-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 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-carboxylic acid methyl ester (140 mg, 75%) was obtained as a solid.

[0683] 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):

[0684] Following the procedures described in steps 2 and 3 for the preparation of Example 39 2-(7-azabicyclo[2.2.1]hept-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 0.52 mmol of the intermediate compound 2-[(3R)-3-fluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester was used, followed by coupling with 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (1.1 equiv.)amide, and the reaction mixture was purified by column chromatography on silica gel (Isolera One, Biotage) using a mixture of DCM / MeOH (from 100 / 0 to 80 / 20) followed by recrystallization in MeOH instead of preparative-HPLC purification to give 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 as a solid (35 mg, 20% over two steps). 1 H NMR (300MHz, DMSO-d6) δ10.65(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).

[0685] 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):

[0686]

[0687] Preparation of methyl 2-[(3R)-3-fluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate:

[0688] Following the procedure described in step 1 for the preparation of Example 39 2-(7-azabicyclo[2.2.1]hept-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, using 0.7 mmol of 2-chloro-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate and 1.5 mmol of (3S)-3-fluoropyrrolidine hydrochloride, the intermediate product 2-[(3R)-3-fluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester (140 mg, 75%) was obtained as a solid.

[0689] 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):

[0690] Following a similar procedure as described for steps 2 and 3 of the preparation of Example 39 2-(7-azabicyclo[2.2.1]hept-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 0.52 mmol of the intermediate compound 2-[(3S)-3-fluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester was used, followed by coupling with 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (1.1 equiv.)amide, and the reaction mixture was purified by column chromatography on silica gel (Isolera One, Biotage) using a mixture of DCM / MeOH (from 100 / 0 to 80 / 20) followed by recrystallization in MeOH instead of preparative-HPLC purification to give 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 as a solid (15 mg, 20% over two steps). 1 H NMR (300MHz, DMSO-d6) δ10.65(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=53.8Hz,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).

[0691] 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):

[0692]

[0693] Preparation of 2-[racemic-(3R,4S)-3,4-difluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester:

[0694] Following the procedure described in step 1 for the preparation of Example 39 2-(7-azabicyclo[2.2.1]hept-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, using 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, using DCM / MeOH (from 100 / 0 to 85 / 15) eluent system for purification, the intermediate product 2-[rac-(3R,4S)-3,4-difluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester (140 mg, 70%) was obtained as a solid. 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).

[0695] 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):

[0696] Following the procedures described in steps 2 and 3 for the preparation of Example 39 2-(7-azabicyclo[2.2.1]hept-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, 0.49 mmol of the intermediate compound 2-[rac-(3R,4S)-3,4-difluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine was used. -3-methyl carboxylate, followed by coupling with 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (1.1 equiv.) amide to give 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% over two steps).

[0697] 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):

[0698]

[0699] Preparation of methyl 2-[racemic-(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylate:

[0700] Following the procedure described in step 1 for the preparation of Example 39 2-(7-azabicyclo[2.2.1]hept-7-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide, using 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, using DCM / MeOH (from 100 / 0 to 85 / 15) eluent system for purification, the intermediate product 2-[rac-(3S,4S)-3,4-difluoropyrrolidin-1-yl]-5,7-dihydrofuro[3,4-b]pyridine-3-carboxylic acid methyl ester (160 mg, 80%) was obtained as a solid. 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).

[0701] 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):

[0702] Following the procedures described in steps 2 and 3 for the preparation of Example 39 2-(7-azabicyclo[2.2.1]hept-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 was used. Methyl pyridine-3-carboxylate was then coupled with 6-amino-8-methoxy-4-methyl-1H-quinolin-2-one (1.1 equiv.) amide to give 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 (118 mg, 78%) as a solid.

[0703] The binding affinity of the compounds was determined using the bromoscan assay and the phosphodiesterase III assay.

[0704] Bromoscan assays are run 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 can be used to establish the selectivity properties of the compounds of interest. In order to run the Bromoscan assay, T7 phage strains displaying the relevant bromodomains are grown in parallel in 24-well plates in an E. coli host derived from a BL21 strain. E. coli is grown to logarithmic phase and infected with T7 phage from a frozen stock solution (infection multiplicity = 0.4), and incubated at 32 ° C with shaking until lysis (90-150 minutes). The lysate is centrifuged (5,000 × g) and filtered (0.2 μm) to remove cell debris. Streptavidin-coated magnetic beads are treated with biotinylated small molecules or acetylated peptide ligands at room temperature for 30 minutes to generate affinity resins for bromodomain assays. The ligand-treated 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-treated 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 produce a stock solution of 100X screening concentration (the resulting stock solution was 10% DMSO / 90% MEG). The compounds were then diluted directly into the assay so that the final concentrations of DMSO and MEG were 0.1% and 0.9%, respectively. All reactions were performed in polystyrene 96-well plates with a final volume of 0.135 ml. The assay plate was incubated at room temperature with shaking for 1 hour, and the affinity beads were washed with wash buffer (1×PBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (1×PBS, 0.05% Tween20, 2 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The bromodomain concentration in the eluate was measured by qPCR (quantitative real-time polymerase chain reaction). The binding constant (Kds) was calculated using the Hill equation using a standard dose-response curve: response = background + ((signal - background) / (1 + Kd 希尔斜率 / dose 希尔斜率)). The Hill slope was set to -1. The curves were fitted using a nonlinear least squares fit using the Levenberg-Marquardt algorithm.

[0705] Radiometric PDE3A assay

[0706] Partially purified human recombinant phosphodiesterase (PDE3A) was obtained by cloning cDNA and expressing in S. frugiperda insect cells using a baculovirus expression system. Cells were harvested from the culture by centrifugation at 400×g for 5 minutes. 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 / 200 ml of culture plus protease inhibitors (100 μl / 10 ml) and incubated on ice for 10-20 minutes, then spun at 3500× g for 10 minutes at 4°C. The supernatant was retained and the pellet discarded. Tritiated cyclic AMP was hydrolyzed to 5'-AMP by PDE3A. 5'-AMP was then further hydrolyzed to adenosine by nucleotidase in snake venom. The anion exchange resin binds all charged nucleotides and leaves [ 3 H] adenosine was used as the sole labeling compound by liquid scintillation counting. The radiometric assay was a modification of the two-step method of Thompson and Appleman [Biochemistry 10; 311-316; 1971] adapted to a 96-well plate format. 50 μl of diluted PDE3A was mixed with 50 μl of [ 3[H]-cAMP (specific activity 25 Ci / mmol) and 11 μl of 50% DMSO (or compound dilution) were incubated at 30°C for 20 minutes. The 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). The reaction was performed in a Greiner 96 deep well 1 ml master plate. The plate was centrifuged for 9 seconds and then incubated for 20 minutes. The reaction was terminated by denaturing the PDE enzyme (2 minutes at 70°C, cooling the plate on ice for 10 minutes), after which 25 μl of snake venom nucleotidase (225 μg / ml final concentration) was added and incubated for 10 minutes (at 30°C), the plate was centrifuged for 9 seconds, and then incubated. After incubation, 200 μl of Dowex resin (1×8, 200-400 mesh) was added and the plate was shaken for 20 minutes and then centrifuged at 1000×g for 3 minutes. 50 μl of supernatant was removed and added to 200 μl of MicroScint-20 in a white plate (Greiner 96-well Optiplate) and shaken for 30 minutes before reading on a PerkinElmer TopCount scintillation counter. GraphPad Prism TM IC50 values ​​were calculated using a sigmoidal dose response (variable slope). The analysis measured 4 parameters including the best fit value for the bottom and top fits of the curve, the Hill slope value, and the IC50 value.

[0707] A suitable range for PDE3A inhibitory activity is PDE3A IC50>6 μM, and the most preferred range is PDE3A IC50>10 μM.

[0708] The resulting table:

[0709]

[0710]

[0711] *Comparative Example is described as Example 128 in WO 2016 / 016316 *Comparative Example is described as Example 99 in WO 2016 / 016316

[0712] *Comparative Example is described as Example 107 in WO 2016 / 016316

[0713] a Where multiple measurements were made, the reported values ​​are geometric means.

[0714] As can be seen in the table of results, the compounds disclosed herein show general selectivity for binding to the first bromodomain of BRD4 - BRD4(1) relative to PDE3A inhibition. Comparing the compounds disclosed herein under formula (I), the pharmaceutical properties are greatly improved compared to the compounds considered to be relevant prior art and disclosed in WO 2016 / 016316. For example, when comparing the compounds disclosed herein with Example 128 of WO 2016 / 016316, which is considered by the inventors to be the best compound disclosed in the prior art, it is recognized that the compounds disclosed herein under formula (I) have significantly improved selectivity for PDE3A inhibition (beneficial cardiovascular risk properties).

[0715] In some aspects, the compounds and pharmaceutically acceptable salts disclosed herein have a binding constant to the first bromodomain of BRD4 of less than 500 nM (e.g., less than 100 nM). In some aspects, the compounds disclosed herein are considered to be selective, i.e., the selectivity for the first bromodomain of BRD4 is at least 10-fold, e.g., at least 30-fold, as calculated by BRD4(2)Kd / BRD4(1)Kd compared to the second bromodomain of BRD4. In other aspects, the compounds disclosed herein have a binding constant to the first bromodomain of BRD4 of less than 500 nM (e.g., less than 100 nM), and the selectivity for the first bromodomain of BRD4 is at least 10-fold, e.g., at least 30-fold.

[0716] In some aspects, the compounds and pharmaceutically acceptable salts disclosed herein have a PDE3A IC50 of at least 6 μM (eg, at least 10 μM) (>10 μM).

[0717] In some aspects, the compounds and pharmaceutically 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 to the first bromodomain of BRD4 of less than 500 nM (e.g., less than 100 nM), and a selectivity for the first bromodomain over the second bromodomain of BRD4 of at least 10-fold, e.g., at least 30-fold.

[0718] In vivo PD studies

[0719] The in vivo efficacy of the compounds described herein can be evaluated after administration (e.g., oral administration) in animal (e.g., mouse) models for various diseases (e.g., cancer or atopic dermatitis (AD)) (e.g., Li et al., 2006, PNAS [Proceedings of the National Academy of Sciences of the United States of America], 103(31), 11736-11741). For example, the MC903 mouse model of atopic dermatitis can be used, in which mice (e.g., BALB / c mice) are treated with the vitamin D3 analog MC903 (calcipotriol) and applied topically for a certain number of days (e.g., 10-12 days) to induce allergic skin inflammation similar to AD. The compounds described herein are appropriately formulated and administered to see if improvements in ear inflammation can be observed. For each compound administered, ear thickness, terminal plasma exposure, and pro-inflammatory markers in mouse ear homogenates (e.g., Th1 / Th2 cytokine levels, chemokine CCL2 levels) are measured.

Claims

1. A compound according to formula (I) or pharmaceutically 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 selected from hydrogen and C 1-4 A group consisting of alkyl groups; A is selected from the group consisting of: an unsubstituted or substituted 5- or 6-membered alicyclic ring system; an unsubstituted or substituted 5-10-membered heteroalicyclic ring system; and -NR8R9; R1 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 -OR 10 , where R 10 Selected from C 3-6 Cycloalkyl, 4-6 membered heteroalicyclic 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 be simultaneously selected from hydrogen; or R1, R2 and the carbon atom to which they are attached are taken together to form a ring; R3 may be absent or present 1 or 2 times, and when present is C 1-4 alkyl; R4 and R5 are independently selected from the group consisting of 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 Alkoxy, -OH and -CN; R6 is selected from the group consisting of hydrogen and unsubstituted or substituted C 1-6 Alkyl, unsubstituted or substituted C 3-6 Cycloalkyl, unsubstituted or substituted C 2-6 heteroalicyclic groups; and R8 and R9 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 R8 and R9 is selected from the group consisting of: unsubstituted or substituted C 1-4 Alkyl and unsubstituted or substituted C 3-4 Cycloalkyl.

2. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to claim 1, wherein: X is -C(R4R5)-, wherein R4 and R5 are independently hydrogen or C 1-4 alkyl.

3. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to claim 2, wherein: R4 and R5 are both hydrogen.

4. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to claim 1, wherein: X is -N(R6)-, wherein R6 is selected from hydrogen, C 1-4 Alkyl, C 1-4 The group consisting of a haloalkyl group and a 4- or 5-membered heteroalicyclic group.

5. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to claim 4, wherein: R6 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl and tetrahydrofuranyl.

6. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to claim 4 or 5, wherein: R6 is hydrogen, methyl or ethyl.

7. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer of claim 1, wherein: X is -O-.

8. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to any one of claims 1 to 7, wherein: Y is -N-.

9. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to any one of claims 1 to 8, wherein: R1 is selected from the group consisting of hydrogen, hydroxy, fluorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, butoxy, -O-azetidinyl, -O-CH2CH2OH, -O-CH2CH2NHCH3.

10. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to any one of claims 1 to 9, wherein: R1 is methyl, methoxy, or ethoxy.

11. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to any one of claims 1 to 8, wherein: R1 is methoxy.

12. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to any one of claims 1 to 11, wherein: R2 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy and butoxy.

13. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to any one of claims 1 to 12, wherein: R2 is hydrogen.

14. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to any one of claims 1 to 8, wherein: R1, R2 and the carbon atom to which they are attached are taken together to form a 5 or 6 membered ring system containing one or more oxygen atoms.

15. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to any one of claims 1 to 8, wherein: R1, R2 and the carbon atom to which they are attached are combined to form 2,3-dihydro-1,4-dioxin or 2,3-dihydrofuran.

16. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to any one of claims 1 to 15, wherein: R3 is absent or is methyl.

17. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to any one of claims 1 to 16, wherein: A is selected from the group consisting of unsubstituted or substituted morpholine, unsubstituted or substituted morpholine derivatives and unsubstituted or substituted 5-10 membered heteroalicyclic ring systems other than unsubstituted or substituted morpholine or unsubstituted or substituted morpholine derivatives.

18. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to any one of claims 1 to 17, wherein: A is selected from the group consisting of: Where 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 1, 2 or 3 times, and when present is selected from halogen, hydroxyl, C 1-4 Alkyl and C 1-4 Alkoxy group.

19. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer of claim 17, wherein: The unsubstituted or substituted morpholine or unsubstituted or substituted morpholine derivative is selected from the group consisting of:

20. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer of claim 19, wherein: R 11 , R 13 , R 16 and R 17 is absent or present 1 or 2 times, and when present is independently selected from the group consisting of hydroxy, fluoro, methyl, ethyl and propyl.

21. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer of claim 20, wherein: R 11 , R 13 , R 16 and R 17 Does not exist.

22. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to any one of claims 1 to 17, wherein: The 5-10 membered heteroalicyclic ring system other than unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative is selected from the group consisting of:

23. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer of claim 22, wherein: R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 is independently absent or present 1 or 2 times, and when present is independently selected from the group consisting of hydroxy, fluoro, methyl, ethyl and propyl.

24. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer of claim 23, wherein: R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 is present once and is independently selected from the group consisting of fluoro and methyl.

25. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to any one of claims 1 to 17, wherein: The 5-10 membered heteroalicyclic ring system other than unsubstituted or substituted morpholine or an unsubstituted or substituted morpholine derivative is selected from the group consisting of:

26. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer of claim 25, wherein: R 12 , R 14 and R 15 is absent or present 1 or 2 times, and when present is selected from the group consisting of hydroxy, fluoro, methyl, ethyl and propyl.

27. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer of claim 25, wherein: R 12 , R 14 and R 15 is present once and is selected from the group consisting of hydroxy, fluoro, and methyl.

28. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer of claim 1 having the following formula (III): Where R1 is C 1-4 alkoxy; R2 is hydrogen; R3 is absent or present once and when present is selected from methyl; R 11 Absent; Y is -N- or -CH-; X is -O- or -N(R6)-, wherein R6 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl and oxetanyl.

29. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer of claim 28, wherein: The R1 is methoxy; R3 is absent; Y is -N- and X is -O-.

30. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer of claim 28, wherein: The R1 is methoxy; R3 is absent; Y is -CH- and X is -O-.

31. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer according to any one of claims 1 to 17, wherein: A is selected from -NR8R9, wherein R8 and R9 are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, cyclopropyl and cyclopropylmethyl, wherein at least one of R8 and R9 is selected from the group consisting of methyl, ethyl, propyl, cyclopropyl and cyclopropylmethyl.

32. The compound, pharmaceutically acceptable salt, polymorph, stereoisomer and tautomer of claim 31, wherein: R8 and R9 are independently methyl or cyclopropylmethyl.

33. The compound according to claim 1, wherein The compound is selected from the group consisting of: 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]hept-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]hept-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-(Cyclopenten-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]hex-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]hept-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]hex-3-yl)-N-(8-methoxy-4-methyl-2-oxo-1H-quinolin-6-yl)-5,7-dihydrofuro[3,4-b]pyridine-3-carboxamide.

34. A pharmaceutical composition comprising a compound according to any one of the preceding claims and at least one pharmaceutically acceptable excipient.

35. A compound according to any one of claims 1 to 33 or a composition according to claim 34 for use in the treatment of a disease or condition selected from the group consisting of or 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 for the prevention and treatment of viral infections.

36. A compound according to any one of claims 1 to 33 or a composition according to claim 34 for use in treating a disease or condition such as 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 spondylitis , lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune eye disease, Sjögren's syndrome, optic neuritis, neuromyelitis optica, myasthenia gravis, Guillain-Barré 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, and acute rejection of a transplanted organ; or Treatment of diseases or conditions such as acute gout, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including giant cell arteritis, polyarteritis nodosa, Behcet's disease, Wegener's granulomatosis, Kawasaki disease, Takayasu's arteritis, vasculitis with organ involvement, and acute rejection of a transplanted organ; or Treatment of sepsis, septic syndrome, septic shock, endotoxemia, systemic 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, postoperative syndrome, sarcoidosis, Herksheimer's reaction, encephalitis, myelitis, meningitis, malaria, and SIRS associated with viral infections such as influenza, herpes zoster, 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 grafting, cardiopulmonary bypass surgery, pulmonary, renal, hepatic, gastrointestinal, or peripheral limb embolism; or Treating disorders or conditions such as hypercholesterolemia, atherosclerosis, and Alzheimer's disease; or Treating disorders or conditions such as idiopathic pulmonary fibrosis, pulmonary fibrosis, intestinal fibrosis, liver fibrosis, nonalcoholic steatohepatitis, liver cirrhosis, renal fibrosis, post-operative stenosis, myelofibrosis, keloid formation, skin fibrosis, hand fibrosis, systemic sclerosis, scleroderma, and cardiac fibrosis; or Treat or prevent viral infections such as herpes virus, human papillomavirus, human immunodeficiency virus (HIV), adenovirus, and poxvirus; or Treats colon cancer, midline cancer, sarcoma, mesenchymal, liver, kidney and neural tumors; acute lymphocytic leukemia, acute myeloid leukemia, adult T-cell leukemia / lymphoma, bladder cancer, blastoma, bone cancer, breast cancer, brain cancer, Burkitt's lymphoma, 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 tumour, non-Hodgkin's lymphoma, intestinal cancer, kidney cancer, laryngeal cancer, leukaemia, lung cancer, lymphoma, liver cancer, small cell lung cancer, non-small cell lung cancer, melanoma, mesothelioma, multiple myeloma, eye cancer, optic nerve tumour, oral cancer, ovarian cancer, pituitary tumour, primary central nervous system lymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, rectal cancer, sarcoma, skin cancer, spinal cord tumour, small intestine cancer, stomach cancer, T-cell lymphoma, testicular cancer, thyroid cancer, laryngeal cancer, genitourinary cancer, urothelial carcinoma, uterine cancer, vaginal cancer, or Wilms' tumour; or Treating obesity such as that associated with cancer treatment or that associated with diabetes and cardiac hypertrophy.

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