Azetidine and pyrrolidine PARP1 inhibitors and uses thereof

Abstract

To provide azetidine and pyrrolidine PARP1 inhibitors and uses thereof.SOLUTION: Described herein are azetidine and pyrrolidine PARP1 inhibitors and pharmaceutical compositions comprising the inhibitors. The subject compounds and compositions are useful for the treatment of cancer. Poly(ADP-ribose)polymerase (PARP) or poly(ADP-ribose)synthase (PARS) has an essential role in facilitating DNA repair, controlling RNA transcription, mediating cell death, and regulating immune response.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (cross reference) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 251,469, filed October 1, 2021, U.S. Provisional Patent Application No. 63 / 339,597, filed May 9, 2022, and U.S. Provisional Patent Application No. 63 / 402,835, filed August 31, 2022, which are incorporated by reference herein in their entireties. [Background technology]

[0002] Poly(ADP-ribose) polymerase (PARP) or poly(ADP-ribose) synthase (PARS) plays a key role in promoting DNA repair, controlling RNA transcription, mediating cell death, and regulating immune responses. These actions make PARP inhibitors targets for a wide range of diseases. PARP inhibitors have demonstrated efficacy in numerous models of disease, particularly in models of ischemia-reperfusion injury, inflammatory and degenerative diseases, protection from the adverse effects of cytotoxic compounds, and enhancement of cytotoxic cancer therapy. PARP has also been implicated in retroviral infection, and thus inhibitors may be used in antiretroviral therapy. PARP inhibitors are effective in preventing ischemia-reperfusion injury in models of myocardial infarction, stroke, other neurotrauma, 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 utility in several models of degenerative diseases, including diabetes (and its complications) and Parkinson's disease. PARP inhibitors can ameliorate liver toxicity after acetaminophen overdose, cardiac and renal toxicity from doxorubicin and platinum-based antitumor drugs, and skin damage secondary to sulfur mustard. In various cancer models, PARP inhibitors have been shown to enhance radiation and chemotherapy by increasing cancer cell death, limiting tumor growth, reducing metastasis, and prolonging the survival of tumor-bearing animals.

[0003] PARP1 and PARP2 are the most widely studied PARPs for their role in DNA damage repair. PARP1 is activated by DNA damage incisions 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 the DNA lesion.

[0004] Following completion of this recruitment role, auto-PARylation of PARP releases it from DNA, allowing it access to other DNA repair proteins to complete the repair. Thus, PARP binding to the damage site, its catalytic activity, and its eventual release from DNA are all critical steps for cancer cell response to DNA damage caused by chemotherapy drugs and radiation therapy.

[0005] Inhibition of PARP family enzymes has been utilized as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Numerous preclinical and clinical studies have demonstrated that tumor cells harboring 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 are defective in the homologous recombination repair (HRR) pathway and depend on PARP enzyme function for survival. While PARP inhibitor therapy primarily targets SRCA-mutated cancers, PARP inhibitors are currently undergoing clinical trials in non-SRCA-mutated tumors, i.e., tumors exhibiting homologous recombination deficiency (HRD). is being carried out.

[0006] PARP inhibitors with improved selectivity for PARP1 are believed to have improved efficacy and reduced toxicity compared to other clinical PARP1 / 2 inhibitors. Furthermore, selective and potent inhibition of PARP1 is thought to trap PARP1 in DNA, leading to DNA double-strand breaks (DSBs) caused by S-phase replication fork collapse. PARP1-DNA trapping is also thought to be an effective mechanism for selectively killing tumor cells with HRD. Therefore, there is an unmet medical need for effective and safe PARP inhibitors. In particular, PARP inhibitors with selectivity for PARP1 are believed to be effective. Summary of the Invention

[0007] Disclosed herein are compounds of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R 1 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; X is N or CR 2 and R 2 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Or R 1 and R 2 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; Z is N or CR 4 and R 4 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Y is N or CR 5 and R 5 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 6 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Each R 7 are independently hydrogen, deuterium, fluoro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R 7 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; n is 1 or 2, 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 Rd , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or, two R on the same carbon 8 together to form oxo, or Or, two R on the same carbon or adjacent carbons 8 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; p is 0 to 4; W is absent, -C(R 9 )2-, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR W )- or -NR W - and Each R 9 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R 9 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; R W is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; 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)Ra , -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 deuteroalkyl, 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; q is 0 to 4; Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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; Each R bare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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; Each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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; Or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently selected from 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or, two R on the same atom form an oxo, However, the compound of formula (I) [ka] isn't it.

[0008] Also disclosed herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, X 1 and X 2 Ring B taken together with is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; X 1 is C, CH, or N, X 2 is C, CH, or N, Each R 11 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; m is 0 to 3; Z is N or CR 4 and R 4 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Y is N or CR 5 and R 5 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 6 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Each R 7 are independently hydrogen, deuterium, fluoro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R 7 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; n is 1 or 2, 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or, two R on the same carbon 8 together to form oxo, or Or, two R on the same carbon or adjacent carbons 8 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; p is 0 to 4; W is absent, -C(R 9 )2-, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR W )- or -NR W - and Each R 9 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R 9 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; R W is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 10are 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 deuteroalkyl, 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; q is 0 to 4; Each R ais independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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; Each R b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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; Each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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; Or Rc and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently selected from 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R on the same atom form an oxo.

[0009] Also disclosed herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0010] Also disclosed herein are methods of treating cancer in a subject in need thereof, 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, hematological cancer, gastrointestinal cancer, or lung cancer.

[0011] Also disclosed herein are methods of treating cancer harboring a BRCA1 and / or BRCA2 mutation in a subject in need thereof, the methods comprising administering a compound of any one of claims 1-70, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the cancer is bladder cancer, brain and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, gastric cancer, thyroid cancer, or uterine cancer. Incorporation by Reference

[0012] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0013] definition In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the present invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless otherwise required by context, the word "comprise" and variations thereof, such as "comprises" and "comprising" will be used throughout the following specification and claims. ) should be interpreted in an open and inclusive sense, i.e., "including, but not limited to." Furthermore, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0014] References throughout this specification to "some embodiments" or "embodiments" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Note also that the term "or" is generally used in its sense to include "and / or" unless the content clearly dictates otherwise.

[0015] As used herein, the following terms have the following meanings unless otherwise indicated.

[0016] "Oxo" refers to =O.

[0017] "Carboxyl" refers to --COOH.

[0018] "Cyano" refers to -CN.

[0019] "Alkyl" refers to a straight- or branched-chain saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, more preferably 1 to 6 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, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, and the like. Wherever it appears herein, a numerical range such as "C1-C6 alkyl" or "C1-6 alkyl" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is a C1- 10In some embodiments, the alkyl is an alkyl. In some embodiments, the alkyl is a C1-6 alkyl. In some embodiments, the alkyl is a C1-5 alkyl. In some embodiments, the alkyl is a C1-4 alkyl. In some embodiments, the alkyl is a C1-3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl is optionally substituted with oxo, halogen, —CN, —COOH, —COOMe, —OH, —OMe, —NH2, or —NO2. In some embodiments, the alkyl is optionally substituted with halogen, —CN, —OH, or —OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0020] "Alkenyl" refers to a straight- or branched-chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. This group can be in either the cis or trans conformation about the double bond and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH), 1-propenyl (-CHCH=CH), isopropenyl [-C(CH=CH], butenyl, 1,3-butadienyl, and the like. Wherever it appears herein, a numerical range such as "C2-C6 alkenyl" or "C2-6 alkenyl" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; however, this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. Unless specifically stated otherwise in this specification, an alkenyl group can be any group, for example, For example, alkenyl may be optionally substituted with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkenyl is optionally substituted with oxo, halogen, —CN, —COOH, —COOMe, —OH, —OMe, —NH, or —NO. In some embodiments, alkenyl is optionally substituted with halogen, —CN, —OH, or —OMe. In some embodiments, alkenyl is optionally substituted with halogen.

[0021] "Alkynyl" refers to a straight- or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadinyl, and the like. Wherever it appears herein, a numerical range such as "C2-C6 alkynyl" or "C2-6 alkynyl" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; however, this definition also encompasses occurrences of the term "alkynyl" without a specified numerical range. Unless stated otherwise specifically in the specification, alkynyl groups may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0022] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, alkylene groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkylene is optionally substituted with halogen.

[0023] "Alkoxy" means a group of the formula -OR a refers to the radical of R a is an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0024] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems and may include fused ring systems (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. In some embodiments, an aryl is a 6- to 10-membered aryl. In some embodiments, an aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, an aryl is optionally substituted with halogen.

[0025] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused ring systems (when fused to an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. In some embodiments, a cycloalkyl is fully saturated. Representative cycloalkyls include those having 3 to 15 carbon atoms (C3 to C6). 15 Cycloalkyl or C3-C 15Cycloalkenyl), 3 to 10 carbon atoms (C3 to C 10 Cycloalkyl or C3-C 10Examples of cycloalkyls include, but are not limited to, cycloalkyls having 3 to 8 carbon atoms (C-C cycloalkyl or C-C cycloalkenyl), 3 to 6 carbon atoms (C-C cycloalkyl or C-C cycloalkenyl), 3 to 5 carbon atoms (C-C cycloalkyl or C-C cycloalkenyl), or 3 to 4 carbon atoms (C-C cycloalkyl or C-C cycloalkenyl). In some embodiments, a cycloalkyl is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, a cycloalkyl is a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, a cycloalkyl is a 5- to 6-membered cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl include 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]heptanyl. Examples of partially saturated cycloalkyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, cycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, 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, —CF, —OH, —OMe, —NH, or —NO.In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0026] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0027] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, 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.

[0028] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0029] "Aminoalkyl" refers to an alkyl radical, as defined above, substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyls include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0030] "Cyanoalkyl" refers to an alkyl radical, as defined above, that is substituted with one or more cyano groups. In some embodiments, the alkyl is substituted with one cyano. In some embodiments, the alkyl is substituted with one or two cyano. Cyanoalkyl includes, for example, cyanomethyl.

[0031] "Deuteroalkyl" refers to an alkyl radical, as defined above, that is substituted with one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyls include, for example, CD3, CHD, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0032] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl consists of 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof, and the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH, -CHCHOCH, -CHCHOCHCHOCH, -CH(CH)OCH, -CHNHCH, -CHN(CH), -CHCHNHCH, or -CHCHN(CH). Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, a heteroalkyl is optionally substituted with halogen.

[0033] "Heterocycloalkyl" refers to a 3- to 24-membered partially or fully saturated ring radical 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, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heterocycloalkyl contains 1 to 3 nitrogens. In some embodiments, a heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, a heterocycloalkyl contains 1 nitrogen. In some embodiments, a heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless stated otherwise specifically in the specification, a heterocycloalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and can include fused ring systems (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Representative heterocycloalkyls include those having 2 to 15 carbon atoms (C2 to C6). 15 Heterocycloalkyl or C2-C 15 heterocycloalkenyl), 2 to 10 carbon atoms (C2 to C 10 Heterocycloalkyl or C2-C 10heterocycloalkenyl), 2 to 8 carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (C2-C6 heterocycloalkyl or C2-C6 heterocycloalkenyl), 2 to 5 carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, and pyrrolidinyl. Examples of heterocycloalkyl include, but are not limited to, pyrazolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 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. The term heterocycloalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyls have 2 to 10 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number (including heteroatoms) of atoms comprising the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl.In some embodiments, a heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, a heterocycloalkyl is optionally substituted with halogen.

[0034] "Heteroaryl" refers to a 5-14 membered ring system radical containing 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, a heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heteroaryl contains 1-3 nitrogens. In some embodiments, a heteroaryl contains 1 or 2 nitrogens. In some embodiments, a heteroaryl contains 1 nitrogen. A heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is attached through an aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. In some embodiments, heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, heteroaryl is a 6-membered heteroaryl. In some embodiments, heteroaryl is a 5-membered heteroaryl. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, and benzodioxolyl. , benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl , isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyranidyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, heteroaryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, heteroaryl is optionally substituted with halogen.

[0035] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances when the event or circumstance occurs and instances when the event or circumstance does not. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined above. Furthermore, an optionally substituted group may be unsubstituted (e.g., -CHCH), fully substituted (e.g., -CFCF), monosubstituted (e.g., -CHCHF), or substituted at any level between fully and monosubstituted (e.g., -CHCHF, -CHCF, -CFCH, -CFHCHF, etc.). Those of skill in the art will understand 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., a substituted alkyl may include an optionally substituted cycloalkyl group, which may continue indefinitely as defined to include an optionally substituted alkyl group). Thus, any substituent described should generally be understood to have a maximum molecular weight of up to about 1,000 daltons, more typically up to about 500 daltons.

[0036] An "effective amount" or "therapeutically effective amount" refers to the amount of a compound administered to a mammalian subject, either in a single dose or as part of a series, effective to produce a desired therapeutic effect.

[0037] "Treatment" of an individual (e.g., a mammal such as a human) or cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition following the onset of a pathological event or contact with a pathogen, and includes stabilization of the condition (e.g., the condition does not worsen) or alleviation of the condition.

[0038] "Synergistic" or "synergizing" refers to an effect of the combination that is greater than the additive effect of each component alone at the same dose.

[0039] As used herein, "PARP-associated disease or disorder" or "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.

[0040] As used herein, "PARP1-associated disease or disorder" or "PARP1-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. compound

[0041] Described herein are compounds of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, that are useful for the treatment of cancer.

[0042] Disclosed herein are compounds of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R 1 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; X is N or CR 2 and R 2 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Or R 1 and R2 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; Z is N or CR 4 and R 4 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Y is N or CR 5 and R 5 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 6 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Each R 7 are independently hydrogen, deuterium, fluoro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R 7 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; n is 1 or 2, Each R 8 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR cR d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or, two R on the same carbon 8 together to form oxo, or Or, two R on the same carbon or adjacent carbons 8 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; p is 0 to 4; W is absent, -C(R 9 )2-, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR W )- or -NR W - and Each R 9 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R 9 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; R W is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; 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 deuteroalkyl, 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; q is 0 to 4; Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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; Each R bare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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; Each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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; Or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently selected from 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or, two R on the same atom form an oxo, However, the compound of formula (I) [ka] isn't it.

[0043] Disclosed herein are compounds of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R 1 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; X is N or CR 2 and R 2 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Or R 1 and R 2 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; Z is N or CR 4 and R 4 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Y is N or CR 5 and R 5 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 6 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Each R 7 are independently hydrogen, deuterium, fluoro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R 7together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; n is 1 or 2, 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or, two R on the same carbon 8 together to form oxo, or Or, two R on the same carbon or adjacent carbons 8 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; p is 0 to 4; W is -C(R 9 )2-, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR W )- or -NR W - and Each R 9 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R 9 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; R Wis hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; 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 deuteroalkyl, 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; q is 0 to 4; Each R ais independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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; Each R b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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; Each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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; Or Rc and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently selected from 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or, two R on the same atom form an oxo, However, the compound of formula (I) [ka] isn't it.

[0044] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound is of Formula (Ia): [ka]

[0045] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound is of Formula (Ib): [ka] In the formula, each R 8a is deuterium, halogen, -CN, -NO2, -OH, -OR a , -NRc R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; p' is 0 to 3.

[0046] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound is of Formula (Ic): [ka]

[0047] In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 represents hydrogen, deuterium, halogens, -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.

[0048] In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is 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.

[0049] In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1 alkyl, C3-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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 a 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 deuteroalkyl, or cycloalkyl. In some embodiments of a 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 a 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 a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1is ethyl.

[0050] In some embodiments of a 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a 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 a 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 deuteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a 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 a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cyclopropyl.

[0051] In some embodiments of a 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a 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 deuteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a 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.

[0052] In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is N. In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is CR 2 is.

[0053] In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 2is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a 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 a 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 a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen.

[0054] In some embodiments of a 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 of which is optionally substituted with one or more R. In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 taken together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R. In some embodiments of a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 taken together form an aryl or heteroaryl, each optionally substituted with one or more R.

[0055] Disclosed herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, X 1 and X 2 Ring B taken together with is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; X 1 is C, CH, or N, X 2 is C, CH, or N, Each R 11 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; m is 0 to 3; Z is N or CR 4 and R 4 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Y is N or CR 5 and R 5 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 6 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Each R 7 are independently hydrogen, deuterium, fluoro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R 7 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; n is 1 or 2, 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or, two R on the same carbon 8 together to form oxo, or Or, two R on the same carbon or adjacent carbons 8 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; p is 0 to 4; W is absent, -C(R 9 )2-, -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR W )- or -NR W - and Each R 9 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NRc R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R 9 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; R W is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; 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 deuteroalkyl, 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; q is 0 to 4; Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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; Each R b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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; Each R c and R dare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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; Or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently selected from 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R on the same atom form an oxo.

[0056] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 and X 2and ring B taken together is a 5-membered heterocycloalkyl. In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 and X 2 and Ring B taken together is pyrrolidinyl or furanyl. In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 and X 2 and Ring B taken together is a 5-membered heteroaryl. In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 and X 2 and Ring B taken together is pyrrolyl, pyrazolyl, imidazolyl, or triazolyl. In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 and X 2 and Ring B taken together is pyrazolyl or imidazolyl. In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 and X 2 and ring B taken together is pyrazolyl. In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 and X 2 Ring B taken together with is a furanyl.

[0057] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is 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 2is 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.

[0058] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is N. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is CR 4 is.

[0059] In some embodiments of a 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 deuteroalkyl. In some embodiments of a 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 a 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 a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 is hydrogen.

[0060] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is N. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is CR 5 is.

[0061] In some embodiments of a 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 deuteroalkyl. In some embodiments of a 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 a 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 a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 5 is hydrogen.

[0062] In some embodiments of a 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 deuteroalkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 6is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of a 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 a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 6 is hydrogen.

[0063] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 7 are independently hydrogen, deuterium, fluoro, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl.

[0064] In some embodiments of a 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, fluoro, or C1-C6 alkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 7 is independently hydrogen, fluoro, or C1-C6 alkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 7 is independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 7is independently hydrogen or fluoro. In some embodiments of a 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 a 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 is a C1-C6 alkyl.

[0065] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, two R 7 are taken together to form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R. In some embodiments of a 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 a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, two R 7 together form a cycloalkyl.

[0066] In some embodiments of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 1. In some embodiments of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 2.

[0067] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 8are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a 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 deuteroalkyl. In some embodiments of a 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 a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 8 is independently —CN or C1-C6 alkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 8 is independently C1 to C6 alkyl.

[0068] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, two R 8 taken together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R. In some embodiments of a 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 taken together form a cycloalkyl or heterocycloalkyl.

[0069] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, two R 8 are taken together to form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, two R 8 taken together form a cycloalkyl or heterocycloalkyl.

[0070] In some embodiments of a compound of Formula (I), (Ia), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 0 to 3. In some embodiments of a compound of Formula (I), (Ia), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 0 to 2. In some embodiments of a 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 a compound of Formula (I), (Ia), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 2 to 4. In some embodiments of a 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 a compound of Formula (I), (Ia), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 1 to 4. In some embodiments of a compound of Formula (I), (Ia), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 1 to 3. In some embodiments of a 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 a compound of Formula (I), (Ia), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 0. In some embodiments of a compound of Formula (I), (Ia), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 1. In some embodiments of a compound of Formula (I), (Ia), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 2. In some embodiments of a compound of Formula (I), (Ia), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 3.

[0071] In some embodiments of a compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p' is 0 to 2. In some embodiments of a compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p' is 0 or 1. In some embodiments of a compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p' is 2 or 3. In some embodiments of a compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p' is 1 to 3. In some embodiments of a compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p' is 1 or 2. In some embodiments of a 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.

[0072] In some embodiments of the compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 8a is deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. 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 deuteroalkyl. In some embodiments of a compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 8ais deuterium, halogen, —CN, or C1-C6 alkyl. In some embodiments of a 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 is a C1-C6 alkyl.

[0073] In some embodiments of a 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 a 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 a 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 a 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 a 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)-, or -S(=O)(=NR W)-. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, W is -S-, -S(=O)-, or -S(=O)2-. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, W is -O-. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, W is -NR W2 In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, W is absent.

[0074] In some embodiments of a 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, fluoro, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a 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, fluoro, or C1-C6 alkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 9 is independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 9is independently hydrogen, fluoro, or C1-C6 alkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 9 is independently hydrogen or fluoro. In some embodiments of a 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 a 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 is a C1-C6 alkyl.

[0075] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, two R 9 are taken together to form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R. In some embodiments of a 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 a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, two R 9 together form a cycloalkyl.

[0076] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R Wis hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R W is hydrogen.

[0077] In some embodiments of a 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 a 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 a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is heterocycloalkyl.

[0078] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is aryl or heteroaryl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is phenyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is heteroaryl.

[0079] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is a 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is a 5-membered heteroaryl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is a 6-membered heteroaryl.

[0080] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is not pyridinyl. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, ring A is [ka] isn't it.

[0081] In some embodiments of a 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, provided that one R 10 is not —C(═O)NHCH. In some embodiments of a 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, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a 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 deuteroalkyl.

[0082] In some embodiments of a 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 deuteroalkyl.

[0083] In some embodiments of a 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 is.

[0084] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, q is 0 to 3. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, q is 0 to 2. In some embodiments of a 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 a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, q is 1 to 4. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, q is 1 to 3. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, q is 2 to 4. In some embodiments of a 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 a 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 a 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 a 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 a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, q is 3.

[0085] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, [ka] teeth, [ka] isn't it.

[0086] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, [ka] teeth, [ka] is.

[0087] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, [ka] teeth, [ka] is.

[0088] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R ais independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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 a 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 deuteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a 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, and each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a 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, and each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a 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, each alkyl independently and optionally substituted with one or more R.

[0089] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R bis independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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 a 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, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a 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, and each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a 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, and each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a 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, and each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R bis independently hydrogen or C1-C6 alkyl independently and optionally substituted with one or more R.

[0090] In some embodiments of a 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, C1-C6 deuteroalkyl, 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 a 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, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a 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, and each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R c and R dis independently hydrogen, C1-C6 alkyl, or cycloalkyl, and each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a 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, and each alkyl is independently and optionally substituted with one or more R. In some embodiments of a 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 or C1-C6 alkyl independently and optionally substituted with one or more R. In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R c is cycloalkyl and R d is hydrogen.

[0091] In some embodiments of a 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 form a heterocycloalkyl optionally substituted with one or more R. In some embodiments of a 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 atom to which they are attached form a heterocycloalkyl.

[0092] In some embodiments of a 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, —OCi-C6 alkyl, —NH, —NHCi-C6 alkyl, —N(Ci-C6 alkyl), —C(═O)Ci-C6 alkyl, —C(═O)OH, —C(═O)OCi-C6 alkyl, —C(═O)NH, —C(═O)N(Ci-C6 alkyl), —C(═O)NHCi-C6 alkyl, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 deuteroalkyl, or two R on the same atom form oxo. In some embodiments of a 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, —OCi-C alkyl, —NH, —NHCi-C alkyl, —N(Ci-C alkyl) , Ci-C alkyl, Ci-C haloalkyl, or Ci-C deuteroalkyl, or two R on the same atom form oxo. In some embodiments of a 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, —O—C alkyl, —C alkyl, C haloalkyl, or C deuteroalkyl, or two R on the same atom form oxo.

[0093] In some embodiments of the compounds disclosed herein, each R a , R b , R c , R d , R 1 and R 2 a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl formed when two R 7 Cycloalkyl and heterocycloalkyl formed when two R 8Cycloalkyl and heterocycloalkyl formed when two R 9 taken together, cycloalkyl and heterocycloalkyl formed when R c and R d taken together, the heterocycloalkyl formed is independently substituted with 1, 2, 3, or 4 substituents as defined herein. In some embodiments of the compounds disclosed herein, each R a , R b , R c , R d , R 1 and R 2 a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl formed when two R 7 Cycloalkyl and heterocycloalkyl formed when two R 8 Cycloalkyl and heterocycloalkyl formed when two R 9 taken together, cycloalkyl and heterocycloalkyl formed when R c and R d taken together, the heterocycloalkyl formed is independently substituted with 1, 2, or 3 substituents as defined herein. In some embodiments of the compounds disclosed herein, each R a , R b , R c , R d , R 1 and R 2 a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl formed when two R 7 Cycloalkyl and heterocycloalkyl formed when two R 8 Cycloalkyl and heterocycloalkyl formed when two R 9 taken together, cycloalkyl and heterocycloalkyl formed when R c and R dtaken together form a heterocycloalkyl, which is independently substituted with one or two substituents as defined herein.

[0094] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0095] In some embodiments, the compound disclosed herein is a compound selected from Table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12]

[0096] The absolute label (abs) is added to the chiral center to indicate that it is a pure sample of the specifically depicted stereoisomer.

[0097] The OR label (or) indicates a pure substance, but the absolute configuration of the stereochemical centers is unknown. After chiral separation with isolated pure structures, multiple OR labels with the same numerical value (OR indicates purity) indicate that the sample is one of a pair of pure enantiomers (but the absolute configuration of the stereochemical centers is unknown). Further forms of the compounds disclosed herein Isomers / stereoisomers

[0098] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds described herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as their corresponding mixtures. In some circumstances, the compounds described herein possess one or more chiral centers, with each center existing in either the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers obtained from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereoisomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomers are then recovered, along with the resolving agent, by any practical means that does not result in racemization. labeled compound

[0099] In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those listed herein, except for the fact that one or more atoms have been replaced by an atom having an atomic mass or mass number different from that usually 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, for example, 2 H, 3 H, 13 C. 14 C. l5 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Compounds described herein, and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds, e.g., 3 H and 14 Those in which a radioactive isotope such as 3C is incorporated are useful in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, heavy isotopes such as deuterium, i.e., 2 Substitution by, for example, H may confer particular therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0100] 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. pharmaceutically acceptable salts

[0101] In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt as a pharmaceutical composition.

[0102] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number 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 solvates or stereoisomers thereof, or by separately reacting the purified compounds in free form with the appropriate acid or base and isolating the salt thus formed.

[0103] Examples of pharmaceutically acceptable salts include salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, etc. Salt, 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, iodide The salts include benzoate, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, 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, tosylate undeconate, and xylenesulfonate.

[0104] Additionally, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including 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, 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, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, are used in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, their solvates, or stereoisomers, and their pharmaceutically acceptable acid addition salts.

[0105] In some embodiments, compounds described herein containing free acid groups are reacted with a suitable base, such as a hydroxide, carbonate, bicarbonate, or sulfate salt of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Specific examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl)4.

[0106] Representative organic amines useful for the formation of 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- or oil-soluble or dispersible products are obtained by such quaternization. solvate

[0107] 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 further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0108] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and, in some embodiments, are formed using pharmaceutically acceptable solvents such as water, ethanol, and the like. 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 processes described herein. For example, 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. Furthermore, the compounds provided herein can exist in unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein. tautomers

[0109] In some situations, 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 a hydrogen atom, accompanied by the switching of a single bond and an adjacent double bond. In bonding configurations where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Treatment method

[0110] Disclosed herein are methods for treating diseases in which inhibition of PARP is beneficial, the methods comprising administering a compound disclosed herein. Also disclosed herein are methods for 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, hematological 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.

[0111] In some embodiments, the cancer comprises a BRCA1 and / or BRCA2 mutation.

[0112] In some embodiments, the cancer containing a BRCA1 and / or BRCA2 mutation is bladder cancer, brain and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin's lymphoma, non-Hodgkin's 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.

[0113] In some embodiments, the cancer is a cancer with a deficiency in homologous recombination (FIR)-dependent DNA DSB repair activity. The FIR-dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA via a homologous mechanism and reforms a continuous DNA helix. Components of the FIR-dependent DNA DSB repair pathway include 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), and MRE1 (NM_001111). A (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, a cancer deficient in FIR-dependent DNA DSB repair comprises one or more cancer cells that have reduced or eliminated ability to repair DNA DSBs via the pathway compared to normal cells, i.e., activity of the FIR-dependent DNA DSB repair pathway may be reduced or eliminated in one or more cancer cells.

[0114] 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 with a cancer that is deficient in FIR-dependent DNA DSB repair.

[0115] In some embodiments, cancer cells have a BRCA1 and / or BRCA2-deficient phenotype, i.e., BRCA1 and / or BRCA2 activity is reduced or absent in the cancer cells. Cancer cells with this phenotype may be BRCA1 and / or BRCA2-deficient, i.e., BRCA1 and / or BRCA2 expression and / or activity may be reduced or absent in the cancer cells, for example, due to a mutation or polymorphism in the encoding nucleic acid, or due to amplification, mutation, or polymorphism in a gene encoding a regulator, such as the EMSY gene encoding the BRCA2 regulator. BRCA1 and BRCA2 are known tumor suppressors whose wild-type alleles are frequently lost in tumors of heterozygous carriers. Amplification of the EMSY gene, which encodes a BRCA2-binding factor, is also known to be associated with breast and ovarian cancer. Carriers of mutations in BRCA1 and / or BRCA2 are also at increased risk of certain cancers, including breast, ovarian, pancreatic, prostate, hematological, gastrointestinal, and lung cancers. Administration

[0116] In certain embodiments, compositions containing the compounds described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest at least one symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous medications, the patient's health status, weight, and response to the medication, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0117] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose." For this use, the precise amount will also depend on the patient's health, weight, and the like. When used in a patient, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous medications, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatment involves administering a pharmaceutical composition containing a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal that has previously experienced at least one symptom or risk factor of the disease being treated and is now in remission, to prevent the recurrence of symptoms of the disease or condition.

[0118] In certain embodiments in which the patient's condition does not improve, at the physician's discretion, administration of the compound is administered chronically, i.e., for an extended period of time, including the entire lifespan of the patient, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0119] In certain embodiments where the patient's condition improves, the dose of the administered drug is temporarily reduced or temporarily stopped for a specified 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, by way of 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. The dose reduction during the drug holiday is, by way of example only, between 10% and 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0120] Once the patient's condition has improved, a maintenance dose is administered as needed. Thereafter, in specific embodiments, the dosage or frequency of administration, or both, is reduced, depending on the symptoms, to a level at which the improved disease, disorder, or condition is maintained. However, in certain embodiments, the patient requires long-term, intermittent, or daily treatment upon any recurrence of symptoms.

[0121] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0122] In general, however, doses used for adult treatment typically range from 0.01 mg to 5000 mg per day. In one aspect, doses used for adult treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented as a single dose or as divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four or more divided doses per day.

[0123] In one embodiment, a suitable daily dosage for a compound described herein or a pharmaceutically acceptable salt thereof is about 0.01 to about 50 mg / kg of body weight. In some embodiments, the daily dosage or amount of active agent in a dosage form is lower or higher than the ranges set forth herein, based on a number of variables related to the particular treatment regimen. In various embodiments, the daily dosage and unit dosage amount will vary depending on several variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0124] The toxicity and therapeutic efficacy of such treatment regimens include, but are not limited to, LD 10 and ED 90The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating therapeutically effective daily dose ranges and / or therapeutically effective unit doses for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is such that the ED 50 In certain embodiments, the daily dosage range and / or unit dosage amount varies within this range depending on the dosage form employed and the route of administration utilized.

[0125] In any of the foregoing aspects, in further embodiments, 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 by injection to a mammal, and / or (e) administered topically to a mammal, and / or (f) administered non-systemically or topically to a mammal.

[0126] In any of the foregoing aspects, further embodiments include a single administration of an effective amount of the compound, including further embodiments where (i) the compound is administered once daily, or (ii) the compound is administered multiple times over a daily period to the mammal.

[0127] In any of the foregoing aspects, further embodiments include multiple administrations of an effective amount of the compound, including further embodiments where (i) the compound is administered continuously or intermittently as a single dose, (ii) the time between multiple administrations is every 6 hours, (iii) the compound is administered to the mammal every 8 hours, (iv) the compound is administered to the subject every 12 hours, or (v) the compound is administered to the subject every 24 hours. In further or alternative embodiments, the method includes a drug holiday, during which administration of the compound is temporarily suspended or the dose of the administered compound is temporarily reduced, and at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday ranges from two days to one year. Route of administration

[0128] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Further, by way of example only, parenteral administration includes intramuscular, subcutaneous, intravenous, intrathecal injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0129] In certain embodiments, the compounds described herein are administered in a local rather than systemic manner, for example, via direct injection of the compound into an organ, often in a depot or sustained-release preparation. In specific embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, 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 embodiments, the liposome targets the organ and is selectively taken up by the organ. In still other embodiments, the compounds described herein are provided in the form of an immediate-release formulation, a sustained-release formulation, or an intermediate-release formulation. In still other embodiments, the compounds described herein are administered locally. Pharmaceutical Compositions / Formulations

[0130] The compounds described herein are administered to a subject in need thereof, in accordance with standard pharmaceutical practice, either alone or in a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, excipient, or diluent. In one embodiment, the compounds of the present invention can be administered to animals. The compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

[0131] In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein or its pharmaceutically acceptable salt, solvate, or stereoisomer 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 the processing of the active compound into a pharmaceutically usable preparation.The appropriate formulation depends on the selected route of administration. Summary summaries of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0132] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, coloring agents, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, and any combination thereof.

[0133] 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-melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed-release formulations, sustained-release formulations, pulsatile-release formulations, multiparticulate formulations, and combined immediate- and controlled-release formulations.

[0134] Pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are manufactured by conventional means, including, by way of example only, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compressing processes.

[0135] Pharmaceutical compositions for oral use can be prepared by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and optionally adding suitable additives to obtain tablets or dragee cores, followed by processing the resulting granules. 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 gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or others, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Optionally, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, are added. In some embodiments, dyes or pigments are added to tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0136] Orally administered pharmaceutical compositions 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 in a mixture of fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optional stabilizers. In soft capsules, the active compound is dissolved or suspended in a suitable liquid (e.g., fatty oils, liquid paraffin, or liquid polyethylene glycol). In some embodiments, stabilizers are added.

[0137] Pharmaceutical compositions for parenteral use are formulated for infusion or injection. In some embodiments, pharmaceutical compositions suitable for injection or infusion comprise a sterile aqueous solution or dispersion, or a sterile powder, containing a compound described herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium, including, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and any combination thereof. In some embodiments, the pharmaceutical composition further comprises a preservative to prevent the growth of microorganisms. combination

[0138] Disclosed herein are methods of treating cancer using the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, in combination with an additional therapeutic agent.

[0139] In some embodiments, the additional therapeutic agent is an anti-cancer agent. [Example]

[0140] In some embodiments, the additional therapeutic agent is administered simultaneously with the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered before administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound disclosed herein. Example 1 [ka] Step 1: Preparation of methyl 5-{[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylate:

[0141] To a stirred solution of methyl 5-hydroxypyridine-2-carboxylate (1.00 g, 6.53 mmol, 1.00 equiv.), tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (1.83 g, 9.79 mmol, 1.50 equiv.), and PPh3 (2.57 g, 9.79 mmol, 1.50 equiv.) in toluene (10 mL) was added DBAD (2.26 g, 9.79 mmol, 1.50 equiv.) in toluene (5 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h. The mixture was warmed to room temperature and stirred for 1 h. 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. Step 2: Preparation of tert-butyl (3S)-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate: A solution of methyl 5-{[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylate (2.00 g, 6.20 mmol, 1.00 equiv.) and methylamine (8.6 mL, 25% in water) in MeOH (8.6 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. 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. Step 3: Preparation of N-methyl-5-[(3S)-pyrrolidin-3-yloxy]pyridine-2-carboxamide, HCl salt:

[0142] A solution of tert-butyl (3S)-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate (1.00 g, crude) and HCl (gas) in 1,4-dioxane (8.0 mL 4M) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The product was precipitated by the addition of 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. Step 4: Preparation of 5-{[(3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide:

[0143] 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 a nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 2 hours under a nitrogen atmosphere. 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). Example 2 [ka] Step 1: Preparation of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylate:

[0144] 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 to 0 °C under a nitrogen atmosphere. To the above mixture, DEAD (2.27 g, 13.06 mmol, 2.00 equiv.) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 1 h. 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 Combiflash chromatography. This resulted in 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. Step 2: Preparation of tert-butyl (3R)-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate:

[0145] To a stirred solution of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylate (containing 3.80 g crude TPPO) in MeOH (20 mL) was added methylamine (20 mL, 25-30 wt % in water) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The desired product could be detected by LCMS. The solvent was removed under reduced pressure. The residue was purified by reverse-phase Combiflash chromatography. This yielded 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. Step 3: Preparation of N-methyl-5-[(3R)-pyrrolidin-3-yloxy]pyridine-2-carboxamide, HCl salt:

[0146] In a 100 mL round-bottom flask, tert-butyl (3R)-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate (3.80 g, containing crude TPPO) and HCl (gas) were added in 1,4-dioxane (40 mL) at room temperature. The resulting mixture was stirred at room temperature under an air atmosphere for 1 hour. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase Combiflash chromatography. This resulted in 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. Step 4: Preparation of 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide:

[0147] 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 hours. 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. 1H NMR(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).

[0148] The following examples were prepared using procedures similar to those set forth in Example 2. [Table 3] Example 3 [ka] Step 1: Preparation of ethyl 2-bromo-2-cyclopropylacetate:

[0149] To a stirred solution of ethyl 2-cyclopropylacetate (10.00 g, 78.02 mmol, 1.00 equiv) in THF (100 mL) was added LDA (42.9 mL, 85.82 mmol, 1.10 equiv, 2.0 M in THF) dropwise at −78° C. under a nitrogen atmosphere. The reaction was stirred for 1 hour, then TMSCl (8.48 g, 78.02 mmol, 1.00 equiv) was added dropwise, and the reaction was stirred for 3 hours while warming to room temperature. The reaction was cooled to −78° C., and NBS (15.28 g, 85.82 mmol, 1.10 equiv) in 50 mL of THF was added dropwise. The reaction was then stirred for 2 hours while warming to room temperature. The reaction was monitored by LCMS. The reaction was quenched by adding saturated NH4Cl (aq) (50 mL) at 0° C. The resulting mixture was extracted with EtO (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase Combiflash chromatography to give ethyl 2-bromo-2-cyclopropylacetate (5.00 g, 30.95%) as a yellow liquid. 1 H 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). Step 2: Preparation of ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate:

[0150] A solution of ethyl 2-bromo-2-cyclopropyl acetate (5.00 g, 24.14 mmol, 1.00 equiv) and triethyl phosphite (5.22 g, 31.39 mmol, 1.30 equiv) was stirred under a nitrogen atmosphere at 130° C. for 24 hours. The residue was purified by reverse-phase Combiflash chromatography to give ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate (2.40 g, 37.61%) as a yellow liquid. 1H NMR (300 MHz, chloroform-d) δ 4.26-4.07 (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).

[0151] Step 3: Preparation of methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate: 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.) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 10 minutes, then warmed to 40° C. and stirred under a nitrogen atmosphere for 10 minutes. The resulting mixture was cooled to −78° C., followed by the dropwise 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. for 30 minutes under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of saturated NH4Cl(aq.) (5 mL) at 0° C. The resulting mixture was added with 20 mL of water and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 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. Step 4: Preparation of ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate:

[0152] To a stirred mixture of methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate (600 mg, 1.87 mmol, 1.00 equiv.) and Fe (1.04 g, 18.73 mmol, 10.00 equiv.) in EtOH (10 mL), CaCl (1.24 g, 11.24 mmol, 6.00 equiv.) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere overnight. The reaction was monitored by LCMS. The mixture was allowed to cool 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, which was then extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2 x 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-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (200 mg, 41.34%). LC-MS: (ES+H, m / z): [M+H] + =259.0. Step 5: Preparation of 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one:

[0153] 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 LiAlH (0.50 mL, 1.23 mmol, 2.00 equiv., 2.5 M in THF) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The reaction was quenched by the addition of 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-naphthyridin-2-one (100 mg, 74.65%). LC-MS: (ES+H, m / z): [M+H] + =217.2. Step 6: Preparation of 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one:

[0154] 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 SOCl (264 mg, 2.22 mmol, 6.00 equiv.) dropwise 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 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. Step 7: Preparation of 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide:

[0155] 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 a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was allowed to cool 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).

[0156] The following examples were prepared using procedures similar to those set forth in Example 3. [Table 4] Example 4 [ka] Step 1: Preparation of 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylic acid:

[0157] To a stirred mixture of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylate (16.00 g, 1.00 equiv., crude) in MeOH (160 mL) was added dropwise LiOH in HO (50 mL, 2 M) at 0 °C. The mixture was stirred at 25 °C under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The reaction mixture was diluted with HO (50 mL), and the aqueous phase was extracted with EA (100 mL × 3). The aqueous phase was then adjusted to pH 5-6 with HPO 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 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylic acid (6 g, crude) as a white oil. LC-MS: (ES+H, m / z): [M+H] + =309.2. Step 2: Preparation of tert-butyl (3R)-3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate:

[0158] 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), T3P (16.52 g, 25.94 mmol, 4.00 equiv., 50 wt. % in EA) was added dropwise at 0° C. under a nitrogen atmosphere. The mixture was stirred at 25° C. for 1 h. The reaction was monitored by LCMS. The reaction mixture was diluted with HO (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 gave tert-butyl (3R)-3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate (1.5 g, crude) as an orange oil. LC-MS: (ES+H, m / z): [M+H] + =348.2 Step 3: Preparation of N-cyclopropyl-5-[(3R)-pyrrolidin-3-yloxy]pyridine-2-carboxamide:

[0159] A mixture of tert-butyl (3R)-3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate (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 a 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 combi-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 Step 4: Preparation of N-cyclopropyl-5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl}oxy}pyridine-2-carboxamide:

[0160] 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 a 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). Example 5 [ka] Step 1: Preparation of methyl 5-{[(3R,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyridine-2-carboxylate:

[0161] To a stirred solution of methyl 5-hydroxypyridine-2-carboxylate (0.30 g, 1.95 mmol, 1.00 equiv.), tert-butyl (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 DBAD (0.90 g, 3.91 mmol, 2.00 equiv.) in toluene (5 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 3 h. 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). The resulting mixture was used directly in the next step. LC-MS: (ES+H, m / z): [M+H] + =341.2. Step 2: Preparation of tert-butyl (3R,4R)-3-fluoro-4-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate:

[0162] A solution of methyl 5-{[(3R,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyridine-2-carboxylate (1.00 g, crude) and methylamine (4.0 mL, 25% in water) in MeOH (4.0 mL) was stirred at room temperature under a 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. Step 3: Preparation of 5-{[(3R,4R)-4-fluoropyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide, HCl salt:

[0163] A solution of tert-butyl (3R,4R)-3-fluoro-4-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate (1.00 g, crude) and HCl (gas) in 1,4-dioxane (8 mL, 4 M) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The product was precipitated by the addition of 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. Step 4: Preparation of 5-{[(3R,4R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-4-fluoropyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide:

[0164] 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), 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.) were added at room temperature. The resulting mixture was stirred at 80° C. under a 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-{[(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). 19 F NMR (377MHz, DMSO-d6) δ-179.44. Example 6 [ka] Step 1: Preparation of methyl 5-(((3S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)picolinate:

[0165] 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), DBAD (902 mg, 3.92 mmol, 2.00 equiv.) was added under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at 60° C. under a 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. Step 2: Preparation of tert-butyl (3S,4S)-3-fluoro-4-((6-(methylcarbamoyl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate:

[0166] To a stirred solution of methyl 5-{[(3S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyridine-2-carboxylate (4 g, crude) in MeOH (5 mL) was added dropwise at room temperature under a nitrogen atmosphere, followed by methylamine (5 mL, 25-30 wt%). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The resulting mixture was diluted with saturated NH4Cl(aq) (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. Step 3: Preparation of 5-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpicolinamide, HCl salt:

[0167] To a stirred solution of tert-butyl (3S,4S)-3-fluoro-4-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate (2.7 g, crude) in DCM (20 mL) was added dropwise 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 under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (3 x 20 mL). The precipitated solid was collected by filtration and washed with EtOAc (3 x 10 mL). This yields 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 Step 4: Preparation of 5-(((3S,4S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpicolinamide:

[0168] 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 a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was allowed to cool 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 NaSO. 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°; 1 H 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). 19F NMR(377MHz,DMSO-d6)δ-179.43. Example 7 [ka] Step 1: Preparation of 5-bromo-3-nitropicolinaldehyde:

[0169] 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 could be detected by LCMS. The mixture was allowed to cool 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 washed with THF (3 × 300 mL). The resulting mixture was concentrated under reduced pressure to give 5-bromo-3-nitropicolinaldehyde (21 g, crude). 1 H NMR (400MHz, DMSO-d6) δ10.08(s,1H), 9.22(d,1H), 8.95(d,1H). Step 2: Preparation of ethyl (2Z)-3-(5-bromo-3-nitropyridin-2-yl)-2-methylprop-2-enoate:

[0170] 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)propanoate (29.39 g, 123.37 mmol, 1.50 equiv) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 15 minutes and at 40° C. for 30 minutes under a nitrogen atmosphere. To the above mixture was added 5-bromo-3-nitropyridine-2-carbaldehyde (19.00 g, 82.25 mmol, 1.00 equiv) in THF (50 mL) dropwise over 30 minutes at −78° C. The resulting mixture was stirred at −78° C. for an additional 1 hour. The desired product could be detected by LCMS. The reaction was quenched with saturated NH4Cl (aq) at 0° C. The resulting mixture was added with water (600 mL) and extracted with EtOAc (3×600 mL). The combined organic layers were washed with brine (2×300 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography to give ethyl (2Z)-3-(5-bromo-3-nitropyridin-2-yl)-2-methylprop-2-enoate (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). Step 3: Preparation of 7-bromo-3-methyl-1H-1,5-naphthyridin-2-one:

[0171] To a stirred mixture of ethyl (2Z)-3-(5-bromo-3-nitropyridin-2-yl)-2-methylprop-2-enoate (7.60 g, 24.12 mmol, 1.00 equiv.) and Fe (8.08 g, 144.71 mmol, 6.00 equiv.) in EtOH (200 mL), CaCl (16.06 g, 144.71 mmol, 6.00 equiv.) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C 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 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 resulted in 7-bromo-3-methyl-1H-1,5-naphthyridin-2-one (5.00 g, 87%). LC-MS: (ES+H, m / z): [M+H] + =239 / 241. 1 H NMR (300MHz, DMSO-d6) δ 11.96 (s, 1H), 8.52 (d, 1H), 7.86-7.78 (m, 2H), 2.13 (d, 3H). Step 4: Preparation of ethyl 7-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate:

[0172] 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), NEt3 (6.35 g, 62.74 mmol, 3.00 equiv.) was added. 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 to give ethyl 7-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (4.5 g, 93%). LC-MS: (ES+H, m / z): [M+H] + =233. 1H 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). Step 5: Preparation of 7-(hydroxymethyl)-3-methyl-1H-1,5-naphthyridin-2-one:

[0173] 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 LiAlH (15.5 mL, 38.75 mmol, 2.00 equiv., 2.5 M in THF) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The reaction was quenched by the addition of 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 to give 7-(hydroxymethyl)-3-methyl-1H-1,5-naphthyridin-2-one (2 g, 54%). LC-MS: (ES+H, m / z): [M+H] + =191.1. 1 H 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). Step 6: Preparation of 7-(chloromethyl)-3-methyl-1H-1,5-naphthyridin-2-one:

[0174] 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 SOCl (0.6 mL, 7.88 mmol, 6.00 equiv.) dropwise 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 desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. This resulted in 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 Step 7: Preparation of N-cyclopropyl-5-{[(3R)-1-[(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]oxy}pyridine-2-carboxamide:

[0175] 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 a 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).

[0176] The following examples were prepared using procedures similar to those set forth in Example 7. [Table 5] Example 8 [ka] Step 1: Preparation of methyl 5-{[(3R,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyridine-2-carboxylate:

[0177] To a stirred mixture of tert-butyl (3S,4S)-3-fluoro-4-hydroxypyrrolidine-1-carboxylate (500 mg, 2.44 mmol, 1.00 equiv.) and methyl 5-hydroxypyridine-2-carboxylate (373 mg, 2.44 mmol, 1.00 equiv.) and PPh3 (1.34 g, 5.12 mmol, 2.10 equiv.) in tetrahydrofuran (10 mL), DBAD (1.12 g, 4.87 mmol, 2.00 equiv.) in THF (5 mL) was added dropwise 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 allowed to cool 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), which was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =341.1. Step 2: Preparation of tert-butyl (3S,4R)-3-fluoro-4-{[6-(methylcarbamoyl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate:

[0178] To a stirred solution of methyl 5-{[(3R,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyridine-2-carboxylate (2 g, crude) in CH3OH (7 mL) was added dropwise CH3NH2 in water (7 mL, 25-30 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(aq) (2x30 mL). The organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude product tert-butyl (3S,4R)-3-fluoro-4-{[6-(methylcarbamoyl)pyridin-3-yl)oxy)}pyrrolidine-1-carboxylate (2 g, crude) was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =340.1. Step 3: Preparation of 5-{[(3R,4S)-4-fluoropyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide, HCl salt:

[0179] To a stirred solution of tert-butyl (3S,4R)-3-fluoro-4-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate (2 g, crude) in CHCl (5 mL) was added dropwise under a nitrogen atmosphere at 0° C. HCl in dioxane (8 mL, 4 M) was added dropwise. 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 ethyl ether / n-hexane (3×10 mL). The resulting mixture was concentrated under vacuum. 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. Step 4: Preparation of 5-{[(3R,4S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-4-fluoropyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide:

[0180] 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), KI (56 mg, 0.34 mmol, 0.50 equiv.) and DIEA (432 mg, 3.35 mmol, 5.00 equiv.) were added 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 allowed to cool to room temperature. The residue was purified by silica gel column chromatography. The residue was then 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. Example 9 [ka] Step 1: Preparation of methyl 5-{[(3S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyridine-2-carboxylate:

[0181] 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), DBAD (1.12 g, 4.87 mmol, 2.00 equiv.) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred overnight at 60 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool 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 give methyl 5-{[(3S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyridine-2-carboxylate (3.5 g, crude). LC-MS: (ES+H, m / z): [M+H] + =341.2. Step 2: Preparation of tert-butyl (3R,4S)-3-fluoro-4-((6-(methylcarbamoyl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate:

[0182] 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, 25-30 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. Step 3: Preparation of 5-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpicolinamide, HCl salt:

[0183] To a stirred solution of tert-butyl (3R,4S)-3-fluoro-4-((6-(methylcarbamoyl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate (2.2 g, crude) in DCM (20 mL) was added HCl (gas) in 1,4-dioxane (10 mL, 4 M) dropwise 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 hexane (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. Step 4: Preparation of 5-(((3S,4R)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpicolinamide:

[0184] 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 a 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 CHCl / i-PrOH (3 / 1, 3×50 mL). The combined organic layers were washed with brine (1×50 mL) and dried over anhydrous NaSO. 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°; 1 H 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 F NMR (282MHz, DMSO-d6) δ-195.59. Example 10 [ka] Step 1: Preparation of tert-butyl (3R)-3-({6-[(2,2-difluoroethyl)carbamoyl]pyridin-3-yl}oxy)pyrrolidine-1-carboxylate:

[0185] 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-difluoroethanamine (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. % in EA) dropwise 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 diluted with water (50 mL). The resulting mixture was extracted with CHCl (3 × 50 mL). The combined organic layers were washed with brine (1×100 mL) and dried over anhydrous NaSO. 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. 1 H 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). Step 2: Preparation of N-(2,2-difluoroethyl)-5-[(3R)-pyrrolidin-3-yloxy]pyridine-2-carboxamide, TFA salt:

[0186] To a stirred solution of tert-butyl (3R)-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 a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. 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. LC-MS: (ES+H, m / z): [M+H] + =272.2. Step 3: Preparation of 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:

[0187] 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), KI (22 mg, 0.14 mmol, 0.20 equiv.) and DIEA (440 mg, 3.40 mmol, 5.00 equiv.) were added 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 allowed to cool 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. 1 H NMR(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,1 H),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 Example 11 [ka] Step 1: Preparation of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl](methyl)amino}pyridine-2-carboxylate:

[0188] 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.), CsCO (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. overnight under a nitrogen atmosphere. The mixture was allowed to cool 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). Step 2: Preparation of tert-butyl (3R)-3-{methyl[6-(methylcarbamoyl)pyridin-3-yl]amino}pyrrolidine-1-carboxylate:

[0189] A mixture of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl](methyl)amino}pyridine-2-carboxylate (488 mg, 1.46 mmol, 1.00 equiv.) and aqueous methylamine (3 mL, 25-30 wt%) in MeOH (6 mL) was stirred at room temperature for 4 h. 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). Step 3: Preparation of N-methyl-5-[methyl((3R)-pyrrolidin-3-yl)amino]pyridine-2-carboxamide, HCl salt:

[0190] A mixture of tert-butyl (3R)-3-{methyl[6-(methylcarbamoyl)pyridin-3-yl]amino}pyrrolidine-1-carboxylate (450 mg, 1.35 mmol, 1.00 equiv.) in HCl (gas) in 1,4-dioxane (5 mL, 4 M) 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. Step 4: Preparation of 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl](methyl)amino}-N-methylpyridine-2-carboxamide:

[0191] A mixture of N-methyl-5-[methyl((3R)-pyrrolidin-3-yl)amino]pyridine-2-carboxamide (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. for 1 h under a nitrogen atmosphere. The mixture was allowed to cool 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). Example 12 [ka] Step 1: Preparation of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)-3-methylpyrrolidin-3-yl]oxy}pyridine-2-carboxylate:

[0192] To a stirred mixture of NaH (139 mg, 3.47 mmol, 1.4 equiv, 60 wt%) in DMF (10 mL) was added tert-butyl (3R)-3-hydroxy-3-methylpyrrolidine-1-carboxylate (500 mg, 2.48 mmol, 1.00 equiv) in DMF (1 mL) dropwise 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 methyl 5-fluoropyridine-2-carboxylate (462 mg, 2.98 mmol, 1.20 equiv) dropwise at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The reaction was quenched with MeOH at 0°C. The residue was purified by reverse Combiflash 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). Step 2: Preparation of tert-butyl (3R)-3-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate:

[0193] 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, 25-30 wt % in water) in CH3OH (5 mL) was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was extracted with CHCl2 (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. Step 3: Preparation of N-methyl-5-{[(3R)-3-methylpyrrolidin-3-yl]oxy}pyridine-2-carboxamide, HCl salt:

[0194] To a stirred solution of tert-butyl (3R)-3-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate (300 mg, 0.89 mmol, 1.00 equiv) in DCM (5 mL) was added dropwise HCl (gas) in 1,4-dioxane (2.5 mL, 4 M) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with ethyl 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. Step 4: Preparation of 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-3-methylpyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide:

[0195] 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 a 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°; 1 H 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).

[0196] The following examples were prepared using procedures similar to those set forth in Example 12. [Table 6] Example 13 [ka] Step 1: Preparation of tert-butyl (3R)-3-(bromomethyl)pyrrolidine-1-carboxylate:

[0197] To a stirred mixture of tert-butyl (3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (3.00 g, 14.91 mmol, 1.00 equiv.) and CBr (7.41 g, 22.34 mmol, 1.50 equiv.) in DCM (20 mL) was added a solution of PPh (3.91 g, 14.91 mmol, 1.00 equiv.) in DCM (5 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was monitored by TLC (PE:EA = 3:1, R f =0.4). 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 H NMR (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). Step 2: Preparation of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]methyl}pyridine-2-carboxylate:

[0198] A mixture of 1,2-dimethoxyethane dihydrochloride nickel (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 a nitrogen atmosphere for 1 h. The nickel mixture was added to a mixture of tert-butyl (3R)-3-(bromomethyl)pyrrolidine-1-carboxylate (300 mg, 1.14 mmol, 1.00 equiv.), methyl 5-bromopyridine-2-carboxylate (245 mg, 1.14 mmol, 1.00 equiv.), tris(trimethylsilyl)silane (282 mg, 1.14 mmol, 1.00 equiv.), CsCO (740 mg, 2.27 mmol, 2.00 equiv.), and Ir[dF(CF)ppy](dtpby)PF (38 mg, 0.03 mmol, 0.03 equiv.) at room temperature under a nitrogen atmosphere. The reaction was stirred for 2 days and irradiated with a blue LED (30 watts). The reaction was monitored by LCMS. The reaction 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). Step 3: Preparation of tert-butyl (3R)-3-{[6-(methylcarbamoyl)pyridin-3-yl]amino}pyrrolidine-1-carboxylate:

[0199] To a stirred mixture of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylate (190 mg, 0.66 mmol, 1.00 equiv.) in MeOH (2 mL) was added methylamine (2 mL, 25-30 wt % in water) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. 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). LC-MS: (ES+H, m / z): [M+H] + =320.3. Step 4: Preparation of N-methyl-5-[(3R)-pyrrolidin-3-ylmethyl]pyridine-2-carboxamide, HCl salt: A mixture of tert-butyl (3R)-3-{[6-(methylcarbamoyl)pyridin-3-yl]methyl}pyrrolidine-1-carboxylate (190 mg, crude) and HCl (gas) in 1,4-dioxane (4 M, 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 Step 5: Preparation of 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]methyl}-N-methylpyridine-2-carboxamide:

[0200] 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 a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The mixture 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). Example 14 [ka] Step 1: Preparation of methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]amino}pyridine-2-carboxylate:

[0201] 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), Xantphos (1.07 g, 1.85 mmol, 0.20 equiv.), Pd(dba) (0.84 g, 0.90 mmol, 0.10 equiv.), and CsCO (9.05 g, 27.77 mmol, 3.00 equiv.) were added at room temperature. The resulting mixture was stirred at 110 °C under a 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase Combiflash chromatography, which 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). Step 2: Preparation of tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]amino}azetidine-1-carboxylate:

[0202] To a stirred solution of methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]amino}pyridine-2-carboxylate (500 mg, 1.62 mmol, 1.00 equiv.) in MeOH (5 mL) was added methylamine (5 mL, 25-30 wt. % in water) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The desired product could be detected by LCMS. The solvent was removed under reduced pressure. The residue was purified by reverse-phase Combiflash chromatography. This yielded 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. Step 3: Preparation of 5-(azetidin-3-ylamino)-N-methylpyridine-2-carboxamide, HCl salt:

[0203] In a 100 mL round-bottom flask, tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]amino}azetidine-1-carboxylate (500 mg, 1.63 mmol, 1.00 equivalents) in 1,4-dioxane (10 mL) and HCl (gas) were added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The desired product could be detected by LCMS. The resulting mixture was concentrated in vacuo. This resulted in 5-(azetidin-3-ylamino)-N-methylpyridine-2-carboxamide, HCl salt (400 mg, crude). The resulting crude mixture was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =207.2. Step 4: Preparation of 5-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidin-3-yl}amino)-N-methylpyridine-2-carboxamide:

[0204] 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 an additional 2 hours. The desired product could 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). Example 15 [ka] Step 1: Preparation of methyl 5-{[1-(tert-butoxycarbonyl)-3-methylazetidin-3-yl]oxy}pyridine-2-carboxylate:

[0205] To a stirred solution of NaH (1.08 g, 27.08 mmol, 1.40 equiv., 60 wt%) in DMF (40 mL) was added tert-butyl 3-hydroxy-3-methylazetidine-1-carboxylate (4.71 g, 25.14 mmol, 1.30 equiv.) in DMF (5 mL) dropwise at room temperature under a nitrogen atmosphere. The above mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. To the resulting mixture was then added methyl 5-fluoropyridine-2-carboxylate (3.00 g, 19.34 mmol, 1.00 equiv.) in DMF (5 mL) dropwise at room temperature. The resulting mixture was stirred for an additional 2 hours at room temperature. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The reaction was quenched by adding MeOH (20 mL) at 0 °C. The resulting mixture was diluted with EA (100 mL) and washed with water (3 x 30 mL). The organic layer was concentrated in vacuo. The residue was purified by reverse Combiflash chromatography to give methyl 5-{[1-(tert-butoxycarbonyl)-3-methylazetidin-3-yl]oxy}pyridine-2-carboxylate (1.1 g, 17.64%). 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). Step 2: Preparation of tert-butyl 3-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate:

[0206] To a stirred solution of methyl 5-{[1-(tert-butoxycarbonyl)-3-methylazetidin-3-yl]oxy}pyridine-2-carboxylate (500 mg, 1.55 mmol, 1.00 equiv.) in MeOH (5 mL) was added dropwise CH3NH2 (5 mL, 25.0-30.0 wt % in water) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The desired product could 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 (508 mg, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =322.2. Step 3: Preparation of N-methyl-5-[(3-methylazetidin-3-yl)oxy]pyridine-2-carboxamide, TFA:

[0207] To a stirred solution of tert-butyl 3-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (468 mg, 1.46 mmol, 1.00 equiv.) in DCM (6 mL) was added TFA (2 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The resulting mixture was concentrated in vacuo to give N-methyl-5-[(3-methylazetidin-3-yl)oxy]pyridine-2-carboxamide, TFA salt (396 mg, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =222.2. Step 4: Preparation of 5-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-3-methylazetidin-3-yl}oxy)-N-methylpyridine-2-carboxamide:

[0208] 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), DIEA (467 mg, 3.62 mmol, 4.00 equiv.) and KI (30 mg, 0.18 mmol, 0.20 equiv.) were added portionwise 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 could be detected by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with CHCl / 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. 1 H NMR(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). Example 16 [ka] Step 1: Preparation of methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylate:

[0209] A mixture of DEAD (5.69 g, 32.65 mmol, 5.00 equiv.) and PPh3 (10.90 g, 39.18 mmol, 6.00 equiv.) in THF (100 ml) was stirred at 0° C. for 1 hour under a nitrogen atmosphere. The mixture was added dropwise to methyl 5-hydroxypyridine-2-carboxylate (1.00 g, 6.53 mmol, 1.00 equiv.) and tert-butyl 3-hydroxyazetidine-1-carboxylate (1.70 g, 9.79 mmol, 1.50 equiv.) in THF (100 ml) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for an additional 2 hours. 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. Step 2: Preparation of tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate:

[0210] A mixture of methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylate (3.50 g, crude, containing TPPO) and CH3NH2 (20 mL, 25-30 wt % in water) 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, which was then 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 afforded tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (3.3 g, crude, containing TPPO). LC-MS: (ES+H, m / z): [M+H] + =308.1 Step 3: Preparation of 5-(azetidin-3-yloxy)-N-methylpyridine-2-carboxamide, HCl salt:

[0211] To a mixture of tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (3.30 g, crude, containing TPPO) in DCM (10 mL) was added HCl (gas) in 1,4-dioxane (10 mL, 4 M in dioxane) portionwise at room temperature 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 EtOAc (3 × 20 mL). The precipitated solid was collected by filtration and concentrated under reduced pressure. This resulted in 5-(azetidin-3-yloxy)-N-methylpyridine-2-carboxamide, HCl salt (600 mg, crude). LC-MS: (ES+H, m / z): [M+H] + =208.2. Step 4: Preparation of 5-({1-[(7-cyclopropyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidin-3-yl}oxy)-N-methylpyridine-2-carboxamide:

[0212] 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 at 80° C. for 2 hours 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 trituration with MeOH (5 mL) at 50° C. The precipitated solid was collected by filtration and washed with MeOH (2 x 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-3yl}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).

[0213] The following examples were made using procedures similar to those set forth in Example 16. [Table 7] Example 17 [ka] Step 1: Preparation of methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate:

[0214] To a stirred mixture of tert-butyl (2R,3R)-3-hydroxy-2-methylazetidine-1-carboxylate (300 mg, 1.60 mmol, 1.00 equiv.) and methyl 5-hydroxypyridine-2-carboxylate (245 mg, 1.60 mmol, 1.00 equiv.) and PPh3 (882 mg, 3.36 mmol, 2.10 equiv.) in THF (15 mL) was added DBAD (738 mg, 3.20 mmol, 2.00 equiv.) in THF (5 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 3 h. The reaction was monitored by LCMS. The mixture was allowed to cool 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 HO (2 × 30 mL) and dried over anhydrous NaSO4. 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. Step 2: Preparation of tert-butyl (2R,3S)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate:

[0215] A solution of methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate (1.5 g, crude) and CH3NH2 (7 mL, 25-30 wt % in water) in CH3CN (7 mL) 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(aq) (2 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product, tert-butyl (2R,3S)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (1.5 g, crude), was used directly in the next step without further purification. LC-MS:(ES+H,m / z):[M+H]+=322.1.

[0216] Step 3: Preparation of N-methyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy]pyridine-2-carboxamide, TFA salt: To a stirred solution of tert-butyl (2R,3S)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (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 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 ethyl ether / n-hexane (3×10 mL). The resulting mixture was concentrated under vacuum. The crude product, N-methyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide, TFA salt (0.6 g, crude), was used directly in the next step without further purification. LC-MS:(ES+H,m / z):[M+H]+=222.2. Step 4: Preparation of 5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide:

[0217] 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 CHCN (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 allowed to cool 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 Combiflash. 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 [α] 25 D (c=0.5, MeOH):-4.8°; 1 H 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).

[0218] The following examples were made using procedures similar to those set forth in Example 17. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] Example 18 [ka] Step 1: Preparation of methyl 5-{[(2S,3R)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate:

[0219] To a stirred solution of methyl 5-hydroxypyridine-2-carboxylate (0.35 g, 2.28 mmol, 1.00 equiv.), tert-butyl (2S,3S)-3-hydroxy-2-methylazetidine-1-carboxylate (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 DBAD (1.05 g, 4.57 mmol, 2.00 equiv.) in toluene (5 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h. The reaction was monitored by LCMS. The mixture was allowed to cool 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). The crude product was used directly in the next step. LC-MS: (ES+H, m / z): [M+H] + =323.1. Step 2: Preparation of tert-butyl (2S,3R)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate:

[0220] A solution of methyl 5-{[(2S,3R)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate (1.00 g, crude) and methylamine (2 mL, 25-30 wt % in water) in MeOH (2 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure to give tert-butyl (2S,3R)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (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. Step 3: Preparation of N-methyl-5-{[(2S,3R)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide, HCl salt:

[0221] A solution of tert-butyl (2S,3R)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (1.00 g, crude) in HCl (gas) in 1,4-dioxane (4 mL, 4 M) 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 product was precipitated by the addition of EtOAc. The precipitated solid was collected by filtration and washed with PE (3 × 10 mL) to give N-methyl-5-{[(2S,3R)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide, HCl salt (200 mg, 67.95%, 3 steps). LC-MS: (ES+H, m / z): [M+H] + =222.2. Step 4: Preparation of 5-{[(2S,3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide:

[0222] 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 a 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, 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°; 1 H 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). Example 19 [ka] Step 1: Preparation of methyl 5-{[(2R,3R)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate:

[0223] To a stirred solution of methyl 5-hydroxypyridine-2-carboxylate (245 mg, 1.60 mmol, 1.00 equiv.) and tert-butyl (2R,3S)-3-hydroxy-2-methylazetidine-1-carboxylate (300 mg, 1.60 mmol, 1.00 equiv.) and Ph3P (840 mg, 3.20 mmol, 2.00 equiv.) in THF (5 mL) was added DBAD (738 mg, 3.20 mmol, 2.00 equiv.) in THF (2 mL) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 1 hour. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere overnight. 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 PhPO) as a grey oil. The resulting mixture was used directly in the next step. LC-MS: (ES+H, m / z): [M+H] + =323.2. Step 2: Preparation of tert-butyl (2R,3R)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate:

[0224] A solution of methyl 5-{[(2R,3R)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate (1.60 g, 4.96 mmol, 1.00 equiv.) and methylamine (4 mL, 25-30 wt % in water) in MeOH (4 mL) was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to give tert-butyl (2R,3R)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (1.53 g, containing PhPO) as a gray oil. The crude product was used directly in the next step. LC-MS: (ES+H, m / z): [M+H] + =322.2 Step 3: Preparation of N-methyl-5-{[(2R,3R)-2-methylazetidin-3-yl]oxy]pyridine-2-carboxamide, TFA salt:

[0225] A solution of tert-butyl (2R,3R)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (1.53 g, containing PhPO) 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 x 10 mL) to give N-methyl-5-{[(2R,3R)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide, TFA salt (810 mg, containing PhPO). LC-MS: (ES+H, m / z): [M+H] + =222.1. Step 4: Preparation of 5-{[(2R,3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide:

[0226] 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 a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a 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,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). Example 20 [ka] Step 1: Preparation of methyl 5-(((2S,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl)oxy)picolinate:

[0227] 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 methylbenzene (10 mL), DBAD (1.20 g, 5.22 mmol, 2.00 equiv.) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C under a 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 the crude product (3.6 g, crude), which was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =323.1. Step 2: Preparation of tert-butyl (2S,3S)-2-methyl-3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)azetidine-1-carboxylate:

[0228] To a stirred mixture 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, 25-30 wt% in water) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The resulting mixture was diluted with saturated NH4Cl (100 mL). The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (3 x 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 Step 3: Preparation of N-methyl-5-(((2S,3S)-2-methylazetidin-3-yl)oxy)picolinamide, HCl salt:

[0229] To a stirred solution of tert-butyl (2S,3S)-2-methyl-3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)azetidine-1-carboxylate (3.5 g, crude) in DCM (10 mL) was added HCl (gas) in 1,4-dioxane (10 mL, 4 M) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture 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 and purified by trituration with ethyl acetate (20 mL) to give the crude product (1.6 g, crude). LC-MS: (ES+H, m / z): [M+H] + =222.0 Step 4: Preparation of 5-(((2S,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methylazetidin-3-yl)oxy)-N-methylpicolinamide:

[0230] To a stirred mixture of N-methyl-5-(((2S,3S)-2-methylazetidin-3-yl)oxy)picolinamide (298 mg, assumed 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 a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was allowed to cool 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 x 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. 1 H NMR(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). Example 21 [ka] Step 1: Preparation of methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylate:

[0231] To a stirred mixture of methyl 5-hydroxypyridine-2-carboxylate (5.00 g, 32.65 mmol, 1.00 equiv.), PPh3 (17.13 g, 65.30 mmol, 2.00 equiv.), and tert-butyl 3-hydroxyazetidine-1-carboxylate (5.66 g, 32.65 mmol, 1.00 equiv.) in toluene (80 mL) was added DBAD (15.04 g, 65.30 mmol, 2.00 equiv.) in toluene (40 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2 hours. The desired product could be detected by LCMS. The mixture was allowed to cool 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 x 100 mL) and dried over anhydrous NaSO. 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) as a grey oil. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =309.1 Step 2: Preparation of 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylic acid:

[0232] A mixture of methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylate (9.00 g, 8.76 mmol, 1.00 equiv., estimated 30% yield) and LiOH (0.84 g, 35.03 mmol, 4.00 equiv.) in THF (40 mL) and HO (10 mL) was stirred at room temperature under a nitrogen atmosphere for 3 h. The desired product could 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 (aq.). 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 NaSO. 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). Step 3: Preparation of tert-butyl 3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate:

[0233] 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. % in EA) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The desired product could 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 give tert-butyl 3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (780 mg, crude). LC-MS: (ES+H, m / z): [M+H] + =334.0. 1 H 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). Step 4: Preparation of 5-(azetidin-3-yloxy)-N-cyclopropylpyridine-2-carboxamide, TFA salt:

[0234] 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. This gave 5-(azetidin-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 Step 5: Preparation of N-cyclopropyl-5-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl}azetidin-3-yl}oxy)pyridine-2-carboxamide:

[0235] 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) was added 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.). 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 reaction 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse Combiflash, 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. 1H NMR(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(d d,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).

[0236] The following examples were made using procedures similar to those set forth in Example 21. [Table 9] Example 22 [ka] Step 1: Preparation of tert-butyl 3-(4-cyanophenoxy)azetidine-1-carboxylate:

[0237] To a stirred solution of benzonitrile, 4-fluoro- (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 under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The reaction was poured into water (80 mL) at room temperature. 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 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. 1H NMR (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). Step 2: Preparation of 4-(azetidin-3-yloxy)benzonitrile, TFA salt:

[0238] 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) was added TFA (1 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 4-(azetidin-3-yloxy)benzonitrile, TFA salt (232 mg, crude) as a brown oil. LC-MS: (ES+H, m / z): [M+H] + =175.0 Step 3: Preparation of 4-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidin-3-yl}oxy)benzonitrile:

[0239] 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 a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a 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 NaSO. 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%, 2 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). The following examples were made using procedures similar to those set forth in Example 22. [Table 10] Example 43 [ka] Step 1: Preparation of tert-butyl (2R,3S)-3-((6-cyanopyridin-3-yl)oxy)-2-methylazetidine-1-carboxylate:

[0240] To a stirred mixture of NaH (1.49 g, 37.37 mmol, 1.20 equiv., 60% in oil) in THF (30 mL) was added tert-butyl (2R,3S)-3-hydroxy-2-methylazetidine-1-carboxylate (6.99 g, 37.35 mmol, 1.20 equiv.) in THF (30 mL) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. To the above mixture was added 5-fluoropyridine-2-carbonyl (3.8 g, 31.12 mmol, 1.00 equiv.) in THF (30 mL) dropwise over 15 minutes at 0° C. The resulting mixture was stirred at room temperature for an additional 1 hour. The reaction was monitored by LCMS. The reaction was quenched by the addition of water (10 mL) at 0° C. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with CH2Cl2 (3 x 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. Step 2: Preparation of 5-(((2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl)oxy)picolinic acid:

[0241] To a stirred mixture of tert-butyl (2R,3S)-3-[(6-cyanopyridin-3-yl)oxy]-2-methylazetidine-1-carboxylate (6.6 g, 22.81 mmol, 1.00 equiv.) in water (40 mL) was added NaOH (20 mL, 2N in water) portionwise at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by TLC. The mixture was allowed to cool to room temperature. To the above mixture, THF (40 mL) and BocO (9.96 g, 45.62 mmol, 2.00 equiv.) were added portionwise over 10 min at 0 °C. The resulting mixture was stirred at room temperature for an additional 6 h. The reaction was monitored by LCMS. The mixture was acidified to pH 3-4 with citric acid. The resulting mixture was extracted with CHCl (3 × 50 mL). The combined organic layers were dried over anhydrous NaSO. 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). Step 3: Preparation of tert-butyl (2R,3S)-3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}-2-methylazetidine-1-carboxylate:

[0242] 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.), 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 extracted with CHCl (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 Step 4: Preparation of N-cyclopropyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide HCl salt:

[0243] To a stirred solution of tert-butyl (2R,3S)-3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}-2-methylazetidine-1-carboxylate (500 mg, 1.44 mmol, 1.00 equiv) in DCM (3 mL) was added dropwise 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 under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with EtO (2×10 mL). The resulting mixture was concentrated under reduced pressure to give N-cyclopropyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide, HCl salt (400 mg, crude). LC-MS: (ES+H, m / z): [M+H] + =248.2. Step 5: Preparation of 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:

[0244] To a stirred mixture of N-cyclopropyl-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 CHCN (8 mL), KI (56 mg, 0.34 mmol, 0.5 equiv.) and DIEA (697 mg, 5.39 mmol, 8 equiv.) were added 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 allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The residue was then purified by reverse Combiflash 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 [α] 25 D (c=0.25, DCM / MeOH=10 / 1):-12°; 1H 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). Example 44 [ka] Step 1: Preparation of methyl 5-(((2R,3S)-2-methylazetidin-3-yl)oxy)picolinate, HCl salt:

[0245] 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 a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was allowed to cool 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. Step 2: Preparation of methyl 5-(((2R,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methylazetidin-3-yl)oxy)picolinate:

[0246] To a stirred mixture of methyl 5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate (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 CHCN (5 mL) was added DIEA (884 mg, 6.84 mmol, 4.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with CHCl (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 Step 3: Preparation of 5-(((2R,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methylazetidin-3-yl)oxy)picolinic acid:

[0247] To a stirred solution of methyl 5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate (300 mg, 0.73 mmol, 1.00 equiv) in MeOH (3 mL) was added NaOH (aqueous, 3 mL, 2N in HO) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The aqueous phase was extracted with CHCl (2 × 30 mL). The mixture was acidified to pH 6-7 with HCl (aqueous). The organic 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. Step 4: Preparation of 5-(((2R,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methylazetidin-3-yl)oxy)-N-(oxetan-3-yl)picolinamide:

[0248] 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 oxetan-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 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 diluted with water (30 mL). The resulting mixture was extracted with CHCl (3 × 20 mL). The combined organic layers were washed with water (1×30 mL) and dried over anhydrous NaSO. 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-methylazetidin-3-yl)oxy)-N-(oxetan-3-yl)picolinamide (15.6 mg, 6.6%). LC-MS: (ES+H, m / z): [M+H] + =450.2. 1 H 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). Examples 54 and 55 [ka] Step 1: Preparation of 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid:

[0249] To a solution of methyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (1.15 g, 4.95 mmol, 1.00 equiv.) in MeOH (15 mL) and HO (3 mL) was added NaOH (0.59 g, 14.86 mmol, 3.00 equiv.) portionwise 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). Step 2: Preparation of 7-ethyl-N-methoxy-N-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxamide:

[0250] 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.) portionwise at room temperature 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 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 NaSO. 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). Step 3: Preparation of 7-acetyl-3-ethyl-1H-1,5-naphthyridin-2-one:

[0251] 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 CHMgBr (1.4 mL, 4.13 mmol, 2.00 equiv, 3 M in THF) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. 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 NaSO. 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-naphthyridin-2-one (397 mg, 88.83%). LC-MS: (ES+H, m / z): [M+H] + =217.1. 1 H 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). Step 4: Preparation of 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:

[0252] 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 at room temperature under a nitrogen atmosphere for 15 minutes. The resulting mixture was concentrated under reduced pressure. To the above mixture was added tetrakis(propan-2-yloxy)titanium (1.58 g, 5.55 mmol, 3.00 equiv.). The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 4 hours. The residue was dissolved in EtOH (10 mL). To the above mixture was added NaBHCN (233 mg, 3.70 mmol, 2.00 equiv.). The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 4 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was filtered, and the filter cake was washed with CHCl / 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)methyl)-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (160 mg, 20.52%). 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 * Preparation of]-1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide:

[0253] Racemic 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 (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%) was obtained.

[0254] 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).

[0255] 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).

[0256] The following examples were made using procedures similar to those set forth in Examples 54 and 55. [Table 11] Example 63 [ka] Step 1: Preparation of tert-butyl (2R,3R)-2-methyl-3-{[4-(trifluoromethyl)benzenesulfonyl]oxy}azetidine-1-carboxylate: To a stirred solution of tert-butyl (2R,3R)-3-hydroxy-2-methylazetidine-1-carboxylate (1.00 g, 5.34 mmol, 1.00 equiv.), EtN (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 4-(trifluoromethyl)benzenesulfonyl chloride (1.44 g, 5.87 mmol, 1.10 equiv.) in DCM (10 mL) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. under a nitrogen atmosphere for 2 hours. The reaction was monitored by TLC (PE / EA=2 / 1, KMnO). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 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). Step 2: Preparation of tert-butyl (2R,3S)-3-[5-(methoxycarbonyl)pyrrolo[3,2-b]pyridin-1-yl]-2-methylazetidine-1-carboxylate:

[0257] To a stirred solution of tert-butyl (2R,3R)-2-methyl-3-{[4-(trifluoromethyl)benzenesulfonyl]oxy}azetidine-1-carboxylate (1.00 g, 2.52 mmol, 1.00 equiv.) and methyl 1H-pyrrolo[3,2-b]pyridine-5-carboxylate (445 mg, 2.52 mmol, 1.00 equiv.) in DMF (20 mL) was added CsCO (1.65 g, 5.05 mmol, 2.00 equiv.) at room temperature. The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (200 mL). The resulting mixture was washed with H2O (3 x 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 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). Step 3: Preparation of tert-butyl (2R,3S)-2-methyl-3-[5-(methylcarbamoyl)pyrrolo[3,2-b]pyridin-1-yl]azetidine-1-carboxylate:

[0258] To a stirred solution of tert-butyl (2R,3S)-3-[5-(methoxycarbonyl)pyrrolo[3,2-b]pyridin-1-yl]-2-methylazetidine-1-carboxylate (460 mg, 1.39 mmol, 1.00 equiv.) and ACN (3 mL), CH3NH2 in water (3 mL, 30 wt%) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 6 hours. 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). Step 4: Preparation of N-methyl-1-[(2R,3S)-2-methylazetidin-3-yl]pyrrolo[3,2-b]pyridine-5-carboxamide hydrochloride:

[0259] To a stirred mixture of tert-butyl (2R,3S)-2-methyl-3-[5-(methylcarbamoyl)pyrrolo[3,2-b]pyridin-1-yl]azetidine-1-carboxylate (450 mg, 1.30 mmol, 1.00 equiv.) and HCl (gas) in 1,4-dioxane (5 mL, 4 M / L in dioxane). 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-methylazetidin-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 Step 5: Preparation of 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:

[0260] 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, assumed 100% yield, 0.98 mmol, 1.10 equiv.) and KI (29 mg, 0.18 mmol, 0.20 equiv.) in ACN (5 mL), DIEA (580 mg, 4.49 mmol, 5.00 equiv.) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. 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 obtain a crude product. The residue was dissolved in DMSO (3 mL). The residue was purified by preparative HPLC. The pure fractions were concentrated under vacuum and then lyophilized to obtain 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).

[0261] The following examples were made using procedures similar to those set forth in Example 63. [Table 12] Example 66 [ka] Step 1: Preparation of methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-3-fluoropyridine-2-carboxylate:

[0262] A solution of methyl 3-fluoro-5-hydroxypyridine-2-carboxylate (500 mg, 2.92 mmol, 1.00 equiv.), tert-butyl (2R,3R)-3-hydroxy-2-methylazetidine-1-carboxylate (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 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 h. The mixture was allowed to cool 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure to give methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-3-fluoropyridine-2-carboxylate (4.2 g, crude) 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. Step 2: Preparation of 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-3-fluoropyridine-2-carboxylic acid:

[0263] A solution of methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-3-fluoropyridine-2-carboxylate (4.00 g, crude) in THF (14 mL) was treated with NaOH (0.94 g, 23.50 mmol, 2.00 equiv) in HO (7 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. 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 (aqueous solution 1 mol / L). 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-3-fluoropyridine-2-carboxylic acid (900 mg, 94.2%, over two steps). LC-MS: (ES+H, m / z): [M+H] + =327.1. Step 3: Preparation of tert-butyl (2R,3S)-3-{[6-(cyclopropylcarbamoyl)-5-fluoropyridin-3-yl]oxy}-2-methylazetidine-1-carboxylate:

[0264] 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.) at room temperature for 10 minutes, followed by the addition of aminocyclopropane (524 mg, 9.19 mmol, 5.00 equiv.) and DIEA (950 mg, 7.35 mmol, 4.00 equiv.) at room temperature. The resulting mixture was stirred at room temperature for an additional 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). Step 4: Preparation of N-cyclopropyl-3-fluoro-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide hydrochloride: A solution of tert-butyl (2R,3S)-3-{[6-(cyclopropylcarbamoyl)-5-fluoropyridin-3-yl]oxy}-2-methylazetidine-1-carboxylate (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 resulted in N-cyclopropyl-3-fluoro-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide hydrochloride (600 mg, crude). LC-MS: (ES+H, m / z): [M+H] + =266.05. Step 5: Preparation of N-cyclopropyl-5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy}-3-fluoropyridine-2-carboxamide:

[0265] To a stirred mixture of N-cyclopropyl-3-fluoro-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide hydrochloride (285 mg, assumed 100% yield, 1.07 mmol, 1.20 equiv.) and DIEA (464 mg, 3.59 mmol, 4.00 equiv.) in MeCN (10 mL) 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.) at room temperature. The resulting mixture was stirred at 80° C. for an additional 2 hours. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with CHCl (3×40 mL). The combined organic layers were washed with brine (1×30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase Combiflash chromatography. The resulting mixture was concentrated under reduced pressure to give N-cyclopropyl-5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-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°; 1 H 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. Example 75 [ka] Step 1: Preparation of 7-bromo-1H-1,5-naphthyridin-2-one:

[0266] 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 a nitrogen atmosphere. The resulting mixture was stirred at 70° C. under a 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 NaSO. 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-naphthyridin-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). Step 2: Preparation of 7-bromo-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one:

[0267] 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 HO (6 mL), sodium difluoromethanesulfinate (3.53 g, 20.44 mmol, 2.00 equiv., 80 wt %) and potassium peroxydisulfate (11.05 g, 40.88 mmol, 4.00 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a 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. Step 3: Preparation of 3-(difluoromethyl)-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one:

[0268] To a stirred mixture 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), (tributylstannyl)methanol (2.83 g, 8.79 mmol, 1.10 equiv.) and 2nd Generation XPhos Precatalyst (314 mg, 0.40 mmol, 0.05 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80° C. under a 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-(difluoromethyl)-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (650 mg, 35.9%). LC-MS: (ES+H, m / z): [M+H] + =227.1. 1 H 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. Step 4: Preparation of 7-(chloromethyl)-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one:

[0269] 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), DMF (9 mg, 0.12 mmol, 0.10 equiv.) and SOCl (0.93 mL, 12.82 mmol, 10.00 equiv.) were added dropwise 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 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. Step 5: Preparation of N-cyclopropyl-5-{[(2R,3S)-1-{[7-(difluoromethyl)-6-oxo-5H-1,5-naphthyridin-3-yl]methyl}-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide:

[0270] 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 a nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 1 hour. The reaction was monitored by LCMS. The mixture was allowed to cool 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give the crude product (90 mg). The crude product was isolated by preparative HPLC to give N-cyclopropyl-5-{[(2R,3S)-1-{[7-(difluoromethyl)-6-oxo-5H-1,5-naphthyridin-3-yl]methyl}-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide (54.6 mg, 26.39%, 99.0% purity, [a] D 25 = -9.800 (tested with C=1, MeOH:DCM=1:1) LC-MS: (ES+H, m / z): [M+H] + =456.15. 1H 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. Example 76 [ka] Step 1: Preparation of 3-bromo-2-methoxy-6-methyl-5-nitropyridine:

[0271] 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), NaOMe (15.76 g, 87.49 mmol, 1.10 equiv., 30 wt.%) was added dropwise 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 TLC (PE:EA=1:1, R f =0.4). 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 NaSO. 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). Step 2: Preparation of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N,N-dimethylethen-1-amine:

[0272] 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 at 100° C. overnight under a nitrogen atmosphere. The reaction was monitored by TLC. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. Step 3: Preparation of 5-bromo-6-methoxy-3-nitropicolinaldehyde

[0273] To a stirred mixture of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)ethenyl]dimethylamine (18.01 g, crude) in THF (100 mL) and HO (100 mL) was added NaIO (28.00 g, 131.07 mmol, 2.20 equiv) portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was monitored by TLC. The reaction was quenched by adding saturated sodium hyposulfite (aq) (100 mL) at room temperature. 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 NaSO. 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). Step 4: Preparation of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate:

[0274] To a stirred mixture of 5-bromo-6-methoxy-3-nitropyridine-2-carbaldehyde (7.00 g, crude) and ethyl 3,3-diethoxypropanoate (20.40 g, 107.27 mmol, 4.00 equiv.) in EtOH (100 mL) was added SnCl (26.25 g, 134.09 mmol, 5.00 equiv.) portionwise 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 allowed to cool 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 give the crude product. The crude product was purified by trituration with hexane (50 mL) to give ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (3.50 g, 18.5%, over three steps). LC-MS: (ES+H, m / z): [M+H] + =311.0 / 313.0. 1 H NMR (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(t3H). Step 5: Preparation of ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate:

[0275] 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 allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (20 mL). The resulting mixture was washed with 3 x 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. 1 H NMR (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). Step 6: Preparation of ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate:

[0276] To a stirred mixture of ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate (800 mg, 3.00 mmol, 1.00 equiv) in CHCN (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 allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (50 mL). The aqueous layer was washed with 3 × 50 mL of water (10% EtN). The combined organic layers were washed with brine (50 mL) and dried over anhydrous NaSO. 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. 1H 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). Step 7: Preparation of 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one:

[0277] 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 LiAlH (2.5 mL, 5.85 mmol, 2.00 equiv.) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. for an additional 2 h. The reaction was monitored by LCMS. The mixture was acidified to pH 5 with 1 M 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-naphthyridin-2-one (250 mg, 40.53%). LC-MS: (ES+H, m / z): [M+H] + =211.00. 1 H 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). Step 8: Preparation of 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one:

[0278] To a stirred mixture of 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (250 mg, 1.18 mmol, 1.00 equiv.) in CHCl (5 mL), SOCl (423 mg, 3.56 mmol, 3.00 equiv.) and DMF (8 mg, 0.11 mmol, 0.10 equiv.) were added dropwise at room temperature under a 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 to give 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (280 mg, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =228.95. Step 9: Preparation of 5-{[(2R,3S)-1-[(7-chloro-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy}-N-cyclopropylpyridine-2-carboxamide:

[0279] 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 NaSO. 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. 1 H NMR(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(d d,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). Example 106 [ka] Step 1: Preparation of (2E)-N-(3-bromo-2-fluorophenyl)-3-ethoxyprop-2-enamide:

[0280] To a stirred mixture of 3-bromo-2-fluoroaniline (20.00 g, 105.25 mmol, 1.00 equiv) in DCM (300 mL) was added pyridine (14.99 g, 189.45 mmol, 1.80 equiv) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 minutes under a nitrogen atmosphere. To the above mixture was added (2E)-3-ethoxyprop-2-enoyl chloride (21.24 g, 157.88 mmol, 1.50 equiv) dropwise over 5 minutes at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours. 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 x 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. Step 2: Preparation of 7-bromo-8-fluoro-1H-quinolin-2-one:

[0281] 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 a nitrogen atmosphere 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 x 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. Step 3: Preparation of 7-bromo-3-chloro-8-fluoro-1H-quinolin-2-one:

[0282] 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 a nitrogen atmosphere. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. 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 7-bromo-3-chloro-8-fluoro-1H-quinolin-2-one (2.48 g, crude). 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). Step 4: Preparation of 3-chloro-7-ethyl-8-fluoro-1H-quinolin-2-one:

[0283] 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)Cl (0.33 g, 0.44 mmol, 0.05 equiv.), and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.38 g, 8.97 mmol, 1.00 equiv.) in dioxane (50 mL), HO (5 mL) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. 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 3-chloro-7-ethenyl-8-fluoro-1H-quinolin-2-one (750 mg, 37.3%). LC-MS: (ES+H, m / z): [M+H] + =224.0. 1H 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). Step 5: Preparation of 3-chloro-8-fluoro-2-oxo-1H-quinoline-7-carbaldehyde:

[0284] To a stirred mixture of 3-chloro-7-ethenyl-8-fluoro-1H-quinolin-2-one (750 mg, 3.35 mmol, 1.00 equiv.), KOsO(OH) (123 mg, 0.33 mmol, 0.10 equiv.), NaIO (2.87 g, 13.41 mmol, 4.00 equiv.), and 2,6-dimethylpyridine (718 mg, 6.70 mmol, 2.00 equiv.) in THF (15 mL) was added HO (1.5 mL) dropwise 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 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. Step 6: Preparation of 5-{[(2R,3S)-1-[(3-chloro-8-fluoro-2-oxo-1H-quinolin-7-yl)methyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide:

[0285] 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 at room temperature under a nitrogen atmosphere for 10 minutes. The resulting mixture was concentrated under reduced pressure. To the above mixture, CH3COOH (13 mg, 0.22 mmol, 0.50 equiv.) and EtOH (10 mL) were added at room temperature. The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for an additional 4 hours. The reaction was monitored by LCMS. To the above mixture, NaBH3CN (56 mg, 0.88 mmol, 2.00 equiv.) was added at room temperature. The resulting mixture was further stirred at room temperature overnight. The reaction was monitored by LCMS. The reaction was quenched with water (3 mL) 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-quinolin-7-yl)methyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (180 mg, crude). The crude product was purified by preparative HPLC to give 5-{[(2R,3S)-1-[(3-chloro-8-fluoro-2-oxo-1H-quinolin-7-yl)methyl)-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (97.2 mg, 50.8%). LC-MS: (ES+H, m / z): [M+H] + =431.05.Optical rotation [a] 25 D (c=0.27, MeOH): +38.5°; 1H 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). 19 F NMR(377MHz,DMSO-d6)δ-135.11.

[0286] The following examples were made using procedures similar to those set forth in Example 106. [Table 13] Example 110 [ka] Step 1: Preparation of methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-6-fluoropyridine-2-carboxylate:

[0287] 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 CHI (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-fluoropyridine-2-carboxylate (500 mg, 56.6%). LC-MS: (ES+H, m / z): [M+H] + =323.1. Step 2: Preparation of methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-6-fluoropyridine-2-carboxylate:

[0288] To a stirred mixture of 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate (400 mg, 1.24 mmol, 1.00 equiv.) in MeCN (10 mL) was added silver difluoromethane (904 mg, 6.20 mmol, 5.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 40° C. under a nitrogen atmosphere. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The resulting mixture was filtered, and the filter cake was washed with CHCl (250 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-6-fluoropyridine-2-carboxylate (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. Step 3: Preparation of 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-6-fluoropyridine-2-carboxylic acid:

[0289] To a stirred mixture of methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-6-fluoropyridine-2-carboxylate (900 mg, 2.64 mmol, 1.00 equiv.) in THF (5 mL) was added LiOH.HO (222 mg, 5.28 mmol, 2.00 equiv.) (in 1 mL of water) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (100 mL). The aqueous layer was acidified to pH 3 with HCl (aq. 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-6-fluoropyridine-2-carboxylic acid (800 mg, 92.7%). LC-MS: (ES-H, m / z): [MH] - =325.3. Step 4: Preparation of tert-butyl (3S)-3-({2-fluoro-6-(methyl-d3carbamoyl)pyridin-3-yl]oxy}-2-methylazetidine-1-carboxylate:

[0290] 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 methan-d-amine, hydrochloride (259 mg, 3.67 mmol, 3.00 equiv.) in CHCl (5 mL), DIEA (792 mg, 6.13 mmol, 5.00 equiv.) and TP (1 g, 3.67 mmol, 3.00 equiv., 50% in CHCl) were added at room temperature 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 desired product could 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. Step 5: Preparation of 6-fluoro-N-methyl-d3-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide hydrochloride:

[0291] To a stirred mixture of tert-butyl (3S)-3-({2-fluoro-6-[(2H)methylcarbamoyl]pyridin-3-yl}oxy)-2-methylazetidine-1-carboxylate (350 mg, 1.02 mmol, 1.00 equiv.) in CHCl (5 mL) was added HCl (gas) in 1,4-dioxane (5 mL, 4 M in dioxane) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure to give 6-fluoro-N-methyl-d-5-{[(2R,3S)-2-methylazetidin-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. Step 6: Preparation of 5-{[(2R,3S)-1-[(2-ethyl-5-fluoro-3-oxo-4H-quinolin-6-yl)methyl]-2-methylazetidin-3-yl]oxy}-6-fluoro-N-methyl-d3pyridine-2-carboxamide:

[0292] 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, assumed 100% yield, 1.00 equiv.) and 7-(bromomethyl)-3-ethyl-8-fluoro-1H-quinolin-2-one (204 mg, 0.71 mmol, 1.00 equiv.) in MeCN (5 mL), KI (23 mg, 0.14 mmol, 0.20 equiv.) and DIEA (463 mg, 3.59 mmol, 5.00 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with CHCl / 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 under vacuum and lyophilized to give 5-{[(2R,3S)-1-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]-2-methylazetidin-3-yl]oxy}-6-fluoro-N-methyl-dpyridine-2-carboxamide (163.8 mg, 50.5%). LC-MS: (ES+H, m / z): [M+H] + =447.15. 1 H 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. Example [ka] Step 1-Step 2: Preparation of N-(3-bromo-2,6-difluorophenyl)-2H-pyrazole-3-carboxamide:

[0293] 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 allowed to cool 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}]dodeca-3,5,9,11-tetraene-2,8-dione (2.3 g), was used directly in the next step without further purification.

[0294] To a stirred solution of 1,6,7,12-tetraazatricyclo[7.3.0.0^{3,7}]dodeca-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 an additional 2 h. 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 HO (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 NaSO. 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. 1H 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. Step 3: Preparation of 7-bromo-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one:

[0295] 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%) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 120° C. under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The reaction was 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 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). Step 4: Preparation of 6-fluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin-4-one:

[0296] To a stirred solution of 7-bromo-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-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), 2nd Generation XPhos Precatalyst (279 mg, 0.35 mmol, 0.10 equiv.) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a 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]quinoxalin-4-one (400 mg, 45.9%). LC-MS: (ES+H, m / z): [M+H] + =234.0. 1 H 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). Step 5: Preparation of 7-(chloromethyl)-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one:

[0297] 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), SOCl (765 mg, 6.43 mmol, 5.00 equiv.) and DMF (5 mg, 0.07 mmol, 0.05 equiv.) were added dropwise 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 Step 6: Preparation of 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:

[0298] 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), KI (15 mg, 0.09 mmol, 0.20 equiv.) and DIEA (246 mg, 1.90 mmol, 4.00 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a 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. 1H 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.

[0299] The following examples were made using procedures similar to those set forth in Example 113. [Table 14] Example 115 [ka] Step 1: Preparation of methyl 3-amino-2-fluoro-4-iodobenzoate:

[0300] 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse Combiflash 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. 1 H NMR (300MHz, DMSO-d6) δ7.52 (dd, J = 8.4, 1.5 Hz, 1H), 6.81 (dd, J = 8.3, 6.7 Hz, 1H), 5.43 (s, 2H), 3.83 (s, 3H). Step 2: Preparation of methyl 2-fluoro-3-(furan-3-amido)-4-iodobenzoate:

[0301] In a 250 mL round-bottom flask, methyl 3-amino-2-fluoro-4-iodobenzoate (4.00 g, 13.55 mmol, 1.00 equiv.), 3-furoic acid (1.52 g, 13.55 mmol, 1.00 equiv.), T3P (43.14 g, 67.78 mmol, 5.00 equiv., 50% in EA), and DIEA (2.08 g, 16.10 mmol, 5.00 equiv.) were added at room temperature. The resulting mixture was stirred overnight at 100° C. under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool 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 NaSO. 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). Step 3: Preparation of methyl 3-[N-(tert-butoxycarbonyl)furan-3-amido]-2-fluoro-4-iodobenzoate:

[0302] To a stirred mixture of methyl 2-fluoro-3-(furan-3-amido)-4-iodobenzoate (2.60 g, 6.68 mmol, 1.00 equiv.) and (Boc)O (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.) portionwise 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 TLC (PE:EA = 5:1). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 3-[N-(tert-butoxycarbonyl)furan-3-amido]-2-fluoro-4-iodobenzoate (3.00 g, 91.7%). Step 4: Preparation of methyl 6-fluoro-4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate:

[0303] To a stirred solution of methyl 3-[N-(tert-butoxycarbonyl)furan-3-amido]-2-fluoro-4-iodobenzoate (3.00 g, 6.13 mmol, 1.00 equiv.) in DMF (30 mL), PCy (344 mg, 1.22 mmol, 0.20 equiv.), Pd(OAc) (275 mg, 1.22 mmol, 0.20 equiv.), and KCO (1.69 g, 12.26 mmol, 2.00 equiv.) were added at room temperature under a nitrogen atmosphere. The final reaction mixture was irradiated with microwave radiation at 120 °C for 2 h. 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 NaSO. 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. Step 5: Preparation of methyl 6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c]quinoline-7-carboxylate:

[0304] To a stirred solution of methyl 6-fluoro-4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate (200 mg, 0.76 mmol, 1.00 equiv.) in CF3CH2OH (50 mL) was added Pd / C (163 mg, 10%) at room temperature. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered. The filter cake was washed with CHCl2 / MeOH (10:1, 3×50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c]quinoline-7-carboxylate (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. Step 6: Preparation of 6-fluoro-7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one:

[0305] 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 LiAlH (0.18 mL, 0.45 mmol, 2.00 equiv., 2.5 M in THF) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. under a 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 Step 7: Preparation of 7-(chloromethyl)-6-fluoro-2H,3H,5H-furo[3,2-c]quinolin-4-one:

[0306] 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 SOCl (253 mg, 2.13 mmol, 10.00 equiv.) dropwise 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 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 Step 8: Preparation of 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

[0307] 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.) under a nitrogen atmosphere at room temperature 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 a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. 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-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. 1 H 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.

[0308] The following examples were made using procedures similar to those set forth in Example 113. [Table 15] Example 121 [ka] Step 1: Preparation of ethyl 4-fluoro-2H-pyrazole-3-carboxylate:

[0309] To a stirred solution of 4-fluoro-2H-pyrazole-3-carboxylic acid (850 mg, 6.53 mmol, 1.00 equiv.) in EtOH (15 mL) was added SOCl (4.66 g, 39.21 mmol, 6.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70° C. under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure to give ethyl 4-fluoro-2H-pyrazole-3-carboxylate (1.00 g, Y=96.7%). LC-MS: (ES-H, m / z): [MH] - =157.1. 1 H NMR (300MHz, DMSO-d6) δ7.60(d,J=4.5Hz,1H),4.38(q,J=7.1Hz,2H),1.35(t,J=7.1Hz,3H). Step 2: Preparation of ethyl 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylate and ethyl 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylate and ethyl 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylate:

[0310] To a stirred solution of ethyl 4-fluoro-2H-pyrazole-3-carboxylate (1.00 g, 6.32 mmol, 1.00 equiv.) and K2CO3 (2.62 g, 18.97 mmol, 3.00 equiv.) in DMF (30 mL) was added (bromomethyl)benzene (2.16 g, 12.64 mmol, 2.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (150 mL). The resulting mixture was washed with 2 x 100 mL of water 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 a mixture of ethyl 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylate and ethyl 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylate (1.30 g, Y=82.8%). LC-MS: (ES+H, m / z): [M+H] + =249.0. 1 H NMR(300MHz,DMSO-d6)δ7.50-7.29(m,6H),7.28-7.20(m,4H),5.69(s,1H),5.32(s,2H),4 .46(q,J=7.2Hz,2H),4.36(q,J=7.1Hz,1H),1.43(t,J=7.1Hz,3H),1.36(t,J=7.1Hz,2H). Step 3: Preparation of 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylic acid and 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylic acid:

[0311] To a stirred solution of ethyl 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylate and ethyl 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylate (1.30 g, 5.23 mmol, 1.00 equiv.) in THF (15 mL) was added LiOH (15 mL, 30.00 mmol, 5.73 equiv., 2 M in water) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL). The aqueous layer was extracted with EtOAc (1×80 mL). The aqueous layer was acidified to pH 6 with citric acid. The aqueous layer was extracted with EtOAc (3×100 mL). The organic layer was dried over Na2SO4. The resulting mixture was concentrated under reduced pressure to give 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylic acid and 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylic acid (1.10 g, Y=95.4%). LC-MS: (ES-H, m / z): [M−H] - =219.1. Step 4: Preparation of 2-benzyl-N-(3-bromo-2,6-difluorophenyl)-5-fluoropyrazole-3-carboxamide and 1-benzyl-N-(3-bromo-2,6-difluorophen...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, 【Chemistry 53】 During the ceremony, R 1 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl; X is N or CR 2 ; R 2 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; or R 1 and R 2 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; Z is N or CR 4 ; R 4 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Y is N or CR 5 ; R 5 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 6 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; each R 7 is independently hydrogen, deuterium, fluoro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; or two R 7 together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; n is 1 or 2; each R 8 is independently deuterium, halogen, —CN, —NO 2 , —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; or two R 8 s on the same carbon taken together form an oxo; or two R 8 on the same carbon or adjacent carbons join together to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; p is 1 to 4; W is absent, —C(R 9 ) 2 —, —O—, —S—, —S(═O)—, —S(═O) 2 —, —S(═O)(═NR W )—, or —NR W —; each R 9 is independently hydrogen, deuterium, halogen, —CN, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; or two R 9 together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; R W is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 10 is independently deuterium, halogen, —CN, —NO 2 , —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) 2 R a , —S(═O) 2 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 , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; q is 0 to 4; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently deuterium, halogen, —CN, —OH, —OC 1 -C 6 alkyl, —S(═O)C 1 -C 6 alkyl, —S(═O) 2 C 1 -C 6 alkyl, —S(═O) 2 NH 2 , —S(═O) 2 NHC 1 -C 6 alkyl, —S(═O) 2 N(C 1 -C 6 alkyl) 2 , —NH 2 , —NHC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , —NHC(═O)OC 1 -C 6 alkyl, —C(═O)C 1 -C 6 alkyl, —C(═O)OH, —C(═O)OC 1 -C 6 alkyl, —C(═O)NH 2 , —C(═O)N(C 1 -C 6 alkyl) 2 , —C(═O)NHC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; Or, a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R on the same atom form oxo.

2. R 1 is hydrogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl; or R 1 is methyl or ethyl; Optionally, X is N, or X is CR 2 :

10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, optionally wherein R2 is hydrogen.

3. A compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, 【Chemistry 55】 During the ceremony, Ring B taken together with X 1 and X 2 is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; X 1 is C, CH, or N; X 2 is C, CH, or N; each R 11 is independently hydrogen, deuterium, halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl; m is 0 to 3; Z is N or CR 4 ; R 4 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Y is N or CR 5 ; R 5 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 6 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; each R 7 is independently hydrogen, deuterium, fluoro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; or two R 7 together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; n is 1 or 2; each R 8 is independently deuterium, halogen, —CN, —NO 2 , —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; or two R 8 s on the same carbon taken together form an oxo; or two R 8 on the same carbon or adjacent carbons join together to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; p is 0 to 4; W is absent, —C(R 9 ) 2 —, —O—, —S—, —S(═O)—, —S(═O) 2 —, —S(═O)(═NR W )—, or —NR W —; each R 9 is independently hydrogen, deuterium, halogen, —CN, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; or two R 9 together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; R W is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 10 is independently deuterium, halogen, —CN, —NO 2 , —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) 2 R a , —S(═O) 2 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 , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; q is 0 to 4; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently deuterium, halogen, —CN, —OH, —OC 1 -C 6 alkyl, —S(═O)C 1 -C 6 alkyl, —S(═O) 2 C 1 -C 6 alkyl, —S(═O) 2 NH 2 , —S(═O) 2 NHC 1 -C 6 alkyl, —S(═O) 2 N(C 1 -C 6 alkyl) 2 , —NH 2 , —NHC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , —NHC(═O)OC 1 -C 6 alkyl, —C(═O)C 1 -C 6 alkyl, —C(═O)OH, —C(═O)OC 1 -C 6 alkyl, —C(═O)NH 2 , —C(═O)N(C 1 -C 6 alkyl) 2 , —C(═O)NHC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; or a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R on the same atom form oxo.

4. The compound of claim 3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring B taken together with X 1 and X 2 is a 5-membered heterocycloalkyl.

5. Z is CR 4 , Optionally, R 4 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Y is N.

7. Y is CR 5 , optionally, R 5 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; or R 5 is hydrogen; 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

8. R 6 is hydrogen, and / or each R 7 is hydrogen; 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

9. Each R 8 is independently deuterium, halogen, —CN, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; or each R 8 is independently C 1 -C 6 alkyl; Optionally, p is 1; 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is -O-.

11. Ring A is heteroaryl, or 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is a 5- or 6-membered heteroaryl.

12. Each R 10 is independently deuterium, halogen, —CN, —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; Optionally, q is 1; 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 【Request 13】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 【Table 1-23】 【Table 1-24】 【Table 1-25】 【Table 1-26】 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

15. A composition for treating cancer in a subject in need thereof, comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

16. The cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, or lung cancer, Optionally, the cancer comprises a BRCA1 and / or BRCA2 mutation; Optionally, the cancer is bladder cancer, brain and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin's lymphoma, non-Hodgkin's 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.

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