Azetidine and pyrrolidine PARP1 inhibitors and their uses

Abstract

This article describes PARP1 inhibitors of azacyclobutane and pyrrolidine and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions may be used to treat cancer.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 251,469 filed on October 1, 2021, U.S. Provisional Application Serial No. 63 / 339,597 filed on May 9, 2022, and U.S. Provisional Application Serial No. 63 / 402,835 filed on August 31, 2022, which are hereby incorporated by reference in their entirety. Background Art

[0003] Poly (ADP-ribose) polymerase (PARP) or poly (ADP-ribose) synthase (PARS) plays an important role in promoting DNA repair, controlling RNA transcription, mediating cell death and regulating immune responses. These effects make PARP inhibitors targeted drugs for a wide variety of diseases. PARP inhibitors have demonstrated efficacy in many disease models, particularly in models of ischemia-reperfusion injury, inflammatory diseases, and degenerative diseases, demonstrating protection against the adverse effects of cytotoxic compounds and synergistic effects of cytotoxic cancer therapy. PARP is also suitable for retroviral infection, so inhibitors can be used in antiretroviral therapy. PARP inhibitors are effective in preventing ischemia-reperfusion injury in models of myocardial infarction, stroke, other neurological trauma, organ transplantation, and reperfusion of the eye, kidney, intestine, and skeletal muscle. Inhibitors are effective in inflammatory diseases such as arthritis, gout, inflammatory bowel disease, CNS inflammation such as MS and allergic encephalitis, sepsis, septic shock, hemorrhagic shock, pulmonary fibrosis, and uveitis. PARP inhibitors have also shown benefit in several models of degenerative diseases, including diabetes (and complications) and Parkinson's disease. PARP inhibitors can ameliorate liver toxicity following acetaminophen overdose, cardio- and renal toxicity from doxorubicin and platinum-based antineoplastic agents, and skin damage secondary to sulfur mustard. In various cancer models, PARP inhibitors have been shown to enhance radiation and chemotherapy by increasing cell death of cancer cells, limiting tumor growth, reducing metastasis, and prolonging survival of tumor-bearing animals.

[0004] PARP1 and PARP2 are the most extensively studied PARPs due to their roles in DNA damage repair. PARP1 is activated by DNA damage breaks and functions to catalyze the addition of poly(ADP-ribose) (PAR) chains to target proteins. This post-translational modification, known as PARylation, mediates the recruitment of additional DNA repair factors to DNA lesions.

[0005] After this recruitment is complete, PARP autoPARylation triggers the release of bound PARP from DNA to allow access to other DNA repair proteins to complete the repair. Therefore, the binding of PARP to the damage site, its catalytic activity and its eventual release from DNA are all important steps in the cancer cell response to DNA damage caused by chemotherapeutic agents and radiation therapy.

[0006] Inhibition of PARP family enzymes has been developed as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Many preclinical and clinical studies have demonstrated that tumor cells carrying deleterious alterations in BRCA1 or BRCA2, key tumor suppressor proteins involved in double-strand DNA break (DSB) repair by homologous recombination (HR), are selectively sensitive to small molecule inhibitors of the PARP family of DNA repair enzymes. Such tumors have defective homologous recombination repair (HRR) pathways and rely on the function of PARP enzymes for survival. Although PARP inhibitor therapy primarily targets SRCA mutant cancers, clinical trials of PARP inhibitors have been conducted in non-SRCA mutant tumors that exhibit homologous recombination deficiency (HRD).

[0007] It is believed that PARP inhibitors with improved selectivity for PARP1 may have improved efficacy and reduced toxicity compared to other clinical PARP1 / 2 inhibitors. It is also believed that selective and strong inhibition of PARP1 will lead to the capture of PARP1 on DNA, resulting in DNA double-strand breaks (DSBs) through S-phase replication fork collapse. It is also believed that PARP1-DNA capture is an effective mechanism for selective killing of tumor cells with HRD. Therefore, there is an unmet medical need for effective and safe PARP inhibitors. In particular, PARP inhibitors that are selective for PARP1. Summary of the invention

[0008] Disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0009]

[0010] in:

[0011] R 1 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl;

[0012] X is N or CR 2 ;

[0013] R 2 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0014] or R 1 and R 2 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally substituted with one or more R;

[0015] Z is N or CR 4 ;

[0016] R 4 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0017] Y is N or CR 5 ;

[0018] R 5 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0019] R 6 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0020] Each R 7 are independently hydrogen, deuterium, fluorine, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0021] Or two R 7 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0022] n is 1 or 2;

[0023] Each R 8are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0024] Or two R on the same carbon 8 Together they form an oxo group;

[0025] or two R on the same carbon or adjacent carbons 8 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0026] p is 0-4;

[0027] W does not exist, is -C(R 9 )2-, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR W )-or-NR W -;

[0028] Each R 9 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0029] Or two R 9 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0030] R W is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl;

[0031] Ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0032] Each R 10 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c Rd , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0033] q is 0-4;

[0034] Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl) or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0035] Each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl) or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0036] Each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl) or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0037] or R c and R d together with the atoms to which they are attached form heterocycloalkyl, optionally substituted with one or more R; and

[0038] Each R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC C1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0039] Or two R on the same atom form an oxo group;

[0040] Provided that the compound of formula (I) is not

[0041] Also disclosed herein is a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0042]

[0043] in:

[0044] With X 1 and X 2 Ring B together is a 5-membered heterocycloalkyl or a 5-membered heteroaryl;

[0045] X1 is C, CH or N;

[0046] X 2 is C, CH or N;

[0047] Each R 11 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl;

[0048] m is 0-3;

[0049] Z is N or CR 4 ;

[0050] R 4 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0051] Y is N or CR 5 ;

[0052] R 5 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0053] R 6 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0054] Each R 7 are independently hydrogen, deuterium, fluorine, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0055] Or two R 7 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0056] n is 1 or 2;

[0057] Each R 8 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0058] Or two R on the same carbon 8 Together they form an oxo group;

[0059] or two R on the same carbon or adjacent carbons 8 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0060] p is 0-4;

[0061] W does not exist, is -C(R 9 )2-, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR W )-or-NR W -;

[0062] Each R 9 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0063] Or two R 9 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0064] R W is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl;

[0065] Ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0066] Each R 10 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0067] q is 0-4;

[0068] Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl) or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0069] Each R bis independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl) or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0070] Each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl) or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0071] or R c and R d together with the atoms to which they are attached form heterocycloalkyl, optionally substituted with one or more R; and

[0072] Each R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl, - C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; or two R on the same atom form an oxo group.

[0073] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0074] Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer or lung cancer.

[0075] Also disclosed herein is a method of treating a cancer comprising a BRCA1 and / or BRCA2 mutation in a subject in need thereof, the method comprising administering a compound according to any one of claims 1 to 70, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the cancer is bladder cancer, brain cancer and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterine cancer.

[0076] Incorporated by Reference

[0077] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION

[0078] definition

[0079] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, those skilled in the art will appreciate that the present invention can be practiced without these details. In other cases, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout the specification and the subsequent claims, the word "include" and its variations such as "comprises" and "containing" should be interpreted in an open, inclusive sense, i.e., interpreted as "including but not limited to". In addition, the titles provided herein are for convenience only and do not explain the scope or meaning of the claimed invention.

[0080] References throughout this specification to "some embodiments" or "an embodiment" mean that a particular feature, structure, or characteristic described in conjunction with the embodiment is included in at least one embodiment. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing in multiple places throughout this specification do not necessarily all refer to the same embodiment. In addition, in one or more embodiments, the particular features, structures, or characteristics may be combined in any suitable manner. In addition, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense including "and / or" unless clearly specified otherwise.

[0081] As used herein, unless otherwise indicated, the following terms have the following meanings:

[0082] "Oxo" refers to =0.

[0083] "Carboxyl" refers to -COOH.

[0084] "Cyano" refers to -CN.

[0085] "Alkyl" refers to a straight or branched chain saturated hydrocarbon monovalent radical having one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever it appears in this document, a numerical range such as "C1-C6 alkyl" or "C 1-6 The term "alkyl" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the definition also covers the occurrence of the term "alkyl" in which no numerical range is specified. In some embodiments, the alkyl group is C 1-10 In some embodiments, the alkyl group is C1-6 alkyl. In some embodiments, the alkyl group is C 1-5 In some embodiments, the alkyl group is C 1-4 In some embodiments, the alkyl group is C 1-3Alkyl. Unless otherwise specifically stated in the specification, alkyl can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH or -NO. In some embodiments, alkyl is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, alkyl is optionally substituted by halogen.

[0086] "Alkenyl" refers to a straight or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. The group can be in a cis or trans conformation about the double bond, and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever it appears in this article, a numerical range such as "C2-C6 alkenyl" or "C 2-6 "Alkenyl" means that the alkenyl group may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the present definition also covers the occurrence of the term "alkenyl" in which no numerical range is specified. Unless otherwise specifically stated in the specification, the alkenyl group may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl group is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkenyl group is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkenyl group is optionally substituted by halogen.

[0087] "Alkynyl" refers to a straight or branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever a numerical range such as "C2-C6 alkynyl" or "C 2-6"Alkynyl" means that the alkynyl group may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the present definition also covers the occurrence of the term "alkynyl" in which no numerical range is specified. Unless otherwise specifically stated in the specification, the alkynyl group may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl group is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkynyl group is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkynyl group is optionally substituted by halogen.

[0088] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specifically stated in the specification, alkylene may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH or -NO. In some embodiments, alkylene is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, alkylene is optionally substituted by halogen.

[0089] "Alkoxy" refers to a group of the formula -OR a A group in which R a It is an alkyl group as defined. Unless specifically stated otherwise in the specification, alkoxy may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkoxy is optionally substituted by halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH or -NO. In some embodiments, alkoxy is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, alkoxy is optionally substituted by halogen.

[0090] "Aryl" refers to a group derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused ring system (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl group is bonded through an aromatic ring atom) or a bridged ring system. In some embodiments, the aryl group is a 6-10 membered aryl group. In some embodiments, the aryl group is a 6-membered aryl group (phenyl). Aryl groups include, but are not limited to, aryl groups derived from anthracene, naphthylene, phenanthrenyl, anthracene, azulene, benzene, Fluoranthene, fluorene, asymmetric indene, symmetric indene, indane, indene, naphthalene, phenanthene, pyrene, pyrene and triphenylene hydrocarbon ring system aryl. Unless otherwise specifically stated in the specification, aryl can be optionally substituted, for example, by halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. Replaced. In some embodiments, aryl is optionally substituted by halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, aryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, aryl is optionally substituted by halogen.

[0091] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include a fused ring system (when fused to an aryl or heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or a bridged ring system. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having three to fifteen carbon atoms (C3-C 15 Cycloalkyl or C3-C 15 cycloalkenyl), cycloalkyl (C3-C 10 Cycloalkyl or C3-C 10In some embodiments, the cycloalkyl group is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 5- to 6-membered cycloalkyl or a 5- to 6-membered cycloalkenyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptane. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Unless otherwise specifically stated in the specification, cycloalkyls may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0092] "Halo" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, halogen is fluorine or chlorine. In some embodiments, halogen is fluorine.

[0093] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0094] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0095] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0096] "Cyanoalkyl" refers to an alkyl group as defined above substituted with one or more cyano groups. In some embodiments, the alkyl group is substituted with one cyano group. In some embodiments, the alkyl group is substituted with one or two cyano groups. Cyanoalkyl groups include, for example, cyanomethyl.

[0097] "Deuterated alkyl" refers to an alkyl group as defined above that is substituted with one or more deuteriums. In some embodiments, the alkyl group is substituted with one deuterium. In some embodiments, the alkyl group is substituted with one, two, or three deuteriums. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six deuteriums. Deuterated alkyl groups include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuterated alkyl group is CD3.

[0098] "Assorted alkyl" refers to an alkyl group in which one or more backbone atoms of the alkyl group are selected from atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof). Assorted alkyl groups are connected to the rest of the molecule at the carbon atom of the assorted alkyl group. In one aspect, assorted alkyl groups are C1-C6 assorted alkyl groups, wherein the assorted alkyl group is composed of 1 to 6 carbon atoms and one or more atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof), wherein the assorted alkyl group is connected to the rest of the molecule at the carbon atom of the assorted alkyl group. The example of such assorted alkyl groups is, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specifically stated in the specification, heteroalkyl can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, heteroalkyl is optionally substituted by halogen.

[0099] "Heterocycloalkyl" refers to a 3 to 24-membered partially or fully saturated cyclic group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur. In some embodiments, heterocycloalkyl is fully saturated. In some embodiments, heterocycloalkyl contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, heterocycloalkyl contains one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, heterocycloalkyl contains one to three nitrogens. In some embodiments, heterocycloalkyl contains one or two nitrogens. In some embodiments, heterocycloalkyl contains one nitrogen. In some embodiments, heterocycloalkyl contains one nitrogen and one oxygen. Unless otherwise specifically stated in the specification, heterocycloalkyl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused ring system (when fused with an aryl or heteroaryl ring, the heterocycloalkyl is bonded by a non-aromatic ring atom) or a bridged ring system; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl can be optionally oxidized; the nitrogen atom can be optionally quaternized. Representative heterocycloalkyl groups include, but are not limited to, heterocycloalkyl groups having two to fifteen carbon atoms (C2-C 15 Heterocycloalkyl or C2-C 15 heterocycloalkenyl), heterocycloalkyl (C2-C10 Heterocycloalkyl or C2-C 10C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C6 heterocycloalkyl or C2-C6 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl). Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrrolid ... Oxazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl -2-oxo-1,3-dioxol-4-yl and 2-oxo-1,3-dioxol-4-yl.Term heterocycloalkyl also includes all ring forms of carbohydrate, including but not limited to monosaccharide, disaccharide and oligosaccharide.Unless otherwise indicated, heterocycloalkyl has 2 to 10 carbons in the ring.It should be understood that when referring to the number of carbon atoms in heterocycloalkyl, the number of carbon atoms in heterocycloalkyl is different from the total number of atoms (including heteroatoms) (that is, the skeleton atoms of heterocycloalkyl ring) constituting heterocycloalkyl. In some embodiments, heterocycloalkyl is 3 to 8-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 3 to 7-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 3 to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 4 to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 5 to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 3 to 8-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 3 to 7-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 3 to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 4 to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 5 to 6-membered heterocycloalkenyl. Unless otherwise specifically stated in the specification, heterocycloalkyl may be optionally substituted as described below, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.In some embodiments, heterocycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, heterocycloalkyl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, heterocycloalkyl is optionally substituted by halogen.

[0100] "Heteroaryl" refers to a 5 to 14 ring system group containing one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, the heteroaryl group contains one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl group contains one to three nitrogens. In some embodiments, the heteroaryl group contains one or two nitrogens. In some embodiments, the heteroaryl group contains one nitrogen. The heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused ring system (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl group is bonded by an aromatic ring atom) or a bridged ring system; and the nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized. In some embodiments, the heteroaryl group is a 5 to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5 to 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, aza yl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepenyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranyl, thiophene, benzothiophene (benzophenylthio), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzophenylthio, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepine The heteroaryl group may be optionally substituted, for example, by halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, heteroaryl is optionally substituted by halogen.

[0101] The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes instances in which the event or situation occurs and instances in which the event or situation does not occur. For example, "optionally substituted alkyl" refers to "alkyl" or "substituted alkyl" as defined above. In addition, the optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at any level between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It should be understood by those skilled in the art that with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical and / or synthetically unfeasible (e.g., substituted alkyl includes optionally substituted cycloalkyl, which is in turn defined to include optionally substituted alkyl, possibly infinite). Therefore, any substituent described is generally understood to have a maximum molecular weight of about 1,000 Daltons, and more typically, up to about 500 Daltons.

[0102] "Effective amount" or "therapeutically effective amount" refers to that amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce the desired therapeutic effect.

[0103] "Treatment" of an individual (e.g., a mammal such as a human) or cell is any type of intervention used to attempt to alter the natural course of an individual or cell. In some embodiments, treatment includes administering a pharmaceutical composition after a pathological event has been initiated or contact with a pathogen, and includes stabilizing the condition (e.g., the condition does not worsen) or alleviating the condition.

[0104] "Synergy" or "acting synergistically" means that the effect of the combination is greater than the sum of the effects of each component alone at the same dose.

[0105] As used herein, a "disease or disorder associated with PARP" or alternatively a "PARP-mediated disease or disorder" means any disease or other deleterious condition in which PARP or a mutant thereof is known or suspected to play a role.

[0106] As used herein, a "disease or disorder associated with PARP1" or alternatively a "PARPl-mediated disease or disorder" means any disease or other deleterious condition in which PARP or a mutant thereof is known or suspected to play a role.

[0107] Compound

[0108] Described herein are compounds of formula (I) or pharmaceutically acceptable salts, solvates or stereoisomers thereof that are useful for treating cancer.

[0109] Disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0110]

[0111] in:

[0112] R 1 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl;

[0113] X is N or CR 2 ;

[0114] R 2 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0115] or R1 and R 2 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally substituted with one or more R;

[0116] Z is N or CR 4 ;

[0117] R 4 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0118] Y is N or CR 5 ;

[0119] R 5 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0120] R 6 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0121] Each R 7 are independently hydrogen, deuterium, fluorine, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0122] Or two R 7 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0123] n is 1 or 2;

[0124] Each R 8 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0125] Or two R on the same carbon 8 Together they form an oxo group;

[0126] or two R on the same carbon or adjacent carbons 8 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0127] p is 0-4;

[0128] W does not exist, is -C(R 9 )2-, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR W )-or-NR W -;

[0129] Each R 9 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0130] Or two R 9 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0131] R W is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl;

[0132] Ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0133] Each R 10 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NRb C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0134] q is 0-4;

[0135] Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl) or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0136] Each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl) or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0137] Each R c and R dis independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl) or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0138] or R c and R d together with the atoms to which they are attached form heterocycloalkyl, optionally substituted with one or more R; and

[0139] Each R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC C1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0140] Or two R on the same atom form an oxo group;

[0141] Provided that the compound of formula (I) is not

[0142] Disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0143]

[0144] in:

[0145] R 1 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl;

[0146] X is N or CR 2 ;

[0147] R 2 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0148] or R 1 and R 2 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally substituted with one or more R;

[0149] Z is N or CR 4 ;

[0150] R 4 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0151] Y is N or CR 5 ;

[0152] R 5 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0153] R 6 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0154] Each R 7 are independently hydrogen, deuterium, fluorine, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0155] Or two R 7 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0156] n is 1 or 2;

[0157] Each R 8 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0158] Or two R on the same carbon 8 Together they form an oxo group;

[0159] or two R on the same carbon or adjacent carbons 8 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0160] p is 0-4;

[0161] W is -C(R 9 )2-, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR W )-or-NR W -;

[0162] Each R 9 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0163] Or two R 9 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0164] R W is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl;

[0165] Ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0166] Each R 10 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)ORb 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0167] q is 0-4;

[0168] Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl) or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0169] Each R bis independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl) or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0170] Each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl) or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0171] or R c and R d together with the atoms to which they are attached form heterocycloalkyl, optionally substituted with one or more R; and

[0172] Each R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC C1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0173] Or two R on the same atom form an oxo group;

[0174] Provided that the compound of formula (I) is not

[0175] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, the compound has Formula (Ia):

[0176]

[0177] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, the compound has Formula (Ib):

[0178]

[0179] Where R 8a Deuterium, halogen, -CN, -NO2, -OH, -OR a 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; and

[0180] p' is 0-3.

[0181] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, the compound has Formula (Ic):

[0182]

[0183] In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl.

[0184] In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 Halogen, -CN, -OH, -OR a , C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl.

[0185] In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1 alkyl, C3-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl or cycloalkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 is C1-C6 alkyl or cycloalkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 is C1 alkyl or C3-C6 alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 It is ethyl.

[0186] In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1is deuterium, halogen, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 is deuterium, halogen, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 is halogen, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 is halogen, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 It is cyclopropyl.

[0187] In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 is halogen, C1-C6 alkyl or cycloalkyl.

[0188] In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, X is N. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, X is CR 2 .

[0189] In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 2 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 2 is hydrogen, halogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 2 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 2 For hydrogen.

[0190] In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 and R 2 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally substituted with one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 and R 2 together form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 and R 2together form an aryl or heteroaryl group; each optionally substituted by one or more R.

[0191] Disclosed herein is a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0192]

[0193] in:

[0194] With X 1 and X 2 Ring B together is a 5-membered heterocycloalkyl or a 5-membered heteroaryl;

[0195] X 1 is C, CH or N;

[0196] X 2 is C, CH or N;

[0197] Each R 11 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl;

[0198] m is 0-3;

[0199] Z is N or CR 4 ;

[0200] R 4 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0201] Y is N or CR 5 ;

[0202] R 5 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0203] R 6 Hydrogen, deuterium, halogen, -CN, -OH, -OR a, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0204] Each R 7 are independently hydrogen, deuterium, fluorine, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0205] Or two R 7 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0206] n is 1 or 2;

[0207] Each R 8 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-NR c R d 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0208] Or two R on the same carbon 8 Together they form an oxo group;

[0209] or two R on the same carbon or adjacent carbons 8 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0210] p is 0-4;

[0211] W does not exist, is -C(R 9 )2-, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR W )-or-NR W -;

[0212] Each R 9 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0213] Or two R 9 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0214] R W is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl;

[0215] Ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0216] Each R 10 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0217] q is 0-4;

[0218] Each R ais independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl) or C1-C6 alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0219] Each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl) or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0220] Each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl) or C1-C6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0221] or R c and R d together with the atoms to which they are attached form heterocycloalkyl, optionally substituted with one or more R; and

[0222] Each R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC C1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0223] Alternatively, two R's on the same atom form an oxo group.

[0224] In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, ring B and X 1 and X 2 In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, ring B and X are 1 and X 2 In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, ring B and X are pyrrolidinyl or furanyl. 1 and X 2 In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, ring B and X are 1 and X 2 In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, ring B and X are pyrrolyl, pyrazolyl, imidazolyl or triazolyl. 1 and X 2 In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, ring B and X are pyrazolyl or imidazolyl. 1 and X 2 In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, ring B and X are pyrazolyl. 1 and X 2 Together they are furanyl.

[0225] In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, X 1 C. In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, X 1 In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, X 1 is N. In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, X 2 C. In some embodiments of the compound of Formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, X 2 In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, X 2 is N.

[0226] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (II), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, Z is N. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (II), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, Z is CR 4 .

[0227] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 4 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 4 is hydrogen, halogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 4 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 4 For hydrogen.

[0228] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (II), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, Y is N. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (II), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, Y is CR 5 .

[0229] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 5 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 5 is hydrogen, halogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 5 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 5 For hydrogen.

[0230] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 6 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 6 is hydrogen, halogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 6 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 6 For hydrogen.

[0231] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R7 are independently hydrogen, deuterium, fluorine, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl.

[0232] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 7 is independently hydrogen, deuterium, fluorine or C1-C6 alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 7 In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 7 In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 7 In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 7 In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, one R 7 is hydrogen and the other R 7 It is a C1-C6 alkyl group.

[0233] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, both R 7 together form a cycloalkyl or heterocycloalkyl group; each optionally substituted by one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, two R 7 In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, two R 7 Together they form a cycloalkyl group.

[0234] In some embodiments of the compound of formula (I) or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 1. In some embodiments of the compound of formula (I) or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 2.

[0235] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 8 are independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 8 is independently deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 8 is independently deuterium, halogen, -CN or C1-C6 alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 8 In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 8 are independently C1-C6 alkyl.

[0236] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (II), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, two R 8 together form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, two R on the same carbon 8 Together they form a cycloalkyl or heterocycloalkyl.

[0237] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (II), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, two R on adjacent carbons are8 together form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, two R on adjacent carbons 8 Together they form a cycloalkyl or heterocycloalkyl.

[0238] In some embodiments of the compound of Formula (I), (Ia), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p is 0-3. In some embodiments of the compound of Formula (I), (Ia), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p is 0-2. In some embodiments of the compound of Formula (I), (Ia), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p is 0 or 1. In some embodiments of the compound of Formula (I), (Ia), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p is 2-4. In some embodiments of the compound of Formula (I), (Ia), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p is 2 or 3. In some embodiments of the compound of Formula (I), (Ia), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p is 1-4. In some embodiments of the compound of Formula (I), (Ia), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p is 1-3. In some embodiments of the compound of Formula (I), (Ia), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p is 1 or 2. In some embodiments of the compound of Formula (I), (Ia), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p is 0. In some embodiments of the compound of Formula (I), (Ia), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p is 1. In some embodiments of the compound of Formula (I), (Ia), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p is 2. In some embodiments of the compound of Formula (I), (Ia), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p is 3.

[0239] In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p' is 0-2. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p' is 0 or 1. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p' is 2 or 3. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p' is 1-3. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p' is 1 or 2. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p' is 0. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p' is 1. In some embodiments of the compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p' is 2. In some embodiments of the compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p' is 3.

[0240] In some embodiments of the compound of Formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 8a Deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 8a is deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 8a is deuterium, halogen, -CN or C1-C6 alkyl. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 8a is -CN or C1-C6 alkyl. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 8a It is a C1-C6 alkyl group.

[0241] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, W is -C(R 9)2-, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR W )-or-NR W In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, W is absent, -C(R 9 )2-, -O- or -NR W In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, W is -C(R 9 )2-, -O- or -NR W In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, W is -O- or -NR W In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, W is -S-, -S(=O)-, -S(=O)2- or -S(=O)(=NR W )-. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (II), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, W is -S-, -S(=O)- or -S(=O)2-. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (II), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, W is -O-. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (II), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, W is -NR W2 -. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, W is absent.

[0242] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 9 is independently hydrogen, deuterium, fluorine, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 9is independently hydrogen, deuterium, fluorine or C1-C6 alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 9 In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 9 In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 9 In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 9 In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, one R 9 is hydrogen and the other R 9 It is a C1-C6 alkyl group.

[0243] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, both R 9 together form a cycloalkyl or heterocycloalkyl group; each optionally substituted by one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, two R 9 In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, two R 9 Together they form a cycloalkyl group.

[0244] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R W is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R W For hydrogen.

[0245] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, Ring A is cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, Ring A is cycloalkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, Ring A is heterocycloalkyl.

[0246] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (II), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, Ring A is aryl or heteroaryl. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (II), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, Ring A is phenyl. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (II), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, Ring A is heteroaryl.

[0247] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (II), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, Ring A is a 5- or 6-membered heteroaryl. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (II), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, Ring A is a 5-membered heteroaryl. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (II), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, Ring A is a 6-membered heteroaryl.

[0248] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (II), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, Ring A is not pyridinyl. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (II), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, Ring A is not

[0249] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 10 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; provided that one R 10 is not -C(=O)NHCH3. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 10 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d , -SH, -SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR bS(=O)2R a 、-C(=O)R a 、-C(=O)OR b , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 10 are independently deuterium, halogen, -CN, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 10 are independently deuterium, halogen, -CN, -OC(=O)NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl.

[0250] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 10 are independently deuterium, halogen, -CN, -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl.

[0251] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R 10 are independently -C(=O)NR c R d .

[0252] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, q is 0-3. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, q is 0-2. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, q is 0 or 1. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, q is 1-4. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, q is 1-3. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, q is 2-4. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, q is 2 or 3. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, q is 1 or 2. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, q is 1. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, q is 2. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, q is 3.

[0253] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, no

[0254] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, for

[0255] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, for

[0256] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted by one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R a is independently C1-C6 alkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted by one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R a is independently C1-C6 alkyl or C1-C6 haloalkyl; wherein each alkyl is independently and optionally substituted by one or more R.

[0257] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R bR is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R b is independently hydrogen, C1-C6 alkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted by one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R b is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R b independently hydrogen or independently and optionally substituted by one or more R, C1-C6 alkyl.

[0258] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R c and R dR is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R c and R d R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R c and R d is independently hydrogen, C1-C6 alkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted by one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R c and R d is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R c and R d Each is independently hydrogen or C1-C6 alkyl which is independently and optionally substituted with one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R c is a cycloalkyl group and R d For hydrogen.

[0259] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, Rc and R d Together with the atoms to which they are attached, they form a heterocycloalkyl group optionally substituted with one or more R. In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R c and R d Together with the atoms to which they are attached they form a heterocycloalkyl.

[0260] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic) or (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, each R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl; or two R on the same atom form an oxo group. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (II), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl; or two R on the same atom form an oxo group. In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) or (II), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl; or two R on the same atom form an oxo group.

[0261] In some embodiments of the compounds disclosed herein, each R a , R b , R c , R d When R 1 and R 2 When combined, they form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group. 7 When combined, the cycloalkyl and heterocycloalkyl groups are formed. 8 When combined, the cycloalkyl and heterocycloalkyl groups are formed. 9 When combined, they form cycloalkyl and heterocycloalkyl groups, and when Rc and R d The heterocycloalkyl group formed when taken together is independently substituted with one, two, three or four substituents as defined herein. In some embodiments of the compounds disclosed herein, each R a , R b , R c , R d When R 1 and R 2 When combined, they form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group. 7 When combined, the cycloalkyl and heterocycloalkyl groups are formed. 8 When combined, the cycloalkyl and heterocycloalkyl groups are formed. 9 When combined, they form cycloalkyl and heterocycloalkyl groups, and when R c and R d The heterocycloalkyl group formed when taken together is independently substituted with one, two or three substituents as defined herein. In some embodiments of the compounds disclosed herein, each R a , R b , R c , R d When R 1 and R 2 When combined, they form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group. 7 When combined, the cycloalkyl and heterocycloalkyl groups are formed. 8 When combined, the cycloalkyl and heterocycloalkyl groups are formed. 9 When combined, they form cycloalkyl and heterocycloalkyl groups, and when R c and R d The heterocycloalkyl groups formed when taken together are independently substituted with one or two substituents as defined herein.

[0262] Any combination of the various groups of variables described above is contemplated herein. Throughout the specification, groups and substituents thereof are selected by one skilled in the art to provide stable moieties and compounds.

[0263] In some embodiments, the compound disclosed herein is a compound selected from Table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0264] Table 1

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278] The absolute designation (abs) is added to the chiral center to indicate that it is unequivocally a pure sample of the drawn stereoisomer.

[0279] The OR notation (or) indicates a pure substance, but the absolute configuration of the stereochemical center is unknown. After chiral separation with an isolated pure structure, multiple OR notations with the same value (OR stands for purity) will indicate that the sample is one of a pair of pure enantiomers (but the absolute configuration of the stereochemical center is unknown).

[0280] Other forms of the compounds disclosed herein

[0281] Isomers / stereoisomers

[0282] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis (cis), trans (trans), cis (syn), trans (anti), trans (entgegen) (E) and cis (zusammen) (Z) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, and each center exists in R configuration or S configuration. The compounds described herein include all diastereomers, enantiomers and diastereomeric forms and their corresponding mixtures. In other embodiments of the compounds and methods provided herein, the enantiomers and / or diastereoisomer mixtures produced by a single preparation step, combination or interconversion can be used for the applications described herein. In some embodiments, a pair of diastereomeric compounds are formed by reacting the racemic mixture of the compound with an optically active resolving agent, separating the diastereomers and recovering the optically pure enantiomers, and the compounds described herein are prepared as their individual stereoisomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.), and are separated by utilizing these differences. In some embodiments, diastereomers are separated by chiral chromatography, or preferably by separation / resolution techniques based on solubility differences. In some embodiments, optically pure enantiomers and resolving agents are then recovered by any practical means that do not result in racemization.

[0283] Labeled compounds

[0284] In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds as pharmaceutical compositions. Therefore, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are the same as those described herein, but one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H. 3 H. 13 C. 14 C. l5 N. 18 O. 17 O. 31 P.32 P. 35 S. 18 F and 36 Cl. Compounds described herein and pharmaceutically acceptable salts, solvates or stereoisomers thereof containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds, for example, compounds incorporating radioactive isotopes such as 3 H and 14 C, can be used for drug and / or substrate tissue distribution assays. Particularly preferred are tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes because of their ease of preparation and detectability. In addition, heavy isotopes such as deuterium (i.e., 2 H) Substitutions may confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0285] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0286] Pharmaceutically acceptable salts

[0287] In some embodiments, the compounds described herein exist in the form of pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0288] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with any of a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or their solvates or stereoisomers, or by reacting the purified compound in its free form with a suitable acid or base separately and isolating the salt thus formed.

[0289] Examples of pharmaceutically acceptable salts include those prepared by reacting a compound described herein with an inorganic, organic or inorganic base, such salts include acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, hexanoate, octanoate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate , hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, undecanoate toluenesulfonate, and xylenesulfonate.

[0290] In addition, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid or organic acid, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, Acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid. In some embodiments, other acids, such as oxalic acid, while not pharmaceutically acceptable in themselves, are used to prepare salts that can be used as intermediates to obtain the compounds disclosed herein, their solvates or stereoisomers, and pharmaceutically acceptable acid addition salts thereof.

[0291] In some embodiments, those compounds described herein that contain free acid groups are reacted with a suitable base (such as a pharmaceutically acceptable metal cation hydroxide, carbonate, bicarbonate, sulfate), with ammonia or with a pharmaceutically acceptable organic primary, secondary, tertiary or quaternary amine. Representative salts include alkali metal salts or alkaline earth metal salts, such as lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts and aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 Alkyl)4, etc.

[0292] Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water-soluble or oil-soluble or dispersible products are obtained by such quaternization.

[0293] Solvate

[0294] In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating diseases by administering such solvates. The present invention also provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0295] Solvates contain a stoichiometric or non-stoichiometric amount of solvent, and in some embodiments, are formed during use of a pharmaceutically acceptable solvent such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the process of the methods described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from aqueous / organic solvent mixtures using organic solvents including but not limited to dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in non-solvated forms as well as solvated forms. Generally, for the purposes of the compounds and methods provided herein, solvated forms are considered to be equivalent to non-solvated forms.

[0296] Tautomer

[0297] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can be interconverted by the migration of hydrogen atoms, with the conversion of single bonds and adjacent double bonds. In the bonding arrangements where tautomerism may occur, there will be a chemical equilibrium of tautomers. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0298] Treatment

[0299] Disclosed herein are methods of treating diseases in which inhibition of PARP is beneficial, the methods comprising administering a compound disclosed herein. Also disclosed herein are methods of treating diseases in which inhibition of PARP1 is beneficial, the methods comprising administering a compound disclosed herein. In some embodiments, the disease is cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer (such as gastric cancer and colorectal cancer), or lung cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In some embodiments, the cancer is leukemia, colon cancer, glioblastoma, lymphoma, melanoma, or cervical cancer.

[0300] In some embodiments, the cancer comprises a BRCA1 and / or BRCA2 mutation.

[0301] In some embodiments, the cancer comprising a BRCA1 and / or BRCA2 mutation is bladder cancer, brain and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterine cancer.

[0302] In some embodiments, the cancer is a cancer that lacks Flomologous Recombination (FIR)-dependent DNA DSB repair activity.The FIR-dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA via homologous mechanisms to reform a continuous DNA helix. Components of the FIR-dependent DNA DSB repair pathway include, but are not limited to, ATM (NM_000051), RAD51 (NM_002875), RAD51 L1 (NM_002877), RAD51 C (NM_002876), RAD51 L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432), RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), MRE1 (NM_007068). 1A (NM_005590) and NBS1 (NM_002485). Other proteins involved in the FIR-dependent DNA DSB repair pathway include regulatory factors such as EMSY. In some embodiments, the cancer lacking FIR-dependent DNA DSB repair comprises one or more cancer cells whose ability to repair DNA DSB by this pathway is reduced or eliminated relative to normal cells, that is, the activity of the FIR-dependent DNA DSB repair pathway may be reduced or eliminated in the one or more cancer cells.

[0303] In some embodiments, the activity of one or more components of the FIR-dependent DNA DSB repair pathway is abolished in one or more cancer cells of an individual suffering from a cancer deficient in FIR-dependent DNA DSB repair.

[0304] In some embodiments, the cancer cells have a BRCA1 and / or BRCA2 defective phenotype, i.e., the activity of BRCA1 and / or BRCA2 is reduced or eliminated in the cancer cells. Cancer cells with this phenotype may lack BRCA1 and / or BRCA2, i.e., the expression and / or activity of BRCA1 and / or BRCA2 in the cancer cells may be reduced or eliminated, for example, by mutations or polymorphisms in the encoding nucleic acid, or by amplification, mutation or polymorphism of genes encoding regulatory factors (e.g., the EMSY gene encoding BRCA2 regulatory factors). BRCA1 and BRCA2 are known tumor suppressor genes, and their wild-type alleles are often lost in tumors of heterozygous carriers. It is also known that the amplification of the EMSY gene encoding BRCA2 binding factors is associated with breast cancer and ovarian cancer. Carriers of BRCA1 and / or BRCA2 mutations are also at high risk for certain cancers, including breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer and lung cancer.

[0305] Drug administration

[0306] In certain embodiments, compositions containing compounds described herein are administered for preventive and / or therapeutic treatment. In certain therapeutic applications, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially suppress at least one symptom of the disease or condition. The effective amount for this use depends on the severity and course of the disease or condition, previous treatment, the patient's health, body weight, and response to the drug, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0307] In preventive applications, compositions containing the compounds described herein are administered to patients who are susceptible to or otherwise at risk for a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose". In this use, the exact amount also depends on the patient's health, weight, etc. When used for a patient, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous treatment, the patient's health and response to the drug, and the judgment of the treating physician. In one aspect, preventive treatment includes administering a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof to a mammal that has previously experienced at least one symptom or risk factor for the disease being treated and is currently in a state of remission to prevent the recurrence of symptoms of the disease or condition.

[0308] In certain embodiments where the patient's condition does not improve, at the physician's discretion, administration of the compound is chronic, i.e., for an extended period of time, including the entire duration of the patient's life, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0309] In certain embodiments where the patient's condition does improve, the dose of the administered drug is temporarily reduced or temporarily suspended for a period of time (i.e., a "drug holiday"). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including, for example, only 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. For example, the dose reduction during the drug holiday is only 10%-100%, including, for example, only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0310] Once the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, as symptoms change, the dose or frequency of administration, or both, is reduced to a level that maintains the improved disease, disorder, or condition. However, in certain embodiments, after any recurrence of symptoms, the patient requires long-term intermittent or daily treatment.

[0311] The amount of a given agent that corresponds to such an amount varies depending on factors such as the specific compound, the disease condition and its severity, the identity of the subject or host in need of treatment (e.g., weight, sex), but will still be determined according to the specific circumstances surrounding the case, including, for example, the specific agent administered, the route of administration, the condition being treated, and the subject or host being treated.

[0312] However, in general, dosages for adult treatment are generally in the range of 0.01 mg to 5000 mg per day. In one aspect, dosages for adult treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dosage is conveniently provided in a single dose or in divided doses administered simultaneously or at appropriate intervals, e.g., two, three, four or more sub-doses per day.

[0313] In one embodiment, the daily dose suitable for the compound described herein or its pharmaceutically acceptable salt is about 0.01 mg / kg body weight to about 50 mg / kg body weight. In some embodiments, based on multiple variables related to individual treatment regimens, the amount of active substance in the daily dose or dosage form is lower or higher than the range indicated herein. In various embodiments, the daily dose and unit dose vary according to many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the needs of the individual subject, the severity of the disease or condition to be treated, and the judgment of the doctor.

[0314] Toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell culture or experimental animals, including but not limited to LD10 and ED 90 The dose ratio between toxic and therapeutic effects is the therapeutic index, expressed as LD 50 With ED 50 In certain embodiments, the data obtained from cell culture assays and animal studies are used to formulate therapeutically effective daily dose ranges and / or therapeutically effective unit doses for mammals (including humans). In some embodiments, the daily dose of the compounds described herein is within the range that includes the ED with minimal toxicity. 50 In certain embodiments, the daily dosage range and / or the unit dosage varies within this range, depending on the dosage form employed and the route of administration employed.

[0315] In any of the foregoing aspects are further embodiments wherein an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) administered systemically to a mammal; and / or (b) administered orally to a mammal; and / or (c) administered intravenously to a mammal; and / or (d) administered to a mammal by injection; and / or (e) administered topically to a mammal; and / or (f) administered non-systemically or topically to a mammal.

[0316] Within any of the foregoing aspects are additional embodiments comprising a single administration of an effective amount of the compound, including additional embodiments wherein (i) the compound is administered once daily; or (ii) the compound is administered to the mammal multiple times over the course of a day.

[0317] In any of the foregoing aspects are further embodiments comprising multiple administrations of an effective amount of the compound, including further embodiments wherein (i) the compound is administered continuously or intermittently: such as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to a mammal every 8 hours; (iv) the compound is administered to a subject every 12 hours; (v) the compound is administered to a subject every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein administration of the compound is temporarily suspended or the dose of the administered compound is temporarily reduced; at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday ranges from 2 days to 1 year.

[0318] Route of administration

[0319] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ear, nasal and topical administration. In addition, for example, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic and intranasal injection.

[0320] In certain embodiments, the compounds as described herein are applied in a local rather than systemic manner, for example, by injecting the compound directly into an organ, usually in the form of a reservoir formulation or a sustained release formulation. In a specific embodiment, the long-acting preparation is applied by implantation (for example, subcutaneous or intramuscular) or by intramuscular injection. In addition, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such an embodiment, the liposome is targeted to an organ and selectively absorbed by the organ. In other embodiments, the compounds as described herein are provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. In other embodiments, the compounds as described herein are applied topically.

[0321] Pharmaceutical compositions / preparations

[0322] According to standard pharmaceutical practice, the compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, excipient or diluent in the form of a pharmaceutical composition to a subject in need thereof. In one embodiment, the compounds of the invention can be administered to animals. These compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

[0323] In another aspect, provided herein is a pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compound into a pharmaceutically usable formulation. Appropriate formulations depend on the selected route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventeenth Edition (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0324] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, humectants, defoamers, antioxidants, preservatives, and any combination thereof.

[0325] The pharmaceutical compositions described herein are administered to a subject by a suitable route of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal or transdermal routes of administration. Pharmaceutical formulations described herein include but are not limited to aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast dissolving formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multi-particulate formulations, and mixed immediate release formulations and controlled release formulations.

[0326] Pharmaceutical compositions containing a compound described herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, are manufactured in a conventional manner, such as, by way of example only, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0327] The pharmaceutical composition for oral use is obtained in such a way that one or more solid excipients are mixed with one or more compounds described herein, the resulting mixture is optionally ground, and if necessary, the granular mixture is processed after adding suitable auxiliary agents to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others, such as polyvinyl pyrrolidone (PVP or povidone) or calcium phosphate. If necessary, disintegrants such as cross-linked sodium carboxymethylcellulose, polyvinyl pyrrolidone, agar or alginic acid or its salts such as sodium alginate are added. In some embodiments, colorants or pigments are added to tablets or dragee coatings to identify or characterize different combinations of active compound dosages.

[0328] Pharmaceutical compositions for oral administration include push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules contain the active ingredient mixed with a filler, such as lactose, a binder, such as starch, and / or a lubricant, such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound is dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added.

[0329] The pharmaceutical composition for parenteral use is formulated as an infusion or injection. In some embodiments, the pharmaceutical composition suitable for injection or infusion includes a sterile aqueous solution, dispersion or sterile powder comprising a compound as described herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, the pharmaceutical composition includes a liquid carrier. In some embodiments, the liquid carrier is a solvent or a liquid dispersion medium, including, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glycerides and any combination thereof. In some embodiments, the pharmaceutical composition also includes a preservative to prevent microbial growth.

[0330] combination

[0331] Disclosed herein are methods of treating cancer using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0332] In some embodiments, the additional therapeutic agent is an anti-cancer agent.

[0333] In some embodiments, the additional therapeutic agent is administered simultaneously with the compounds disclosed herein. In some embodiments, the additional therapeutic agent and the compounds disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered before the compounds disclosed herein are administered. In some embodiments, the additional therapeutic agent is administered after the compounds disclosed herein are administered.

[0334] Example

[0335] Example 1

[0336]

[0337] Step 1: Preparation of methyl 5-{[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylate Preparation :

[0338] At 0°C under nitrogen atmosphere, a solution of DBAD (2.26 g, 9.79 mmol, 1.50 equiv) in toluene (5 mL) was added dropwise to a stirred solution of 5-hydroxypyridine-2-carboxylic acid methyl ester (1.00 g, 6.53 mmol, 1.00 equiv), (3R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (1.83 g, 9.79 mmol, 1.50 equiv) and PPh3 (2.57 g, 9.79 mmol, 1.50 equiv) in toluene (10 mL). The resulting mixture was stirred at 0°C for 1 hour. The mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was monitored by LCMS. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 5-{[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylate (4.0 g, containing PPh3 and Ph3PO). The resulting mixture was used directly in the next step. LC-MS: (ES+H, m / z): [M+H] + =323.1.

[0339] Step 2: Preparation of tert-butyl (3S)-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate Preparation :

[0340] A solution of methyl 5-{[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyrrolidine-2-carboxylate (2.00 g, 6.20 mmol, 1.00 equiv) and methylamine (8.6 mL, 25% aqueous solution) in MeOH (8.6 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (3S)-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate (1.50 g, containing PPh3 and Ph3PO). The crude product was used directly in the next step. LC-MS: (ES+H, m / z): [M+H] + =322.1.

[0341] Step 3: Preparation of N-methyl-5-[(3S)-pyrrolidin-3-yloxy]pyridine-2-carboxamide HCl salt :

[0342] A solution of (3S)-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g, crude) and HCl (gas) in 1,4-dioxane (8.0 mL 4M) was stirred at room temperature for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The product was precipitated by adding EtOAc. The precipitated solid was collected by filtration and washed with PE (3×10 mL) to give N-methyl-5-[(3S)-pyrrolidin-3-yloxy]pyridine-2-carboxamide HCl salt (800 mg, crude). LC-MS: (ES+H, m / z): [M+H] + =222.2.

[0343] Step 4: 5-{[(3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]oxy Preparation of 1-methyl-N-methylpyridine-2-carboxamide :

[0344] To a stirred solution of N-methyl-5-[(3S)-pyrrolidin-3-yloxy]pyridine-2-carboxamide (250 mg, crude) and DIEA (580 mg, 4.49 mmol, 5.00 equiv) in MeCN (5 mL) was added KI (30 mg, 0.18 mmol, 0.20 equiv) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (200 mg, 0.90 mmol, 1.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-{[(3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (143.7 mg, 39.1%). LC-MS: (ES+H, m / z): [M+H] + =407.90.1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.55(d,1H),8.39(s,1H),8.24(d,1H),7.95(d,1H),7.74(s,1H),7.61(s,1H),7.48(dd, 1H),5.10-5.04(m,1H),3.73(s,2H),2.91-2.64(m,6H),2.55-2.52(m,2H),2.49-2.30(m,2H),1.89-1.77(m,1H),1.18(t,3H).

[0345] Example 2

[0346]

[0347] Step 1: Preparation of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylate Preparation :

[0348] To a stirred solution of methyl 5-hydroxypyridine-2-carboxylate (1.00 g, 6.53 mmol, 1.00 equiv) and tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (1.83 g, 9.79 mmol, 1.50 equiv) in THF (10 mL) was added PPh3 (3.43 g, 13.06 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred under nitrogen atmosphere until 0°C. DEAD (2.27 g, 13.06 mmol, 2.00 equiv) was added dropwise to the above mixture at 0°C. The resulting mixture was stirred at room temperature for another 1 hour. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase combi-flash chromatography. This gave methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylate (4.00 g, containing TPPO). LC-MS: (ES+H, m / z): [M+H] + =323.2.

[0349] Step 2: Preparation of tert-butyl (3R)-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate Preparation :

[0350] Methylamine (20 mL, 25 wt %-30 wt % aqueous solution) was added to a stirred solution of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyrrolidine-2-carboxylate (3.80 g crude product, containing TPPO) in MeOH (20 mL) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The desired product can be detected by LCMS. The solvent was removed under reduced pressure. The residue was purified by reverse phase combi-flash chromatography. This gave tert-butyl (3R)-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate (3.80 g, containing TPPO). LC-MS: (ES+H, m / z): [M+H] + =322.1.

[0351] Step 3: Preparation of N-methyl-5-[(3R)-pyrrolidin-3-yloxy]pyridine-2-carboxamide HCl salt :

[0352] To a 100 mL round bottom flask was added tert-butyl (3R)-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate (3.80 g, crude, containing TPPO) and HCl (gas) in 1,4-dioxane (40 mL) at room temperature. The resulting mixture was stirred at room temperature under air atmosphere for 1 hour. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase combi-flash chromatography. This gave N-methyl-5-[(3R)-pyrrolidin-3-yloxy]pyridine-2-carboxamide HCl salt (400 mg, crude). LC-MS: (ES+H, m / z): [M+H] + =222.0.

[0353] Step 4: 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]oxy Preparation of 1-methyl-N-methylpyridine-2-carboxamide :

[0354] To a stirred solution of N-methyl-5-[(3R)-pyrrolidin-3-yloxy]pyridine-2-carboxamide (200 mg, crude) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (120 mg, 0.53 mmol, 1.00 equiv) in ACN (5 mL) was added DIEA (348 mg, 2.69 mmol, 5.00 equiv) and KI (9 mg, 0.05 mmol, 0.10 equiv). The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was concentrated in vacuo. The crude product (700 mg) was purified by preparative HPLC, and the pure fractions were concentrated and lyophilized to give 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (106.9 mg, 48.49%). LC-MS: (ES+H, m / z): [M+H] +=407.85. 1 HNMR(300MHz,DMSO-d6)δ11.86(s,1H),8.55(d,1H),8.39(d,1H),8.24(d,1H),7.95(d,1H),7.74(s,1H),7.60(d,1H),7.48(dd,1H),5.10-5.04 (m,1H),3.74(s,2H),2.96-2.86(m,1H),2.77(d,3H),2.76-2.70(m,2H) ,2.61-2.52(m,1H),2.49-2.31(m,3H),1.88-1.77(m,1H),1.18(t,3H).

[0355] The following examples were carried out using a similar procedure as shown for Example 2:

[0356]

[0357]

[0358] Example 3

[0359]

[0360] Step 1: Preparation of ethyl 2-bromo-2-cyclopropylacetate :

[0361] At -78 ° C under nitrogen atmosphere, LDA (42.9 mL, 85.82 mmol, 1.10 equivalents, 2.0 M THF solution) was added dropwise to a stirred solution of ethyl 2-cyclopropylacetate (10.00 g, 78.02 mmol, 1.00 equivalents) in THF (100 mL). The reaction was stirred for 1 hour, then TMSCl (8.48 g, 78.02 mmol, 1.00 equivalents) was added dropwise, and the reaction was stirred for 3 hours while it was warmed to room temperature. The reaction was cooled to -78 ° C, and NBS (15.28 g, 85.82 mmol, 1.10 equivalents) was added dropwise in 50 mL THF. The reaction was then stirred for 2 hours and allowed to warm to room temperature. The reaction was monitored by LCMS. The reaction was quenched at 0 ° C by adding saturated NH4Cl (aqueous solution) (50 mL). The resulting mixture was extracted with Et2O (3 × 200 mL). The combined organic layers were washed with brine (3×200 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase combi-flash chromatography to give ethyl 2-bromo-2-cyclopropylacetate (5.00 g, 30.95%) as a yellow liquid. 1H NMR (300 MHz, chloroform-d) δ 4.25 (q, 2H), 3.58 (d, 1H), 1.65-1.55 (m, 1H), 1.31 (t, 3H), 0.92-0.76 (m, 2H), 0.61-0.53 (m, 1H), 0.48-0.40 (m, 1H).

[0362] Step 2: Preparation of ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate :

[0363] A solution of ethyl 2-bromo-2-cyclopropylacetate (5.00 g, 24.14 mmol, 1.00 equiv) and triethyl phosphite (5.22 g, 31.39 mmol, 1.30 equiv) was stirred at 130° C. under a nitrogen atmosphere for 24 hours. The residue was purified by reverse phase combi-flash chromatography to give ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate (2.40 g, 37.61%) as a yellow liquid. 1 H NMR (300MHz, chloroform-d) δ4.26-4.07(m,6H),2.19(dd,1H),1.30(dt,10H),0.71(dddd,1H),0.60(ddddd,1H),0.47-0.37(m,1H),0.24(ddtd,1H).

[0364] Step 3: 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylic acid Preparation of methyl ester :

[0365] To a stirred mixture of NaH (0.29 g, 7.14 mmol, 1.50 equiv., 60 wt%) in THF (20 mL) was added ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate (1.89 g, 7.14 mmol, 1.50 equiv.) at 0°C under nitrogen. The resulting mixture was stirred at 0°C for 10 minutes, then warmed to 40°C and stirred for 10 minutes under nitrogen. The resulting mixture was cooled to -78°C, followed by the addition of methyl 6-formyl-5-nitropyridine-3-carboxylate (1.00 g, 4.76 mmol, 1.00 equiv.) in THF (20 mL). The resulting mixture was stirred at -78°C under nitrogen for 30 minutes. The reaction was monitored by LCMS. The reaction was quenched at 0°C by the addition of saturated NH4Cl (aqueous solution) (5 mL). To the resulting mixture was added 20 mL of water and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (1×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate (700 mg, 45.93%) as a brown oil. LC-MS: (ES+H, m / z): [M+H] + =320.8.

[0366] Step 4: Preparation of ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate :

[0367] To a stirred mixture of 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylic acid methyl ester (600 mg, 1.87 mmol, 1.00 equiv) and Fe (1.04 g, 18.73 mmol, 10.00 equiv) in EtOH (10 mL) was added CaCl2 (1.24 g, 11.24 mmol, 6.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 90 ° C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (2×50 mL). The filtrate was concentrated under reduced pressure. 50 mL of water was added to the resulting mixture and extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine (2×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (200 mg, 41.34%). LC-MS: (ES+H, m / z): [M+H] + =259.0.

[0368] Step 5: Preparation of 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one :

[0369] To a stirred solution of ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (160 mg, 0.62 mmol, 1.00 equiv) was added dropwise LiAlH4 (0.50 mL, 1.23 mmol, 2.00 equiv, 2.5 M in THF) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The reaction was quenched by adding 1 M aqueous HCl (1 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridine-2-one (100 mg, 74.65%). LC-MS: (ES+H, m / z): [M+H] + =217.2.

[0370] Step 6: Preparation of 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one :

[0371] To a stirred mixture of 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (80 mg, 0.37 mmol, 1.00 equiv) and DMF (3 mg, 0.04 mmol, 0.10 equiv) in DCM (10 mL) was added dropwise SOCl2 (264 mg, 2.22 mmol, 6.00 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =235.0.

[0372] Step 7: 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]oxy Preparation of 1-methyl-N-methylpyridine-2-carboxamide :

[0373] To a stirred solution of (R)-N-methyl-5-(pyrrolidin-3-yloxy)picolinamide HCl salt (170 mg, crude) and 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one (120 mg, 0.51 mmol, 1.00 equiv) in ACN (10 mL) was added KI (8 mg, 0.05 mmol, 0.10 equiv) and DIEA (330 mg, 2.55 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. The crude product (900 mg) was purified by preparative HPLC, and the pure fractions were concentrated under reduced pressure and then lyophilized to give 5-{[(3R)-1-[(7-cyclopropyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (75.6 mg, 35.14%). LC-MS: (ES+H, m / z): [M+H] + =420.2. 1 H NMR(400MHz,DMSO-d6)δ11.89(s,1H),8.55(d,1H),8.36(d,1H),8.24(d,1H),7.94 (d,1H),7.60-7.55(m,1H),7.47(dd,1H),7.41(s,1H),5.05(m,1H),3.78-3.66(m, 2H),2.90(dd,1H),2.78(d,3H),2.76-2.67(m,2H),2.49-2.42(m,1H),2.41-2.30( m,1H),2.18-2.12(m,1H),1.86-1.78(m,1H),0.99-0.94(m,2H),0.86-0.77(m,2H).

[0374] The following examples were carried out using a similar procedure as shown for Example 3:

[0375]

[0376] Example 4

[0377]

[0378] Step 1: Preparation of 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylic acid :

[0379] At 0 ° C, to the stirred mixture of 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylic acid methyl ester (16.00g, 1.00 equivalents, crude) in MeOH (160mL), LiOH in H2O solution (50mL, 2M) was added dropwise. The mixture was stirred at 25 ° C under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The reaction mixture was diluted with H2O (50mL), and the aqueous phase was extracted with EA (100mL*3). The aqueous phase was then adjusted to pH 5-6 with H3PO4 and extracted with EA (100mL*3). The combined organic layer was washed with brine (100mL), dried over sodium sulfate, filtered and concentrated in vacuo. 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylic acid (6g, crude) was obtained by vacuum concentration as a white oil. LC-MS: (ES+H, m / z): [M+H] + =309.2.

[0380] Step 2: Preparation of tert-butyl (3R)-3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate preparation :

[0381] To a mixture of 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylic acid (2.00 g, 6.49 mmol, 1.00 equiv), aminocyclopropane (444 mg, 7.78 mmol, 1.20 equiv) and DIEA (3.35 g, 25.94 mmol, 4.00 equiv) in DCM (20 mL) was added T3P (16.52 g, 25.94 mmol, 4.00 equiv, 50 wt % solution in EA) dropwise at 0°C under a nitrogen atmosphere. The mixture was stirred at 25°C for 1 hour. The reaction was monitored by LCMS. The reaction mixture was diluted with H2O (50 mL) and extracted with EA (100 mL*3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Concentration in vacuo afforded tert-butyl (3R)-3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate (1.5 g, crude product) as an orange oil. LC-MS: (ES+H, m / z): [M+H] + =348.2

[0382] Step 3: Preparation of N-cyclopropyl-5-[(3R)-pyrrolidin-3-yloxy]pyridine-2-carboxamide :

[0383] A mixture of (3R)-3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylic acid tert-butyl ester (2.00 g, 5.76 mmol, 1.00 equiv) and HCl (gas) in 1,4-dioxane (10 mL, 4 M) in MeOH (10 mL) was stirred at 25 ° C under nitrogen atmosphere for 30 minutes. The reaction was monitored by LCMS. The solvent was removed under reduced pressure. The crude product was purified by reverse mixed phase flash to give N-cyclopropyl-5-[(3R)-pyrrolidin-3-yloxy]pyridine-2-carboxamide (900 mg, 63.22%) as an off-white oil. LC-MS: (ES+H, m / z): [M+H] + =248.0

[0384] Step 4: N-cyclopropyl-5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrole Preparation of 3-alkyl]oxy}pyridine-2-carboxamide :

[0385] A mixture of 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (120 mg, 0.54 mmol, 1.00 equiv), N-cyclopropyl-5-[(3R)-pyrrolidin-3-yloxy]pyridine-2-carboxamide (159 mg, 0.65 mmol, 1.20 equiv), DIEA (208 mg, 1.62 mmol, 3.00 equiv) and KI (9 mg, 0.05 mmol, 0.10 equiv) in MeCN (5 mL) was stirred at 80 °C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC. The pure fractions were concentrated and lyophilized to give N-cyclopropyl-5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]oxy}pyridine-2-carboxamide (121 mg, 51.79%). LC-MS: (ES+H, m / z): [M+H] + =434.2. 1 H NMR(400MHz,DMSO-d6)δ11.83(s,1H),8.49(d,1H),8.39(d,1H),8.21(d,1H),7.94(d,1H),7.74(s,1H),7.60(d,1H),7.47(dd,1H),5.05(m ,1H),3.73(s,2H),2.87(ddt,2H),2.74(dd,2H),2.59-2.52(m,2H),2.49-2.32(m,2H),1.86-1.78(m,1H),1.18(t,3H),0.72-0.59(m,4H).

[0386] Example 5

[0387]

[0388] Step 1: 5-{[(3R,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyridine-2-carboxylic acid methyl Preparation of esters :

[0389] To a stirred solution of methyl 5-hydroxypyridine-2-carboxylate (0.30 g, 1.95 mmol, 1.00 equiv), (3R, 4S)-3-fluoro-4-hydroxypyrrolidine-1-carboxylate (0.40 g, 1.96 mmol, 1.00 equiv) and PPh3 (1.03 g, 3.91 mmol, 2.00 equiv) in toluene (10 mL) was added dropwise a solution of DBAD (0.90 g, 3.91 mmol, 2.00 equiv) in toluene (5 mL) at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred at 60 ° C for 3 hours. The reaction was monitored by LCMS. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were concentrated under reduced pressure to give methyl 5-{[(3R,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyridine-2-carboxylate (2.00 g, crude product). The resulting mixture was used directly in the next step. LC-MS: (ES+H, m / z): [M+H] + =341.2.

[0390] Step 2: (3R,4R)-3-fluoro-4-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylic acid tert- Preparation of Butyl Ester :

[0391] A solution of methyl 5-{[(3R,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyrrolidine-2-carboxylate (1.00 g, crude) and methylamine (4.0 mL, 25% aqueous solution) in MeOH (4.0 mL) was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure to give tert-butyl (3R,4R)-3-fluoro-4-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate (1.00 g, crude). The crude product was used directly in the next step. LC-MS: (ES+H, m / z): [M+H] + =340.2.

[0392] Step 3: Preparation of 5-{[(3R,4R)-4-fluoropyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide HCl salt Preparation :

[0393] A solution of (3R, 4R)-3-fluoro-4-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g, crude) and HCl (gas) in 1,4-dioxane (8 mL, 4M) was stirred at room temperature for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The product was precipitated by adding EtOAc (10 mL). The precipitated solid was collected by filtration and washed with PE (3×10 mL) to give 5-{[(3R, 4R)-4-fluoropyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide HCl salt (400 mg, crude). LC-MS: (ES+H, m / z): [M+H] + =240.2.

[0394] Step 4: 5-{[(3R,4R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-4-fluoropyrrole Preparation of alkyl-3-yl]oxy}-N-methylpyridine-2-carboxamide :

[0395] To a stirred solution of 5-{[(3R,4R)-4-fluoropyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide HCl salt (400 mg, crude) and DIEA (290 mg, 2.24 mmol, 5.00 equiv) in MeCN (5 mL) was added KI (15 mg, 0.09 mmol, 0.20 equiv) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (100 mg, 0.44 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-{[(3R,4R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-4-fluoropyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (56.80 mg, 28.98%). LC-MS: (ES+H, m / z): [M+H] + =426.1.Optical rotation[a] 25 D (c=0.5,MeOH):+1.8°; 1 H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.59(d,1H),8.45-8.25(m,2H),7.99(d,1H),7.75(s,1H),7.65-7.44(m,2H), 5.28-5.11(m,2H),3.79(t,2H),3.43-3.33(m,1H),2.94-2.88(m,2H),2.79(d,3H),2.55-2.08(m,3H),1.18(t,3H). 19F NMR(377MHz,DMSO-d6)δ-179.44.

[0396] Example 6

[0397]

[0398] Step 1: Methyl 5-(((3S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)picolinate Preparation :

[0399] To a stirred mixture of methyl 5-hydroxypyridine-2-carboxylate (300 mg, 1.96 mmol, 1.00 equiv), tert-butyl (3S, 4R)-3-fluoro-4-hydroxypyrrolidine-1-carboxylate (402 mg, 1.96 mmol, 1.00 equiv) and PPh3 (1.03 g, 3.92 mmol, 2.00 equiv) in toluene (50 mL) was added DBAD (902 mg, 3.92 mmol, 2.00 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 60°C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture methyl 5-{[(3S, 4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyridine-2-carboxylate (4 g, crude) was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =341.1.

[0400] Step 2: tert-(3S,4S)-3-fluoro-4-((6-(methylcarbamoyl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylic acid Preparation of Butyl Ester :

[0401] Methylamine (5 mL, 25 wt %-30 wt %) was added dropwise to a stirred solution of 5-{[(3S, 4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyridine-2-carboxylic acid methyl ester (4 g, crude) in MeOH (5 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with saturated NH4Cl (aqueous solution) (100 mL). The resulting mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl (3S, 4S)-3-fluoro-4-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate (2.7 g, crude). LC-MS: (ES+H, m / z): [M+H] + =340.2.

[0402] Step 3: Preparation of 5-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpicolinamide HCl salt :

[0403] To a stirred solution of (3S,4S)-3-fluoro-4-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylic acid tert-butyl ester (2.7 g, crude) in DCM (20 mL) was added a solution of HCl (gas) in 1,4-dioxane (5 mL, 4 M) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (3×20 mL). The precipitated solid was collected by filtration and washed with EtOAc (3×10 mL). This gave 5-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpicolinamide HCl salt (1 g, crude). LC-MS: (ES+H, m / z): [M+H] + =240.2

[0404] Step 4: 5-(((3S,4S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-4-fluoro Preparation of pyrrolidin-3-yl)oxy)-N-methylpicolinamide :

[0405] To a stirred mixture of 5-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpicolinamide HCl salt (322 mg, crude) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (150 mg, 0.67 mmol, 1.00 equiv) in MeCN (10 mL) was added KI (22 mg, 0.14 mmol, 0.20 equiv) and DIEA (435 mg, 3.37 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC. The pure fractions were concentrated and lyophilized to give 5-(((3S,4S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpicolinamide (91.6 mg, 31.81%). LC-MS: (ES+H, m / z): [M+H] + =426.2.Optical rotation[a] 25 D (c=0.5,MeOH):+0.4°; 1H NMR (400MHz, DMSO-d6) δ11.88(s,1H),8.59(q,1H),8.39(d,1H),8.31(d,1H),7.99(d,1H),7.75(s,1H),7.60(d,1H),7.54( dd,1H),5.36-5.00(m,2H),3.84-3.72(m,2H),3.36(d,1H),3.00-2.85(m,2H),2.79(d,3H),2.58-2.52(m,3H),1.18(t,3H). 19 FNMR(377MHz,DMSO-d6)δ-179.43.

[0406] Example 7

[0407]

[0408] Step 1: Preparation of 5-bromo-3-nitropyridine aldehyde :

[0409] A mixture of 5-bromo-2-methyl-3-nitropyridine (20.00 g, 92.16 mmol, 1.00 equiv) and SeO2 (51.13 g, 460.79 mmol, 5.00 equiv) in dioxane (300 mL) was stirred overnight at 110 ° C under a nitrogen atmosphere. The desired product can be detected by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (3×400 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with THF (3×300 mL). The resulting mixture was concentrated under reduced pressure to give 5-bromo-3-nitropyridine aldehyde (21 g, crude product). 1 H NMR (400MHz, DMSO-d6) δ10.08(s,1H),9.22(d,1H),8.95(d,1H).

[0410] Step 2: Preparation of ethyl (2Z)-3-(5-bromo-3-nitropyridin-2-yl)-2-methylprop-2-enoate :

[0411] To a stirred mixture of NaH (4.93 g, 123.37 mmol, 1.50 equiv., 60 wt. %) in THF (250 mL) was added ethyl 2-(diethoxyphosphoryl)propionate (29.39 g, 123.37 mmol, 1.50 equiv.) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 15 minutes and at 40°C for 30 minutes. A solution of 5-bromo-3-nitropyridine-2-carboxaldehyde (19.00 g, 82.25 mmol, 1.00 equiv.) in THF (50 mL) was added dropwise at -78°C within 30 minutes. The resulting mixture was stirred at -78°C for another hour. The desired product can be detected by LCMS. The reaction was quenched at 0°C with saturated NH4Cl (aqueous solution). Water (600 mL) was added to the resulting mixture and extracted with EtOAc (3×600 mL). The combined organic layers were washed with brine (2×300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography to give (2Z)-3-(5-bromo-3-nitropyridin-2-yl)-2-methylprop-2-enoic acid ethyl ester (13.20 g, 51%). LC-MS: (ES+H, m / z): [M+H] + =315 / 317. 1 H NMR (300 MHz, chloroform-d) δ 8.96 (d, 1H), 8.50 (d, 1H), 7.85 (q, 1H), 4.32 (q, 2H), 2.17 (d, 3H), 1.38 (t, 3H).

[0412] Step 3: Preparation of 7-bromo-3-methyl-1H-1,5-naphthyridin-2-one :

[0413] To a stirred mixture of (2Z)-3-(5-bromo-3-nitropyridin-2-yl)-2-methylprop-2-enoic acid ethyl ester (7.60 g, 24.12 mmol, 1.00 equiv) and Fe (8.08 g, 144.71 mmol, 6.00 equiv) in EtOH (200 ml) was added CaCl2 (16.06 g, 144.71 mmol, 6.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90°C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography. The resulting mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with water (3×10 mL). The resulting mixture was concentrated under reduced pressure. This gave 7-bromo-3-methyl-1H-1,5-naphthyridine-2-one (5.00 g, 87%). LC-MS: (ES+H, m / z): [M+H] + =239 / 241. 1H NMR (300MHz, DMSO-d6) δ11.96(s,1H),8.52(d,1H),7.86-7.78(m,2H),2.13(d,3H).

[0414] Step 4: Preparation of ethyl 7-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate

[0415] To a mixture of 7-bromo-3-methyl-1H-1,5-naphthyridin-2-one (5.00 g, 20.91 mmol, 1.00 equiv) and Pd(PPh3)2Cl2 (1.47 g, 2.09 mmol, 0.10 equiv) in EtOH (100 ml) was added NEt3 (6.35 g, 62.74 mmol, 3.00 equiv). The resulting mixture was stirred overnight at 100°C under a carbon monoxide atmosphere (30 atm). The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The resulting mixture was concentrated under reduced pressure. This gave ethyl 7-methyl-6-oxo-5H-1,5-naphthyridin-3-carboxylate (4.5 g, 93%). LC-MS: (ES+H, m / z): [M+H] + =233. 1 H NMR (300MHz, DMSO-d6) δ12.06(s,1H),8.88(d,1H),8.15(dd,1H),7.94-7.87(m,1H),4.38(q,2H),2.18(d,3H),1.35(t,3H).

[0416] Step 5: Preparation of 7-(hydroxymethyl)-3-methyl-1H-1,5-naphthyridin-2-one :

[0417] To a stirred solution of ethyl 7-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (4.50 g, 19.38 mmol, 1.00 equiv) in THF (100 mL) was added dropwise LiAlH4 (15.5 mL, 38.75 mmol, 2.00 equiv, 2.5 M in THF) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The reaction was quenched by adding aqueous HCl (20 ml, 1 M) at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The resulting mixture was concentrated under reduced pressure. This gave 7-(hydroxymethyl)-3-methyl-1H-1,5-naphthyridine-2-one (2 g, 54%). LC-MS: (ES+H, m / z): [M+H] + =191.1. 1H NMR (300MHz, DMSO-d6) δ11.91(s,1H),8.37(d,1H),7.82(s,1H),7.61(s,1H),5.46(t,1H),4.62(d,2H),2.17-2.10(m,3H).

[0418] Step 6: Preparation of 7-(chloromethyl)-3-methyl-1H-1,5-naphthyridin-2-one :

[0419] To a stirred mixture of 7-(hydroxymethyl)-3-methyl-1H-1,5-naphthyridin-2-one (250 mg, 1.31 mmol, 1.00 equiv) and DMF (10 mg, 0.13 mmol, 0.10 equiv) in DCM (5 mL) was added dropwise SOCl2 (0.6 mL, 7.88 mmol, 6.00 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. The reaction was monitored by LCMS. The desired product can be detected by LCMS. The resulting mixture was concentrated under reduced pressure. This gave 7-(chloromethyl)-3-methyl-1H-1,5-naphthyridin-2-one (310 mg, crude). The crude product mixture was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =209.0

[0420] Step 7: N-cyclopropyl-5-{[(3R)-1-[(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrole Preparation of 3-alkyl]oxy}pyridine-2-carboxamide :

[0421] A mixture of N-cyclopropyl-5-[(3R)-pyrrolidin-3-yloxy]pyridine-2-carboxamide (170 mg, 0.69 mmol, 1.20 equiv), 7-(chloromethyl)-3-methyl-1H-1,5-naphthyridin-2-one (120 mg, 0.58 mmol, 1.00 equiv), DIEA (223 mg, 1.73 mmol, 3.00 equiv) and KI (9.55 mg, 0.06 mmol, 0.10 equiv) in MeCN (5 mL) was stirred at 80 °C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC. The pure fractions were concentrated and lyophilized to give N-cyclopropyl-5-{[(3R)-1-[(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]oxy}pyridine-2-carboxamide (125.3 mg, 51.94%). LC-MS: (ES+H, m / z): [M+H] + =420.2. 1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),8.49(d,1H),8.38(d,1H),8.21(d,1H),7.94(d,1H),7.84-7.79(m,1H),7.59(d,1H),7.4 7(dd,1H),5.05(m,1H),3.72(d,2H),2.95-2.67(m,4H),2.48-2.31(m,2H),2.13(d,3H),1.87-1.77(m,1H),0.72-0.58(m,4H).

[0422] The following examples were carried out using a similar procedure as shown for Example 7:

[0423]

[0424]

[0425] Example 8

[0426]

[0427] Step 1: 5-{[(3R,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyridine-2-carboxylic acid methyl Preparation of esters :

[0428] To a stirred mixture of (3S,4S)-3-fluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.44 mmol, 1.00 equiv) and 5-hydroxypyridine-2-carboxylic acid methyl ester (373 mg, 2.44 mmol, 1.00 equiv) and PPh3 (1.34 g, 5.12 mmol, 2.10 equiv) in tetrahydrofuran (10 mL) was added dropwise a solution of DBAD (1.12 g, 4.87 mmol, 2.00 equiv) in THF (5 mL) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 60°C under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with ethyl acetate (100 mL). The resulting mixture was washed with water (2×30 mL). The organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo to give methyl 5-{[(3R,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyridine-2-carboxylate (2 g, crude product). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =341.1.

[0429] Step 2: (3S,4R)-3-fluoro-4-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylic acid tert- Preparation of Butyl Ester :

[0430] To a stirred solution of 5-{[(3R,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyridine-2-carboxylic acid methyl ester (2 g, crude) in CH3OH (7 mL) was added dropwise an aqueous solution of CH3NH2 (7 mL, 25 wt%-30 wt%) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with ethyl acetate (100 mL). The residue was washed with NH4Cl (aqueous solution) (2×30 mL). The organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The crude product (3S,4R)-3-fluoro-4-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylic acid tert-butyl ester (2 g; crude) was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =340.1.

[0431] Step 3: Preparation of 5-{[(3R,4S)-4-fluoropyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide HCl salt Preparation :

[0432] To a stirred solution of (3S,4R)-3-fluoro-4-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, crude) in CH2Cl2 (5 mL) was added dropwise a solution of HCl in dioxane (8 mL, 4 M) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with ether / n-hexane (3×10 mL). The resulting mixture was concentrated in vacuo. The crude product 5-{[(3R,4S)-4-fluoropyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide HCl salt (0.8 g, crude) was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =240.2.

[0433] Step 4: 5-{[(3R,4S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-4-fluoropyrrole Preparation of alkyl-3-yl]oxy}-N-methylpyridine-2-carboxamide :

[0434] To a stirred mixture of 5-{[(3R,4S)-4-fluoropyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (160 mg, 0.67 mmol, 1.00 equiv) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one HCl salt (300 mg, crude) in acetonitrile (6 mL) was added KI (56 mg, 0.34 mmol, 0.50 equiv) and DIEA (432 mg, 3.35 mmol, 5.00 equiv) dropwise at room temperature. The resulting mixture was stirred at 80 ° C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The residue was purified by silica gel column chromatography. Afterwards, the residue was purified by preparative HPLC chromatography. The pure fractions were concentrated and lyophilized to give 5-{[(3R,4S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-4-fluoropyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (36.0 mg, 12.55%). LC-MS: (ES+H, m / z): [M+H] + =426.05.Optical rotation[a] 25 D (c=0.5, MeOH): -17°; 1 H NMR(300MHz,DMSO-d6)δ11.88(s,1H),8.58-8.56(m,1H),8.40-8.37(dd,2H),7.98-7.95(d,1H),7.75(s,1H),7.65-7.61(m,2H),5.51-5.33( m,1H),5.15-5.05(m,1H),3.85-3.75(m,2H),3.08-2.94(m,2H),2.92- 2.84(m,2H),2.80-2.79(d,3H),2.58-2.51(m,2H),1.23-1.16(t,3H). 19 F NMR(282MHz,DMSO-d6)δ-195.59.

[0435] Example 9

[0436]

[0437] Step 1: 5-{[(3S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyridine-2-carboxylic acid methyl Preparation of esters :

[0438] To a stirred mixture of methyl 5-hydroxypyridine-2-carboxylate (373 mg, 2.44 mmol, 1.00 equiv), PPh3 (1.28 g, 4.87 mmol, 2.00 equiv) and tert-butyl (3R, 4R)-3-fluoro-4-hydroxypyrrolidine-1-carboxylate (500 mg, 2.44 mmol, 1.00 equiv) in toluene (10 mL) was added DBAD (1.12 g, 4.87 mmol, 2.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at 60°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (30 mL). The mixture was washed with saturated NaHCO3 (1×20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain methyl 5-{[(3S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyridine-2-carboxylate (3.5 g, crude product). LC-MS: (ES+H, m / z): [M+H] + =341.2.

[0439] Step 2: tert-(3R,4S)-3-fluoro-4-((6-(methylcarbamoyl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylic acid Preparation of Butyl Ester :

[0440] To a stirred mixture of methyl 5-(((3S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)picolinate (3.5 g, crude) in MeOH (30 mL) was added methylamine (10 mL, 25 wt%-30 wt% in water) at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. Saturated NH4Cl (50 mL) was added to the resulting mixture and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (1×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl (3R,4S)-3-fluoro-4-((6-(methylcarbamoyl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate (2.2 g, crude). LC-MS: (ES+H, m / z): [M+H] + =340.2.

[0441] Step 3: Preparation of 5-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpicolinamide HCl salt :

[0442] To a stirred solution of (3R,4S)-3-fluoro-4-((6-(methylcarbamoyl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (2.2 g, crude) in DCM (20 mL) was added dropwise a solution of HCl (gas) in 1,4-dioxane (10 mL, 4 M) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with DCM (20 mL). The precipitated solid was collected by filtration and washed with hexanes (3×5 mL). The precipitated solid was concentrated under reduced pressure to give 5-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpicolinamide HCl salt (750 mg, 82.98%). LC-MS: (ES+H, m / z): [M+H] + =240.0.

[0443] Step 4: 5-(((3S,4R)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-4-fluoro Preparation of pyrrolidin-3-yl)oxy)-N-methylpicolinamide :

[0444] To a stirred mixture of 5-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpicolinamide HCl salt (300 mg, crude) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (200 mg, 0.90 mmol, 1.00 equiv) in ACN (6 mL) was added DIEA (580 mg, 4.49 mmol, 5.00 equiv) and KI (15 mg, 0.09 mmol, 0.10 equiv) at room temperature. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The reaction mixture was poured into water (50 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 / i-PrOH (3 / 1, 3×50 mL). The combined organic layers were washed with brine (1×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC, and the pure fractions were concentrated and then lyophilized to give 5-(((3S,4R)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpicolinamide (49.5 mg, 10.76%). LC-MS: (ES+H, m / z): [M+H] + =426.1.Optical rotation[a] 25 D (c=0.5, MeOH):+19°; 1H NMR(300MHz,DMSO-d6)δ11.88(s,1H),8.57(q,1H),8.41(d,1H),8.34(d,1H),7.96(d,1H),7.75(d,1H),7.63(dd,2H),5.57-5.26 (m,1H),5.18-5.03(m,1H),3.88-3.71(m,2H),3.10-2.95(m,2H),2.94-2.83(m,2H),2.79(d,3H),2.61-2.52(m,2H),1.18(t,3H). 19 FNMR(282MHz,DMSO-d6)δ-195.59.

[0445] Example 10

[0446]

[0447] Step 1: (3R)-3-({6-[(2,2-difluoroethyl)carbamoyl]pyridin-3-yl}oxy)pyrrolidine-1-carboxylic acid Preparation of tert-butyl ester :

[0448] To a stirred mixture of 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylic acid (1.00 g, 3.24 mmol, 1.00 equiv), 2,2-difluoroethylamine (0.29 g, 3.57 mmol, 1.10 equiv) and DIEA (2.10 g, 16.22 mmol, 5.00 equiv) in DCM (28 mL) was added T3P (6.19 g, 9.73 mmol, 3.00 equiv, 50 wt % solution in EA) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine (1×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (3R)-3-({6-[(2,2-difluoroethyl)carbamoyl]pyridin-3-yl}oxy)pyrrolidine-1-carboxylate (310 mg, 25.74%) as an off-white oil. LC-MS: (ES+H, m / z): [M+Ht-Bu] + =316.0. 1H NMR(300MHz,DMSO-d6)δ8.97-8.84(t,1H),8.39-8.27(m,1H),8.02(d,1H),7.62-7 .58(m,1H),6.29-5.78(m,1H),3.74-3.34(m,8H),2.20-2.03(m,1H),1.40(d,9H).

[0449] Step 2: Preparation of TFA salt of N-(2,2-difluoroethyl)-5-[(3R)-pyrrolidin-3-yloxy]pyridine-2-carboxamide Preparation :

[0450] To a stirred solution of (3R)-tert-butyl 3-({6-[(2,2-difluoroethyl)carbamoyl]pyridin-3-yl}oxy)pyrrolidine-1-carboxylate (230 mg, 0.62 mmol, 1.00 equiv) in DCM (6 mL) was added TFA (2 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0451] LC-MS: (ES+H, m / z): [M+H] + =272.2.

[0452] Step 3: N-(2,2-difluoroethyl)-5-{[(3R)-1-[(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl Preparation of pyrrolidin-3-yl]oxy}pyridine-2-carboxamide :

[0453] To a stirred solution of N-(2,2-difluoroethyl)-5-[(3R)-pyrrolidin-3-yloxy]pyridine-2-carboxamide TFA salt (168 mg, crude) and 7-(chloromethyl)-3-methyl-1H-1,5-naphthyridin-2-one (142 mg, 0.68 mmol, 1.0 equiv) in MeCN (10 mL) was added KI (22 mg, 0.14 mmol, 0.20 equiv) and DIEA (440 mg, 3.40 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the pure fractions were concentrated and then lyophilized to give N-(2,2-difluoroethyl)-5-{[(3R)-1-[(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]oxy}pyridine-2-carboxamide (82.1 mg, 29.75%). LC-MS: (ES+H, m / z): [M+H] + =444.0. 1HNMR(300MHz,DMSO-d6)δ11.87(s,1H),8.86(t,1H),8.39(d,1H),8.29(d,1H),7.98(d,1H),7.85-7.79(m,1H),7.62-7.55(m,1H),7.51(dd, 1H),6.40-5.85(m,1H),5.08(s,1H),3.81-3.58(m,4H),2.92(dd,1H), 2.83-2.68(q,2H),2.48-2.25(m,2H),2.14(d,3H),1.74-1.88(m,1H). 19 F NMR(282MHz,DMSO-d6)δ-122.05

[0454] Embodiment 11

[0455]

[0456] Step 1: 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl](methyl)amino}pyridine-2-carboxylic acid methyl ester Preparation :

[0457] A mixture of methyl 5-bromopyridine-2-carboxylate (800 mg, 3.70 mmol, 1.00 equiv), tert-butyl (3R)-3-(methylamino)pyrrolidine-1-carboxylate (890 mg, 4.44 mmol, 1.20 equiv), Cs2CO3 (2.41 g, 7.41 mmol, 2.00 equiv) and RuPhos Palladacycle Gen.3 (310 mg, 0.37 mmol, 0.10 equiv) in 1,4-dioxane (10 mL) was stirred at 110 °C under nitrogen atmosphere overnight. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (20 mL). The resulting mixture was filtered and the filter cake was washed with EtOAc (3×20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl](methyl)amino}pyridine-2-carboxylate (488 mg, 39.29%). LC-MS: (ES+H, m / z): [M+H] + =336.25. 1 H NMR(400MHz,DMSO-d6)δ8.30(d,1H),7.86(d,1H),7.26(dd,1H),4.79-4.6(m,1H),3.8 0(s,3H),3.58-3.40(m,2H),3.24-3.20(m,2H),2.89(s,3H),2.04(d,2H),1.41(s,9H).

[0458] Step 2: (3R)-tert-butyl 3-{methyl[6-(methylcarbamoyl)pyridin-3-yl]amino}pyrrolidine-1-carboxylate Preparation :

[0459] A mixture of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl](methyl)amino}pyrrolidine-2-carboxylate (488 mg, 1.46 mmol, 1.00 equiv) in MeOH (6 mL) and aqueous methylamine (3 mL, 25 wt%-30 wt%) was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo to give tert-butyl (3R)-3-{methyl[6-(methylcarbamoyl)pyridin-3-yl]amino}pyrrolidine-1-carboxylate (450 mg, 92.48%). LC-MS: (ES+H, m / z): [M+H] + =335.2. 1 H NMR(400MHz,DMSO-d6)δ8.34(d,1H),8.18(d,1H),7.81(d,1H),7.31(dd,1H),4.70-4.62(m,1H) 3.57-3.39(m,3H),3.24-3.20(m,1H),2.87(d,3H),2.78(d.3H),2.05-2.02(m,2H),1.41(s,9H).

[0460] Step 3: Preparation of N-methyl-5-[methyl((3R)-pyrrolidin-3-yl)amino]pyridine-2-carboxamide HCl salt :

[0461] A mixture of (3R)-3-{methyl[6-(methylcarbamoyl)pyridin-3-yl]amino}pyrrolidine-1-carboxylic acid tert-butyl ester (450 mg, 1.35 mmol, 1.00 equiv) in HCl(g) in 1,4-dioxane (5 mL, 4M) was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo to give N-methyl-5-[methyl((3R)-pyrrolidin-3-yl)amino]pyridine-2-carboxamide HCl salt (300 mg, crude). LC-MS: (ES+H, m / z): [M+H] + =235.2.

[0462] Step 4: 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl] Preparation of (methyl)amino}-N-methylpyridine-2-carboxamide :

[0463] A mixture of N-methyl-5-[methyl((3R)-pyrrolidin-3-yl)amino]pyridine-2-carboxamide HCl salt (237 mg, 1.01 mmol, 1.5 equiv), 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (150 mg, 0.67 mmol, 1.00 equiv), KI (20 mg, 0.12 mmol, 0.18 equiv) and DIEA (261 mg, 2.02 mmol, 3.00 equiv) in ACN (6 mL) was stirred at 80 °C under nitrogen atmosphere for 1 hour. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (15 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC, and the pure fractions were concentrated under reduced pressure and then lyophilized to give 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl](methyl)amino}-N-methylpyridine-2-carboxamide (78.7 mg, 27.78%). LC-MS: (ES+H, m / z): [M+H] + =421.15.Optical rotation[a] 25 D (c=0.5,MeOH):+6.6°; 1 H NMR(300MHz,DMSO-d6)δ11.90(s,1H),8.41(d,1H),8.30(d,1H),8.11(d,1H ),7.88-7.71(m,2H),7.63(d,1H),7.23(dd,1H),4.63-4.61(m,1H),3.79(d, 1H),3.64(d,1H),2.96(s,3H),2.93-2.85(m,1H),2.77(d,3H),2.74-2.68(m ,1H),2.61-2.52(m,3H),2.43-2.13(m,2H),1.92-1.60(m,1H),1.18(t,3H).

[0464] Example 12

[0465]

[0466] Step 1: 5-{[(3R)-1-(tert-butoxycarbonyl)-3-methylpyrrolidin-3-yl]oxy}pyridine-2-carboxylic acid methyl Preparation of esters :

[0467] To a stirred mixture of NaH (139 mg, 3.47 mmol, 1.4 eq., 60 wt%) in DMF (10 mL) was added a solution of (3R)-3-hydroxy-3-methylpyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.48 mmol, 1.00 eq.) in DMF (1 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. To the above mixture was added 5-fluoropyridine-2-carboxylic acid methyl ester (462 mg, 2.98 mmol, 1.20 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with MeOH at 0°C. The residue was purified by reverse combi-flash chromatography to give methyl 5-{[(3R)-1-(tert-butoxycarbonyl)-3-methylpyrrolidin-3-yl]oxy}pyridine-2-carboxylate (310 mg, 37.10%). LC-MS: (ES+H, m / z): [M+H] + =337.2.Optical rotation[a] 25 D (c=0.5, MeOH): -23.9°; 1 H NMR(400MHz,DMSO-d6)δ8.35(d,1H),8.01(dd,1H),7.62(dd,1H),3.85(s,3H),3.68( dd,1H),3.33(m,2H),2.32-2.28(m,1H),2.14-1.99(m,2H),1.55(s,3H),1.38(d,9H).

[0468] Step 2: (3R)-3-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylic acid tert- Preparation of Butyl Ester :

[0469] A mixture of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)-3-methylpyrrolidin-3-yl]oxy}pyridine-2-carboxylate (337 mg, 1.00 mmol, 1.00 equiv) and CH3NH2 (5 mL, 25 wt%-30 wt% in water) in CH3OH (5 mL) was stirred at room temperature for 2 hours under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with CH2Cl2 (3×30 mL). The combined organic layers were washed with brine (3×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl (3R)-3-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate (319 mg, 95.23%). LC-MS: (ES+H, m / z): [M+H] + =336.2.

[0470] Step 3: Preparation of N-methyl-5-{[(3R)-3-methylpyrrolidin-3-yl]oxy}pyridine-2-carboxamide HCl salt Preparation :

[0471] To a stirred solution of (3R)-3-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 0.89 mmol, 1.00 equiv) in DCM (5 mL) was added dropwise a solution of HCl (gas) in 1,4-dioxane (2.5 mL, 4 M) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 minutes under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with diethyl ether (20 mL) to give N-methyl-5-{[(3R)-3-methylpyrrolidin-3-yl]oxy}pyridine-2-carboxamide HCl salt (230 mg, 94.62%). LC-MS: (ES+H, m / z): [M+H] + =236.2.

[0472] Step 4: 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-3-methylpyrrolidine- Preparation of 3-amino-1-[3-yl]oxy]-N-methylpyridine-2-carboxamide :

[0473] A mixture of N-methyl-5-{[(3R)-3-methylpyrrolidin-3-yl]oxy}pyridine-2-carboxamide HCl salt (205 mg, 0.75 mmol, 1.00 equiv), 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (218 mg, 0.98 mmol, 1.30 equiv), DIEA (488 mg, 3.77 mmol, 5.00 equiv) and KI (25 mg, 0.15 mmol, 0.20 equiv) in ACN (5 mL) was stirred at 80 ° C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with water (30 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the pure fractions were concentrated and then lyophilized to give 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-3-methylpyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (140 mg, 44.03%). LC-MS: (ES+H, m / z): [M+H] + =422.10.Optical rotation[a] 25 D (c=0.5, MeOH): -21.6°; 1H NMR(300MHz,DMSO-d6)δ11.88(s,1H),8.55(d,1H),8.39(d,1H),8.22(dd,1H),7.95(dd,1H),7.75(s,1H),7.65-7.54(m,2H),3.73(s,2H ),2.96(d,1H),2.82-2.76(m,4H),2.75-2.67(m,1H),2.68-2.53(m,3H),2.33-2.21(m,1H),2.13-1.99(m,1H),1.55(s,3H),1.19(t,3H).

[0474] The following examples were carried out using a similar procedure as shown for Example 12:

[0475]

[0476] Example 13

[0477]

[0478] Step 1: Preparation of tert-butyl (3R)-3-(bromomethyl)pyrrolidine-1-carboxylate :

[0479] To a stirred mixture of (3R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (3.00 g, 14.91 mmol, 1.00 equiv) and CBr4 (7.41 g, 22.34 mmol, 1.50 equiv) in DCM (20 mL) was added dropwise a solution of PPh3 (3.91 g, 14.91 mmol, 1.00 equiv) in DCM (5 mL) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The results were analyzed by TLC (PE:EA=3:1, R f =0.4) to monitor the reaction. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (3R)-3-(bromomethyl)pyrrolidine-1-carboxylate (2.5 g, 63.4%). 1 HNMR (300 MHz, chloroform-d) δ 3.70-3.66 (m, 1H), 3.59-3.52 (m, 1H), 3.49-3.48 (m, 1H), 3.48-3.34 (m, 2H), 3.21-3.14 (m, 1H), 2.75-2.60 (m, 1H), 2.18-2.10 (m, 1H), 1.90-1.70 (m, 1H), 1.54 (s, 9H).

[0480] Step 2: Preparation of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]methyl}pyridine-2-carboxylate Preparation :

[0481] A mixture of 1,2-dimethoxyethane nickel dihydrochloride (25 mg, 0.11 mmol, 0.10 equiv) and 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine (31 mg, 0.11 mmol, 0.10 equiv) in DME (3 mL) was stirred at room temperature under nitrogen atmosphere for 1 hour. At room temperature under nitrogen atmosphere, the nickel mixture was added to a mixture of (3R)-3-(bromomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 1.14 mmol, 1.00 equiv), 5-bromopyridine-2-carboxylic acid methyl ester (245 mg, 1.14 mmol, 1.00 equiv), tris(trimethylsilyl)silane (282 mg, 1.14 mmol, 1.00 equiv), Cs2CO3 (740 mg, 2.27 mmol, 2.00 equiv) and Ir[dF(CF3)ppy]2(dtpby)PF6 (38 mg, 0.03 mmol, 0.03 equiv). The reaction was stirred for 2 days and irradiated with a blue LED (30 watts). The reaction was monitored by LCMS. The reactant was poured into water (20 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]methyl}pyridine-2-carboxylate (200 mg, 54.9%). LC-MS: (ES+H, m / z): [M+H] + =321.1.Optical rotation[a] 25 D (c=0.5,MeOH):+17.6°; 1 H NMR(400MHz,DMSO-d6)δ8.59(dd,1H),8.07-7.95(m,1H),7.85(dd,1H),3.87(s,3H),3.39-3.34(m,1H),3.31-3.22(m,1H) ,3.20-3.12(m,1H),2.95-2.86(m,1H),2.77(t,2H),2.50-2.40(m,1H),1.88-1.53(m,1H),1.63-1.47(m,1H),1.38(s,9H).

[0482] Step 3: Preparation of tert-butyl (3R)-3-{[6-(methylcarbamoyl)pyridin-3-yl]methyl}pyrrolidine-1-carboxylate Preparation :

[0483] To a stirred mixture of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]methyl}pyrrolidine-2-carboxylate (190 mg, 0.66 mmol, 1.00 equiv) in MeOH (2 mL) was added methylamine (2 mL, 25 wt %-30 wt % aqueous solution) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 hour at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give tert-butyl (3R)-3-{[6-(methylcarbamoyl)pyridin-3-yl]methyl}pyrrolidine-1-carboxylate (190 mg, crude product).

[0484] LC-MS: (ES+H, m / z): [M+H] + =320.3.

[0485] Step 4: Preparation of N-methyl-5-[(3R)-pyrrolidin-3-ylmethyl]pyridine-2-carboxamide HCl salt :

[0486] A mixture of (3R)-3-{[6-(methylcarbamoyl)pyridin-3-yl]methyl}pyrrolidine-1-carboxylic acid tert-butyl ester (190 mg, crude) in HCl (gas) in 1,4-dioxane (4M, 2 mL) was stirred at room temperature for 0.5 hours. The reaction was monitored by LCMS. The mixture was concentrated under reduced pressure to give N-methyl-5-[(3R)-pyrrolidin-3-ylmethyl]pyridine-2-carboxamide HCl salt (190 mg, crude). LC-MS: (ES+H, m / z): [M+H] + =220.1

[0487] Step 5: 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]methyl Preparation of 1-methyl-N-methylpyridine-2-carboxamide :

[0488] A mixture of N-methyl-5-[(3R)-pyrrolidin-3-ylmethyl]pyridine-2-carboxamide HCl salt (150 mg, crude), 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (150 mg, 0.68 mmol, 1.00 equiv), DIEA (436 mg, 3.38 mmol, 5.00 equiv) and KI (22 mg, 0.14 mmol, 0.20 equiv) in ACN (5 mL) was stirred at 80 °C under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reactant was poured into water (30 mL). The aqueous layer was extracted with EtOAc (4×20 mL). The combined organic layers were concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC, and the pure fractions were concentrated and then lyophilized to give 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]methyl}-N-methylpyridine-2-carboxamide (62.6 mg, 22.9%). LC-MS: (ES+H, m / z): [M+H] + =406.10.Optical rotation[a] 25 D (c=0.5, MeOH):+18.4°; 1 H NMR(400MHz,DMSO-d6)δ11.83(s,1H),8.69-8.66(m,1H),8.47(d,1H),8.36(d,1H),7.92(d,1H),7.81(dd,1H),7.73(s,1H),7.58(d,1H),3.74 -3.58(m,2H),2.85-2.77(m,5H),2.62-2.52(m,4H),2.50-2.46(m,2H) ,2.22-2.16(m,1H),1.93-1.80(m,1H),1.51-1.38(m,1H),1.18(t,3H).

[0489] Embodiment 14

[0490]

[0491] Step 1: Preparation of methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]amino}pyridine-2-carboxylate :

[0492] To a stirred solution of methyl 5-bromopyridine-2-carboxylate (2.00 g, 9.25 mmol, 1.00 equiv) and tert-butyl 3-aminoazetidine-1-carboxylate (1.75 g, 10.18 mmol, 1.10 equiv) in toluene (20 mL) was added XantPhos (1.07 g, 1.85 mmol, 0.20 equiv), Pd2(dba)3 (0.84 g, 0.90 mmol, 0.10 equiv) and Cs2CO3 (9.05 g, 27.77 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at 110°C under nitrogen atmosphere for 2 hours. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (1×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase combi-flash chromatography. This gave methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]amino}pyridine-2-carboxylate (1.00 g, 31.98%). LC-MS: (ES+H, m / z): [M+H] + =308.1. 1 H NMR (400MHz, DMSO-d6) δ8.00(d,1H),7.83(d,1H),7.37(d,1H),6.87(dd,1H),4.30-4.23(m,3H),3.79(m,3H),3.68(m,2H),1.39(s,9H).

[0493] Step 2: Preparation of tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]amino}azetidine-1-carboxylate Preparation :

[0494] Methylamine (5 mL, 25 wt %-30 wt % aqueous solution) was added to a stirred solution of 5-{[1-(tert-butoxycarbonyl)azetidine-3-yl]amino}pyridine-2-carboxylic acid methyl ester (500 mg, 1.62 mmol, 1.00 equiv) in MeOH (5 mL) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The desired product can be detected by LCMS. The solvent was removed under reduced pressure. The residue was purified by reverse phase combi-flash chromatography. This gave tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]amino}azetidine-1-carboxylate (500 mg, 94.30%). LC-MS: (ES+H, m / z): [M+H] + =307.1.

[0495] Step 3: Preparation of 5-(azetidin-3-ylamino)-N-methylpyridine-2-carboxamide HCl salt :

[0496] At room temperature, tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]amino}azetidine-1-carboxylate (500 mg, 1.63 mmol, 1.00 equiv) and HCl (gas) in 1,4-dioxane (10 mL) were added to a 100 mL round-bottom flask. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The desired product can be detected by LCMS. The resulting mixture was concentrated in vacuo. This gave 5-(azetidine-3-ylamino)-N-methylpyridine-2-carboxamide HCl salt (400 mg, crude product). The resulting crude mixture was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =207.2.

[0497] Step 4: 5-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidin-3-yl}amino Preparation of 2-methylpyridine-2-carboxamide :

[0498] To a stirred solution of 5-(azetidin-3-ylamino)-N-methylpyridine-2-carboxamide HCl salt (200 mg, crude) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (120 mg, 0.53 mmol, 1.00 equiv) in ACN (5 mL) was added DIEA (348 mg, 2.69 mmol, 5.00 equiv) and KI (9 mg, 0.05 mmol, 0.10 equiv) at room temperature. The resulting mixture was stirred at 80 ° C for another 2 hours. The desired product can be detected by LCMS. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC, and the pure fractions were concentrated under reduced pressure and lyophilized to give 5-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidin-3-yl}amino)-N-methylpyridine-2-carboxamide (65.6 mg, 30.30%). LC-MS: (ES+H, m / z): [M+H] + =393.2. 1 H NMR(300MHz,DMSO-d6)δ11.87(s,1H),8.36(d,1H),8.30(d,1H),7.89(d,1H),7.78-7.69(t,2H),7.56(s,1H), 7.00-6.87(m,2H),4.11(q,1H),3.75-3.64(m,4H),2.95(t,2H),2.76(d,3H),2.60-2.52(m,2H),1.18(t,3H).

[0499] Embodiment 15

[0500]

[0501] Step 1: 5-{[1-(tert-Butyloxycarbonyl)-3-methylazetidin-3-yl]oxy}pyridine-2-carboxylic acid methyl ester Preparation :

[0502] At room temperature under nitrogen atmosphere, to a stirred solution of NaH (1.08g, 27.08mmol, 1.40 equivalents, 60 wt%) in DMF (40mL) was added a DMF (5mL) solution of 3-hydroxy-3-methylazetidine-1-carboxylic acid tert-butyl ester (4.71g, 25.14mmol, 1.30 equivalents). The above mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. Then, a DMF (5mL) solution of 5-fluoropyridine-2-carboxylic acid methyl ester (3.00g, 19.34mmol, 1.00 equivalents) was added dropwise to the resulting mixture at room temperature. The resulting mixture was stirred for another 2 hours at room temperature. The reaction was monitored by LCMS. The desired product can be detected by LCMS. The reaction was quenched by adding MeOH (20mL) at 0°C. The resulting mixture was diluted with EA (100mL) and washed with water (3×30mL). The organic layer was concentrated in vacuo. The residue was purified by reverse combi-flash chromatography to give methyl 5-{[1-(tert-butoxycarbonyl)-3-methylazetidin-3-yl]oxy}pyridine-2-carboxylate (1.1 g, 17.64%) as a white oil. LC-MS: (ES+H, m / z): [M+H] + =323.2. 1 H NMR (400MHz, DMSO-d6) δ8.28(d,1H),8.00(d,1H),7.33(dd,1H),4.10-4.02(m,4H),3.85(s,3H),1.65(s,3H),1.39(s,9H).

[0503] Step 2: tert-butyl 3-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate Preparation of esters :

[0504] At room temperature, CH3NH2 (5mL, 25.0 wt%-30.0 wt% aqueous solution) was added dropwise to a stirred solution of 5-{[1-(tert-butoxycarbonyl)-3-methylazetidine-3-yl]oxy}pyridine-2-carboxylic acid methyl ester (500mg, 1.55mmol, 1.00 equiv) in MeOH (5mL). The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction was monitored by LCMS. The desired product can be detected by LCMS. The resulting mixture was concentrated in vacuo to give tert-butyl 3-methyl-3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)azetidine-1-carboxylate (508mg, crude product). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =322.2.

[0505] Step 3: Preparation of N-methyl-5-[(3-methylazetidin-3-yl)oxy]pyridine-2-carboxamide TFA salt :

[0506] At room temperature, TFA (2mL) was added dropwise to a stirred solution of 3-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylic acid tert-butyl ester (468mg, 1.46mmol, 1.00 equivalent) in DCM (6mL). The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction was monitored by LCMS. The desired product can be detected by LCMS. The resulting mixture was concentrated in vacuo to give N-methyl-5-[(3-methylazetidine-3-yl)oxy]pyridine-2-carboxamide TFA salt (396mg, crude product). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =222.2.

[0507] Step 4: 5-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-3-methylazetidine- Preparation of 3-methyl}oxy)-N-methylpyridine-2-carboxamide :

[0508] To a stirred solution of N-methyl-5-[(3-methylazetidin-3-yl)oxy]pyridine-2-carboxamide TFA salt (250 mg, crude) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (201 mg, 0.90 mmol, 1.00 equiv) in MeCN (5 mL) was added DIEA (467 mg, 3.62 mmol, 4.00 equiv) and KI (30 mg, 0.18 mmol, 0.20 equiv) in batches at room temperature. The resulting mixture was stirred at 80 ° C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The desired product can be detected by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with CH2Cl2 / MeOH (10: 1) (150 mL). The filtrate was concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC, and the pure fractions were concentrated and then lyophilized to give 5-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-3-methylazetidin-3-yl}oxy)-N-methylpyridine-2-carboxamide (90.8 mg, 24.65%). LC-MS: (ES+H, m / z): [M+H] + =408.15. 1HNMR(400MHz,DMSO-d6)δ11.85(s,1H),8.54(q,1H),8.37(d,1H),8.13(d,1H),7.92(d,1H),7.73(s,1H),7.56(s,1H),7.28( dd,1H),3.77(s,2H),3.59-3.57(m,2H),3.29-3.32(m,2H),2.79(d,3H),2.56-2.50(m,2H),1.64(s,3H),1.18-1.12(t,3H).

[0509] Example 16

[0510]

[0511] Step 1: Preparation of methyl 5-{[1-(tert-butyloxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylate :

[0512] At 0 ℃ under nitrogen atmosphere, a mixture of DEAD (5.69g, 32.65mmol, 5.00 equivalents) and PPh3 (10.90g, 39.18mmol, 6.00 equivalents) in THF (100ml) was stirred for 1 hour. At 0 ℃ under nitrogen atmosphere, the mixture was added dropwise to a THF (100ml) solution of 5-hydroxypyridine-2-formic acid methyl ester (1.00g, 6.53mmol, 1.00 equivalents) and 3-hydroxyazetidine-1-formic acid tert-butyl ester (1.70g, 9.79mmol, 1.50 equivalents). The resulting mixture was stirred for another 2 hours at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylate (4.5 g, crude, containing TPPO). LC-MS: (ES+H, m / z): [M+H] + =309.1.

[0513] Step 2: Preparation of tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate Preparation :

[0514] A mixture of 5-{[1-(tert-butyloxycarbonyl)azetidine-3-yl]oxy}pyridine-2-carboxylic acid methyl ester (3.50 g, crude product, containing TPPO) and CH3NH2 (20 mL, 25 wt%-30 wt% aqueous solution) in MeOH (20 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. Saturated NH4Cl (100 mL) was added to the resulting mixture and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (1×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (3.3 g, crude product, containing TPPO). LC-MS: (ES+H, m / z): [M+H] + =308.1

[0515] Step 3: Preparation of 5-(azetidin-3-yloxy)-N-methylpyridine-2-carboxamide HCl salt :

[0516] At room temperature under nitrogen atmosphere, HCl (gas) (10 mL, 4 M dioxane solution) in 1,4-dioxane was added in batches to a mixture of 3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylic acid tert-butyl ester (3.30 g, crude, containing TPPO) in DCM (10 mL) under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by grinding with EtOAc (3×20 mL). The precipitated solid was collected by filtration and concentrated under reduced pressure. This gave 5-(azetidine-3-yloxy)-N-methylpyridine-2-carboxamide HCl salt (600 mg, crude).

[0517] LC-MS: (ES+H, m / z): [M+H] + =208.2.

[0518] Step 4: 5-({1-[(7-cyclopropyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidin-3-yl} Preparation of (2-(2-(2-oxy)-N-methylpyridine-2-carboxamide :

[0519] A mixture of 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one (200 mg, 0.85 mmol, 1.00 equiv), 5-(azetidin-3-yloxy)-N-methylpyridine-2-carboxamide HCl salt (249 mg, crude), DIEA (550 mg, 4.26 mmol, 5.00 equiv) and KI (28 mg, 0.17 mmol, 0.20 equiv) in ACN (10 mL) was stirred for 2 hours at 80 ° C under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography. The resulting mixture was concentrated under reduced pressure. The residue was purified by grinding with MeOH (5 mL) at 50 ° C. The precipitated solid was collected by filtration and washed with MeOH (2×1 mL). The pure fractions were concentrated and lyophilized to give 5-({1-[(7-cyclopropyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidin-3-yl}oxy)-N-methylpyridine-2-carboxamide (35.9 mg, 10.24%). LC-MS: (ES+H, m / z): [M+H] + =406.25. 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),8.56(q,1H),8.34(d,1H),8.22(d,1H),7.94(d,1H),7.54(d,1H),7.40(q,2H),5. 01(p,1H),3.79-3.75(m,4H),3.17-3.14(m,2H),2.78(d,3H),2.16-2.10(m,1H),0.98-0.95(m,2H),0.88-0.77(m,2H).

[0520] The following examples were carried out using a similar procedure as shown for Example 16:

[0521]

[0522] Embodiment 17

[0523]

[0524] Step 1: 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-yl Preparation of methyl formate :

[0525] To a stirred mixture of (2R, 3R)-3-hydroxy-2-methylazetidine-1-carboxylic acid tert-butyl ester (300 mg, 1.60 mmol, 1.00 equiv) and 5-hydroxypyridine-2-carboxylic acid methyl ester (245 mg, 1.60 mmol, 1.00 equiv) and PPh3 (882 mg, 3.36 mmol, 2.10 equiv) in THF (15 mL) was added dropwise a solution of DBAD (738 mg, 3.20 mmol, 2.00 equiv) in THF (5 mL) at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred at 60 ° C under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with EtOAc (100 mL). The residue was washed with H2O (2×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate (1.5 g, crude) was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H]+=323.1.

[0526] Step 2: (2R,3S)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1- Preparation of tert-butyl formate :

[0527] A solution of 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylic acid methyl ester (1.5 g, crude) and CH3NH2 (7 mL, 25 wt%-30 wt% aqueous solution) in CH3CN (7 mL) was stirred for 2 hours at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with ethyl acetate (100 mL). The residue was washed with NH4Cl (aqueous solution) (2×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (2R,3S)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylic acid tert-butyl ester (1.5 g, crude) was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H]+=322.1.

[0528] Step 3: N-methyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide TFA Salt preparation :

[0529] To a stirred solution of (2R, 3S)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylic acid tert-butyl ester (1.5 g, crude) in DCM (10 mL) was added TFA (7 mL) dropwise at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by grinding with ether / n-hexane (3×10 mL). The resulting mixture was concentrated in vacuo. The crude product N-methyl-5-{[(2R, 3S)-2-methylazetidine-3-yl]oxy}pyridine-2-carboxamide TFA salt (0.6 g, crude) was used directly in the next step without further purification.

[0530] LC-MS: (ES+H, m / z): [M+H]+=222.2.

[0531] Step 4: 5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazepine Preparation of cyclobutane-3-yl]oxy}-N-methylpyridine-2-carboxamide :

[0532] To a stirred mixture of N-methyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide TFA salt (300 mg, 1.36 mmol, 1.00 equiv) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (332 mg, 1.49 mmol, 1.10 equiv) in CH3CN (10 mL) was added KI (45 mg, 0.27 mmol, 0.20 equiv) and DIEA (700 mg, 5.42 mmol, 4.00 equiv) dropwise at room temperature. The mixture was stirred at 80 ° C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The residue was purified by reverse phase combi-flash. The pure fractions were concentrated in vacuo and then lyophilized to give 5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (56.8 mg, 10.22%). LC-MS: (ES+H, m / z): [M+H]+=408.2. Optical rotation [a] 25 D (c=0.5, MeOH): -4.8°; 1H NMR(300MHz,DMSO-d6)δ11.86(s,1H),8.58-8.57(q,1H),8.39(d,1H),8.24(d,1H),7.94(d,1H),7.74(s,1H),7.59(s,1H),7.43(dd,1H),4.65-4 .59(m,1H),3.95-3.90(m,1H),3.84-3.80(m,1H),3.66-3.62(m,1H),3.3 9-3.34(m,1H),2.80-2.78(m,4H),2.58-2.51(m,2H),1.21-1.16(m,6H).

[0533] The following examples were carried out using a similar procedure as shown for Example 17:

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541] Embodiment 18

[0542]

[0543] Step 1: 5-{[(2S,3R)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-yl Preparation of methyl formate :

[0544] To a stirred solution of 5-hydroxypyridine-2-carboxylic acid methyl ester (0.35 g, 2.28 mmol, 1.00 equiv), (2S, 3S)-3-hydroxy-2-methylazetidine-1-carboxylic acid tert-butyl ester (0.43 g, 2.28 mmol, 1.00 equiv) and PPh3 (1.20 g, 4.57 mmol, 2.00 equiv) in toluene (10 mL) was added dropwise a solution of DBAD (1.05 g, 4.57 mmol, 2.00 equiv) in toluene (5 mL) at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred at 80 ° C for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were concentrated under reduced pressure to give methyl 5-{[(2S,3R)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate (2.00 g, crude product). The crude product was used directly in the next step. LC-MS: (ES+H, m / z): [M+H] + =323.1.

[0545] Step 2: (2S,3R)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1- Preparation of tert-butyl formate :

[0546] At room temperature under nitrogen atmosphere, a solution of 5-{[(2S, 3R)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylic acid methyl ester (1.00 g, crude) and methylamine (2 mL, 25 wt%-30 wt% aqueous solution) in MeOH (2 mL) was stirred for 2 hours. The resulting mixture was concentrated under reduced pressure to give (2S, 3R)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylic acid tert-butyl ester (1.00 g, crude) as a brown oil. The crude product was used directly in the next step. LC-MS: (ES+H, m / z): [M+H] + =322.1.

[0547] Step 3: N-methyl-5-{[(2S,3R)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide HCl Salt preparation :

[0548] A solution of (2S, 3R)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylic acid tert-butyl ester (1.00 g, crude) in 1,4-dioxane (4 mL, 4 M) solution of HCl (gas) was stirred for 2 hours at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The product was precipitated by adding EtOAc. The precipitated solid was collected by filtration and washed with PE (3×10 mL) to give N-methyl-5-{[(2S, 3R)-2-methylazetidine-3-yl]oxy}pyridine-2-carboxamide HCl salt (200 mg, 67.95%, 3 steps). LC-MS: (ES+H, m / z): [M+H] + =222.2.

[0549] Step 4: 5-{[(2S,3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazepine Preparation of cyclobutane-3-yl]oxy}-N-methylpyridine-2-carboxamide :

[0550] To a stirred solution of N-methyl-5-{[(2S,3R)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide HCl salt (200 mg, 0.90 mmol, 1.10 equiv) and DIEA (531 mg, 4.11 mmol, 5.00 equiv) in MeCN (10 mL) was added KI (27 mg, 0.16 mmol, 0.20 equiv) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (157 mg, 0.82 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the pure fractions were concentrated and then lyophilized to give 5-{[(2S,3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (73.6 mg, 25.36%). LC-MS: (ES+H, m / z): [M+H] + =408.2.Optical rotation[a] 25 D (c=0.5,MeOH):+8°; 1H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.57(d,1H),8.38(s,1H),8.23(d,1H),7.94(d,1H),7.74(s,1H),7.59(s,1H),7.43(dd,1H),4 .62(q,1H),3.92(d,1H),3.82(t,1H),3.65-3.62(m,1H),3.38-3.35(m,1H),2.80-2.75(m,4H),2.55-2.52(m,2H),1.27-1.08(m,6H).

[0551] Embodiment 19

[0552]

[0553] Step 1: 5-{[(2R,3R)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-yl Preparation of methyl formate :

[0554] To a stirred solution of 5-hydroxypyridine-2-carboxylic acid methyl ester (245 mg, 1.60 mmol, 1.00 equiv), (2R, 3S)-3-hydroxy-2-methylazetidine-1-carboxylic acid tert-butyl ester (300 mg, 1.60 mmol, 1.00 equiv) and Ph3P (840 mg, 3.20 mmol, 2.00 equiv) in THF (5 mL) was added dropwise a solution of DBAD (738 mg, 3.20 mmol, 2.00 equiv) in THF (2 mL) at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred at 0 ° C for 1 hour. The resulting mixture was stirred overnight at 80 ° C under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were concentrated under reduced pressure to give methyl 5-{[(2R,3R)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate (1.6 g, containing Ph3PO) as a gray oil. The resulting mixture was used directly in the next step. LC-MS: (ES+H, m / z): [M+H] + =323.2.

[0555] Step 2: (2R,3R)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1- Preparation of tert-butyl formate :

[0556] At room temperature under nitrogen atmosphere, a solution of 5-{[(2R, 3R)-1-(tert-butoxycarbonyl)-2-methylazetidine-3-yl]oxy}pyridine-2-carboxylic acid methyl ester (1.60 g, 4.96 mmol, 1.00 equivalent) and methylamine (4 mL, 25 wt%-30 wt% aqueous solution) in MeOH (4 mL) was stirred overnight. The resulting mixture was concentrated under reduced pressure to give (2R, 3R)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylic acid tert-butyl ester (1.53 g, containing Ph3PO) as a gray oil. The crude product was used directly in the next step. LC-MS: (ES+H, m / z): [M+H] + =322.2

[0557] Step 3: N-methyl-5-{[(2R,3R)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide TFA Salt preparation :

[0558] A solution of (2R, 3R)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylic acid tert-butyl ester (1.53 g, containing Ph3PO) and TFA (3 mL) in DCM (3 mL) was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The resulting mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with ether (3×10 mL) to give N-methyl-5-{[(2R, 3R)-2-methylazetidine-3-yl]oxy}pyridine-2-carboxamide TFA salt (810 mg, containing Ph3PO). LC-MS: (ES+H, m / z): [M+H] + =222.1.

[0559] Step 4: 5-{[(2R,3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazepine Preparation of cyclobutane-3-yl]oxy}-N-methylpyridine-2-carboxamide :

[0560] To a stirred solution of N-methyl-5-{[(2R,3R)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide (546 mg, 2.47 mmol, 1.10 equiv) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (500 mg, 2.24 mmol, 1.00 equiv) in MeCN (5 mL) was added KI (74 mg, 0.45 mmol, 0.20 equiv) and DIEA (1.45 g, 11.22 mmol, 5.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-{[(2R,3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (26.2 mg, 2.86%). LC-MS: (ES+H, m / z): [M+H] + =408.20. 1 H NMR(300MHz,DMSO-d6)δ11.80(s,1H),8.56(d,1H),8.37(d,1H),8.26(d,1H),7.95(d,1H),7.74(s,1H),7.59(d,1H),7.42(dd,1H),5. 05-4.95(m,1H),3.88(d,1H),3.76(q,1H),3.66(d,1H),3.37-3.35(m,2H),2.79(d,3H),2.60-2.51(m,2H),1.18(t,3H),1.04(d,3H).

[0561] Embodiment 20

[0562]

[0563] Step 1: 5-(((2S,3S)-1-(tert-Butyloxycarbonyl)-2-methylazetidin-3-yl)oxy)pyridine Preparation of methyl ester :

[0564] To a stirred mixture of methyl 5-hydroxypyridine-2-carboxylate (400 mg, 2.61 mmol, 1.00 equiv) and tert-butyl (2S, 3R)-3-hydroxy-2-methylazetidine-1-carboxylate (489 mg, 2.61 mmol, 1.00 equiv) and PPh3 (1.40 g, 5.22 mmol, 2.00 equiv) in toluene (10 mL) was added DBAD (1.20 g, 5.22 mmol, 2.00 equiv) dropwise at 0 ° C under nitrogen atmosphere. The resulting mixture was stirred overnight at 80 ° C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a crude product (3.6 g, crude product). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =323.1.

[0565] Step 2: (2S,3S)-2-methyl-3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)azetidine-1-yl Preparation of tert-butyl formate :

[0566] To a stirred solution of methyl 5-(((2S,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl)oxy)picolinate (3.6 g, crude) in MeOH (10 mL) was added CH3NH2 (10 mL, 25 wt%-30 wt% in water) at room temperature. The resulting mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with saturated NH4Cl (100 mL). The resulting mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the crude product (3.5 g, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =322.2

[0567] Step 3: Preparation of N-methyl-5-(((2S,3S)-2-methylazetidin-3-yl)oxy)picolinamide HCl salt Preparation :

[0568] To a stirred solution of (2S,3S)-2-methyl-3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)azetidine-1-carboxylic acid tert-butyl ester (3.5 g, crude) in DCM (10 mL) was added dropwise a solution of HCl (gas) in 1,4-dioxane (10 mL, 4 M) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure and purified by trituration with ethyl acetate (20 mL) to give a crude product (1.6 g, crude). LC-MS: (ES+H, m / z): [M+H] + =222.0

[0569] Step 4: 5-(((2S,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methyl Preparation of (4-(2-(2-(-azetidin-3-yl)oxy)-N-methylpicolinamide) :

[0570] To a stirred mixture of N-methyl-5-(((2S,3S)-2-methylazetidin-3-yl)oxy)picolinamide (298 mg, assuming 100% yield, 1.35 mmol, 2.00 equiv) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (150 mg, 0.67 mmol, 1.00 equiv) in MeCN (10 mL) was added KI (22 mg, 0.14 mmol, 0.20 equiv) and DIEA (435 mg, 3.37 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC. The pure fractions were concentrated and lyophilized to give 5-(((2S,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methylazetidin-3-yl)oxy)-N-methylpicolinamide (29.1 mg, 10.60%). LC-MS: (ES+H, m / z): [M+H] + =408.2. 1HNMR(300MHz,DMSO-d6)δ11.80(s,1H),8.57(d,1H),8.37(d,1H),8.26(d,1H),7.96(d,1H),7.74(s,1H),7.59(s,1H),7.44(dd,1H) ,5.08-5.03(m,1H),3.88(d,1H),3.80-3.74(m,1H),3.66(d,1H),3.34(s,2H),2.79(d,3H),2.56(d,2H),1.18(t,3H),1.04(d,3H).

[0571] Embodiment 21

[0572]

[0573] Step 1: Preparation of methyl 5-{[1-(tert-butyloxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylate :

[0574] To a stirred mixture of 5-hydroxypyridine-2-carboxylic acid methyl ester (5.00 g, 32.65 mmol, 1.00 equiv), PPh3 (17.13 g, 65.30 mmol, 2.00 equiv) and 3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (5.66 g, 32.65 mmol, 1.00 equiv) in toluene (80 mL) was added dropwise a solution of DBAD (15.04 g, 65.30 mmol, 2.00 equiv) in toluene (40 mL) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 60°C under nitrogen atmosphere for 2 hours. The desired product can be detected by LCMS. The mixture was cooled to room temperature. The resulting mixture was poured into water (400 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure to give methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylate (45 g, crude product) as a gray oil. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =309.1

[0575] Step 2: Preparation of 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylic acid :

[0576] A mixture of 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylic acid methyl ester (9.00 g, 8.76 mmol, 1.00 equiv., assuming 30% yield) and LiOH (0.84 g, 35.03 mmol, 4.00 equiv.) in THF (40 mL) and H2O (10 mL) was stirred for 3 hours at room temperature under a nitrogen atmosphere. The desired product can be detected by LCMS. The resulting mixture was poured into water (200 mL) and extracted with EtOAc (1×200 mL). The aqueous layer was acidified to pH 4-6 with HCl (aqueous solution). The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (1×100 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure to give 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylic acid (2.3 g, 89.25%). LC-MS: (ES+H, m / z): [M+H] + =295.1. 1 H NMR(300MHz,DMSO-d6)δ12.92(s,1H),8.33(dd,1H),8.02(dd,1H),7.38(dd ,1H),5.20-5.17(m,1H),4.41-4.28(m,2H),3.91-3.80(m,2H),1.39(s,9H).

[0577] Step 3: Preparation of tert-butyl 3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate preparation :

[0578] To a stirred mixture of 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylic acid (500 mg, 1.70 mmol, 1.00 equiv) and DIEA (1.10 g, 8.50 mmol, 5.00 equiv) in DCM (15 mL) was added aminocyclopropane (107 mg, 1.87 mmol, 1.10 equiv) and T3P (4.32 g, 6.80 mmol, 4.00 equiv, 50 wt % solution in EA) at room temperature. The resulting mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. The desired product can be detected by LCMS. The resulting mixture was poured into water (150 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (1×80 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure to obtain tert-butyl 3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (780 mg, crude product). LC-MS: (ES+H, m / z): [M+H] + =334.0. 1H NMR(300MHz,DMSO-d6)δ8.55(d,1H),8.21(d,1H),7.97(d,1H),7.40(dd,1H),5.17-5.12 (m,1H),4.34(dd,2H),3.84(dd,2H),2.94-2.82(m,1H),1.39(s,9H),0.78-0.61(m,4H).

[0579] Step 4: Preparation of 5-(azetidin-3-yloxy)-N-cyclopropylpyridine-2-carboxamide TFA salt :

[0580] A solution of tert-butyl 3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (700 mg, 2.10 mmol, 1.00 equiv) and TFA (7.20 g, 63.00 mmol, 30.00 equiv) in DCM (20 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. This gave 5-(azetidine-3-yloxy)-N-cyclopropylpyridine-2-carboxamide TFA salt (1.2 g, crude) as a brown crude oil. LC-MS: (ES+H, m / z): [M+H]+=234.2

[0581] Step 5: N-cyclopropyl-5-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidine Preparation of 2-( ... :

[0582] 7-(Chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (150 mg, 0.67 mmol, 1.00 equiv) and KI (22 mg, 0.14 mmol, 0.20 equiv) were added to a solution of 5-(azetidin-3-yloxy)-N-cyclopropylpyridine-2-carboxamide TFA salt (300 mg, crude) and DIEA (871 mg, 6.74 mmol, 10.00 equiv) in MeCN (2 mL). The mixture was stirred at 50 ° C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. After cooling to room temperature, the resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (1×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase combi-flash, and the pure fractions were concentrated and then lyophilized to give N-cyclopropyl-5-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidin-3-yl}oxy)pyridine-2-carboxamide (96.2 mg, 33.50%). LC-MS: (ES+H, m / z): [M+H] + =420.3. 1HNMR(300MHz,DMSO-d6)δ11.86(s,1H),8.52(d,1H),8.37(d,1H),8.20(d,1H),7.95(d,1H),7.74(s,1H),7.57(d,1H),7.41( dd,1H),5.02(p,1H),3.83-3.75(m,4H),3.24-3.12(m,2H),2.87(td,1H),2.57-2.52(m,2H),1.18(t,3H),0.68-0.65(m,4H).

[0583] The following examples were carried out using a similar procedure as shown for Example 21:

[0584]

[0585] Embodiment 22

[0586]

[0587] Step 1: Preparation of tert-butyl 3-(4-cyanophenoxy)azetidine-1-carboxylate :

[0588] To a stirred solution of 4-fluorobenzonitrile (1.00 g, 8.26 mmol, 1.00 equiv) and tert-butyl 3-hydroxyazetidine-1-carboxylate (2.15 g, 12.39 mmol, 1.50 equiv) in DMF (20 mL) was added K2CO3 (3.42 g, 24.77 mmol, 3.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 ° C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reactant was poured into water (80 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×80 mL). The combined organic layer was washed with brine (3×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the filtrate was concentrated under reduced pressure to give tert-butyl 3-(4-cyanophenoxy)azetidine-1-carboxylate (170 mg, 7.51%). LC-MS: (ES+H, m / z): [M-tBu+ACN] + =260.0. 1 HNMR (300MHz, DMSO-d6) δ7.84-7.75(m,2H),7.05-6.98(m,2H),5.17-5.05(m,1H),4.49-4.24(m,2H),3.86-3.76(m,2H),1.39(s,9H).

[0589] Step 2: Preparation of 4-(azetidin-3-yloxy)benzonitrile TFA salt :

[0590] At room temperature under nitrogen atmosphere, TFA (1 mL) was added dropwise to a stirred solution of tert-butyl 3-(4-cyanophenoxy)azetidine-1-carboxylate (160 mg, 0.58 mmol, 1.00 equiv) in DCM (3 mL). The resulting mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 4-(azetidine-3-yloxy)benzonitrile TFA salt (232 mg, crude product) as a brown oil. LC-MS: (ES+H, m / z): [M+H] + =175.0

[0591] Step 3: 4-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidin-3-yl}oxy Preparation of 1-(2-(4-(4-yl)benzonitrile) :

[0592] To a stirred solution of 4-(azetidin-3-yloxy)benzonitrile (221 mg, 0.58 mmol, 1.00 equiv., 46 wt%) and DIEA (377 mg, 2.92 mmol, 5.00 equiv.) in MeCN (5 mL) was added 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (130 mg, 0.58 mmol, 1.00 equiv.) and KI (4 mg, 0.02 mmol, 0.04 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 ° C. under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was poured into water (60 mL). The resulting mixture was extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (3×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC, and the pure fractions were concentrated under reduced pressure and then lyophilized to give 4-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidin-3-yl}oxy)benzonitrile (86.7 mg, 41.24%, two steps). LC-MS: (ES+H, m / z): [M+H] + =361.10. 1 H NMR(400MHz,DMSO-d6)δ11.84(s,1H),8.36(d,1H),7.82-7.66(m,3H),7.56(s,1H),7.02(d,2 H),5.01-4.90(m,1H),3.85-3.65(m,4H),3.21-3.04(m,2H),2.59-2.52(m,2H),1.18(t,3H).

[0593] The following examples were carried out using a similar procedure as shown for Example 22:

[0594]

[0595]

[0596] Embodiment 43

[0597]

[0598] Step 1: tert-Butyl (2R,3S)-3-((6-cyanopyridin-3-yl)oxy)-2-methylazetidine-1-carboxylate Preparation :

[0599] To a stirred mixture of NaH (1.49 g, 37.37 mmol, 1.20 equiv., 60% oil solution) in THF (30 mL) was added a solution of (2R, 3S)-3-hydroxy-2-methylazetidine-1-carboxylic acid tert-butyl ester (6.99 g, 37.35 mmol, 1.20 equiv.) in THF (30 mL) at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. A solution of 5-fluoropyridine-2-carbonitrile (3.8 g, 31.12 mmol, 1.00 equiv.) in THF (30 mL) was added dropwise to the above mixture at 0 ° C within 15 minutes. The resulting mixture was stirred at room temperature for another 1 hour. The reaction was monitored by LCMS. The reaction was quenched by adding water (10 mL) at 0 ° C. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (2R, 3S)-3-((6-cyanopyridin-3-yl)oxy)-2-methylazetidine-1-carboxylate (6.24 g, 65.0%). LC-MS: (ES+H, m / z): [M+H-tBu] + =234.1.

[0600] Step 2: 5-(((2R,3S)-1-(tert-Butyloxycarbonyl)-2-methylazetidin-3-yl)oxy)pyridine Acid preparation :

[0601] To a stirred mixture of (2R,3S)-3-[(6-cyanopyridin-3-yl)oxy]-2-methylazetidine-1-carboxylic acid tert-butyl ester (6.6 g, 22.81 mmol, 1.00 equiv) in water (40 mL) was added NaOH (20 mL, 2N aqueous solution) in portions at room temperature. The resulting mixture was stirred at 100 ° C under a nitrogen atmosphere for 2 hours. The reaction was monitored by TLC. The mixture was cooled to room temperature. THF (40 mL) and Boc2O (9.96 g, 45.62 mmol, 2.00 equiv) were added to the above mixture in portions within 10 minutes at 0 ° C. The resulting mixture was stirred for another 6 hours at room temperature. The reaction was monitored by LCMS. The mixture was acidified to pH 3-4 with citric acid. The resulting mixture was extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-(((2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl)oxy)picolinic acid (6.2 g, 88.2%). LC-MS: (ES+H, m / z): [M+H] + =309.2. 1 H NMR (300MHz, DMSO-d6) δ8.33(d,1H),8.02(d,1H),7.38(dd,1H),4.82-4.65(m,1H),4.30-4.21(m,2H),3.72-3.56(m,1H),1.45(s,3H),1.37(s,9H).

[0602] Step 3: (2R,3S)-3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}-2-methylazetidine- Preparation of tert-butyl 1-formate :

[0603] To a stirred solution of 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylic acid (600 mg, 1.95 mmol, 1.00 equiv) and HATU (1.11 g, 2.92 mmol, 1.50 equiv) and DIEA (503 mg, 3.89 mmol, 2.00 equiv) in DCM (5 mL) was added aminocyclopropane (133 mg, 2.33 mmol, 1.20 equiv) at 0 ° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with CH2Cl2 (100 mL). The resulting mixture was washed with water (3×20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (2R,3S)-3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}-2-methylazetidine-1-carboxylate (600 mg, 88.7%). LC-MS: (ES+H, m / z): [M+H]+=348.1

[0604] Step 4: N-cyclopropyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide Preparation of HCl salt :

[0605] To a stirred solution of (2R,3S)-3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}-2-methylazetidine-1-carboxylic acid tert-butyl ester (500 mg, 1.44 mmol, 1.00 equiv) in DCM (3 mL) was added dropwise a solution of HCl (gas) in 1,4-dioxane (5 mL, 4 mol / L) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with Et2O (2×10 mL). The resulting mixture was concentrated under reduced pressure to give N-cyclopropyl-5-{[(2R,3S)-2-methylazetidine-3-yl]oxy}pyridine-2-carboxamide HCl salt (400 mg, crude). LC-MS: (ES+H, m / z): [M+H] + =248.2.

[0606] Step 5: N-cyclopropyl-5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]- Preparation of 2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide :

[0607] To a stirred mixture of N-methyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide HCl salt (200 mg, crude) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (150 mg, 0.67 mmol, 1.00 equiv) in CH3CN (8 mL) was added KI (56 mg, 0.34 mmol, 0.5 equiv) and DIEA (697 mg, 5.39 mmol, 8 equiv) dropwise at room temperature. The resulting mixture was stirred at 60 ° C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. After that, the residue was purified by reverse phase combi-flash chromatography, and the pure fractions were concentrated in vacuo to give N-cyclopropyl-5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide (109.3 mg, 37.3%). LC-MS: (ES+H, m / z): [MH]+=434.25, optical rotation [a] 25 D (c=0.25, DCM / MeOH=10 / 1): -12°; 1 H NMR(300MHz,DMSO-d6)δ11.86(s,1H),8.54-8.52(d,1H),8.39-8.38(d,1H),8.22-8. 21(d,1H),7.96-7.93(d,1H),7.74(s,1H),7.59-7.58(d,1H),7.45-7.42(dd,1H),4. 64-4.58(q,1H),3.94-3.90(d,1H),3.83-3.79(t,1H),3.66-3.62(d,1H),3.39-3.34 (q,1H),2.91-2.76(m,2H),2.58-2.50(m,2H),1.21-1.16(m,6H),0.71-0.60(m,4H).

[0608] Embodiment 44

[0609]

[0610] Step 1: Preparation of methyl 5-(((2R,3S)-2-methylazetidin-3-yl)oxy)picolinate HCl salt :

[0611] To a stirred mixture of tert-butyl 3-{[6-(dihydroxymethyl)piperidin-3-yl]oxy}-2-methylazetidine-1-carboxylate (600 mg, 1.90 mmol, 1.00 equiv) in MeOH (10 mL) was added SOCl2 (1.13 g, 9.48 mmol, 5.00 equiv) dropwise at room temperature. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo, and the crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =223.2.

[0612] Step 2: 5-(((2R,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methyl Preparation of methyl 2-(2-(2-azetidin-3-yl)oxy)picolinate :

[0613] To a stirred mixture of 5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylic acid methyl ester (380 mg, 1.71 mmol, 1.00 equiv), KI (28 mg, 0.17 mmol, 0.10 equiv) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (456 mg, 2.05 mmol, 1.20 equiv) in CH3CN (5 mL) was added DIEA (884 mg, 6.84 mmol, 4.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 ° C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate (400 mg, 57.3%) as a brown oil. LC-MS: (ES+H, m / z): [M+H] + =409.2

[0614] Step 3: 5-(((2R,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methyl Preparation of 2-(2-(2-(-azetidin-3-yl)oxy)picolinic acid :

[0615] To a stirred solution of 5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylic acid methyl ester (300 mg, 0.73 mmol, 1.00 equiv) in MeOH (3 mL) was added NaOH (aqueous solution, 3 mL, 2N H2O solution) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. The reaction was monitored by LCMS. The aqueous layer was extracted with CH2Cl2 (2×30 mL). The mixture was acidified to pH 6-7 with HCl (aqueous solution). The aqueous layer was concentrated in vacuo. The residue was purified by trituration with MeOH (40 mL). The resulting mixture was filtered and the filter cake was washed with MeOH (1×20 mL). The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =395.2.

[0616] Step 4: 5-(((2R,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methyl Preparation of (4-(2-((2-((-azetidin-3-yl)oxy)-N-(oxetane-3-yl)pyridineamide)) :

[0617] To a stirred mixture of 5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylic acid (200 mg, 0.51 mmol, 1.00 equiv), DIEA (262 mg, 2.03 mmol, 4.00 equiv) and oxetane-3-amine (45 mg, 0.61 mmol, 1.20 equiv) in DMF (5 mL) was added HATU (289 mg, 0.76 mmol, 1.50 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with water (1×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (130 mg) was purified by preparative HPLC to give 5-(((2R, 3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-(oxetane-3-yl)picolinamide (15.6 mg, 6.6%). LC-MS: (ES+H, m / z): [M+H] + =450.2. 1H NMR(300MHz,DMSO-d6)δ11.86(s,1H),9.29(d,1H),8.39(d,1H),8.28(d,1H),7.94(d,1H),7.75(s,1H),7.59(s,1H),7.45(d d,1H),5.01(q,1H),4.75-4.61(m,5H),3.93(d,1H),3.82(t,1H),3.65(d,1H),2.80(t,1H),2.57(d,2H),1.24-1.14(m,6H).

[0618] Examples 54 and 55 .

[0619]

[0620] Step 1: Preparation of 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid :

[0621] To a solution of 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid methyl ester (1.15 g, 4.95 mmol, 1.00 equiv) in MeOH (15 mL) and H2O (3 mL) was added NaOH (0.59 g, 14.86 mmol, 3.00 equiv) in portions at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The residue was acidified to pH 4 with 6N HCl (aq). The resulting mixture was filtered and the solid was concentrated under reduced pressure to give 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid (800.0 mg, crude). LC-MS: (ES+H, m / z): [M+H] + =218.9. 1 H NMR (400MHz, DMSO-d6) δ13.43(s,1H),12.08(s,1H),8.89(d,1H),8.15(d,1H),7.82(s,1H),2.62-2.54(m,2H),1.20(t,3H).

[0622] Step 2: Preparation of 7-ethyl-N-methoxy-N-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxamide :

[0623] To a solution of 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid (800 mg, crude) and N,O-dimethylhydroxylamine (336 mg, 5.50 mmol, 1.50 equiv) in DMF (8 mL) was added EDCI (2.10 g, 11.00 mmol, 3.00 equiv) in batches at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-ethyl-N-methoxy-N-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxamide (540 mg, 45.44%). LC-MS: (ES+H, m / z): [M+H] + =262.1. 1 H NMR (400MHz, DMSO-d6) δ12.02(s,1H),8.64(d,1H),7.89(dd,1H),7.80(s,1H),3.58(s,3H),3.31(s,3H),2.57(q,2H),1.20(t,3H).

[0624] Step 3: Preparation of 7-acetyl-3-ethyl-1H-1,5-naphthyridin-2-one :

[0625] To a solution of 7-ethyl-N-methoxy-N-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxamide (540 mg, 2.07 mmol, 1.00 equiv) in THF (5 mL) was added dropwise CH3MgBr (1.4 mL, 4.13 mmol, 2.00 equiv, 3 M in THF) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with water at 0°C. The resulting mixture was diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×60 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-acetyl-3-ethyl-1H-1,5-naphthyridine-2-one (397 mg, 88.83%). LC-MS: (ES+H, m / z): [M+H] + =217.1. 1H NMR (400MHz, DMSO-d6) δ12.06(s,1H),8.98(s,1H),8.09(d,1H),7.84(d,1H),2.67(s,3H),2.58(q,2H),1.20(t,3H).

[0626] Step 4: 5-{[(2R,3S)-1-[1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylnitrogen Preparation of heterocyclobutane-3-yl]oxy}-N-methylpyridine-2-carboxamide :

[0627] A mixture of 7-acetyl-3-ethyl-1H-1,5-naphthyridin-2-one (400 mg, 1.85 mmol, 1.00 equiv) and N-methyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide (614 mg, 2.78 mmol, 1.50 equiv) in DCM (5 mL) was stirred for 15 minutes at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. Tetrakis(propan-2-yloxy)titanium (1.58 g, 5.55 mmol, 3.00 equiv) was added to the above mixture. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 4 hours. The residue was dissolved in EtOH (10 mL). NaBH3CN (233 mg, 3.70 mmol, 2.00 equiv) was added to the above mixture. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 4 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reaction was quenched by adding water (20 mL) at room temperature. The resulting mixture was filtered and the filter cake was washed with CH2Cl2 / MeOH=1:1 (3×40 mL). The filtrate was concentrated under reduced pressure. The crude product (350 mg) was purified by preparative HPLC to give 5-{[(2R, 3S)-1-[1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]-2-methylazetidine-3-yl]oxy}-N-methylpyridine-2-carboxamide (160 mg, 20.52%).

[0628] Step 5: 5-{[(2R,3S)-1-[(1R*)-1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]-2- Methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide and 5-{[(2R,3S)-1-[(1R*)-1-(7-ethyl [(6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-methyl Preparation of amide :

[0629] The racemate 5-{[(2R,3S)-1-[1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (160 mg) was separated by preparative chiral HPLC to give 5-{[(2R,3S)-1-[(1R*)-1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide )ethyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (66.6 mg, ee=100%) and 5-{[(2R,3S)-1-[(1R*)-1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (48.6 mg, ee=100%).

[0630] Example 54: LC-MS: (ES+H, m / z): [M+H] + =422.15. 1 H NMR(300MHz,DMSO-d6)δ11.81(s,1H),8.55(d,1H),8.39(s,1H),8.21(d,1H),7.91(d,1H),7.73(s,1H),7.58(s,1H), 7.41-7.35(m,1H),4.55(d,1H),3.72-3.40(m,4H),2.77(d,3H),2.56(m,2H),1.43(d,3H),1.28(d,3H),1.17(t,3H).

[0631] Example 55: LC-MS: (ES+H, m / z): [M+H] + =422.15. 1 H NMR(300MHz,DMSO-d6)δ11.89(s,1H),8.58(q,1H),8.45(d,1H),8.24(d,1H),7.96(d,1H),7.74(s,1H),7.63(d,1H),7.45(dd, 1H),4.55(q,1H),4.02(t,1H),3.60-3.49(m,1H),3.25(t,1H),2.92-2.73(m,4H),2.60-2.52(m,2H),1.19(q,6H),0.70(d,3H).

[0632] The following examples were carried out using similar procedures as shown for Examples 54 and 55:

[0633]

[0634] Embodiment 63

[0635]

[0636] Step 1: (2R,3R)-2-methyl-3-{[4-(trifluoromethyl)benzenesulfonyl]oxy}azetidine-1-carboxylic acid Preparation of tert-butyl ester :

[0637] To a stirred solution of (2R, 3R)-3-hydroxy-2-methylazetidine-1-carboxylic acid tert-butyl ester (1.00 g, 5.34 mmol, 1.00 equiv) and Et3N (1.62 g, 16.02 mmol, 3.00 equiv) and DMAP (0.03 g, 0.26 mmol, 0.05 equiv) in DCM (20 mL) was added a solution of 4-(trifluoromethyl)benzenesulfonyl chloride (1.44 g, 5.87 mmol, 1.10 equiv) in DCM (10 mL) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C under nitrogen atmosphere for 2 hours. The reaction was monitored by TLC (PE / EA=2 / 1, KMnO4). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (2R,3R)-2-methyl-3-{[4-(trifluoromethyl)benzenesulfonyl]oxy}azetidine-1-carboxylate (1.7 g, 76.4%). 1 H NMR (300 MHz, chloroform-d) δ 8.08-8.04 (m, 2H), 7.88-7.85 (m, 2H), 5.13-5.12 (m, 1H), 4.52-4.50 (m, 1H), 4.13 (dd, 1H), 3.86 (dd, 1H), 1.43 (s, 9H), 1.36 (d, 3H).

[0638] Step 2: (2R,3S)-3-[5-(methoxycarbonyl)pyrrolo[3,2-b]pyridin-1-yl]-2-methylazetidine Preparation of tert-butyl 1-oxanecarboxylate :

[0639] To a stirred solution of (2R,3R)-2-methyl-3-{[4-(trifluoromethyl)benzenesulfonyl]oxy}azetidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.52 mmol, 1.00 equiv) and 1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid methyl ester (445 mg, 2.52 mmol, 1.00 equiv) in DMF (20 mL) was added Cs2CO3 (1.65 g, 5.05 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred at 110 ° C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (200 mL). The resulting mixture was washed with H2O (3×100 mL). The organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (2R,3S)-3-[5-(methoxycarbonyl)pyrrolo[3,2-b]pyridin-1-yl]-2-methylazetidine-1-carboxylate (460 mg, 52.2%). LC-MS: (ES+H, m / z): [M+H] + =346.1

[0640] 1 H NMR(300MHz,DMSO-d6)δ8.24(d,1H),8.07(d,1H),7.92(d,1H),6.83(d,1H),5.08-5.06(m,1H), 4.53-4.50(m,1H),4.27-4.25(m,1H),4.21-4.10(m,1H),3.89(s,3H),1.47(d,3H),1.43(s,9H).

[0641] Step 3: (2R,3S)-2-methyl-3-[5-(methylcarbamoyl)pyrrolo[3,2-b]pyridin-1-yl]azacyclic Preparation of tert-butyl butane-1-carboxylate :

[0642] To a stirred solution of (2R,3S)-3-[5-(methoxycarbonyl)pyrrolo[3,2-b]pyridin-1-yl]-2-methylazetidine-1-carboxylic acid tert-butyl ester (460 mg, 1.39 mmol, 1.00 equiv) and ACN (3 mL) was added dropwise an aqueous solution of CH3NH2 (3 mL, 30 wt %) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 6 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with saturated NH4Cl (aqueous solution, 50 mL). The resulting mixture was extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (2R,3S)-2-methyl-3-[5-(methylcarbamoyl)pyrrolo[3,2-b]pyridin-1-yl]azetidine-1-carboxylate (450 mg, 93.2%). LC-MS: (ES+H, m / z): [M+H] + =345.2. 1 H NMR(300MHz,DMSO-d6)δ8.66-8.64(m,1H),8.18(d,1H),8.09-8.03(m,1H),7.90(d,1H),6.75(d,1H),5 .07-5.03(m,1H),4.53-4.51(m,1H),4.27(t,1H),4.14(dd,1H),2.84(d,3H),1.47(d,3H),1.43(s,9H).

[0643] Step 4: N-methyl-1-[(2R,3S)-2-methylazetidin-3-yl]pyrrolo[3,2-b]pyridine-5-carboxylate Preparation of amide hydrochloride :

[0644] To a stirred mixture of (2R, 3S)-2-methyl-3-[5-(methylcarbamoyl)pyrrolo[3,2-b]pyridin-1-yl]azetidine-1-carboxylic acid tert-butyl ester (450 mg, 1.30 mmol, 1.00 equiv) and HCl (gas) in 1,4-dioxane (5 mL, 4M / L dioxane solution). The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with hexane / Et2O=1:1 (50 mL). The crude product N-methyl-1-[(2R, 3S)-2-methylazetidine-3-yl]pyrrolo[3,2-b]pyridine-5-carboxamide hydrochloride (320 mg) was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =245.1

[0645] Step 5: 1-[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazepine Preparation of cyclobutane-3-yl]-N-methylpyrrolo[3,2-b]pyridine-5-carboxamide :

[0646] To a stirred solution of 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (200 mg, 0.89 mmol, 1.00 equiv) and N-methyl-1-[(2R,3S)-2-methylazetidin-3-yl]pyrrolo[3,2-b]pyridine-5-carboxamide hydrochloride (241 mg, assuming 100% yield, 0.98 mmol, 1.10 equiv) and KI (29 mg, 0.18 mmol, 0.20 equiv) in ACN (5 mL) was added DIEA (580 mg, 4.49 mmol, 5.00 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 ° C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a crude product. The residue was dissolved in DMSO (3 mL). The residue was purified by preparative HPLC. The pure fractions were concentrated in vacuo and then lyophilized to give 1-[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]-N-methylpyrrolo[3,2-b]pyridine-5-carboxamide (126.2 mg, 32.2%). LC-MS: (ES+H, m / z): [M+H] + =431.15.Optical rotation[a] 25 D (c=0.5, MeOH): -26.4°; 1 H NMR(300MHz,DMSO-d6)δ11.91(s,1H),8.65(d,1H),8.45(d,1H),8.18-8.11(m,2H),7.87(d,1H),7.76(s,1H),7.65(d,1H),6.75(d,1H ),4.86(d,1H),4.1(d,1H),3.82-3.76(m,2H),3.68-3.63(m,1H),3.31-3.29(m,1H),2.84(d,3H),2.56-2.51(m,2H),1.2-1.16(m,6H).

[0647] The following examples were carried out using a similar procedure as shown for Example 63:

[0648]

[0649]

[0650] Embodiment 66

[0651]

[0652] Step 1: 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-3-fluoropyrrolidone Preparation of methyl 2-pyridinecarboxylate :

[0653] A solution of 3-fluoro-5-hydroxypyridine-2-carboxylic acid methyl ester (500 mg, 2.92 mmol, 1.00 equiv), (2R, 3R)-3-hydroxy-2-methylazetidine-1-carboxylic acid tert-butyl ester (547 mg, 2.92 mmol, 1.00 equiv) and PPh3 (1.53 g, 5.84 mmol, 2.00 equiv) in PhMe (20 mL) was treated with a solution of DBAD (1.35 g, 5.84 mmol, 2.00 equiv) in PhCH3 (5 mL) at 0°C. The resulting mixture was stirred at 60°C for 2 hours. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (1×40 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-3-fluoropyridine-2-carboxylic acid methyl ester (4.2 g, crude product) as a black oil. The resulting crude mixture was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =341.05.

[0654] Step 2: 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-3-fluoropyrrolidone Preparation of 2-pyridinecarboxylic acid :

[0655] A solution of 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-3-fluoropyridine-2-carboxylic acid methyl ester (4.00 g, crude) in THF (14 mL) was treated with a solution of NaOH (0.94 g, 23.50 mmol, 2.00 equiv) in H2O (7 mL) at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The resulting mixture was diluted with water (40 ml). The resulting mixture was extracted with EtOAc (3×70 mL). The aqueous layer was acidified to pH 4 with HCl (1 mol / L aqueous solution). The resulting mixture was extracted with EtOAc (3×70 mL). The combined organic layers were washed with brine (1×60 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-3-fluoropicolinic acid (900 mg, 94.2% for two steps).

[0656] LC-MS: (ES+H, m / z): [M+H] + =327.1.

[0657] Step 3: (2R,3S)-3-{[6-(cyclopropylcarbamoyl)-5-fluoropyridin-3-yl]oxy}-2-methylazacyclo Preparation of tert-butyl butane-1-carboxylate :

[0658] A solution of 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-3-fluoropyridine-2-carboxylic acid (600 mg, 1.83 mmol, 1.00 equiv) in DMF (10 mL) was treated with HATU (1.05 g, 2.75 mmol, 1.50 equiv) for 10 minutes at room temperature, followed by the addition of aminocyclopropane (524 mg, 9.19 mmol, 5.00 equiv) and DIEA (950 mg, 7.35 mmol, 4.00 equiv). The resulting mixture was stirred at room temperature for another 1.5 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (1×80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (2R,3S)-3-{[6-(cyclopropylcarbamoyl)-5-fluoropyridin-3-yl]oxy}-2-methylazetidine-1-carboxylate (600 mg, 89.3%). LC-MS: (ES+H, m / z): [M+H] + =366.10. 1 H NMR (300MHz, DMSO-d6): δ8.48(d,1H),8.12(dd,1H),7.40(dd,1H),4.83-4.78(m,1H),4.31-4.22(m,2 H),3.64(dd,1H),2.87-2.81(m,1H),1.39(s,9H),1.43(d,3H),0.71-0.65(m,2H),0.62-0.57(m,2H).

[0659] Step 4: N-cyclopropyl-3-fluoro-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate Preparation of amide hydrochloride :

[0660] A solution of (2R,3S)-3-{[6-(cyclopropylcarbamoyl)-5-fluoropyridin-3-yl]oxy}-2-methylazetidine-1-carboxylic acid tert-butyl ester (600 mg, 1.64 mmol, 1.00 equiv) in EA (20 mL) was treated with HCl (gas) in 1,4-dioxane (10 mL, 4 M) at 0°C. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This gave N-cyclopropyl-3-fluoro-5-{[(2R,3S)-2-methylazetidine-3-yl]oxy}pyridine-2-carboxamide hydrochloride (600 mg, crude). LC-MS: (ES+H, m / z): [M+H] + =266.05.

[0661] Step 5: N-cyclopropyl-5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]- Preparation of 2-methylazetidin-3-yl]oxy}-3-fluoropyridine-2-carboxamide :

[0662] To a stirred mixture of N-cyclopropyl-3-fluoro-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide hydrochloride (285 mg, assuming 100% yield, 1.07 mmol, 1.20 equiv) and DIEA (464 mg, 3.59 mmol, 4.00 equiv) in MeCN (10 mL) at room temperature was added 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (200 mg, 0.89 mmol, 1.00 equiv) and KI (29.82 mg, 0.18 mmol, 0.20 equiv). The resulting mixture was stirred at 80 ° C for another 2 hours. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with CH2Cl2 (3×40 mL). The combined organic layers were washed with brine (1×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase combi-flash chromatography. The resulting mixture was concentrated under reduced pressure. This gave N-cyclopropyl-5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidine-3-yl]oxy}-3-fluoropyridine-2-carboxamide (112.9 mg, 27.8%). LC-MS: (ES+H, m / z): [M+H] + =452.20.Optical rotation[a] 25 D (c=0.1, MeOH): -6.0°; 1H NMR (400MHz, DMSO-d6): δ11.86(s,1H),8.46(d,1H),8.38(d,1H),8.15(d,1H),7.74(s,1H),7.58(d,1H),7.41(dd,1H),4.64(q,1H),3.91 (d,1H),3.82(t,1H),3.64(d,1H),3.38(t,1H),2.85-2.75(m,2H),2.56-2.53(m,2H),1.28(m,6H),0.69-0.63(m,2H),0.61-0.56(m,2H). 19 F NMR(377MHz,DMSO-d6)δ-118.55.

[0663] Embodiment 75

[0664]

[0665] Step 1: Preparation of 7-bromo-1H-1,5-naphthyridin-2-one :

[0666] To a stirred mixture of 5-aminopyridin-2-ol (5.00 g, 45.41 mmol, 1.00 equiv) in AcOH (60 mL) was added 2,2,3-tribromopropanal (13.38 g, 45.40 mmol, 1.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70 ° C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-bromo-1H-1,5-naphthyridine-2-one (2.50 g, 24.4%). LC-MS: (ES+H, m / z): [M+H] + =225.00 / 227.00. 1 H NMR (400MHz, DMSO-d6) δ11.95(s,1H),8.55(d,J=2.1Hz,1H),7.92(d,J=9.8Hz,1H),7.85(d,J=2.1Hz,1H),6.78(d,J=9.8Hz,1H).

[0667] Step 2: Preparation of 7-bromo-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one :

[0668] To a stirred mixture of 7-bromo-1H-1,5-naphthyridin-2-one (2.30 g, 10.22 mmol, 1.00 equiv) in MeCN (20 mL) and H2O (6 mL) was added sodium difluoromethanesulfinate (3.53 g, 20.44 mmol, 2.00 equiv, 80 wt%) and potassium peroxodisulfate (11.05 g, 40.88 mmol, 4.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere overnight. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was filtered; the filter cake was washed with DCM / MeOH (10:1) (3×100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-bromo-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one (490 mg, 17.4%). LC-MS: (ES+H, m / z): [M+H] + =275.00 / 277.00. 1 H NMR (300MHz, DMSO-d6) δ12.40(s,1H),8.66(d,J=2.1Hz,1H),8.16(d,J=1.8Hz,1H),7.91(d,J=2.1Hz,1H),7.17-6.76(m,1H). 19 F NMR(282MHz,DMSO-d6)δ-119.76.

[0669] Step 3: Preparation of 3-(difluoromethyl)-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one :

[0670] To a stirred solution of 7-bromo-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one (2.20 g, 7.99 mmol, 1.00 equiv) in 1,4-dioxane (30 mL) was added dropwise (tributylstannyl)methanol (2.83 g, 8.79 mmol, 1.10 equiv) and second generation XPhos precatalyst (314 mg, 0.40 mmol, 0.05 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 ° C. under nitrogen atmosphere overnight. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-(difluoromethyl)-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (650 mg, 35.9%). LC-MS: (ES+H, m / z): [M+H] + =227.1. 1H NMR (300MHz, DMSO-d6) δ12.36(s,1H),8.50(d,J=1.8Hz,1H),8.16(d,J=1.8Hz,1H),7 .70(d,J=1.9Hz,1H),7.18-6.78(m,1H),5.57(t,J=5.6Hz,1H),4.67(d,J=5.6Hz,2H). 19 F NMR(282MHz,DMSO-d6)δ-119.24.

[0671] Step 4: Preparation of 7-(chloromethyl)-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one :

[0672] To a stirred mixture of 3-(difluoromethyl)-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (290 mg, 1.28 mmol, 1.00 equiv) in DCM (5 mL) was added dropwise DMF (9 mg, 0.12 mmol, 0.10 equiv) and SOCl2 (0.93 mL, 12.82 mmol, 10.00 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one (310 mg, crude). LC-MS: (ES+H, m / z): [M+H] + =245.1.

[0673] Step 5: N-cyclopropyl-5-{[(2R,3S)-1-{[7-(difluoromethyl)-6-oxo-5H-1,5-naphthyridin-3-yl] Preparation of methyl}-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide :

[0674] To a stirred solution of 7-(chloromethyl)-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one (110 mg, 0.45 mmol, 1.00 equiv), N-cyclopropyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide (144 mg, 0.58 mmol, 1.30 equiv) and KI (14 mg, 0.09 mmol, 0.20 equiv) in ACN (5 mL) was added DIEA (290 mg, 2.25 mmol, 5.00 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 ° C for 1 hour. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The residue was dissolved in water (50 mL). The solution was extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a crude product (90 mg). The crude product was separated by PREP_HPLC to give: N-cyclopropyl-5-{[(2R, 3S)-1-{[7-(difluoromethyl)-6-oxo-5H-1,5-naphthyridin-3-yl]methyl}-2-methylazetidine-3-yl]oxy}pyridine-2-carboxamide (54.6 mg, 26.39%, 99.0% purity, [a] D 25 =-9.800 (C=1, MeOH:DCM=1:1), tested in PHA). LC-MS: (ES+H, m / z): [M+H] + =456.15. 1 H NMR(300MHz,DMSO-d6)δ12.30(s,1H),8.54-8.47(m,2H),8.22(d,1H),8.16(s,1H),7.95(d,1H),7.68(d,1H),7.44(dd,1H),6.98(t,1H) ,4.72-4.51(m,1H),3.98(d,1H),3.89-3.78(m,1H),3.71(d,1H),3.45-3.35(m,1H),2.95-2.74(m,2H),1.22(d,3H),0.73-0.55(m,4H). 19 F NMR(282MHz,DMSO-d6)δ-119.30.

[0675] Embodiment 76

[0676]

[0677] Step 1: Preparation of 3-bromo-2-methoxy-6-methyl-5-nitropyridine :

[0678] To a stirred mixture of 3-bromo-2-chloro-6-methyl-5-nitropyridine (20.00 g, 79.54 mmol, 1.00 equiv) in MeOH (50 mL) was added NaOMe (15.76 g, 87.49 mmol, 1.10 equiv, 30 wt%) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The results were analyzed by TLC (PE:EA=1:1, R f =0.4) to monitor the reaction. The resulting mixture was concentrated under reduced pressure, and water (100 mL) was added. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (1×200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 3-bromo-2-methoxy-6-methyl-5-nitropyridine (20 g, 99%). 1 H NMR (400MHz, DMSO-d6) δ8.66(s,1H),4.04(s,3H),2.70(s,3H).

[0679] Step 2: Preparation of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N,N-dimethylethan-1-amine :

[0680] A mixture of 3-bromo-2-methoxy-6-methyl-5-nitropyridine (15.00 g, 60.72 mmol, 1.00 equiv) in DMF-DMA (100 mL) and DMF (100 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction was monitored by TLC. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0681] Step 3: Preparation of 5-bromo-6-methoxy-3-nitropyridine aldehyde :

[0682] To a stirred mixture of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)vinyl]dimethylamine (18.01 g, crude) in THF (100 mL) and H2O (100 mL) was added NaIO4 (28.00 g, 131.07 mmol, 2.20 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. The reaction was monitored by TLC. The reaction was quenched at room temperature by adding saturated sodium thiosulfate (aqueous solution) (100 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),8.87(s,1H),4.10(s,3H).

[0683] Step 4: Preparation of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate :

[0684] To a stirred mixture of 5-bromo-6-methoxy-3-nitropyridine-2-carboxaldehyde (7.00 g, crude) and ethyl 3,3-diethoxypropionate (20.40 g, 107.27 mmol, 4.00 equiv) in EtOH (100 mL) was added SnCl2 (26.25 g, 134.09 mmol, 5.00 equiv) in batches at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 90 ° C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude mixture was poured into saturated sodium bicarbonate (100 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a crude product. The crude product was purified by trituration with hexanes (50 mL) to give ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (3.50 g, 18.5%, three steps). LC-MS: (ES+H, m / z): [M+H] + =311.0 / 313.0. 1 HNMR (400MHz, DMSO-d6) δ9.22(s,1H),8.78(s,1H),8.58(s,1H),4.42(q,2H),4.12(s,3H),1.39(t 3H).

[0685] Step 5: Preparation of ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate :

[0686] To a stirred mixture of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (1.20 g, 3.85 mmol, 1.00 equiv) in DMF (10 mL) was added CuCl (0.57 g, 5.78 mmol, 1.50 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 120 ° C overnight. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (20 mL). The resulting mixture was washed with 3×30 mL of water (10% NH3×H2O). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate (800 mg, 77.78%). LC-MS: (ES+H, m / z): [M+H] + =267.0. 1HNMR(300MHz,DMSO-d6)δ9.27(d,1H),8.63(d,1H),8.57(s,1H),4.41(q,2H),4.12(s,3H),1.37(t,3H).

[0687] Step 6: Preparation of ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate :

[0688] To a stirred mixture of ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate (800 mg, 3.00 mmol, 1.00 equiv) in CH3CN (8 mL) was added TMSI (1.80 g, 9.00 mmol, 3.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50 ° C for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (50 mL). The aqueous layer was washed with 3×50 mL of water (10% Et3N). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate (740 mg, 97.64%). LC-MS: (ES+H, m / z): [M+H] + =252.9. 1 H NMR (300MHz, DMSO-d6) δ12.61(s,1H),8.94(d,1H),8.37(d,1H),8.20(s,1H),4.39(q,2H),1.36(t,3H).

[0689] Step 7: Preparation of 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one :

[0690] To a stirred mixture of ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate (740 mg, 2.92 mmol, 1.00 equiv) in THF (6 mL) was added dropwise LiAlH4 (2.5 mL, 5.85 mmol, 2.00 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for another 2 hours. The reaction was monitored by LCMS. The mixture was acidified to pH 5 with 1M HCl. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridine-2-one (250 mg, 40.53%). LC-MS: (ES+H, m / z): [M+H] + =211.00. 1H NMR (400MHz, DMSO-d6) δ12.49(s,1H),8.45(d,1H),8.28(s,1H),7.69(d,1H),5.53(t,1H),4.64(d,2H).

[0691] Step 8: Preparation of 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one :

[0692] To a stirred mixture of 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridine-2-one (250 mg, 1.18 mmol, 1.00 equiv) in CH2Cl2 (5 mL) was added dropwise SOCl2 (423 mg, 3.56 mmol, 3.00 equiv) and DMF (8 mg, 0.11 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This gave 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridine-2-one (280 mg, crude). The crude product was used directly in the next step without further purification.

[0693] LC-MS: (ES+H, m / z): [M+H] + =228.95.

[0694] Step 9: 5-{[(2R,3S)-1-[(7-chloro-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazacyclo Preparation of [butane-3-yl]oxy]-N-cyclopropylpyridine-2-carboxamide :

[0695] A mixture of N-cyclopropyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide hydrochloride (178 mg, 0.72 mmol, 1.10 equiv), 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (150 mg, 0.65 mmol, 1.00 equiv), KI (21 mg, 0.13 mmol, 0.20 equiv) and DIEA (423 mg, 3.27 mmol, 5.00 equiv) in ACN (3 mL) was stirred at 50 ° C under a nitrogen atmosphere for 8 hours. The reaction was monitored by LCMS. The resulting mixture was cooled to room temperature and poured into 50 mL of water. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 5-{[(2R,3S)-1-[(7-chloro-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy}-N-cyclopropylpyridine-2-carboxamide (82.1 mg, 27.93%). LC-MS: (ES+H, m / z): [M+H] + =440.15. 1HNMR(300MHz,DMSO-d6)δ12.45(s,1H),8.52(d,1H),8.46(d,1H),8.27(s,1H),8.21(d,1H),7.95(d,1H),7.66(d,1H),7.44( dd,1H),4.62(q,1H),3.95(d,1H),3.82(t,1H),3.67(d,1H),3.40(q,1H),2.93-2.74(m,2H),1.21(d,3H),0.76-0.57(m,4H).

[0696] Embodiment 106

[0697]

[0698] Step 1: Preparation of (2E)-N-(3-bromo-2-fluorophenyl)-3-ethoxypropan-2-amide :

[0699] Pyridine (14.99 g, 189.45 mmol, 1.80 equiv) was added dropwise to a stirred mixture of 3-bromo-2-fluoroaniline (20.00 g, 105.25 mmol, 1.00 equiv) in DCM (300 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 hours under a nitrogen atmosphere. (2E)-3-ethoxyprop-2-enoyl chloride (21.24 g, 157.88 mmol, 1.50 equiv) was added dropwise to the above mixture over 5 minutes at room temperature. The resulting mixture was stirred for another 2 hours at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (500 mL). The resulting mixture was washed with water (3×500 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (2E)-N-(3-bromo-2-fluorophenyl)-3-ethoxyprop-2-enamide (24.6 g, 81.1%). LC-MS: (ES+H, m / z): [M+H] + =288.0 / 290.0.

[0700] Step 2: Preparation of 7-bromo-8-fluoro-1H-quinolin-2-one :

[0701] A mixture of (2E)-N-(3-bromo-2-fluorophenyl)-3-ethoxyprop-2-enamide (17.00 g, 59.00 mmol, 1.00 equiv) in H2SO4 (85 mL) was stirred at room temperature under nitrogen for 3 hours. The resulting mixture was added dropwise to ice water (1 L) and stirred for 1 hour. The precipitated solid was collected by filtration and washed with water (3×200 mL). The resulting mixture was concentrated under reduced pressure to give 7-bromo-8-fluoro-1H-quinolin-2-one (14.30 g, crude). LC-MS: (ES+H, m / z): [M+H] + =242.0 / 244.0.

[0702] Step 3: Preparation of 7-bromo-3-chloro-8-fluoro-1H-quinolin-2-one :

[0703] To a stirred mixture of 7-bromo-8-fluoro-1H-quinolin-2-one (3.00 g, 12.39 mmol, 1.00 equiv) and NCS (2.65 g, 19.83 mmol, 1.60 equiv) in CH3COOH (50 mL) was added 2,2-dichloroacetic acid (0.32 g, 2.47 mmol, 0.20 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 100 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-bromo-3-chloro-8-fluoro-1H-quinolin-2-one (2.48 g, crude product). LC-MS: (ES+H, m / z): [M+H] + =275.9 / 277.9. 1 H NMR (400MHz, DMSO-d6) δ12.52 (s, 1H), 8.38 (d, J = 1.6Hz, 1H), 7.52-7.42 (m, 2H).

[0704] Step 4: Preparation of 3-chloro-7-vinyl-8-fluoro-1H-quinolin-2-one :

[0705] To a stirred mixture of 7-bromo-3-chloro-8-fluoro-1H-quinolin-2-one (2.48 g, 8.97 mmol, 1.00 equiv), CsF (4.09 g, 26.91 mmol, 3.00 equiv), Pd(dppf)Cl2 (0.33 g, 0.44 mmol, 0.05 equiv) and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.38 g, 8.97 mmol, 1.00 equiv) in dioxane (50 mL) was added dropwise H2O (5 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-7-vinyl-8-fluoro-1H-quinolin-2-one (750 mg, 37.3%). LC-MS: (ES+H, m / z): [M+H] + =224.0. 1 H NMR(300MHz,DMSO-d6)δ12.38(s,1H),8.34(d,J=1.6Hz,1H),7.53-7.46(m,2H),6.95 (dd,J=17.7,11.2Hz,1H), 6.07(dd,J=17.7,1.0Hz,1H), 5.57(dd,J=11.2,1.0Hz,1H).

[0706] Step 5: Preparation of 3-chloro-8-fluoro-2-oxo-1H-quinoline-7-carbaldehyde :

[0707] To a stirred mixture of 3-chloro-7-vinyl-8-fluoro-1H-quinolin-2-one (750 mg, 3.35 mmol, 1.00 equiv), K2OsO2(OH)4 (123 mg, 0.33 mmol, 0.10 equiv), NaIO4 (2.87 g, 13.41 mmol, 4.00 equiv) and 2,6-lutidine (718 mg, 6.70 mmol, 2.00 equiv) in THF (15 mL) was added dropwise H2O (1.5 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-8-fluoro-2-oxo-1H-quinoline-7-carbaldehyde (630 mg, 83.2%). LC-MS: (ES-H, m / z): [MH] - =224.1.

[0708] Step 6: 5-{[(2R,3S)-1-[(3-chloro-8-fluoro-2-oxo-1H-quinolin-7-yl)methyl]-2-methylazepine Preparation of cyclobutane-3-yl]oxy}-N-methylpyridine-2-carboxamide :

[0709] A mixture of 3-chloro-8-fluoro-2-oxo-1H-quinoline-7-carbaldehyde (100 mg, 0.44 mmol, 1.00 equiv) and N-methyl-5-{[(2R, 3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide (98 mg, 0.44 mmol, 1.00 equiv) in DCM (10 mL) was stirred for 10 minutes at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. CH3COOH (13 mg, 0.22 mmol, 0.50 equiv) and EtOH (10 mL) were added to the above mixture at room temperature. The resulting mixture was stirred for another 4 hours at 50 ° C under a nitrogen atmosphere. The reaction was monitored by LCMS. NaBH3CN (56 mg, 0.88 mmol, 2.00 equiv) was added to the above mixture at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The reactant was quenched with water (3mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-{[(2R, 3S)-1-[(3-chloro-8-fluoro-2-oxo-1H-quinoline-7-yl)methyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (180mg, crude product). The crude product was purified by preparative HPLC to give 5-{[(2R, 3S)-1-[(3-chloro-8-fluoro-2-oxo-1H-quinoline-7-yl)methyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (97.2mg, 50.8%). LC-MS:(ES+H,m / z):[M+H] + =431.05.Optical rotation[a] 25 D (c=0.27,MeOH):+38.5°; 1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),8.57(q,J=4.7Hz,1H),8.35(d,J=1.3Hz,1H),8.22(d ,J=2.9Hz,1H),7.94(d,J=8.7Hz,1H),7.47(d,J=8.1Hz,1H),7.42(dd,J=8.7,2.9Hz,1H),7 .24(dd,J=8.1,6.3Hz,1H),4.58(q,J=5.9Hz,1H),3.96-3.87(m,1H),3.81(t,J=6.4Hz,1H) ,3.73-3.64(m,1H),3.39-3.34(m,1H),2.79(dd,J=8.1,5.7Hz,4H),1.20(d,J=6.2Hz,3H). 19F NMR(377MHz,DMSO-d6)δ-135.11.

[0710] The following examples were carried out using a similar procedure as shown for Example 106:

[0711]

[0712] Embodiment 110

[0713]

[0714] Step 1: 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-6-fluoropyrrolidone Preparation of methyl 2-pyridinecarboxylate :

[0715] To a stirred mixture of 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylic acid (800 mg, 2.59 mmol, 1.00 equiv) in DMF (10 mL) was added DIEA (1.00 g, 10.38 mmol, 4.00 equiv) and CH3I (320 μL, 5.19 mmol, 2.00 equiv) at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with ethyl acetate (100 mL) and washed with brine (50×2 mL). The organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography to give methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-6-fluoropicolinate (500 mg, 56.6%). LC-MS: (ES+H, m / z): [M+H] + =323.1.

[0716] Step 2: 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-6-fluoropyrrolidone Preparation of methyl 2-pyridinecarboxylate :

[0717] To a stirred mixture of 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylic acid methyl ester (400 mg, 1.24 mmol, 1.00 equiv) in MeCN (10 mL) was added difluorosilver (904 mg, 6.20 mmol, 5.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 40 ° C. under nitrogen atmosphere. The reaction was monitored by LCMS. The desired product can be detected by LCMS. The resulting mixture was filtered and the filter cake was washed with CH2Cl2 (250 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-6-fluoropyridine-2-carboxylic acid methyl ester (250 mg, 59.2%). LC-MS: (ES+H, m / z): [M+H] + =341.1. 1 H NMR(400MHz, DMSO-d6)δ7.99(d,J=8.2Hz,1H),7.53(dd,J=10.1,8.2Hz,1H),4.89-4.79(m, 1H),4.37-4.19(m,2H),3.85(s,3H),3.73-3.67(m,1H),1.45(d,J=6.5Hz,3H),1.39(s,9H). 19 F NMR(400MHz,DMSO-d6)δ-82.91.

[0718] Step 3: 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-6-fluoropyrrolidone Preparation of 2-pyridinecarboxylic acid :

[0719] To a stirred mixture of 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-6-fluoropyridine-2-carboxylic acid methyl ester (900 mg, 2.64 mmol, 1.00 equiv) in THF (5 mL) was added LiOH.HO (222 mg, 5.28 mmol, 2.00 equiv) (1 mL aqueous solution) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 50 ° C for 3 hours under nitrogen atmosphere. The reaction was monitored by LCMS. The desired product can be detected by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (100 mL). The aqueous layer was acidified to pH 3 with HCl (aqueous solution, 1N). The aqueous layer was extracted with EA (2×100 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-6-fluoropicolinic acid (800 mg, 92.7%). LC-MS: (ES-H, m / z): [MH] - =325.3.

[0720] Step 4: (3S)-3-({2-fluoro-6-(methyl-d3carbamoyl)pyridin-3-yl}oxy)-2-methylazetidine Preparation of tert-butyl 1-oxanecarboxylate :

[0721] To a stirred mixture of 5-{[(2S,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-6-fluoropyridine-2-carboxylic acid (400 mg, 1.22 mmol, 1.00 equiv) and methyl-d3-amine hydrochloride (259 mg, 3.67 mmol, 3.00 equiv) in CH2Cl2 (5 mL) was added DIEA (792 mg, 6.13 mmol, 5.00 equiv) and T3P (1 g, 3.67 mmol, 3.00 equiv, 50% CH2Cl2 solution) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The desired product can be detected by LCMS. The resulting mixture was diluted with ethyl acetate (100 mL) and washed with brine (2×100 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:1) to give tert-butyl (3S)-3-({2-fluoro-6-(methyl-d3carbamoyl)pyridin-3-yl}oxy)-2-methylazetidine-1-carboxylate (350 mg, 83.4%). LC-MS: (ES+H, m / z): [M+H-tBu] + =287.1.

[0722] Step 5: 6-Fluoro-N-methyl-d3-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate Preparation of amide hydrochloride :

[0723] To a stirred mixture of (3S)-3-({2-fluoro-6-[(2H3)methylcarbamoyl]pyridin-3-yl}oxy)-2-methylazetidine-1-carboxylic acid tert-butyl ester (350 mg, 1.02 mmol, 1.00 equiv) in CH2Cl2 (5 mL) was added dropwise a solution of HCl (gas) in 1,4-dioxane (5 mL, 4M in dioxane) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction was monitored by LCMS. The desired product can be detected by LCMS. The resulting mixture was concentrated under reduced pressure to give 6-fluoro-N-methyl-d3-5-{[(2R,3S)-2-methylazetidine-3-yl]oxy}pyridine-2-carboxamide hydrochloride (300 mg, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =243.2.

[0724] Step 6: 5-{[(2R,3S)-1-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]-2-methyl Preparation of azetidin-3-yl]oxy}-6-fluoro-N-methyl-d3-pyridine-2-carboxamide :

[0725] To a stirred mixture of 6-fluoro-N-methyl-d3-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide hydrochloride (200 mg, 0.71 mmol, assuming 100% yield, 1.00 equiv) and 7-(bromomethyl)-3-ethyl-8-fluoro-1H-quinoxalin-2-one (204 mg, 0.71 mmol, 1.00 equiv) in MeCN (5 mL) was added KI (23 mg, 0.14 mmol, 0.20 equiv) and DIEA (463 mg, 3.59 mmol, 5.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The desired product can be detected by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with CH2Cl2 / MeOH (10:1, 200 mL). The filtrate was concentrated under reduced pressure. The crude product (400 mg) was purified by HP-FLASH, and the pure fractions were concentrated in vacuo and freeze-dried to give 5-{[(2R, 3S)-1-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxaline-6-yl)methyl]-2-methylazetidine-3-yl]oxy}-6-fluoro-N-methyl-d3pyridine-2-carboxamide (163.8 mg, 50.5%). LC-MS: (ES+H, m / z): [M+H] + =447.15. 1H NMR (400MHz, DMSO-d6) δ12.40(s,1H),8.44(s,1H),7.85(d,J=8.2Hz,1H),7.61(dd,J=10.2,8.2Hz,1H),7.53(d,J=8.3Hz,1H),7.26(t,J=7.3H z,1H),4.60(q,J=5.9Hz,1H),3.90(d,1H),3.81(t,J=6.4Hz,1H),3.69(d,1H),3.40(q,J=6.0Hz,1H),2.81(q,J=7.3Hz,3H),1.23-1.19(m,6H). 19 F NMR(400MHz,DMSO-d6)δ-84.70,136.09.

[0726] Example

[0727]

[0728] Step 1-Step 2: Preparation of N-(3-bromo-2,6-difluorophenyl)-2H-pyrazole-3-carboxamide :

[0729] A stirred solution of 2H-pyrazole-3-carboxylic acid (3.00 g, 26.76 mmol, 1.00 equiv) in SOCl2 (30 mL) was stirred overnight at 90 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with toluene (3×50 mL). The resulting mixture was concentrated under reduced pressure. The crude product 1,6,7,12-tetraazatricyclo[7.3.0.0^{3,7}]twelve-3,5,9,11-tetraene-2,8-dione (2.3 g) was used directly in the next step without further purification.

[0730] To a stirred solution of 1,6,7,12-tetraazatricyclo[7.3.0.0^{3,7}]twelve-3,5,9,11-tetraene-2,8-dione (2.30 g, 12.22 mmol, 1.00 equiv) and 3-bromo-2,6-difluoroaniline (5.09 g, 24.45 mmol, 2.00 equiv) in THF (100 mL) was added NaHMDS (2 mol / L, 30.56 mL, 61.12 mmol, 5.00 equiv) dropwise at -10 °C. The resulting mixture was stirred at -10 °C for another 2 hours. The reaction was monitored by LCMS. The mixture was neutralized to pH 7 with CH3COOH. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in H2O (100 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give N-(3-bromo-2,6-difluorophenyl)-2H-pyrazole-3-carboxamide (6 g, 74.4%). LC-MS: (ES+H, m / z): [M+H] + =301.9. 1 H NMR (300MHz, DMSO-d6) δ13.49(s,1H),10.01(s,1H),7.92(d,J=2.4Hz,1H),7.78-7.66(m,1H),7.25(td,J=9.1,1.9Hz,1H),6.77(d,J=2.2Hz,1H). 19 F NMR(282MHz,DMSO-d6)δ-109.45,-117.16.

[0731] Step 3: Preparation of 7-bromo-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one :

[0732] To a stirred solution of N-(3-bromo-2,6-difluorophenyl)-2H-pyrazole-3-carboxamide (5.80 g, 19.20 mmol, 1.00 equiv) in DMA (2 mL) was added NaH (1.15 g, 28.80 mmol, 1.50 equiv, 60%) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 120 ° C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reactants were quenched with water (50 mL) at 0 ° C. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (3×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO (20 mL). The residue was purified by reverse phase flash chromatography to give 7-bromo-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one (1.5 g, 26.3%). LC-MS: (ES+H, m / z): [M+H] + =281.9. 1 H NMR (400MHz, DMSO-d6) δ12.14(s,1H),8.13(s,1H),7.89(d,J=8.9Hz,1H),7.58(t,J=7.7Hz,1H),7.21(s,1H).

[0733] Step 4: Preparation of 6-fluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin-4-one :

[0734] To a stirred solution of 7-bromo-6-fluoro-5H-pyrazolo[1,5-a]quinoxaline-4-one (1.00 g, 3.54 mmol, 1.00 equiv) and (tributylstannyl)methanol (1366 mg, 4.25 mmol, 1.20 equiv) in dioxane (16 mL) was added the second generation XPhos precatalyst (279 mg, 0.35 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 ° C. under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with DCM / MeOH=(1:5) (3×150 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6-fluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxaline-4-one (400 mg, 45.9%). LC-MS: (ES+H, m / z): [M+H] + =234.0. 1H NMR (300MHz, DMSO-d6) δ11.95(s,1H),8.10(d,J=2.1Hz,1H),7.93(dd,J=8.5,1.4Hz,1H),7.38( dd,J=8.5,7.0Hz,1H),7.19(d,J=2.1Hz,1H),5.42(t,J=5.8Hz,1H),4.63(dd,J=5.8,1.5Hz,2H).

[0735] Step 5: Preparation of 7-(chloromethyl)-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one :

[0736] To a stirred solution of 6-fluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin-4-one (300 mg, 1.28 mmol, 1.00 equiv) in DCM (8 mL) was added dropwise SOCl2 (765 mg, 6.43 mmol, 5.00 equiv) and DMF (5 mg, 0.07 mmol, 0.05 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The precipitated solid was collected by filtration and washed with DCM (3×30 mL). The crude product (7-(chloromethyl)-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one) was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =252.0

[0737] Step 6: 5-{[(2R,3S)-1-({6-fluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxalin-7-yl}methyl)- Preparation of 2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide :

[0738] To a stirred solution of 7-(chloromethyl)-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one (120 mg, 0.47 mmol, 1.00 equiv) and N-methyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide hydrochloride (147 mg, 0.57 mmol, 1.20 equiv) in MeCN (6 mL) was added KI (15 mg, 0.09 mmol, 0.20 equiv) and DIEA (246 mg, 1.90 mmol, 4.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-{[(2R,3S)-1-({6-fluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxalin-7-yl}methyl)-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (88 mg, 42.2%). LC-MS: (ES+H, m / z): [M+H] + =437.1.1 H NMR (300MHz, DMSO-d6) δ11.97(s,1H),8.57(d,J=5.0Hz,1H),8.23(d,J=2.8Hz,1H),8.11 (d,J=2.1Hz,1H),7.99-7.88(m,2H),7.43(dd,J=8.7,2.9Hz,1H),7.34(t,J=7.7Hz,1H), 7.20(d,J=2.1Hz,1H),4.59(d,J=5.9Hz,1H),3.91(d,J=13.2Hz,1H),3.83(t,J=6.3Hz,1 H),3.69(d,J=13.3Hz,1H),3.41-3.38(m,1H),2.85-2.75(m,4H),1.22(d,J=6.1Hz,3H). 19 F NMR(282MHz,DMSO-d6)δ-131.63.

[0739] The following examples were carried out using a similar procedure as shown for Example 113:

[0740]

[0741] Embodiment 115

[0742]

[0743] Step 1: Preparation of methyl 3-amino-2-fluoro-4-iodobenzoate :

[0744] A solution of methyl 3-amino-2-fluorobenzoate (20.00 g, 118.23 mmol, 1.00 equiv) and NIS (23.94 g, 106.41 mmol, 0.90 equiv) in AcOH (250 mL) was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase combi-flash chromatography to give methyl 3-amino-2-fluoro-4-iodobenzoate (4.00 g, 11.4%). LC-MS: (ES+H, m / z): [M+H] + =295.80. 1H NMR (300MHz, DMSO-d6) δ7.52 (dd, J=8.4, 1.5Hz, 1H), 6.81 (dd, J=8.3, 6.7Hz, 1H), 5.43 (s, 2H), 3.83 (s, 3H).

[0745] Step 2: Preparation of methyl 2-fluoro-3-(furan-3-amido)-4-iodobenzoate :

[0746] To a 250 mL round-bottom flask was added methyl 3-amino-2-fluoro-4-iodobenzoate (4.00 g, 13.55 mmol, 1.00 equiv), 3-furancarboxylic acid (1.52 g, 13.55 mmol, 1.00 equiv), T3P (43.14 g, 67.78 mmol, 5.00 equiv, 50% EA solution) and DIEA (2.08 g, 16.10 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred at 100 ° C under nitrogen atmosphere overnight. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 2-fluoro-3-(furan-3-amido)-4-iodobenzoate (4.50 g, 85.3%). LC-MS: (ES+H, m / z): [M+H] + =389.85. 1 H NMR (300MHz, DMSO-d6) δ9.99 (s, 1H), 8.40 (s, 1H), 7.91 (dd, J = 8.4, 1.2Hz, 1H), 7. 83(t,J=1.7Hz,1H),7.61(dd,J=8.4,7.0Hz,1H),7.02-6.96(m,1H),3.86(s,3H).

[0747] Step 3: Preparation of methyl 3-[N-(tert-butoxycarbonyl)furan-3-amido]-2-fluoro-4-iodobenzoate :

[0748] To a stirred mixture of 2-fluoro-3-(furan-3-amide)-4-iodobenzoic acid methyl ester (2.60 g, 6.68 mmol, 1.00 equiv) and (Boc)2O (2.92 g, 13.36 mmol, 2.00 equiv) in DCE (50 mL) was added DMAP (0.82 g, 6.68 mmol, 1.00 equiv) in batches at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by TLC (PE:EA=5:1). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-[N-(tert-butoxycarbonyl)furan-3-amide]-2-fluoro-4-iodobenzoic acid methyl ester (3.00 g, 91.7%).

[0749] Step 4: Preparation of methyl 6-fluoro-4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate :

[0750] PCy3 (344 mg, 1.22 mmol, 0.20 equiv), Pd(OAc)2 (275 mg, 1.22 mmol, 0.20 equiv), K2CO3 (1.69 g, 12.26 mmol, 2.00 equiv) were added to a stirred solution of methyl 3-[N-(tert-butoxycarbonyl)furan-3-amide]-2-fluoro-4-iodobenzoate (3.00 g, 6.13 mmol, 1.00 equiv) in DMF (30 mL) at room temperature under nitrogen atmosphere. The final reaction mixture was irradiated with microwave radiation at 120°C for 2 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 6-fluoro-4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate (310 mg, 19.3%). LC-MS: (ES+H, m / z): [M+H+MeCN] + =302.95.

[0751] Step 5: Preparation of methyl 6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c]quinoline-7-carboxylate :

[0752] To a stirred solution of 6-fluoro-4-oxo-5H-furo[3,2-c]quinoline-7-carboxylic acid methyl ester (200 mg, 0.76 mmol, 1.00 equiv) in CF3CH2OH (50 mL) at room temperature was added Pd / C (163 mg, 10%). The resulting mixture was stirred at room temperature overnight under a hydrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered; the filter cake was washed with CH2Cl2 / MeOH (10:1, 3×50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c]quinoline-7-carboxylic acid methyl ester (70 mg, 34.7%). LC-MS: (ES+H, m / z): [M+H] + =263.95. 1 H NMR (300MHz, DMSO-d6) δ11.68(s,1H),7.58(dd,J=8.4,6.1Hz,1H),7.49(d,J=8.5Hz,1H),4.85(t,J=9.4Hz,2H),3.89(s,3H),3.10(t,J=9.4Hz,2H). 19 F NMR(377MHz,DMSO-d6)δ-124.45.

[0753] Step 6: Preparation of 6-fluoro-7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one :

[0754] To a stirred solution of methyl 6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c]quinoline-7-carboxylate (60 mg, 0.22 mmol, 1.00 equiv) in THF (5 mL) was added dropwise LiAlH4 (0.18 mL, 0.45 mmol, 2.00 equiv, 2.5 M in THF) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The reaction was quenched by the addition of aqueous HCl (1 M, 0.5 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6-fluoro-7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (50 mg, 93.2%). LC-MS: (ES+H, m / z): [M+H] + =236.0

[0755] Step 7: Preparation of 7-(chloromethyl)-6-fluoro-2H,3H,5H-furo[3,2-c]quinolin-4-one :

[0756] To a stirred solution of 6-fluoro-7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (50 mg, 0.21 mmol, 1.00 equiv) and DMF (2 mg, 0.02 mmol, 0.10 equiv) in DCM (10 mL) was added dropwise SOCl2 (253 mg, 2.13 mmol, 10.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-6-fluoro-2H,3H,5H-furo[3,2-c]quinolin-4-one (50 mg, 92.7%). LC-MS: (ES+H, m / z): [M+H] + =254.0

[0757] Step 8: 5-{[(2R,3S)-1-({6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c]quinolin-7-yl}methyl Preparation of 2-methyl-1,2-dihydro-2-nitro-1-yl]-2-methyl-azetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide :

[0758] A solution of N-methyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide (62 mg, 0.28 mmol, 1.10 equiv) in MeCN (3 mL) was treated with DIEA (132 mg, 1.02 mmol, 4.00 equiv) at room temperature under nitrogen atmosphere for 5 minutes, followed by the addition of KI (4 mg, 0.02 mmol, 0.10 equiv) and 7-(chloromethyl)-6-fluoro-2H,3H,5H-furo[3,2-c]quinolin-4-one (65 mg, 0.25 mmol, 1.00 equiv). The resulting mixture was stirred at 80 ° C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-{[(2R,3S)-1-({6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c]quinolin-7-yl}methyl)-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (62.0 mg, 54.0%). LC-MS: (ES+H, m / z): [M+H] + =439.10. 1H NMR (300MHz, DMSO-d6) δ11.40(s,1H),8.57(d,J=4.9Hz,1H),8.22(d,J=2.8Hz, 1H),7.94(d,J=8.7Hz,1H),7.46-7.34(m,2H),7.24-7.15(m,1H),4.82(t,J=9. 3Hz,2H),4.58(q,J=5.9Hz,1H),3.96-3.76(m,2H),3.69(d,J=13.3Hz,1H),3.4 0-3.36(m,1H),3.07(t,J=9.2Hz,2H),2.81-2.74(m,4H),1.19(d,J=6.2Hz,3H). 19 F NMR(282MHz,DMSO-d6)δ-133.55.

[0759] The following examples were carried out using a similar procedure as shown for Example 113:...

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

2. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

3. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

4. The compound of claim 1, which is:

5. The compound of claim 2, which is:

6. The compound of claim 3, which is:

7. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

8. A pharmaceutical composition comprising the compound of claim 4 and a pharmaceutically acceptable excipient.

9. A pharmaceutical composition comprising the compound of claim 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

10. A pharmaceutical composition comprising the compound of claim 5 and a pharmaceutically acceptable excipient.

11. A pharmaceutical composition comprising the compound of claim 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

12. A pharmaceutical composition comprising the compound of claim 6 and a pharmaceutically acceptable excipient.

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