Cannabinoid receptor type 2 (CB2) modulators and their use

Abstract

To provide cannabinoid receptor type 2 (CB2) modulators and their uses. [Solution] The compound of formula (I) and methods for modulating cannabinoid receptor 2 (CB2) with the compounds and compositions disclosed herein are disclosed herein. Methods for treating diseases or conditions that are mediated by or benefit from the modulation of cannabinoid receptor 2 (CB2) are also described herein. JPEG2026063050000586.jpg3760

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 020,489, filed on 5 May 2020, and U.S. Provisional Application No. 63 / 054,096, filed on 20 July 2020, which are each incorporated herein by whole by reference.

[0002] Compounds, methods for producing such compounds, pharmaceutical compositions and drugs comprising such compounds, and methods for using such compounds to treat conditions, diseases, or disorders for which benefits may be obtained from the reduction or inhibition of cannabinoid receptor CB2 activity are described herein. [Background technology]

[0003] The cannabinoid CB2 receptor (CB2R) modulates the immune response during inflammatory processes within the tumor microenvironment. Endogenous and exogenous cannabinoids exert immunosuppressive properties in various ways, including induction of apoptosis of T cells, NK cells, and B cells; inhibition of T cell, NK cell, and B cell proliferation; inhibition of immunostimulatory cytokine and chemokine production; and induction of immunosuppressive cytokine production and regulatory T cells. Therefore, CB2R antagonism should restore the function of T cells, NK cells, and B cells and alleviate innate and adaptive immunosuppression caused by endogenous cannabinoids. The development of CB2 receptor antagonists represents a novel approach to treating cancer by enhancing the anti-tumor immune response. [Overview of the project] [Means for solving the problem]

[0004] The compounds described in this specification are CB2 receptor (CB2R) modulators, including their pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates. In some embodiments, the CB2R modulator is a CB2R antagonist. In some embodiments, the CB2R modulator is a CB2R inverse agonist.

[0005] In one aspect, it is a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,

Chemical Structure

[0006] In another embodiment, a compound having the structure of formula (X), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, [ka] During the ceremony, R 1 However, hydrogen, -OH, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 deuteroalkyl, C1-C4 deuteroalkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 heteroalkyl, C3-C6 cycloalkyl, one N atom and 0 or one O or k is a C3-C6 heterocycloalkyl group containing an S atom, or a C3-C6 heterocycloalkyl group containing 0 or 1 N atom and 1 O or S atom. L 1 However, it either does not exist, or it is a C1-C4 alkylene or a C3-C5 cycloalkylene. R 2 However, either it is not substituted, or it contains 1, 2, 3, or 4 Rs. a Ring A is substituted with, Ring A is a C3-C6 heterocycloalkyl containing 1-2 N atoms and 0 or 1 O or S atom, a C3-C6 heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom, phenyl, C3-C 10 It is a cycloalkyl, a 5-membered heteroaryl, or a 6-membered heteroaryl. Each R a However, independently, halogen, -CN, -OH, -OR 12 , -SR 12 -S(=O)R 12 -S(=O)2R 12 -S(=O)2N(R 13 )2, -NR 13S(=O)2R 12 , -N(R 13 )2, -OC(=O)(R 12 ), -CO2R 13 -C(=O)N(R 13 )2, -NR 13 C(=O)(R 12 ), -NR 13 C(=O)O(R 12 ), -OC(=O)N(R 13 )2, -NR 13 C(=O)N(R 13 )2. Selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, or substituted or unsubstituted monocyclic C3-C6 heterocycloalkyl, R 3 However, it is H or C1-C4 alkyl, R 4 but, [ka] And u is 1 or 2, and v is 1 or 2, Or R 4 However, -L 2 -R 5 And, L 2 However, it does not exist, or -CR 10 R 11 -and, R 10 However, it is -CH3, R 11 However, is it H or -CH3? Or R 10 and R 11 However, together with the carbon atoms to which they are bonded, they form cyclopropyl-1,1-diyl, R 5 However, either it is not substituted, or it contains 1, 2, 3, or 4 Rs. b Ring B is substituted with, Ring B is bridged C5-C 12 It is a cycloalkyl, phenyl, naphthyl, or heteroaryl compound. Each R b However, independently, halogen, -CN, -OH, -N(R) 13 )2, -OC(=O)(R 12 ), -CO2R 13 -C(=O)N(R 13 )2, -NR 13 C(=O)(R 12 ), -NR 15 C(=O)O(R 12 ), -OC(=O)N(R 13 )2, -NR 13 C(=O)N(R 13 )2. Selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 deuteroalkyl, C1-C4 deuteroalkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 heteroalkyl, or substituted or unsubstituted monocyclic C3-C6 heterocycloalkyl, Or two R atoms bonded to the same carbon atom b However, together with carbon atoms, they form C3-C6 cycloalkyl or C3-C6 heterocycloalkyl groups. R 6 However, either it is not substituted, or it contains 1, 2, 3, or 4 Rs. c It is a ring C that is substituted with, The C ring is phenyl, naphthyl, heteroaryl, C3-C 12 Cycloalkyl, or C2-C 10 Is it heterocycloalkyl? Or R 6 However, hydrogen, halogen, -CN, -OH, -OR 12 , -SR 12 , -S( =O)R 12 -S(=O)2R 12 -S(=O)2N(R 13 )2, -NR 13 S(=O)2R 12 , -N(R 13 )2, -OC(=O)(R 12 ), -CO2R 13 -C(=O)N(R 13 )2, -NR15 C(=O)(R 12 ), -NR 13 C(=O)O(R 12 ), -OC(=O)N(R 13 )2, -NR 13 C(=O)N(R 13 )2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, or substituted or unsubstituted monocyclic C3-C6 heterocycloalkyl, Each R c However, independently, halogen, -CN, -OH, -OR 12 , -SR 12 -S(=O)R 12 -S(=O)2R 12 -S(=O)2N(R 13 )2, -NR 13 S(=O)2R 12 , -N(R 13 )2, -OC(=O)(R 12 ), -CO2R 13 -C(=O)N(R 13 )2, -NR 13 C(=O)(R 12 ), -NR 13 C(=O)O(R 12 ), -OC(=O)N(R 13 )2, -NR 13 C(=O)N(R 13 )2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, or a 1,4-dioxanyl ring condensed to ring C, R 7 However, H, halogen, -CN, -OH, -N(R 13)2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 deuteroalkyl, C1-C4 deuteroalkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, or C1-C4 heteroalkyl, X 1 However, N is X 2 However, CR 8 or N Or X 1 However, CR 8 or N, X 2 However, N is, R 8 However, H, halogen, -CN, -OH, -N(R 13 )2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 deuteroalkyl, C1-C4 deuteroalkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, or C1-C4 heteroalkyl, Each R 12 However, independently selected from the group consisting of C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl, Each R 13 However, independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl, However, R 1 When H, R 4 Compounds other than cyclohexyls substituted with 0, 1, 2, 3, or 4 methyl groups, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are described herein.

[0007] In another embodiment, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient is described herein.

[0008] In some embodiments, the pharmaceutical composition is formulated for administration to mammals by oral, intravenous, or subcutaneous administration.

[0009] In some embodiments, the pharmaceutical composition is in the form of tablets, pills, capsules, liquids, suspensions, dispersants, solutions, or emulsions.

[0010] In another embodiment, a method for regulating the activity of cannabinoid 2 receptors (CB2Rs) in a mammal is described herein, comprising administering to the mammal a compound described herein, or any pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0011] In another embodiment, a method for treating a disease or disorder in a mammal mediated by the action of a cannabinoid 2 receptor (CB2R) is described herein, comprising administering to the mammal a compound described herein, or any pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0012] In another embodiment, a method for treating cancer in a mammal, comprising administering a selective cannabinoid 2 receptor (CB2R) modulator to the mammal, is described herein. In some embodiments, the selective cannabinoid 2 receptor (CB2R) modulator is a selective cannabinoid 2 receptor (CB2R) antagonist. In some embodiments, the selective cannabinoid 2 receptor (CB2R) modulator is a selective cannabinoid 2 receptor (CB2R) inverse agonist. In some embodiments, the selective cannabinoid 2 receptor (CB2R) modulator is a compound of formula (I) or formula (X), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0013] In another embodiment, a method for treating cancer in a mammal is described herein, comprising administering to a mammal a compound of formula (I) or formula (X) or any of the formulas described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is bladder cancer, colon cancer, brain tumor, breast cancer, endometrial cancer, cardiac tumor, kidney cancer, lung cancer, liver cancer, uterine cancer, blood and lymphoid tumor, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, or skin cancer. In some embodiments, the cancer is prostate cancer, breast cancer, colon cancer, or lung cancer. In some embodiments, the cancer is a sarcoma, carcinoma, or lymphoma.

[0014] In some embodiments, the method further includes administering at least one additional therapy to a mammal.

[0015] In some embodiments, the mammal is a human.

[0016] In any of the embodiments described herein, an effective amount of the compound or a pharmaceutically acceptable salt thereof is administered (a) systemically to a mammal and / or (b) orally to a mammal and / or (c) intravenously to a mammal and / or (d) by injection to a mammal.

[0017] In any of the embodiments described above, the compound is administered to a mammal once daily, or further embodiments include a single effective dose of the compound, in which the compound is administered to a mammal multiple times over a day. In some embodiments, the compound is administered in a continuous dosing schedule. In some embodiments, the compound is administered in a continuous daily dosing schedule.

[0018] A manufactured article is provided, comprising packaging material, a formulation contained within the packaging material (for example, a formulation suitable for topical administration), and a label indicating that the compound or composition, or a pharmaceutically acceptable salt or solvate thereof, is used to modulate CB2 activity, or to treat, prevent, or improve one or more symptoms of a disease or disorder associated with or potentially benefiting from CB2 activity.

[0019] Other purposes, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples are provided for illustrative purposes only, although they illustrate specific embodiments, for various changes and modifications within the spirit and scope of this disclosure will become apparent to those skilled in the art from this detailed description. [Modes for carrying out the invention]

[0020] Cannabinoids are a group of compounds found in the marijuana plant. Marijuana has been used for both recreational and medicinal purposes for centuries. Cannabinoids have been shown to be effective in treating nausea and vomiting associated with cancer chemotherapy, anorexia and cachexia seen in HIV / AIDS patients, and neuropathic pain and spasticity in multiple sclerosis. More recently, the anti-inflammatory properties of cannabinoids have attracted considerable attention. Research on marijuana cannabinoids has led to the discovery of cannabinoid CB1 and CB2 receptors (CB1R and CB2R), as well as their endogenous ligands, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), which constitute what is known as the endogenous cannabinoid system. Both CB1R and CB2R are heterotrimers G i / o These are protein-coupled receptors. CB1R is mainly expressed in the central nervous system (CNS), while CB2R is mainly expressed in immune cells (B cells > natural killer cells > monocytes > neutrophils > CD8 leukocytes > CD4 leukocytes).

[0021] The mechanisms of immunosuppression by endogenous and exogenous cannabinoids have been investigated in both in vitro and in vivo studies. CB2 receptors modulate immune responses in inflammatory processes, and their immunosuppressive effects have been studied in numerous disease models, including allogeneic mouse tumors, multiple sclerosis, diabetes mellitus, septic shock, rheumatoid arthritis, and allergic asthma. Studies in these disease models, along with numerous in vitro experiments, have shown that endogenous and exogenous cannabinoids exert their immunosuppressive properties in four main ways: (1) induction of apoptosis of T, NK, and B cells; (2) inhibition of T, NK, and B cell proliferation; (3) inhibition of immunostimulatory cytokine and chemokine production (e.g., GM-CSF, IL2, IL8, IL12, IFNγ, TNFα); and (4) induction of immunosuppressive cytokine production (e.g., IL10, TGFβ1) and regulatory T cells. In addition, cannabis users exhibit decreased NK cell counts, reduced lymphocyte proliferation responses to inflammatory stimuli, and lower levels of IL-2. Conversely, cannabis users also show increased levels of the immunosuppressive cytokines IL-10 and TGFβ1. Furthermore, retrospective analysis of clinical data revealed that cannabis use during cancer immunotherapy significantly reduced the anti-PD-1 nivolumab response in patients with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma. In the tumor microenvironment, CB2R expression is elevated because both cancer cells and immune cells produce the endogenous cannabinoids AEA and 2-AG. Therefore, CB2R antagonism should restore the function of T cells, NK cells, and B cells, mitigating innate and adaptive immunosuppression caused by endogenous cannabinoids. The development of CB2 receptor antagonists represents a novel approach to treating cancer by enhancing the anti-tumor immune response.

[0022] cancer In some embodiments, methods for treating cancer using the CB2 modulator described herein, or a pharmaceutically acceptable salt or solvate thereof, are disclosed herein.

[0023] As used herein, the term “cancer” refers to the abnormal growth of cells that tend to grow uncontrollably and, in some cases, metastasize (spread). Types of cancer include solid tumors (bladder, intestine, brain, breast, endometrium, heart) at any stage, with or without metastasis. This includes, but is not limited to, the organs, kidneys, lungs, liver, uterus, lymphoid tissue (lymphoma), ovaries, pancreas or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma), or hematological malignancies (leukemia and lymphoma).

[0024] In some embodiments, the mammal treated with the compounds described herein has cancer or a tumor, or a disease or disorder associated therewith. For this reason, in some embodiments, the mammal is a human who is a tumor patient. Such diseases and disorders, as well as cancer, include carcinomas, sarcomas, benign tumors, primary tumors, tumor metastases, solid tumors, non-solid tumors, hematological malignancies, leukemias and lymphomas, and primary and metastatic tumors.

[0025] In some embodiments, the CB2 receptor modulators described herein are used to treat solid tumors. Solid tumors are abnormal tissue masses that typically do not contain cysts or fluid areas. Solid tumors can be benign (not cancerous) or malignant (cancerous). Different types of solid tumors are named after the types of cells that form them. Examples of solid tumors include carcinomas, sarcomas, and lymphomas.

[0026] Carcinomas include, but are not limited to, esophageal cancer, hepatocellular carcinoma, basal cell carcinoma, squamous cell carcinoma, bladder cancer, bronchogenic lung cancer, colon cancer, colorectal cancer, gastric cancer, lung cancer including small cell and non-small cell lung cancer, adrenocortical carcinoma, thyroid cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, adenocarcinoma, renal cell carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, osteogenic carcinoma, epithelial carcinoma, and nasopharyngeal carcinoma.

[0027] Sarcomas include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, chordoma, osteogenic sarcoma, osteosarcoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangiosarcoma, synoviomas, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, and other soft tissue sarcomas.

[0028] Leukemia includes, but is not limited to, a) chronic myeloproliferative syndrome (a neoplastic disease of pluripotent hematopoietic stem cells), b) acute myeloid leukemia, c) chronic lymphocytic leukemia (CLL), including B-cell CLL, T-cell prelymphoblastic leukemia, and hairy cell leukemia, and d) acute lymphoblastic leukemia (characterized by the accumulation of lymphoblasts). Lymphoma includes, but is not limited to, B-cell lymphoma (e.g., Burkitt lymphoma) and Hodgkin lymphoma.

[0029] Benign tumors include, for example, hemangiomas, hepatocellular adenomas, cavernous hemangiomas, focal nodular hyperplasia, acoustic neuromas, neurofibromas, cholangioadenomas, cholangiocystomas, fibromas, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia, trachomas, and pyogenic granulomas.

[0030] Primary and metastatic tumors include, for example, lung cancer, breast cancer, colorectal cancer, anal cancer, pancreatic cancer, prostate cancer, ovarian cancer, hepatic and bile duct cancer, esophageal cancer, bladder cancer, uterine cancer, glioma, glioblastoma, medulloblastoma, and other brain tumors, kidney cancer, head and neck cancer, stomach cancer, multiple myeloma, testicular cancer, germ cell tumors, neuroendocrine tumors, cervical cancer, carcinoid tumors of the gastrointestinal tract, breast, and other organs.

[0031] In one embodiment, the CB2R modifiers described herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, reduce, improve, or inhibit cancer-associated immunosuppression and cell proliferation.

[0032] compound The compounds described herein include their pharmaceutically acceptable salts, prodrugs, and active metabolites. These, including their solvates, are CB2 receptor (CB2R) modulators. In some embodiments, the CB2R modulator is a CB2R antagonist. In some embodiments, the CB2R modulator is a CB2R inverse agonist.

[0033] In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, [ka] During the ceremony, R 1 However, -OH, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 deuteroalkyl, C1-C4 deuteroalkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl containing 1-2 N atoms and 0 or 1 O or S atom, or C3-C6 heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom. L 1 However, it either does not exist, or it is a C1-C4 alkylene or a C3-C5 cycloalkylene. R 2 However, either it is not substituted, or it contains 1, 2, 3, or 4 Rs. a Ring A is substituted with, Ring A is a C3-C6 heterocycloalkyl containing 1-2 N atoms and 0 or 1 O or S atom, a C3-C6 heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom, phenyl, C3-C 10 It is a cycloalkyl, a 5-membered heteroaryl, or a 6-membered heteroaryl. Each R a However, independently, halogen, -CN, -OH, -OR 12 , -SR 12 -S(=O)R 12 -S(=O)2R 12 -S(=O)2N(R 13 )2, -NR 13S(=O)2R 12 , -N(R 13 )2, -OC(=O)(R 12 ), -CO2R 13 -C(=O)N(R 12 )2, -NR 13 C(=O)(R 12 ), -NR 13 C(=O)O(R 12 ), -OC(=O)N(R 13 )2, -NR 13 C(=O)N(R 13 )2. Selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, or substituted or unsubstituted monocyclic C3-C6 heterocycloalkyl, R 3 However, it is H or C1-C4 alkyl, R 4 However, -L 2 -R 5 And, L 2 However, it does not exist, or -CR 10 R 11 -and, R 5 However, either it is not substituted, or it contains 1, 2, 3, or 4 Rs. b Ring B is substituted with, Ring B is C3-C 12 Cycloalkyl, C2-C 10 It is a heterocycloalkyl, phenyl, naphthyl, or heteroaryl compound. Each R b However, independently, halogen, -CN, -OH, -N(R) 13 )2, -OC(=O)(R 12 ), -CO2R 13 -C(=O)N(R 13 )2, -NR 13 C(=O)(R 12 ), -NR 13 C(=O)O(R 12 ), -OC(=O)N(R 13 )2, -NR 13 C(=O)N(R 13)2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 deuteroalkyl, C1-C4 du Selected from the group consisting of tetraalkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 heteroalkyl, or substituted or unsubstituted monocyclic C3-C6 heterocycloalkyl, Or two R atoms bonded to the same carbon atom b However, together with carbon atoms, they form C3-C6 cycloalkyl or C3-C6 heterocycloalkyl groups. R 10 and R 11 However, independently, it is selected from H or -CH3, Or R 10 and R 11 However, together with the carbon atoms to which they are bonded, they form a C3-C6 cycloalkyl group. R 6 However, either it is not substituted, or it contains 1, 2, 3, or 4 Rs. c It is a ring C that is substituted with, The C ring is phenyl, naphthyl, heteroaryl, C3-C 12 Cycloalkyl, or C2-C 10 Is it heterocycloalkyl? Or R 6 However, hydrogen, halogen, -CN, -OH, -OR 12 , -SR 12 -S(=O)R 12 -S(=O)2R 12 -S(=O)2N(R 13 )2, -NR 13 S(=O)2R 12 , -N(R 13 )2, -OC(=O)(R 12 ), -CO2R 13 -C(=O)N(R 13 )2, -NR 13 C(=O)(R 12 ), -NR 13 C(=O)O(R 12 ), -OC(=O)N(R 13 )2, -NR 13C(=O)N(R 13 )2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, or substituted or unsubstituted monocyclic C3-C6 heterocycloalkyl, Each R c However, independently, halogen, -CN, -OH, -OR 12 , -SR 12 -S(=O)R 12 -S(=O)2R 12 -S(=O)2N(R 13 )2, -NR 13 S(=O)2R 12 , -N(R 13 )2, -OC(=O)(R 12 ), -CO2R 13 -C(=O)N(R 13 )2, -NR 13 C(=O)(R 12 ), -NR 13 C(=O)O(R 12 ), -OC(=O)N(R 13 )2, -NR 13 C(=O)N(R 13 )2. Selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, or a 1,4-dioxanyl ring condensed to ring C, R 7 However, H, halogen, -CN, -OH, -N(R 13 )2, C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 deuteroalkyl, C1-C4 deuteroalkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, or C1-C4 heteroalkyl or C3-C6 heterocycloalkyl, X 1 However, N is X2 However, CR 8 or N Or X 1 However, CR 8 or N, X 2 However, N is, R 8 However, H, halogen, -CN, -OH, -N(R 13 )2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 deuteroalkyl, C1-C4 deuteroalkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C3-C6 cycloalkyl, C1-C4 heteroalkyl, or C3-C6 heterocycloalkyl, Each R 12 However, independently selected from the group consisting of C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl, Each R 13 However, independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl Compounds, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are described herein.

[0034] In some embodiments of equation (I), R 6 When H, R 4 is cyclohexyl, 4-methylcyclohexyl, or cycloheptyl. In some embodiments, R 6 H is R 4 It is cis-4-methylcyclohexyl.

[0035] In some embodiments, R3 is H or -CH3, and L 1 It is either absent, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, or cyclopropyl-1,1-diyl, R 10 and R 11 This is independently selected from H or -CH3, or R 10 and R 11 These, together with the carbon atoms to which they are bonded, form cyclopropyl-1,1-diyl, X 1 is N, and X 2 CR 8 is or X 1 CR 8 X 2 It is N.

[0036] In some embodiments, R 1 is -OH, -CH3, -OCH3, -CD3, -OCD3, -CFH2, -CHF2, -CF3, -OCFH2, -OCHF2, -OCF3, cyclopropyl, azilidinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperadinyl, or piperidinyl. In some embodiments, R 1 These are -OH, -CH3, -OCH3, -OC(CH3)2, -CD3, -OCD3, -CFH2, -CHF2, -CF3, -OCFH2, -OCHF2, -OCF3, cyclopropyl, azilidinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperadinyl, or piperidinyl.

[0037] In some embodiments, R 1 is -OH or -CH3. In some embodiments, R 1 It is an -O-C1-C3 alkyl group.

[0038] In some embodiments, the compound of formula (I) has the following structure of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [ka] In the formula, L 1 , R 2 , R 4 , R 6 , and R 7 This is defined in some or any embodiment of formula (I).

[0039] In some embodiments, R 5 is either not substituted, or has 1, 2, 3, or 4 R's. b Ring B is a substituted ring, and ring B is either a monocyclic C3-C8 cycloalkyl or a condensed bicyclic C5-C 12 Cycloalkyl, cross-linked bicyclic C5-C 12 Cycloalkyl or spironicyclic C5-C 12 Cycloalkyl bicyclic C5-C 12 It is a cycloalkyl group, or ring B is a monocyclic C2-C6 heterocycloalkyl group, or a condensed bicyclic C5-C8 heterocycloalkyl group, a cross-linked bicyclic C5-C8 heterocycloalkyl group, or a bicyclic C5-C8 heterocycloalkyl group that is a spiro-bicyclic C5-C8 heterocycloalkyl group, or ring B is phenyl, or ring B is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetra It is a monocyclic heteroaryl selected from torazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, and triazinyl.

[0040] In some embodiments, L 2 It does not exist, R 5 is either not substituted, or has 1, 2, 3, or 4 R's. b Ring B is a substituted ring, and ring B is either a monocyclic C3-C8 cycloalkyl or a condensed bicyclic C5-C 12 Cycloalkyl, cross-linked bicyclic C5-C 12 Cycloalkyl or spironicyclic C5-C 12 Cycloalkyl bicyclic C5-C12 The ring B is either a cycloalkyl group or a bicyclic C5-C8 heterocycloalkyl group which is a monocyclic C3-C6 heterocycloalkyl group, a condensed bicyclic C5-C8 heterocycloalkyl group, a bridged bicyclic C5-C8 heterocycloalkyl group, or a spiro-bicyclic C5-C8 heterocycloalkyl group.

[0041] In some embodiments, L 2 It does not exist, R 5 is either not substituted, or has 1, 2, 3, or 4 R's. b A bicyclic C5-C molecule where ring B is substituted with cyclobutyl, cyclopentyl, or cyclohexyl, or where ring B is spiro[2.2]pentanyl, spiro[3.3]heptanyl, spiro[4.3]octanyl, spiro[3.4]octanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[4.5]decanyl, spiro[5.4]decanyl, spiro[5.5]undecanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.1]heptanyl, adamantyl, or dekalinyl. 12 It is a cycloalkyl group.

[0042] In some embodiments, L 2 It does not exist, R 5 is either not substituted, or has 1, 2, 3, or 4 R's. b Ring B is substituted with cyclobutyl, cyclopentyl, or cyclohexyl, or ring B is spiro[3.3]heptanyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl.

[0043] In some embodiments, L 2 It does not exist, R 5 is either not substituted, or has 1, 2, 3, or 4 R's. b Ring B is a ring that is substituted with, and ring B is [ka] Either ring B is, [ka] That is the case.

[0044] In some embodiments, R 4 teeth, [ka] That is the case.

[0045] Several embodiments, each R b R is independently selected from the group consisting of F, Cl, Br, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -CH3, -OCH3, -CD3, -OCD3, -CFH2, -CHF2, -CF3, -OCFH2, -OCHF2, and -OCF3, or two R bonded to the same carbon atom. b It combines with its carbon atom to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, thiomorpholinyl, or piperidinyl.

[0046] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth [ka] In some embodiments, R 4 teeth [ka] In some embodiments, R 4 teeth [ka] That is the case.

[0047] In some embodiments, for any formula described herein, R 4 teeth, [ka] That is the case.

[0048] In some embodiments, for any formula described herein, R 4 teeth, [ka] That is the case.

[0049] In some embodiments, for any formula described herein, R 4 teeth, [ka] Selected from bridged C5-C 12 It is a cycloalkyl group.

[0050] In some embodiments, L 2 It does not exist, or -CR 10 R 11 - and R 10 and R 11 This is independently selected from H or -CH3, or R 10 and R 11 Together with the carbon atoms to which they are bonded, cyclopropyl-1,1-di Forming a circle, R 5 is either not substituted, or has 1, 2, 3, or 4 R's. b Ring B is substituted with a phenyl compound or a monocyclic heteroaryl compound.

[0051] In some embodiments, ring B is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridadinyl.

[0052] In some embodiments, L 2It does not exist, or -CR 10 R 11 - and R 10 and R 11 This is independently selected from H or -CH3, or R 10 and R 11 These, together with the carbon atoms to which they are bonded, form cyclopropyl-1,1-diyl, R 5 teeth, [ka] And m is 0, 1, or 2.

[0053] Several embodiments, each R b The following are independently selected from the group consisting of F, Cl, Br, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -CH3, -OCH3, -CD3, -OCD3, -CFH2, -CHF2, -CF3, -OCFH2, -OCHF2, and -OCF3.

[0054] In some embodiments, R 4 teeth [ka] And R 10 and R 11 This is independently selected from H or -CH3, or R 10 and R 11 These, together with the carbon atoms to which they are bonded, form cyclopropyl-1,1-diyl, where m is 0, 1, or 2, and each R b The following are independently selected from the group consisting of F, Cl, Br, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -CH3, -OCH3, -CD3, -OCD3, -CFH2, -CHF2, -CF3, -OCFH2, -OCHF2, and -OCF3.

[0055] In some embodiments, L 1 It is -CH2CH2- and R 2 is either not substituted, or has 1, 2, 3, or 4 R's.a Ring A is substituted with, and ring A is a C3-C6 heterocycloalkyl group containing 1-2 N atoms and 0 or 1 O or S atom, or a C4-C7 heterocycloalkyl group containing 0 or 1 N atom and 1 O or S atom, R 6 is either not substituted, or has 1, 2, 3, or 4 R's. c The ring C is substituted with phenyl, naphthyl, heteroaryl, and C3-C 12 It is a cycloalkyl or C3-C6 heterocycloalkyl group.

[0056] In some embodiments, L 1 It is -CH2CH2- and R 2 is either not substituted, or has 1, 2, 3, or 4 R's. a Ring A is substituted with azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, or piperazinyl. In some embodiments, for any of the formulas described herein, -L 1 -R 2 teeth, [ka] That is the case.

[0057] In some embodiments, the compound of formula (I) has the following structure of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [ka] In the formula, R 4 , R 6 , and R 7 This is defined in some or any embodiment of formula (I).

[0058] In some embodiments, R 6 is either not substituted, or has 1, 2, 3, or 4 R's. cThe ring C is substituted with phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, thiomorpholinyl, or piperidinyl.

[0059] In some embodiments, R 6 teeth, [ka] And n is 0, 1, or 2.

[0060] Several embodiments, each R c These are independently F, Cl, Br, -CN, -OH, -OCH3, -OCD3, -OCFH2, -OCHF2, -OCF3, -O-cyclopropyl, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2N(CH3)2, -NHS(=O)2CH3, -NH2, -NH(CH3), -N(CH3)2, -OC(=O)CH3, -CO2H, -CO2CH3, -CO2CH2CH3, -C(=O)N(R 15 Selected from the group consisting of )2, -C(=O)-NH2, -C(=O)NH(CH3), -C(=O)N(CH3)2, -NHC(=O)CH3, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CD3, -CFH2, -CHF2, -CF3, -CH=CH2, -C(CH3)=CH2, -CH≡CH, -CH≡CCH3, cyclopropyl, or oxetanyl.

[0061] In some embodiments, for any formula described herein, R 6 teeth, [ka] In some such embodiments, R c is CN, CH3, F, O-C1-C3 alkyl, or O-C1-C3 haloalkyl. In some embodiments, R 6 teeth, [ka] In some embodiments, R 6 is not H. In some embodiments, R 6 teeth It's Hello.

[0062] In some embodiments, the compound of formula (I) has the following structure of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [ka] In the formula, R 2 , R 4 , R 6 , and R 7 This is defined in some or any embodiment of formula (I).

[0063] In some embodiments, L 1 is -CH2-, -CH(CH3)-, -C(CH3)2-, or cyclopropyl-1,1-diyl, R 2 is either not substituted, or has 1, 2, 3, or 4 R's. a Ring A is substituted with a phenyl compound or a 6-membered heteroaryl compound.

[0064] In some embodiments, R 2 teeth, [ka] And q is 0, 1, or 2.

[0065] In some embodiments, R 2 teeth, [ka] That is the case.

[0066] Several embodiments, each R aThese are independently F, Cl, Br, -CN, -OH, -OCH3, -OCD3, -OCFH2, -OCHF2, -OCF3, -O-cyclopropyl, -S(=O)2CH3, -NH2, -NH(CH3), -N(CH3)2, -CH3 Selected from the group consisting of -CH2CH3, -CH(CH3)2, -C(CH3)3, -CD3, -CFH2, -CHF2, -CF3, cyclopropyl, or oxetanyl.

[0067] In some embodiments, for any formula described herein, R 6 is H, F, Cl, Br, -CN, -OH, -OCH3, -OCD3, -OCFH2, -OCHF2, -OCF3, -O-cyclopropyl, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NH(CH3 ), -S(=O)2N(CH3)2, -NHS(=O)2CH3, -NH2, -NH(CH3), -N(CH3)2, -OC(=O)CH3, -CO2H, -CO2CH3, -CO2CH2CH3, -C(=O)N(R 15 )2, -C(=O)-NH2, -C(=O)NH(CH3), -C(=O)N(CH3)2, -NHC(=O)CH3, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CD3, -CFH2, -CHF2, -CF3, -CH=CH2, -C(CH3)=CH2, -CH≡CH, -CH≡CCH3, cyclopropyl, or oxetanyl.

[0068] In some embodiments, for any formula described herein, R 6 These are H, F, Cl, Br, -CN, -OH, -OCH3, -OCD3, -OCFH2, -OCHF2, -OCF3, -O-cyclopropyl, -S(=O)2CH3, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CD3, -CFH2, -CHF2, -CF3, -CH=CH2, -C(CH3)=CH2, cyclopropyl, or oxetanyl.

[0069] In another embodiment, a compound having the structure of formula (X), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, [ka] During the ceremony, R 1 However, it is hydrogen, -OH, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 deuteroalkyl, C1-C4 deuteroalkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 heteroalkyl, C3-C6 cycloalkyl, a C3-C6 heterocycloalkyl containing one N atom and 0 or 1 O or S atom, or a C3-C6 heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom. L 1 However, it either does not exist, or it is a C1-C4 alkylene or a C3-C5 cycloalkylene. R 2 However, either it is not substituted, or it contains 1, 2, 3, or 4 Rs. a Ring A is substituted with, Ring A is a C3-C6 heterocycloalkyl containing 1-2 N atoms and 0 or 1 O or S atom, a C3-C6 heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom, phenyl, C3-C 10 It is a cycloalkyl, a 5-membered heteroaryl, or a 6-membered heteroaryl. Each R a However, independently, halogen, -CN, -OH, -OR 12 , -SR 12 -S(=O)R 12 -S(=O)2R 12 -S(=O)2N(R 13 )2, -NR 13 S(=O)2R 12 , -N(R 13 )2, -OC(=O)(R 12 ), -CO2R 13 -C(=O)N(R 13 )2, -NR 13 C(=O)(R 12 ), -NR 13 C(=O)O( R 12), -OC(=O)N(R 13 )2, -NR 13 C(=O)N(R 13 )2. Selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, or substituted or unsubstituted monocyclic C3-C6 heterocycloalkyl, R 3 However, it is H or C1-C4 alkyl, R 4 but, [ka] And u is 1 or 2, and v is 1 or 2, Or R 4 However, -L 2 -R 5 And, L 2 However, it does not exist, or -CR 10 R 11 -and, R 10 However, it is -CH3, R 11 However, is it H or -CH3? Or R 10 and R 11 However, together with the carbon atoms to which they are bonded, they form cyclopropyl-1,1-diyl, R 5 However, either it is not substituted, or it contains 1, 2, 3, or 4 Rs. b Ring B is substituted with, Ring B is bridged C5-C 12 It is a cycloalkyl, phenyl, naphthyl, or heteroaryl compound. Each R b However, independently, halogen, -CN, -OH, -N(R) 13 )2, -OC(=O)(R 12 ), -CO2R 13 -C(=O)N(R 13 )2, -NR 13 C(=O)(R 12 ), -NR 15C(=O)O(R 12 ), -OC(=O)N(R 13 )2, -NR 13 C(=O)N(R 13 )2. Selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 deuteroalkyl, C1-C4 deuteroalkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 heteroalkyl, or substituted or unsubstituted monocyclic C3-C6 heterocycloalkyl, Or two R atoms bonded to the same carbon atom b However, together with carbon atoms, they form C3-C6 cycloalkyl or C3-C6 heterocycloalkyl groups. R 6 However, either it is not substituted, or it contains 1, 2, 3, or 4 Rs. c It is a ring C that is substituted with, The C ring is phenyl, naphthyl, heteroaryl, C3-C 12 Cycloalkyl, or C2-C 10 Is it heterocycloalkyl? Or R 6 However, hydrogen, halogen, -CN, -OH, -OR 12 , -SR 12 -S(=O)R 12 -S(=O)2R 12 -S(=O)2N(R 13 )2, -NR 13 S(=O)2R 12 , -N(R 13 )2, -OC(=O)(R 12 ), -CO2R 13 -C(=O)N(R 13 )2, -NR 15 C(=O)(R 12 ), -NR 13 C(=O)O(R 12 ), -OC(=O)N(R 13 )2, -NR 13 C(=O)N(R 13)2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, or substituted or unsubstituted monocyclic C3-C6 heterocycloalkyl, Each R c However, independently, halogen, -CN, -OH, -OR 12 , -SR 12 -S(=O)R 12 -S(=O)2R 12 -S(=O)2N(R 13 )2, -NR 13 S(=O)2R 12 , -N(R 13 )2, -OC(=O)(R 12 ), -CO2R 13 -C(=O)N(R 13 )2, -NR 13 C(=O)(R 12 ), -NR 13 C(=O)O(R 12 ), -OC(=O)N(R 13 )2, -NR 13 C(=O)N(R 13 )2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, substituted or unsubstituted A substituted C3-C6 cycloalkyl, a substituted or unsubstituted C3-C6 heterocycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted monocyclic heteroaryl, or a 1,4-dioxanyl ring condensed to ring C, R 7 However, H, halogen, -CN, -OH, -N(R 13 )2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 deuteroalkyl, C1-C4 deuteroalkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, or C1-C4 heteroalkyl, X 1 However, N is X 2 However, CR 8 or N Or X1 However, CR 8 or N, X 2 However, N is, R 8 However, H, halogen, -CN, -OH, -N(R 13 )2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 deuteroalkyl, C1-C4 deuteroalkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, or C1-C4 heteroalkyl, Each R 12 However, independently selected from the group consisting of C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl, Each R 13 Compounds selected independently from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof are described herein.

[0070] In some embodiments of equation (X), R 1 When H, R 4 This is not a cyclohexyl substituted with 0, 1, 2, 3, or 4 methyl groups. In some embodiments, the crosslinked cycloalkyl is a crosslinked bicyclic C5-C 12 It is a cycloalkyl group.

[0071] In some embodiments, R 3 is H or -CH3, and L 1It is either absent, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, or cyclopropyl-1,1-diyl, X 1 is N, and X 2 CR 8 is or X 1 CR 8 X 2 It is N.

[0072] In some embodiments, R 1 These are hydrogen, -OH, -CH3, -OCH3, -CD3, -OCD3, -CFH2, -CHF2, -CF3, -OCFH2, -OCHF2, -OCF3, cyclopropyl, azilidinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperadinyl, or piperidinyl.

[0073] In some embodiments, R 1 However, it is hydrogen, -OH, or -CH3.

[0074] In some embodiments, the compound of formula (X) has the following structure of formula (XI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [ka] In the formula, L 1 , R b u, v, R 1 , R 2 , R 4 , R 6 , and R 7 This is as defined in some or any embodiment of formula (X).

[0075] In some embodiments, [ka] teeth, [ka] That is the case.

[0076] In some embodiments, [ka] teeth [ka] That is the case.

[0077] Several embodiments, each R b R is independently selected from the group consisting of F, Cl, Br, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -CH3, -OCH3, -CD3, -OCD3, -CFH2, -CHF2, -CF3, -OCFH2, -OCHF2, and -OCF3, or two R bonded to the same carbon atom. b It combines with its carbon atom to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, thiomorpholinyl, or piperidinyl.

[0078] In some embodiments, [ka] teeth, [ka] That is the case.

[0079] In some embodiments, the compound of formula (X) has the following structure of formula (XII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [ka] Equation (XII) In the formula, X 1 , X 2 , L 1 , R 1 , R 2 , R 6 , and R 7This is as defined in some or any embodiment of formula (X), where n1, n2, and n3 are each independently 1, 2, or 3. R d Halogen, -CN, -OH, -N(R) 13 )2, -OC(=O)(R 12 ), -CO2R 13 -C(=O)N(R 13 )2, -NR 13 C(=O)(R 12 ), -NR 15 C(=O)O(R 12 ), -OC(=O)N(R 13 )2, -NR 13 C(=O)N(R 13 )2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 deuteroalkyl, C1-C4 deuteroalkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 heteroalkyl, or substituted or unsubstituted monocyclic C3-C6 heterocycloalkyl.

[0080] In some embodiments, the compound of formula (X) has the following structure of formula (XIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [ka] In the formula, L 1 , R 1 , R 2 , R 5 , R 6 , R 7 , R 10 , and R 11 This is as defined in some or any embodiment of formula (X).

[0081] In some embodiments, R 5 is either not substituted, or 1, 2, 3, or 4 Individual R b Ring B is substituted with a phenyl compound or a monocyclic heteroaryl compound.

[0082] In some embodiments, R 5 is either not substituted, or has 1, 2, 3, or 4 R's. b Ring B is substituted with phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.

[0083] In some embodiments, ring B is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridadinyl.

[0084] In some embodiments, R 5 teeth, [ka] And m is 0, 1, or 2.

[0085] Several embodiments, each R b The following are independently selected from the group consisting of F, Cl, Br, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -CH3, -OCH3, -CD3, -OCD3, -CFH2, -CHF2, -CF3, -OCFH2, -OCHF2, and -OCF3.

[0086] In some embodiments, L 1 It is -CH2CH2- and R 2 is either not substituted, or has 1, 2, 3, or 4 R's. a Ring A is substituted with, and ring A is a C3-C6 heterocycloalkyl group containing 1-2 N atoms and 0 or 1 O or S atom, or a C3-C6 heterocycloalkyl group containing 0 or 1 N atom and 1 O or S atom, R 6 is either not substituted, or has 1, 2, 3, or 4 R's. cThe ring C is substituted with phenyl, naphthyl, heteroaryl, and C3-C 12 Cycloalkyl, or C2-C 10 It is heterocycloalkyl.

[0087] In some embodiments, L 1 It is -CH2CH2- and R 2 is either not substituted, or has 1, 2, 3, or 4 R's. a Ring A is substituted with azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, or piperazinyl.

[0088] In some embodiments, the compound of formula (X) has the following structure of formula (XIA), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [ka] In the formula, R b u, v, R 1 , R 6 , and R 7 This is as defined in some or any embodiment of formula (X).

[0089] In some embodiments, the compound of formula (X) has the following structure of formula (XIIA), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [ka] In the formula, X 1 , X 2 , R 1 , R 6 , and R 7 This is as defined in some or any embodiment of formula (X), where n1, n2, and n3 are each independently 1, 2, or 3. R d Halogen, -CN, -OH, -N(R) 13 )2, -OC(=O)(R 12 ), -CO2R 13-C(=O)N(R 13 )2, -NR 13 C(=O)(R 12 ), -NR 15 C(=O)O(R 12 ), -OC(=O)N(R 13 )2, -NR 13 C(=O)N(R 13 )2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 deuteroalkyl, C1-C4 deuteroalkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 heteroalkyl, or substituted or unsubstituted monocyclic C3-C6 heterocycloalkyl.

[0090] In some embodiments, the compound of formula (X) has the following structure of formula (XIIIA), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [ka] In the formula, R 1 , R 5 , R 6 , R 7 , R 10 , and R 11 This is as defined in some or any embodiment of formula (X).

[0091] In some embodiments, R 6 is either not substituted, or has 1, 2, 3, or 4 R's. c The ring C is substituted with phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, thiomorpholinyl, or piperidinyl.

[0092] In some embodiments, R 6 teeth, [ka] And n is 0, 1, or 2.

[0093] Several embodiments, each R c These are independently F, Cl, Br, -CN, -OH, -OCH3, -OCD3, -OCFH2, -OCHF2, -OCF3, -O-cyclopropyl, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NH(CH3), -S(=O)2N(CH3)2, -NHS(=O)2CH3, -NH2, -NH(CH3), -N(CH3)2, -OC(=O)CH3, -CO2H, -CO2CH3, -CO2CH2CH3, -C(=O)N(R 15 Selected from the group consisting of )2, -C(=O)-NH2, -C(=O)NH(CH3), -C(=O)N(CH3)2, -NHC(=O)CH3, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CD3, -CFH2, -CHF2, -CF3, -CH=CH2, -C(CH3)=CH2, -CH≡CH, -CH≡CCH3, cyclopropyl, or oxetanyl.

[0094] In some embodiments, R 6 teeth, [ka] That is the case.

[0095] In some embodiments, L 1 is -CH2-, -CH(CH3)-, -C(CH3)2-, or cyclopropyl-1,1-diyl, R 2 is either not substituted, or has 1, 2, 3, or 4 R's. a Ring A is substituted with phenyl, C3-C 10 It is a cycloalkyl, a 5-membered heteroaryl, or a 6-membered heteroaryl.

[0096] In some embodiments, the compound of formula (X) has the following structure of formula (XI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [ka] In the formula, R b u, v, R 1 , R 2 , R 6 , and R 7 This is as defined in some or any embodiment of formula (X).

[0097] In some embodiments, the compound of formula (X) has the following structure of formula (XIIB), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [ka] In the formula, R 1 , R 2 , R 6 , and R 7 This is as defined in some or any embodiment of formula (X), where n1, n2, and n3 are each independently 1, 2, or 3. R d Halogen, -CN, -OH, -N(R) 13 )2, -OC(=O)(R 12 ), -CO2R 13 -C(=O)N(R 13 )2, -NR 13 C(=O)(R 12 ), -NR 15 C(=O)O(R 12 ), -OC(=O)N(R 13 )2, -NR 13 C(=O)N(R 13 )2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 deuteroalkyl, C1-C4 deuteroalkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 heteroalkyl, or substituted or unsubstituted monocyclic C3-C6 heterocycloalkyl.

[0098] In some embodiments, the compound of formula (X) has the following structure of formula (XII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [ka] In the formula, R 1 , R 5 , R 6 , R 7 , R 10 , and R 11 This is as defined in some or any embodiment of formula (X).

[0099] In some embodiments, R 2 teeth, [ka] And q is 0, 1, or 2.

[0100] In some embodiments, R 2 teeth, [ka] That is the case.

[0101] Several embodiments, each R a The following are independently selected from the group consisting of F, Cl, Br, -CN, -OH, -OCH3, -OCD3, -OCFH2, -OCHF2, -OCF3, -O-cyclopropyl, -S(=O)2CH3, -NH2, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CD3, -CFH2, -CHF2, -CF3, cyclopropyl, or oxetanyl.

[0102] In some embodiments, for any formula described herein, R 6 H, F, Cl, Br, -CN, -OH, -OCH3, -OCD3, -OCFH2, -OCHF2, -OCF3, -O-cyclopropyl, -S(=O)2CH3, -S(=O)2NH2, -S( =O)2NH(CH3), -S(=O)2N(CH3)2, -NHS(=O)2CH3, -NH2, -NH(CH3), -N(CH3)2, -OC(=O)CH3, -CO2H, -CO2CH3, -CO2CH2CH3, -C(=O)N(R 15 )2, -C(=O)-NH2, -C(=O)NH(CH3), -C(=O)N(CH3)2, -NHC(=O)CH3, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CD3, -CFH2, -CHF2, -CF3, -CH=CH2, -C(CH3)=CH2, -CH≡CH, -CH≡CCH3, cyclopropyl, or oxetanyl.

[0103] In some embodiments, for any formula described herein, R 6 These are H, F, Cl, Br, -CN, -OH, -OCH3, -OCD3, -OCFH2, -OCHF2, -OCF3, -O-cyclopropyl, -S(=O)2CH3, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CD3, -CFH2, -CHF2, -CF3, -CH=CH2, -C(CH3)=CH2, cyclopropyl, or oxetanyl.

[0104] In some embodiments, for any formula described herein, R 6 is either not substituted, or has 1, 2, 3, or 4 R's. c It is a ring C that is substituted with, Ring C is phenyl, naphthyl, heteroaryl, C3-C 12 Cycloalkyl, or C2-C 10 Is it heterocycloalkyl? Or R 6 These are halogen, -CN, -OH, -OR 12 , -SR 12 -S(=O)R 12 -S(=O)2R 12 -S(=O)2N(R 13 )2, -NR 13 S(=O)2R 12 , -N(R 13 )2, -OC(=O)(R12 ), -CO2R 13 -C(=O)N(R 13 )2, -NR 13 C(=O)(R 12 ), -NR 13 C(=O)O(R 12 ), -OC(=O)N(R 13 )2, -NR 13 C(=O)N(R 13 )2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, or substituted or unsubstituted monocyclic C3-C6 heterocycloalkyl, Each R c These are, independently, halogen, -CN, -OH, and -OR 12 , -SR 12 -S(=O)R 12 -S(=O)2R 12 -S(=O)2N(R 13 )2, -NR 13 S(=O)2R 12 , -N(R 13 )2, -OC(=O)(R 12 ), -CO2R 13 -C(=O)N(R 13 )2, -NR 13 C(=O)(R 12 ), -NR 13 C(=O)O(R 12 ), -OC(=O)N(R 13 )2, -NR 13 C(=O)N(R 13 )2. Selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, or a 1,4-dioxanyl ring condensed to ring C.

[0105] In some embodiments, for any formula described herein, R 6is either not substituted, or has 1, 2, 3, or 4 R's. c It is a ring C that is substituted with (R c (as defined herein), ring C is phenyl, naphthyl, heteroaryl, C3-C6 cycloalkyl, or C2-C6 heterocycloalkyl, and R 4 teeth, [ka] A crosslinked cycloalkyl selected from -L 1 -R 2 The -L option is selected from Table 2. 1 -R 2 In some such embodiments, R 1 is H. In some other such embodiments, R 1 The group is either OH or O-C1-C3 alkyl.

[0106] In some embodiments, for any formula described herein, R 6 is a halo, R 4 teeth, [ka] A crosslinked cycloalkyl selected from -L 1 -R 2 The -L option is selected from Table 2. 1 -R 2 In some such embodiments, R 1 is H. In some other such embodiments, R 1 The group is either OH or O-C1-C3 alkyl.

[0107] In another embodiment, compounds having the structure of any one of the compounds 1 to 109 shown in Table 2, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof are provided herein. In yet another embodiment, compounds selected from compounds 1 to 6, 8 to 11, 13 to 17, 19 to 23, 26 to 63, 65 to 70, 72 to 73, 76 to 112, 114 to 119, 121 to 122, 125, 128, 132 to 135, 137 to 138, 140 to 143, 145, 148 to 150, 152 to 153, 158 to 159, and 161 shown in Table 2, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof are provided herein. In another embodiment, compounds selected from compounds 1-136, 138-142, and 145-180 shown in Table 2, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof are provided herein. In an additional embodiment, compounds selected from compounds 1-136, 138-142, and 145-257 shown in Table 2, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof are provided herein. In yet another embodiment, compounds selected from compounds 1-136, 138-142, 145-220, 223, 225-228, 233a-233b, 237, 242, and 247-248b shown in Table 2, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof are provided herein.

[0108] In another embodiment, compounds having one of the following structures in Table 2, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are described herein. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 [Table 1-57] [Table 1-58] [Table 1-59]

[0109] In a further embodiment, the compound of formula (A) is, [ka] In the formula, R 1 , R 2 , L 1 , X 1 , X 2 , R 6 , and R 7 However, as defined herein for any of the preceding formulas, R A Compounds are provided herein that are H, C1-C6 alkyl, or C1-C6 alkyl-aryl (where the aryl is substituted with C1-C3 alkyl, C1-C3 alkoxy, halo, or NO2).

[0110] Further forms of compounds In one embodiment, the compounds described herein (compounds of formulas (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB)) are in the form of pharmaceutically acceptable salts. Similarly, active metabolites of compounds having the same type of activity are also included in the scope of this disclosure. In addition, the compounds described herein can exist in non-solvated forms and in solvated forms with pharmaceutically acceptable solvents, such as water and ethanol. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0111] As used herein, "pharmaceutically acceptable" means that the compound does not negate the biological activity or properties of the compound and is relatively non-toxic; that is, the material does not produce undesirable biological effects. This refers to a material, such as a carrier or diluent, that is administered to an individual without any harmful interaction with any of the components of a composition containing it.

[0112] The term "pharmaceutically acceptable salt" refers to a cationic form of a therapeutic agent combined with a suitable anion, or, in alternative embodiments, a form of a therapeutic agent consisting of an anionic form of a therapeutic agent combined with a suitable cation. (Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SMBerge, LDBighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PHStahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002.) Pharmaceutical salts are typically more readily soluble and rapidly soluble in gastric and intestinal fluids than nonionic species, making them useful in solid dosage forms. Furthermore, since their solubility is often a function of pH, selective dissolution in one or another parts of the digestive tract is possible, and this ability can be manipulated as a form of delayed release and sustained release behavior. In addition, salt-forming molecules can be in equilibrium with a neutral form, thus regulating their passage through biological membranes.

[0113] In some embodiments, pharmaceutically acceptable salts are obtained by reacting compounds of formulas (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) with an acid. In some embodiments, compounds of formulas (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) (i.e., in free base form) are basic and react with organic or inorganic acids. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphor acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), This includes, but is not limited to, gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid.

[0114] In some embodiments, pharmaceutically acceptable salts are obtained by reacting compounds of formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) with a base. In some embodiments, the chemical reaction of formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) The compounds are acidic and react with bases. In such situations, the acidic protons of the compounds of formulas (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) are replaced by metal ions, such as lithium, sodium, potassium, magnesium, calcium, or aluminum ions. In some cases, the compounds described herein coordinate with organic bases, including but not limited to ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids, such as, non-limitingly, arginine and lysine. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, and lithium hydroxide. In some embodiments, the compounds provided herein are prepared as sodium salts, calcium salts, potassium salts, magnesium salts, meglumine salts, N-methylglucamine salts, or ammonium salts.

[0115] It should be understood that references to pharmaceutically acceptable salts include solvated forms. In some embodiments, the solvates are formed during a crystallization process with a pharmaceutically acceptable solvent, such as water or ethanol, comprising stoichiometric or non-stoichiometric amounts of solvent. When the solvent is water, a hydrate is formed, or when the solvent is alcohol, an alcoholic acid salt is formed. The solvates of the compounds described herein are readily prepared or formed during the processes described herein. In addition, the compounds provided herein are optionally available in both unsolvated and solvated forms.

[0116] The methods and formulations described herein include the use of N-oxides (where appropriate), or pharmaceutically acceptable salts of compounds having the structure of formulas (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB), as well as active metabolites of these compounds having the same type of activity.

[0117] In some embodiments, the sites on the organic radicals of compounds of formulas (I), (II), (III), (IV), (X), ((XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) (e.g., alkyl groups, aromatic rings) are susceptible to various metabolic reactions. By incorporating appropriate substituents into the organic radical, these metabolic pathways are reduced, minimized, or eliminated. In certain embodiments, suitable substituents to reduce or eliminate the sensitivity of the aromatic ring to metabolic reactions are, simply as examples, halogens, deutherium, alkyl groups, haloalkyl groups, or deuteroalkyl groups.

[0118] In another embodiment, the compounds described herein are labeled with isotopes (e.g., by radioactive isotopes), or by other means including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0119] The compounds described herein include isotope-labeled compounds, which are identical to those enumerated in the various formulas and structures presented herein, but in which one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into these compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, and phosphorus, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl, 123 I, 124 I, 125 I, 131 I, 32 P, and 33 P is included. In one embodiment, as described herein Isotope-labeled compounds, for example, 3 H and 14 Compounds incorporating radioactive isotopes such as 13C are useful in drug and / or substrate tissue distribution assays. In one embodiment, substitution with an isotope such as deuterium results in certain therapeutic benefits due to improved metabolic stability, such as an increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogens in the compound of formula (I) are substituted with deuterium.

[0120] In some embodiments, compounds of formulas (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) possess one or more stereocenters, each stereocenter existing independently in either an R configuration or an S configuration. In some embodiments, compounds of formulas (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) exist in an R configuration. In some embodiments, compounds of formulas (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) exist in the S configuration. The compounds presented herein include all diastereomers, individual enantiomers, atrop isomers, and epimer forms, as well as suitable mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and thusanmen (Z) isomers, as well as suitable mixtures thereof.

[0121] Individual stereoisomers can be obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatography columns, or separation of diastereomers by non-chiral or chiral chromatography columns, or crystallization and recrystallization in a suitable solvent or mixture of solvents. In certain embodiments, the compounds of formulas (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) 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 diastereomer compounds / salts, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, the separation of individual enantiomers is carried out using covalently bonded diastereomer derivatives of the compounds described herein. In other embodiments, the diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, the separation of stereoisomers is performed by chromatography, or by the formation of diastereomer salts and separation by recrystallization, chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions," John Wiley and Sons, Inc., 1981. In some embodiments, the stereoisomers are obtained by stereoselective synthesis.

[0122] In some embodiments, the compounds described herein are prepared as prodrugs. A “prodrug” refers to a drug that is converted to a parent drug in vivo. Prodrugs are often useful because they are sometimes easier to administer than their parent drugs. For example, they are bioavailable by oral administration, but their parent is different. Furthermore, prodrugs also have improved solubility in pharmaceutical compositions than their parent drugs. In some embodiments, the design of the prodrug increases its effective water solubility. A non-limiting example of a prodrug is a compound described herein that is administered as an ester ("prodrug") but is subsequently metabolized and hydrolyzed to provide an active entity. A further example of a prodrug is a short peptide (polyamino acid) bonded to an acidic group, which is the site where the peptide is metabolized to reveal the active site. In certain embodiments, during in vivo administration, pro Drugs are chemically converted into biologically, pharmaceutically, or therapeutically active forms of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to become a biologically, pharmaceutically, or therapeutically active form of the compound.

[0123] The prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N-alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonic acid esters. For example, *Design of Prodrugs*, Bundgaard, A. Ed., Elseview, 1985, and *Method in Enzymology*, Widder, K. et al., Ed.; Academic, 1985, vol. 42, pp. 309-396; Bundgaard, HA, "Design and Application of Prodrugs" in *Textbook of Drug Design and Development*, Krosgaard-Larsen. See and H. Bundgaard, Ed., 1991, Chapter 5, pp. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38. Each of these is incorporated herein by reference. In some embodiments, the hydroxyl group in the compounds disclosed herein is used to form a prodrug, which is incorporated into acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sugar esters, ethers, etc. In some embodiments, the hydroxyl group in the compounds disclosed herein is a prodrug, in which the hydroxyl is subsequently metabolized in vivo to provide a carboxylic acid group. In some embodiments, the carboxyl group is used to provide an ester or amide (i.e., a prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs.

[0124] Prodrug forms of the compounds described herein, which are metabolized in vivo to produce compounds of formulas (I), (II), (III), (IV), (X), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) as shown herein, are included within the claims. In some cases, some of the compounds described herein are prodrugs for other derivatives or active compounds.

[0125] In some embodiments, one of a hydroxyl group, an amino group, and / or a carboxylic acid group is functionalized in a preferred manner to provide a prodrug moiety. In some embodiments, the prodrug moiety is as described above.

[0126] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism that needs to produce metabolites, which are subsequently used to produce desired effects, including the desired therapeutic effect.

[0127] The “metabolites” of the compounds disclosed herein are derivatives of the compound formed when the compound is metabolized. The term “active metabolite” refers to a biologically active derivative of the compound formed when the compound is metabolized. As used herein, the term “metabolized” refers to a set of processes (including, but not limited to, hydrolysis and enzyme-catalyzed reactions) in which a particular substance is altered by an organism. For example, enzymes can bring about specific structural modifications in a compound. For instance, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, but uridine diphosphate glucuronyltransferase The enzyme catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Metabolites of the compounds disclosed herein can be optionally identified by administration of the compounds to a host and analysis of tissue samples from the host, or by in vitro incubation of the compounds with hepatocytes and analysis of the resulting compounds.

[0128] Compound synthesis Compounds of formulas (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) described herein can be synthesized using standard synthetic techniques or methods known to those skilled in the art, in combination with the methods described herein.

[0129] Unless otherwise specified, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology will be used.

[0130] The compound is, for example, from March's Advanced Organic Chemistry, 6. thThe preparations are made using standard organic chemistry techniques, such as those described in Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein, such as variations in solvent, reaction temperature, reaction time, and various chemical reagents and other reaction conditions, may also be used.

[0131] In some embodiments, the compounds described herein are synthesized as outlined in the schemes and examples.

[0132] certain term Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term "including," as well as other forms such as "include," "includes," and "included," is non-limiting. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0133] When used herein, C1-C x This includes C1-C2, C1-C3...C1-C x This includes. Simply as an example, a group designated as "C1-C4" indicates a group that has 1 to 4 carbon atoms in its part, i.e., a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Therefore, simply as an example, "C1-C4 alkyl" indicates that 1 to 4 carbon atoms are in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0134] The "alkyl" group refers to an aliphatic hydrocarbon group. Alkyl groups are branched or linear. In some embodiments, the "alkyl" group has 1 to 10 carbon atoms, i.e., C1-C 10It is an alkyl group. Numerical ranges such as "1 to 10" refer to each integer within a given range whenever they appear herein. For example, "1 to 10 carbon atoms" means that the alkyl group consists of up to 10 carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., but this definition also covers instances where the term "alkyl" is used without specifying a numerical range. In some embodiments, the alkyl group is a C1-C6 alkyl group. In one embodiment, the alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and sec-butyl. This includes, but is not limited to, butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0135] The "alkylene" group refers to a divalent alkyl radical. Any of the monovalent alkyl groups mentioned above can be converted to alkylene by abstracting a second hydrogen atom from the alkyl group. In some embodiments, the alkylene is a C1-C6 alkylene. In other embodiments, the alkylene is a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-.

[0136] The term "alkenyl" refers to a type of alkyl group that contains at least one carbon-carbon double bond. In one embodiment, the alkenyl group has the formula -C(R)=CR2, where R is the remaining portion of the alkenyl group, which may be the same or different. In some embodiments, R is H or alkyl. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0137] The term "alkynyl" refers to a type of alkyl group that contains at least one carbon-carbon triple bond. In one embodiment, the alkenyl group has the formula -C≡CR, where R refers to the remaining portion of the alkynyl group. In some embodiments, R is H or alkyl. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -CH2C≡CH.

[0138] The "alkoxy" group refers to an (alkyl)O- group, where alkyl is as defined herein.

[0139] The term "alkylamine" refers to -NH (alkyl) or -N (alkyl)2.

[0140] The term "aromatic" refers to a planar ring having a delocalized n-electron system containing 4n+2n electrons, where n is an integer. The term "aromatic" includes both carbocyclic aryl ("aryl," e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heterocyclic aromatic") groups (e.g., pyridine). This term includes monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) groups.

[0141] The term "carbocyclic" or "carbocyclic" refers to a ring or ring system in which all atoms forming the main chain of the ring are carbon atoms. Therefore, this term distinguishes a carbocyclic from a "heterocyclic" ring or "heterocyclic" ring, in which the main chain contains at least one atom other than carbon. In some embodiments, at least one of the two rings in a bicyclic carbocyclic is aromatic. In some embodiments, both rings in a bicyclic carbocyclic are aromatic.

[0142] As used herein, the term “aryl” refers to an aromatic ring in which each of the ring-forming atoms is a carbon atom. In one embodiment, the aryl is phenyl or naphthyl. In some embodiments, the aryl is phenyl. In some embodiments, the aryl is C6-C 10It is an aryl group. Depending on the structure, the aryl group is either a monoradical or a diradical (i.e., an arylene group).

[0143] The term "cycloalkyl" refers to monocyclic or polycyclic aliphatic non-aromatic radicals in which each of the ring-forming atoms (i.e., skeletal atoms) is a carbon atom. The ring may be saturated or partially saturated. In some embodiments, the cycloalkyl group is a spirocyclic or crosslinked compound. In some embodiments, the cycloalkyl group is optionally condensed with an aromatic ring, and the bonding site is on a carbon atom other than the aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 10 ring atoms. In some embodiments, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicyclic[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, adamantyl, norbornyl, and dekalinyl. In some embodiments, the cycloalkyl group is a C3-C6 cycloalkyl group.

[0144] "Cycloalkylene" refers to a cycloalkyl ring, as defined herein, that is, a cycloalkyl ring bonded to two groups.

[0145] "A 1,4-dioxanyl ring condensed to ring C" is, [ka] It refers to.

[0146] "Deuterazole" is a group of groups in which at least one H is a hydrogen isotope, i.e., deuterium ( 2 H) or tritium (3 This refers to an alkyl group as defined herein, which is substituted by H).

[0147] "Deuteroalkoxy" is a compound in which at least one H is a hydrogen isotope, i.e., deuterium ( 2 H) or tritium ( 3 This refers to the alkoxy group as defined herein, which is substituted by H).

[0148] The terms "halo," or alternatively "halogen" or "halide," mean fluoro, chloro, bromo, or iodine. In some embodiments, halo is fluoro, chloro, or bromo.

[0149] The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms. In one embodiment, a fluoroalkyl group is a C1-C6 fluoroalkyl group.

[0150] "Fluoroalkoxy" refers to an alkoxy group as defined herein in which at least one H is replaced by a fluorine atom.

[0151] The term "heteroalkyl" refers to an alkyl group in which one or more of the alkyl backbone atoms are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or a combination thereof). In heteroalkyls, the carbon atoms of the heteroalkyl are bonded to the rest of the molecule. In one embodiment, the heteroalkyl is a C1-C6 heteroalkyl.

[0152] Examples of such heteroalkyls include, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, and -CH2NH These are CH3, -CH2N(CH3)2, and -CH2SCH3.

[0153] The term "heterocyclic" or "heterocyclic" refers to heterocyclic aromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heterocyclic alicyclic groups) that contain 1 to 4 heteroatoms within the ring, where each heteroatom in the ring is selected from O, S, and N, and each heterocyclic group has 3 to 10 atoms in its ring system, provided that no ring contains two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings with 3 to 10 atoms in their ring system, while aromatic heterocyclic groups include rings with 5 to 10 atoms in their ring system. Heterocyclic groups include benzo-condensed ring systems. Examples of non-aromatic heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinol, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azilidinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithi These are oranil, dihydropyranil, dihydrothienyl, dihydrofuranil, pyrazolidinil, imidazolinil, imidazolidinil, 3-azabicyclo[3.1.0]hexanil, 3-azabicyclo[4.1.0]heptanil, 3H-indolyl, indoline-2-onyl, isoindoline-1-onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinoline-1(2H)-onyl, 3,4-dihydroquinoline-2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazole-2(3H)-onyl, 1H-benzo[d]imidazole-2(3H)-onyl, benzo[d]thiazole-2(3H)-onyl, and quinolidinil.Examples of aromatic heterocyclic groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, sinnolinyl, indazolyl, indolidinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, flazanyl, benzoflazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthylidinyl, and phlopyridinyl. The aforementioned groups are, if possible, either C-bonds (or C-links) or N-bonds. For example, pyrrole-derived groups include both pyrrole-1-yl (N-bonded) or pyrrole-3-yl (C-bonded). Furthermore, imidazole-derived groups include imidazole-1-yl or imidazole-3-yl (both N-bonded), or imidazole-2-yl, imidazole-4-yl, or imidazole-5-yl (all C-bonded). Heterocyclic groups include benzo-condensed ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidine-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic. The terms "heteroaryl" or alternatively "heterocyclic aromatic" refer to aryl groups containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Specific examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and flazanil.Bicyclic heteroaryls include indidine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolidine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. It contains . In some embodiments, the heteroaryl contains 0 to 4 N atoms in the ring. In some embodiments, the heteroaryl contains 1 to 4 N atoms in the ring. In some embodiments, the heteroaryl contains 0 to 4 N atoms, 0 to 1 O atom, and 0 to 1 S atom in the ring. In some embodiments, the heteroaryl contains 1 to 4 N atoms, 0 to 1 O atom, and 0 to 1 S atom in the ring. In some embodiments, the heteroaryl is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl.

[0154] A "heterocycloalkyl" or "heteroalicyclic" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl group is condensed with an aryl or heteroaryl group. In some embodiments, the heterocycloalkyl group is oxazolidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidine-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinyl, imidazolidinyl, imidazolidinyl-2-onyl, or thiazolidinyl-2-onyl. In some embodiments, the sulfur atom in the heterocycloalkyl group is not oxidized. The term heteroalicyclic also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In one embodiment, the heterocycloalkyl group is C2-C 10It is a heterocycloalkyl. In another embodiment, the heterocycloalkyl is C4-C 10 It is a heterocycloalkyl. In some embodiments, the heterocycloalkyl contains 0 to 2 N atoms in the ring. In some embodiments, the heterocycloalkyl contains 0 to 2 N atoms, 0 to 2 O atoms, and 0 to 1 S atom in the ring.

[0155] The terms “bond” or “single bond” refer to a chemical bond between two atoms, or between two parts if the atoms joined by the bond are considered to be part of a larger substructure. In one embodiment, if the group described herein is a bond, the group referred to is absent, and therefore a bond is formed between the remaining identified groups.

[0156] The term "part" refers to a specific segment or functional group of a molecule. Chemical parts are often recognized as chemical substances embedded in or added to a molecule.

[0157] The terms "optionally substituted" or "substituted" mean that the group referred to is optionally substituted with one or more additional groups selected from halogens, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are, independently, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -SC1-C4 alkyl, -S(=O)C1-C The substituents are selected from 4-alkyl and -S(=O)2C1-C4 alkyl groups. In some embodiments, optional substituents are independently selected from halogens, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, the substituents are substituted with one or two of the aforementioned groups. In some embodiments, optional substituents on aliphatic carbon atoms (acyclic or cyclic) include oxo (=O).

[0158] As used herein, the term “acceptable” with respect to a formulation, composition, or component means that it does not have any permanent adverse effects on the general health of the subject being treated.

[0159] As used herein, the term “modulate” means interacting with a target directly or indirectly to alter its activity, which includes, by example, enhancing, inhibiting, limiting, or prolonging the activity of the target. In some embodiments, “modulate” means interacting with a target directly or indirectly to reduce or inhibit receptor activity.

[0160] As used herein, the term “modulator” refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, interactions between agonists, partial agonists, inverse agonists, antagonists, or combinations thereof. In some embodiments, the modulator is an antagonist. Receptor antagonists are inhibitors of receptor activity. Antagonists mimic ligands that bind to the receptor, preventing receptor activation by the native ligand. Prevention of activity can have many effects. If a native agonist that binds to a receptor results in increased cellular function, an antagonist that binds to and blocks this receptor will reduce its function.

[0161] As used herein, terms such as “administer,” “give delivery,” and “dosage” refer to methods that may be used to enable the delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal administration. Those skilled in the art will be familiar with the administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds described herein are administered orally.

[0162] As used herein, terms such as “concurrent administration” mean the administration of a selected therapeutic agent to a single patient and are intended to include therapeutic regimens in which the agents are administered via the same or different routes of administration, or simultaneously or at different times.

[0163] As used herein, the terms “effective dose” or “therapeutic effective dose” refer to a sufficient amount of an administered drug or compound that will alleviate, to some extent, one or more symptoms of the disease or condition being treated. Results may include reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desirable modification of the biological system. For example, an “effective dose” for therapeutic use is the amount of a composition containing the compounds disclosed herein required to provide a clinically significant reduction of disease symptoms. An appropriate “effective” dose in any individual case may be determined at arbitrary discretion using techniques such as dose-escalation studies.

[0164] As used herein, the terms “enhance” or “enhance” mean to increase or extend the potency or duration of a desired effect. Therefore, with respect to enhancing the effect of a therapeutic agent, “enhance” refers to the ability to increase or extend the effect of another therapeutic agent on a system, either in terms of potency or duration. As used herein, “enhancement effective dose” is sufficient to enhance the effect of another therapeutic agent on a desired system. It refers to quantity.

[0165] The terms "kit" and "manufactured item" are used as synonyms.

[0166] The terms “subject” or “patient” encompass mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees, and other apes and monkey species; domestic animals such as cattle, horses, sheep, goats, and pigs; farm animals such as rabbits, dogs, and cats; and laboratory animals such as rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0167] As used herein, the terms “to treat,” “to treat,” or “to cure” include alleviating, reducing, or improving at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, for example, preventing the development of a disease or condition, alleviating a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or stopping the symptoms of a disease or condition preventively and / or therapeutically.

[0168] Pharmaceutical composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inert components that facilitate the treatment of the active compound into the preparation to be pharmaceutically used. The appropriate formulation depends on the chosen route of administration. Outlines of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975, Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosures.

[0169] In some embodiments, the compounds described herein are administered alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents in a pharmaceutical composition. Administration of the compounds and compositions described herein can be carried out by any method that enables delivery of the compound to the site of action. These methods include, but are not limited to, enteral routes (oral, gastric or duodenal feeding tube, rectal suppositories, and rectal enemas), parenteral routes (injection or infusion, including intra-arterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, subarachnoid, intravascular, intravenous, intravitreous, epidural, and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal, and topical (including skin surface, skin, enema, eye drops, ear drops, intranasal, and vaginal) administration, and the most preferred route may depend, for example, on the recipient's condition and impairments. As merely an example, the compounds described herein may be administered topically to an area requiring treatment, for example, by local injection during surgery, topical application such as a cream or ointment, injection, catheter, or implant. Administration may also be by direct injection into the site of the affected tissue or organ.

[0170] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as separate units such as capsules, cachets, or tablets, and as powders or granules, in aqueous or liquid form. Each solution or suspension in an aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion, contains a predetermined amount of the active ingredient. In some embodiments, the active ingredient is provided as a bolus, a lick, or a paste.

[0171] Pharmaceutical compositions that can be used orally include tablets, gelatin-based press-fit capsules ("gel caps"), and flexible-seal capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets may be prepared by compression or molding with one or more optional auxiliary components. Compressed tablets may be prepared by compressing a free-flowing active ingredient, such as a powder or granules, in a suitable machine, which is optionally mixed with a binder, an inert diluent, or a lubricant, surfactant, or dispersant. Molded tablets may be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. In some embodiments, tablets are coated or split and formulated to provide sustained or controlled release of the active ingredient. All formulations for oral administration should be in a dosage suitable for such administration. Press-fit capsules may contain the active ingredient in mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added. The core of the sugar-coated tablet is coated with a suitable coating. For this purpose, a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or sugar-coated tablet coating for identification or to characterize different combinations of active compound doses.

[0172] In some embodiments, the pharmaceutical composition is formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. The injectable formulation is presented in unit dosage forms, such as ampoules or multi-dose containers, with added preservatives. The composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain compounding agents such as suspending agents, stabilizers, and / or dispersants. The composition may be presented in unit or multi-dose containers, such as sealed ampoules and vials, and may be stored in powder form or freeze-dried state, requiring only the addition of a sterile liquid carrier, such as physiological saline or sterile pyrogen-free water, immediately before use. Immediate injection solutions and suspensions may be prepared from the aforementioned types of sterile powders, granules, and tablets.

[0173] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oil-based) sterile injection solutions of active compounds, which may contain antioxidants, buffers, bacteriostatic agents, and solutes that are isotonic with the blood of the recipient to whom the formulation is intended, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickeners. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may also contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound, enabling the preparation of high-concentration solutions.

[0174] In addition to the components specifically described above, the compounds and compositions described herein may also include other agents commonly used in the art, depending on the type of formulation in question. For example, flavoring agents may be included if they are suitable for oral administration.

[0175] Treatment method Compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof. The compound is useful for regulating cannabinoid receptors. In some embodiments, the cannabinoid receptor regulated by this compound and method is the cannabinoid 2 receptor (CB2R).

[0176] Provided herein are CB2R modulators useful for treating one or more diseases or disorders associated with or benefiting from the modulation of CB2R activity.

[0177] In some embodiments, methods for treating a disease or disorder, where the disease or disorder is cancer, a hyperproliferative disorder, an autoimmune disorder, or an inflammatory disorder, are described herein.

[0178] In some embodiments, methods for regulating the activity of cannabinoid 2 receptors (CB2Rs) in mammals are provided herein, comprising administering to a mammal a compound described herein, or any pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0179] In some embodiments, methods for treating a disease or disorder in a mammal mediated by the action of a cannabinoid 2 receptor (CB2R) are provided herein, comprising administering to the mammal a compound described herein, or any pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0180] In some embodiments, methods for treating cancer in mammals are provided herein, comprising administering a selective cannabinoid 2 receptor (CB2R) modulator to the mammal. In some embodiments, the selective cannabinoid 2 receptor (CB2R) modulator is a selective cannabinoid 2 receptor (CB2R) antagonist. In some embodiments, the selective cannabinoid 2 receptor (CB2R) modulator is a selective cannabinoid 2 receptor (CB2R) inverse agonist.

[0181] In some embodiments, the selective cannabinoid 2 receptor (CB2R) modulator is a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0182] In some embodiments, methods for treating cancer in mammals are provided herein, comprising administering a CB2R antagonist or a CB2R inverse agonist to the mammal. In some embodiments, the CB2R antagonist or CB2R inverse agonist is a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0183] In some embodiments, the CB2R antagonist or CB2R inverse agonist is 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide (SR144528), [6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole-3-yl](4-methoxyphenyl)-methanone (AM630), or N-(1,3-benzodioxol-5-ylmethyl)-1,2-dihydro-7-methoxy-2-oxo-8-(pentyloxy)-3-quinolinecarboxamide (JTE 907), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0184] In some or all of the preceding embodiments, cancer is a solid tumor.

[0185] In some or any of the preceding embodiments, cancer is bladder cancer, colon cancer These include brain tumors, breast cancer, endometrial cancer, cardiac tumors, kidney cancer, lung cancer, liver cancer, uterine cancer, blood and lymphoid tumors, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, or skin cancer.

[0186] In some or any of the preceding embodiments, the cancer is prostate cancer, breast cancer, colon cancer, or lung cancer.

[0187] In some or any of the preceding embodiments, cancer is a sarcoma, carcinoma, or lymphoma.

[0188] In some or any of the prior embodiments, the method includes administering at least one additional therapy to a mammal.

[0189] In some or any of the prior embodiments, the method includes administering at least one immune checkpoint inhibitor to a mammal. In some or any of the prior embodiments, the immune checkpoint inhibitor is an anti-PD-1 agent or an anti-PD-L1 agent. In some or any of the prior embodiments, the anti-PD-1 agent or anti-PD-L1 agent is nivolumab, pembrolizumab, semipirimab, labrolizumab, avelumab, durvalumab, or atezolizumab.

[0190] In some embodiments, the mammal is a human.

[0191] Anti-PD-1 / anti-PD-L1 agents In some embodiments, the compounds described herein (i.e., CB2R antagonists or inverse agonists) or pharmaceutically acceptable salts thereof are administered in combination with an immune checkpoint inhibitor. The immune checkpoint inhibitor includes, but is not limited to, anti-PD-1, anti-PD-L1, or programmed cell death protein 1 antiligand 2 (PD-L2) agents / inhibitors. In some embodiments, the immune checkpoint inhibitor includes, but is not limited to, anti-PD-1, anti-PD-L1, or programmed cell death protein 1 antiligand 2 (PD-L2) antibodies.

[0192] "PD-1" or "PD1" refers to the programmed cell death 1 (PD-1) receptor. Other names include programmed cell death protein 1 and CD279 (surface antigen classification 279). PD-1 has two ligands, PD-L1 and PD-L2. In some embodiments, targeting of PD-1 restores immune function in the tumor microenvironment.

[0193] As used herein, “PD-L1” or “PDL1” refers to programmed cell death ligand 1 (PD-L1).

[0194] As used herein, “PD-L2” or “PDL2” refers to programmed cell death ligand 2 (PD-L2).

[0195] In some embodiments, the anti-PD-1 or anti-PDL-1 agent is an antibody, peptide, small molecule, or nucleic acid.

[0196] In some embodiments, the compounds described herein (i.e., CB2R antagonists or inverse agonists) or pharmaceutically acceptable salts thereof are administered in combination with an anti-PD-1 or anti-PD-L1 agent. In some embodiments, the anti-PD-1 agent is an anti-PD-1 antibody. In some embodiments, the anti-PD-L1 agent is an anti-PD-L1 antibody.

[0197] In some embodiments, anti-PD-1 agents for use in combination with the compounds described herein (i.e., CB2R antagonists or inverse agonists) or pharmaceutically acceptable salts thereof include nivolumab, pembrolizumab, atezolizumab, durvalumab, pidilizumab, avelumab, TSR-042, PDR-001, tislerizumab (BGB-A317), semipirimab (REGN2810), LY-3300054, and JNJ-6372. 3283, MGA012, BI-754091, IBI-308, Camrelizumab (HR-301210), BCD-100, JS-001, CX-072, BGB-A333, AMP-514 (MEDI-0680), AGEN-2034, CSIOOI, Sym-021, SHR-1316, PF-06801591, LZM009, KN-035, AB122, Genolimbumab (CBT-501), FAZ-053, CK-301, AK These are 104, or GLS-010, BGB-108, SHR-1210, PDR-001, PF-06801591, STI-1110, mDX-400, spartalizumab (PDR001), camrelizumab (SHR1210), cintilimab (IBI308), tisrelizumab (BGB-A317), tripalizumab (JS 001), dostallizumab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, or AMP-514 (MEDI0680).

[0198] In some embodiments, the anti-PD-1 agent is an anti-PD-1 antibody.

[0199] An "anti-PD-1 antibody" refers to an antibody directed at programmed cell death protein 1 (PD1). In some embodiments, the anti-PD-1 antibody binds to an epitope of PD-1 that blocks PD-1 from binding to one or more of its putative ligands. In some embodiments, the anti-PD1 antibody binds to an epitope of the PD-1 protein that blocks PD-1 from binding to PD-L1 and / or PD-L2.

[0200] Examples of anti-PD-1 antibodies include, but are not limited to, nivolumab / MDX-106 / BMS-9300 / ONO1152, the fully human IgG4 anti-PD-1 monoclonal antibody; pidilizumab (MDV9300 / CT-011), the humanized IgG1 monoclonal antibody; pembrolizumab (MK-3475 / pembrolizumab / lambrolizumab), the humanized monoclonal IgG4 antibody; durvalumab (MEDI-4736), and atezolizumab.

[0201] In some embodiments, the anti-PD-1 antibody is nivolumab (OPDIVO®, Bristol-Myers Squibb), pembrolizumab (KEYTRUDA®, Merck), semipirimab (Libtayo), labrolizumab (Merck), or BGB-A317.

[0202] In some embodiments, the anti-PD1 antibody is the antibody shown in U.S. Patent Nos. 7,029,674, 7,488,802, 7,521,051, 8,008,449, 8,354,509, 8,617,546, 8,709,417, or WO2014 / 179664.

[0203] As used herein, the term “antibody” (singular and plural) includes all types of immunoglobulins or their fragments, including IgG, IgM, IgA, IgD, and IgE, which may be appropriate for the medical uses disclosed herein. Antibodies may be monoclonal or polyclonal and may originate from any species, including, for example, mouse, rat, rabbit, horse, or human. Antibody fragments that hold specific binding to proteins or epitopes conjugated by antibodies used in this disclosure, such as PD-L1 or PD-1, are included in the scope of the term “antibody.” Antibodies may be chimeric or humanized, especially when used for therapeutic purposes. Antibodies and antibody fragments are prepared using various methods. It can be obtained or prepared by [method].

[0204] In some embodiments, anti-PD-1 agents for use in combination with the compounds described herein (i.e., CB2R antagonists or inverse agonists) or pharmaceutically acceptable salts thereof include atezolizumab, avelumab, AMP-224, MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI-A1014, CX-072, BMS-936559, KN035, CK-301 (Checkpoint Therapeutics), AUNP12, CA-170 (Aurigene / Curis), MEDI4736, MSB0010718C, MDX1105-01, and BMS-986189.

[0205] In some embodiments, the anti-PD-L1 agent is an anti-PD-L1 antibody.

[0206] An "anti-PD-L1 antibody" refers to an antibody targeted at programmed cell death ligand 1 (PD-L1).

[0207] Anti-PD-L1 antibodies for use in combination with the compounds described herein (i.e., CB2R antagonists or inverse agonists) or their pharmaceutically acceptable salts include avelumab; BMS-936559, a fully human IgG4 antibody; atezolizumab (MPDL3280A / RG-7446), a human monoclonal; MEDI4736; MSB0010718C, and MDX 1105-01.

[0208] In some embodiments, the anti-PD-L1 antibody is avelumab (Bavencio®, Merck KGA / Pfizer), durvalumab (AstraZeneca), and atezolizumab (TECENTRIQ®, Roche).

[0209] Additional examples of antibodies include, but are not limited to, those described in U.S. Patent Nos. 8,217,149, 8,383,796, 8,552,154, and 8,617,546.

[0210] Peptide anti-PD-1 / PD-L1 agents include AUNP12 (a 29-mer peptide by Pierre Fabre of Aurigene and Laboratoires), CA-170 (Aurigene / Curis), and BMS-986189 (a macrocyclic peptide by BMS).

[0211] Small molecule anti-PD-1 / PD-L1 agents include WO / 2020 / 086556, WO / 2020 / 014643, WO / 2019 / 204609, WO / 2019 / 160882, WO / 2018 / 195321, WO2018026971, US20180044329, US20180044305, US201 80044304, US20180044303, US20180044350, US20180057455, US20180057486, US201 80045142, WO20180044963, WO2018044783, WO2018009505, WO20180044329, WO20170 66227, WO2017087777, US20170145025, WO2017079669, W02017070089, US201710721 6, WO2017222976, US20170262253, WO2017205464, US20170320875, WO2017192961, W O2017112730, US20170174679, WO2017106634, WO2017202744, WO2017202275, WO201 7202273, WO2017202274, WO2017202276, WO2017180769, WO2017118762, W020160415 This includes those described in 11, WO2016039749, WO2016142835, WO2016142852, WO2016142886, WO2016142894, and WO2016142833. In some embodiments, the small molecule anti-PD-1 / PD-L1 agent is GS-4224. In some embodiments, GS-4224 is administered in doses of approximately 400 mg to approximately 1000 mg.

[0212] Medication and treatment regimens In one embodiment, the compounds described herein or pharmaceutically acceptable salts thereof are used in the preparation of pharmaceuticals for treating diseases or conditions in mammals that benefit from inhibition or reduction of CB2R activity. A method for treating any of the diseases or conditions described herein in a mammal requiring such treatment involves administering a pharmaceutical composition comprising at least one of the compounds described herein, or a pharmaceutically acceptable salt thereof, an active metabolite, a prodrug, or a pharmaceutically acceptable solvate thereof, in a therapeutically effective amount to the mammal.

[0213] In certain embodiments, compositions comprising the compounds described herein are administered for prophylactic and / or therapeutic purposes. In certain therapeutic uses, the composition is administered to a mammal already suffering from a disease or condition in an amount sufficient to cure or at least partially inhibit at least one of the symptoms of the disease or condition. The effective dose for this use depends on the severity and course of the disease or condition, previous therapies, the mammal's health status, body weight, and response to the drug, as well as the judgment of the healthcare professional. The therapeutically effective dose may be determined at will by means of a choice including, but not limited to, dose escalation and / or dose-range clinical trials.

[0214] For preventive purposes, compositions comprising the compounds described herein are administered to mammals that are susceptible to, or otherwise at risk of, a particular disease, disorder, or condition. Such amounts are defined as “a prophylactically effective amount or dose.” In this use, the exact amount will also depend on the mammal’s health, body weight, etc. When used in mammals, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous treatments, the mammal’s health, and response to the drug, as well as the judgment of a medical professional. In one embodiment, a preventive measure involves administering a pharmaceutical composition comprising the compounds described herein or a pharmaceutically acceptable salt thereof to a mammal that has previously experienced at least one symptom of the disease being treated and is currently in remission, in order to prevent recurrence of symptoms of the disease or condition.

[0215] In certain embodiments where the mammalian condition does not improve, the compound may be administered chronically, i.e., for a long period including the mammal's entire lifespan, at the discretion of the medical professional, to improve, or otherwise control or limit the symptoms of the mammalian disease or condition.

[0216] In certain embodiments where the condition of the mammal is improved, the dose of the administered drug is temporarily reduced or temporarily withheld for a certain period (i.e., a “drug-free period”). In certain embodiments, the length of the drug-free period is from 2 days to 1 year and includes, simply as examples, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during the drug-free period is, simply as examples, from 10% to 100%, and includes, simply as examples, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0217] After an improvement in the patient's condition occurs, a maintenance dose is administered as needed. Subsequently, in certain embodiments, the dosage, frequency, or both of these are reduced to a level in which the improved disease, disorder, or condition is maintained as a function of the symptoms. However, in certain embodiments, the mammal requires long-term, intermittent treatment at any relapse of symptoms.

[0218] The amount of a given drug corresponding to such a quantity will vary depending on factors such as the specific compound, the disease state and its severity, and the identity of the person or host requiring treatment (e.g., weight, sex), but will be determined according to the specific circumstances surrounding the case, including, for example, the specific drug administered, the route of administration, the condition being treated, and the person or host being treated.

[0219] However, generally speaking, the doses used for treating adults are typically in the range of 0.01 mg to 5000 mg per day. In one embodiment, the dose used for treating adults is approximately 1 mg to approximately 1000 mg per day. In one embodiment, the desired dose is conveniently presented as a single dose, or as divided doses administered simultaneously or at appropriate intervals, for example, as two, three, or four or more partial doses per day.

[0220] In one embodiment, a suitable daily dose for the compounds described herein or their pharmaceutically acceptable salts is about 0.01 to about 50 mg per kg of body weight. In some embodiments, the daily dose or the amount of active ingredient in the dosage form may be lower or higher than the range shown herein, based on a number of variables relating to the individual treatment regimen. In various embodiments, the daily dose and unit dose may be modified depending on a number of variables, including but not limited to the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0221] The toxicity and therapeutic effect of such treatment regimens are LD 50 and ED 50 This is determined by standard pharmaceutical procedures in cell culture or experimental animals, including but not limited to the determination of the LD50. The dose-to-toxicity ratio is the therapeutic index, and LD50 is the dose-to-toxicity ratio. 50 / ED 50 Expressed as a ratio. In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating therapeutically effective daily dose ranges and / or therapeutically effective unit doses for use in mammals, including humans. In some embodiments, the daily doses of the compounds described herein are those with minimal toxicity. 50 It is within the range of circulating concentrations, including [the specified substance]. In certain embodiments, the daily dose varies within this range depending on the dosage form used and the route of administration utilized.

[0222] In any of the embodiments described herein, an effective amount of the compound or a pharmaceutically acceptable salt thereof is administered (a) systemically to a mammal, and / or (b) orally to a mammal, and / or (c) intravenously to a mammal, and / or (d) by injection to a mammal, and / or (e) topically to a mammal, and / or (f) non-systemically or topically to a mammal.

[0223] In any of the embodiments described above, further embodiments include a single dose of an effective amount of the compound, in which (i) the compound is administered once daily, or (ii) the compound is administered to a mammal multiple times over a day.

[0224] Further embodiments include multiple administrations of an effective amount of the compound, including any of the embodiments described above, in which (i) the compound is administered as a single dose, continuously or intermittently; (ii) the interval between multiple administrations is 6 hours; (iii) the compound is administered to a mammal every 8 hours; (iv) the compound is administered to a mammal every 12 hours; or (v) the compound is administered to a mammal every 24 hours. In further or alternative embodiments, the method includes a drug-free period in which the administration of the compound is temporarily withheld or the dose of the compound administered is temporarily reduced, and the administration of the compound is resumed at the end of the drug-free period. In one embodiment, the length of the drug-free period varies from 2 days to 1 year.

[0225] In certain cases, it is appropriate to administer at least one compound described herein or a pharmaceutically acceptable salt thereof in combination with one or more therapeutic agents. In certain embodiments, the pharmaceutical composition further comprises one or more anticancer agents.

[0226] In one embodiment, the therapeutic efficacy of one of the compounds described herein is enhanced by the administration of an adjuvant (i.e., the adjuvant itself has minimal therapeutic benefit, but when combined with another therapeutic agent, it enhances the overall therapeutic benefit to the patient). Alternatively, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein together with another agent (including a therapeutic regimen) that has a similar therapeutic benefit.

[0227] In one particular embodiment, the compound described herein or a pharmaceutically acceptable salt thereof is administered concurrently with a second therapeutic agent, in which the compound described herein or a pharmaceutically acceptable salt thereof and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing a greater overall benefit than administering either therapeutic agent alone.

[0228] In any case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient is either simply the sum of the two therapeutic agents, or the patient experiences a synergistic effect.

[0229] In certain embodiments, different therapeutically effective dosages of the compounds disclosed herein will be utilized in the formulation of pharmaceutical compositions and / or in therapeutic regimens in which the compounds disclosed herein are administered in combination with one or more additional agents, such as additional therapeutically effective drugs, adjuvants, etc. The therapeutically effective dosages of the drugs and other agents for use in combination therapeutic regimens will be optionally determined by means similar to those described above for the active ingredients themselves. Furthermore, the prevention / treatment methods described herein include the use of metronome dosing, i.e., providing lower doses more frequently to minimize toxic side effects. In some embodiments, the combination therapeutic regimens include therapeutic regimens in which the administration of the compounds disclosed herein or pharmaceutically acceptable salts thereof is initiated before, during, or after treatment with a second agent described herein and continues until any point during treatment with the second agent or until after the completion of treatment with the second agent. This also includes treatments in which the compounds described herein or pharmaceutically acceptable salts thereof, and a second agent used in combination, are administered simultaneously or at different times and / or at intervals that are gradually increased or decreased during the course of treatment. Combination therapy further includes periodic treatments that are initiated and stopped at various points in time to support the clinical management of the patient.

[0230] Medication regimens for treating, preventing, or improving diseases requiring relief are modified according to various factors (e.g., the disease or disorder the subject is suffering from, the subject's age, weight, sex, diet, and medical condition). Therefore, in some cases, the medication regimens actually used will vary, and in some embodiments, they will deviate from the medication regimens described herein.

[0231] In the combination therapies described herein, the dosage of the compound administered concurrently varies depending on the type of concomitant drug used, the specific drug used, the disease or condition being treated, etc. In additional embodiments, when administered concurrently with one or more other therapeutic agents, the compounds provided herein are administered simultaneously with or consecutively with one or more other therapeutic agents.

[0232] In combination therapy, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order, or even simultaneously. When administered simultaneously, the multiple therapeutic agents may be administered, for example, in a single, unified form, or in multiple forms (e.g., a single pill). It is offered as medicine, or as two separate pills.

[0233] The compounds described herein or their pharmaceutically acceptable salts, and combination therapies, are administered before, during, or after the onset of a disease or condition, and the timing of administration of compositions containing the compounds varies. For example, in one embodiment, the compounds described herein are used as prophylactic agents, continuously administered to subjects prone to developing a condition or disease to prevent its onset. In another embodiment, the compounds and compositions are administered to subjects as soon as possible during or after the onset of symptoms. In a particular embodiment, the compounds described herein are administered as soon as feasible after the onset of a disease or condition is detected or suspected, for the duration necessary to treat the disease. In some embodiments, the length of treatment varies, and the length of treatment is adjusted to meet the specific needs of each subject. For example, in a particular embodiment, the compounds described herein or formulations containing the compounds are administered for at least two weeks, approximately one month, to approximately five years.

[0234] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are administered in combination with chemotherapy, radiotherapy, monoclonal antibodies, or a combination thereof.

[0235] Chemotherapy involves the use of anticancer drugs.

[0236] In addition to the above CB2R antagonists or inverse agonists, the following CB2R antagonists or inverse agonists are intended in the combination therapies described herein for use in the treatment of cancer: 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide (SR144528), [6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole-3-yl](4-methoxyphenyl)-methanone (AM630), or N-(1,3-benzodioxol-5-ylmethyl)-1,2-dihydro-7-methoxy-2-oxo-8-(pentyloxy)-3-quinolinecarboxamide (JTE One of the CB2R antagonists or inverse agonists described in 907) or V. Lucchesi et al., J. Med. Chem. 2014, 57, 8777-8791. Abbreviation [Table 2]

[0237] General synthesis methods The compounds of formula (I) and / or (X) are prepared as described in the following scheme.

[0238] Scheme 1 shows embodiments for preparing compounds of formula (I) and / or formula (X). [ka]

[0239] Compound 1-1(X 1 and X 2 Starting with (where R is H, halo, or triflate group, or any other suitable leaving group), 3-chloro Compound 1-2 can be obtained by reacting it with ethyl 3-oxopropanoate, and compound 1-3 can be obtained by cyclizing it in the presence of a base and a protic solvent. Compound 1-3 can then be converted to compounds of formula (I) and / or formula (X). Suitable bases for cyclization include sodium methoxide and sodium ethoxide. Suitable solvents include methanol and ethanol.

[0240] Scheme 2 shows further embodiments for the preparation of compounds of formula (I) and / or formula (X). [ka]

[0241] Starting with compound 2-1 (where R is H, a halo, a triflate group, or any other suitable leaving group), compound 2-2 can be obtained by reacting it with dibenzyl malonate, which can then be converted to compounds of formula (I) and / or formula (X).

[0242] Scheme 3 shows an embodiment for the preparation of the compound of formula (X). [ka]

[0243] Compound 3-1(X 1 and X 2 Starting with (where R is as defined herein, and R may be H, a halo, a triflate group, or any other suitable leaving group), compound 3-2 can be obtained by reacting it with diethyl malonate in the presence of a base (e.g., piperidine), and compound 3-3 can be obtained by cyclizing it in the presence of a metal (e.g., Fe) and an acid (e.g., acetic acid), and this compound 3-3 can be converted to the compound of formula (X).

[0244] Scheme 4 is R 1The present invention illustrates an embodiment in which the compound 1-3 and / or 2-3 and / or 3-3 (collectively summarized with compound 4-1) shown above can be converted into the compound of formula (I) and / or formula (X). [ka]

[0245] Compound 1-3, 2-3, or 3-3 (X) are summarized together with Compound 4-1. 1 and X 2 Starting with (where R is as defined herein, and R' may be H, a halo, or a triflate group, or any other suitable leaving group, and R' is a C1-C3 alkyl or benzyl), compound 4-1 is reacted with compound 4-2 to obtain compound 4-3. Any suitable base can be used in this reaction (e.g., K2CO3, Cs2CO3). 2 The R of compound 4-5 is as defined herein, and LG is any suitable leaving group (e.g., halo). Compound 4-4 is obtained by hydrolyzing the ester of compound 4-3. Compound 4-6 is obtained by coupling compound 4-4 with compound 4-5 under any suitable amide coupling conditions (e.g., HATU, EDCI). 4 The term is as defined herein. Compound 4-6 was converted to compound 4-7 using any suitable boronating agent. Each R'' in compound 4-7 is independently H, C1-C3 alkyl, or phenyl, or two R''s together with the atom to which they are bonded form a dioxaborolane ring. Compound 4-7 is coupled with a suitable compound 4-8 to obtain a compound of formula (I) or formula (X). In compound 4-8, R 6 is as defined herein, where LG'' is any suitable leaving group (e.g., halo). The coupling reaction between compound 4-7 and compound 4-8 may be mediated with any suitable palladium catalyst or by any other similar organometallic coupling method known to those skilled in the art.

[0246] Scheme 5 is R1 The present invention illustrates an embodiment in which the compound 1-3 and / or 2-3 and / or 3-3 (collectively summarized with compound 4-1) shown above can be converted into the compound of formula (I) and / or formula (X). [ka]

[0247] Compound 1-3, 2-3, or 3-3 (X) are summarized together with Compound 4-1. 1 and X 2 Starting with (where R is as defined herein, and R' may be H, a halo, or a triflate group, or any other suitable leaving group, and R' is a C1-C3 alkyl or benzyl), compound 4-1 is reacted with compound 4-2 to obtain compound 4-3. Any suitable base can be used in this reaction (e.g., K2CO3, Cs2CO3). 2 is as defined herein, and LG is any suitable leaving group (e.g., halo). Compound 4-3 was converted to compound 5-1 using any suitable boronating agent. Each R'' in compound 5-1 is independently H, C1-C3 alkyl, or phenyl, or two R'' together with the atom to which they are bonded form a dioxaborolane ring. Compound 5-1 was coupled with a suitable compound 4-8 to obtain compound 5-2. The coupling reaction between compound 5-1 and compound 4-8 may be mediated with any suitable palladium catalyst or by any other similar organometallic coupling method known to those skilled in the art. In compound 4-8, R 6 is as defined herein, and LG'' is any suitable leaving group (e.g., halo). Compound 5-3 is obtained by hydrolyzing the ester of compound 5-2. Compound 5-3 is coupled with compound 4-5 under any suitable amide coupling conditions (e.g., HATU, EDCI) to obtain compounds of formula (I) and / or formula (X).

[0248] Scheme 6 is R 1The present invention illustrates an embodiment in which the compound 1-3 and / or 2-3 and / or 3-3 (collectively summarized with compound 4-1) shown above can be converted into the compound of formula (I) and / or formula (X). [ka]

[0249] Compound 1-3, 2-3, or 3-3 (X) are summarized together with Compound 4-1. 1 and X 2 Compound 6-2 is obtained by reacting 2-bromo-1,1-diethoxyethane with compound 6-2, starting with (where R is as defined herein, and R may be H, a halo, or a triflate group, or any other suitable leaving group, and R' is a C1-C3 alkyl or benzyl). Compound 6-2 is coupled with boronate 6-3 to obtain compound 6-4. In compound 6-3, R 6 The terms are as defined herein. In compound 6-3, each R'' is independently H, C1-C3 alkyl, or phenyl, or two R'' together with the atom to which they are bonded form a dioxaborolane ring. The coupling reaction between compound 6-2 and compound 6-3 may be mediated with any suitable palladium catalyst or by any other similar organometallic coupling method known to those skilled in the art. Compound 6-4 is mediated with compound 4-5 (R 4 The compound 6-5 is converted to amide 6-5 via a reaction with (as defined herein). The ketal of compound 6-5 is hydrolyzed under acidic conditions (e.g., HCl) to obtain aldehyde 6-6, which is aminated with compound 6-7 to obtain compounds of formula (I) and / or (X). The R of compound 6-7 2 This is defined herein.

[0250] Scheme 7 is R 1 Embodiments for the preparation of compounds of formula (I) and / or (X) in which is alkyl are shown. [ka]

[0251] Compound 7-1(X 1 and X 2 Compound 7-2 is obtained by converting to Weinreb amide, starting with (where R is as defined herein, and R may be H, a halo, or a triflate group, or any other suitable leaving group). Compound 7-3 is obtained by reacting with a suitable Grignard reagent, which is then converted to compound 7-4 by reacting with ethyl 3-chloro-3-oxopropanoate. Compound 7-4 is cyclized in the presence of a base to obtain compound 7-5, which is then converted to compounds of formula (I) and / or (X) using the method described in Scheme 4-6.

[0252] Scheme 8 is R 1 Embodiments for the preparation of compounds of formula (I) and / or (X) in which is an alkoxy are shown. [ka]

[0253] Compound 8-1(X 1 and X 2 Compound 8-2 (where R''' is C1-C3 alkyl or benzyl) is reacted with an alkylating agent as defined herein, where R is H, halo, or triflate, or any other suitable leaving group, and R' is C1-C3 alkyl or benzyl) to obtain compound 8-2, which can then be converted to compounds of formula (I) and / or (X) using the method described in Scheme 4-6. For example, compound 8-1 is reacted with DMSO to obtain R'''methyl, and compound 8-1 is reacted with propyl iodide to obtain R'''isopropyl.

[0254] Any combination of the above steps may be used to prepare the compounds described herein, including any procedure described in the Examples section.

[0255] The compounds of this disclosure can be prepared, for example, from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions may also be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reactants or solvent used, but such conditions can be determined by routine optimization procedures for those skilled in the art.

[0256] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, numerous protecting groups are described in TW Greene and GMWuts (1999), *Protecting Groups in Organic Synthesis*, 3rd Edition, Wiley, New York, and the references cited therein.

[0257] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Therefore, if necessary, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as a concentrated mixture of stereoisomers. Unless otherwise specified, all such stereoisomers (and concentrated mixtures) are included in the scope of this disclosure. Pure stereoisomers (or concentrated mixtures) may be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral decomposition agents, etc.

[0258] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemie, or Sigma (St. Louis, Missouri, USA). Others are available from Fieser and Fieser's Reagents for Organic Synthesis,Volumes 1-15(John Wiley,and Sons,1991), Rodd's Chemistry of Carbon Compounds,Volumes 1-5,and Supplementals(Elsevier Science Publishers,1989)organic Reactions,Volumes 1-40(John Wiley,and Sons,1991), March's Advanced Organic Chemistry,(John Wiley,and Sons,5 th It can be prepared by the procedures described in standard reference texts such as Edition, 2001, and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or by obvious modifications thereof. [Examples]

[0259] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein. Unless otherwise specified, all starting materials are commercially available.

[0260] Example 1-6 Synthesis of bromo-1-(4-fluorobenzyl)-N-(1-(4-fluorophenyl)ethyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (Compound 1) [ka] Step 1: Preparation of 5-bromo-2-(3-ethoxy-3-oxopropanamide) ethyl nicotinate [ka]

[0261] A solution of methyl 2-amino-5-bromopyridine-3-carboxylate (0.5 g, 2.16 mmol, 1 equivalent) in DCM (10 mL) was mixed with a solution of ethyl 3-chloro-3-oxopropanoate (390.99 mg, 2.60 mmol, 325.82 μL, 1.2 equivalents) in DCM (10 mL) at 0°C. The mixture was stirred at 20°C for 2 hours. TLC showed complete consumption of the starting material and formation of new spots. The mixture was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated.

[0262] The residue was purified by flash silica gel chromatography (PE / EA = 50:1 to 5:1) to obtain 5-bromo-2-(3-ethoxy-3-oxopropanamide) ethyl nicotinate (1 g, 2.90 mmol) as a white solid.

[0263] 1 H NMR(400MHz,CDCl3)δ=11.01(br s,1H),8.56(d,J=2.5Hz,1H),8.43(d,J=2.5Hz,1H),4.31-4.20(m,4H),3.79(s,2H),1.32(t,J=7.3Hz,3H),1.29-1.26(m,3H).

[0264] Step 2: Preparation of ethyl 6-bromo-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate [ka]

[0265] To a solution of methyl 5-bromo-2-[(3-ethoxy-3-oxo-propanoyl)amino]pyridine-3-carboxylate (0.5 g, 1.45 mmol, 1 equivalent) in MeOH (10 mL), NaOMe (469.57 mg, 8.69 mmol, 6 equivalents) was added at 20°C. The reaction mixture was stirred at 70°C for 1 hour. TLC showed complete consumption of the starting material and formation of new spots.

[0266] The reaction mixture was acidified to pH=5 by adding 2N hydrochloric acid dropwise at 0°C. The mixture was filtered, and the resulting solid was washed with water (5 mL) to obtain 6-bromo-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxylate (730 mg, 2.33 mmol) as a white solid (which was used without further purification).

[0267] 1 H NMR (400MHz, DMSO-d6) δ=10.25(s,1H),8.34(d,J=2.5Hz,1H),8.15(d,J=2.0Hz,1H),4.05(q,J=7.2Hz,2H),1.19(t,J=7.3Hz,3H).

[0268] Step 3: Preparation of 6-bromo-1-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl [ka]

[0269] A mixture of ethyl 6-bromo-4-hydroxy-2-oxo-1H-1,8-naphthyridine-3-carboxylate (480 mg, 1.53 mmol, 1 equivalent) and 1-(bromomethyl)-4-fluorobenzene (318.76 mg, 1.69 mmol, 208.34 μL, 1.1 equivalent) in DMF (5 mL) was added to Cs2CO3 (1.50 g, 4.60 mmol, 3 equivalents). The mixture was stirred at 90°C for 12 hours. LC-MS and TLC showed complete consumption of the starting materials and the formation of new peaks.

[0270] The mixture was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic phase was dried over Na₂SO₄, filtered, and vacuum concentrated. The residue was purified by flash silica gel chromatography (petroleum ether / ethyl acetate = 50:1 to 10:1) to obtain 6-bromo-1-(4-fluorobenzyl)-4-hydroxy-2-o Xo-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl (600 mg) was obtained as a yellow solid (which was used without further purification).

[0271] 1 H NMR(400MHz,CDCl3)δ=14.55-14.00(m,1H),8.72(d,J=2.5Hz,1H),8.53(d,J=2.5Hz ,1H),7.35(s,2H),7.08-7.07(m,2H),4.52(d,J=3.0Hz,2H),1.48(t,J=7.3Hz,3H). LCMS(ESI+):m / z 421.1,423.1[M+H] + ,Rt:2.315 minutes.

[0272] LCMS method 5-95 AB-HPLC:LCMS (Positive Electrospray Ionization) (The gradient was 5 to 95%B at 2.20 min, 0.5%B at 0.01 min, 5 to 95%B at 1.81 min (0.01-1.00 min), 95 to 100%B (1.00-1.80 min), 5%B, and retention at 5%B for 0.40 min. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC-grade acetonitrile. The column used for chromatography was HALO AQ-C18 2.1×30 mm (2.7 μm particles). The detection method was diode array (DAD).

[0273] Step 4: Preparation of 6-bromo-1-(4-fluorobenzyl)-N-(1-(4-fluorophenyl)ethyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide [ka]

[0274] A mixture of ethyl 6-bromo-1-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,8-naphthyrizine-3-carboxylate (100 mg, 237.41 μmol, 1 equivalent) and 1-(4-fluorophenyl)ethanamine (39.65 mg, 284.89 μmol, 37.40 μL, 1.2 equivalents) in toluene (1 mL) was to which DIEA (92.05 mg, 712.22 μmol, 124.06 μL, 3 equivalents) was added. The mixture was stirred at 120 °C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0275] The mixture was concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 60% to 85%, 10 min) to obtain 6-bromo-1-(4-fluorobenzyl)-N-(1-(4-fluorophenyl)ethyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (2.2 mg, 4.28 μmol) as a white solid.

[0276] 1 H NMR(400MHz,CDCl3)δ=10.51(br d,J=7.3Hz,1H),8.72(d,J=2.4Hz,1H),8.57(d,J=2.4Hz,1H),7.39(ddd,J=5.4,8.4,17.0Hz,4H),7 .06(t,J=8.7Hz,2H),6.97(t,J=8.6Hz,2H),5.63(s,2H),5.30-5.19(m,1H),1.62(d,J=7.0Hz,3H). Generate LCMS (ESI+) for material: m / z 514.0, 516.0 [M+H] + ,Rt:3.419 minutes.

[0277] LCMS method 5-95 AB-HPLC:LCMS (positive electrospray ionization) (The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.00 min, held at 95%B for 1.00 min, and then 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50×2.1 mm column (5 μm particles). Detection methods included diode array (DAD), evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0278] Example 2-6 Synthesis of Bromo-1-(4-Fluorobenzyl)-4-Hydroxy-2-Oxo-N-(Spiro[3,3]Heptan-2-yl)-1,2-Dihydro-1,8-Naphthyridine-3-Carboxamide (Compound 2) [ka] Preparation of 6-bromo-1-(4-fluorobenzyl)-4-hydroxy-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0279] To a mixture of ethyl 6-bromo-1-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,8-naphthyrizine-3-carboxylate (100 mg, 237.41 μmol, 1 equivalent) and spiro[3.3]heptan-2-amine (42.06 mg, 284.89 μmol, 1.2 equivalents, HCl) in toluene (1 mL), DIEA (92.05 mg, 712.22 μmol, 124.06 μL, 3 equivalents) was added. The mixture was stirred at 120 °C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0280] The formed solid was collected by filtration and air-dried to obtain 6-bromo-1-(4-fluorobenzyl)-4-hydroxy-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (21.9 mg, 45.03 μmol) as a white solid.

[0281] 1 H NMR(400MHz,DMSO-d6)δ=10.31-10.14(m,1H),8.90(d,J=2.5Hz,1H),8.58(d,J=2.5Hz,1H),7.34-7.27(m,2H),7.09(t,J=9.0Hz,2H),5.55(s,2H), 4.27(q,J=8.0Hz,1H),2.68-2.66(m,1H),2.45-2.39(m,2H),2.33(td,J= 1.6,3.8Hz,1H),2.08-1.99(m,4H),1.97-1.91(m,2H),1.84-1.76(m,2H). LC-MS (ESI+) of the product: m / z 486.0, 488.0 [M+H] + ,Rt:2.989 minutes.

[0282] LCMS method 50-50 AB-HPLC:LCMS (positive electrospray ionization) (The gradient was 50%B at 0.40 min, then 50% to 100%B from 0.40 to 3.00 min, held at 100%B for 1.00 min, and then 100% to 50%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods included diode array (DAD), evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0283] Example 3-6 Synthesis of bromo-N-(1-(4-cyanophenyl)ethyl)-1-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 3) [ka] Preparation of 6-bromo-N-(1-(4-cyanophenyl)ethyl)-1-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0284] A mixture of ethyl 6-bromo-1-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,8-naphthyridine-3-carboxylate (100 mg, 237.41 μmol, 1 equivalent) and 4-(1-aminoethyl)benzonitrile (38.18 mg, 261.15 μmol, 1.1 equivalent) in toluene (1 mL) was to which DIEA (92.05 mg, 712.22 μmol, 124.05 μL, 3 equivalents) was added. The mixture was stirred at 120 °C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0285] The mixture was filtered. The filtrate was separated and purified by preparative HPLC (column: Luna Omega 5u Polar C18 100A; mobile phase: [water (0.04% HCl)-ACN]; B%: 70% to 98%, 7 min) to obtain 6-bromo-N-(1-(4-cyanophenyl)ethyl)-1-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (8.5 mg, 14.69 μmol, HCl) as a white solid.

[0286] 1H NMR(400MHz,CDCl3)δ=10.61(br d,J=7.1Hz,1H),8.73(d,J=2.5Hz,1H),8.56(d,J=2.4Hz,1H),7.67(d,J=8.4Hz,2H),7.53-7.47(m,2H),7. 42(dd,J=5.4,8.6Hz,2H),7.02-6.94(m,2H),5.64(s,2H),5.26(quin,J=7.2Hz,1H),1.63(d,J=7.0Hz,3H). LCMS (ESI+) for product: m / z 521.1,523.1[M+H] + ,Rt:3.259 minutes.

[0287] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.00 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). The detection method was diode array (DAD).

[0288] Example 4-6 Synthesis of Bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (Compound 4) [ka] Step 1: Preparation of 6-bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl [ka]

[0289] Method A: 6-bromo-4-hydroxy-2-oxo-1H-1,8-naphthyridine-3-carboxylate ethyl (900 mg, 2.87 mmol, 1 equivalent) in DMF (1 mL) and To a solution of 4-(2-chloroethyl)morpholine (516.08 mg, 3.45 mmol, 1.2 equivalents), Cs2CO3 (7.49 g, 23.00 mmol, 8 equivalents) was added. The mixture was stirred at 50°C for 12 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0290] The mixture was filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (under 0.1% HCl conditions) to obtain 6-bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl (400 mg) as a yellow solid.

[0291] LC-MS (ESI+) for the product: m / z 426.1 [M+H] + ,Rt:0.740 minutes.

[0292] 5-95AB-2 min: The column used for chromatography was Luna-C 18 2.0 × 30 mm (3 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in HPLC-grade acetonitrile. The gradients were 5 to 95%B at 2.00 min, 5%B at 0.01 min, 5 to 95%B (0.01 to 1.00 min), 95 to 100%B (1.00 to 1.80 min), 5%B at 1.81 min, and retention at 5%B for 0.19 min. The flow rates were 1.0 mL / min (0.00 to 1.80 min) and 1.2 mL / min (1.81 to 2.00 min).

[0293] Method B: To a mixture of ethyl 6-bromo-4-hydroxy-2-oxo-1H-1,8-naphthyridine-3-carboxylate (1 g, 3.19 mmol, 1 equivalent) and 4-(2-chloroethyl)morpholine (653.74 mg, 3.51 mmol, 1.1 equivalent, HCl) in DMF (20 mL), Cs2CO3 (8.32 g, 25.55 mmol, 8 equivalents) was added under N2. The mixture was stirred at 50°C for 5 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak. The mixture was purified by preparative HPLC (neutral conditions) to obtain the desired product (0.85 g) as a yellow solid (which was used without further purification).

[0294] LC-MS (ESI+) of the product: m / z 426.1, 428.1 [M+H] + ,Rt:1.726 minutes.

[0295] The column used for chromatography was a HALO AQ-C18 2.1×30 mm (2.7 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC-grade acetonitrile. The gradient was 5 to 95% B at 2.20 min, 5% B at 0.01 min, 5 to 95% B (0.01 to 1.00 min), 95 to 100% B (1.00 to 1.80 min), 5% B at 1.81 min, and retained at 5% B for 0.40 min. The flow rate was 1.0 mL / min.

[0296] Step 2: Preparation of 6-bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0297] To a solution of ethyl 6-bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate (30 mg, 70.38 μmol, 1 equivalent) and spiro[3.3]heptan-2-amine (7.83 mg, 70.38 μmol, 1 equivalent) in toluene (1 mL), DIEA (9.10 mg, 70.38 μmol, 12.26 μL, 1 equivalent) was added. The mixture was stirred at 120 °C for 2 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0298] The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (HCl conditions) to obtain 6-bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (6 mg, 12.21 μmol) as a white solid.

[0299] 1 H NMR(400MHz,CDCl3)δ=13.54-13.39(m,1H),9.88(br d,J=6.4Hz,1H),8.62(br s,1H),8.51(s,1H),4.89(br s,2H),4.36-4.20(m,3H),3.94(br d,J=11.5Hz,2H),3.64(br s,2H),3.27(br s,2H),2.93(br d,J=1.4Hz,2H),2.49-2.40(m,2H),2.05-1.99(m,2H),1.98-1.88(m,4H),1.84-1.74(m,2H). LC-MS (ESI+) of the product: m / z 491.1,493.1 [M+H] + ,Rt:2.440 minutes.

[0300] LCMS method 5-95AB-6min-220-254-ELSD: The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.00 min, held at 95%B for 1.00 min, and then 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization.

[0301] Example 5-6 Synthesis of (4-fluorophenyl)-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (Compound 5) [ka] Step 1: Synthesis of 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl [ka]

[0302] To a mixture of ethyl 6-bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate (200 mg, 469.20 μmol, 1 equivalent), K2CO3 (194.54 mg, 1.41 mmol, 3 equivalents), and (4-fluorophenyl)boronic acid (78.78 mg, 563.04 μmol, 1.2 equivalents) in dioxane (0.2 mL) and H2O (0.02 mL), Pd(PPh3)4 (54.22 mg, 46.92 μmol, 0.1 equivalent) was added under N2. The mixture was stirred at 100°C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0303] The mixture was filtered, and the filtrate was separated and purified by HPLC (column: Luna Omega 5u Polar C18 100A; mobile phase: [water (0.04% HCl)-ACN]; B%: 25% to 55%, 7 min) to obtain 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxylate ethyl (110 mg, 249.18 μmol) as a white solid.

[0304] 1 H NMR(400MHz,CDCl3)δ=13.37-13.13(m,1H),8.89(d,J=2.1Hz,1H),8.59(d,J=2.1Hz,1H),7. 60(dd,J=5.2,8.6Hz,2H),7.23-7.19(m,2H),5.07-4.98(m,2H),4.61-4.49(m,2H),4.36(br t,J=12.0Hz,2H),4.07-3.94(m,2H),3.76(br d,J=11.6Hz,2H),3.43(br s,2H),3.11-2.95(m,2H),1.50(t,J=7.1Hz,3H). LC-MS (ESI+) analysis of the product: m / z 442.3 [M+H] + ,Rt:1.877 minutes.

[0305] 5-95AB: The column used for chromatography was HALO AQ-C18 2.1×30 mm (2.7 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 The value was ~1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC-grade acetonitrile. The gradient was 5 to 95% B at 2.20 min, 5% B at 0.01 min, 5 to 95% B (0.01 to 1.00 min), 95 to 100% B (1.00 to 1.80 min), 5% B at 1.81 min, and held at 5% B for 0.40 min. The flow rate was 1.0 mL / min.

[0306] Step 2: Preparation of 6-(4-fluorophenyl)-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide [ka]

[0307] A mixture of ethyl 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate (20 mg, 45.31 μmol, 1 equivalent) and 4-methylcyclohexaneamine (6.15 mg, 54.37 μmol, 7.20 μL, 1.2 equivalents) in toluene (0.5 mL) was to which DIEA (5.86 mg, 45.31 μmol, 7.89 μL, 1 equivalent) was added. The mixture was stirred at 120 °C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0308] The mixture was filtered and concentrated under reduced pressure. The residue was smeared with MeOH (0.3 mL) and filtered to obtain 6-(4-fluorophenyl)-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (11.1 mg, 21.83 μmol) as a white solid.

[0309] 1 H NMR(400MHz,CDCl3)δ=10.57-10.10(m,1H),8.88(d,J=2.5Hz,1H),8.60(d,J=2.5Hz,1H) ,7.68-7.58(m,2H),7.21(t,J=8.5Hz,2H),4.72-4.65(m,2H),4.28-3.81(m,1H),3.71(br d,J=4.0Hz,4H),2.77-2.55(m,6H),2.12-1.58(m,5H),1.46-1.04(m,4H),1.01-0.92(m,3H). LCMS for product (ESI-): m / z 509.3[M+H] + ,Rt:2.818 minutes.

[0310] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.40 min, held at 95%B for 0.45 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 0.8 ml / min. Mobile phase A was H2O + 10 mM NH4HCO3, and mobile phase B was acetonitrile. The column used for chromatography was Xbridge Shield. The RP18 2.1 × 50 mm column (5 μm particles) was used. Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization. The MS range was 100 to 1000.

[0311] Example 6 - Synthesis of 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 6) [ka] Preparation of 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0312] To a mixture of ethyl 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate (50 mg, 113.26 μmol, 1 equivalent) and spiro[3.3]heptan-2-amine (20.07 mg, 135.92 μmol, 1.2 equivalents, HCl) in toluene (0.5 mL), DIEA (14.64 mg, 113.26 μmol, 19.73 μL, 1 equivalent) was added at 20 °C. The mixture was stirred at 120 °C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0313] The mixture was filtered, concentrated, and the residue was polished with MeOH (0.5 mL) and filtered to obtain 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3.3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (27.3 mg, 53.30 μmol) as a white solid.

[0314] 1 H NMR(400MHz,CDCl3)δ=10.31(br d,J=8.5Hz,1H),8.88(d,J=2.0Hz,1H),8.59(d,J=2.0Hz,1H),7.62(dd,J=5.3,8.8Hz,2H),7.23-7.17(m,2H),4.69(br t,J=7.0Hz,2H),4.46-4.34(m,1H),3.71(br s,4H),2.78-2.56(m,6H),2.55-2.48(m,2H),2.14-1.95(m,6H),1.92-1.82(m,2H). LCMS (ESI+) for product: m / z 507.3[M+H] + ,Rt:2.603 minutes.

[0315] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.00 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization.

[0316] Example 7: Synthesis of -N-(4,4-difluorocyclohexyl)-6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (Compound 7) [ka] Preparation of N-(4,4-difluorocyclohexyl)-6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0317] A mixture of ethyl 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate (5 mg, 11.33 μmol, 1 equivalent) and 4,4-difluorocyclohexaneamine (2.33 mg, 13.59 μmol, 1.2 equivalents, HCl) in toluene (0.2 mL) was to be mixed with DIEA (1.46 mg, 11.33 μmol, 1.97 μL, 1 equivalent) at 20 °C. The mixture was stirred at 120 °C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0318] The mixture was filtered and concentrated, and the residue was purified by preparative HPLC (column: Kromasil C18 (250 × 50 mm × 10 μm); mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 60% to 85%, 10 min) to obtain N-(4,4-difluorocyclohexyl)-6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (6.1 mg, 11.47 μmol) as a white solid.

[0319] 1H NMR(400MHz,CDCl3)δ=10.38(br d,J=8.0Hz,1H),8.90(d,J=2.0Hz,1H),8.60(d,J=2.0Hz,1H),7.63(dd,J=5.0,8.5Hz,2H),7.22(br t,J=8.5Hz,2H),4.68(br t,J=7.3Hz,2H),4.17-4.05(m,1H),3.71(br t,J=4.3Hz,4H),2.71(br t,J=7.3Hz,2H),2.63(br s,4H),2.23-2.06(m,4H),2.03-1.76(m,4H). LCMS (ESI+) for product: m / z 531.3[M+H] + ,Rt:2.429 minutes.

[0320] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.00 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization.

[0321] Example 8: Synthesis of -N-(bicyclo[1.1.1]pentan-1-yl)-6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 8) [ka] Preparation of N-(bicyclo[1.1.1]pentan-1-yl)-6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0322] To a mixture of ethyl 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate (5 mg, 11.33 μmol, 1 equivalent) and [1.1.1]pentan-1-amine HCl (1.63 mg, 13.59 μmol, 1.2 equivalents, HCl) in toluene (0.3 mL), DIEA (1.46 mg, 11.33 μmol, 1.97 μL, 1 equivalent) was added at 20°C. The mixture was stirred at 120°C for 1 hour. LC-MS revealed complete consumption of the starting material and the formation of a new peak.

[0323] The mixture was filtered, concentrated, and the residue was polished with MeOH (0.5 mL) and filtered to obtain N-(bicyclo[1.1.1]pentan-1-yl)-6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (7.2 mg, 14.99 μmol) as a white solid. 1 H NMR(400MHz,CDCl3)δ=10.51(br s,1H),8.89(d,J=2.0Hz,1H),8.60(d,J=2.5Hz,1H),7.63(dd,J=5.0,8.5Hz,2H),7.21(t,J=8.8Hz,2H),4.68(br t,J=7.0Hz,2H),3.71(br t,J=4.3Hz,4H),2.70(br t,J=7.0Hz,2H),2.63(br s,4H),2.54(s,1H),2.23(s,6H). LCMS (ESI+) for product: m / z 479.2[M+H] + ,Rt:2.444 minutes.

[0324] LCMS method: The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.00 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization.

[0325] Example 9 - Synthesis of 6-(4-fluorophenyl)-N-(1-(4-fluorophenyl)ethyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 9) [ka] Preparation of 6-(4-fluorophenyl)-N-(1-(4-fluorophenyl)ethyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0326] A mixture of ethyl 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate (39 mg, 88.34 μmol, 1 equivalent) and 1-(4-fluorophenyl)ethanamine (14.75 mg, 106.01 μmol, 13.92 μL, 1.2 equivalents) in toluene (1 mL) was mixed with DIEA (11.42 mg, 88.34 μmol, 15.39 μL, 1 equivalent). The mixture was stirred at 120 °C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0327] The mixture was filtered, concentrated under reduced pressure, and the residue was purified using HPLC (neutral conditions) to obtain 6-(4-fluorophenyl)-N-(1-(4-fluorophenyl)ethyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (15.8 mg, 28.97 μmol) as a white solid.

[0328] 1 H NMR(400MHz,CDCl3)δ=10.69-10.62(m,1H),8.89(d,J=2.4Hz,1H),8.59(d,J=2.1H z,1H),7.67-7.58(m,2H),7.39(dd,J=5.4,8.6Hz,2H),7.23-7.19(m,2H),7.06(br t,J=8.6Hz,2H),5.26(quin,J=7.1Hz,1H),4.72-4.65(m,2H),3.70(br t,J=4.4Hz,4H),2.76-2.68(m,2H),2.63(br s, 4H), 1.63 (d, J=6.9Hz, 3H). LC-MS (ESI+) of the product: m / z 535.2 [M+H] + ,Rt:2.510 minutes.

[0329] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.00 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization.

[0330] Example 10 - Synthesis of 4-hydroxy-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 10) [ka] Step 1: Preparation of 4-hydroxy-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl [ka]

[0331] Pd(PPh3)4 (27.11 mg, 23.46 μmol, 0.1 equivalent) was added to a mixture of ethyl 6-bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthiridine-3-carboxylate (100 mg, 234.60 μmol, 1 equivalent), K2CO3 (97.27 mg, 703.79 μmol, 3 equivalents), and (4-methoxyphenyl)boronic acid (53.47 mg, 351.90 μmol, 1.5 equivalents) under N2 conditions. The mixture was stirred at 100°C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0332] The mixture was filtered and concentrated, and the residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 15% to 35%, 10 min) to obtain ethyl 4-hydroxy-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxylate (15 mg, 33.08 μmol) as a yellow solid.

[0333] 1H NMR(400MHz,CDCl3)δ=14.45(s,1H),8.91(d,J=1.9Hz,1H),8.58(d,J=1.9Hz,1H),7.57(d,J=8.6Hz,2H),7.05(d,J=8.6Hz,2H),5.02(br t,J=6.3Hz,2H),4.55(q,J=7.0Hz,2H),4.37(br t,J=12.1Hz,2H),4.00(br d,J=11.9Hz,2H),3.89(s,3H),3.74(br d,J=11.3Hz,2H),3.41(br s,2H),3.05(br d,J=9.6Hz,2H),1.54-1.43(m,3H).

[0334] Step 2: Preparation of 4-hydroxy-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0335] 4-hydroxy-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate ethyl (15 mg, 33.08 μmol, 1 equivalent) and spiro[3.3]heptan-2-amine (5. To a mixture of 86 mg, 39.69 μmol, 1.2 equivalents, HCl, DIEA (4.27 mg, 33.08 μmol, 5.76 μL, 1 equivalent) was added at 20°C. The mixture was stirred at 120°C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0336] The mixture was filtered, concentrated, the residue was polished with MeOH, filtered (0.5 mL), and filtered again to obtain -hydroxy-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3.3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (10.4 mg, 20.05 μmol) as a white solid.

[0337] 1 H NMR(400MHz,CDCl3)δ=10.34(br d,J=7.6Hz,1H),8.90(d,J=2.5Hz,1H),8.59(d,J=2.5Hz,1H),7.59(d,J=8.6Hz,2H),7.05(d,J=8.6Hz,2H ),4.73-4.62(m,2H),4.40(sxt,J=8.0Hz,1H),3.89(s,3H),3.76-3.66(m,4H),2.75-2.68(m,2H),2.64(br s,4H),2.56-2.48(m,2H),2.14-1.95(m,6H),1.91-1.82(m,2H). LC-MS (ESI+) analysis of the product: m / z 519.3 [M+H] + ,Rt:2.570 minutes.

[0338] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.40 min, held at 95%B for 0.45 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 0.8 ml / min. Mobile phase A was H2O + 10 mM NH4HCO3, and mobile phase B was acetonitrile. The column used for chromatography was Xbridge Shield. The RP18 2.1 × 50 mm column (5 μm particles) was used. The detection methods included diode array (DAD) detection, evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0339] Example 11 - Synthesis of 6-(4-chlorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 11) [ka] Step 1: 6-(4-chlorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl [ka]

[0340] To a mixture of ethyl 6-bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate (100 mg, 234.60 μmol, 1 equivalent), K2CO3 (97.27 mg, 703.79 μmol, 3 equivalents), and (4-chlorophenyl)boronic acid (44.02 mg, 281.52 μmol, 1.2 equivalents) in dioxane (1 mL) and H2O (0.1 mL), Pd(PPh3)4 (27.11 mg, 23.46 μmol, 0.1 equivalent) was added under N2. The mixture was stirred at 100°C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0341] The mixture was filtered, concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5μm; mobile phase: [water (0.04%HCl)-ACN]; B%: 25% to 45%, 10 min) to obtain the desired product (33 mg) as a white solid (which was used without further purification).

[0342] LC-MS (ESI+) analysis of the product: m / z 458.2 [M+H] + ,Rt:1.583 minutes.

[0343] LCMS method The column used for chromatography was a HALO AQ-C18 2.1×30 mm (2.7 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC-grade acetonitrile. The gradient was 5 to 95% B at 2.20 min, 5% B at 0.01 min, 5 to 95% B (0.01 to 1.00 min), 95 to 100% B (1.00 to 1.80 min), 5% B at 1.81 min, and retained at 5% B for 0.40 min. The flow rate was 1.0 mL / min.

[0344] Step 2: Preparation of 6-(4-chlorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0345] To a mixture of ethyl 6-(4-chlorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate (32 mg, 69.88 μmol, 1 equivalent) and spiro[3.3]heptan-2-amine (12.38 mg, 83.86 μmol, 1.2 equivalents, HCl) in toluene (1 mL), DIEA (9.03 mg, 69.88 μmol, 12.17 μL, 1 equivalent) was added. The mixture was stirred at 120 °C for 1 hour. TLC showed completion of the reaction and formation of new spots.

[0346] The mixture was filtered, concentrated under reduced pressure, and the residue was polished with MeOH (0.5 mL) and filtered to obtain the desired product (10.4 mg, 19.49 μmol) as a white solid.

[0347] 1 H NMR(400MHz,CDCl3)δ=10.34-10.27(m,1H),8.90(d,J=2.3Hz,1H),8.61(d,J=2.4Hz,1H),7.59(d,J=8.6Hz,2H),7.49(br d,J=8.3Hz,2H),4.70-4.65(m,2H),4.45-4.36(m,1H),3.75-3.67(m,4H),2.75-2.68(m,2H),2.63(br s,4H),2.56-2.49(m,2H),2.12-1.96(m,6H),1.92-1.82(m,2H). LCMS (ESI+) for product: m / z 523.2[M+H] + ,Rt:2.711 minutes.

[0348] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.00 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization.

[0349] Example 12: Synthesis of 2-N-(bicyclo[1.1.1]pentan-1-yl)-6-(4-(difluoromethoxy)phenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 12) [ka] Step 1: Preparation of N-(bicyclo[1.1.1]pentan-1-yl)-6-bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0350] To a solution of ethyl 6-bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate (200 mg, 469.20 μmol, 1 equivalent) and bicyclo[1.1.1]pentan-3-amine (61.72 mg, 516.12 μmol, 1.1 equivalent, HCl) in toluene (1 mL), DIEA (60.64 mg, 469.20 μmol, 81.73 μL, 1 equivalent) was added. The mixture was stirred at 120 °C for 12 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0351] The mixture was concentrated to obtain N-(bicyclo[1.1.1]pentan-1-yl)-6-bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (240 mg) as a brownish solid (which was used without further purification).

[0352] LC-MS (ESI+) analysis of the product: m / z 465.3, 463.3[M+H]+, Rt: 0.687 mins.

[0353] LCMS method The gradient was 5 to 95%B at 0.7 min, 95 to 95%B at 0.45 min, 95 to 5%B at 0.01 min, and then retained at 0%B for 0.44 minutes (flow rate 1.5 mL / min). Mobile phase A was 0.0375% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Chromolith Flash RP-18e 25-2 mm column. Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization (MS).

[0354] Step 2: Preparation of N-(bicyclo[1.1.1]pentan-1-yl)-6-(4-(difluoromethoxy)phenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0355] To a solution of N-(3-bicyclo[1.1.1]pentanyl)-6-bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthirizine-3-carboxamide (120 mg, 259.00 μmol, 1 equivalent) and [4-(difluoromethoxy)phenyl]boronic acid (58.41 mg, 310.80 μmol, 1.2 equivalents) in dioxane (1 mL) and H2O (0.25 mL), K2CO3 (107.39 mg, 776.99 μmol, 3 equivalents) and Pd(PPh3)4 (29.93 mg, 25.90 μmol, 0.1 equivalent) were added. The mixture was stirred under N2 at 80°C for 2 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0356] The mixture is concentrated and the residue is separated by HPLC (neutral conditions; column: mobile phase: water (10 mM)). The mixture was purified using [NH4HCO3)-ACN]; B%: 75% to 95%, 10 min) to obtain N-(bicyclo[1.1.1]pentan-1-yl)-6-(4-(difluoromethoxy)phenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (21.2 mg, 40.26 μmol) as a white solid.

[0357] 1 H NMR(400MHz,CDCl3)δ=10.51(br s,1H),8.90(d,J=2.1Hz,1H),8.61(d,J=2.1Hz,1H),7.66(br d,J=8.6Hz,2H),7.31-7.28(m,2H),6.83-6.34(m,1H),4.68(br t,J=6.9Hz,2H),3.72(br d,J=3.5Hz,4H),2.73-2.52(m,7H),2.23(s,6H). LCMS (ESI+) for product: m / z 527.2[M+H]+, Rt: 3.692 min.

[0358] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.40 min, held at 95%B for 0.45 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 0.8 ml / min. Mobile phase A was H2O + 10 mM NH4HCO3, and mobile phase B was acetonitrile. The column used for chromatography was Xbridge Shield. The RP18 2.1×50mm column (5µm particles) was used. The detection methods were diode array (DAD) and positive electrospray ionization.

[0359] Example 13: Synthesis of N-(bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 13) [ka] Preparation of N-(bicyclo[1.1.1]pentan-1-yl)-4-hydroxy-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0360] To a solution of N-(3-bicyclo[1.1.1]pentanyl)-6-bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthirizine-3-carboxamide (60 mg, 129.50 μmol, 1 equivalent) and (4-methoxyphenyl)boronic acid (23.61 mg, 155.40 μmol, 1.2 equivalents) in dioxane (1 mL) and H2O (0.25 mL), K2CO3 (53.69 mg, 388.50 μmol, 3 equivalents) and Pd(PPh3)4 (14.96 mg, 12.95 μmol, 0.1 equivalent) were added. The mixture was stirred under N2 at 80°C for 2 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0361] The mixture was concentrated, and the residue was purified by preparative HPLC (neutral conditions) to obtain the desired product (7 mg, 14.27 μmol) as a white solid.

[0362] 1 H NMR(400MHz,CDCl3)δ=10.53(br s,1H),8.89(br s,1H),8.59(br s,1H),7.59(br d,J=8.3Hz,2H),7.04(br d,J=8.3Hz,2H),4.68(br t,J=6.7Hz,2H),3.88(s,3H),3.71(br s,4H),2.86-2.48(m,7H),2.23(s,6H). LCMS (ESI+) for product: m / z 491.2[M+H]+, Rt: 3.746 min.

[0363] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.40 min, held at 95%B for 0.45 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 0.8 ml / min. Mobile phase A was H2O + 10 mM NH4HCO3, and mobile phase B was acetonitrile. The column used for chromatography was Xbridge Shield. The RP18 2.1×50mm column (5µm particles) was used. The detection methods were diode array (DAD) and positive electrospray ionization.

[0364] Example 14 - Synthesis of 4-hydroxy-1-(2-morpholinoethyl)-2-oxo-6-phenyl-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 14) [ka] Step 1: 4-Hydroxy-1-(2-morpholinoethyl)-2-oxo-6-phenyl-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl [ka]

[0365] A mixture of 6-bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate ethyl (200 mg, 469.20 μmol, 1 equivalent), phenylboronic acid (57.21 mg, 469.20 μmol, 1 equivalent), K2CO3 (194.54 mg, 1.41 mmol, 3 equivalents), and Pd(PPh3)4 (54.22 mg, 46.92 μmol, 0.1 equivalent) in water (0.5 mL) and dioxane (2 mL) was degassed, purged three times with N2, and then stirred at 120°C for 2 hours under an N2 atmosphere. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0366] The mixture was filtered, concentrated under reduced pressure, and the residue was purified by preparative HPLC (neutral conditions) to obtain 4-hydroxy-1-(2-morpholinoethyl)-2-oxo-6-phenyl-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl (100 mg, 236.15 μmol) as a white solid.

[0367] 1 H NMR(400MHz,DMSO-d6)δ=8.89-8.82(m,1H),8.54-8.48(m,1H),8.02(s,3H),7.53(s,2H),4.54-4.44(m,2H),4.21-4.12(m,2H),3.64(br s,4H),2.67(br d,J=1.8Hz,2H),2.54(br s,4H),1.25(s,3H). LCMS (ESI+) for product: m / z 426.1[M+H] + ,Rt:0.740 minutes.

[0368] LCMS method 5-95AB_2 min: The column used for chromatography was Luna-C 18 2.0 × 30 mm (3 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in HPLC-grade acetonitrile. The gradient was 5 to 95%B at 2.00 min, 5%B at 0.01 min, and 5 to 95%B (0.01 to 1.0 The levels were 0 min, 95 to 100% B (1.00 to 1.80 min), 5% B at 1.81 min, and held at 5% B for 0.19 min. The flow rates were 1.0 mL / min (0.00 to 1.80 min) and 1.2 mL / min (1.81 to 2.00 min).

[0369] Step 2: Preparation of 4-hydroxy-1-(2-morpholinoethyl)-2-oxo-6-phenyl-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0370] To a solution of spiro[3,3]heptan-2-amine (23.63 mg, 212.53 μmol, 1 equivalent) and ethyl 4-hydroxy-1-(2-morpholinoethyl)-2-oxo-6-phenyl-1,8-naphthyrizine-3-carboxylate (90 mg, 212.53 μmol, 1 equivalent) in toluene (1 mL), DIEA (54.94 mg, 425.07 μmol, 74.04 μL, 2 equivalents) was added. The mixture was stirred at 120 °C for 2 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0371] The mixture was filtered, concentrated under reduced pressure, and the residue was purified by preparative HPLC (HCl conditions) to obtain the desired product (21 mg, 42.98 μmol) as a white solid.

[0372] 1H NMR(400MHz,CDCl3)δ=13.68-13.57(m,1H),10.08-10.01(m,1H),8.93(d,J=2.2Hz,1H),8.6 7(d,J=2.2Hz,1H),7.65(d,J=7.5Hz,2H),7.53(t,J=7.5Hz,2H),7.49-7.42(m,1H),5.10-5.0 2(m,2H),4.45-4.35(m,3H),4.08-3.98(m,2H),3.77-3.67(m,2H),3.48-3.36(m,2H),3.13- 3.00(m,2H),2.57-2.50(m,2H),2.11(t,J=7.5Hz,2H),2.07-1.99(m,4H),1.91-1.85(m,2H). LCMS (ESI+) for product: m / z 489.3[M+H] + ,Rt:2.587 minutes.

[0373] LCMS method 5_95AB_6 min-220-254-ELSD: The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.00 min, held at 95%B for 1.00 min, and then 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization.

[0374] Example 15 - Synthesis of 6-(4-(difluoromethoxy)phenyl)-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (Compound 15) [ka] Preparation of 2-[[4-(3-isoquinolylmethyl)pyrazolo[1,5-a]pyridine-3-carbonyl]amino]spiro[3,3]heptane-6-carboxylic acid 1-phenylethyl [ka]

[0375] A mixture of 6-bromo-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyrizine-3-carboxamide (90 mg, 182.41 μmol, 1 equivalent), [4-(difluoromethoxy)phenyl]boronic acid (41.14 mg, 218.89 μmol, 1.2 equivalents), Pd(dppf)Cl2.CH2Cl2 (14.90 mg, 18.24 μmol, 0.1 equivalent), and Na2CO3 (29.00 mg, 273.62 μmol, 1.5 equivalents) in dioxane (2 mL) and water (0.2 mL) was stirred under N2 at 90°C for 2 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0376] The mixture was concentrated, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 70% to 90%, 6 min) to obtain 2-[[4-(3-isoquinolylmethyl)pyrazolo[1,5-a]pyridine-3-carbonyl]amino]spiro[3.3]heptane-6-carboxylic acid 1-phenylethyl (31.2 mg, 55.21 μmol) as a yellow solid.

[0377] 1H NMR(400MHz,CDCl3)δ=10.61-10.07(m,1H),8.89(d,J=2.5Hz,1H),8.62(d,J=2.5Hz,1H),7.66( d,J=8.6Hz,2H),7.29(s,2H),6.83-6.30(m,1H),4.80-4.59(m,2H),4.30-3.81(m,1H),3.71(br d,J=3.9Hz,4H),2.72(q,J=7.2Hz,2H),2.63(br s,4H), 2.12-2.00(m,1H), 1.92-1.76(m,2H), 1.73-1.63(m,2H), 1.46-1.22(m,3H), 1.21-1.05(m,1H), 1.04-0.90(m,3H). LCMS (ESI+) of the product: m / z 557.3[M+H]+, Rt: 3.903 mins.

[0378] LCMS method The gradient was 0 to 80%B in 3.4 mins, 80 to 100%B in 0.45 mins, 100 to 0%B in 0.01 mins, and then retained at 0%B for 0.65 minutes (flow rate 0.6 mL / min). Mobile phase A was 0.0375% CF3CO2H in water, and mobile phase B was 0.018% CF3CO2H in CH3CN. The column used for chromatography was a 2.0 × 50 mm phenomenex Luna-C18 column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization (MS).

[0379] Example 16 - Synthesis of 6-(4-cyanophenyl)-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 16) [ka] Preparation of 6-(4-cyanophenyl)-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0380] A mixture of 6-bromo-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyrizine-3-carboxamide (90 mg, 182.41 μmol, 1 equivalent), (4-cyanophenyl)boronic acid (32.16 mg, 218.89 μmol, 1.2 equivalents), Pd(dppf)Cl2.CH2Cl2 (14.90 mg, 18.24 μmol, 0.1 equivalent), and Na2CO3 (29.00 mg, 273.62 μmol, 1.5 equivalents) in dioxane (2 mL) and water (0.2 mL) was stirred at 90°C under N2 for 2 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0381] The mixture was concentrated, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 70% to 98%, 8 min) to obtain 6-(4-cyanophenyl)-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (26.6 mg, 51.02 μmol) as a yellow solid.

[0382] 1 H NMR(400MHz,CDCl3)δ=10.61-9.94(m,1H),8.92(d,J=2.5Hz,1H),8.66(d,J= 2.5Hz,1H),7.94-7.69(m,4H),4.77-4.59(m,2H),4.34-3.79(m,1H),3.69(br s,4H),2.71(q,J=6.9Hz,2H),2.62(br s,4H),2.15-2.00(m,1H),1.93-1.74(m,2H),1.72-1.64(m,2H),1.43-1.25(m,3H),1.19-1.04(m,1H),1.01-0.91(m,3H). LC-MS (ESI+) analysis of the product: m / z 516.3[M+H]+, Rt: 3.753 mins.

[0383] LCMS method The gradient was 0 to 80%B in 3.4 mins, 80 to 100%B in 0.45 mins, 100 to 0%B in 0.01 mins, and then retained at 0%B for 0.65 minutes (flow rate 0.6 mL / min). Mobile phase A was 0.0375% CF3CO2H in water, and mobile phase B was 0.018% CF3CO2H in CH3CN. The column used for chromatography was a 2.0 × 50 mm phenomenex Luna-C18 column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization (MS).

[0384] Example 17 - Synthesis of 6-(4-cyclopropylphenyl)-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (Compound 17) [ka] Preparation of 6-(4-cyclopropylphenyl)-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0385] 6-bromo-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyrizine-3-carboxamide (90 mg, 182.41 μmol, 1 equivalent), (4-cyclopropylphenyl)boronic acid (35.46 mg, 218.89 μmol, 1.2 equivalents), Pd(dppf)Cl2.CH2Cl2 (14.90 mg, 18.24 μmol) in dioxane (2 mL) and water (0.2 mL). A mixture of 0.1 equivalent of the starting material and Na2CO3 (29.00 mg, 273.62 μmol, 1.5 equivalent) was stirred at 90°C under N2 for 2 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0386] The mixture was concentrated, and the residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100×25mm×5μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 85% to 98%, 10 min) to obtain 6-(4-cyclopropylphenyl)-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (11.3 mg, 21.29 μmol) as a yellow solid.

[0387] 1 H NMR(400MHz,CDCl3)δ=10.78-9.87(m,1H),8.90(br s,1H),8.61(br s,1H),7.55(br d,J=6.4Hz,2H),7.21(br d,J=6.8Hz,2H),4.68(br d,J=6.0Hz,2H),4.38-3.81(m,1H),3.70(br s,4H),2.94-2.45(m,6H),2.16-1.94(m,2H),1.91-1.76(m,2H),1.69(br s,1H),1.50-1.22(m,4H),1.13(br s,1H),1.02(br dd, J=5.9, 17.3Hz, 3H), 0.94(br d, J=5.1Hz, 2H), 0.77(br s, 2H). LCMS (ESI+) of the product: m / z 531.3[M+H]+, Rt: 4.174 mins.

[0388] LCMS method The gradient was 0 to 80%B in 3.4 mins, 80 to 100%B in 0.45 mins, 100 to 0%B in 0.01 mins, and then retained at 0%B for 0.65 minutes (flow rate 0.6 mL / min). Mobile phase A was 0.0375% CF3CO2H in water, and mobile phase B was 0.018% CF3CO2H in CH3CN. The column used for chromatography was a 2.0 × 50 mm phenomenex Luna-C18 column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization (MS).

[0389] Example 18 - Synthesis of 4-hydroxy-6-(4-isopropoxyphenyl)-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (Compound 18) [ka] Preparation of 4-hydroxy-6-(4-isopropoxyphenyl)-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0390] A mixture of 6-bromo-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyrizine-3-carboxamide (150 mg, 304.02 μmol, 1 equivalent), (4-isopropoxyphenyl)boronic acid (65.67 mg, 364.82 μmol, 1.2 equivalents), Pd(dppf)Cl2.CH2Cl2 (24.83 mg, 30.40 μmol, 0.1 equivalent), and Na2CO3 (48.33 mg, 456.03 μmol, 1.5 equivalents) in dioxane (1 mL) and water (0.2 mL) was stirred under N2 at 90°C for 2 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0391] The mixture was concentrated, and the residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100×25mm×5μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 70% to 95%, 10 min) to obtain 4-hydroxy-6-(4-isopropoxyphenyl)-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (51.2 mg, 93.32 μmol) as a yellow solid.

[0392] 1 H NMR(400MHz,CDCl3)δ=10.63-10.10(m,1H),8.89(d,J=2.5Hz,1H),8.59(d,J=2.5Hz,1H),7 .58(d,J=7.8Hz,2H),7.02(d,J=8.8Hz,2H),4.80-4.57(m,3H),4.30-3.83(m,1H),3.70(br s,4H),2.80-2.52(m,6H),2.08(br dd, J=1.9, 13.3Hz, 1H), 1.92-1.76(m, 2H), 1.73-1.63(m, 2H), 1.39(d, J=6.0Hz, 9H), 1.19-1.05(m, 1H), 1.04-0.91(m, 3H). LCMS (ESI+) of the product: m / z 549.3[M+H]+, Rt: 4.085 mins.

[0393] LCMS method The gradient was 0 to 80%B in 3.4 mins, 80 to 100%B in 0.45 mins, 100 to 0%B in 0.01 mins, and then retained at 0%B for 0.65 minutes (flow rate 0.6 mL / min). Mobile phase A was 0.0375% CF3CO2H in water, and mobile phase B was 0.018% CF3CO2H in CH3CN. The column used for chromatography was a 2.0 × 50 mm phenomenex Luna-C18 column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization (MS).

[0394] Example 19 - Synthesis of 6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 19) [ka] Preparation of 6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0395] A mixture of 6-bromo-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxamide (90 mg, 182.41 μmol, 1 equivalent), 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (39.39 mg, 218.89 μmol, 1.2 equivalents), Pd(dppf)Cl2.CH2Cl2 (14.90 mg, 18.24 μmol, 0.1 equivalent), and Na2CO3 (29.00 mg, 273.62 μmol, 1.5 equivalents) in dioxane (1 mL) and water (0.1 mL) was stirred at 90°C under N2 for 2 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0396] The mixture was concentrated, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 75% to 99%, 6 min) to obtain 6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (8.3 mg, 14.64 μmol) as a white solid.

[0397] 1 H NMR(400MHz,CDCl3)δ=10.64-10.05(m,1H),8.86(d,J=2.4Hz,1H),8.57(d,J=2.4Hz,1H),7.19- 7.12(m,2H),7.00(d,J=8.1Hz,1H),4.77-4.54(m,2H),4.33(s,4H),4.27-3.84(m,1H),3.70(br s,4H), 2.80-2.55(m,6H), 2.11-2.04(m,1H), 1.90-1.75(m,2H), 1.73-1.58(m,2H), 1.45-1.29(m,3H), 1.15-1.08(m,1H), 1.02-0.90(m,3H). LCMS (ESI+) of the product: m / z 549.3[M+H]+, Rt: 3.898 mins.

[0398] LCMS method The gradient was 0 to 80%B in 3.4 mins, 80 to 100%B in 0.45 mins, 100 to 0%B in 0.01 mins, and then retained at 0%B for 0.65 minutes (flow rate 0.6 mL / min). Mobile phase A was 0.0375% CF3CO2H in water, and mobile phase B was 0.018% CF3CO2H in CH3CN. The column used for chromatography was a 2.0 × 50 mm phenomenex Luna-C18 column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization (MS).

[0399] Example 20: Synthesis of 4-hydroxy-6-(4-methoxyphenyl)-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (Compound 20) [ka] Preparation of 4-hydroxy-6-(4-methoxyphenyl)-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0400] A mixture of 6-bromo-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyrizine-3-carboxamide (56 mg, 113.50 μmol, 1 equivalent), (4-methoxyphenyl)boronic acid (20.70 mg, 136.20 μmol, 1.2 equivalents), Pd(dppf)Cl2.CH2Cl2 (9.27 mg, 11.35 μmol, 0.1 equivalent), and Na2CO3 (18.04 mg, 170.25 μmol, 1.5 equivalents) in dioxane (2 mL) and water (0.2 mL) was stirred at 90°C under N2 for 2 hours. LC-MS showed that the starting material was consumed and the desired product was detected.

[0401] The mixture was concentrated, and the residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100×25mm×5μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 70% to 95%, 10 min) to obtain 4-hydroxy-6-(4-methoxyphenyl)-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (11.1 mg, 21.24 μmol) as a white solid.

[0402] 1H NMR(400MHz,CDCl3)δ=10.71-9.86(m,1H),8.89(br s,1H),8.59(br s,1H),7.59(br d,J=7.8Hz,2H),7.04(br d,J=7.9Hz,2H),4.68(br d,J=6.6Hz,2H),3.88(s,4H),3.70(br s,4H),2.98-2.42(m,6H),2.08(br d,J=10.8Hz,1H),1.95-1.77(m,2H),1.73-1.62(m,2H),1.45-1.24(m,3H),1.18-1.04(m,1H),1.02-0.86(m,3H). LC-MS (ESI+) analysis of the product: m / z 521.3[M+H]+, Rt: 3.948 mins.

[0403] LCMS method The gradient was 0 to 80%B in 3.4 mins, 80 to 100%B in 0.45 mins, 100 to 0%B in 0.01 mins, and then retained at 0%B for 0.65 minutes (flow rate 0.6 mL / min). Mobile phase A was 0.0375% CF3CO2H in water, and mobile phase B was 0.018% CF3CO2H in CH3CN. The column used for chromatography was a 2.0 × 50 mm phenomenex Luna-C18 column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization (MS).

[0404] Example 21 - Synthesis of 6-(5-cyanopyridine-2-yl)-N-(1-(4-fluorophenyl)ethyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 21) [ka] Step 1: 4-Hydroxy-1-(2-morpholinoethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl [ka]

[0405] DMSO (20 mL) contains 6-bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyrizine-3-carboxylate ethyl (800 mg, 1.88 mmol, 1 equivalent), KOAc (552.58 mg, 5.63 mmol, 3 equivalents), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-di)ethyl carboxylate. A mixture of oxaborolan-2-yl)-1,3,2-dioxaborolan (4.77 g, 18.77 mmol, 10 equivalents) was mixed with Pd(PPh3)2Cl2 (131.73 mg, 187.68 μmol, 0.1 equivalent) under N2 conditions. The mixture was stirred at 80°C for 1 hour. LC-MS revealed complete consumption of the starting material and the formation of a new peak.

[0406] The mixture was filtered, and the residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10-movement μm; phase: [water (0.05% HCl)-ACN]; B%: 0% to 30%, 20 min) to obtain 4-hydroxy-1-(2-morpholinoethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl (400 mg) as a yellow oil (which was used in the next step without further purification).

[0407] LC-MS (ESI+) analysis of the product: m / z 474.3 [M+H] + ,Rt:1.453 minutes.

[0408] LCMS method The column used for chromatography was a HALO AQ-C18 2.1×30 mm (2.7 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC-grade acetonitrile. The gradient was 5 to 95% B at 2.20 min, 5% B at 0.01 min, 5 to 95% B (0.01 to 1.00 min), 95 to 100% B (1.00 to 1.80 min), 5% B at 1.81 min, and retained at 5% B for 0.40 min. The flow rate was 1.0 mL / min.

[0409] Step 2: 6-(5-cyanopyridine-2-yl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl [ka]

[0410] Pd(PPh3)4 (65.92 mg, 57.04 μmol, 0.1 equivalent) was added to a mixture of 4-hydroxy-1-(2-morpholinoethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,8-naphthyridine-3-carboxylate ethyl (270 mg, 570.43 μmol, 1 equivalent), K2CO3 (473.02 mg, 3.42 mmol, 6 equivalents), and 6-bromopyridine-3-carbonitride (125.27 mg, 684.52 μmol, 1.2 equivalents) under N2 conditions. The mixture was stirred at 100°C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0411] The mixture was filtered and concentrated under reduced pressure. The residue was separated and subjected to preparative HPLC (column: Phenomene). The substance was purified using x luna C18 (250 × 50 mm × 10 μm) mobile phase (water (0.05% HCl)-ACN); B%: 5% to 35%, 10 min) to obtain 6-(5-cyanopyridine-2-yl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl (120 mg, 266.99 μmol) as a white solid.

[0412] 1 ¹H NMR (ET26059-546-P1C, 400MHz, DMSO-d6): δ=9.48 (d, J=2.5Hz, 1H), 8.51 (s, 1H), 8.44 (s, 1H), 8.39-8.35 (m, 1H), 4.77-4.69 (m, 4H), 4.34 (q, J=7.0Hz, 4H), 4.04-4.00 (m, 2H), 3.52 (br s, 4H), 1.31 (s, 3H). LC-MS (ESI+) of the product: m / z 450.2 [M+H] + ,Rt:1.213 minutes.

[0413] LCMS method The column used for chromatography was a HALO AQ-C18 2.1×30 mm (2.7 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC-grade acetonitrile. The gradient was 5 to 95% B at 2.20 min, 5% B at 0.01 min, 5 to 95% B (0.01 to 1.00 min), 95 to 100% B (1.00 to 1.80 min), 5% B at 1.81 min, and retained at 5% B for 0.40 min. The flow rate was 1.0 mL / min.

[0414] Step 3: Preparation of 6-(5-cyanopyridine-2-yl)-N-(1-(4-fluorophenyl)ethyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0415] A mixture of ethyl 6-(5-cyano-2-pyridyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyrizine-3-carboxylate (30 mg, 66.75 μmol, 1 equivalent) and 1-(4-fluorophenyl)ethanamine (11.15 mg, 80.10 μmol, 10.52 μL, 1.2 equivalents) in toluene (0.5 mL) was to which DIEA (8.63 mg, 66.75 μmol, 11.63 μL, 1 equivalent) was added. The mixture was stirred at 120 °C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0416] The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 50% to 80%, 10 min) to obtain 6-(5-cyanopyridine-2-yl)-N-(1-(4-fluorophenyl)ethyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (11.5 mg, 20.77 μmol) as a white solid. It was obtained as such.

[0417] 1 H NMR(400MHz,CDCl3)δ=10.23(br d,J=7.6Hz,1H),9.44(d,J=2.4Hz,1H),9.05(d,J=2.4Hz,1H),8.99(d,J=1.6Hz,1H),8.09(dd,J=2.1,8.4Hz,1H),7.9 7(d,J=8.3Hz,1H),4.70(t,J=7.1Hz,2H),4.40(sxt,J=8.0Hz,1H),3.74-3.67(m,4H),2.71(t,J=7.1Hz,2H),2.63(br s,4H),2.56-2.49(m,2H),2.02(br s,6H), 1.91-1.83(m,2H). LCMS (ESI+) of the product: m / z 543.2[M+H]+, Rt: 2.366 mins.

[0418] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.00 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization.

[0419] Example 22 - Synthesis of 6-(5-cyanopyridine-2-yl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 22) [ka] Preparation of 6-(5-cyanopyridine-2-yl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0420] 6-(5-cyano-2-pyridyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate ethyl (30 mg, 66.75 μmol, 1 equivalent) and spiro[3.3]heptan-2-amine in toluene (0.5 mL) A mixture of 8.91 mg (80.10 μmol, 1.2 equivalents) was mixed with DIEA (8.63 mg, 66.75 μmol, 11.63 μL, 1 equivalent). The mixture was stirred at 120°C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0421] The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 55% to 85%, 10 min) to obtain 6-(5-cyanopyridine-2-yl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthiridine-3-carboxamide (8.1 mg, 15.43 μmol) as a white solid.

[0422] 1 H NMR(400MHz,CDCl3)δ=10.23(br d,J=7.6Hz,1H),9.44(d,J=2.4Hz,1H),9.05(d,J=2.4Hz,1H),8.99(d,J=1.6Hz,1H),8.09(dd,J=2.1,8.4Hz,1H),7.9 7(d,J=8.3Hz,1H),4.70(t,J=7.1Hz,2H),4.40(sxt,J=8.0Hz,1H),3.74-3.67(m,4H),2.71(t,J=7.1Hz,2H),2.63(br s,4H),2.56-2.49(m,2H),2.02(br s,6H), 1.91-1.83(m,2H). LC-MS (ESI+) of the product: m / z 515.3[M+H] + ,Rt:2.436 minutes.

[0423] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.00 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization.

[0424] Example 23 - Synthesis of 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydroquinoline-3-carboxamide (compound 23) [ka] Step 1: 6-Bromo-1-(2-morpholinoethyl)-2H-benzo[d][1,3]oxazine-2,4(1H)-dione [ka]

[0425] To a solution of 6-bromo-1H-3,1-benzoxazine-2,4-dione (300 mg, 1.24 mmol, 1 equivalent) in DCM (3 mL), 2-morpholinoethanol (195.11 mg, 1.49 mmol, 182.35 μL, 1.2 equivalents), PPh3 (487.67 mg, 1.86 mmol, 1.5 equivalents), and DIAD (375.97 mg, 1.86 mmol, 361.51 μL, 1.5 equivalents) were added. The mixture was stirred at 25°C for 2 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0426] The mixture was washed with water (2 × 5 mL), the organic layer was washed with brine (5 mL), and dried over Na₂SO₄. The mixture was concentrated to obtain 6-bromo-1-(2-morpholinoethyl)-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (350 mg, 985.41 μmol) as a brown solid (which was used without further purification).

[0427] Step 2: 6-Bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydroquinoline-3-carboxylate ethyl [ka]

[0428] To a mixture of NaH (78.82 mg, 1.97 mmol, 60% purity, 2 equivalents) in DMF (3 mL), diethyl propanedione (789.15 mg, 4.93 mmol, 744.48 μL, 5 equivalents) and a solution of 6-bromo-1-(2-morpholinoethyl)-3,1-benzoxazine-2,4-dione (350 mg, 985.41 μmol, 1 equivalent) in DMF (2 mL) were added at 0°C. The mixture was stirred at 90°C for 2 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak. The mixture was poured into water (20 mL), and the aqueous layer was extracted with SiO2 (2 × 20 mL).

[0429] The aqueous phase was acidified to pH 3 by dropwise addition of 2N hydrochloric acid. The resulting solid was collected by filtration to obtain 6-bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydroquinoline-3-carboxylate ethyl (280 mg, 658.40 μmol) as a white solid.

[0430] 1 H NMR(400MHz,DMSO-d6)δ=8.19(d,J=2.1Hz,1H),7.90(dd,J=2.3,9.0Hz,1H),7.70(d,J=9.1 Hz, 1H), 4.56 (br t, J=7.1Hz, 2H), 4.32 (q, J=7.2Hz, 2H), 3.97-3.74 (m, 4H), 1.29 (t, J=7.1Hz, 3H). LCMS (ESI+) of the product: m / z 425.0, 427.0 [M+H]+, Rt: 0.902 mins.

[0431] LCMS method The gradient was 5 to 95%B at 0.7 min, 95 to 95%B at 0.45 min, 95 to 5%B at 0.01 min, and then retained at 0%B for 0.44 minutes (flow rate 1.5 mL / min). Mobile phase A was 0.0375% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Chromolith Flash RP-18e 25-2 mm column. Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization (MS).

[0432] Step 3: 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydroquinoline-3-carboxylate ethyl [ka]

[0433] A mixture of (4-fluorophenyl)boronic acid (151.35 mg, 1.08 mmol, 2 equivalents), 6-bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-quinoline-3-carboxylate ethyl (230 mg, 540.83 μmol, 1 equivalent), Na2CO3 (114.64 mg, 1.08 mmol, 2 equivalents), and Pd(dppf)Cl2.CH2Cl2 (44.17 mg, 54.08 μmol, 0.1 equivalent) in dioxane (2.5 mL) and H2O (0.5 mL) was degassed, purged three times with N2, and then stirred at 100°C for 2 hours under N2. LCMS showed complete consumption of the starting material and the formation of a new peak. The mixture was poured into water (10 mL), and the aqueous layer was extracted with SiO2 (3 × 20 mL). The combined organic layers were washed with brine (10 mL) and dried with Na2SO4.

[0434] The mixture was concentrated, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:2 to 0:1) to obtain 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydroquinoline-3-carboxylate ethyl (130 mg, 295.14 μmol) as a yellow solid.

[0435] LC-MS (ESI+) analysis of the product: m / z 441.1[M+H]+, Rt: 1.00 min.

[0436] LCMS method The gradient was 5 to 95%B at 0.7 min, 95 to 95%B at 0.45 min, 95 to 5%B at 0.01 min, and then held at 0%B for 0.44 minutes (flow rate 1.5 mL / min). Mobile phase A was 0.0375% trifluoroacetic acid in water, and mobile phase B was 0.0 in acetonitrile. The solution was 18% trifluoroacetic acid. The column used for chromatography was a Chromolith Flash RP-18e 25-2mm column. Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization (MS).

[0437] Step 4: Preparation of 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydroquinoline-3-carboxamide [ka]

[0438] To a solution of ethyl 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-quinoline-3-carboxylate (99.78 mg, 226.53 μmol, 1 equivalent) in toluene (2 mL), spiro[3.3]heptan-2-amine (40.13 mg, 271.83 μmol, 1.2 equivalents, HCl) was added. The mixture was stirred at 110 °C for 6 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0439] The mixture was concentrated, and the residue was purified by preparative HPLC (neutral conditions) to obtain 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydroquinoline-3-carboxamide (22 mg, 42.82 μmol) as a white solid.

[0440] 1 H NMR(400MHz,CDCl3)δ=10.35(br d,J=7.8Hz,1H),8.40(d,J=2.1Hz,1H),7.88(dd,J=2.1,8.9Hz,1H),7.66-7.58(m,2H),7.48(d,J=8.9Hz,1H),7.17(t,J=8. 6Hz,2H),4.47-4.36(m,3H),3.78-3.72(m,4H),2.72-2.59(m,6H),2.55-2.46(m,2H),2.13-1.93(m,6H),1.91-1.81(m,2H). LC-MS (ESI+) analysis of the product: m / z 506.3[M+H]+, Rt: 3.906 mins.

[0441] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.40 min, held at 95%B for 0.45 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 0.8 ml / min. Mobile phase A was H2O + 10 mM NH4HCO3, and mobile phase B was acetonitrile. The column used for chromatography was Xbridge Shield. The RP18 2.1×50mm column (5µm particles) was used. The detection methods were diode array (DAD) and positive electrospray ionization.

[0442] Example 24-N-(1-(4-cyanophenyl)ethyl)-6-(5-cyanopyridine-2-yl)-1-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-di Synthesis of hydro-1,8-naphthyrizine-3-carboxamide (compound 24) [ka] Preparation of N-(1-(4-cyanophenyl)ethyl)-6-(5-cyanopyridine-2-yl)-1-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide [ka]

[0443] A mixture of ethyl 1-[(4-fluorophenyl)methyl]-4-hydroxy-6-(5-isocyano-2-pyridyl)-2-oxo-1,8-naphthyrizine-3-carboxylate (100 mg, 225.02 μmol, 1 equivalent) and 4-(1-aminoethyl)benzonitrile (36.18 mg, 247.52 μmol, 1.1 equivalent) in toluene (1 mL) was to which DIEA (87.24 mg, 675.05 μmol, 117.58 μL, 3 equivalents) was added. The mixture was stirred at 120 °C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0444] The mixture was filtered, and the filtrate was separated and purified by HPLC (column: Luna Omega 5u Polar C18 100A; mobile phase: [water (0.04% HCl)-ACN]; B%: 70% to 90%, 7 min) to obtain N-(1-(4-cyanophenyl)ethyl)-6-(5-cyanopyridine-2-yl)-1-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (4.2 mg, 7.09 μmol, HCl) as a white solid.

[0445] 1 H NMR(400MHz,CDCl3)δ=10.62(br d,J=7.5Hz,1H),9.48(d,J=2.5Hz,1H),9.08(d,J=2.5Hz,1H),9.01(d,J=1.5Hz,1H),8.10(dd,J=2.0,8.5Hz,1H),7.97(d,J=8.5Hz,1H) ),7.69(d,J=8.0Hz,2H),7.56-7.47(m,4H),7.01(t,J=8.8Hz,2H),5.80-5.70(m,2H),5.30(quin,J=7.0Hz,1H),1.66(d,J=7.0Hz,3H). LC-MS (ESI+) analysis of the product: m / z 545.2 [M+H] + ,Rt:3.138 minutes.

[0446] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.00 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was The column used was a Kinetex C18 50×2.1 mm column (5 μm particles). The detection methods included diode array (DAD) detection, evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0447] Example 25 - Synthesis of 6-(5-(difluoromethoxy)pyridine-2-yl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 25) [ka] Step 1: 2-Bromo-5-(difluoromethoxy)pyridine [ka]

[0448] Potassium carbonate (476.59 mg, 3.45 mmol, 1.5 equivalent) was added to a mixture of 6-bromopyridine-3-ol (400 mg, 2.30 mmol, 1 equivalent) and (2-chloro-2,2-difluoroacetyl)oxysodium (700.98 mg, 4.60 mmol, 2 equivalents) in DMF (4 mL) under N2 conditions. The mixture was stirred at 80°C for 12 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak. The mixture was poured into water (40 mL) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated.

[0449] The residue was purified by flash silica gel chromatography (petroleum ether / ethyl acetate = 20:1 to 1:1) to obtain 2-bromo-5-(difluoromethoxy)pyridine (300 mg, 1.34 mmol) as a colorless oil.

[0450] 1 H NMR (400MHz, CDCl3) δ=8.28(d,J=3.0Hz,1H),7.50(d,J=8.5Hz,1H),7.38(dd,J=3.0,9.0Hz,1H),6.80-6.25(m,1H).

[0451] Step 2: 6-(5-(difluoromethoxy)pyridine-2-yl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl [ka]

[0452] Pd(PPh3)4 (24.41 mg, 21.13 μmol, 0.1 equivalent) was added to a mixture of 4-hydroxy-1-(2-morpholinoethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,8-naphthyridine-3-carboxylate ethyl (100 mg, 211.27 μmol, 1 equivalent), K2CO3 (175.20 mg, 1.27 mmol, 6 equivalents), and 2-bromo-5-(difluoromethoxy)pyridine (70.99 mg, 316.91 μmol, 1.5 equivalents) under N2. The mixture was stirred at 100°C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0453] The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 10% to 40%, 10 min) to obtain 6-(5-(difluoromethoxy)pyridine-2-yl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl (68 mg, 138.65 μmol) as a white solid.

[0454] 1H NMR(ET26059-548-P1C,400MHz,DMSO-d6)δ=9.39(d,J=2.5Hz,1H),9.08(d,J=2.0Hz,1H),8.65(d,J=2.5H z,1H),8.26(d,J=8.5Hz,1H),7.86(dd,J=3.0,8.5Hz,1H),7.59(s,1H),7.41(s,1H),7.23(s,1H),4.71(br t,J=6.0Hz,2H),4.34(q,J=7.3Hz,2H),3.54-3.41(m,4H),3.17(s,2H),2.53-2.52(m,4H),1.31(t,J=7.0Hz,3H). LC-MS (ESI+) analysis of the product: m / z 491.3 [M+H] + ,Rt:1.370 minutes.

[0455] LCMS method The column used for chromatography was a HALO AQ-C18 2.1×30 mm (2.7 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC-grade acetonitrile. The gradient was 5 to 95% B at 2.20 min, 5% B at 0.01 min, 5 to 95% B (0.01 to 1.00 min), 95 to 100% B (1.00 to 1.80 min), 5% B at 1.81 min, and retained at 5% B for 0.40 min. The flow rate was 1.0 mL / min.

[0456] Step 3: Preparation of 6-(5-(difluoromethoxy)pyridine-2-yl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0457] To a mixture of ethyl 6-[5-(difluoromethoxy)-2-pyridyl]-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyl-lysine-3-carboxylate (39 mg, 79.52 μmol, 1 equivalent) and spiro[3.3]heptan-2-amine (10.61 mg, 95.42 μmol, 1.2 equivalents) in toluene (1 mL), DIEA (10.28 mg, 79.52 μmol, 13.85 μL, 1 equivalent) was added. The mixture was stirred at 120 °C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0458] The reaction mixture was concentrated, and the residue was polished with MeOH (0.5 mL) to obtain 6-(5-(difluoromethoxy)pyridine-2-yl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3.3]heptan-2-yl)-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (20.1 mg, 35.46 μmol) as a white solid.

[0459] 1 H NMR(400MHz,DMSO-d6)δ=10.31(td,J=1.6,3.8Hz,1H),9.48(d,J=2.3Hz,1H),9.02(d,J=2.4Hz,1H), 8.64(d,J=2.8Hz,1H),8.29(d,J=8.9Hz,1H),7.83(dd,J=2.9,8.6Hz,1H),7.62-7.21(m,1H),4.57(br t,J=7.1Hz,2H),4.34-4.25(m,1H),3.54(br d,J=4.4Hz,4H),2.59(br t,J=6.0Hz,2H),2.55-2.51(m,4H),2.42(br d, J=2.8Hz, 2H), 2.09-2.01(m, 4H), 1.99-1.93(m, 2H), 1.85-1.77(m, 2H). LCMS (ESI+) of the product: m / z 556.3[M+H] + ,Rt:2.535 minutes.

[0460] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.00 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization. The MS range was 100 to 1000.

[0461] Example 26 Synthesis of -N-(4,4-dimethylcyclohexyl)-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 26) [ka] Step 1: 6-Bromo-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl [ka]

[0462] To a solution of ethyl 6-bromo-2-oxo-1H-1,8-naphthyridine-3-carboxylate (2 g, 6.73 mmol, 1 equivalent) in DMF (15 mL), Cs2CO3 (6.14 g, 18.85 mmol, 2.8 equivalents) was added at 20°C. The mixture was stirred at 20°C for 1 hour, and 4-(2-chloroethyl)morpholine (2.51 g, 13.46 mmol, 2 equivalents, HCl) was added to the mixture at 20°C. The mixture was stirred at 50°C for 14 hours. TLC showed that all starting material had been consumed and that a major spot had formed. The residue was poured into water (200 mL), and the aqueous phase was extracted with ethyl acetate (3 × 100 mL).

[0463] The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 0:1) 6-bromo-1-(2-morpholinoethyl)-2-oxo-1,8-naphthiridine-3-carboxylate ethyl ester to obtain 6-bromo-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthiridine-3-carboxylate ethyl ester (2 g, 4.87 mmol) as a yellow solid.

[0464] Step 2: 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid [ka]

[0465] To a solution of (4-methoxyphenyl)boronic acid (1.26 g, 8.29 mmol, 2 equivalents) and 6-bromo-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate ethyl (1.7 g, 4.14 mmol, 1 equivalent) in H2O (5 mL) and dioxane (20 mL), Na2CO3 (878.38 mg, 8.29 mmol, 2 equivalents) and Pd(dppf)Cl2.CH2Cl2 (338.39 mg, 414.37 μmol, 0.1 equivalent) were added under N2 conditions at 20°C. The mixture was stirred at 100°C for 15 hours. LC-MS showed that all starting materials were consumed and that a major peak was formed.

[0466] The mixture was filtered. The filtrate was separated and purified by preparative HPLC (column: Phenomenex Luna C18 150×30mm×5μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 20% to 32%, 10 min) to obtain 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid (1.3 g, 2.98 mmol) as a pale yellow solid.

[0467] 1H NMR(400MHz,DMSO-d6)δ=9.15(s,1H),8.96(s,1H),8.81(s,1H),7.77(br d,J=8.4Hz,2H),7.12(br d,J=8.6Hz,2H),4.80(br s,2H),3.86-3.57(m,7H). LCMS (ESI+) for product: m / z 410.3[M+H]+, Rt: 0.739 min.

[0468] LCMS method The gradient was 5 to 95%B at 0.7 min, 95 to 95%B at 0.45 min, 95 to 5%B at 0.01 min, and then retained at 0%B for 0.44 minutes (flow rate 1.5 mL / min). Mobile phase A was 0.0375% CF3CO2H in water, and mobile phase B was 0.018% CF3CO2H in CH3CN. The column used for chromatography was a Chromolith Flash RP-18e 25-2 mm column. Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization (MS).

[0469] Step 3: Preparation of N-(4,4-dimethylcyclohexyl)-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0470] To a solution of 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyrizine-3-carboxylic acid (70 mg, 170.97 μmol, 1 equivalent) in DMF (1 mL), HATU (130.01 mg, 341.94 μmol, 2 equivalents) and DIEA (66.29 mg, 512.90 μmol, 89.34 μL, 3 equivalents) were added at 20°C. 4,4-dimethylcyclohexaneamine (26.10 mg, 205.16 μmol, 1.2 equivalents) was added to the mixture at 20°C, and the mixture was stirred at 20°C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0471] The mixture was filtered, and the filtrate was separated and purified by HPLC (column: Waters Xbridge BEH C18 100×25mm×5μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 50% to 85%, 8 min) to obtain N-(4,4-dimethylcyclohexyl)-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (38.7 mg, 72.60 μmol) as a pale yellow solid.

[0472] 1 H NMR(400MHz,CDCl3)δ=9.95-9.60(m,1H),8.93(s,1H),8.90(d,J=1.5Hz,1H),8.18(d,J=1.8Hz,1H),7.57(d,J=8.8Hz,2H),7.06(d,J=8.6Hz,2H),4. 85-4.77(m,2H),4.01-3.94(m,1H),3.89(s,3H),3.77-3.62(m,4H),2.84- 2.57(m,6H),1.98-1.82(m,2H),1.57-1.26(m,6H),0.97(d,J=7.1Hz,6H). LC-MS (ESI+) analysis of the product: m / z 519.2[M+H]+, Rt: 2.341 mins.

[0473] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.4 to 3.0 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods were diode array (DAD) and positive electrospray ionization.

[0474] Example 27 Synthesis of -N-(4,4-difluorocyclohexyl)-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (Compound 27) [ka] Preparation of N-(4,4-difluorocyclohexyl)-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0475] To a solution of 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyrizine-3-carboxylic acid (70 mg, 170.97 μmol, 1 equivalent) in DMF (1 mL), HATU (130.01 mg, 341.94 μmol, 2 equivalents) and DIEA (66.29 mg, 512.90 μmol, 89.34 μL, 3 equivalents) were added at 20°C. 4,4-difluorocyclohexaneamine (35.21 mg, 205.16 μmol, 1.2 equivalents, HCl) was added to the mixture at 20°C, and the mixture was stirred at 20°C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0476] The mixture was filtered, and the filtrate was separated and purified by HPLC (column: Waters Xbridge BEH C18 100×25mm×5μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 50% to 85%, 8 min) to obtain N-(4,4-difluorocyclohexyl)-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (26.5 mg, 49.67 μmol) as a pale yellow solid.

[0477] 1H NMR(400MHz,CDCl3)δ= 9.91(br d,J=7.7Hz,1H),8.93-8.87(m,2H),8.17(d,J=2.4Hz,1H),7.56(d,J=8.6Hz,2H),7.05(d,J=8.6Hz,2H),4.78(br t,J=7.1Hz,2H),4.14(br s,1H),3.88(s,3H),3.68(br d,J=4.0Hz,4H),2.74(br t,J=6.9Hz,2H),2.63(br s,4H),2.12(br s,4H),1.93(br s,2H),1.84-1.70(m,2H). LC-MS (ESI+) analysis of the product: m / z 527.1[M+H]+, Rt: 2.141 mins.

[0478] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.4 to 3.0 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods were diode array (DAD) and positive electrospray ionization.

[0479] Example 28 - Synthesis of 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[2.5]octan-6-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 28) [ka] Step 1: (4-methylenecyclohexyl)carbamate tert-butyl (F2) [ka]

[0480] To a solution of methyltriphenylphosphonium bromide (16.75 g, 46.89 mmol, 2 equivalents) in THF (40 mL), potassium;2-methylpropane-2-oleate (1 M, 47.0 mL, 2 equivalents) was added under N2 conditions at -20°C. The mixture was stirred at -20°C for 0.5 hours, and N-(4-oxocyclohexyl)carbamate tert-butyl (5 g, 23.44 mmol, 5.00 mL, 1 equivalent) was added to the mixture at 0°C. The mixture was stirred at 20°C for 14.5 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak. TLC showed that all the starting material had been consumed and a new major spot was the desired product. The reaction mixture was poured into water (500 mL), and the aqueous phase was extracted with ethyl acetate (3 × 100 mL).

[0481] The combined organic phases were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, silica gel of 100-200 mesh, petroleum ether:ethyl acetate = 10:1 to 0:1) to obtain (4-methylenecyclohexyl)carbamate tert-butyl (4 g, 18.93 mmol) as a white solid.

[0482] Step 2: Spiro[2.5]octane-6-ylcarbamate tert-butyl(F3) [ka]

[0483] To a solution of tert-butyl N-(4-methylenecyclohexyl)carbamate (200 mg, 946.52 μmol, 1 equivalent) in DCM (30 mL), diazomethane (39.79 mg, 946.52 μmol, 1 equivalent) and Pd(OAc)2 (21.25 mg, 94.65 μmol, 0.1 equivalent) were added at -78°C. The mixture was stirred at -78°C for 30 minutes, then warmed to 20°C, and the mixture was stirred at 20°C for 15 hours.

[0484] LC-MS was used to determine the formation of the desired product and its desired mass. The mixture was concentrated, dissolved in DMF (1 mL), and purified by preparative HPLC (column: Phenomenex Luna C18 100 × 30 mm × 5 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 45% to 75%, 12 min) to obtain tert-butyl spiro[2.5]octane-6-ylcarbamate (6 mg, 26.63 μmol, yield 2.81%) as a white solid.

[0485] 1 H NMR(400MHz,CDCl3)δ=4.54-4.36(m,1H),3.57-3.43(m,1H),1.95-1.86(m,2H),1.76-1.66(m, 2H),1.46(s,9H),1.37-1.26(m,2H),1.03-0.94(m,2H),0.34-0.26(m,2H),0.23-0.17(m,2H).

[0486] Step 3: Spiro[2.5]octane-6-amine(F) [ka]

[0487] To a solution of tert-butyl N-spiro[2.5]octane-6-ylcarbamate (5 mg, 22.19 μmol, 1 equivalent) in DCM (0.2 mL), TFA (77.00 mg, 675.30 μmol, 0.05 mL, 30.43 equivalents) was added at 20°C, and the mixture was stirred at 20°C for 1 hour.

[0488] LC-MS demonstrated complete consumption of the starting material and the formation of a new peak. The mixture was concentrated to obtain spiro[2.5]octane-6-amine (2.5 mg) as a yellow oil (which was used without further purification).

[0489] LC-MS (ESI+) analysis of the product: m / z 126.4[M+1]+, Rt: 0.161 min.

[0490] LCMS method The gradient was 10 to 90% B over 1.15 minutes, held at 90% B for 0.4 minutes, 90 to 10% B over 0.01 minutes, and then held at 10% B for 0.54 minutes (flow rate 1.0 mL / min). Mobile phase A was 0.0375% CF3CO2H in water, and mobile phase B was 0.018% CF3CO2H in CH3CN. The column used for chromatography was 2.1 × 30 mm. The phenomenex Luna-C18 column (5 μm particles) was used. Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization (MS).

[0491] Step 4: Preparation of 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[2.5]octan-6-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0492] To a solution of 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyrizine-3-carboxylic acid (8 mg, 19.54 μmol, 1 equivalent) in DMF (0.5 mL), HATU (14.86 mg, 39.08 μmol, 2 equivalents) and DIEA (7.58 mg, 58.62 μmol, 89.34 μL, 3 equivalents) were added at 20°C. (4-fluorophenyl)methaneamine (25.67 mg, 205.16 μmol, 10.21 μL, 3 equivalents) was added to the mixture at 20°C, and the mixture was stirred at 20°C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0493] The mixture was filtered, and the filtrate was separated and purified by HPLC (column: Waters Xbridge BEH C18 100×25mm×5μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 50% to 85%, 8 min) to obtain 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[2.5]octan-6-yl)-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (2.3 mg, 4.43 μmol) as a pale yellow solid.

[0494] 1 H NMR(400MHz,CDCl3)δ=9.82(br d,J=8.4Hz,1H),8.94(s,1H),8.90(d,J=2.4Hz,1H),8.19(d,J=2.4Hz,1H) ,7.57(d,J=8.6Hz,2H),7.06(d,J=8.6Hz,2H),4.83-4.77(m,2H),4.12(br s,1H),3.89(s,3H),3.71(t,J=4.5Hz,4H),2.76(t,J=7.4Hz,2H),2.65(br s,4H),2.02(br d,J=8.6Hz,2H),1.80-1.71(m,2H),1.65-1.62(m,2H),1.13(br d,J=13.5Hz,2H),0.36-0.31(m,2H),0.30-0.24(m,2H). LCMS (ESI+) of the product: m / z 517.3[M+H]+, Rt:2.282 mins.

[0495] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.4 to 3.0 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). The detection method was: This involves diode arrays (DADs) and positive electrospray ionization.

[0496] Example 29 - Synthesis of 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 29) [ka] Preparation of 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0497] To a solution of 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyrizine-3-carboxylic acid (75 mg, 183.18 μmol, 1 equivalent) in DMF (1 mL), HATU (139.30 mg, 366.36 μmol, 2 equivalents) and DIEA (71.02 mg, 549.54 μmol, 95.72 μL, 3 equivalents) were added at 20°C. Spiro[3.3]heptan-2-amine (24.44 mg, 219.82 μmol, 1.2 equivalents) was added to the mixture at 20°C, and the mixture was stirred at 20°C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0498] The mixture was filtered, and the filtrate was separated and purified by HPLC (column: Waters Xbridge BEH C18 100×25mm×5μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 50% to 85%, 8 min) to obtain 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (37.3 mg, 73.69 μmol) as a pale yellow solid.

[0499] 1H NMR(400MHz,CDCl3)δ=9.87(br d,J=7.5Hz,1H),8.95-8.86(m,2H),8.17(d,J=2.4Hz,1H),7.65-7.47(m,2H),7.06(d,J=8.8Hz,2H), 4.87-4.69(m,2H),4.57-4.40(m,1H),3.89(s,3H),3.71(t,J=4.5Hz,4H),2.83-2.71(m,2H),2.65(br s,4H),2.58-2.46(m,2H),2.10(t,J=7.3Hz,2H ), 2.05-1.95 (m, 4H), 1.90-1.81 (m, 2H). LCMS (ESI+) of the product: m / z 503.3[M+H]+, Rt: 2.236 mins.

[0500] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.4 to 3.0 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods were diode array (DAD) and positive electrospray ionization.

[0501] Example 30 Synthesis of -N-(1-(4-fluorophenyl)ethyl)-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 30) [ka] Preparation of N-(1-(4-fluorophenyl)ethyl)-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0502] To a solution of 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyrizine-3-carboxylic acid (70 mg, 170.97 μmol, 1 equivalent) in DMF (1 mL), HATU (130.01 mg, 341.94 μmol, 2 equivalents) and DIEA (66.29 mg, 512.90 μmol, 89.34 μL, 3 equivalents) were added at 20°C. 1-(4-fluorophenyl)ethanamine (26.17 mg, 188.06 μmol, 24.69 μL, 1.1 equivalents) was added to the mixture at 20°C, and the mixture was stirred at 20°C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0503] The mixture was filtered, and the filtrate was separated and purified by HPLC (column: Waters Xbridge BEH C18 100×25mm×5μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 50% to 85%, 8 min) to obtain N-(1-(4-fluorocarbon). Phenyl)ethyl)-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (12.1 mg, 22.35 μmol) was obtained as a pale yellow solid.

[0504] 1 H NMR(400MHz,CDCl3)δ=10.20(br d,J=7.7Hz,1H),9.07-8.72(m,2H),8.16(d,J=2.0Hz,1H),7.56(br d,J=8.6Hz,2H),7.48-7.36(m,2H),7.15-6.94(m,4H),5.42-5.23(m,1H),4.92-4.66(m,2H),3.89(s,3H),3.70(br t,J=4.0Hz,4H),2.76(br t,J=7.2Hz,2H),2.65(brs,4H),1.61(brs,3H). LC-MS (ESI+) analysis of the product: m / z 531.3[M+H]+, Rt: 2.226 mins.

[0505] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.4 to 3.0 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods were diode array (DAD) and positive electrospray ionization.

[0506] Example 31 - Synthesis of 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-N-(2-oxaspiro[3,3]heptan-6-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 31) [ka] Preparation of 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-N-(2-oxaspiro[3,3]heptan-6-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0507] 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyrizine-3-carboxylic acid (70 mg, 170.97 μmol) in DMF (1 mL) To a solution of 1 (1 equivalent), HATU (130.01 mg, 341.94 μmol, 2 equivalents) and DIEA (66.29 mg, 512.90 μmol, 89.34 μL, 3 equivalents) were added at 20°C. 2-Oxaspiro[3.3]heptan-6-amine (28.14 mg, 188.06 μmol, 1.1 equivalents, HCl) was added to the mixture at 20°C, and the mixture was stirred at 20°C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0508] The mixture was filtered, and the filtrate was separated and purified by HPLC (column: Waters Xbridge BEH C18 100×25mm×5μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 50% to 85%, 8 min) to obtain 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-N-(2-oxaspiro[3,3]heptan-6-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (21.2 mg, 41.76 μmol) as a pale yellow solid.

[0509] 1 H NMR(400MHz,CDCl3)δ=10.03-9.90(m,1H),8.91(s,2H),8.17(d,J=2.2Hz,1H),7.56(d,J=8.6Hz,2H),7.06(d,J=8.4Hz, 2H),4.86-4.74(m,4H),4.67(s,2H),4.47-4.31(m,1H),3.89(s,3H),3.70(t,J=4.5Hz,4H),2.87-2.71(m,4H),2.64(br s,4H),2.37-2.21(m,2H). LCMS (ESI+) for product: m / z 505.2[M+H]+, Rt: 1.912 min.

[0510] LCMS method 5_95AB_6 min-220: The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.4 to 3.0 min, held at 95%B for 1.00 min, and then 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). The detection methods were diode array (DAD) and positive electrospray ionization.

[0511] Example 32 - Synthesis of 6-(4-fluorophenyl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 32) [ka] Step 1: (4-Methylenecyclohexyl)carbamate tert-butyl [ka]

[0512] Solutions of 2-amino-5-bromopyridine-3-carbaldehyde (6 g, 29.9 mmol, 1 equivalent), diethyl propanedione (47.8 g, 298 mmol, 45 mL, 10 equivalents), and piperidine (12.7 g, 149 mmol, 14.7 mL, 5.0 equivalents) were heated at 100°C for 12 hours.

[0513] TLC (petroleum ether / ethyl acetate = 1 / 1) showed that the starting material had been consumed and new spots had been detected. The reaction mixture was cooled to 0°C. The mixture was filtered, and the resulting solid was collected by filtration and washed with methyl tert-butyl ether (30 mL) to obtain (4-methylenecyclohexyl)carbamate tert-butyl (6 g, 20.2 mmol) as a white solid (this was used in the next step without purification).

[0514] 1 H NMR (400MHz, DMSO-d6) δ=12.61(s,1H),8.69(s,1H),8.55(s,1H),8.44(s,1H),4.28(q,J=6.8Hz,2H),1.29(t,J=7.6Hz,3H).

[0515] Step 2: 6-Bromo-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl [ka]

[0516] Ethyl 6-bromo-2-oxo-1H-1,8-naphthyridine-3-carboxylate (3 g, 10.1 mmol, 1 equivalent) and 4-(2-chloroethyl)morpholine (3.76 g, 20.2 mmol, 2.0 equivalent) were dissolved in DMF (50 mL). Cs2CO3 (9.87 g, 30.3 mmol, 3.0 equivalent) was added to the reaction solution. The solution was stirred at 50°C for 12 hours. LC-MS showed complete consumption of the starting materials and the formation of a new peak. Water (100 mL) and ethyl acetate (50 mL) were added, and the mixture was stirred for 5 minutes. The two phases were separated, and the aqueous phase was extracted with ethyl acetate (3 × 50 mL).

[0517] The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated. The residue was washed with methyl tert-butyl ether (30 mL) to obtain 6-bromo-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl (3 g, 7.31 mmol) as a white solid.

[0518] 1 H NMR(400MHz,CHLOROFORM-d)δ=8.68(d,J=2.0Hz,1H),8.25(s,1H),8.08(d,J=2.4Hz,1H),4 .72-4.62(m,2H),4.43(q,J=7.3Hz,2H),3.67(t,J=4.6Hz,4H),2.70(t,J=7.1Hz,2H),2.61(br d,J=3.9Hz,4H),1.42(t,J=7.1Hz,3H).

[0519] Step 3: 6-Bromo-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid [ka]

[0520] Ethyl 6-bromo-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate (1 g, 2.44 mmol, 1 equivalent) was dissolved in THF (5 mL), MeOH (5 mL), and H2O (5 mL). LiOH.H2O (409 mg, 9.75 mmol, 4.0 equivalents) was added to the reaction solution. The solution was stirred at 30°C for 12 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak. 6 N HCl was added dropwise to the reaction mixture to adjust the pH to 4-5. The reaction solution was stirred at 30°C for 5 minutes.

[0521] The obtained solid was collected by filtration and dried under reduced pressure to obtain 6-bromo-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid (0.8 g, 2.09 mmol) as a white solid.

[0522] 1 H NMR(400MHz,DMSO-d6)δ=8.92(s,1H),8.91-8.80(m,2H),4.80(t,J=6.0Hz,2H),3.94(br s,2H),3.76(br s,2H),3.64(br s,2H),3.50(br s,2H),3.16(br s,2H).

[0523] Step 4: 6-Bromo-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0524] 6-Bromo-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylic acid (700 mg, 1.83 mmol, 1 equivalent), spiro[3.3]heptane- 2-amine (270 mg, 1.83 mmol, 1.0 equivalent, HCl), EDCI (702 mg, 3.66 mmol, 2.0 equivalent), and HOBt (495 mg, 3.66 mmol, 2.0 equivalent) were dissolved in DMF (10 mL). The solution was stirred at 30°C for 5 minutes. Then, TEA (927 mg, 9.16 mmol, 1.27 mL, 5.0 equivalent) was added to the reaction solution. The solution was stirred at 30°C for 12 hours. LC-MS showed complete consumption of the starting materials and the formation of a new peak. Methyl tert-butyl ether (20 mL) was added to the reaction solution.

[0525] The suspension was stirred at 30°C for 5 minutes, collected by solid filtration, washed with H2O (10 mL), and dried under reduced pressure to obtain 6-bromo-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3.3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (500 mg, 1.05 mmol) as a white solid (this was used in the next step without purification).

[0526] 1 H NMR(400MHz,DMSO-d6)δ=9.67(d,J=7.8Hz,1H),8.88(d,J=2.4Hz,1H),8.82(s,1H),8.79(d,J=2.4Hz,1H),4.59(br t,J=7.1Hz,2H),4.29(d,J=7.8Hz,1H),3.53(br t,J=4.2Hz,4H),2.59(br s, 2H), 2.42 (ddd, J=2.4, 7.2, 9.4Hz, 2H), 2.09-2.01 (m, 2H), 1.99-1.90 (m, 4H), 1.85-1.76 (m, 2H).

[0527] Step 5: Preparation of 6-(4-fluorophenyl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0528] 6-Bromo-1-(2-morpholinoethyl)-2-oxo-N-spiro[3.3]heptan-2-yl-1,8-naphthyridine-3-carboxamide (10 mg, 21.0 μmol, 1 equivalent), (4-fluorophenyl)boronic acid (4.42 mg, 31.6 μmol, 1.5 equivalent), Pd(PPh3)4 (2.43 mg, 2.10 μmol, 0.1 equivalent), and K2CO3 (7.27 mg, 52.6 μmol, 2.5 equivalent) were dissolved in dioxane (0.5 mL) and H2O (0.1 mL). The suspension was stirred at 90°C for 12 hours. LC-MS showed complete consumption of the starting material and formation of a new peak. One additional vial was set up as described above, and the reaction mixture was combined.

[0529] The solvent is removed under reduced pressure, and the residue is separated by HPLC (column: Phenomenex Luna). The sample was purified using C18 150×30mm×5μm; mobile phase: [water (0.04% HCl)-CH3CN]; B%: 35% to 63%, 10 min) to obtain 6-(4-fluorophenyl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthirizine-3-carboxamide (10 mg, 17.8 μmol, HCl) as a white solid.

[0530] 1 H NMR(400MHz,METHANOL-d4)δ=9.05(d,J=2.4Hz,1H),8.97(s,1H),8.63(s,1H),7.84-7.74(m,2H),7.34-7.20(m,2H),5.01(br t,J=5.9Hz,2H),4.37(t,J=8.1Hz,1H),4.06-3.47(m,10H),2.59-2.46(m,2H),2.17-2.09(m,2H),2.05-1.96(m,4H),1.92-1.83(m,2H). LCMS(ESI+):m / z 491.2(M+H) + ,Rt:2.28 minutes.

[0531] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.00 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization.

[0532] Example 33 - Synthesis of 6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 33) [ka] Preparation of 6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0533] 6-Bromo-1-(2-morpholinoethyl)-2-oxo-N-spiro[3.3]heptan-2-yl-1,8-naphthyridine-3-carboxamide (30 mg, 63.1 μmol, 1 equivalent), 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (11.4 mg, 63.1 μmol, 1 equivalent), Pd(PPh3)4 (7.29 mg, 6.31 μmol, 0.1 equivalent), and K2CO3 (21.8 mg, 158 μmol, 2.5 equivalent) The starting material was dissolved in dioxane (1 mL) and H2O (0.5 mL). The suspension was stirred at 90°C for 2 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak. One additional vial was set up as described above, and the reaction mixture was combined.

[0534] The solvent is removed under reduced pressure, and the residue is separated by HPLC (column: Phenomenex Luna). The mixture was purified using C18 150×30mm×5μm; mobile phase: [water (0.04% HCl)-CH3CN]; B%: 35% to 65%, 10 min) to obtain 6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthirizine-3-carboxamide (14 mg, 24.5 μmol, HCl) as a yellow solid.

[0535] 1 H NMR(400MHz,METHANOL-d4)δ=9.93(br d,J=7.3Hz,1H),9.00(d,J=2.0Hz,1H),8.95(s,1H),8.55(d,J=2.4Hz,1H),7.29-7.19( m,2H),6.99(d,J=8.3Hz,1H),5.02(t,J=6.1Hz,2H),4.40-4.33(m,1H),4.11-3.37(m,10 H),2.55-2.47(m,2H),2.15-2.10(m,2H),2.05-1.96(m,4H),1.93-1.84(m,2H). LCMS(ESI+):m / z 531.3(M+H) + ,Rt:2.264 minutes.

[0536] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.00 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization.

[0537] Example 34 - Synthesis of 1-(2-morpholinoethyl)-2-oxo-6-(pyridine-2-yl)-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 34) [ka] Preparation of 1-(2-morpholinoethyl)-2-oxo-6-(pyridine-2-yl)-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0538] 6-Bromo-1-(2-morpholinoethyl)-2-oxo-N-spiro[3.3]heptan-2-yl-1,8-naphthyridine-3-carboxamide (10 mg, 21.0 μmol, 1 equivalent), tributyl(2-pyridyl)stannan (11.6 mg, 31.6 μmol, 1.5 equivalent), and Pd(PPh3)4 (2.43 mg, 2.10 μmol, 0.1 equivalent) were dissolved in toluene (0.5 mL). The suspension was stirred at 120 °C for 2 hours. LC-MS showed complete consumption of the starting material and formation of a new peak. One additional vial was set up as described above, and all two reaction mixtures were combined. One additional vial was set up as described above, and all two reaction mixtures were combined.

[0539] The solvent is removed under reduced pressure, and the residue is separated by HPLC (column: Phenomenex Luna). The mixture was purified using C18 150×30mm×5μm; mobile phase: [water (0.04% HCl)-CH3CN]; B%: 25% to 55%, 10 min) to obtain 1-(2-morpholinoethyl)-2-oxo-6-(pyridine-2-yl)-N-(spiro[3.3]heptan-2-yl)-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (4.5 mg, 8.82 μmol, HCl) as a white solid.

[0540] 1 H NMR(400MHz,METHANOL-d4)δ=9.37(d,J=2.0Hz,1H),9.00(s,1H),8.96(d,J=2.0Hz,1H),8.85(br d,J=5.4Hz,1H),8.39-8.34(m,1H),8.31-8.27(m,1H),7.79(br t,J=6.4Hz,1H),5.06(br t,J=5.9Hz,2H),4.38(t,J=7.8Hz,1H),4.13(br d,J=11.7Hz,2H),3.91-3.77(m,4H),3.73(br t,J=5.9Hz,2H), 3.38-3.32(m,2H), 2.57-2.45(m,2H), 2.17-2.11(m,2H), 2.05-1.97(m,4H), 1.90(q,J=7.8Hz,2H). LCMS(ESI+) of the product: m / z 474.2(M+H) + ,Rt:2.003 minutes.

[0541] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.00 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization.

[0542] Example 35 - Synthesis of 1-(2-morpholinoethyl)-2-oxo-6-(pyrimidine-4-yl)-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 35) [ka] Preparation of 1-(2-morpholinoethyl)-2-oxo-6-(pyrimidine-4-yl)-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0543] 6-Bromo-1-(2-morpholinoethyl)-2-oxo-N-spiro[3.3]heptan-2-yl-1,8-naphthyridine-3-carboxamide (10 mg, 21.04 μmol, 1 equivalent), tributyl(pyrimidine-4-yl) stannan (11.7 mg, 31.6 μmol, 1.5 equivalent), and Pd(PPh3)4 (2.43 mg, 2.10 μmol, 0.1 equivalent) were dissolved in toluene (0.5 mL). The suspension was stirred at 120°C for 12 hours. LC-MS showed complete consumption of the starting material and formation of a new peak. One additional vial was set up as described above, and the reaction mixture was combined.

[0544] The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5μm; mobile phase: [water (0.04% HCl)-CH3CN]; B%: 15% to 40%, 10 min) to obtain 1-(2-morpholinoethyl)-2-oxo-6-(pyrimidine-4-yl)-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (6.5 mg, 12.7 μmol, HCl) as a white solid.

[0545] 1 H NMR(400MHz,METHANOL-d4)δ=9.60(d,J=2.4Hz,1H),9.29(d,J=1.0Hz,1H),9.17(d,J =2.4Hz,1H),9.02(s,1H),8.91(d,J=5.4Hz,1H),8.19(dd,J=1.5,5.4Hz,1H),5.07(t, J=5.9Hz, 2H), 4.38(t,J=7.8Hz, 1H), 4.19-4.09(m,2H), 3.91-3.70(m,6H), 3.40-3.33(m,2H), 2.57-2.50(m,2H), 2.17-2.11(m,2H), 2.05-1.98(m,4H), 1.94-1.86(m,2H). LCMS (ESI+) of the product: m / z 475.3(M+H) + ,Rt:1.915 minutes.

[0546] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.00 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization.

[0547] Example 36 - Synthesis of 6-(5-cyanopyridine-2-yl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 36) [ka] Step 1: 1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0548] 6-Bromo-1-(2-morpholinoethyl)-2-oxo-N-spiro[3.3]heptan-2-yl-1,8-naphthyridine-3-carboxamide (250 mg, 526 μmol, 1 equivalent), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (200 mg, 789 μmol, 1.5 equivalent), KOAc (155 mg, 1.58 mmol, 3 equivalents), and Pd(PPh3)2Cl2 (36.9 mg, 52.6 μmol, 0.1 equivalent) were dissolved in dioxane (10 mL). The suspension was heated at 80°C for 12 hours. LC-MS showed complete consumption of the starting materials and the formation of new peaks. Water (20 mL) and ethyl acetate (30 mL) were added, and the mixture was stirred for 5 minutes. The two phases were separated, and the aqueous phase was extracted with ethyl acetate (3 × 10 mL).

[0549] The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain 1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (300 mg) as a black solid (this was used in the next step without further purification). Ta).

[0550] LC-MS (ESI+) of the product: m / z 441.2 (M-82) + ,Rt:1.024 minutes.

[0551] LCMS method The gradient was 5 to 95%B at 0.7 min, 95 to 95%B at 0.45 min, 95 to 5%B at 0.01 min, and then retained at 0%B for 0.44 minutes (flow rate 1.5 mL / min). Mobile phase A was 0.0375% CF3CO2H in water, and mobile phase B was 0.018% CF3CO2H in CH3CN. The column used for chromatography was a Chromolith Flash RP-18e 25-2 mm column. Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization (MS).

[0552] Step 2: Preparation of 6-(5-isocyanopyridine-2-yl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyrizine-3-carboxamide [ka]

[0553] 1-(2-morpholinoethyl)-2-oxo-N-spiro[3.3]heptan-2-yl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,8-naphthirizine-3-carboxamide (50 mg, 95.7 μmol, 1 equivalent), 6-bromopyridine-3-carbonitrile (26.3 mg, 144 μmol, 1.5 equivalent), Pd(PPh3)4 (11.1 mg, 9.57 μmol, 0.1 equivalent), and K2CO3 (26.5 mg, 191 μmol, 2.0 equivalent) were dissolved in dioxane (2 mL) and H2O (0.5 mL). The suspension was heated at 80°C for 3 hours. LC-MS showed complete consumption of the starting materials and the formation of new peaks.

[0554] The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC (Gilson Auto-Purification System) to obtain 6-(5-isocyanopyridine-2-yl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3.3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (2.0 mg, 3.74 μmol, HCl) as a white solid.

[0555] 1 H NMR(400MHz,METHANOL-d4)δ=9.56(d,J=2.4Hz,1H),9.12(d,J=2.0Hz,1H),9.06(s,1H),9.01(s,1H),8.35-8.23(m,2H),5.05(br t,J=5.9Hz,2H),4.38(br t,J=8.1Hz,1H),4.20-3.62(m,8H),3.31(s,2H),2.53(br s,2H),2.16-2.10(m,2H),2.05-1.96(m,4H),1.93-1.84(m,2H). LCMS (ESI+) for product: m / z 499.3(M+H) + Rt:2.09 5 minutes.

[0556] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.00 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization.

[0557] Example 37 - Synthesis of 6-(5-fluoropyridine-2-yl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 37) [ka] Preparation of 6-(5-fluoropyridine-2-yl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0558] 1-(2-morpholinoethyl)-2-oxo-N-spiro[3.3]heptan-2-yl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,8-naphthyridine-3-carboxamide (50 mg, 95.7 μmol, 1 equivalent), 2-bromo-5-fluoropyridine (25.3 mg, 143 μmol, 1.5 equivalent), Pd(PPh3)4 (11.1 mg, 9.57 μmol, 0.1 equivalent), and K2CO3 (26.5 mg, 191 μmol, 2.0 equivalent) were dissolved in dioxane (2 mL) and H2O (0.5 mL). The suspension was heated at 80°C for 12 hours. LC-MS showed complete consumption of the starting materials and the formation of new peaks.

[0559] The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC (Gilson Auto-Purification System). (Lu)-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (2.0 mg, 3.74 μmol, HCl) was obtained as a white solid.

[0560] 1 H NMR(400MHz,METHANOL-d4)δ=9.43(d,J=2.0Hz,1H),8.98(s,1H),8.95(d,J=2.4Hz,1H),8.62(d,J=2.9H z,1H),8.11(dd,J=3.9,8.8Hz,1H),7.80-7.75(m,1H),5.05(t,J=5.9Hz,2H),4.41-4.32(m,1H),4.13(br d,J=13.2Hz,2H),3.89-3.70(m,6H),3.35(br d,J=3.4Hz,2H),2.56-2.47(m,2H),2.16-2.11(m,2H),2.05-1.97(m,4H),1.90-1.88(m,2H). LCMS(ESI+) of the product: m / z 492.2(M+H) + ,Rt:2.100 minutes.

[0561] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.00 min, held at 95%B for 1.00 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization.

[0562] Example 38-1 Synthesis of 1-(2-morpholinoethyl)-2-oxo-6-(pyrimidine-2-yl)-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 38) [ka] Preparation of 1-(2-morpholinoethyl)-2-oxo-6-(pyrimidine-2-yl)-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0563] 1-(2-morpholinoethyl)-2-oxo-N-spiro[3.3]heptane-2-i Lu-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,8-naphthirizine-3-carboxamide (70 mg, 134 μmol, 1 equivalent), 2-bromopyrimidine (32.0 mg, 201 μmol, 1.5 equivalents), Pd(PPh3)4 (15.5 mg, 13.4 μmol, 0.1 equivalent), and K2CO3 (37.0 mg, 268 μmol, 2.0 equivalents) were dissolved in dioxane (5 mL) and H2O (1 mL). The suspension was heated at 80°C for 12 hours. LC-MS showed complete consumption of the starting materials and the formation of new peaks.

[0564] The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5μm; mobile phase: [water (0.04%HCl)-CH3CN]; B%: 20% to 45%, 10 min) to obtain 1-(2-morpholinoethyl)-2-oxo-6-(pyrimidine-2-yl)-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthirizine-3-carboxamide (9 mg, 19.0 μmol) as a white solid.

[0565] 11H NMR (400 MHz, methanol-d4) δ = 9.77 (d, J = 2.0 Hz, 1H), 9.32 (d, J = 2.0 Hz, 1H), 9.03 (s, 1H), 8.94 (d, J = 4.9 Hz, 2H), 7.48 (t, J = 4.9 Hz, 1H), 5.07 (br t, J = 6.1 Hz, 2H), 4.37 (t, J = 7.8 Hz, 1H), 4.23 - 3.43 (m, 8H), 2.55 - 2.52 (m, 2H), 2.15 - 2.13 (m, 2H), 1.99 - 1.92 (m, 4H), 1.90 - 1.88 (m, 2H). LCMS (ESI+) for the product: m / z 475.3 (M + H) + , Rt: 1.954 min.

[0566] LCMS method The gradient was 5% B at 0.40 min, 5 to 95% B from 0.40 to 3.00 min, held at 95% B for 1.00 min, then 95 to 5% B in 0.01 min, and the flow rate was 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50×2.1 mm column (5 µm particles). The detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0567] Synthesis of Example 39 - N-(4,4 - dimethylcyclohexyl)-6-(4 - methoxyphenyl)-1-(2 - morpholinoethyl)-2 - oxo - 1,2 - dihydroquinoline - 3 - carboxamide (Compound 39)

Chemical Structure

Chemical Structure

[0568] To a solution of 5-bromo-2-nitrobenzaldehyde (2 g, 8.70 mmol, 1 equivalent) in diethyl propanedione (8.36 g, 52.17 mmol, 7.9 mL, 6 equivalents), AcOH (2.09 g, 34.78 mmol, 2.0 mL, 4 equivalents) and piperidine (888.44 mg, 10.43 mmol, 1.0 mL, 1.2 equivalents) were added at 25°C. The mixture was stirred at 80°C for 2 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak. The mixture was poured into NaHCO3 (100 mL), extracted with ethyl acetate (3 × 50 mL), the organic layer was washed with brine (30 mL), dried over Na2SO4 (50 g), and concentrated.

[0569] The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1 to 1:1) to obtain 2-(5-bromo-2-nitrobenzylidene)malonate diethyl (4 g, 7.52 mmol) as a yellow oil.

[0570] 1 H NMR(400MHz,DMSO-d6)δ=8.19(d,J=8.9Hz,1H),8.14(s,1H),7.96(dd,J=1.6,8.8Hz,1H),7.64(d,J =1.6Hz,1H),4.30(q,J=7.0Hz,2H),4.06-4.00(m,2H),1.29(t,J=7.1Hz,3H),1.01(t,J=7.1Hz,3H). LCMS (ESI+) for product: m / z 372.0,374.0[M+H] + ,Rt:2.359 minutes.

[0571] LCMS method 5-95AB_4.5 min: The column used for chromatography was HALO AQ-C18 2.1 × 30 mm (2.7 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC-grade acetonitrile. The gradient was 5 to 95%B at 4.30 min, 5%B at 0.01 min, 5 to 95%B (0.01 to 3.00 min), retained at 95%B for 0.50 min, 95 to 5%B (3.50 to 3.51 min), 5%B at 3.51 min, and retained at 5%B for 0.79 min. The flow rate was 1.0 mL / min.

[0572] Step 2: 6-Bromo-2-oxo-1,2-dihydroquinoline-3-carboxylate ethyl [ka]

[0573] To a solution of diethyl 2-[(5-bromo-2-nitrophenyl)methylene]propanedione (3.3 g, 8.87 mmol, 1 equivalent) in AcOH (20 mL), Fe (1.24 g, 22.17 mmol, 2.5 equivalents) was added at 25°C. The mixture was incubated at 85°C for 2 hours. The mixture was stirred. LC-MS revealed complete consumption of the starting material and the formation of a new peak.

[0574] The mixture was filtered, and the resulting red solid was collected by filtration (ethyl 6-bromo-2-oxo-1,2-dihydroquinoline-3-carboxylate, 2 g, 6.75 mmol, used without further purification).

[0575] 1¹H NMR (400MHz, DMSO-d6): δ = 12.34–11.88 (m, 1H), 8.66–8.36 (m, 1H), 8.32–7.99 (m, 1H), 7.98–7.66 (m, 1H), 7.47–7.01 (m, 1H), 4.29 (br d, J=3.1Hz, 2H), 1.51–1.22 (m, 3H). LC-MS (ESI+) of the product: m / z 295.9, 297.9 [M+H] + ,Rt:1.383 minutes.

[0576] LCMS method The column used for chromatography was a HALO AQ-C18 2.1×30 mm (2.7 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC-grade acetonitrile. The gradient was 5 to 95%B at 4.30 min, 5%B at 0.01 min, 5 to 95%B (0.01 to 3.00 min), retained at 95%B for 0.50 min, 95 to 5%B (3.50 to 3.51 min), 5%B at 3.51 min, and retained at 5%B for 0.79 min. The flow rate was 1.0 mL / min.

[0577] Step 3: 6-Bromo-1-(2-morpholinoethyl)-2-oxo-1,2-dihydroquinoline-3-carboxylate ethyl [ka]

[0578] To a solution of ethyl 6-bromo-2-oxo-1H-quinoline-3-carboxylate (1 g, 3.38 mmol, 1 equivalent) in DMF (20 mL), Cs2CO3 (4.95 g, 15.20 mmol, 4.5 equivalents) was added at 25°C. The mixture was stirred at 50°C for 1 hour. 4-(2-chloroethyl)morpholine (2.51 g, 13.51 mmol, 4 equivalents, HCl) was added to the mixture at 50°C, and the mixture was stirred at 50°C for 11 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak. The mixture was poured into HCl (200 mL, 0.1 M), extracted with ethyl acetate (3 × 50 mL), the organic layer was washed with brine (30 mL), dried over Na2SO4 (50 g), and concentrated.

[0579] The residual product was purified by silica gel column chromatography (ethyl acetate / methanol = 100:1 to 1:1) to obtain 6-bromo-1-(2-morpholinoethyl)-2-oxo-1,2-dihydroquinoline-3-carboxylate ethyl (180 mg, 439.80 μmol) as a yellow solid.

[0580] 1 H NMR(400MHz,CDCl3)δ=8.30(s,1H),7.80(d ,J=2.3Hz,1H),7.73(dd,J=2.3,9.1Hz,1H),7.33(d,J=9.1Hz,1H),4.43(q,J=7.2Hz,4H),3.78-3.66(m,4H),2.74-2.48(m,6H),1.42(t,J=7.1Hz,3H). LCMS(ESI+) of the product: m / z 409.0,411.0[M+H] + ,Rt:1.921 minutes.

[0581] LCMS method The column used for chromatography was an Xbridge Shield RP18 2.1×50 mm (5 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 10 mM ammonium bicarbonate in water, and mobile phase B was HPLC-grade acetonitrile. The gradients were 5 to 95% B at 4.30 min, 5% B at 0.01 min, 5 to 95% B (0.01 to 3.00 min), retained at 95% B for less than 0.5 min, 95 to 5% B (3.50 to 3.51 min), and retained at 5% B for 0.79 min. The flow rate was 1.0 mL / min (0.01 to 4.30 min).

[0582] Step 4: 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydroquinoline-3-carboxylate ethyl [ka]

[0583] To a solution of ethyl 6-bromo-1-(2-morpholinoethyl)-2-oxo-quinoline-3-carboxylate (160 mg, 390.94 μmol, 1 equivalent) in dioxane (1.6 mL) and water (0.4 mL), Na2CO3 (82.87 mg, 781.87 μmol, 2 equivalents), (4-methoxyphenyl)boronic acid (118.81 mg, 781.87 μmol, 2 equivalents), and Pd(dppf)Cl2.CH2Cl2 (31.93 mg, 39.09 μmol, 0.1 equivalent) were added under nitrogen at 25°C. The mixture was stirred at 100°C for 12 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0584] The mixture was poured into NH4Cl (15 mL), extracted with ethyl acetate (3 × 5 mL), the organic layer was washed with brine (3 mL), dried over Na2SO4 (5 g), concentrated to give ethyl 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydroquinoline-3-carboxylate (110 mg, 252.01 μmol) as a yellow oil (used without further purification).

[0585] LCMS (ESI+) for the product: m / z 437.1 [M+H] + , Rt: 2.118 min.

[0586] LCMS method The column used for chromatography was Xbridge Shield RP18 2.1×50 mm (5 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 - 1000. Mobile phase A was 10 mM ammonium bicarbonate in water and mobile phase B was HPLC grade acetonitrile. The gradient was 5 to 95% B in 4.30 min, 5% B in 0.01 min, 5 to 95% B (0.01 - 3.00 min), held at 95% B for within 0.5 min, 95 to 5% B (3.50 - 3.51 min), held at 5% B for 0.79 min. The flow rate was 1.0 mL / min (0.01 - 4.30 min).

[0587] Step 5: 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydroquinoline-3-carboxylic acid

Chemical formula

[0588] To a solution of ethyl 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-quinoline-3-carboxylate (99.77 mg, 228.58 μmol, 1 equivalent) in dioxane (2 mL), NaOH (2 M, 0.8 mL, 7.00 equivalent) was added at 25 °C. The mixture was stirred at 80 °C for 2 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak. The mixture was poured into HCl (20 mL, 0.5 N), extracted with ethyl acetate (3 × 50 mL), the organic layer was washed with brine (30 mL), dried over Na₂SO₄ (20 g), and concentrated to obtain the desired product (93 mg, 227.69 μmol) as brown oil.

[0589] The mixture was poured into NH4Cl (15 mL), extracted with ethyl acetate (3 × 5 mL), washed with brine (3 mL), dried over Na2SO4 (5 g), and concentrated to obtain 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydroquinoline-3-carboxylate ethyl (110 mg, 252.01 μmol) as a yellow oil (which was used without further purification).

[0590] 1 H NMR(400MHz,CDCl3)δ=8.98(s,1H),8.03-7.94(m,2H),7.57(s,2H),7.05(d,J=8.8Hz,2H),6.79(s,1H),4.60(br t,J=7.3Hz,2H),3.89(s,3H),3.75-3.72(m,4H),2.77(t,J=7.3Hz,2H),2.64(br d,J=4.2Hz,4H). LCMS (ESI+) for product: m / z 409.2[M+H] + ,Rt:1.427 minutes.

[0591] LCMS method The column used for chromatography was an Xbridge Shield RP18 2.1×50 mm (5 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 10 mM ammonium bicarbonate in water, and mobile phase B was HPLC-grade acetonitrile. The gradient was 5 to 95% B at 4.30 min, 5% B at 0.01 min, 5 to 95% B (0.01 to 3.00 min), and held at 95% B for less than 0.5 min. The retention period was 95 to 5% B (3.50-3.51 mins), and 5% B was held for 0.79 minutes. The flow rate was 1.0 mL / min (0.01-4.30 mins).

[0592] Step 6: Preparation of N-(4,4-dimethylcyclohexyl)-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydroquinoline-3-carboxamide [ka]

[0593] To a solution of 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-quinoline-3-carboxylic acid (90 mg, 220.35 μmol, 1 equivalent) in DMF (1 mL), HATU (125.67 mg, 330.52 μmol, 1.5 equivalent), DIEA (56.96 mg, 440.69 μmol, 76 μL, 2 equivalents) and 4,4-dimethylcyclohexaneamine (33.64 mg, 264.42 μmol, 1.2 equivalents) were added at 25°C. The mixture was stirred at 25°C for 2 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0594] The mixture was filtered, and the filtrate was separated and purified by HPLC (column: Waters Xbridge BEH C18 100×30mm×10μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 45% to 75%, 10 min) to obtain N-(4,4-dimethylcyclohexyl)-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (20 mg, 38.17 μmol, yield 17.32%, purity 98.8%) as a pale yellow solid.

[0595] 1 H NMR(400MHz,CDCl3)δ=9.80(br d,J=7.8Hz,1H),8.96(s,1H),7.95-7.85(m,2H),7.60-7.51(m,3H),7.03(d,J=8.8Hz,2H),4.60-4.46(m,2H),3.97(br dd,J=3.2,7.3Hz,1H),3.88(s,3H),3.80-3.64(m,4H),2.79-2.70(m,2H),2.64(br d,J=4.1Hz,4H), 1.95-1.85(m,2H), 1.54-1.30(m,6H), 0.97(d,J=6.4Hz,6H). LCMS(ESI+) of the product: m / z 518.4[M+H] + ,Rt:1.128 minutes.

[0596] LCMS method The column used for chromatography was an Xbridge Shield RP18 2.1×50 mm (5 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 10 mM ammonium bicarbonate in water, and mobile phase B was HPLC-grade acetonitrile. The gradients were 5 to 95% B at 4.30 min, 5% B at 0.01 min, 5 to 95% B (0.01 to 3.00 min), retained at 95% B for less than 0.5 min, 95 to 5% B (3.50 to 3.51 min), and retained at 5% B for 0.79 min. The flow rate was 1.0 mL / min (0.01 to 4.30 min).

[0597] Example 40 - Synthesis of 6-(5-cyanopyridine-2-yl)-N-(2-(4-fluorophenyl)propan-2-yl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 40) [ka] Step 1: 1-(2-morpholinoethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid [ka]

[0598] Method 1: A mixture of 6-bromo-1-(2-morpholinoethyl)-2-oxo-1,8-naphthirizine-3-carboxylic acid (350 mg, 915.73 μmol, 1 equivalent), BPD (1.86 g, 7.33 mmol, 8 equivalents), Pd(PPh3)2Cl2 (64.27 mg, 91.57 μmol, 0.1 equivalent), and KOAc (269.62 mg, 2.75 mmol, 3 equivalents) in dioxane (3 mL) was stirred at 80°C for 2 hours.

[0599] LC-MS demonstrated complete consumption of the starting material and the formation of a new peak at the desired mass. The mixture was diluted with 5 mL of water and extracted with ethyl acetate (3 × 3 mL).

[0600] The combined aqueous layers were washed with 2M HCl (3 mL), the resulting solid was filtered, and concentrated under reduced pressure to obtain 1-(2-morpholinoethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid (200 mg, 465.90 μmol) as a white solid.

[0601] LC-MS (ESI+) of the product: m / z 348.2 [M+H] +,Rt:0.454 minutes.

[0602] LCMS method The column used for chromatography was Luna-C 18 2.0×30 mm (3 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was HPLC grade The solution was 0.018% trifluoroacetic acid in cetonitrile. The gradient was 5 to 95% B at 4.50 min, 5% B at 0.25 min, 5 to 95% B (0.25 to 2.25 min), 95 to 100% B (2.25 to 4.05 min), 5% B at 1.81 min, and held at 5% B for 0.43 min. The flow rates were 1.0 mL / min (0.00 to 4.05 min) and 1.2 mL / min (4.05 to 4.5 min).

[0603] Method 2: A mixture of 6-bromo-1-(2-morpholinoethyl)-2-oxo-1,8-naphthirizine-3-carboxylic acid (120 mg, 313.96 μmol, 1 equivalent), BPD (637.82 mg, 2.51 mmol, 8 equivalents), KOAc (92.44 mg, 941.89 μmol, 3 equivalents), and Pd(PPh3)2Cl2 (22.04 mg, 31.40 μmol, 0.1 equivalent) in dioxane (7 mL) was degassed, purged three times with N2, and then stirred at 80°C for 2 hours under an N2 atmosphere. LC-MS showed complete consumption of the starting materials and the formation of a new peak at the desired mass.

[0604] The mixture was diluted with water (3 mL), extracted with ethyl acetate (3 × 3 mL), and concentrated under reduced pressure to obtain 1-(2-morpholinoethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-1,8-naphthyrizine-3-carboxylic acid (80 mg, 186.36 μmol) as a white solid (which was used without further purification).

[0605] LC-MS (ESI+) of the product: m / z 348.2 [M+H] + ,Rt:0.532 minutes.

[0606] LCMS method The column used for chromatography was Luna-C 18 2.0×30 mm (3 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in HPLC-grade acetonitrile. The gradients were 5 to 95% B at 2.00 min, 5% B at 0.01 min, 5 to 95% B (0.01 to 1.00 min), 95 to 100% B (1.00 to 1.80 min), 5% B at 1.81 min, and retention at 5% B for 0.19 min. The flow rates were 1.0 mL / min (0.00 to 1.80 min) and 1.2 mL / min (1.81 to 2.00 min).

[0607] Step 2: 6-(5-cyanopyridine-2-yl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid [ka]

[0608] Method 1: Dioxane (1 mL) and water (0.25 mL) contain 6-bromopyridine-3-carbon A mixture of tolyl (63.95 mg, 349.43 μmol, 1 equivalent), 1-(2-morpholinoethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,8-naphthirizine-3-carboxylic acid (150 mg, 349.43 μmol, 1 equivalent), K2CO3 (144.88 mg, 1.05 mmol, 3 equivalents), and Pd(PPh3)4 (40.38 mg, 34.94 μmol, 0.1 equivalent) was degassed, purged three times with N2, and then stirred at 80°C for 2 hours under an N2 atmosphere. LCMS showed complete consumption of the starting material and the formation of a new peak at the desired mass.

[0609] The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (HCl conditions) to obtain 6-(5-cyanopyridine-2-yl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid (30 mg, 74.00 μmol, 21.1) as a yellow solid.

[0610] LC-MS (ESI+) analysis of the product: m / z 406.2 [M+H] + ,Rt:0.878 minutes.

[0611] LCMS method The column used for chromatography was Luna-C 18 2.0×30 mm (3 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in HPLC-grade acetonitrile. The gradients were 5 to 95% B at 4.50 min, 5% B at 0.25 min, 5 to 95% B (0.25 to 2.25 min), 95 to 100% B (2.25 to 4.05 min), 5% B at 1.81 min, and retention at 5% B for 0.43 min. The flow rates were 1.0 mL / min (0.00 to 4.05 min) and 1.2 mL / min (4.05 to 4.5 min).

[0612] Method 2: A mixture of 6-bromopyridine-3-carbonitride (42.63 mg, 232.95 μmol, 1 equivalent), 1-(2-morpholinoethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,8-naphthiridine-3-carboxylic acid (100 mg, 232.95 μmol, 1 equivalent), K2CO3 (96.59 mg, 698.86 μmol, 3 equivalents), and Pd(PPh3)4 (26.92 mg, 23.30 μmol, 0.1 equivalent) in dioxane (1 mL) and water (0.25 mL) was degassed, purged three times with N2, and then stirred at 80°C for 2 hours under an N2 atmosphere. LCMS showed complete consumption of the starting material and the formation of a new peak at the desired mass.

[0613] The mixture was filtered, concentrated under reduced pressure, and the residue was purified by preparative HPLC (HCl conditions) to obtain 6-(5-cyanopyridine-2-yl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid (60 mg, 148.00 μmol) as a white solid.

[0614] LC-MS (ESI+) analysis of the product: m / z 406.2 [M+H] + ,Rt:1.038 minutes.

[0615] LCMS method The column used for chromatography was Luna-C 18 2.0×30 mm (3 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was HPLC grade The solution was 0.018% trifluoroacetic acid in cetonitrile. The gradient was 5 to 95% B at 2.00 min, 5% B at 0.01 min, 5 to 95% B (0.01 to 1.00 min), 95 to 100% B (1.00 to 1.80 min), 5% B at 1.81 min, and held at 5% B for 0.19 min. The flow rates were 1.0 mL / min (0.00 to 1.80 min) and 1.2 mL / min (1.81 to 2.00 min).

[0616] Step 3: Preparation of 6-(5-cyanopyridine-2-yl)-N-(2-(4-fluorophenyl)propan-2-yl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0617] A mixture of 2-(4-fluorophenyl)propan-2-amine (30.23 mg, 197.33 μmol, 2 equivalents), 6-(5-cyano-2-pyridyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyrizine-3-carboxylic acid (40 mg, 98.67 μmol, 1 equivalent), DIEA (76.51 mg, 592.00 μmol, 103.12 μL, 6 equivalents), and T3P (251.15 mg, 394.67 μmol, 234.72 μL, 50% purity, 4 equivalents) in DMF (0.5 mL) was stirred at 20°C for 2 hours. LC-MS showed complete consumption of the starting materials and the formation of a new peak at the desired mass.

[0618] The reaction mixture was filtered, concentrated under reduced pressure, and the filtrate was purified by preparative HPLC (neutral conditions) to obtain 6-(5-cyanopyridine-2-yl)-N-(2-(4-fluorophenyl)propan-2-yl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (20 mg, 37.00 μmol) as a white solid.

[0619] 1H NMR(400MHz,DMSO-d6)δ=10.05(s,1H),9.52(d,J=2.0Hz,1H),9.20-9.15(m,2H),8.88(s,1H),8.49(dd,J=1.4 ,8.5Hz,1H),8.37-8.32(m,1H),7.45(dd,J=5.5,8.4Hz,2H),7.13(t,J=8.7Hz,2H),4.75-4.64(m,2H),3.54(br t,J=3.7Hz,4H),2.69-2.62(m,2H),2.54-2.51(m,4H),1.72(s,6H). LCMS (ESI+) for product: m / z 541.3[M+H] + ,Rt:3.137 minutes.

[0620] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.40 min, held at 95%B for 0.45 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 0.8 ml / min. Mobile phase A was H2O + 10 mM NH4HCO3, and mobile phase B was acetonitrile. The column used for chromatography was xbridge shield. The RP18 2.1 × 50 mm column (5 μm particles) was used. Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization. The MS range was 100 to 1000.

[0621] Example 41 Synthesis of 1-N-(1-(4-cyanophenyl)ethyl)-6-(5-cyanopyridine-2-yl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 41) [ka] Preparation of N-(1-(4-cyanophenyl)ethyl)-6-(5-cyanopyridine-2-yl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide [ka]

[0622] To a solution of 6-(5-cyano-2-pyridyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyrizine-3-carboxylic acid (40 mg, 98.67 μmol, 1 equivalent) and 4-(1-aminoethyl)benzonitrile (21.64 mg, 148.00 μmol, 1.5 equivalents) in DMF (1 mL), DIEA (76.51 mg, 592.00 μmol, 103.12 μL, 6 equivalents) and T3P (125.58 mg, 197.33 μmol, 117.36 μL, 50% purity, 2 equivalents) were added. The mixture was stirred at 25°C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak.

[0623] The mixture was filtered, and the filtrate was purified by preparative HPLC (neutral conditions) to obtain N-(1-(4-cyanophenyl)ethyl)-6-(5-cyanopyridine-2-yl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (27.9 mg, 52.29 μmol) as a white solid.

[0624] 1 H NMR(400MHz,DMSO-d6)δ=10.01-9.94(m,1H),9.52(d,J=2.0Hz,1H),9.19(d,J=2 .2Hz,1H),9.15(d,J=0.7Hz,1H),8.95-8.88(m,1H),8.49(dd,J=1.7,8.3Hz,1H), 8.36-8.29(m,1H),7.83(d,J=8.2Hz,2H),7.61(d,J=8.2Hz,2H),5.18(s,1H),4.7 3-4.63(m,2H),3.58-3.49(m,4H),2.69-2.61(m,2H),2.57-2.51(m,4H),1.54(br d, J=7.1Hz, 3H). LCMS (ESI+) of the product: m / z 534.3[M+H] + ,Rt:2.919 minutes.

[0625] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.40 min, held at 95%B for 0.45 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 0.8 mL / min. Mobile phase A was H2O + 10 mM NH4HCO3, and mobile phase B was acetonitrile. The column used for chromatography was an xbridgeShield RP18 2.1 × 50 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization.

[0626] Example 42 - Synthesis of 6-(5-cyanopyridine-2-yl)-N-(1-(4-fluorophenyl)cyclopropyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 42) [ka] Preparation of 6-(5-cyanopyridine-2-yl)-N-(1-(4-fluorophenyl)cyclopropyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide [ka]

[0627] A mixture of 1-(4-fluorophenyl)cyclopropanamine (29.83 mg, 197.34 μmol, 2 equivalents), 6-(5-cyano-2-pyridyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyrizine-3-carboxylic acid (40 mg, 98.67 μmol, 1 equivalent), DIEA (76.51 mg, 592.02 μmol, 103.12 μL, 6 equivalents), and T3P (125.58 mg, 197.34 μmol, 117.36 μL, 50% purity, 2 equivalents) in DMF (1 mL) was stirred at 20°C for 2 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak at the desired mass.

[0628] The mixture was filtered, and the filtrate was purified by preparative HPLC (neutral conditions) to obtain 6-(5-cyanopyridine-2-yl)-N-(1-(4-fluorophenyl)cyclopropyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (7.9 mg, 14.67 μmol) as a white solid.

[0629] 1 H NMR(400MHz,DMSO-d6)δ=10.10-10.04(m,1H),9.53(d,J=2.0Hz,1H),9.21(d,J=1.3Hz,1H) ,9.18-9.15(m,1H),8.93(s,1H),8.54-8.45(m,1H),8.37-8.33(m,1H),7.34- 7.28(m,2H),7.15-7.08(m,2H),4.72-4.63(m,2H),3.58-3.51(m,4H),2.64(br d,J=7.1Hz,2H),2.55-2.52(m,4H),1.30(s,4H). LCMS (ESI+) for product: m / z 539.3[M+H] + ,Rt:3.042 minutes.

[0630] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.40 min, held at 95%B for 0.45 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 0.8 ml / min. Mobile phase A was H2O + 10 mM NH4HCO3, and mobile phase B was acetonitrile. The column used for chromatography was xbridge Shield. The RP18 2.1 × 50 mm column (5 μm particles) was used. The detection methods included diode array (DAD) detection, evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0631] Example 43 - Synthesis of 6-(5-(difluoromethoxy)pyridine-2-yl)-1-(4-fluorobenzyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 43) [ka] Step 1: Preparation of 1-(4-fluorobenzyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl [ka]

[0632] Pd(PPh3)4 (42.78 mg, 37.02 μmol, 0.1 equivalent) was added to a mixture of 6-bromo-1-[(4-fluorophenyl)methyl]-2-oxo-1,8-naphthirizine-3-carboxylate ethyl (150 mg, 370.17 μmol, 1 equivalent), KOAc (363.29 mg, 3.70 mmol, 10 equivalents), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (940.01 mg, 3.70 mmol, 10 equivalents) in DMSO (2 mL) under N2 conditions. The mixture was stirred at 80°C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak at the desired mass.

[0633] The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3 × 5 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and vacuum concentrated to obtain 1-(4-fluorobenzyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl (120 mg, 265.32 μmol), which was used without further purification.

[0634] LC-MS (ESI+) analysis of the product: m / z 453.3 [M+H] + ,Rt:1.240 minutes.

[0635] LCMS method The column used for chromatography was a HALO AQ-C18 2.1×30 mm (2.7 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC-grade acetonitrile. The gradient was 5 to 95% B at 2.20 min, 5% B at 0.01 min, 5 to 95% B (0.01 to 1.00 min), 95 to 100% B (1.00 to 1.80 min), 5% B at 1.81 min, and retained at 5% B for 0.40 min. The flow rate was 1.0 mL / min.

[0636] Step 2: Preparation of 6-(5-(difluoromethoxy)pyridine-2-yl)-1-(4-fluorobenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl [ka]

[0637] Pd(PPh3)4 (30.66 mg, 26.53 μmol, 0.1 equivalent) was added to a mixture of 1-[(4-fluorophenyl)methyl]-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,8-naphthyridine-3-carboxylate ethyl (120 mg, 265.32 μmol, 1 equivalent), K2CO3 (110.01 mg, 795.96 μmol, 3 equivalents), and 2-bromo-5-(difluoromethoxy)pyridine (71.32 mg, 318.39 μmol, 1.2 equivalents) under N2 conditions. The mixture was stirred at 100°C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak at the desired mass. The reaction mixture was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (3 × 5 mL).

[0638] The combined organic phase was dried with anhydrous Na2SO4, filtered, and vacuum concentrated to obtain 6-(5-(difluoromethoxy)pyridine-2-yl)-1-(4-fluorobenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate ethyl (90 mg), which was used without further purification.

[0639] LC-MS (ESI+) of the product: m / z 470.2 [M+H] + ,Rt:1.150 minutes.

[0640] LCMS method The column used for chromatography was a HALO AQ-C18 2.1×30 mm (2.7 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC-grade acetonitrile. The gradient was 5 to 95% B at 2.20 min, 5% B at 0.01 min, 5 to 95% B (0.01 to 1.00 min), 95 to 100% B (1.00 to 1.80 min), 5% B at 1.81 min, and retained at 5% B for 0.40 min. The flow rate was 1.0 mL / min.

[0641] Step 3: Preparation of 6-(5-(difluoromethoxy)pyridine-2-yl)-1-(4-fluorobenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid [ka]

[0642] A mixture of 6-[5-(difluoromethoxy)-2-pyridyl]-1-[(4-fluorophenyl)methyl]-2-oxo-1,8-naphthyrizine-3-carboxylate ethyl (90 mg, 191.73 μmol, 1 equivalent) in DMSO (5 mL) was mixed with NaOH (2 M, 958.65 μL, 10 equivalents). The mixture was stirred at 50°C for 2 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak at the desired mass. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3 × 5 mL).

[0643] The combined organic phases were dried over anhydrous Na2SO4, filtered, and vacuum concentrated to obtain 6-(5-(difluoromethoxy)pyridine-2-yl)-1-(4-fluorobenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid (65 mg) as a yellow solid (which was used without further purification).

[0644] LC-MS (ESI+) analysis of the product: m / z 442.2 [M+H] + ,Rt:1.149 minutes.

[0645] LCMS method The column used for chromatography was a HALO AQ-C18 2.1×30 mm (2.7 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC-grade acetonitrile. The gradient was 5 to 95% B at 2.20 min, 5% B at 0.01 min, 5 to 95% B (0.01 to 1.00 min), 95 to 100% B (1.00 to 1.80 min), 5% B at 1.81 min, and retained at 5% B for 0.40 min. The flow rate was 1.0 mL / min.

[0646] Step 4: Preparation of 6-(5-(difluoromethoxy)pyridine-2-yl)-1-(4-fluorobenzyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyrizine-3-carboxamide [ka]

[0647] To a mixture of 6-[5-(difluoromethoxy)-2-pyridyl]-1-[(4-fluorophenyl)methyl]-2-oxo-1,8-naphthyrizine-3-carboxylic acid (32 mg, 72.50 μmol, 1 equivalent) and spiro[3.3]heptan-2-amine (12.85 mg, 87.00 μmol, 1.2 equivalents, HCl) in DMF (1 mL), DIEA (56.22 mg, 435.02 μmol, 75.77 μL, 6 equivalents) and T3P (92.28 mg, 145.01 μmol, 86.24 μL, 50% purity, 2 equivalents) were added. The mixture was stirred at 20°C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak at the desired mass.

[0648] The mixture was filtered, and the filtrate was separated and purified by HPLC (column: Phenomenex Gemini-NX 150×30mm×5μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 55% to 85%, 8 min) to obtain 6-(5-(difluoromethoxy)pyridine-2-yl)-1-(4-fluorobenzyl)-2-oxo-N-(spiro[3.3]heptan-2-yl)-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (4.6 mg, 8.26 μmol) as a white solid.

[0649] 1H NMR(400MHz,CDCl3)δ=9.76(br d,J=7.1Hz,1H),9.33(d,J=2.3Hz,1H),8.98(s,1H),8.65(d,J=2.3Hz,1H),8.62(d ,J=2.5Hz,1H),7.82(d,J=8.6Hz,1H),7.64(dd,J=2.7,8.7Hz,1H),7.51(dd,J=5.5, 8.6Hz, 2H), 6.99(t,J=8.7Hz, 2H), 6.84-6.42(m,1H), 5.83(s,2H), 4.56-4.39(m,1H), 2.59-2.47(m,2H), 2.10(t,J=7.4Hz, 2H), 2.05-1.96(m,4H), 1.92-1.82(m,2H). LCMS(ESI-) of the product: m / z 535.2[M+H] + ,Rt:3.680 minutes.

[0650] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.40 min, held at 95%B for 0.45 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 0.8 ml / min. Mobile phase A was H2O + 10 mM NH4HCO3, and mobile phase B was acetonitrile. The column used for chromatography was Xbridge Shield. The RP18 2.1 × 50 mm column (5 μm particles) was used. The detection methods included diode array (DAD) detection, evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0651] Example 44: Synthesis of 6-(4-cyanophenyl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 44) [ka] Step 1: Preparation of 6-(4-cyanophenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid [ka]

[0652] To a mixture of 6-bromo-1-(2-morpholinoethyl)-2-oxo-1,8-naphthirizine-3-carboxylic acid (190 mg, 497.11 μmol, 1 equivalent) in dioxane (2 mL) and water (0.2 mL), (4-cyanophenyl)boronic acid (87.65 mg, 596.53 μmol, 1.2 equivalents), K2CO3 (206.11 mg, 1.49 mmol, 3 equivalents), and Pd(PPh3)4 (57.44 mg, 49.71 μmol, 0.1 equivalent) were added. The mixture was stirred under N2 at 80°C for 2 hours. LC-MS showed complete consumption of the starting material and the formation of a new peak at the desired mass.

[0653] The mixture was concentrated, and the residue was purified by preparative HPLC (neutral conditions) to obtain 6-(4-cyanophenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid (90 mg, 222.54 μmol) as a white solid.

[0654] LC-MS (ESI+) analysis of the product: m / z 405.2 [M+H] + ,Rt:1.058 minutes.

[0655] LCMS method The column used for chromatography was a ZORBAX Eclipse XDB-C18 2.1×30 mm (3.5 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in HPLC-grade acetonitrile. The gradient was 5 to 95% B at 2.20 min, 5% B at 0.01 min, 5 to 95% B (0.01 to 1.00 min), 95 to 100% B (1.00 to 1.80 min), 5% B at 1.81 min, and retained at 5% B for 0.39 min. The flow rate was 1.0 mL / min.

[0656] Step 2: 6-(4-cyanophenyl)-1-(2-morpholinoethyl)-2-oxo Preparation of -N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0657] To a mixture of 6-(4-cyanophenyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyrizine-3-carboxylic acid (25 mg, 61.82 μmol, 1 equivalent) in DMF (0.5 mL), spiro[3.3]heptan-2-amine (10.95 mg, 74.18 μmol, 1.2 equivalents, HCl), T3P (39.34 mg, 123.63 μmol, 36.76 μL, 2 equivalents), and DIEA (47.94 mg, 370.90 μmol, 64.60 μL, 6 equivalents) were added.

[0658] The mixture was stirred at 25°C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak at the desired mass. The mixture was purified by preparative HPLC (neutral conditions) to obtain 6-(4-cyanophenyl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthirizine-3-carboxamide (9 mg, 18.09 μmol) as a white solid.

[0659] 1H NMR(400MHz,DMSO-d6)δ=9.71(br d,J=7.6Hz,1H),9.21(d,J=2.3Hz,1H),8.96-8.86(m,2H),8.09-7.98(m,4H),4.66(br t,J=6.9Hz,2H),4.30(sxt,J=7.9Hz,1H),3.54(br s,4H),2.62(br t,J=7.1Hz,2H),2.56-2.51(m,4H),2.45-2.40(m,2H),2.06(br t,J=7.2Hz,2H),1.99-1.92(m,4H),1.86-1.77(m,2H). LC-MS (ESI+) analysis of the product: m / z 498.3 [M+H] + ,Rt:3.283 minutes.

[0660] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.40 min, held at 95%B for 0.45 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 0.8 ml / min. Mobile phase A was H2O + 10 mM NH4HCO3, and mobile phase B was acetonitrile. The column used for chromatography was Xbridge Shield. The RP18 2.1 × 50 mm column (5 μm particles) was used. The detection methods included diode array (DAD) detection, evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0661] Example 45 - Synthesis of 6-(4-cyanophenyl)-N-(1-(4-fluorophenyl)ethyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 45) [ka] Preparation of 6-(4-cyanophenyl)-N-(1-(4-fluorophenyl)ethyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0662] To a mixture of 6-(4-cyanophenyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyrizine-3-carboxylic acid (20 mg, 49.45 μmol, 1 equivalent) in DMF (0.5 mL), 1-(4-fluorophenyl)ethanamine (10.42 mg, 59.34 μmol, 9.83 μL, 1.2 equivalents, HCl), T3P (31.47 mg, 98.91 μmol, 29.41 μL, 2 equivalents), and DIEA (38.35 mg, 296.72 μmol, 51.68 μL, 6 equivalents) were added. The mixture was stirred at 25°C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak at the desired mass.

[0663] The mixture was purified by preparative HPLC (neutral conditions) to obtain 6-(4-cyanophenyl)-N-(1-(4-fluorophenyl)ethyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (4.8 mg, 9.13 μmol) as a white solid.

[0664] 1 H NMR(400MHz,DMSO-d6)δ=9.98(br d,J=7.9Hz,1H),9.23(d,J=2.0Hz,1H),8.93(s,2H),8.11-7.99(m,4H),7.46(br dd,J=5.6,8.2Hz,2H),7.19(br t,J=8.8Hz,2H),5.19(quin,J=6.9Hz,1H),4.68(br t,J=6.2Hz,2H),3.54(br s,4H),2.63(br t,J=6.9Hz,2H),2.57-2.52(m,4H),1.52(br d,J=6.9Hz,3H). LC-MS (ESI+) analysis of the product: m / z 526.3 [M+H] + ,Rt:3.184 minutes.

[0665] LCMS method The gradient is 5%B in 0.40 min, then 5% to 95%B from 0.40 to 3.40 min, held at 95%B for 0.45 min, and then 95% to 5%B in 0.01 min, with a flow rate of 0.8 ml / min. The mobile phase A was H2O + 10 mM NH4HCO3, and the mobile phase B was acetonitrile. The column used for chromatography was Xbridge Shield. The RP18 2.1 × 50 mm column (5 μm particles) was used. The detection methods included diode array (DAD) detection, evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0666] Example 46 Synthesis of N-(bicyclo[1.1.1]pentan-1-yl)-6-(4-cyanophenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 46) [ka] Preparation of 1-(2-morpholinoethyl)-2-oxo-6-(pyridine-2-yl)-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0667] To a mixture of 6-(4-cyanophenyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylic acid (25 mg, 61.82 μmol, 1 equivalent) in DMF (0.5 mL), bicyclo[1.1.1]pentan-3-amine (8.87 mg, 74.18 μmol, 2.46 μL, 1.2 equivalents, HCl), T3P (39.34 mg, 123.63 μmol, 36.76 μL, 2 equivalents), and DIEA (47.94 mg, 370.90 μmol, 64.60 μL, 6 equivalents) were added. The mixture was stirred at 25°C for 1 hour. LC-MS showed complete consumption of the starting material and the formation of a new peak at the desired mass.

[0668] The mixture was purified by preparative HPLC (neutral conditions) to obtain 1-(2-morpholinoethyl)-2-oxo-6-(pyridine-2-yl)-N-(spiro[3.3]heptan-2-yl)-1,2-dihydro-1,8-naphthyrizine-3-carboxamide (9 mg, 19.09 μmol) as a white solid.

[0669] 1 H NMR(400MHz,DMSO-d6)δ=9.82(s,1H),9.56(br s,1H),9.20(d,J=2.1Hz,1H),9.03-8.93(m,2H),8.11-8.02(m,4H),4.86(br s,2H),4.01(br s,2H),3.76-3.56(m,6H),3.24-3.14(m,2H) ,2.52(br s,1H),2.14(s,6H). LCMS (ESI+) of the product: m / z 470.3[M+H] + ,Rt:3.092 minutes.

[0670] LCMS method The gradient was 5%B at 0.40 min, then 5% to 95%B from 0.40 to 3.40 min, held at 95%B for 0.45 min, followed by 95% to 5%B at 0.01 min, with a flow rate of 0.8 ml / min. Mobile phase A was H2O + 10 mM NH4HCO3, and mobile phase B was acetonitrile. The column used for chromatography was Xbridge Shield. The RP18 2.1 × 50 mm column (5 μm particles) was used. The detection methods included diode array (DAD) detection, evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0671] Example 47 - Synthesis of 6-(5-(difluoromethoxy)pyridine-2-yl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (compound 47) [ka] Step 1: Preparation of 6-(5-(difluoromethoxy)pyridine-2-yl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid [ka]

[0672] To a mixture of dioxane (2 mL) and 1-(2-morpholinoethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,8-naphthyridine-3-carboxylic acid (10 mg, 23.30 μmol, 1 equivalent) in H2O (0.2 mL), 2-bromo-5-(difluoromethoxy)pyridine (5.22 mg, 23.30 μmol, 1 equivalent), Pd(PPh3)4 (2.69 mg, 2.33 μmol, 0.1 equivalent), and K2CO3 (9.66 mg, 69.89 μmol, 3 equivalents) were added under N2. The mixture was stirred under N2 at 80°C for 2 hours. Sixteen additional vials were set up as described above. LC-MS showed complete consumption of the starting material and the formation of a new peak at the desired mass. All 17 reaction signals were combined.

[0673] The mixture was poured into water (100 mL) and extracted with acetyl (200 mL). The aqueous phase was adjusted to pH=3 with HCl (1M), and the resulting solid was collected by filtration to obtain the desired product (100 mg, 224.01 μmol) as a yellow solid.

[0674] LC-MS (ESI+) of the product: m / z 447.1 [M+H] + ,Rt:1.078 minutes.

[0675] LCMS method The column used for chromatography was a ZORBAX Eclipse XDB-C18 2.1×30 mm (3.5 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in HPLC-grade acetonitrile. The gradient was 5 to 95% B at 2.20 min, 5% B at 0.01 min, 5 to 95% B (0.01 to 1.00 min), 95 to 100% B (1.00 to 1.80 min), 5% B at 1.81 min, and retained at 5% B for 0.39 min. The flow rate was 1.0 mL / min.

[0676] Step 2: Preparation of 6-(5-(difluoromethoxy)pyridine-2-yl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3,3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0677] To a mixture of 6-[5-(difluoromethoxy)-2-pyridyl]-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyrizine-3-carboxylic acid (30 mg, 67.20 μmol, 1 equivalent) in DMF (0.5 mL), spiro[3.3]heptan-2-amine (11.91 mg, 80.64 μmol, 1.2 equivalents, HCl), DIEA (52.11 mg, 403.22 μmol, 70.23 μL, 6 equivalents), and T3P (42.77 mg, 134.41 μmol, 39.97 μL, 2 equivalents) were added under N2. The mixture was stirred under N2 at 25°C for 1 hour. LCMS showed complete consumption of the starting material and the formation of a new peak at the desired mass.

[0678] The mixture was filtered, and the filtrate was purified by preparative HPLC (neutral conditions) to obtain 6-(5-(diflu...

Claims

[Claim 1] The invention described in the specification.

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