Azetidine and pyrrolidine PARP1 inhibitors and uses thereof

Abstract

Azetidine and pyrrolidine PARP1 inhibitors and pharmaceutical compositions comprising the inhibitors are described herein. The subject compounds and compositions are useful for the treatment of cancer.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202280064954.1 (entitled "Azetidine and Pyrrolidine PARP1 Inhibitors and Their Uses", with a filing date of September 30, 2022, and a PCT application number of PCT / US2022 / 045415).

[0002] Cross - References

[0003] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 251,469, filed October 1, 2021; U.S. Provisional Application Serial No. 63 / 339,597, filed May 9, 2022; and U.S. Provisional Application Serial No. 63 / 402,835, filed August 31, 2022, which are hereby incorporated by reference in their entireties. Background of the Invention

[0004] Poly(ADP - ribose) polymerase (PARP) or poly(ADP - ribose) synthase (PARS) plays important roles in promoting DNA repair, controlling RNA transcription, mediating cell death, and regulating immune responses. These roles make PARP inhibitors targeted drugs for a variety of diseases. PARP inhibitors have shown efficacy in many disease models, particularly in models of ischemia - reperfusion injury, inflammatory diseases, and degenerative diseases, demonstrating protection against the adverse effects of cytotoxic compounds and potentiation of cytotoxic cancer therapies. PARP is also applicable to retroviral infections, so inhibitors can be used in antiretroviral therapy. In models of myocardial infarction, stroke, other nerve traumas, organ transplantation, and reperfusion of the eye, kidney, intestine, and skeletal muscle, PARP inhibitors are effective in preventing ischemia - reperfusion injury. The 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 benefits in several degenerative disease models, including diabetes (and its complications) and Parkinson's disease. PARP inhibitors can improve hepatotoxicity after acetaminophen overdose, cardiac and renal toxicity from doxorubicin and platinum - based anti - tumor agents, and skin damage secondary to sulfur mustard gas. In various cancer models, PARP inhibitors have been shown to enhance radiotherapy and chemotherapy by increasing cancer cell death, restricting tumor growth, reducing metastasis, and prolonging the survival of tumor - bearing animals.

[0005] PARP1 and PARP2 are the most widely studied PARPs because of their roles in DNA damage repair. PARP1 is activated by DNA damage breaks and catalyzes the addition of poly(ADP-ribose) (PAR) chains to target proteins. This post-translational modification (called PARylation) mediates the recruitment of additional DNA repair factors to DNA lesions.

[0006] After this recruitment function is completed, auto-PARylation of PARP triggers the release of the bound PARP from the DNA to allow access to other DNA repair proteins to complete the repair. Thus, the binding of PARP to the damage site, its catalytic activity, and its final release from the DNA are all important steps in the response of cancer cells to DNA damage caused by chemotherapeutic agents and radiotherapy.

[0007] Inhibition of PARP family enzymes has been developed as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Many preclinical and clinical studies have demonstrated that tumor cells carrying deleterious alterations in BRCA1 or BRCA2 (key tumor suppressor proteins involved in the repair of double-strand DNA breaks (DSBs) by homologous recombination (HR)) are selectively sensitive to small molecule inhibitors of PARP family DNA repair enzymes. Such tumors have defective homologous recombination repair (HRR) pathways and rely on the function of PARP enzymes for survival. Although PARP inhibitor therapy mainly targets SRCA mutant cancers, clinical trials of PARP inhibitors have been conducted in non-SRCA mutant tumors that exhibit homologous recombination deficiency (HRD).

[0008] It is believed that PARP inhibitors with improved selectivity for PARP1 may have improved efficacy and reduced toxicity compared to other clinical PARP1 / 2 inhibitors. It is also believed that strong inhibition of PARP1 selectivity will lead to the capture of PARP1 on DNA, resulting in DNA double-strand breaks (DSBs) caused by S-phase replication fork collapse. It is also believed that PARP1-DNA capture is 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 that are selective for PARP1. Summary of the Invention

[0009] Disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0010]

[0011] Wherein:

[0012] R 1 is hydrogen, deuterium, halogen, -CN, -OH, -ORa , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 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;

[0013] X is N or CR 2 ;

[0014] R 2 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0015] Or R 1 and R 2 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally substituted by one or more R;

[0016] Z is N or CR 4 ;

[0017] R 4 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0018] Y is N or CR 5 ;

[0019] R 5 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0020] R 6 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0021] Each R 7 is independently hydrogen, deuterium, fluorine, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl;

[0022] Or two Rs 7Together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0023] n is 1 or 2;

[0024] 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 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl;

[0025] Or two Rs on the same carbon 8 together form an oxo group;

[0026] Or two Rs on the same carbon or adjacent carbons 8 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0027] p is 0 - 4;

[0028] W is absent, -C(R 9 ) 2 -, -O-, -S-, -S(=O)-, -S(=O) 2 -, -S(=O)(=NR W )-

[0029] or -NR W -;

[0030] 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 -C6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl;

[0031] Or two Rs 9 Together form cycloalkyl or heteroalkyl; each optionally substituted by one or more Rs;

[0032] R W Is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Halogenated alkyl or C 1 -C 6 Deuterated alkyl;

[0033] Ring A is cycloalkyl, heteroalkyl, aryl or heteroaryl;

[0034] Each R 10 Independently is 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 , -NR 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 -C 6 , Alkyl, C1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 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 by one or more R;

[0035] q is 0 - 4;

[0036] each R a independently is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 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 by one or more R;

[0037] each R b independently is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 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, heteroalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl(cycloalkyl), C 1 -C 6 Alkyl(heteroalkyl), C 1 -C 6 Alkyl(aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0038] Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Halogenated alkyl, C 1 -C 6 Deuterated alkyl, 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, heteroalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl(cycloalkyl), C 1 -C 6 Alkyl(heteroalkyl), C 1 -C 6 Alkyl(aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0039] Or R c and R d together with the atom to which they are attached form a heteroalkyl, optionally substituted by one or more R; and

[0040] Each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 6alkyl, -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 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl;

[0041] Or two Rs on the same atom form an oxo group;

[0042] Provided that the compound of formula (I) is not

[0043] Also disclosed herein is a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0044]

[0045] Wherein:

[0046] Ring B together with X 1 and X 2 is a 5 - membered heteroalkyl or 5 - membered heteroaryl;

[0047] X 1 is C, CH or N;

[0048] X 2 is C, CH or N;

[0049] 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 deuterated alkyl, 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 heteroalkyl;

[0050] m is 0 - 3;

[0051] Z is N or CR 4 ;

[0052] R 4 is hydrogen, deuterium, halogen, - CN, - OH, - OR a , C 1 - C 6 alkyl, C 1 - C 6 haloalkyl, C 1 - C 6 deuterated alkyl, C 1 - C 6 hydroxyalkyl, C 1 - C 6 aminoalkyl, C 1 - C 6 heteroalkyl, cycloalkyl or heteroalkyl;

[0053] Y is N or CR 5 ;

[0054] R 5 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0055] R 6 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0056] Each R 7 is independently hydrogen, deuterium, fluorine, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl;

[0057] Or two Rs 7 together form a cycloalkyl or heterocycloalkyl; each is optionally substituted by one or more Rs;

[0058] n is 1 or 2;

[0059] Each R 8 is independently deuterium, halogen, -CN, -NO 2 , -OH, -ORa , -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 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl;

[0060] Or two Rs on the same carbon 8 together form an oxo group;

[0061] Or two Rs on the same or adjacent carbons 8 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more Rs;

[0062] p is 0 - 4;

[0063] W is absent, -C(R 9 ) 2 -, -O-, -S-, -S(=O)-, -S(=O) 2 -, -S(=O)(=NR W )-, or -NR W -;

[0064] 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 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl;

[0065] Or two Rs 9Together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0066] R W is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl;

[0067] Ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0068] 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 , deuterated alkyl, C 1 , -C 6 , hydroxyalkyl, C 1 , -C 6 , aminoalkyl, C 1 , -C 6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0069] q is 0 - 4;

[0070] each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 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 by one or more R;

[0071] each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 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 -C6 alkyl(heteroalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R;

[0072] Each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 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, heteroalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heteroalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R;

[0073] Or R c and R d together with the atom to which they are attached form a heteroalkyl, optionally substituted with one or more R; and

[0074] 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 NHC1 -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 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl;

[0075] Alternatively, two Rs on the same atom form an oxo group.

[0076] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0077] Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer or lung cancer.

[0078] The present disclosure also provides a method of treating a cancer in a subject in need thereof that comprises a BRCA1 and / or BRCA2 mutation, the method comprising administering a compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof according to any one of claims 1-70. In some embodiments, the cancer is bladder cancer, brain cancer and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer or uterine cancer.

[0079] Incorporated by reference

[0080] All publications, patents, and patent applications mentioned in this specification are incorporated herein 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

[0081] Definition

[0082] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments. However, one skilled in the art will understand that the 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 the context requires otherwise, throughout the specification and the following claims, the word "comprise" and variations such as "comprises" and "comprising" are to be construed in an open, inclusive sense, i.e., as "including but not limited to." Further, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0083] As used herein, unless otherwise specified, the following terms have the following meanings:

[0084] "oxo group" means ═O.

[0085] "oxo group" means ═O.

[0086] "Carboxyl" means -COOH.

[0087] "Cyano" means -CN.

[0088] "Alkyl" means a straight-chain or branched-chain saturated hydrocarbon monovalent group having from one to about ten carbon atoms, more preferably from one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever it appears herein, a numerical range such as "C 1 -C 6 alkyl" or "C 1-6 alkyl" means that the alkyl can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also encompasses the occurrence of the term "alkyl" where no numerical range is specified. In some embodiments, the alkyl is C 1-10 alkyl. In some embodiments, the alkyl is C 1 - 6 alkyl. In some embodiments, the alkyl is C 1-5 alkyl. In some embodiments, the alkyl is C 1-4 alkyl. In some embodiments, the alkyl is C 1-3 alkyl. Unless specifically stated otherwise in the specification, the alkyl can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or -NO 2 substituted. In some embodiments, the alkyl is optionally substituted by halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted by halogen.

[0089] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon monovalent group having one or more carbon-carbon double bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. The group may be in a cis or trans conformation with respect to the double bond, and is to be understood as including both isomers. Examples include, but are not limited to, vinyl (-CH=CH 2 ), 1-propenyl (-CH 2 CH=CH 2 ), isopropenyl [-C(CH 3 )=CH 2 , butenyl, 1,3-butadienyl, and the like. Whenever it appears herein, numerical ranges such as "C 2 -C 6 alkenyl" or "C 2-6 alkenyl" mean that the alkenyl may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but this definition also encompasses the occurrences of the term "alkenyl" where no numerical range is specified. Unless specifically stated otherwise in the specification, the alkenyl may be optionally substituted, for example, by oxo group, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl is optionally substituted by oxo group, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or -NO 2 . In some embodiments, the alkenyl is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkenyl is optionally substituted by halogen.

[0090] "Alkynyl" refers to a straight-chain or branched-chain hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever it appears herein, numerical ranges such as "C 2 -C 6 alkynyl" or "C 2-6 alkynyl" mean that the alkynyl may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but this definition also encompasses the occurrences of the term "alkynyl" where no numerical range is specified. Unless specifically stated otherwise in the specification, the alkynyl may be optionally substituted, for example, by oxo group, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl is optionally substituted by oxo group, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or -NO 2Substituted. In some embodiments, the alkynyl group is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkynyl group is optionally substituted by halogen.

[0091] "Alkylene" refers to a straight-chain or branched-chain divalent hydrocarbon chain. Unless otherwise specifically stated in the specification, the alkylene group may be optionally substituted, for example, by oxo group, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkylene group is optionally substituted by oxo group, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or -NO 2 Substituted. In some embodiments, the alkylene group is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkylene group is optionally substituted by halogen.

[0092] "Alkoxy" refers to a group of the formula -OR a wherein R a is alkyl as defined. Unless otherwise specifically stated in the specification, the alkoxy group may be optionally substituted, for example, by oxo group, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy group is optionally substituted by halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or -NO 2 Substituted. In some embodiments, the alkoxy group is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkoxy group is optionally substituted by halogen.

[0093] "Aryl" refers to a group derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include a fused ring system (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl group is bonded through an aromatic ring atom) or a bridged ring system. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl group (phenyl). Aryl groups include but are not limited to aryl groups derived from hydrocarbon ring systems of anthracenylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, fluoranthene, fluorene, asym-diphenyleneethane, sym-diphenyleneethane, indane, indene, naphthalene, phenalene, phenanthrene, pyrenylene, pyrene and triphenylene. Unless otherwise specifically stated in the specification, the aryl group may be optionally substituted, for example, by halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the aryl group is optionally substituted by halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3 、 -OH, -OMe, -NH 2 or -NO 2 substituted. In some embodiments, the aryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF 3 , -OH or -OMe. In some embodiments, the aryl is optionally substituted by halogen.

[0094] "Cycloalkyl" means a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include a fused ring system (when fused to an aryl or heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or a bridged ring system. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having three to fifteen carbon atoms (C 3 -C 15 cycloalkyl or C 3 -C 15 cycloalkenyl), cycloalkyls having three to ten carbon atoms (C 3 -C 10 cycloalkyl or C 3 -C 10 cycloalkenyl), cycloalkyls having three to eight carbon atoms (C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkenyl), cycloalkyls having three to six carbon atoms (C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkenyl), cycloalkyls having three to five carbon atoms (C 3 -C 5 cycloalkyl or C 3 -C 5 cycloalkenyl) or cycloalkyls having three to four carbon atoms (C 3 -C 4 cycloalkyl or C 3 -C 4cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the 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. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthalene, trans-decahydronaphthalene, 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. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless specifically stated otherwise in the specification, the cycloalkyl may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the cycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 、-OH、-OMe、-NH 2 or -NO 2 substituted. In some embodiments, the cycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF 3 、-OH or -OMe. In some embodiments, the cycloalkyl is optionally substituted by halogen.

[0095] "Halogen" or "halo" means bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0096] "Haloalkyl" means an alkyl as defined above substituted by one or more of the above-defined halogen atoms, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0097] "Hydroxyalkyl" means an alkyl as defined above substituted by one or more hydroxy groups. In some embodiments, the alkyl is substituted by one hydroxy group. In some embodiments, the alkyl is substituted by one, two, or three hydroxy groups. Hydroxyalkyls include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0098] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0099] "Cyanoalkyl" refers to an alkyl group as defined above that is substituted with one or more cyano groups. In some embodiments, the alkyl group is substituted with one cyano group. In some embodiments, the alkyl group is substituted with one or two cyano groups. Cyanoalkyl includes, for example, cyanomethyl.

[0100] "Deuterated alkyl" refers to an alkyl group as defined above that is substituted with one or more deuteriums. In some embodiments, the alkyl group is substituted with one deuterium. In some embodiments, the alkyl group is substituted with one, two, or three deuteriums. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six deuteriums. Deuterated alkyl includes, for example, CD 3 , CH 2 D, CHD 2 , CH 2 CD 3 , CD 2 CD 3 , CHDCD 3 , CH 2 CH 2 D or CH 2 CHD 2 . In some embodiments, the deuterated alkyl is CD 3 .

[0101] "Heteroalkyl" refers to an alkyl group in which one or more of the skeletal atoms of the alkyl group are selected from atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof). The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is C 1 -C 6 heteroalkyl, where the heteroalkyl is composed of 1 to 6 carbon atoms and one or more atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof), and where the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH3 ,-CH(CH 3 )OCH 3 ,-CH 2 NHCH 3 ,-CH 2 N(CH 3 ) 2 ,-CH 2 CH 2 NHCH 3 or -CH 2 CH 2 N(CH 3 ) 2 . Unless otherwise specifically stated in the specification, the heteroalkyl group may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroalkyl group is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 or -NO 2 . In some embodiments, the heteroalkyl group is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH or -OMe. In some embodiments, the heteroalkyl group is optionally substituted by halogen.

[0102] "Heterocycloalkyl" means a 3- to 24-membered partially or fully saturated ring group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the heterocycloalkyl group is fully saturated. In some embodiments, the heterocycloalkyl group contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl group contains one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl group contains one to three nitrogens. In some embodiments, the heterocycloalkyl group contains one or two nitrogens. In some embodiments, the heterocycloalkyl group contains one nitrogen. In some embodiments, the heterocycloalkyl group contains one nitrogen and one oxygen. Unless otherwise specifically stated in the specification, the heterocycloalkyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused ring system (when fused to an aryl or heteroaryl ring, the heterocycloalkyl group is bonded through a non-aromatic ring atom) or a bridged ring system; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl group can be optionally oxidized; the nitrogen atoms can be optionally quaternized. Representative heterocycloalkyl groups include, but are not limited to, heterocycloalkyl groups having two to fifteen carbon atoms (C 2 -C 15 heterocycloalkyl or C 2 -C 15 heterocycloalkenyl), heterocycloalkyl groups having two to ten carbon atoms (C 2-C 10 heterocycloalkyl or C 2 -C 10 -heterocycloalkenyl), heterocycloalkyl having two to eight carbon atoms (C 2 -C 8 heterocycloalkyl or C 2 -C 8 -heterocycloalkenyl), heterocycloalkyl having two to seven carbon atoms (C 2 -C 7 heterocycloalkyl or C 2 -C 7 -heterocycloalkenyl), heterocycloalkyl having two to six carbon atoms (C 2 -C 6 heterocycloalkyl or C 2 -C 6 -heterocycloalkenyl), heterocycloalkyl having two to five carbon atoms (C 2 -C 5 heterocycloalkyl or C 2 -C 5 -heterocycloalkenyl) or heterocycloalkyl having two to four carbon atoms (C 2 -C 4 heterocycloalkyl or C 2 -C 4(heterocycloalkenyl). Examples of such heterocycloalkyls include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyl has 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is different from the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the backbone atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless specifically stated otherwise in the specification, the heterocycloalkyl may be optionally substituted as described below, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heterocycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 , -OH, -OMe, -NH 2 or -NO 2 substituted. In some embodiments, the heterocycloalkyl is optionally substituted by halogen, methyl, ethyl, -CN, -CF 3 , -OH or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted by halogen.

[0103] "Heteroaryl" refers to a 5- to 14-membered ring system group containing one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains one to three nitrogens. In some embodiments, the heteroaryl contains one or two nitrogens. In some embodiments, the heteroaryl contains one nitrogen. The heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include a fused ring system (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or a bridged ring system; and the nitrogen, carbon, or sulfur atoms in the heteroaryl can be optionally oxidized; the nitrogen atoms can be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples include but are not limited to azido group, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranone, benzofuranyl, benzofuranone, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazido group, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 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 phenylthio (i.e., thienyl). Unless specifically stated otherwise in the specification, the heteroaryl can be optionally substituted, for example, by halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3, -OH, -OMe, -NH 2 or -NO 2 substituted. In some embodiments, the heteroaryl is optionally substituted with a halogen, methyl, ethyl, -CN, -CF 3 , -OH or -OMe. In some embodiments, the heteroaryl is optionally substituted with a halogen.

[0104] The term "optional" or "optionally" means that the subsequent described event or situation may or may not occur, and the description includes instances where the described event or situation occurs and instances where the described event or situation does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. In addition, an optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., -CF 2 CF 3 ), monosubstituted (e.g., -CH 2 CH 2 F) or substituted at any level between fully substituted and monosubstituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc.). Those skilled in the art should understand that for any group containing one or more substituents, such groups are not intended to introduce any substitutions or substitution patterns that are spatially unrealistic and / or synthetically infeasible (e.g., substituted alkyl includes optionally substituted cycloalkyl, which is in turn defined to include optionally substituted alkyl, potentially infinitely). Therefore, any described substituent should generally be understood to have a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.

[0105] "Effective amount" or "therapeutically effective amount" means the amount of a compound administered to a mammalian subject as a single dose or as part of a series of doses, which effectively produces the desired therapeutic effect.

[0106] "Treatment" of an individual (e.g., a mammal, such as a human) or a cell is any type of intervention used to attempt to alter the natural processes of the individual or cell. In some embodiments, treatment includes administering a pharmaceutical composition after the initiation of a pathological event or contact with a pathogen, and includes stabilizing the condition (e.g., the condition does not worsen) or alleviating the condition.

[0107] "Synergistic" or "synergize" means that the combined effect is greater than the sum of the effects of each component alone at the same dose.

[0108] As used herein, "PARP-related disease or disorder" or alternatively "PARP-mediated disease or disorder" means any disease or other adverse condition in which PARP or its mutants are known or suspected to play a role.

[0109] As used herein, "PARP1-related disease or disorder" or alternatively "PARP1-mediated disease or disorder" means any disease or other adverse condition in which PARP or its mutants are known or suspected to play a role.

[0110] Compound

[0111] Compounds of formula (I) or pharmaceutically acceptable salts, solvates or stereoisomers thereof useful for treating cancer are described herein.

[0112] A compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is disclosed herein:

[0113]

[0114] Wherein:

[0115] R 1 is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 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;

[0116] X is N or CR 2 ;

[0117] R 2 is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0118] or R 1 and R 2 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally substituted by one or more R;

[0119] Z is N or CR 4 ;

[0120] R 4 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0121] Y is N or CR 5 ;

[0122] R 5 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0123] R 6 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0124] Each R 7 is independently hydrogen, deuterium, fluorine, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl;

[0125] Or two Rs 7 together form cycloalkyl or heterocycloalkyl; each is optionally substituted by one or more Rs;

[0126] n is 1 or 2;

[0127] 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 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl;

[0128] Or two Rs on the same carbon 8 together form an oxo group;

[0129] or two Rs on the same carbon or adjacent carbons 8 together form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more Rs;

[0130] p is 0 - 4;

[0131] W is absent, is -C(R 9 ) 2 -, -O-, -S-, -S(=O)-, -S(=O) 2 -, -S(=O)(=NR W )-

[0132] or -NR W -;

[0133] 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 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl;

[0134] or two Rs 9 together form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more Rs;

[0135] R W is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl;

[0136] Ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0137] each R 10 is independently deuterium, halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR cR 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 、 -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 deuterated alkyl, 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 by one or more R;

[0138] q is 0 - 4;

[0139] Each R a independently is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 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;

[0140] Each R b is independently hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -deuterated alkyl, 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;

[0141] Each R c and R d are independently hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -deuterated alkyl, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 -aminoalkyl, C 1 -C6 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 by one or more R;

[0142] or R c and R d together with the atom to which they are attached form a heterocycloalkyl, optionally substituted by one or more R; and

[0143] 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 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl;

[0144] Or two Rs on the same atom form an oxo group;

[0145] Provided that the compound of formula (I) is not

[0146] Disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0147]

[0148] Wherein:

[0149] R 1 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 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;

[0150] X is N or CR 2 ;

[0151] R 2 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0152] or R 1 and R 2 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally substituted by one or more R;

[0153] Z is N or CR 4 ;

[0154] R 4 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0155] Y is N or CR 5 ;

[0156] R 5 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0157] R 6is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0158] Each R 7 is independently hydrogen, deuterium, fluorine, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl;

[0159] Or two Rs 7 together form a cycloalkyl or heterocycloalkyl; each is optionally substituted by one or more Rs;

[0160] n is 1 or 2;

[0161] 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 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl;

[0162] or two Rs on the same carbon 8 together form an oxo group;

[0163] or two Rs on the same or adjacent carbons 8 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more Rs;

[0164] p is 0 - 4;

[0165] W is -C(R 9 ) 2 -, -O-, -S-, -S(=O)-, -S(=O) 2 -, -S(=O)(=NR W )- or -NR W -;

[0166] Each R 9 independently is 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 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl;

[0167] Or two Rs 9 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more Rs;

[0168] R W is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl;

[0169] Ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0170] Each R 10 independently is 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 , -NR c C(=O)NR d , -NR b , -NR a , -NR b , -NR b , -NR b , -NR 2 S(=O) a R a , -C(=O)R b , -C(=O)OR c R d , C 1 , -C 6 , C 1 , -C 6 , C 1 , -C 6 , C 1 , -C 6 , C 1 , -C 6 , C 1 , -C 6 , -C

[0171] , q is 0 - 4;

[0172] , each R a independently is C 1 , -C 6 , C 1 , -C 6 , C 1 , -C 6 , C 1 , -C 6 , C 1 , -C 6 , C 1 , -C 6Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl(cycloalkyl), C 1 -C 6 Alkyl(heteroalkyl), C 1 -C 6 Alkyl(aryl) or C 1 -C 6 Alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0173] Each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 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, heteroalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heteroalkyl), C 1 -C 6 alkyl(aryl) or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0174] Each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C1 -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 by one or more R;

[0175] or R c and R d together with the atom to which they are attached form a heterocycloalkyl, optionally substituted by one or more R; and

[0176] 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 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl;

[0177] Or two Rs on the same atom form an oxo group;

[0178] Provided that the compound of formula (I) is not

[0179] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, the compound has formula (Ia):

[0180]

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

[0182]

[0183] Wherein R 8a is 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 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6aminoalkyl or C 1 -C 6 heteroalkyl; and

[0184] p’ is from 0 to 3.

[0185] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, the compound has formula (Ic):

[0186]

[0187] In some embodiments of the compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 haloalkyl, 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.

[0188] In some embodiments of the compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 is halogen, -CN, -OH, -OR a , C 1 -C 6 haloalkyl, 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.

[0189] In some embodiments of the compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 alkyl, C 3 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 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. In some embodiments of the compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 is hydrogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl or cycloalkyl. In some embodiments of the compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 is C 1 -C 6 alkyl or cycloalkyl. In some embodiments of the compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 is C 1 alkyl or C 3 -C 6 alkyl. In some embodiments of the compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 is cycloalkyl. In some embodiments of the compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1is cyclopropyl. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, R 1 is methyl or ethyl. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, R 1 is ethyl.

[0190] In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, R 1 is deuterium, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, R 1 is deuterium, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, R 1 is halogen, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, R 1 is halogen, C 1 -C 6Halogenoalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic) or their pharmaceutically acceptable salts, solvates or stereoisomers, R 1 is halogen or cycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic) or their pharmaceutically acceptable salts, solvates or stereoisomers, R 1 is halogen. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic) or their pharmaceutically acceptable salts, solvates or stereoisomers, R 1 is cycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic) or their pharmaceutically acceptable salts, solvates or stereoisomers, R 1 is cyclopropyl.

[0191] In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic) or their pharmaceutically acceptable salts, solvates or stereoisomers, R 1 is halogen, C 1 -C 6 alkyl, C 1 -C 6 halogenoalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic) or their pharmaceutically acceptable salts, solvates or stereoisomers, R 1 is halogen, C 1 -C 6 alkyl, C 1 -C 6 halogenoalkyl, C 1 -C 6 deuterated alkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic) or their pharmaceutically acceptable salts, solvates or stereoisomers, R 1 is halogen, C 1 -C 6 alkyl or cycloalkyl.

[0192] In some embodiments of the compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, X is N. In some embodiments of the compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, X is CR 2 .

[0193] In some embodiments of the compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 2 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl. In some embodiments of the compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 2 is hydrogen, halogen or C 1 -C 6 alkyl. In some embodiments of the compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of the compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 2 is hydrogen.

[0194] In some embodiments of the compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 and R 2 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally substituted by one or more R. In some embodiments of the compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 and R 2 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R. In some embodiments of the compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 1 and R 2 together form an aryl or heteroaryl; each optionally substituted by one or more R.

[0195] The present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0196]

[0197] Wherein:

[0198] Ring B together with X 1 and X 2 is a 5-membered heteroalkyl or 5-membered heteroaryl;

[0199] X 1 is C, CH or N;

[0200] X 2 is C, CH or N;

[0201] 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 deuterated alkyl, 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 heteroalkyl;

[0202] m is 0 - 3;

[0203] Z is N or CR 4 ;

[0204] R 4 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0205] Y is N or CR 5 ;

[0206] R 5 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0207] R 6 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0208] each R 7 is independently hydrogen, deuterium, fluorine, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl;

[0209] or two Rs 7 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more Rs;

[0210] n is 1 or 2;

[0211] Each R 8 is independently deuterium, a 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 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl;

[0212] Or two Rs on the same carbon 8 together form an oxo group;

[0213] Or two Rs on the same or adjacent carbons 8 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more Rs;

[0214] p is 0 - 4;

[0215] W is absent, -C(R 9 ) 2 -, -O-, -S-, -S(=O)-, -S(=O) 2 -, -S(=O)(=NR W )-, or -NR W -;

[0216] Each R 9 is independently hydrogen, deuterium, a halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C6 Heteroalkyl;

[0217] or two Rs 9 together form a cycloalkyl or heteroalkyl; each optionally substituted by one or more Rs;

[0218] R W is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl;

[0219] Ring A is cycloalkyl, heteroalkyl, aryl or heteroaryl;

[0220] 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 , -NR 2 S(=O) a R a , -C(=O)R b , -C(=O)OR c , -C(=O)NR d R 1 , C 6 , -C 1 , -C 6 , haloalkyl, C 1 , -C 6 , deuterated alkyl, C 1 , -C 6 , hydroxyalkyl, C1 -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 by one or more R;

[0221] q is 0 - 4;

[0222] each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 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 by one or more R;

[0223] each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 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, C1 -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;

[0224] each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 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;

[0225] or R c and R d together with the atom(s) to which they are attached form a heterocycloalkyl, optionally substituted with one or more R; and

[0226] 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 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl;

[0227] Or two Rs on the same atom form an oxo group.

[0228] In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, ring B and X 1 and X 2 together are a 5-membered heteroalkyl. In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, ring B and X 1 and X 2 together are pyrrolidinyl or furyl. In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, ring B and X 1 and X 2Together they are a 5-membered heteroaryl. In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, ring B and X 1 and X 2 Together they are pyrrolyl, pyrazolyl, imidazolyl or triazolyl. In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, ring B and X 1 and X 2 Together they are pyrazolyl or imidazolyl. In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, ring B and X 1 and X 2 Together they are pyrazolyl. In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, ring B and X 1 and X 2 Together they are furyl.

[0229] 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 is CH. In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, X 1 is N. In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, X 2 is C. In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, X 2 is CH. In some embodiments of the compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, X 2 is N.

[0230] In some embodiments of the 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 the compound of formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, Z is CR 4 。

[0231] In some embodiments of the compound of formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 4 is hydrogen, deuterium, halogen, C 1 -C6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuterated alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, R 4 is hydrogen, halogen or C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, R 4 is hydrogen or C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, R 4 is hydrogen.

[0232] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, Y is N. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, Y is CR 5 .

[0233] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, R 5 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, R 5 is hydrogen, halogen or C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, R 5 is hydrogen or C 1 -C 6Alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, R 5 is hydrogen.

[0234] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, R 6 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, R 6 is hydrogen, halogen or C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, R 6 is hydrogen or C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, R 6 is hydrogen.

[0235] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R 7 is independently hydrogen, deuterium, fluorine, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl.

[0236] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R 7 is independently hydrogen, deuterium, fluorine or C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R7 Independently hydrogen, fluorine or C 1 -C 6 -alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R 7 Independently hydrogen or C 1 -C 6 -alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R 7 Independently hydrogen or fluorine. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R 7 Is hydrogen. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, one R 7 Is hydrogen and the other R 7 Is C 1 -C 6 -alkyl.

[0237] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, two Rs 7 Together form cycloalkyl or heterocycloalkyl; each optionally substituted by one or more Rs. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, two Rs 7 Together form cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, two Rs 7 Together form cycloalkyl.

[0238] In some embodiments of the compounds of formula (I) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, n is 1. In some embodiments of the compounds of formula (I) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, n is 2.

[0239] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R 8 Independently deuterium, halogen, -CN, -OH, -ORa , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R 8 is independently deuterium, halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R 8 is independently deuterium, halogen, -CN or C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R 8 is independently -CN or C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R 8 is independently C 1 -C 6 alkyl.

[0240] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, two R's on the same carbon 8 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R's. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, two R's on the same carbon 8 together form a cycloalkyl or heterocycloalkyl.

[0241] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, two R's on adjacent carbons8 together form a cycloalkyl or heterocycloalkyl; each is optionally substituted by one or more R. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, two Rs on adjacent carbons 8 together form a cycloalkyl or heterocycloalkyl.

[0242] In some embodiments of the compounds of formula (I), (Ia), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, p is 0 - 3. In some embodiments of the compounds of formula (I), (Ia), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, p is 0 - 2. In some embodiments of the compounds of formula (I), (Ia), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, p is 0 or 1. In some embodiments of the compounds of formula (I), (Ia), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, p is 2 - 4. In some embodiments of the compounds of formula (I), (Ia), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, p is 2 or 3. In some embodiments of the compounds of formula (I), (Ia), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, p is 1 - 4. In some embodiments of the compounds of formula (I), (Ia), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, p is 1 - 3. In some embodiments of the compounds of formula (I), (Ia), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, p is 1 or 2. In some embodiments of the compounds of formula (I), (Ia), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, p is 0. In some embodiments of the compounds of formula (I), (Ia), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, p is 1. In some embodiments of the compounds of formula (I), (Ia), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, p is 2. In some embodiments of the compounds of formula (I), (Ia), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, p is 3.

[0243] In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p' is 0 - 2. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p' is 0 or 1. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p' is 2 or 3. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p' is 1 - 3. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p' is 1 or 2. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p' is 0. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p' is 1. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p' is 2. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, p' is 3.

[0244] 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 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 8a is deuterium, halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 8a is deuterium, halogen, -CN or C 1 -C 6 alkyl. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 8a is -CN or C 1 -C6 Alkyl. In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, R 8a is C 1 -C 6 alkyl.

[0245] In some embodiments of the compound of formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, W is -C(R 9 ) 2 -, -O-, -S-, -S(=O)-, -S(=O) 2 -, -S(=O)(=NR W )- or -NR W -. In some embodiments of the compound of formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, W is absent, -C(R 9 ) 2 -, -O- or -NR W -. In some embodiments of the compound of formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, W is -C(R 9 ) 2 -, -O- or -NR W -. In some embodiments of the compound of formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, W is -O- or -NR W -. In some embodiments of the compound of formula (I), (Ia), (Ib), (Ic) or (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, W is -S-, -S(=O)-, -S(=O) 2 - or -S(=O)(=NR W )-. In some embodiments of the 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 the 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 the 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 the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, W is absent.

[0246] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R 9 is independently hydrogen, deuterium, fluorine, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R 9 is independently hydrogen, deuterium, fluorine or C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R 9 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R 9 is independently hydrogen, fluorine or C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R 9 is independently hydrogen or fluorine. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R 9 is hydrogen. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, one R 9 is hydrogen and the other R 9 is C 1 -C 6 alkyl.

[0247] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, two Rs9 together form a cycloalkyl or heterocycloalkyl group; each is optionally substituted by one or more R. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, two R 9 together form a cycloalkyl or heterocycloalkyl group. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, two R 9 together form a cycloalkyl group.

[0248] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, R W is hydrogen or C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R W is hydrogen.

[0249] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, ring A is a cycloalkyl or heterocycloalkyl group. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, ring A is a cycloalkyl group. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, ring A is a heterocycloalkyl group.

[0250] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, ring A is an aryl or heteroaryl group. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, ring A is a phenyl group. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, ring A is a heteroaryl group.

[0251] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, ring A is a 5- or 6-membered heteroaryl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, ring A is a 5-membered heteroaryl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, ring A is a 6-membered heteroaryl.

[0252] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, ring A is not pyridyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, ring A is not

[0253] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, 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 , -NR 2 S(=O) a , -C(=O)R a , -C(=O)OR b , -C(=O)NR cR d 、 C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl; provided that one R 10 is not -C(=O)NHCH 3 . In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, 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 , -S(=O) c NR d , -NR c R d , -NR b , -NR c C(=O)NR d , -NR b , -NR a , -NR b , -NR b , -NR b , -NR 2 S(=O) a , -C(=O)R a , -C(=O)OR b , C 1 , -C 6 , alkyl, C 1 , -C 6 , haloalkyl, C 1 , -C 6 , deuterated alkyl, C 1 , -C 6 , hydroxyalkyl, C 1 , -C6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R 10 is 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 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R 10 is independently deuterium, halogen, -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)NRc R d 、 C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl.

[0254] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, 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 deuterated alkyl.

[0255] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R 10 is independently -C(=O)NR c R d .

[0256] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, q is 0 - 3. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, q is 0 - 2. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, q is 0 or 1. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, q is 1 - 4. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, q is 1 - 3. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, q is 2 - 4. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, q is 2 or 3. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, q is 1 or 2. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, q is 1. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, q is 2. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, q is 3.

[0257] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, not

[0258] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, is

[0259] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, is

[0260] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted by one or more R. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted by one or more R. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted by one or more R. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R a is independently C 1 -C 6An alkyl or cycloalkyl group; wherein each alkyl and cycloalkyl group is independently and optionally substituted by one or more Rs. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; wherein each alkyl group is independently and optionally substituted by one or more Rs.

[0261] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl group is independently and optionally substituted by one or more Rs. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl group is independently and optionally substituted by one or more Rs. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6A haloalkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted by one or more R. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R b is independently hydrogen, C 1 -C 6 alkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted by one or more R. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R b is independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; wherein each alkyl is independently and optionally substituted by one or more R. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R b is independently hydrogen or C independently and optionally substituted by one or more R 1 -C 6 alkyl.

[0262] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted by one or more R. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C6 haloalkyl, C 1 -C 6 deuterated alkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted by one or more R. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted by one or more R. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R c and R d is independently hydrogen, C 1 -C 6 alkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted by one or more R. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R c and R d is independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; wherein each alkyl is independently and optionally substituted by one or more R. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R c and R d are each independently hydrogen or C independently and optionally substituted by one or more R 1 -C 6 alkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, R c is cycloalkyl and R d is hydrogen.

[0263] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, R c and R dTogether with the atoms to which they are attached, form a heterocycloalkyl optionally substituted with one or more R. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, R c and R d together with the atoms to which they are attached, form a heterocycloalkyl.

[0264] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 6 alkyl, -NH 2 , -NHC 1 -C 6 alkyl, -N(C 1 -C 6 alkyl) 2 , -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 or C 1 -C 6 deuterated alkyl; or two Rs on the same atom form an oxo group. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or their pharmaceutically acceptable salts, solvates or stereoisomers, each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 6 alkyl, -NH 2 , -NHC 1 -C 6 alkyl, -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C6 a deuterated alkyl group; or two Rs on the same atom form an oxo group. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (II) or pharmaceutically acceptable salts, solvates or stereoisomers thereof, each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 6 alkyl, -C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl group; or two Rs on the same atom form an oxo group.

[0265] In some embodiments of the compounds disclosed herein, each R a , R b , R c , R d , when R 1 and R 2 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, a cycloalkyl and heterocycloalkyl group formed when two Rs 7 are taken together, a cycloalkyl and heterocycloalkyl group formed when two Rs 8 are taken together, a cycloalkyl and heterocycloalkyl group formed when two Rs 9 are taken together, and a heterocycloalkyl group formed when R c and R d are taken together is independently substituted with one, two, three or four substituents as defined herein. In some embodiments of the compounds disclosed herein, each R a , R b , R c , R d , when R 1 and R 2 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, a cycloalkyl and heterocycloalkyl group formed when two Rs 7 are taken together, a cycloalkyl and heterocycloalkyl group formed when two Rs 8 are taken together, a cycloalkyl and heterocycloalkyl group formed when two Rs 9 are taken together, and a heterocycloalkyl group formed when R c and R d are taken together is independently substituted with one, two or three substituents as defined herein. In some embodiments of the compounds disclosed herein, each R a , R b , R c , R d , when R 1 and R2 A cycloalkyl, heterocycloalkyl, aryl or heteroaryl formed when taken together, and when two Rs 7 A cycloalkyl and heterocycloalkyl formed when taken together, and when two Rs 8 A cycloalkyl and heterocycloalkyl formed when taken together, and when two Rs 9 A cycloalkyl and heterocycloalkyl formed when taken together, and when R c and R d The heterocycloalkyl formed when taken together is independently substituted by one or two substituents as defined herein.

[0266] Any combination of groups of the above various variables is contemplated herein. Throughout the specification, those skilled in the art select the groups and their substituents to provide stable moieties and compounds.

[0267] In some embodiments, the compounds disclosed herein are compounds selected from Table 1 or pharmaceutically acceptable salts, solvates or stereoisomers thereof.

[0268] Table 1

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281] The absolute label (abs) is added to the chiral center to indicate that it is unambiguously a pure sample of the drawn stereoisomer.

[0282] The OR label (or) indicates a pure substance, but the absolute configuration of the stereochemical center is unknown. After chiral separation with the isolated pure structure, multiple OR labels (OR indicating purity) with the same value will indicate that the sample is one of a pair of pure enantiomers (but the absolute configuration of the stereochemical center is unknown).

[0283] Other forms of the compounds disclosed herein

[0284] Isomers / stereoisomers

[0285] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, and each center exists in the R configuration or the S configuration. The compounds described herein include all diastereomers, enantiomers and epimeric forms and their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination or tautomerization can be used 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 diastereomers and recovering the optically pure enantiomer. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.), and are separated by taking advantage of these differences. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably by separation / splitting techniques based on solubility differences. In some embodiments, the optically pure enantiomer and the resolving agent are then recovered by any practical means that does not cause racemization.

[0286] Labeled compound

[0287] In some embodiments, the compounds described herein exist in their isotopically labeled forms. 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 a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are the same as those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, respectively, 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. Compounds described herein containing the foregoing isotopes and / or other isotopes of other atoms, as well as their pharmaceutically acceptable salts, solvates, or stereoisomers, are within the scope of the invention. Certain isotopically labeled compounds, such as those incorporating radioactive isotopes such as 3 H and 14 C, can be used for drug and / or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred because of their ease of preparation and detectability. In addition, substitution with heavy isotopes such as deuterium (i.e., 2 H) can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0288] In some embodiments, the compounds described herein are labeled by other means, including but not limited to using chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0289] Pharmaceutically acceptable salt

[0290] In some embodiments, the compounds described herein exist in their pharmaceutically acceptable salt forms. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0291] In some embodiments, the compounds described herein have acidic or basic groups and thus react with any of a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the disclosed compounds or their solvates or stereoisomers, or by reacting the purified compound in its free form with a suitable acid or base separately and isolating the salt thus formed.

[0292] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with inorganic, organic or inorganic bases, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, caprate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, mesylate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propynoate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, undecanoate tosylate and xylenesulfonate.

[0293] In addition, 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 but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; 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, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid. In some embodiments, other acids, such as oxalic acid, although not pharmaceutically acceptable in itself, are used to prepare salts that are intermediates for obtaining the compounds, solvates or stereoisomers thereof, and their pharmaceutically acceptable acid addition salts disclosed herein.

[0294] In some embodiments, those compounds containing free acid groups described herein are reacted with a suitable base (such as hydroxides, carbonates, bicarbonates, sulfates of pharmaceutically acceptable metal cations), with ammonia, or with pharmaceutically acceptable organic primary, secondary, tertiary or quaternary amines. Representative salts include alkali metal salts or alkaline earth metal salts, such as lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts and aluminum salts, etc. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 etc.

[0295] Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups contained therein. In some embodiments, water-soluble, oil-soluble or dispersible products are obtained by such quaternization.

[0296] Solvate

[0297] In some embodiments, the compounds described herein exist as solvates. The present invention provides methods for treating diseases by administering such solvates. The present invention also provides methods for treating diseases by administering such solvates as pharmaceutical compositions.

[0298] Solvates contain a stoichiometric or non-stoichiometric amount of solvent and, in some embodiments, are formed during the use of pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is an alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from aqueous / organic solvent mixtures using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. Generally, for the purposes of the compounds and methods provided herein, the solvated forms are considered equivalent to the unsolvated forms.

[0299] Tautomer

[0300] In some cases, compounds exist in tautomeric forms. 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 conversion of a single bond and an adjacent double bond. In the bonding arrangements where tautomerism can occur, there will be a chemical equilibrium of the tautomers. All tautomeric forms of the compounds disclosed herein are contemplated. The exact proportions of the tautomers depend on several factors, including temperature, solvent, and pH.

[0301] Therapeutic method

[0302] Methods for treating diseases in which the inhibition of PARP is beneficial are disclosed herein, the methods comprising administering a compound disclosed herein. Methods for treating diseases in which the inhibition of PARP1 is beneficial are also disclosed herein, the methods comprising administering a compound disclosed herein. In some embodiments, the disease is cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer (such as gastric cancer and colorectal cancer), or lung cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In some embodiments, the cancer is leukemia, colon cancer, glioblastoma, lymphoma, melanoma, or cervical cancer.

[0303] In some embodiments, the cancer comprises a BRCA1 and / or BRCA2 mutation.

[0304] In some embodiments, cancers comprising a BRCA1 and / or BRCA2 mutation are bladder cancer, brain cancer and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, gastric cancer, thyroid cancer, or uterine cancer.

[0305] In some embodiments, the cancer is a cancer lacking Flomologous 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 to reform a continuous DNA helix. Components of the FIR-dependent DNA DSB repair pathway include, but are not limited to, ATM (NM_000051), RAD51 (NM_002875), RAD51 L1 (NM_002877), RAD51 C (NM_002876), RAD51 L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432), RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), MRE1 1A (NM_005590), and NBS1 (NM_002485). Other proteins involved in the FIR-dependent DNA DSB repair pathway include regulators such as EMSY. In some embodiments, a cancer lacking FIR-dependent DNA DSB repair comprises one or more cancer cells having a reduced or eliminated ability to repair DNA DSBs via this pathway relative to normal cells, i.e., the activity of the FIR-dependent DNA DSB repair pathway may be reduced or eliminated in the one or more cancer cells.

[0306] In some embodiments, in one or more cancer cells of an individual having a cancer lacking FIR-dependent DNA DSB repair, the activity of one or more components of the FIR-dependent DNA DSB repair pathway is eliminated.

[0307] In some embodiments, the cancer cells have a BRCA1 and / or BRCA2 defective phenotype, i.e., reduced or eliminated BRCA1 and / or BRCA2 activity in the cancer cells. Cancer cells with such a phenotype may lack BRCA1 and / or BRCA2, i.e., the expression and / or activity of BRCA1 and / or BRCA2 in the cancer cells can be reduced or eliminated, for example, by mutations or polymorphisms in the coding nucleic acid, or by amplification, mutation or polymorphism of a gene encoding a regulatory factor (e.g., the EMSY gene encoding a BRCA2 regulatory factor). BRCA1 and BRCA2 are known tumor suppressor genes, and their wild-type alleles are often lost in tumors of heterozygous carriers. It is also known that amplification of the EMSY gene encoding a BRCA2 binding factor is associated with breast and ovarian cancers. Carriers of BRCA1 and / or BRCA2 mutations are also at high risk of certain cancers, including breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer and lung cancer.

[0308] Administration

[0309] In certain embodiments, a composition containing a compound described herein is administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially inhibit at least one symptom of the disease or condition. The amount effective for such use depends on the severity and course of the disease or condition, previous treatment, the health status, weight and response of the patient to the drug, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0310] In prophylactic applications, a composition containing a compound described herein is administered to a patient susceptible to a particular disease, disorder or condition or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined as a "prophylactically effective amount or dose". In such use, the exact amount also depends on the health status, weight, etc. of the patient. When used in a patient, the effective amount for such use will depend on the severity and course of the disease, disorder or condition, previous treatment, the health status and response of the patient to the drug, and the judgment of the treating physician. In one aspect, prophylactic treatment includes administering to a mammal that has previously experienced at least one symptom or risk factor of the disease being treated and is currently in remission a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof to prevent recurrence of symptoms of the disease or condition.

[0311] In certain embodiments where the patient's condition does not improve, the administration of the compound is, at the discretion of the physician, a long-term administration, i.e., for a prolonged period of time, including the entire duration of the patient's life, to improve or otherwise control or limit the symptoms of the patient's disease or condition.

[0312] In certain embodiments where the patient's condition does improve, the dose of the administered drug is temporarily reduced or temporarily suspended for a period of time (i.e., a "drug holiday"). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including for example only 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days or more than 28 days. For example, the dose reduction during the drug holiday is from only 10% - 100%, including for example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and 100%.

[0313] Once the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, as the symptoms change, the dose or frequency or both of the administered drug are reduced to a level that maintains the improved disease, disorder or condition. However, in certain embodiments, after any symptom recurrence, the patient requires long-term intermittent or daily treatment.

[0314] The amount of a given pharmaceutical agent corresponding to such an amount varies depending on factors such as the specific compound, the disease condition and its severity, the identity of the subject or host to be treated (e.g., weight, gender), but is still determined according to the specific circumstances surrounding the case, including for example the specific pharmaceutical agent administered, the route of administration, the condition being treated and the subject or host being treated.

[0315] However, generally speaking, the dose for adult treatment is usually in the range of 0.01 mg - 5000 mg per day. In one aspect, the dose for adult treatment is from about 1 mg to about 1000 mg per day. In one embodiment, the required dose is conveniently provided as a single dose or as divided doses administered simultaneously or at appropriate intervals, such as two, three, four or more sub-doses per day.

[0316] In one embodiment, the daily dose suitable for the compounds or their pharmaceutically acceptable salts described herein is from about 0.01 mg / kg body weight to about 50 mg / kg body weight. In some embodiments, based on a plurality of variables related to an individual treatment regimen, the amount of the active substance in the daily dose or dosage form is lower or higher than the ranges indicated herein. In various embodiments, the daily dose and unit dose vary according to many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the needs of the individual subject, the severity of the disease or condition to be treated and the judgment of the physician.

[0317] The toxicity and therapeutic efficacy of such treatment regimens are determined in cell cultures or experimental animals by standard pharmaceutical procedures, including but not limited to LD10 and ED 90 determination. The dose ratio between the toxic effect and the therapeutic effect is the therapeutic index, expressed as LD 50 and ED 50 The ratio between. In certain embodiments, data obtained from cell culture assays and animal studies are used to formulate a therapeutically effective daily dose range and / or a therapeutically effective unit dose for mammals, including humans. In some embodiments, the daily dose of the compounds described herein is within the circulating concentration range of ED 50 with minimal toxicity. In certain embodiments, the daily dose range and / or unit dose vary within this range, depending on the dosage form employed and the route of administration employed.

[0318] In any of the foregoing aspects, additional embodiments are those in which an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof is: (a) administered systemically to a mammal; and / or (b) administered orally to a mammal; and / or (c) administered intravenously to a mammal; and / or (d) administered to a mammal by injection; and / or (e) administered topically to a mammal; and / or (f) administered to a mammal non-systemically or topically.

[0319] In any of the foregoing aspects, additional embodiments include single administration of an effective amount of the compound, including additional embodiments in which (i) the compound is administered once daily; or (ii) the compound is administered to the mammal multiple times within a day.

[0320] In any of the foregoing aspects, additional embodiments include multiple administrations of an effective amount of the compound, including additional embodiments in which (i) the compound is administered continuously or intermittently: such as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the subject every 12 hours; (v) the compound is administered to the subject every 24 hours. In additional or alternative embodiments, the method includes a drug holiday, in which the administration of the compound is temporarily suspended or the dose of the administered compound is temporarily reduced; at the end of the drug holiday, administration of the compound is restarted. In one embodiment, the length of the drug holiday ranges from 2 days to 1 year.

[0321] Route of administration

[0322] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, for example, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0323] In certain embodiments, the compounds described herein are administered locally rather than systemically, e.g., by direct injection of the compound into an organ, typically in the form of a depot formulation or sustained release formulation. In a specific embodiment, the long-acting formulation is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Additionally, in other embodiments, the drug is delivered in a targeted drug delivery system, e.g., in liposomes coated with an organ-specific antibody. In such embodiments, the liposomes target the organ and are selectively taken up by the organ. In other embodiments, the compounds described herein are provided in the form of an immediate release formulation, an extended release formulation, or an intermediate release formulation. In other embodiments, the compounds described herein are administered locally.

[0324] Pharmaceutical composition / formulation

[0325] In accordance with standard pharmaceutical practice, the compounds described herein are administered, alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent, in the form of a pharmaceutical composition to a subject in need thereof. In one embodiment, the compounds of the invention can be administered to animals. These compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

[0326] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients which facilitate processing of the active compound into a pharmaceutically useful formulation. Suitable formulations depend on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 17th Edition (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0327] In some embodiments, the pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrants, dispersing agents, surfactants, lubricants, coloring agents, diluents, solubilizing agents, wetting agents, plasticizers, stabilizers, permeation enhancers, humectants, antifoaming agents, antioxidants, preservatives, and any combination thereof.

[0328] 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. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast dissolve formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multi-particulate formulations, and combinations of immediate release and controlled release formulations.

[0329] A pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is prepared in a conventional manner, such as, by way of example only, by conventional mixing, dissolving, granulating, sugar-coating, grinding, emulsifying, encapsulating, entrapping or compressing processes.

[0330] Pharmaceutical compositions for oral use are obtained by mixing one or more solid excipients with one or more compounds as described herein, optionally grinding the resulting mixture, and processing the granule mixture, if desired, after adding suitable auxiliaries, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents are added such as cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate. In some embodiments, colorants or pigments are added to the tablet or dragee coating to identify or characterize different combinations of the active compound dose.

[0331] Pharmaceutical compositions for oral administration include push-fit capsules made of gelatin, as well as soft-sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules contain the active ingredient admixed with a filler such as lactose, a binder such as starch and / or a lubricant such as talc or magnesium stearate and, optionally, a stabilizer. In the soft capsules, the active compound is dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin or liquid polyethylene glycol. In some embodiments, a stabilizer is added.

[0332] Pharmaceutical compositions for parenteral use are formulated as infusion or injection preparations. In some embodiments, a pharmaceutical composition suitable for injection or infusion includes a sterile aqueous solution, dispersion or sterile powder comprising a compound as described herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, the pharmaceutical composition contains 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 glycerides and any combination thereof. In some embodiments, the pharmaceutical composition also contains a preservative to prevent microbial growth.

[0333] Combination

[0334] The present disclosure relates to methods of treating cancer using a compound disclosed herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in combination with an additional therapeutic agent.

[0335] In some embodiments, the additional therapeutic agent is an anti-cancer agent.

[0336] In some embodiments, the additional therapeutic agent is administered concurrently 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 the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the compound disclosed herein.

[0337] Example

[0338] Example 1

[0339]

[0340] Step 1: Preparation of methyl 5-{[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylate Preparation :

[0341] At 0 °C under a nitrogen atmosphere, a solution of DBAD (2.26 g, 9.79 mmol, 1.50 eq) in toluene (5 mL) was added dropwise to a stirred solution of methyl 5-hydroxypyridine-2-carboxylate (1.00 g, 6.53 mmol, 1.00 eq), tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (1.83 g, 9.79 mmol, 1.50 eq), and PPh 3 (2.57 g, 9.79 mmol, 1.50 eq) in toluene (10 mL). The resulting mixture was stirred at 0 °C for 1 hour. The mixture was warmed to room temperature and stirred for 1 hour. The reaction was monitored by LCMS. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 5-{[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylate (4.0 g, containing PPh 3 and Ph 3 PO). The resulting mixture was used directly in the next step. LC-MS: (ES + H, m / z): [M + H] + = 323.1.

[0342] Step 2: Preparation of tert-butyl (3S)-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate Preparation :

[0343] At room temperature under a nitrogen atmosphere, 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% aqueous solution) in MeOH (8.6 mL) was stirred for 2 h. 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 PPh 3 and Ph 3 PO). The crude product was used directly in the next step. LC-MS: (ES + H, m / z): [M + H] + = 322.1.

[0344] Step 3: Preparation of N-methyl-5-[(3S)-pyrrolidin-3-yl]oxypyridine-2-carboxamide HCl salt :

[0345] 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 h. The resulting mixture was concentrated under reduced pressure. The product was precipitated by adding EtOAc. The precipitated solid was collected by filtration and washed with PE (3 × 10 mL) to give N-methyl-5-[(3S)-pyrrolidin-3-yloxy]pyridine-2-carboxamide HCl salt (800 mg, crude). LC-MS: (ES + H, m / z): [M + H] + = 222.2.

[0346] 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 Preparation :

[0347] At room temperature under a nitrogen atmosphere, KI (30 mg, 0.18 mmol, 0.20 equivalent) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (200 mg, 0.90 mmol, 1.00 equivalent) were added 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 equivalents) in MeCN (5 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-{[(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 (400 MHz, DMSO-d 6 ) δ 11.86 (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).

[0348] Example 2

[0349]

[0350] Step 1: Preparation of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylate Preparation :

[0351] At room temperature, PPh 3(3.43 g, 13.06 mmol, 2.00 equivalents). The resulting mixture was stirred under a nitrogen atmosphere until 0 °C. At 0 °C, DEAD (2.27 g, 13.06 mmol, 2.00 equivalents) was added dropwise to the above mixture. The resulting mixture was stirred at room temperature for an additional 1 hour. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na 2 SO 4 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase combi-flash chromatography. Thus, methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylate (4.00 g, containing TPPO) was obtained. LC-MS: (ES + H, m / z): [M + H] + = 323.2.

[0352] Step 2: Preparation of tert-butyl (3R)-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate Preparation :

[0353] At room temperature, methylamine (20 mL, 25 wt%-30 wt% aqueous solution) was added to a stirred solution of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylate (3.80 g crude, containing TPPO) in MeOH (20 mL). 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 combi-flash chromatography. Thus, tert-butyl (3R)-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate (3.80 g, containing TPPO) was obtained. LC-MS: (ES + H, m / z): [M + H] + = 322.1.

[0354] Step 3: Preparation of N-methyl-5-[(3R)-pyrrolidin-3-yl]oxypyridine-2-carboxamide HCl salt :

[0355] At room temperature, a solution of tert-butyl (3R)-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate (3.80 g crude, containing TPPO) and HCl (gas) in 1,4-dioxane (40 mL) was added to a 100 mL round-bottom flask. 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 combi-flash chromatography. Thus, N-methyl-5-[(3R)-pyrrolidin-3-yloxy]pyridine-2-carboxamide HCl salt (400 mg, crude) was obtained. LC-MS: (ES + H, m / z): [M + H] + = 222.0.

[0356] 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 Preparation :

[0357] To a stirred solution of N-methyl-5-[(3R)-pyrrolidin-3-yloxy]pyridine-2-carboxamide (200 mg, crude) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (120 mg, 0.53 mmol, 1.00 equiv) in ACN (5 mL) was added DIEA (348 mg, 2.69 mmol, 5.00 equiv) and KI (9 mg, 0.05 mmol, 0.10 equiv). The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was concentrated in vacuo. The crude product (700 mg) was purified by preparative HPLC, and the pure fractions were concentrated and lyophilized to give 5-{[(3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (106.9 mg, 48.49%). LC-MS: (ES + H, m / z): [M + H] + = 407.85. 1 HNMR (300 MHz, DMSO-d 6 ) δ 11.86 (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).

[0358] The following examples were carried out using a similar procedure as shown for Example 2:

[0359]

[0360] Example 3

[0361]

[0362] Step 1: Preparation of ethyl 2-bromo-2-cyclopropylacetate :

[0363] At -78 °C under a nitrogen atmosphere, LDA (42.9 mL, 85.82 mmol, 1.10 equiv, 2.0 M solution in THF) was added dropwise to a stirred solution of ethyl 2-cyclopropylacetate (10.00 g, 78.02 mmol, 1.00 equiv) in THF (100 mL). The reaction was stirred for 1 h, then TMSCl (8.48 g, 78.02 mmol, 1.00 equiv) was added dropwise, and the reaction was stirred for 3 h while warming to room temperature. The reaction was cooled to -78 °C, and NBS (15.28 g, 85.82 mmol, 1.10 equiv) was added dropwise in 50 mL of THF. Then the reaction was stirred for 2 h and warmed to room temperature. The reaction was monitored by LCMS. The reaction was quenched at 0 °C by adding saturated NH 4 Cl (aqueous solution) (50 mL). The resulting mixture was extracted with Et 2 O (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase combi-flash chromatography to give ethyl 2-bromo-2-cyclopropylacetate as a yellow liquid (5.00 g, 30.95%). 1 1H NMR (300 MHz, chloroform-d) δ 4.25 (q, 2H), 3.58 (d, 1H), 1.65 - 1.55 (m, 1H), 1.31 (t, 3H), 0.92 - 0.76 (m, 2H), 0.61 - 0.53 (m, 1H), 0.48 - 0.40 (m, 1H).

[0364] Step 2: Preparation of ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate :

[0365] A solution of ethyl 2-bromo-2-cyclopropylacetate (5.00 g, 24.14 mmol, 1.00 equiv) and triethyl phosphite (5.22 g, 31.39 mmol, 1.30 equiv) was stirred at 130 °C under a nitrogen atmosphere for 24 h. The residue was purified by reverse-phase combi-flash chromatography to give ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate as a yellow liquid (2.40 g, 37.61%). 1 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).

[0366] Step 3: Preparation of methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate Preparation :

[0367] At 0 °C under a nitrogen atmosphere, ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate (1.89 g, 7.14 mmol, 1.50 equiv) was added dropwise to a stirred mixture of NaH (0.29 g, 7.14 mmol, 1.50 equiv, 60 wt%) in THF (20 mL). The resulting mixture was stirred at 0 °C for 10 minutes, then warmed to 40 °C and stirred for 10 minutes under a nitrogen atmosphere. The resulting mixture was cooled to -78 °C, and then methyl 6-formyl-5-nitropyridine-3-carboxylate (1.00 g, 4.76 mmol, 1.00 equiv) in THF (20 mL) was added dropwise. The resulting mixture was stirred at -78 °C under a nitrogen atmosphere for 30 minutes. The reaction was monitored by LCMS. The reaction was quenched at 0 °C by adding saturated NH 4 Cl (aqueous solution) (5 mL). 20 mL of water was added to the resulting mixture and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na 2 SO 4 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.

[0368] Step 4: Preparation of ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate :

[0369] At room temperature under a nitrogen atmosphere, CaCl 2 (1.24 g, 11.24 mmol, 6.00 equiv) was added 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). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere overnight. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (2 × 50 mL). The filtrate was concentrated under reduced pressure. 50 mL of water was added to the resulting mixture and the mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na 2 SO 4Dry. 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.

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

[0371] At 0 °C under a nitrogen atmosphere, LiAlH 4 (0.50 mL, 1.23 mmol, 2.00 equiv, 2.5 M solution in THF) was added dropwise to a stirred solution of ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (160 mg, 0.62 mmol, 1.00 equiv). The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 1 h. 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.

[0372] Step 6: Preparation of 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one :

[0373] At 0 °C under a nitrogen atmosphere, SOCl 2 (264 mg, 2.22 mmol, 6.00 equiv) was added dropwise 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). The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. 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.

[0374] 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 Preparation :

[0375] At room temperature, 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). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. The crude product (900 mg) was purified by preparative HPLC and the pure fractions were concentrated under reduced pressure and then lyophilized to give 5-{[(3R)-1-[(7-cyclopropyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (75.6 mg, 35.14%). LC-MS: (ES + H, m / z): [M + H] + = 420.2. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.89 (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).

[0376] The following examples were carried out using a similar procedure as shown for Example 3:

[0377]

[0378]

[0379] Example 4

[0380]

[0381] Step 1: Preparation of 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylic acid :

[0382] At 0 °C, a solution of LiOH·H₂O (50 mL, 2 M) was added dropwise to a stirred mixture of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylate (16.00 g, 1.00 equivalent, crude) in MeOH (160 mL). The mixture was stirred at 25 °C under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The reaction mixture was diluted with H₂O (50 mL), and the aqueous phase was extracted with EA (100 mL × 3). Then the aqueous phase was adjusted to pH 5 - 6 with H₃PO₄ 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 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylic acid as a white oil (6 g, crude). LC-MS: (ES⁺H, m / z): [M + H] 2 = 309.2. 2 O(50mL) dilution, and the aqueous phase was extracted with EA(100mL*3). Then the aqueous phase was used H 3 PO 4 Adjusted to pH 5 - 6, and extracted with EA(100mL*3). The combined organic layers were washed with brine(100mL), dried over sodium sulfate, filtered and concentrated in vacuo. Concentration in vacuo gave 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}pyridine-2-carboxylic acid as a white oil(6g, crude). LC-MS:(ES + H,m / z):[M + H] + = 309.2.

[0383] Step 2: Preparation of tert-butyl (3R)-3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate Preparation :

[0384] At 0 °C under a nitrogen atmosphere, 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 equivalent), aminocyclopropane (444 mg, 7.78 mmol, 1.20 equivalents), and DIEA (3.35 g, 25.94 mmol, 4.00 equivalents) in DCM (20 mL) was added dropwise T3P (16.52 g, 25.94 mmol, 4.00 equivalents, 50 wt% solution in EA). The mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LCMS. The reaction mixture was diluted with H₂O (50 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Concentration in vacuo gave tert-butyl (3R)-3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate as an orange oil (1.5 g, crude product). LC-MS: (ES⁺H, m / z): [M + H] 2 O(50mL) dilution and extracted with EA(100mL*3). The combined organic layers were washed with brine(100mL), 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 as an orange oil(1.5g, crude product). LC-MS:(ES + H,m / z):[M + H] + = 348.2

[0385] Step 3: Preparation of N-cyclopropyl-5-[(3R)-pyrrolidin-3-yl]oxypyridine-2-carboxamide :

[0386] 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 a solution of 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-phase mixed-phase flash chromatography to give N-cyclopropyl-5-[(3R)-pyrrolidin-3-yloxy]pyridine-2-carboxamide as an off-white oil (900 mg, 63.22%). LC-MS: (ES + H, m / z): [M + H] + = 248.0

[0387] 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 Preparation :

[0388] 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 (400 MHz, DMSO-d 6 ) δ 11.83 (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).

[0389] Example 5

[0390]

[0391] Step 1: Preparation of methyl 5-{[(3R,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyridine-2-carboxylate Preparation :

[0392] At 0 °C under a nitrogen atmosphere, a solution of DBAD (0.90 g, 3.91 mmol, 2.00 eq) in toluene (5 mL) was added dropwise to a stirred solution of methyl 5-hydroxypyridine-2-carboxylate (0.30 g, 1.95 mmol, 1.00 eq), tert-butyl (3R,4S)-3-fluoro-4-hydroxypyrrolidine-1-carboxylate (0.40 g, 1.96 mmol, 1.00 eq) and PPh 3 (1.03 g, 3.91 mmol, 2.00 eq) in toluene (10 mL). 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.

[0393] Step 2: Preparation of tert-butyl (3R,4R)-3-fluoro-4-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate Preparation :

[0394] At room temperature under a nitrogen atmosphere, 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% aqueous solution) in MeOH (4.0 mL) was stirred for 2 h. 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.

[0395] Step 3: Preparation of 5-{[(3R,4R)-4-fluoropyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide HCl salt Preparation :

[0396] (3R,4R)-tert-Butyl 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) were stirred at room temperature under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The product was precipitated by 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.

[0397] 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 Preparation :

[0398] 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 eq) in MeCN (5 mL) at room temperature were added KI (15 mg, 0.09 mmol, 0.20 eq) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (100 mg, 0.44 mmol, 1.00 eq). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-{[(3R,4R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-4-fluoropyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (56.80 mg, 28.98%). LC-MS: (ES + H, m / z): [M + H] + = 426.1. Optical rotation [α] 25 D (c = 0.5, MeOH): +1.8°; 1 1H NMR (400 MHz, DMSO-d 6 ) δ 11.88 (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). 1919F NMR (377 MHz, DMSO-d 6 ) δ -179.44.

[0399] Example 6

[0400]

[0401] Step 1: Preparation of methyl 5-(((3S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)picolinate Preparation :

[0402] At 0 °C under a nitrogen atmosphere, 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 PPh 3 (1.03 g, 3.92 mmol, 2.00 equiv) in toluene (50 mL) was added DBAD (902 mg, 3.92 mmol, 2.00 equiv). The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2 h. 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.

[0403] Step 2: Preparation of tert-butyl (3S,4S)-3-fluoro-4-((6-(methylcarbamoyl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate Preparation :

[0404] At room temperature under a nitrogen atmosphere, methylamine (5 mL, 25 wt%-30 wt%) was added dropwise 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). 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 NH 4 Cl (aqueous solution) (100 mL). The resulting mixture was extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na 2 SO 4 and filtered. 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.

[0405] Step 3: Preparation of 5-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpyridineamide HCl salt :

[0406] At room temperature under a nitrogen atmosphere, a solution of HCl (gas) in 1,4-dioxane (5 mL, 4 M) was added dropwise 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). The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (3 × 20 mL). The precipitated solid was collected by filtration and washed with EtOAc (3 × 10 mL). Thus, 5-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpyridinecarboxamide HCl salt (1 g, crude) was obtained. LC-MS: (ES + H, m / z): [M + H] + = 240.2

[0407] 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-methylpyridineamide Preparation :

[0408] At room temperature, KI (22 mg, 0.14 mmol, 0.20 equiv) and DIEA (435 mg, 3.37 mmol, 5.00 equiv) were added to a stirred mixture of 5-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpyridinecarboxamide 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). The resulting mixture was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The 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 Na 2 SO 4 2. 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-methylpyridinecarboxamide (91.6 mg, 31.81%). LC-MS: (ES + H, m / z): [M + H] + = 426.2. Specific rotation [α] 25 D (c = 0.5, MeOH): +0.4°; 11H NMR (400 MHz, DMSO-d 6 ) δ 11.88 (s, 1H), 8.59 (q, 1H), 8.39 (d, 1H), 8.31 (d, 1H), 7.99 (d, 1H), 7.75 (s, 1H), 7.60 (d, 1H), 7.54 (dd, 1H), 5.36 - 5.00 (m, 2H), 3.84 - 3.72 (m, 2H), 3.36 (d, 1H), 3.00 - 2.85 (m, 2H), 2.79 (d, 3H), 2.58 - 2.52 (m, 3H), 1.18 (t, 3H). 19 19F NMR (377 MHz, DMSO-d 6 ) δ -179.43.

[0409] Example 7

[0410]

[0411] Step 1: Preparation of 5-bromo-3-nitropyridinecarbaldehyde :

[0412] A mixture of 5-bromo-2-methyl-3-nitropyridine (20.00 g, 92.16 mmol, 1.00 eq) and SeO2 (51.13 g, 460.79 mmol, 5.00 eq) 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 cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 × 400 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with THF (3 × 300 mL). The resulting mixture was concentrated under reduced pressure to give 5-bromo-3-nitropyridinealdehyde (21 g, crude). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 10.08 (s, 1H), 9.22 (d, 1H), 8.95 (d, 1H).

[0413] Step 2: Preparation of ethyl (2Z)-3-(5-bromo-3-nitropyridin-2-yl)-2-methylprop-2-enoate :

[0414] At 0 °C under a nitrogen atmosphere, ethyl 2-(diethoxyphosphoryl)propionate (29.39 g, 123.37 mmol, 1.50 equiv) was added dropwise to a stirred mixture of NaH (4.93 g, 123.37 mmol, 1.50 equiv, 60 wt%) in THF (250 mL). The resulting mixture was stirred at 0 °C for 15 minutes and at 40 °C for 30 minutes under a nitrogen atmosphere. A solution of 5-bromo-3-nitropyridine-2-carbaldehyde (19.00 g, 82.25 mmol, 1.00 equiv) in THF (50 mL) was added dropwise to the above mixture at -78 °C over 30 minutes. 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 NH 4 Cl (aqueous solution) at 0 °C. Water (600 mL) was added to the resulting mixture and the mixture was extracted with EtOAc (3 × 600 mL). The combined organic layers were washed with brine (2 × 300 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel 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).

[0415] Step 3: Preparation of 7-bromo-3-methyl-1H-1,5-naphthyridin-2-one :

[0416] At room temperature under a nitrogen atmosphere, CaCl 2 (16.06 g, 144.71 mmol, 6.00 equiv) was added 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). 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 column chromatography on silica gel. 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. Thus, 7-bromo-3-methyl-1H-1,5-naphthyridin-2-one (5.00 g, 87%) was obtained. LC-MS: (ES + H, m / z): [M + H]+ = 239 / 241. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.96 (s, 1H), 8.52 (d, 1H), 7.86 - 7.78 (m, 2H), 2.13 (d, 3H).

[0417] Step 4: Preparation of ethyl 7-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate

[0418] 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(PPh 3 ) 2 Cl 2 (1.47 g, 2.09 mmol, 0.10 equiv) in EtOH (100 ml) was added NEt 3 (6.35 g, 62.74 mmol, 3.00 equiv). The resulting mixture was stirred at 100 °C under a carbon monoxide atmosphere (30 atm) overnight. 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. Thus, ethyl 7-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (4.5 g, 93%) was obtained. LC-MS: (ES + H, m / z): [M + H] + = 233. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.06 (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).

[0419] Step 5: Preparation of 7-(hydroxymethyl)-3-methyl-1H-1,5-naphthyridin-2-one :

[0420] At 0 °C under a nitrogen atmosphere, a solution of lithium aluminum hydride (LiAlH 4(15.5 mL, 38.75 mmol, 2.00 equivalents, 2.5 M THF solution). 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 adding aqueous HCl solution (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. Thus, 7-(hydroxymethyl)-3-methyl-1H-1,5-naphthyridin-2-one (2 g, 54%) was obtained. LC-MS: (ES + H, m / z): [M + H] + = 191.1. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.91 (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).

[0421] Step 6: Preparation of 7-(chloromethyl)-3-methyl-1H-1,5-naphthyridin-2-one :

[0422] At 0 °C under a nitrogen atmosphere, SOCl 2 (0.6 mL, 7.88 mmol, 6.00 equivalents) was added dropwise to a stirred mixture of 7-(hydroxymethyl)-3-methyl-1H-1,5-naphthyridin-2-one (250 mg, 1.31 mmol, 1.00 equivalent) and DMF (10 mg, 0.13 mmol, 0.10 equivalent) in DCM (5 mL). 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. Thus, 7-(chloromethyl)-3-methyl-1H-1,5-naphthyridin-2-one (310 mg, crude) was obtained. The crude product mixture was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H] + = 209.0

[0423] 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 Preparation :

[0424] 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 h. 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. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.70 (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), 7.47 (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).

[0425] The following examples were carried out using a similar procedure as shown for Example 7:

[0426]

[0427] Example 8

[0428]

[0429] Step 1: Preparation of methyl 5-{[(3R,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyridine-2-carboxylate Preparation :

[0430] At 0 °C under a nitrogen atmosphere, to (3S,4S)-tert-butyl 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 PPh 3(1.34 g, 5.12 mmol, 2.10 eq) A solution of DBAD (1.12 g, 4.87 mmol, 2.00 eq) in THF (5 mL) was added dropwise to a stirred mixture of it in THF (10 mL). The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 3 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with ethyl acetate (100 mL). The resulting mixture was washed with water (2 × 30 mL). Dried over anhydrous Na 2 SO 4 The organic phase was dried. 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). The crude product was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H] + = 341.1.

[0431] Step 2: Preparation of tert-butyl (3S,4R)-3-fluoro-4-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate Preparation :

[0432] At room temperature under a nitrogen atmosphere, a solution of methyl 5-{[(3R,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyridine-2-carboxylate (2 g, crude) in CH 3 OH (7 mL) was added dropwise to an aqueous solution of CH 3 NH 2 (7 mL, 25 wt%-30 wt%). 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 NH 4 Cl (aqueous solution) (2 × 30 mL). Dried over anhydrous Na 2 SO 4 The organic phase was dried. After filtration, the filtrate was concentrated in vacuo. 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.

[0433] Step 3: Preparation of 5-{[(3R,4S)-4-fluoropyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide HCl salt Preparation :

[0434] At 0 °C under a nitrogen atmosphere, to tert-butyl (3S,4R)-3-fluoro-4-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate (2 g, crude) in CH 2Cl 2 A solution of HCl in dioxane (8 mL, 4 M) was added dropwise to a stirred solution in (5 mL). The resulting mixture was stirred for 2 h 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 trituration with ether / hexane (3 × 10 mL). The resulting mixture was concentrated in vacuo. The crude product 5-{[(3R,4S)-4-fluoropyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide HCl salt (0.8 g, crude) was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H] + = 240.2.

[0435] 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 Preparation :

[0436] At room temperature, KI (56 mg, 0.34 mmol, 0.50 equiv) and DIEA (432 mg, 3.35 mmol, 5.00 equiv) were added dropwise 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). The resulting mixture was stirred for 2 h at 80 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The residue was purified by silica gel column chromatography. Subsequently, the residue was purified by preparative HPLC chromatography. The pure fractions were concentrated and lyophilized to give 5-{[(3R,4S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-4-fluoropyrrolidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (36.0 mg, 12.55%). LC-MS: (ES + H, m / z): [M + H] + = 426.05. Specific rotation [α] 25 D (c = 0.5, MeOH): -17°; 1 H NMR (300 MHz, DMSO-d 6) δ 11.88 (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 (282 MHz, DMSO - d 6 ) δ - 195.59.

[0437] Example 9

[0438]

[0439] Step 1: Preparation of methyl 5-{[(3S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl]oxy}pyridine-2-carboxylate Preparation :

[0440] At 0 °C under a nitrogen atmosphere, dropwise add DBAD (1.12 g, 4.87 mmol, 2.00 equivalents) to a stirred mixture of methyl 5 - hydroxypyridine - 2 - carboxylate (373 mg, 2.44 mmol, 1.00 equivalent), PPh 3 (1.28 g, 4.87 mmol, 2.00 equivalents) and tert - butyl (3R,4R) - 3 - fluoro - 4 - hydroxypyrrolidine - 1 - carboxylate (500 mg, 2.44 mmol, 1.00 equivalent) in toluene (10 mL). Stir the resulting mixture at 60 °C under a nitrogen atmosphere overnight. Monitor the reaction by LCMS. Cool the mixture to room temperature. Concentrate the resulting mixture under reduced pressure. Dissolve the residue in EtOAc (30 mL). Wash the mixture with saturated NaHCO 3 (1×20 mL), and dry over anhydrous Na 2 SO 4 After filtration, concentrate the filtrate under reduced pressure to obtain 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.

[0441] Step 2: Preparation of tert-butyl (3R,4S)-3-fluoro-4-((6-(methylcarbamoyl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate Preparation :

[0442] At room temperature, methylamine (10 mL, 25 wt%-30 wt% aqueous solution) was added 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). 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 NH 4 Cl (50 mL) was added to the resulting mixture and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na 2 SO 4 . 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.

[0443] Step 3: Preparation of 5-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)-N-methylpyridinecarboxamide HCl salt :

[0444] At room temperature, a solution of HCl (gas) in 1,4-dioxane (10 mL, 4 M) was added dropwise 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). 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-methylpyridinecarboxamide HCl salt (750 mg, 82.98%). LC-MS: (ES+H, m / z): [M+H] + = 240.0.

[0445] 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-methylpyridinecarboxamide Preparation :

[0446] At room temperature, 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 equivalent) in ACN (6 mL) was added DIEA (580 mg, 4.49 mmol, 5.00 equivalents) and KI (15 mg, 0.09 mmol, 0.10 equivalent). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. At room temperature, the reaction mixture was poured into water (50 mL). The resulting mixture was extracted with CH 2 Cl 2 / i-PrOH (3 / 1, 3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC, 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. Specific rotation [a] 25 D (c = 0.5, MeOH): +19°; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.88 (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 (282 MHz, DMSO-d 6 ) δ -195.59.

[0447] Example 10

[0448]

[0449] Step 1: Preparation of tert-butyl (3R)-3-({6-[(2,2-difluoroethyl)carbamoyl]pyridin-3-yl}oxy)pyrrolidine-1-carboxylatePreparation :

[0450] At room temperature under a nitrogen atmosphere, T3P (6.19 g, 9.73 mmol, 3.00 equivalents, 50 wt% EA solution) was added dropwise 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 equivalent), 2,2-difluoroethylamine (0.29 g, 3.57 mmol, 1.10 equivalents), and DIEA (2.10 g, 16.22 mmol, 5.00 equivalents) in DCM (28 mL). 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 CH 2 Cl 2 (3 × 50 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous Na 2 SO 4 . 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+H-t-Bu] + = 316.0. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.97 - 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).

[0451] Step 2: Preparation of N-(2,2-difluoroethyl)-5-[(3R)-pyrrolidin-3-yloxy]pyridine-2-carboxamide TFA salt Preparation :

[0452] At 0 °C under a nitrogen atmosphere, TFA (2 mL) was added dropwise 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 equivalent) in DCM (6 mL). The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0453] LC-MS: (ES+H, m / z): [M+H]+ = 272.2.

[0454] 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 Preparation :

[0455] At room temperature, to a stirred solution of N-(2,2-difluoroethyl)-5-[(3R)-pyrrolidin-3-yloxy]pyridine-2-carboxamide TFA salt (168 mg, crude) and 7-(chloromethyl)-3-methyl-1H-1,5-naphthyridin-2-one (142 mg, 0.68 mmol, 1.0 equiv) in MeCN (10 mL) was added KI (22 mg, 0.14 mmol, 0.20 equiv) and DIEA (440 mg, 3.40 mmol, 5.00 equiv). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the pure fractions were concentrated and then lyophilized to give N-(2,2-difluoroethyl)-5-{[(3R)-1-[(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl]oxy}pyridine-2-carboxamide (82.1 mg, 29.75%). LC-MS: (ES+H, m / z): [M+H] + = 444.0. 1 1H NMR (300 MHz, DMSO-d 6 ) δ 11.87 (s, 1H), 8.86 (t, 1H), 8.39 (d, 1H), 8.29 (d, 1H), 7.98 (d, 1H), 7.85 - 7.79 (m, 1H), 7.62 - 7.55 (m, 1H), 7.51 (dd, 1H), 6.40 - 5.85 (m, 1H), 5.08 (s, 1H), 3.81 - 3.58 (m, 4H), 2.92 (dd, 1H), 2.83 - 2.68 (q, 2H), 2.48 - 2.25 (m, 2H), 2.14 (d, 3H), 1.74 - 1.88 (m, 1H). 19 19F NMR (282 MHz, DMSO-d 6 ) δ -122.05

[0456] Example 11

[0457]

[0458] Step 1: Preparation of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl](methyl)amino}pyridine-2-carboxylate Preparation :

[0459] 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), Cs 2 CO 3 (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) were stirred overnight at 110 °C under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (20 mL). The resulting mixture was filtered and the 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 (400 MHz, DMSO-d 6 ) δ 8.30 (d, 1H), 7.86 (d, 1H), 7.26 (dd, 1H), 4.79 - 4.6 (m, 1H), 3.80 (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).

[0460] Step 2: Preparation of tert-butyl (3R)-3-{methyl[6-(methylcarbamoyl)pyridin-3-yl]amino}pyrrolidine-1-carboxylate Preparation :

[0461] 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) in MeOH (6 mL) and aqueous methylamine (3 mL, 25 wt% - 30 wt%) 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 (400 MHz, DMSO-d 6)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).

[0462] Step 3: Preparation of N-methyl-5-[methyl((3R)-pyrrolidin-3-yl)amino]pyridine-2-carboxamide HCl salt :

[0463] 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 a solution of HCl (gas) in 1,4-dioxane (5 mL, 4 M) was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo to afford 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.

[0464] 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 :

[0465] A mixture of N-methyl-5-[methyl((3R)-pyrrolidin-3-yl)amino]pyridine-2-carboxamide HCl salt (237 mg, 1.01 mmol, 1.5 equiv), 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (150 mg, 0.67 mmol, 1.00 equiv), KI (20 mg, 0.12 mmol, 0.18 equiv) and DIEA (261 mg, 2.02 mmol, 3.00 equiv) in ACN (6 mL) was stirred at 80 °C under a nitrogen atmosphere for 1 h. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (15 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL). The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC and the pure fractions were concentrated under reduced pressure and then lyophilized to afford 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°; 11H NMR (300 MHz, DMSO-d 6 ) δ 11.90 (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).

[0466] Example 12

[0467]

[0468] Step 1: Preparation of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)-3-methylpyrrolidin-3-yl]oxy}pyridine-2-carboxylate Preparation :

[0469] At room temperature under a nitrogen atmosphere, a solution of (3R)-3-hydroxy-3-methylpyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.48 mmol, 1.00 equivalent) in DMF (1 mL) was added dropwise to a stirred mixture of NaH (139 mg, 3.47 mmol, 1.4 equivalents, 60 wt%) in DMF (10 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. Methyl 5-fluoropyridine-2-carboxylate (462 mg, 2.98 mmol, 1.20 equivalents) was added dropwise to the above mixture 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 phase combi-flash chromatography to give methyl 5-{[(3R)-1-(tert-butoxycarbonyl)-3-methylpyrrolidin-3-yl]oxy}pyridine-2-carboxylate (310 mg, 37.10%). LC-MS: (ES + H, m / z): [M + H] + = 337.2. Optical rotation [α] 25 D (c = 0.5, MeOH): -23.9°; 1 1H NMR (400 MHz, DMSO-d 6)δ 8.35 (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).

[0470] Step 2: Preparation of tert-butyl (3R)-3-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}pyrrolidine-1-carboxylate Preparation :

[0471] 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 CH 3 NH 2 (5 mL, 25 wt% - 30 wt% aqueous solution) in CH 3 OH (5 mL) was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with CH 2 Cl 2 (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over anhydrous Na 2 SO 4 . 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.

[0472] Step 3: Preparation of N-methyl-5-{[(3R)-3-methylpyrrolidin-3-yl]oxy}pyridine-2-carboxamide HCl salt Preparation :

[0473] Under a nitrogen atmosphere at 0 °C, a solution of HCl (gas) in 1,4-dioxane (2.5 mL, 4 M) was added dropwise 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). The resulting mixture was stirred at room temperature for 30 min under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with 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.

[0474] 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 :

[0475] A mixture of N-methyl-5-{[(3R)-3-methylpyrrolidin-3-yl]oxy}pyridine-2-carboxamide HCl salt (205 mg, 0.75 mmol, 1.00 eq), 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (218 mg, 0.98 mmol, 1.30 eq), DIEA (488 mg, 3.77 mmol, 5.00 eq) and KI (25 mg, 0.15 mmol, 0.20 eq) in ACN (5 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. 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, 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 1H NMR (300 MHz, DMSO-d 6 ) δ 11.88 (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).

[0476] The following examples were carried out using a similar procedure as shown for Example 12:

[0477]

[0478]

[0479] Example 13

[0480]

[0481] Step 1: Preparation of tert-butyl (3R)-3-(bromomethyl)pyrrolidine-1-carboxylate :

[0482] At 0 °C under a nitrogen atmosphere, a solution of PPh 4 (3.91 g, 14.91 mmol, 1.00 equivalent) in DCM (5 mL) was added dropwise to a stirred mixture of (3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.00 g, 14.91 mmol, 1.00 equivalent) and CBr 3 (7.41 g, 22.34 mmol, 1.50 equivalents) in DCM (20 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. 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 (3R)-3-(bromomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.5 g, 63.4%). 1 HNMR (300 MHz, chloroform-d) δ 3.70 - 3.66 (m, 1H), 3.59 - 3.52 (m, 1H), 3.49 - 3.48 (m, 1H), 3.48 - 3.34 (m, 2H), 3.21 - 3.14 (m, 1H), 2.75 - 2.60 (m, 1H), 2.18 - 2.10 (m, 1H), 1.90 - 1.70 (m, 1H), 1.54 (s, 9H).

[0483] Step 2: Preparation of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]methyl}pyridine-2-carboxylate Preparation :

[0484] At room temperature under a nitrogen atmosphere, a mixture of nickel 1,2-dimethoxyethane dihydrochloride (25 mg, 0.11 mmol, 0.10 equivalent) and 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine (31 mg, 0.11 mmol, 0.10 equivalent) in DME (3 mL) was stirred for 1 hour. At room temperature under a nitrogen atmosphere, the nickel mixture was added to (3R)-3-(bromomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 1.14 mmol, 1.00 equivalent), methyl 5-bromopyridine-2-carboxylate (245 mg, 1.14 mmol, 1.00 equivalent), tris(trimethylsilyl)silane (282 mg, 1.14 mmol, 1.00 equivalent), Cs 2 CO 3 (740 mg, 2.27 mmol, 2.00 equivalents) and Ir[dF(CF 3 )ppy] 2 (dtpby)PF 6(38 mg, 0.03 mmol, 0.03 eq) in the mixture. The reaction was stirred for 2 days and irradiated with a blue LED (30 W). The reaction was monitored by LCMS. The reaction mixture 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 [α] 25 D (c = 0.5, MeOH): +17.6°; 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.59 (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).

[0485] Step 3: Preparation of tert-butyl (3R)-3-{[6-(methylcarbamoyl)pyridin-3-yl]methyl}pyrrolidine-1-carboxylate Preparation :

[0486] At room temperature under a nitrogen atmosphere, methylamine (2 mL, 25 wt% - 30 wt% aqueous solution) was added to a stirred mixture of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]methyl}pyridine-2-carboxylate (190 mg, 0.66 mmol, 1.00 eq) in MeOH (2 mL). The resulting mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give tert-butyl (3R)-3-{[6-(methylcarbamoyl)pyridin-3-yl]methyl}pyrrolidine-1-carboxylate (190 mg, crude product).

[0487] LC-MS: (ES + H, m / z): [M + H] + = 320.3.

[0488] Step 4: Preparation of N-methyl-5-[(3R)-pyrrolidin-3-ylmethyl]pyridine-2-carboxamide HCl salt :

[0489] A mixture of tert-butyl (3R)-3-{[6-(methylcarbamoyl)pyridin-3-yl]methyl}pyrrolidine-1-carboxylate (190 mg, crude) in a 1,4-dioxane (4 M, 2 mL) solution of HCl (gas) was stirred at room temperature for 0.5 h. 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

[0490] 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 Preparation :

[0491] At 80 °C, under a nitrogen atmosphere, 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 for 1 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reaction 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 [α] 25 D (c = 0.5, MeOH): +18.4°; 1 H NMR (400 MHz, DMSO-d 6)δ 11.83 (singlet, 1H), 8.69 - 8.66 (multiplet, 1H), 8.47 (doublet, 1H), 8.36 (doublet, 1H), 7.92 (doublet, 1H), 7.81 (doublet of doublets, 1H), 7.73 (singlet, 1H), 7.58 (doublet, 1H), 3.74 - 3.58 (multiplet, 2H), 2.85 - 2.77 (multiplet, 5H), 2.62 - 2.52 (multiplet, 4H), 2.50 - 2.46 (multiplet, 2H), 2.22 - 2.16 (multiplet, 1H), 1.93 - 1.80 (multiplet, 1H), 1.51 - 1.38 (multiplet, 1H), 1.18 (triplet, 3H).

[0492] Example 14

[0493]

[0494] Step 1: Preparation of methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]amino}pyridine-2-carboxylate :

[0495] At room temperature, to a stirred solution of methyl 5 - bromopyridine - 2 - carboxylate (2.00 g, 9.25 mmol, 1.00 equiv) and tert - butyl 3 - aminoazetidine - 1 - carboxylate (1.75 g, 10.18 mmol, 1.10 equiv) in toluene (20 mL) was added XantPhos (1.07 g, 1.85 mmol, 0.20 equiv), Pd 2 (dba) 3 (0.84 g, 0.90 mmol, 0.10 equiv) and Cs 2 CO 3 (9.05 g, 27.77 mmol, 3.00 equiv). The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 2 h. 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 Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse - phase combi - flash chromatography. Thus, methyl 5 - {[1 - (tert - butoxycarbonyl)azetidin - 3 - yl]amino}pyridine - 2 - carboxylate (1.00 g, 31.98%) was obtained. LC - MS: (ES + H, m / z): [M + H] + = 308.1. 1 H NMR (400 MHz, DMSO - d 6)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).

[0496] Step 2: Preparation of tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]amino}azetidine-1-carboxylate Preparation :

[0497] At room temperature, methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]amino}pyridine-2-carboxylate (500 mg, 1.62 mmol, 1.00 equiv) in a stirred solution in MeOH (5 mL) was added with methylamine (5 mL, 25 wt%-30 wt% aqueous solution). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The desired product could be detected by LCMS. The solvent was removed under reduced pressure. The residue was purified by reverse-phase combi-flash chromatography. Thus, tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]amino}azetidine-1-carboxylate (500 mg, 94.30%) was obtained. LC-MS: (ES+H, m / z): [M+H] + = 307.1.

[0498] Step 3: Preparation of 5-(azetidin-3-ylamino)-N-methylpyridine-2-carboxamide HCl salt :

[0499] At room temperature, a solution of tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]amino}azetidine-1-carboxylate (500 mg, 1.63 mmol, 1.00 equiv) and HCl (gas) in 1,4-dioxane (10 mL) was added to a 100 mL round-bottom flask. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The desired product could be detected by LCMS. The resulting mixture was concentrated in vacuo. Thus, 5-(azetidin-3-ylamino)-N-methylpyridine-2-carboxamide HCl salt (400 mg, crude) was obtained. The resulting crude mixture was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + = 207.2.

[0500] 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 Preparation :

[0501] At room temperature, 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). The resulting mixture was stirred at 80 °C for an additional 2 h. The desired product was detected by LCMS. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC, and the pure fractions were concentrated in vacuo 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 (300 MHz, DMSO-d 6 ) δ 11.87 (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).

[0502] Example 15

[0503]

[0504] Step 1: Preparation of methyl 5-{[1-(tert-butoxycarbonyl)-3-methylazetidin-3-yl]oxy}pyridine-2-carboxylate Preparation :

[0505] At room temperature under a nitrogen atmosphere, a solution of 3-hydroxy-3-methylazetidine-1-carboxylic acid tert-butyl ester (4.71 g, 25.14 mmol, 1.30 equiv) in DMF (5 mL) was added dropwise to a stirred solution of NaH (1.08 g, 27.08 mmol, 1.40 equiv, 60 wt%) in DMF (40 mL). The above mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. Then, a solution of methyl 5-fluoropyridine-2-carboxylate (3.00 g, 19.34 mmol, 1.00 equiv) in DMF (5 mL) was added dropwise to the resulting mixture at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours. 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 × 30 mL). The organic layer was concentrated in vacuo. The residue was purified by reverse combi-flash chromatography to give methyl 5-{[1-(tert-butoxycarbonyl)-3-methylazetidin-3-yl]oxy}pyridine-2-carboxylate (1.1 g, 17.64%) as a white oil. LC-MS: (ES + H, m / z): [M + H] + = 323.2. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.28 (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).

[0506] Step 2: Preparation of tert-butyl 3-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate Preparation :

[0507] At room temperature, a 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 to a stirred solution of CH 3 NH 2 (5 mL, 25.0 wt% - 30.0 wt% aqueous solution). 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.

[0508] Step 3: Preparation of N-methyl-5-[(3-methylazetidin-3-yl)oxy]pyridine-2-carboxamide TFA salt :

[0509] At room temperature, trifluoroacetic acid (2 mL) was added dropwise 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). 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.

[0510] 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 Preparation :

[0511] At room temperature, diisopropylethylamine (467 mg, 3.62 mmol, 4.00 equiv) and potassium iodide (30 mg, 0.18 mmol, 0.20 equiv) were added in portions 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). 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 cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with CH 2 Cl 2 / MeOH (10:1) (150 mL). The filtrate was concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC, 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 HNMR (400 MHz, DMSO-d 6)δ 11.85 (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).

[0512] Example 16

[0513]

[0514] Step 1: Preparation of methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylate :

[0515] At 0 °C under a nitrogen atmosphere, a mixture of DEAD (5.69 g, 32.65 mmol, 5.00 eq) and PPh 3 (10.90 g, 39.18 mmol, 6.00 eq) in THF (100 ml) was stirred for 1 hour. At 0 °C under a nitrogen atmosphere, the mixture was added dropwise to a solution of methyl 5-hydroxypyridine-2-carboxylate (1.00 g, 6.53 mmol, 1.00 eq) and tert-butyl 3-hydroxyazetidine-1-carboxylate (1.70 g, 9.79 mmol, 1.50 eq) in THF (100 ml). 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.

[0516] Step 2: Preparation of tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate Preparation :

[0517] A mixture of methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylate (3.50 g, crude, containing TPPO) and CH 3 NH 2 (20 mL, 25 wt% - 30 wt% aqueous solution) in MeOH (20 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. Saturated NH 4Extract with Cl (100 mL) and DCM (3 × 100 mL). Wash the combined organic layers with brine (1 × 100 mL) and dry over anhydrous Na 2 SO 4 Dry. After filtration, concentrate the filtrate under reduced pressure. This gives 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

[0518] Step 3: Preparation of 5-(azetidin-3-yloxy)-N-methylpyridine-2-carboxamide HCl salt :

[0519] At room temperature under a nitrogen atmosphere, add HCl (gas) in 1,4-dioxane (10 mL, 4 M dioxane solution) portionwise 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). Stir the resulting mixture at room temperature under a nitrogen atmosphere for 2 h. Monitor the reaction by LCMS. Concentrate the resulting mixture under reduced pressure. Purify the residue by trituration with EtOAc (3 × 20 mL). Collect the precipitated solid by filtration and concentrate under reduced pressure. This gives 5-(azetidin-3-yloxy)-N-methylpyridine-2-carboxamide HCl salt (600 mg, crude).

[0520] LC-MS: (ES + H, m / z): [M + H] + = 208.2.

[0521] 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 Preparation :

[0522] At 80 °C under a nitrogen atmosphere, a mixture of 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one (200 mg, 0.85 mmol, 1.00 equiv), 5-(azetidin-3-yloxy)-N-methylpyridine-2-carboxamide HCl salt (249 mg, crude), DIEA (550 mg, 4.26 mmol, 5.00 equiv) and KI (28 mg, 0.17 mmol, 0.20 equiv) in ACN (10 mL) was stirred for 2 h. 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 × 1 mL). The pure fraction was concentrated and lyophilized to give 5-({1-[(7-cyclopropyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidin-3-yl}oxy)-N-methylpyridine-2-carboxamide (35.9 mg, 10.24%). LC-MS: (ES + H, m / z): [M + H] + = 406.25. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.88 (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).

[0523] The following examples were carried out using a similar procedure as shown for Example 16:

[0524]

[0525] Example 17

[0526]

[0527] Step 1: Preparation of methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate Preparation :

[0528] At 0 °C under a nitrogen atmosphere, to a stirred mixture of tert-butyl (2R,3R)-3-hydroxy-2-methylazetidine-1-carboxylate (300 mg, 1.60 mmol, 1.00 equiv), methyl 5-hydroxypyridine-2-carboxylate (245 mg, 1.60 mmol, 1.00 equiv) and PPh 3 (882 mg, 3.36 mmol, 2.10 equiv) in THF (15 mL) was added dropwise a solution of DBAD (738 mg, 3.20 mmol, 2.00 equiv) in THF (5 mL). The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 3 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL). The residue was washed with H 2 O (2 × 30 mL), dried over anhydrous Na 2 SO 4 . 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.

[0529] Step 2: Preparation of (2R,3S)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate tert-butyl ester Preparation :

[0530] At room temperature under a nitrogen atmosphere, methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate (1.5 g, crude) and CH 3 NH 2 (7 mL, 25 wt%-30 wt% aqueous solution) in CH 3 CN (7 mL) was stirred for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL). The residue was washed with NH 4 Cl (aqueous solution) (2 × 30 mL), dried over anhydrous Na 2 SO 4 . 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.

[0531] Step 3: Preparation of N-methyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide TFA salt Preparation :

[0532] At 0 °C under a nitrogen atmosphere, trifluoroacetic acid (TFA, 7 mL) was added dropwise 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). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with ether / n-hexane (3 × 10 mL). The resulting mixture was concentrated in vacuo. The crude product, 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.

[0533] LC-MS: (ES + H, m / z): [M + H]+ = 222.2.

[0534] 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 Example 18 :

[0535] At room temperature, potassium iodide (KI, 45 mg, 0.27 mmol, 0.20 equiv) and N,N-diisopropylethylamine (DIEA, 700 mg, 5.42 mmol, 4.00 equiv) were added dropwise 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 CH 3 CN (10 mL). The mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The residue was purified by reverse-phase combi-flash. The pure fractions were concentrated in vacuo and then lyophilized to give 5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (56.8 mg, 10.22%). LC-MS: (ES + H, m / z): [M + H]+ = 408.2. Optical rotation [a] 25 D (c = 0.5, MeOH): -4.8°; 1 H NMR (300 MHz, DMSO-d 6)δ 11.86 (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), 3.39 - 3.34 (m, 1H), 2.80 - 2.78 (m, 4H), 2.58 - 2.51 (m, 2H), 1.21 - 1.16 (m, 6H).

[0536] The following examples were carried out using a similar procedure as shown for Example 17:

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545] Step 1: Preparation of methyl 5-{[(2S,3R)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate

[0546]

[0547] Step 2: Preparation of tert-butyl (2S,3R)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate Step 3: Preparation of N-methyl-5-{[(2S,3R)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide HCl salt :

[0548] At 0 °C under a nitrogen atmosphere, to methyl 5-hydroxypyridine-2-carboxylate (0.35 g, 2.28 mmol, 1.00 eq), tert-butyl (2S,3S)-3-hydroxy-2-methylazetidine-1-carboxylate (0.43 g, 2.28 mmol, 1.00 eq) and PPh 3A solution of DBAD (1.05 g, 4.57 mmol, 2.00 equiv) in toluene (5 mL) was added dropwise to a stirred solution of [[ID=]], + = 323.1.

[0549] 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 Example 19 :

[0550] At room temperature under a nitrogen atmosphere, 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 wt%-30 wt% aqueous solution) in MeOH (2 mL) was stirred 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.

[0551] Step 1: Preparation of methyl 5-{[(2R,3R)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate Step 2: Preparation of tert-butyl (2R,3R)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate :

[0552] At room temperature under a nitrogen atmosphere, a solution of tert-butyl (2S,3R)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (1.00 g, crude) in 1,4-dioxane (4 mL, 4 M) solution of HCl (gas) was stirred for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The product was precipitated by adding EtOAc. The precipitated solid was collected by filtration and washed with PE (3×10 mL) to give N-methyl-5-{[(2S,3R)-2-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.

[0553] Step 3: Preparation of N-methyl-5-{[(2R,3R)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide TFA salt 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 :

[0554] At room temperature, 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) were added 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). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the pure fractions were concentrated and then lyophilized to give 5-{[(2S,3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (73.6 mg, 25.36%). LC-MS: (ES+H, m / z): [M+H] + = 408.2. Specific rotation [α] 25 D (c = 0.5, MeOH): +8°; 1 1H NMR (400 MHz, DMSO-d 6 ) δ 11.86 (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).

[0555] Example 20

[0556]

[0557] Step 1: Preparation of methyl 5-(((2S,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl)oxy)pyridinecarboxylate Step 2: Preparation of (2S,3S)-2-methyl-3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)azetidine-1-carboxylic acid tert-butyl ester :

[0558] At 0 °C under a nitrogen atmosphere, to a stirred solution of methyl 5-hydroxypyridine-2-carboxylate (245 mg, 1.60 mmol, 1.00 equiv), tert-butyl (2R,3S)-3-hydroxy-2-methylazetidine-1-carboxylate (300 mg, 1.60 mmol, 1.00 equiv) and Ph 3 P (840 mg, 3.20 mmol, 2.00 equiv) in THF (5 mL) was added dropwise a solution of DBAD (738 mg, 3.20 mmol, 2.00 equiv) in THF (2 mL). The resulting mixture was stirred at 0 °C for 1 h. 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 Ph 3 PO) as a grey oil. The resulting mixture was used directly in the next step. LC-MS: (ES + H, m / z): [M + H] + = 323.2.

[0559] Step 3: Preparation of N-methyl-5-(((2S,3S)-2-methylazetidin-3-yl)oxy)pyridineamide HCl salt 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-methylpyridineamide :

[0560] At room temperature under a nitrogen atmosphere, 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 wt%-30 wt% aqueous solution) in MeOH (4 mL) was stirred overnight. 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 Ph 3 PO) as a grey oil. The crude product was used directly in the next step. LC-MS: (ES + H, m / z): [M + H] + = 322.2

[0561] Example 21 Step 1: Preparation of methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylate :

[0562] At room temperature under a nitrogen atmosphere, tert-butyl (2R,3R)-2-methyl-3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (1.53 g, containing Ph 3A solution of PO) and TFA (3 mL) in DCM (3 mL) was stirred for 30 minutes. The resulting mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with ether (3 × 10 mL) to give N-methyl-5-{[(2R,3R)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide TFA salt (810 mg, containing Ph 3 PO). LC-MS: (ES + H, m / z): [M + H] + = 222.1.

[0563] Step 2: Preparation of 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylic acid Step 3: Preparation of tert-butyl 3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate :

[0564] At room temperature under a nitrogen atmosphere, KI (74 mg, 0.45 mmol, 0.20 equiv) and DIEA (1.45 g, 11.22 mmol, 5.00 equiv) were added 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). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-{[(2R,3R)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (26.2 mg, 2.86%). LC-MS: (ES + H, m / z): [M + H] + = 408.20. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.80 (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).

[0565] Step 4: Preparation of tert-butyl 3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate

[0566]

[0567] ​ ​ :

[0568] At 0 °C under a nitrogen atmosphere, dropwise add DBAD (1.20 g, 5.22 mmol, 2.00 eq) to a stirred mixture of methyl 5-hydroxypyridine-2-carboxylate (400 mg, 2.61 mmol, 1.00 eq), (2S,3R)-tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate (489 mg, 2.61 mmol, 1.00 eq), and PPh 3 (1.40 g, 5.22 mmol, 2.00 eq) in toluene (10 mL). Stir the resulting mixture at 80 °C under a nitrogen atmosphere overnight. Monitor the reaction by LCMS. Dilute the resulting mixture with water (50 mL). Extract the resulting mixture with EtOAc (3 × 50 mL). Wash the combined organic layers with brine (3 × 50 mL), and dry over anhydrous Na 2 SO 4 dry. After filtration, concentrate the filtrate under reduced pressure to obtain the crude product (3.6 g, crude). Use the crude product directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H] + = 323.1.

[0569] ​ ​ :

[0570] At room temperature, add CH3NH2 (10 mL, 25 wt% - 30 wt% aqueous solution) to a stirred solution of methyl 5-(((2S,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl)oxy)picolinate (3.6 g, crude) in MeOH (10 mL). Stir the resulting mixture at room temperature under a nitrogen atmosphere for 1 hour. Monitor the reaction by LCMS. Dilute the resulting mixture with saturated NH 4 Cl (100 mL). Extract the resulting mixture with DCM (3 × 100 mL). Wash the combined organic layers with brine (3 × 100 mL), and dry over anhydrous Na 2 SO 4 dry. After filtration, concentrate the filtrate under reduced pressure to obtain the crude product (3.5 g, crude). Use the crude product directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H] + = 322.2

[0571] ​ ​ :

[0572] At room temperature under a nitrogen atmosphere, a solution of HCl (gas) in 1,4-dioxane (10 mL, 4 M) was added dropwise 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). 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

[0573] ​ ​ :

[0574] At room temperature, KI (22 mg, 0.14 mmol, 0.20 equiv) and DIEA (435 mg, 3.37 mmol, 5.00 equiv) were added to a stirred mixture of N-methyl-5-(((2S,3S)-2-methylazetidin-3-yl)oxy)picolinamide (298 mg, assuming 100% yield, 1.35 mmol, 2.00 equiv) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (150 mg, 0.67 mmol, 1.00 equiv) in MeCN (10 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The 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 Na 2 SO 4 4. The filtrate was concentrated under reduced pressure after filtration. 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 HNMR (300 MHz, DMSO-d 6)δ 11.80 (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).

[0575] ​

[0576]

[0577] ​ :

[0578] At 0 °C under a nitrogen atmosphere, a solution of DBAD (15.04 g, 65.30 mmol, 2.00 eq) in toluene (40 mL) was added dropwise to a stirred mixture of methyl 5 - hydroxypyridine - 2 - carboxylate (5.00 g, 32.65 mmol, 1.00 eq), PPh 3 (17.13 g, 65.30 mmol, 2.00 eq) and tert - butyl 3 - hydroxyazetidine - 1 - carboxylate (5.66 g, 32.65 mmol, 1.00 eq) in toluene (80 mL). The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2 h. The desired product could be detected by LCMS. The mixture was cooled to room temperature. The resulting mixture was poured into water (400 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na 2 SO 4 dried. 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 gray oil. The crude product was used directly in the next step without further purification. LC - MS: (ES + H, m / z): [M + H] + = 309.1 ​ ​ :

[0579] At room temperature under a nitrogen atmosphere, methyl 5 - {[1 - (tert - butoxycarbonyl)azetidin - 3 - yl]oxy}pyridine - 2 - carboxylate (9.00 g, 8.76 mmol, 1.00 eq, assuming 30% yield) and LiOH (0.84 g, 35.03 mmol, 4.00 eq) in THF (40 mL) and H 2The mixture in O (10 mL) was stirred for 3 hours. The desired product can be detected by LCMS. The resulting mixture was poured into water (200 mL), and extracted with EtOAc (1×200 mL). The aqueous layer was acidified to pH 4 - 6 with HCl (aqueous solution). The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (1×100 mL) and dried over anhydrous Na 2 SO 4 . 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 (300 MHz, DMSO-d 6 ) δ 12.92 (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).

[0580] ​ ​ :

[0581] At room temperature, aminocyclopropane (107 mg, 1.87 mmol, 1.10 equiv) and T3P (4.32 g, 6.80 mmol, 4.00 equiv, 50 wt% solution in EA) were added 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). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The desired product can be detected by LCMS. The resulting mixture was poured into water (150 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (1×80 mL) and dried over anhydrous Na 2 SO 4 . 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 (300 MHz, DMSO-d 6)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).

[0582] Step 4: Preparation of 5-(azetidin-3-yloxy)-N-cyclopropylpicolinamide TFA salt :

[0583] At room temperature under a nitrogen atmosphere, 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 for 2 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The 5-(azetidin-3-yloxy)-N-cyclopropylpyridine-2-carboxamide TFA salt as a brown crude oil (1.2 g, crude) was thus obtained. LC-MS: (ES + H, m / z): [M + H]+ = 234.2

[0584] Step 5: Preparation of N-cyclopropyl-5-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidin ane-3-yloxy}picolinamide :

[0585] 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 h. The reaction was monitored by LCMS. After cooling to room temperature, the resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous Na 2 SO 4 2. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase combi-flash, the pure fractions were concentrated and then lyophilized to give N-cyclopropyl-5-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidin-3-yl}oxy)pyridine-2-carboxamide (96.2 mg, 33.50%). LC-MS: (ES + H, m / z): [M + H] + = 420.3. 1HNMR (300 MHz, DMSO-d 6 ) δ 11.86 (s, 1H), 8.52 (d, 1H), 8.37 (d, 1H), 8.20 (d, 1H), 7.95 (d, 1H), 7.74 (s, 1H), 7.57 (d, 1H), 7.41 (dd, 1H), 5.02 (p, 1H), 3.83 - 3.75 (m, 4H), 3.24 - 3.12 (m, 2H), 2.87 (td, 1H), 2.57 - 2.52 (m, 2H), 1.18 (t, 3H), 0.68 - 0.65 (m, 4H).

[0586] The following examples were carried out using a similar procedure as shown for Example 21:

[0587]

[0588]

[0589] Example 22

[0590]

[0591] Step 1: Preparation of tert-butyl 3-(4-cyanophenoxy)azetidine-1-carboxylate :

[0592] At room temperature under a nitrogen atmosphere, to a stirred solution of 4-fluorobenzonitrile (1.00 g, 8.26 mmol, 1.00 equiv) and tert-butyl 3-hydroxyazetidine-1-carboxylate (2.15 g, 12.39 mmol, 1.50 equiv) in DMF (20 mL) was added K 2 CO 3 (3.42 g, 24.77 mmol, 3.00 equiv). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. At room temperature, the reaction mixture was poured into water (80 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 Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the filtrate was concentrated under reduced pressure to give tert-butyl 3-(4-cyanophenoxy)azetidine-1-carboxylate (170 mg, 7.51%). LC-MS: (ES + H, m / z): [M - tBu + ACN] + = 260.0. 1 HNMR (300 MHz, DMSO-d 6)δ 7.84 - 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).

[0593] Step 2: Preparation of 4-(azetidin-3-yloxy)benzonitrile TFA salt :

[0594] At room temperature under a nitrogen atmosphere, trifluoroacetic acid (TFA, 1 mL) was added dropwise to a stirred solution of tert-butyl 3-(4-cyanophenoxy)azetidine-1-carboxylate (160 mg, 0.58 mmol, 1.00 equiv) in DCM (3 mL). The resulting mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 4-(azetidin-3-yloxy)benzonitrile TFA salt (232 mg, crude) as a brown oil. LC-MS: (ES + H, m / z): [M + H] + = 175.0

[0595] Step 3: Preparation of 4-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidin-3-yl}oxy yl)benzonitrile :

[0596] At room temperature under a nitrogen atmosphere, 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) were added 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). The resulting mixture was stirred at 80 °C for 1 hour under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was poured into water (60 mL). The mixture was extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na 2 SO 4 2. After filtration, the filtrate was concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC, and the pure fractions were concentrated under reduced pressure and then lyophilized to give 4-({1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]azetidin-3-yl}oxy)benzonitrile (86.7 mg, 41.24%, two steps). LC-MS: (ES + H, m / z): [M + H] + = 361.10. 1 H NMR (400 MHz, DMSO-d 6)δ 11.84 (s, 1H), 8.36 (d, 1H), 7.82 - 7.66 (m, 3H), 7.56 (s, 1H), 7.02 (d, 2H), 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).

[0597] The following examples were carried out using a similar procedure as shown for Example 22:

[0598]

[0599]

[0600] Example 43

[0601]

[0602] Step 1: Preparation of (2R,3S)-3-((6-cyanopyridin-3-yl)oxy)-2-methylazetidine-1-carboxylic acid tert-butyl ester :

[0603] At 0 °C under a nitrogen atmosphere, a solution of (2R,3S)-tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate (6.99 g, 37.35 mmol, 1.20 equiv) in THF (30 mL) was added dropwise to a stirred mixture of NaH (1.49 g, 37.37 mmol, 1.20 equiv, 60% oil solution) in THF (30 mL). The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. At 0 °C, a solution of 5-fluoropyridine-2-carbonitrile (3.8 g, 31.12 mmol, 1.00 equiv) in THF (30 mL) was added dropwise to the above mixture over 15 minutes. The resulting mixture was stirred at room temperature for an additional 1 hour. The reaction was monitored by LCMS. The reaction was quenched by adding water (10 mL) at 0 °C. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with CH 2 Cl 2 (3 × 50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . 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.

[0604] Step 2: Preparation of 5-(((2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl)oxy)picolinate acid :

[0605] At room temperature, NaOH (20 mL, 2N aqueous solution) was added portionwise 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). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by TLC. The mixture was cooled to room temperature. THF (40 mL) and Boc2O (9.96 g, 45.62 mmol, 2.00 equiv) were added portionwise to the above mixture at 0 °C over 10 min. 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 CH 2 Cl 2 (3 × 50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography to afford 5-(((2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl)oxy)picolinate (6.2 g, 88.2%). LC-MS: (ES + H, m / z): [M + H] + = 309.2. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.33 (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).

[0606] Step 3: Preparation of (2R,3S)-3-{[6-(cyclopropylcarbamoyl)pyridin-3-yl]oxy}-2-methylazetidine- 1-carboxylic acid tert-butyl ester :

[0607] At 0 °C, aminocyclopropane (133 mg, 2.33 mmol, 1.20 equiv) was added to a stirred solution of 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}picolinic 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). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 h. The reaction was monitored by LCMS. The mixture was extracted with CH 2 Cl 2(100 mL) The resulting mixture was diluted. 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 obtain 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

[0608] Step 4: Preparation of N-cyclopropyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}picolinamide HCl salt :

[0609] At 0 °C under a nitrogen atmosphere, a solution of HCl (gas) in 1,4-dioxane (5 mL, 4 mol / L) was added dropwise 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). 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 Et 2 O (2 × 10 mL). The resulting mixture was concentrated under reduced pressure to obtain 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.

[0610] 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}picolinamide :

[0611] At room temperature, to a mixture of N-methyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide HCl salt (200 mg, crude) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (150 mg, 0.67 mmol, 1.00 equiv) in CH 3To the stirred mixture in CN (8 mL), KI (56 mg, 0.34 mmol, 0.5 eq) and DIEA (697 mg, 5.39 mmol, 8 eq) were added dropwise. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thereafter, the residue was purified by reverse-phase combi-flash chromatography, and the pure fractions were concentrated in vacuo to give N-cyclopropyl-5-{[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide (109.3 mg, 37.3%). LC-MS: (ES + H, m / z): [M - H]+ = 434.25, specific rotation [a] 25 D (c = 0.25, DCM / MeOH = 10 / 1): -12°; 1 1H NMR (300 MHz, DMSO-d 6 ) δ 11.86 (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).

[0612] Example 44

[0613]

[0614] Step 1: Preparation of methyl 5-(((2R,3S)-2-methylazetidin-3-yl)oxy)picolinate HCl salt :

[0615] At room temperature, to the stirred mixture of tert-butyl 3-{[6-(dihydroxymethyl)piperidin-3-yl]oxy}-2-methylazetidine-1-carboxylate (600 mg, 1.90 mmol, 1.00 eq) in MeOH (10 mL), SOCl 2(1.13 g, 9.48 mmol, 5.00 eq). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo, and the crude product was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H] + = 223.2.

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

[0617] At room temperature under a nitrogen atmosphere, to a stirred mixture of methyl 5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate (380 mg, 1.71 mmol, 1.00 eq), KI (28 mg, 0.17 mmol, 0.10 eq) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (456 mg, 2.05 mmol, 1.20 eq) in CH 3 CN (5 mL) was added DIEA (884 mg, 6.84 mmol, 4.00 eq). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with CH 2 Cl 2 (3 × 30 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . 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

[0618] Step 3: Preparation of 5-(((2R,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methyl azetidin-3-yl)oxy)picolinate acid :

[0619] At room temperature under a nitrogen atmosphere, 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 eq) in MeOH (3 mL) was added NaOH (aqueous solution, 3 mL, 2N H 2solution). The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction was monitored by LCMS. Using CH 2 Cl 2 (2 × 30 mL) to extract the aqueous layer. The mixture was acidified to pH 6 - 7 with HCl (aqueous solution). The aqueous layer was concentrated in vacuo. The residue was purified by trituration with MeOH (40 mL). The resulting mixture was filtered and the filter cake was washed with MeOH (1 × 20 mL). The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H] + = 395.2.

[0620] Step 4: Preparation of 5-(((2R,3S)-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methyl azetidin-3-yl)oxy)-N-(oxetan-3-yl)picolinamide :

[0621] At room temperature under a nitrogen atmosphere, 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), HATU (289 mg, 0.76 mmol, 1.50 equiv) was added portionwise. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (30 mL). Using CH 2 Cl 2 (3 × 20 mL) to extract the resulting mixture. The combined organic layers were washed with water (1 × 30 mL) and dried over anhydrous Na 2 SO 4 . 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)pyridinecarboxamide (15.6 mg, 6.6%). LC-MS: (ES + H, m / z): [M + H] + = 450.2. 1 H NMR (300 MHz, DMSO-d 6)δ 11.86 (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 (dd, 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).

[0622] Examples 54 and 55 .

[0623]

[0624] Step 1: Preparation of 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid :

[0625] At room temperature, NaOH (0.59 g, 14.86 mmol, 3.00 equivalents) was added portionwise to a solution of methyl 7 - ethyl - 6 - oxo - 5H - 1,5 - naphthyridine - 3 - carboxylate (1.15 g, 4.95 mmol, 1.00 equivalent) in MeOH (15 mL) and H 2 O (3 mL). 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 (aqueous solution). 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 (400 MHz, DMSO - d 6 )δ 13.43 (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).

[0626] Step 2: Preparation of 7-ethyl-N-methoxy-N-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxamide :

[0627] At room temperature under a nitrogen atmosphere, EDCI (2.10 g, 11.00 mmol, 3.00 equivalents) was added portionwise 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 equivalents) in DMF (8 mL). 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 Na 2 SO 4 . 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 (400 MHz, DMSO-d 6 ) δ 12.02 (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).

[0628] Step 3: Preparation of 7-acetyl-3-ethyl-1H-1,5-naphthyridin-2-one :

[0629] At 0 °C under a nitrogen atmosphere, CH 3 MgBr (1.4 mL, 4.13 mmol, 2.00 equivalents, 3 M solution in THF) was added dropwise 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 equivalent) in THF (5 mL). 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 Na 2 SO 4 . 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 (400 MHz, DMSO-d6 ) δ 12.06 (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).

[0630] Step 4: 5-{[(2R,3S)-1-[1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazido Preparation of [[(azetidin-3-yl)oxy]-N-methylpyridine-2-carboxamide :

[0631] At room temperature under a nitrogen atmosphere, a mixture of 7-acetyl-3-ethyl-1H-1,5-naphthyridin-2-one (400 mg, 1.85 mmol, 1.00 equivalent) and N-methyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide (614 mg, 2.78 mmol, 1.50 equivalents) in DCM (5 mL) was stirred for 15 minutes. The resulting mixture was concentrated under reduced pressure. Tetrakis(prop-2-yloxy)titanium (1.58 g, 5.55 mmol, 3.00 equivalents) was added to the above mixture. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 4 hours. The residue was dissolved in EtOH (10 mL). 3 NaBH 2 CN (233 mg, 3.70 mmol, 2.00 equivalents) was added to the above mixture. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 4 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reaction was quenched by adding water (20 mL) at room temperature. The resulting mixture was filtered, and the filter cake was washed with CH 2 Cl

[0632] Step 5: 5-{[(2R,3S)-1-[(1R*)-1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]-2- methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide and 5-{[(2R,3S)-1-[(1R*)-1-(7-eth yl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-car boxamide :

[0633] The racemate 5-{[(2R,3S)-1-[1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (160 mg) was separated by preparative chiral HPLC to give 5-{[(2R,3S)-1-[(1R*)-1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (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%).

[0634] Example 54: LC-MS: (ES + H, m / z): [M + H] + = 422.15. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.81 (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).

[0635] Example 55: LC-MS: (ES + H, m / z): [M + H] + = 422.15. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.89 (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).

[0636] The following examples were carried out using a similar procedure as shown for Examples 54 and 55:

[0637]

[0638] Example 63

[0639]

[0640] Step 1: Preparation of tert-butyl (2R,3R)-2-methyl-3-{[4-(trifluoromethyl)phenylsulfonyl]oxy}azetidine-1-carboxylate Step 2: Preparation of tert-butyl (2R,3S)-3-[5-(methoxycarbonyl)pyrrolo[3,2-b]pyridin-1-yl]-2-methylazetidine-1-carboxylate :

[0641] At 0 °C under a nitrogen atmosphere, 4-(trifluoromethyl)phenylsulfonyl chloride (1.44 g, 5.87 mmol, 1.10 eq) in DCM (10 mL) was added to a stirred solution of tert-butyl (2R,3R)-3-hydroxy-2-methylazetidine-1-carboxylate (1.00 g, 5.34 mmol, 1.00 eq), Et 3 N (1.62 g, 16.02 mmol, 3.00 eq), and DMAP (0.03 g, 0.26 mmol, 0.05 eq) in DCM (20 mL). The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by TLC (PE / EA = 2 / 1, KMnO4). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (2R,3R)-2-methyl-3-{[4-(trifluoromethyl)phenylsulfonyl]oxy}azetidine-1-carboxylate (1.7 g, 76.4%). 1 1H 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).

[0642] Step 3: Preparation of tert-butyl (2R,3S)-2-methyl-3-[5-(methylcarbamoyl)pyrrolo[3,2-b]pyridin-1-yl]azetidine-1-carboxylate Step 4: Preparation of N-methyl-1-[(2R,3S)-2-methylazetidin-3-yl]pyrrolo[3,2-b]pyridine-5-carboxamide hydrochloride :

[0643] At room temperature, Cs 2 CO 3 (1.65 g, 5.05 mmol, 2.00 eq) was added to a stirred solution of tert-butyl (2R,3R)-2-methyl-3-{[4-(trifluoromethyl)phenylsulfonyl]oxy}azetidine-1-carboxylate (1.00 g, 2.52 mmol, 1.00 eq) and methyl 1H-pyrrolo[3,2-b]pyridine-5-carboxylate (445 mg, 2.52 mmol, 1.00 eq) in DMF (20 mL). The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (200 mL). With H 2Wash the resulting mixture with O (3 × 100 mL). Wash the organic layer with brine (50 mL) and dry over anhydrous Na 2 SO 4 After filtration, concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography to obtain 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

[0644] 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.24 (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).

[0645] 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 Example 66 :

[0646] At room temperature under a nitrogen atmosphere, add an aqueous solution of CH3NH2 (3 mL, 30 wt%) dropwise 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) in ACN (3 mL). Stir the resulting mixture at room temperature under a nitrogen atmosphere for 6 hours. Monitor the reaction by LCMS. Dilute the resulting mixture with saturated NH 4 Cl (aqueous solution, 50 mL). Extract the resulting mixture with CH 2 Cl 2 (3 × 100 mL). Wash the combined organic layers with brine (3 × 50 mL) and dry over anhydrous Na 2 SO 4 After filtration, concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography to obtain 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 (300 MHz, DMSO-d 6)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).

[0647] Step 1: Preparation of methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-3-fluoropyridine-2-carboxylate Step 2: Preparation of 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-3-fluoropyridine-2-carboxylic acid :

[0648] 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 dioxane solution). The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with hexane / Et 2 O = 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

[0649] Step 3: Preparation of tert-butyl (2R,3S)-3-{[6-(cyclopropylcarbamoyl)-5-fluoropyridin-3-yl]oxy}-2-methylazetidine-1-carboxylate Step 4: Preparation of N-cyclopropyl-3-fluoro-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide hydrochloride :

[0650] At room temperature under a nitrogen atmosphere, DIEA (580 mg, 4.49 mmol, 5.00 equiv) was added dropwise to a stirred solution of 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (200 mg, 0.89 mmol, 1.00 equiv), N-methyl-1-[(2R,3S)-2-methylazetidin-3-yl]pyrrolo[3,2-b]pyridine-5-carboxamide hydrochloride (241 mg, assuming 100% yield, 0.98 mmol, 1.10 equiv), and KI (29 mg, 0.18 mmol, 0.20 equiv) in ACN (5 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product. The residue was dissolved in DMSO (3 mL). The residue was purified by preparative HPLC. The pure fractions were concentrated in vacuo and then lyophilized to give 1-[(2R,3S)-1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]-N-methylpyrrolo[3,2-b]pyridine-5-carboxamide (126.2 mg, 32.2%). LC-MS: (ES + H, m / z): [M + H] + = 431.15. Optical rotation [a] 25 D (c = 0.5, MeOH): -26.4°; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.91 (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).

[0651] The following examples were carried out using a similar procedure as shown for Example 63:

[0652]

[0653]

[0654] 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

[0655]

[0656] Example 75 Step 1: Preparation of 7-bromo-1H-1,5-naphthyridin-2-one :

[0657] At 0 °C, 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 PPh 3 (1.53 g, 5.84 mmol, 2.00 equiv) in PhMe (20 mL) was treated with a solution of DBAD (1.35 g, 5.84 mmol, 2.00 equiv) in PhCH 3 (5 mL). The resulting mixture was stirred at 60 °C for 2 h. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (1 × 40 mL), dried over anhydrous Na 2 SO 4 and filtered. After filtration, the filtrate was concentrated under reduced pressure. Methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-3-fluoropyridine-2-carboxylate (4.2 g, crude) was obtained 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.

[0658] Step 2: Preparation of 7-bromo-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one Step 3: Preparation of 3-(difluoromethyl)-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one :

[0659] At 0 °C, 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 a solution of NaOH (0.94 g, 23.50 mmol, 2.00 equiv) in H 2 O (7 mL). 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 (1 mol / L aqueous solution). The resulting mixture was extracted with EtOAc (3 × 70 mL). The combined organic layers were washed with brine (1 × 60 mL), dried over anhydrous Na 2 SO 4Dry. After filtration, the filtrate was concentrated under reduced pressure. Thus, 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-3-fluoropyridine-2-carboxylic acid (900 mg, 94.2%, two steps) was obtained.

[0660] LC-MS: (ES + H, m / z): [M + H] + = 327.1.

[0661] Step 4: Preparation of 7-(chloromethyl)-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one ​ :

[0662] A solution of 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-3-fluoropyridine-2-carboxylic acid (600 mg, 1.83 mmol, 1.00 equiv) in DMF (10 mL) was treated with HATU (1.05 g, 2.75 mmol, 1.50 equiv) for 10 minutes at room temperature, then aminocyclopropane (524 mg, 9.19 mmol, 5.00 equiv) and DIEA (950 mg, 7.35 mmol, 4.00 equiv) were added. 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), dried over anhydrous Na 2 SO 4 Dry. 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 (300 MHz, DMSO-d 6 ): δ 8.48 (d, 1H), 8.12 (dd, 1H), 7.40 (dd, 1H), 4.83 - 4.78 (m, 1H), 4.31 - 4.22 (m, 2H), 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).

[0663] ​ ​ :

[0664] At 0 °C, 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 eq) in EA (20 mL) was treated with a solution of HCl (gas) in 1,4-dioxane (10 mL, 4 M). The resulting mixture was stirred at room temperature for 1.5 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This afforded 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.

[0665] ​ ​ :

[0666] At room temperature, 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (200 mg, 0.89 mmol, 1.00 eq) and KI (29.82 mg, 0.18 mmol, 0.20 eq) were added to a stirred mixture of N-cyclopropyl-3-fluoro-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide hydrochloride (285 mg, assuming 100% yield, 1.07 mmol, 1.20 eq) and DIEA (464 mg, 3.59 mmol, 4.00 eq) in MeCN (10 mL). The resulting mixture was stirred at 80 °C for an additional 2 h. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with CH 2 Cl 2 (3 × 40 mL). The combined organic layers were washed with brine (1 × 30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase combi-flash chromatography. The resulting mixture was concentrated under reduced pressure. This afforded 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 (400 MHz, DMSO-d6 ): δ 11.86 (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 (377 MHz, DMSO - d 6 ) δ - 118.55.

[0667] ​

[0668]

[0669] ​ :

[0670] At room temperature under a nitrogen atmosphere, 2,2,3 - tribromopropionaldehyde (13.38 g, 45.40 mmol, 1.00 equivalent) was added to a stirred mixture of 5 - aminopyridin - 2 - ol (5.00 g, 45.41 mmol, 1.00 equivalent) in AcOH (60 mL). 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), dried over anhydrous Na 2 SO 4 and filtered. 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 (400 MHz, DMSO - d 6 ) δ 11.95 (s, 1H), 8.55 (d, J = 2.1 Hz, 1H), 7.92 (d, J = 9.8 Hz, 1H), 7.85 (d, J = 2.1 Hz, 1H), 6.78 (d, J = 9.8 Hz, 1H).

[0671] ​ :

[0672] At room temperature under a nitrogen atmosphere, 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 H 2 O (6 mL) was added sodium difluoromethanesulfinate (3.53 g, 20.44 mmol, 2.00 equiv, 80 wt%) and potassium persulfate (11.05 g, 40.88 mmol, 4.00 equiv). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere overnight. The reaction was monitored by LCMS. The mixture was cooled 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 afford 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 (300 MHz, DMSO-d 6 ) δ 12.40 (s, 1H), 8.66 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.17 - 6.76 (m, 1H). 19 F NMR (282 MHz, DMSO-d 6 ) δ -119.76.

[0673] ​ :

[0674] At room temperature under a nitrogen atmosphere, to a stirred solution of 7-bromo-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one (2.20 g, 7.99 mmol, 1.00 equiv) in 1,4-dioxane (30 mL) was added dropwise (tributylstannyl)methanol (2.83 g, 8.79 mmol, 1.10 equiv) and a second-generation XPhos precatalyst (314 mg, 0.40 mmol, 0.05 equiv). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere overnight. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 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 (300 MHz, DMSO-d 6)δ 12.36 (s, 1H), 8.50 (d, J = 1.8 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.70 (d, J = 1.9 Hz, 1H), 7.18 - 6.78 (m, 1H), 5.57 (t, J = 5.6 Hz, 1H), 4.67 (d, J = 5.6 Hz, 2H). 19 F NMR (282 MHz, DMSO - d 6 )δ - 119.24.

[0675] ​ :

[0676] At 0 °C under a nitrogen atmosphere, DMF (9 mg, 0.12 mmol, 0.10 equivalent) and SOCl 2 (0.93 mL, 12.82 mmol, 10.00 equivalents) were added dropwise to a stirred mixture of 3 - (difluoromethyl) - 7 - (hydroxymethyl) - 1H - 1,5 - naphthyridin - 2 - one (290 mg, 1.28 mmol, 1.00 equivalent) in DCM (5 mL). 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.

[0677] 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 :

[0678] At room temperature under a nitrogen atmosphere, DIEA (290 mg, 2.25 mmol, 5.00 equivalents) was added dropwise to a stirred solution of 7 - (chloromethyl) - 3 - (difluoromethyl) - 1H - 1,5 - naphthyridin - 2 - one (110 mg, 0.45 mmol, 1.00 equivalent), N - cyclopropyl - 5 - {[(2R,3S) - 2 - methylazetidin - 3 - yl]oxy}pyridine - 2 - carboxamide (144 mg, 0.58 mmol, 1.30 equivalents) and KI (14 mg, 0.09 mmol, 0.20 equivalent) in ACN (5 mL). The resulting mixture was stirred at 80 °C for 1 hour. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The residue was dissolved in water (50 mL). The solution was extracted with EtOAc (3 × 100 mL). With anhydrous Na 2 SO 4Dry the combined organic layers. After filtration, concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography to obtain the crude product (90 mg). Separate the crude product by PREP_HPLC to obtain: 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 (C = 1, MeOH:DCM = 1:1), tested in PHA). LC-MS: (ES + H, m / z): [M + H] + = 456.15. 1 1H NMR (300 MHz, DMSO-d 6 ) δ 12.30 (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 19F NMR (282 MHz, DMSO-d 6 ) δ -119.30.

[0679] Example 76

[0680]

[0681] Step 1: Preparation of 3-bromo-2-methoxy-6-methyl-5-nitropyridine :

[0682] At 0 °C under a nitrogen atmosphere, add NaOMe (15.76 g, 87.49 mmol, 1.10 equivalents, 30 wt%) dropwise to a stirred mixture of 3-bromo-2-chloro-6-methyl-5-nitropyridine (20.00 g, 79.54 mmol, 1.00 equivalent) in MeOH (50 mL). Stir the resulting mixture overnight at room temperature under a nitrogen atmosphere. Monitor the reaction by TLC (PE:EA = 1:1, R f = 0.4). Concentrate the resulting mixture under reduced pressure and add water (100 mL). Extract the resulting mixture with EtOAc (3 × 100 mL). Wash the combined organic layers with brine (1 × 200 mL), over anhydrous Na 2 2SO4 Dry. After filtration, the filtrate was concentrated under reduced pressure to obtain 3-bromo-2-methoxy-6-methyl-5-nitropyridine (20 g, 99%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.66 (s, 1H), 4.04 (s, 3H), 2.70 (s, 3H).

[0683] Step 2: Preparation of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N,N-dimethylethan-1-amine :

[0684] At 100 °C under a nitrogen atmosphere, a mixture of 3-bromo-2-methoxy-6-methyl-5-nitropyridine (15.00 g, 60.72 mmol, 1.00 equiv) in DMF-DMA (100 mL) and DMF (100 mL) was stirred overnight. The reaction was monitored by TLC. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0685] Step 3: Preparation of 5-bromo-6-methoxy-3-nitropyridinecarbaldehyde :

[0686] At 0 °C under a nitrogen atmosphere, NaIO 2 (28.00 g, 131.07 mmol, 2.20 equiv) was added portionwise to a stirred mixture of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)vinyl]dimethylamine (18.01 g, crude) in THF (100 mL) and H 4 O (100 mL). 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 at room temperature by the addition of saturated sodium thiosulfate (aqueous solution) (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous Na 2 SO 4 and filtered. 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 (400 MHz, DMSO-d 6 ) δ 10.16 (s, 1H), 8.87 (s, 1H), 4.10 (s, 3H).

[0687] Step 4: Preparation of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate :

[0688] At room temperature under a nitrogen atmosphere, SnCl was added portionwise to a stirred mixture of 5-bromo-6-methoxy-3-nitropyridine-2-carbaldehyde (7.00 g, crude) and ethyl 3,3-diethoxypropionate (20.40 g, 107.27 mmol, 4.00 equiv) in EtOH (100 mL)2 (26.25 g, 134.09 mmol, 5.00 equivalents). The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude mixture was poured into saturated sodium bicarbonate (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to 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%, three steps). LC-MS: (ES + H, m / z): [M + H] + = 311.0 / 313.0. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.22 (s, 1H), 8.78 (s, 1H), 8.58 (s, 1H), 4.42 (q, 2H), 4.12 (s, 3H), 1.39 (t, 3H).

[0689] Step 5: Preparation of ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate :

[0690] At room temperature under a nitrogen atmosphere, CuCl (0.57 g, 5.78 mmol, 1.50 equivalents) was added to a stirred mixture of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (1.20 g, 3.85 mmol, 1.00 equivalent) in DMF (10 mL). The resulting mixture was stirred overnight at 120 °C. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (20 mL). The resulting mixture was washed with 3 × 30 mL of water (10% NH3×H 2 2O). 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 1H NMR (300 MHz, DMSO-d 6 ) δ 9.27 (d, 1H), 8.63 (d, 1H), 8.57 (s, 1H), 4.41 (q, 2H), 4.12 (s, 3H), 1.37 (t, 3H).

[0691] Step 6: Preparation of ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate :

[0692] At room temperature under a nitrogen atmosphere, to a stirred mixture of ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate (800 mg, 3.00 mmol, 1.00 equiv) in CH 3 CN (8 mL) was added TMSI (1.80 g, 9.00 mmol, 3.00 equiv). The resulting mixture was stirred at 50 °C for 2 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (50 mL). The aqueous layer was washed with 3 × 50 mL of water (10% Et 3 N). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate (740 mg, 97.64%). LC-MS: (ES + H, m / z): [M + H] + = 252.9. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.61 (s, 1H), 8.94 (d, 1H), 8.37 (d, 1H), 8.20 (s, 1H), 4.39 (q, 2H), 1.36 (t, 3H).

[0693] Step 7: Preparation of 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one :

[0694] At 0 °C under a nitrogen atmosphere, to a stirred mixture of ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate (740 mg, 2.92 mmol, 1.00 equiv) in THF (6 mL) was added dropwise LiAlH 4 (2.5 mL, 5.85 mmol, 2.00 equiv). 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 (400 MHz, DMSO-d 6 ) δ 12.49 (s, 1H), 8.45 (d, 1H), 8.28 (s, 1H), 7.69 (d, 1H), 5.53 (t, 1H), 4.64 (d, 2H).

[0695] Step 8: Preparation of 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one :

[0696] At room temperature under nitrogen atmosphere, 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (250 mg, 1.18 mmol, 1.00 equiv) was added to CH 2 Cl 2 SOCl (5 mL) was added dropwise to the stirred mixture. 2 (423 mg, 3.56 mmol, 3.00 equiv) and DMF (8 mg, 0.11 mmol, 0.10 equiv). The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This gave 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (280 mg, crude). The crude product was used directly in the next step without further purification.

[0697] LC-MS: (ES+H, m / z): [M+H] + =228.95.

[0698] Step 9: 5-{[(2R,3S)-1-[(7-chloro-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylazetidin-3-yl]oxy}-N-cyclopropylpyridine-2-carboxamide Preparation :

[0699] 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 purified by anhydrous Na 2 SO 4 Dry. 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 HNMR (300 MHz, DMSO-d 6)δ12.45(s,1H),8.52(d,1H),8.46(d,1H),8.27(s,1H),8.21(d,1H),7.95(d,1H),7.66(d,1H),7.44(dd,1H),4.62(q,1H),3.95(d,1H),3.82(t,1H),3.67(d,1H),3.40(q,1H),2.93 - 2.74(m,2H),1.21(d,3H),0.76 - 0.57(m,4H).

[0700] Example 106

[0701]

[0702] Step 1: Preparation of (2E)-N-(3-bromo-2-fluorophenyl)-3-ethoxypropan-2-amide :

[0703] At room temperature under a nitrogen atmosphere, pyridine (14.99 g, 189.45 mmol, 1.80 eq) was added dropwise to a stirred mixture of 3-bromo-2-fluoroaniline (20.00 g, 105.25 mmol, 1.00 eq) in DCM (300 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 5 h. At room temperature, (2E)-3-ethoxyprop-2-enoyl chloride (21.24 g, 157.88 mmol, 1.50 eq) was added dropwise to the above mixture within 5 min. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (500 mL). The resulting mixture was washed with water (3 × 500 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (2E)-N-(3-bromo-2-fluorophenyl)-3-ethoxyprop-2-enamide (24.6 g, 81.1%). LC-MS: (ES + H, m / z): [M + H] + = 288.0 / 290.0.

[0704] Step 2: Preparation of 7-bromo-8-fluoro-1H-quinolin-2-one :

[0705] At room temperature under a nitrogen atmosphere, (2E)-N-(3-bromo-2-fluorophenyl)-3-ethoxyprop-2-enamide (17.00 g, 59.00 mmol, 1.00 eq) in H 2 SO 4The mixture in (85 mL) was stirred for 3 h. The resulting mixture was added dropwise to ice water (1 L) and stirred for 1 h. The precipitated solid was collected by filtration and washed with water (3 × 200 mL). The resulting mixture was concentrated under reduced pressure to give 7-bromo-8-fluoro-1H-quinolin-2-one (14.30 g, crude). LC-MS: (ES + H, m / z): [M + H] + = 242.0 / 244.0.

[0706] Step 3: Preparation of 7-bromo-3-chloro-8-fluoro-1H-quinolin-2-one :

[0707] At room temperature under a nitrogen atmosphere, 2,2-dichloroacetic acid (0.32 g, 2.47 mmol, 0.20 equiv) was added dropwise 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 CH 3 COOH (50 mL). The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The 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 (400 MHz, DMSO-d 6 ) δ 12.52 (s, 1H), 8.38 (d, J = 1.6 Hz, 1H), 7.52 - 7.42 (m, 2H).

[0708] Step 4: Preparation of 3-chloro-7-ethenyl-8-fluoro-1H-quinolin-2-one :

[0709] At room temperature under a nitrogen atmosphere, H 2 was added dropwise 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 2O (5 mL). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-7-vinyl-8-fluoro-1H-quinolin-2-one (750 mg, 37.3%). LC-MS: (ES + H, m / z): [M + H] + = 224.0. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.38 (s, 1H), 8.34 (d, J = 1.6 Hz, 1H), 7.53 - 7.46 (m, 2H), 6.95 (dd, J = 17.7, 11.2 Hz, 1H), 6.07 (dd, J = 17.7, 1.0 Hz, 1H), 5.57 (dd, J = 11.2, 1.0 Hz, 1H).

[0710] Step 5: Preparation of 3-chloro-8-fluoro-2-oxo-1H-quinoline-7-carbaldehyde :

[0711] At room temperature under a nitrogen atmosphere, to a stirred mixture of 3-chloro-7-vinyl-8-fluoro-1H-quinolin-2-one (750 mg, 3.35 mmol, 1.00 equiv), K 2 OsO 2 (OH) 4 (123 mg, 0.33 mmol, 0.10 equiv), NaIO 4 (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 dropwise H 2 O (1.5 mL). 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): [M - H] - = 224.1.

[0712] Step 6: 5-{[(2R,3S)-1-[(3-chloro-8-fluoro-2-oxo-1H-quinolin-7-yl)methyl]-2-methylazetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide Preparation :

[0713] At room temperature under a nitrogen atmosphere, a mixture of 3-chloro-8-fluoro-2-oxo-1H-quinoline-7-carbaldehyde (100 mg, 0.44 mmol, 1.00 equivalent) and N-methyl-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide (98 mg, 0.44 mmol, 1.00 equivalent) in DCM (10 mL) was stirred for 10 minutes. The resulting mixture was concentrated under reduced pressure. At room temperature, CH 3 COOH (13 mg, 0.22 mmol, 0.50 equivalent) and EtOH (10 mL) were added to the above mixture. The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for an additional 4 hours. The reaction was monitored by LCMS. At room temperature, NaBH 3 CN (56 mg, 0.88 mmol, 2.00 equivalents) was added to the above mixture. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The reaction mixture 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-quinoline-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-quinoline-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. Specific rotation [a] 25 D (c = 0.27, MeOH): +38.5°; 1 1H NMR (400 MHz, DMSO-d 6 ) δ 12.36 (s, 1H), 8.57 (q, J = 4.7 Hz, 1H), 8.35 (d, J = 1.3 Hz, 1H), 8.22 (d, J = 2.9 Hz, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.42 (dd, J = 8.7, 2.9 Hz, 1H), 7.24 (dd, J = 8.1, 6.3 Hz, 1H), 4.58 (q, J = 5.9 Hz, 1H), 3.96 - 3.87 (m, 1H), 3.81 (t, J = 6.4 Hz, 1H), 3.73 - 3.64 (m, 1H), 3.39 - 3.34 (m, 1H), 2.79 (dd, J = 8.1, 5.7 Hz, 4H), 1.20 (d, J = 6.2 Hz, 3H).19 F NMR (377 MHz, DMSO-d 6 ) δ -135.11.

[0714] The following examples were carried out using a similar procedure as shown for Example 106:

[0715]

[0716] Example 110

[0717]

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

[0719] At 0 °C under a nitrogen atmosphere, DIEA (1.00 g, 10.38 mmol, 4.00 eq) and CH 3 I (320 μL, 5.19 mmol, 2.00 eq) were added 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 eq) in DMF (10 mL). 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.

[0720] Step 2: Preparation of methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-6-fluoropyridine-2-carboxylate Preparation :

[0721] At room temperature under a nitrogen atmosphere, silver difluoride (904 mg, 6.20 mmol, 5.00 eq) was added to a stirred mixture of methyl 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxylate (400 mg, 1.24 mmol, 1.00 eq) in MeCN (10 mL). 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 washed with CH 2 Cl 2(250 mL) Wash the filter cake. Concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography to obtain 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 (400 MHz, DMSO-d 6 ) δ 7.99 (d, J = 8.2 Hz, 1H), 7.53 (dd, J = 10.1, 8.2 Hz, 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 = 6.5 Hz, 3H), 1.39 (s, 9H). 19 F NMR (400 MHz, DMSO-d 6 ) δ -82.91.

[0722] Step 3: Preparation of 5-{[(2R,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-6-fluoropyridine-2-carboxylic acid Preparation :

[0723] At room temperature under a nitrogen atmosphere, 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·H 2 O (222 mg, 5.28 mmol, 2.00 equiv) (1 mL aqueous solution). The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 3 h. Monitor the reaction by LCMS. The desired product can be detected by LCMS. Cool the mixture to room temperature. Dilute the resulting mixture with water (100 mL). Acidify the aqueous layer to pH 3 with HCl (aqueous solution, 1 N). Extract the aqueous layer with EA (2 × 100 mL). Wash the combined organic layers with brine (2 × 100 mL), dry over anhydrous Na 2 SO 4 4. After filtration, concentrate the filtrate under reduced pressure to obtain 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): [M - H] - = 325.3.

[0724] Step 4: Preparation of tert-butyl (3S)-3-({2-fluoro-6-(methyl-d3carbamoyl)pyridin-3-yl}oxy)-2-methylazetidine-1-carboxylate Preparation :

[0725] At room temperature under a nitrogen atmosphere, to a stirred mixture of 5-{[(2S,3S)-1-(tert-butoxycarbonyl)-2-methylazetidin-3-yl]oxy}-6-fluoropicolinic acid (400 mg, 1.22 mmol, 1.00 equiv) and methyl-d3-amine hydrochloride (259 mg, 3.67 mmol, 3.00 equiv) in CH 2 Cl 2 (5 mL) was added DIEA (792 mg, 6.13 mmol, 5.00 equiv) and T3P (1 g, 3.67 mmol, 3.00 equiv, 50% CH 2 Cl 2 solution). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. 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.

[0726] Step 5: Preparation of 6-fluoro-N-methyl-d3-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide hydrochloride Preparation :

[0727] At room temperature under a nitrogen atmosphere, to a stirred mixture of tert-butyl (3S)-3-({2-fluoro-6-[(2H3)methylcarbamoyl]pyridin-3-yl}oxy)-2-methylazetidine-1-carboxylate (350 mg, 1.02 mmol, 1.00 equiv) in CH 2 Cl 2 (5 mL) was added dropwise a solution of HCl (gas) in 1,4-dioxane (5 mL, 4 M dioxane solution). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. 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-d3-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}picolinamide 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.

[0728] Step 6: Preparation of 5-{[(2R,3S)-1-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]-2-methyl azetidin-3-yl]oxy}-6-fluoro-N-methyl-d3-pyridine-2-carboxamide :

[0729] At room temperature under a nitrogen atmosphere, KI (23 mg, 0.14 mmol, 0.20 eq) and DIEA (463 mg, 3.59 mmol, 5.00 eq) were added to a stirred mixture of 6-fluoro-N-methyl-d3-5-{[(2R,3S)-2-methylazetidin-3-yl]oxy}pyridine-2-carboxamide hydrochloride (200 mg, 0.71 mmol, assuming 100% yield, 1.00 eq) and 7-(bromomethyl)-3-ethyl-8-fluoro-1H-quinoxalin-2-one (204 mg, 0.71 mmol, 1.00 eq) in MeCN (5 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with CH 2 Cl 2 / MeOH (10:1, 200 mL). The filtrate was concentrated under reduced pressure. The crude product (400 mg) was purified by HP-FLASH, the pure fractions were concentrated in vacuo 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-d3pyridine-2-carboxamide (163.8 mg, 50.5%). LC-MS: (ES+H, m / z): [M+H] + = 447.15. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.40 (s, 1H), 8.44 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.61 (dd, J = 10.2, 8.2 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.26 (t, J = 7.3 Hz, 1H), 4.60 (q, J = 5.9 Hz, 1H), 3.90 (d, 1H), 3.81 (t, J = 6.4 Hz, 1H), 3.69 (d, 1H), 3.40 (q, J = 6.0 Hz, 1H), 2.81 (q, J = 7.3 Hz, 3H), 1.23 - 1.19 (m, 6H). 19 F NMR (400 MHz, DMSO-d 6 ) δ -84.70, 136.09.

[0730] Example

[0731]

[0732] Steps 1 - 2: Preparation of N-(3-bromo-2,6-difluorophenyl)-2H-pyrazole-3-carboxamide :

[0733] At 90 °C under a nitrogen atmosphere, 2H-pyrazole-3-carboxylic acid (3.00 g, 26.76 mmol, 1.00 eq) was stirred in SOCl 2 (30 mL) overnight. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with toluene (3 × 50 mL). The resulting mixture was concentrated under reduced pressure. The crude product 1,6,7,12-tetraazatricyclo[7.3.0.0^{3,7}]dodeca-3,5,9,11-tetraene-2,8-dione (2.3 g) was used directly in the next step without further purification.

[0734] At -10 °C, NaHMDS (2 mol / L, 30.56 mL, 61.12 mmol, 5.00 eq) was added dropwise 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 eq) and 3-bromo-2,6-difluoroaniline (5.09 g, 24.45 mmol, 2.00 eq) in THF (100 mL). 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 CH 3 COOH. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in H 2 O (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give N-(3-bromo-2,6-difluorophenyl)-2H-pyrazole-3-carboxamide (6 g, 74.4%). LC-MS: (ES + H, m / z): [M + H] + = 301.9. 1 H NMR (300 MHz, DMSO-d 6 ) δ 13.49 (s, 1H), 10.01 (s, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.78 - 7.66 (m, 1H), 7.25 (td, J = 9.1, 1.9 Hz, 1H), 6.77 (d, J = 2.2 Hz, 1H). 19 F NMR (282 MHz, DMSO-d 6 ) δ -109.45, -117.16.

[0735] Step 3: Preparation of 7-bromo-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one :

[0736] At room temperature under a nitrogen atmosphere, NaH (1.15 g, 28.80 mmol, 1.50 equiv, 60%) was added 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). The resulting mixture was stirred overnight at 120 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reaction mixture 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 Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO (20 mL). The residue was purified by reverse-phase flash chromatography to give 7-bromo-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one (1.5 g, 26.3%). LC-MS: (ES + H, m / z): [M + H] + = 281.9. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.14 (s, 1H), 8.13 (s, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.21 (s, 1H).

[0737] Step 4: Preparation of 6-fluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin-4-one :

[0738] At room temperature under a nitrogen atmosphere, the second-generation XPhos precatalyst (279 mg, 0.35 mmol, 0.10 equiv) was added 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). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was filtered and the 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 (300 MHz, DMSO-d 6) δ 11.95 (s, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 8.5, 1.4 Hz, 1H), 7.38 (dd, J = 8.5, 7.0 Hz, 1H), 7.19 (d, J = 2.1 Hz, 1H), 5.42 (t, J = 5.8 Hz, 1H), 4.63 (dd, J = 5.8, 1.5 Hz, 2H).

[0739] Step 5: Preparation of 7-(chloromethyl)-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one :

[0740] At room temperature, to a stirred solution of 6-fluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin-4-one (300 mg, 1.28 mmol, 1.00 equiv) in DCM (8 mL) was added dropwise SOCl 2 (765 mg, 6.43 mmol, 5.00 equiv) and DMF (5 mg, 0.07 mmol, 0.05 equiv). 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

[0741] 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 :

[0742] At room temperature under a nitrogen atmosphere, 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) were added KI (15 mg, 0.09 mmol, 0.20 equiv) and DIEA (246 mg, 1.90 mmol, 4.00 equiv). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-{[(2R,3S)-1-({6-fluoro-4-oxo-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. 11H NMR (300 MHz, DMSO-d 6 ) δ 11.97 (s, 1H), 8.57 (d, J = 5.0 Hz, 1H), 8.23 (d, J = 2.8 Hz, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.99 - 7.88 (m, 2H), 7.43 (dd, J = 8.7, 2.9 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.20 (d, J = 2.1 Hz, 1H), 4.59 (d, J = 5.9 Hz, 1H), 3.91 (d, J = 13.2 Hz, 1H), 3.83 (t, J = 6.3 Hz, 1H), 3.69 (d, J = 13.3 Hz, 1H), 3.41 - 3.38 (m, 1H), 2.85 - 2.75 (m, 4H), 1.22 (d, J = 6.1 Hz, 3H). 19 19F NMR (282 MHz, DMSO-d 6 ) δ -131.63.

[0743] The following examples were carried out using a similar procedure as shown for Example 113:

[0744]

[0745] Example 115

[0746]

[0747] Step 1: Preparation of methyl 3-amino-2-fluoro-4-iodobenzoate :

[0748] At room temperature under a nitrogen atmosphere, 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 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 Na 2 2 4 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase combi-flash chromatography to give methyl 3-amino-2-fluoro-4-iodobenzoate (4.00 g, 11.4%). LC-MS: (ES + H, m / z): [M + H] + = 295.80. 1 1H NMR (300 MHz, DMSO-d 6) δ 7.52 (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).

[0749] Step 2: Preparation of methyl 2-fluoro-3-(furan-3-carboxamido)-4-iodobenzoate :

[0750] At room temperature, methyl 3-amino-2-fluoro-4-iodobenzoat...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: Wherein: R 1 is hydrogen, deuterium, a halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 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 deuterated alkyl, 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 group; each optionally substituted by one or more R groups; 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 deuterated alkyl, 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 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl; R 6 is hydrogen, deuterium, a halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 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, fluorine, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -deuterioalkyl, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 -aminoalkyl or C 1 -C 6 -heteroalkyl; or two Rs 7 together form a cycloalkyl or heterocycloalkyl; each is optionally substituted with one or more Rs; n is 1 or 2; Each R 8 is independently deuterium, a 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 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl; or two Rs on the same carbon 8 together form an oxo group; or two Rs on the same carbon or adjacent carbons 8 together form a cycloalkyl or heterocycloalkyl; each is optionally substituted with one or more Rs; p is 0 - 4; W is absent, is -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 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl; or two Rs 9 together form a cycloalkyl or heterocycloalkyl; each is optionally substituted by one or more Rs; R W is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Each R 10 is independently deuterium, a 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 , -NR c C(=O)NR d R b , -NR a C(=O)R b , -NR b C(=O)OR b , -NR 2 S(=O) a R a , -C(=O)R b , -C(=O)OR c , -C(=O)NR d R 1 , -C 6 , alkyl, C 1 , -C 6 , haloalkyl, C 1 , -C 6 , deuterated alkyl, 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 - 4; Each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, 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 by one or more R; Each R b is independently hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -deuterioalkyl, 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 by one or more R; Each R c and R d are independently hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -deuterated alkyl, 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 by one or more R; or R c and R d together with the atoms to which they are attached form a heterocycloalkyl group, optionally substituted with one or more R; and Each R is independently deuterium, a 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 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl; Or two R on the same atom form an oxo group; Provided that the compound of formula (I) is not 2. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 1 is hydrogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl or cycloalkyl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 1 is C 1 -C 6 alkyl or cycloalkyl.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 1 is C 1 alkyl or C 3 -C 6 alkyl.

5. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 1 is a cycloalkyl group.

6. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 1 is methyl or ethyl.

7. A compound according to any one of claims 1 - 3 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 1 is ethyl.

8. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 1 is a halogen.

9. The compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof according to any one of claims 1 - 8, wherein X is N.

10. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof according to any one of claims 1-8, wherein X is CR 2 .

Images