Cannabinoid receptor type 2 (CB2) modulators and uses thereof

Abstract

Disclosed herein are compounds of formula (I) and methods for modulating cannabinoid receptor 2 (CB2) with the compounds and compositions disclosed herein. Methods for treating diseases or conditions mediated by the action of cannabinoid receptor 2 (CB2) or that would benefit from modulating cannabinoid receptor 2 (CB2) are also described. JPEG2023526783000587.jpg3760

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 020,489, filed May 5, 2020, and U.S. Provisional Application No. 63 / 054,096, filed July 20, 2020, each of which is incorporated herein by reference in its entirety.

[0002] Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat conditions, diseases, or disorders that may benefit from reducing or inhibiting cannabinoid receptor CB2 activity. [Background technology]

[0003] The cannabinoid CB2 receptor (CB2R) regulates immune responses during inflammatory processes in the tumor microenvironment. Endogenous and exogenous cannabinoids exert immunosuppressive properties in various ways, including inducing apoptosis of T cells, NK cells, and B cells; inhibiting T cell, NK cell, and B cell proliferation; inhibiting immunostimulatory cytokine and chemokine production; and inducing immunosuppressive cytokine production and regulatory T cells. Therefore, CB2R antagonism should restore T cell, NK cell, and B cell function and alleviate the innate and adaptive immune suppression caused by endocannabinoids. The development of CB2 receptor antagonists represents a novel approach to treating cancer by enhancing antitumor immune responses. Summary of the Invention [Means for solving the problem]

[0004] The compounds described herein, including pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates thereof, 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.

[0005] In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, [ka] During the ceremony, R 1 is —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 to 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 is absent, C1-C4 alkylene, or C3-C5 cycloalkylene; R 2 is unsubstituted or contains 1, 2, 3, or 4 R a and ring A is substituted with Ring A is a C3-C6 heterocycloalkyl containing 1 to 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 cycloalkyl, 5-membered heteroaryl, or 6-membered heteroaryl; Each R a are 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 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, 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 is H or C1-C4 alkyl; R 4 But -L 2 -R 5 and L 2 does not exist or -CR 10 R 11 - and R 5 is unsubstituted or contains 1, 2, 3, or 4 R b and ring B is substituted with Ring B is C3-C 12 Cycloalkyl, C2-C 10 heterocycloalkyl, phenyl, naphthyl, or heteroaryl; Each R b are 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 deuteroalkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 heteroalkyl, or substituted or unsubstituted monocyclic C3-C6 heterocycloalkyl; Or two R attached to the same carbon atom b together with the carbon atoms form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl; R 10 and R 11 is independently selected from H or —CH3; Or R 10 and R 11 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl, R 6 is unsubstituted or contains 1, 2, 3, or 4 R c and ring C is substituted with Ring C is phenyl, naphthyl, heteroaryl, C3-C 12 Cycloalkyl, or C2-C 10 heterocycloalkyl, or Or R 6 But 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(R13 )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 are 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-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, or a 1,4-dioxanyl ring fused to ring C; R 7 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; X1 is N and X 2 But, CR 8 or N, Or X 1 But, CR 8 or N and X 2 is N, R 8 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 is 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 is independently selected from the group consisting of hydrogen, C-C alkyl, C-C deuteroalkyl, C-C fluoroalkyl, C-C heteroalkyl, substituted or unsubstituted C-C cycloalkyl, substituted or unsubstituted C-C heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; However, R 6 When is H, R 4 is not cyclohexyl, 4-methylcyclohexyl, or cycloheptyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0006] In another aspect, a compound having the structure of formula (X), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R 1 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, C3-C6 heterocycloalkyl containing one N atom and zero or one O or S atom, or C3-C6 heterocycloalkyl containing zero or one N atom and one O or S atom; L 1 is absent, C1-C4 alkylene, or C3-C5 cycloalkylene; R 2 is unsubstituted or contains 1, 2, 3, or 4 R a and ring A is substituted with Ring A is a C3-C6 heterocycloalkyl containing 1 to 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 cycloalkyl, 5-membered heteroaryl, or 6-membered heteroaryl; Each R a are 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, or substituted or unsubstituted monocyclic C3-C6 heterocycloalkyl; R 3 is H or C1-C4 alkyl; R 4 but, [ka] wherein u is 1 or 2 and v is 1 or 2; or Or R 4 But -L 2 -R 5 and L 2 does not exist or -CR 10 R 11 - and R 10 is -CH3, R 11 is H or -CH3, Or R 10 and R 11 together with the carbon atoms to which they are attached to form cyclopropyl-1,1-diyl, R 5 is unsubstituted or contains 1, 2, 3, or 4 R b and ring B is substituted with Ring B is a bridged C5-C 12 cycloalkyl, phenyl, naphthyl, or heteroaryl; Each R b are 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 13C(=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; Or two R attached to the same carbon atom b together with the carbon atoms form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl; R 6 is unsubstituted or contains 1, 2, 3, or 4 R c and ring C is substituted with Ring C is phenyl, naphthyl, heteroaryl, C3-C 12 Cycloalkyl, or C2-C 10 heterocycloalkyl, or Or R 6 But 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 Rc are 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 fused to ring C; R 7 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 is N and X 2 But, CR 8 or N, Or X 1 But, CR 8 or N and X 2 is N, R 8 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 is 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 is independently selected from the group consisting of hydrogen, C-C alkyl, C-C deuteroalkyl, C-C fluoroalkyl, C-C heteroalkyl, substituted or unsubstituted C-C cycloalkyl, substituted or unsubstituted C-C heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; However, R 1 When is H, R 4 is not cyclohexyl substituted with 0, 1, 2, 3, or 4 methyl groups, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

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

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

[0009] In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, dispersion, solution, or emulsion.

[0010] In another aspect, described herein is a method for modulating the activity of the cannabinoid 2 receptor (CB2R) in a mammal, the method comprising administering to the mammal a compound described herein, or any pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

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

[0012] In another aspect, described herein are methods for treating cancer in a mammal, comprising administering to the mammal a selective cannabinoid 2 receptor (CB2R) modulator. 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 any pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0013] In another aspect, described herein are methods for treating cancer in a mammal, comprising administering to the mammal a compound of Formula (I) or Formula (X), or any formula described herein, or any 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 cancer, breast cancer, endometrial cancer, heart tumor, kidney cancer, lung cancer, liver cancer, uterine cancer, blood and lymphatic tumors, 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 comprises administering at least one additional therapy to the mammal.

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

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

[0017] In any of the foregoing aspects, further embodiments include a single administration of an effective amount of the compound, including further embodiments in which the compound is administered to the mammal once daily, or in which the compound is administered to the mammal multiple times throughout the day. In some embodiments, the compound is administered on a continuous dosing schedule. In some embodiments, the compound is administered on a continuous daily dosing schedule.

[0018] An article of manufacture is provided that includes packaging material, a formulation within the packaging material (e.g., 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 for modulating CB2 activity or for the treatment, prevention, or amelioration of one or more symptoms of a disease or disorder associated with or that may benefit from CB2 activity.

[0019] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating particular embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF 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 in HIV / AIDS patients, and neuropathic pain and spasticity in multiple sclerosis. Recently, the anti-inflammatory properties of cannabinoids have attracted much attention. Research into marijuana cannabinoids has led to the discovery of the cannabinoid CB1 and CB2 receptors (CB1R and CB2R) and their endogenous ligands, 2-arachidonoyl-glycerol (2-AG) and anandamide (AEA), which comprise what is known as the endocannabinoid system. Both CB1R and CB2R are linked to heterotrimeric G i / o They are protein-coupled receptors. CB1R is predominantly expressed in the central nervous system (CNS), while CB2R is predominantly 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 regulate immune responses during inflammatory processes, and their immunosuppressive effects have been studied in numerous disease models, including allogeneic mouse tumors, multiple sclerosis, diabetes, 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 major 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 cell induction. Additionally, cannabis users have decreased NK cell counts, diminished lymphocyte proliferative responses to inflammatory stimuli, and reduced levels of IL2. In contrast, cannabis users also have elevated levels of the immunosuppressive cytokines IL10 and TGF-β1. Furthermore, a retrospective analysis of clinical data found 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, both cancer and immune cells produce the endogenous cannabinoids AEA and 2-AG, leading to increased CB2R expression. Therefore, CB2R antagonism should restore T cell, NK cell, and B cell function and alleviate the innate and adaptive immune suppression caused by endocannabinoids. The development of CB2 receptor antagonists represents a novel approach to treating cancer by enhancing antitumor immune responses.

[0022] cancer Disclosed herein, in some embodiments, are methods of treating cancer using a CB2 modulator described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0023] As used herein, the term "cancer" refers to an abnormal growth of cells that tend to proliferate in an uncontrolled manner and in some cases metastasize (spread). Types of cancer include, but are not limited to, solid tumors (bladder, bowel, brain, breast, endometrium, heart, kidney, lung, liver, uterus, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma), or blood tumors (leukemia and lymphoma) at any stage, with or without metastasis.

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

[0025] In some embodiments, the CB2 receptor modulators described herein are used to treat solid tumors. A solid tumor is an abnormal mass of tissue that typically does not contain cysts or liquid areas. Solid tumors can be benign (not cancerous) or malignant (cancer). Various types of solid tumors are named for the type of cells that form them. Examples of solid tumors are carcinomas, sarcomas, and lymphomas.

[0026] Carcinomas include, but are not limited to, esophageal carcinoma, hepatocellular carcinoma, basal cell carcinoma, squamous cell carcinoma, bladder carcinoma, bronchogenic carcinoma, colon cancer, colorectal carcinoma, gastric cancer, lung cancer including small cell carcinoma and non-small cell carcinoma of the lung, adrenocortical carcinoma, thyroid carcinoma, 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, lymphangioendothelioma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, and other soft tissue sarcomas.

[0028] Leukemias include, but are not limited to, a) chronic myeloproliferative syndromes (neoplastic disorders of pluripotent hematopoietic stem cells), b) acute myeloid leukemia, c) chronic lymphocytic leukemia (CLL), including B-cell CLL, T-cell CLL prolymphocytic leukemia, and hairy cell leukemia, and d) acute lymphoblastic leukemia (characterized by the accumulation of lymphoblasts). Lymphomas include, but are not limited to, B-cell lymphomas (e.g., Burkitt's lymphoma), Hodgkin's lymphoma, and the like.

[0029] Benign tumors include, for example, hemangioma, hepatocellular adenoma, cavernous hemangioma, focal nodular hyperplasia, acoustic neuroma, neurofibroma, bile duct adenoma, bile duct cystoma, fibroma, lipoma, leiomyoma, mesothelioma, teratoma, myxoma, nodular regenerative hyperplasia, trachoma, and pyogenic granuloma.

[0030] Primary and metastatic tumors include, for example, lung cancer, breast cancer, colon 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, carcinoids of the gastrointestinal tract, breast, and other organs.

[0031] In one aspect, the CB2R modulators described herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, reduce, ameliorate, or inhibit immune suppression and cell proliferation associated with cancer.

[0032] compound The compounds described herein, including pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates thereof, 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 aspect, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, [ka] During the ceremony, R 1 is —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 to 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 is absent, C1-C4 alkylene, or C3-C5 cycloalkylene; R 2 is unsubstituted or contains 1, 2, 3, or 4 R a and ring A is substituted with Ring A is a C3-C6 heterocycloalkyl containing 1 to 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 cycloalkyl, 5-membered heteroaryl, or 6-membered heteroaryl; Each R a are 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 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, 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 is H or C1-C4 alkyl; R 4 But -L 2 -R 5 and L 2 does not exist or -CR 10 R 11 - and R 5 is unsubstituted or contains 1, 2, 3, or 4 R b and ring B is substituted with Ring B is C3-C 12 Cycloalkyl, C2-C 10 heterocycloalkyl, phenyl, naphthyl, or heteroaryl; Each R b are 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 deuteroalkoxy, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 heteroalkyl, or substituted or unsubstituted monocyclic C3-C6 heterocycloalkyl; Or two R attached to the same carbon atom b together with the carbon atoms form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl; R 10 and R 11 is independently selected from H or —CH3; Or R 10 and R 11 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl, R 6 is unsubstituted or contains 1, 2, 3, or 4 R c and ring C is substituted with Ring C is phenyl, naphthyl, heteroaryl, C3-C 12 Cycloalkyl, or C2-C 10 heterocycloalkyl, or Or R 6 But 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(R13 )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 are 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-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, or a 1,4-dioxanyl ring fused to ring C; R 7 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; X1 is N and X 2 But, CR 8 or N, Or X 1 But, CR 8 or N and X 2 is N, R 8 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 is 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 are 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, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

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

[0035] In some embodiments, R 3 is H or -CH3, and L 1 is absent, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, or cyclopropyl-1,1-diyl; R 10 and R 11 are independently selected from H or —CH3, or R 10 and R 11 together with the carbon atoms to which they are attached to form cyclopropyl-1,1-diyl, and X 1 is N and X 2 is CR 8 or X 1 is CR 8 and X 2 is N.

[0036] In some embodiments, R 1 is -OH, -CH, -OCH, -CD, -OCD, -CFH, -CHF, -CF, -OCFH, -OCHF, -OCF, cyclopropyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or piperidinyl. 1 is -OH, -CH3, -OCH3, -OC(CH3)2, -CD3, -OCD3, -CFH2, -CHF2, -CF3, -OCFH2, -OCHF2, -OCF3, cyclopropyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or piperidinyl.

[0037] In some embodiments, R 1 is —OH or —CH. In some embodiments, R 1 is —O—C1-C3 alkyl.

[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 is as defined in some or any embodiment of formula (I).

[0039] In some embodiments, R 5 is unsubstituted or contains 1, 2, 3, or 4 R b and Ring B is a monocyclic C3-C8 cycloalkyl or a fused bicyclic C5-C 12 Cycloalkyl, Bridged Bicyclic C5-C 12 Cycloalkyl or spiro bicyclic C5-C 12 Cycloalkyl Bicyclic C5-C 12 cycloalkyl, or Ring B is a monocyclic C2-C6 heterocycloalkyl, or a bicyclic C5-C8 heterocycloalkyl that is a fused bicyclic C5-C8 heterocycloalkyl, a bridged bicyclic C5-C8 heterocycloalkyl, or a spiro bicyclic C5-C8 heterocycloalkyl, or Ring B is phenyl, or Ring B is a monocyclic heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.

[0040] In some embodiments, L 2 does not exist, R 5 is unsubstituted or contains 1, 2, 3, or 4 R b and Ring B is a monocyclic C3-C8 cycloalkyl or a fused bicyclic C5-C 12 Cycloalkyl, Bridged Bicyclic C5-C 12 Cycloalkyl or spiro bicyclic C5-C 12 Cycloalkyl Bicyclic C5-C12 Alternatively, Ring B is a monocyclic C3-C6 heterocycloalkyl, or a bicyclic C5-C8 heterocycloalkyl that is a fused bicyclic C5-C8 heterocycloalkyl, a bridged bicyclic C5-C8 heterocycloalkyl, or a spiro bicyclic C5-C8 heterocycloalkyl.

[0041] In some embodiments, L 2 does not exist, R 5 is unsubstituted or contains 1, 2, 3, or 4 R b wherein Ring B is cyclobutyl, cyclopentyl, or cyclohexyl; or 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 decalinyl. 12 It is cycloalkyl.

[0042] In some embodiments, L 2 does not exist, R 5 is unsubstituted or contains 1, 2, 3, or 4 R b and Ring B is 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 does not exist, R 5 is unsubstituted or contains 1, 2, 3, or 4 R b and ring B is substituted with [ka] or ring B is [ka] is.

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

[0045] In some embodiments, each R b 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, or two R are bonded to the same carbon atom; b together with its carbon atom 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] is.

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

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

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

[0050] In some embodiments, L 2 is not present or -CR 10 R 11 - and R 10 and R 11 are independently selected from H or —CH3, or R 10 and R 11 together with the carbon atoms to which they are attached to form cyclopropyl-1,1-diyl, and R 5 is unsubstituted or contains 1, 2, 3, or 4 R b and Ring B is phenyl or monocyclic heteroaryl.

[0051] In some embodiments, Ring B is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0052] In some embodiments, L 2 is not present or -CR10 R 11 - and R 10 and R 11 are independently selected from H or —CH3, or R 10 and R 11 together with the carbon atoms to which they are attached to form cyclopropyl-1,1-diyl, and R 5 teeth, [ka] and m is 0, 1, or 2.

[0053] In some embodiments, each R b are independently selected from the group consisting of F, Cl, Br, -CN, -OH, -NH, -NH(CH), -N(CH), -CH, -OCH, -CD, -OCD, -CFH, -CHF, -CF, -OCFH, -OCHF, and -OCF.

[0054] In some embodiments, R 4 teeth [ka] and R 10 and R 11 are independently selected from H or —CH3, or R 10 and R 11 together with the carbon atoms to which they are attached form cyclopropyl-1,1-diyl, m is 0, 1, or 2, and each R b are independently selected from the group consisting of F, Cl, Br, -CN, -OH, -NH, -NH(CH), -N(CH), -CH, -OCH, -CD, -OCD, -CFH, -CHF, -CF, -OCFH, -OCHF, and -OCF.

[0055] In some embodiments, L 1 is -CH2CH2- and R 2 is unsubstituted or contains 1, 2, 3, or 4 R aRing A is a C3-C6 heterocycloalkyl containing 1-2 N atoms and 0 or 1 O or S atom, or a C4-C7 heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom, and R 6 is unsubstituted or contains 1, 2, 3, or 4 R c Ring C is substituted with phenyl, naphthyl, heteroaryl, C3-C 12 cycloalkyl, or C3-C6 heterocycloalkyl.

[0056] In some embodiments, L 1 is -CH2CH2- and R 2 is unsubstituted or contains 1, 2, 3, or 4 R a and ring A is azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, or piperazinyl. 1 -R 2 teeth, [ka] is.

[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 is as defined in some or any embodiment of formula (I).

[0058] In some embodiments, R 6 is unsubstituted or contains 1, 2, 3, or 4 R cand Ring C is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 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] In some embodiments, each R c 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 )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, CH, F, O-C-C alkyl, or O-C-C haloalkyl. 6 teeth, [ka] In some embodiments, R 6 is not H. In some embodiments, R 6 is a halo.

[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 is as 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, and R 2 is unsubstituted or contains 1, 2, 3, or 4 R a and ring A is phenyl or 6-membered heteroaryl.

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

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

[0066] In some embodiments, each R aare 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.

[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 is 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 aspect, a compound having the structure of formula (X), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, [ka] During the ceremony, R 1 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, C3-C6 heterocycloalkyl containing one N atom and zero or one O or S atom, or C3-C6 heterocycloalkyl containing zero or one N atom and one O or S atom; L 1 is absent, C1-C4 alkylene, or C3-C5 cycloalkylene; R 2 is unsubstituted or contains 1, 2, 3, or 4 R a and ring A is substituted with Ring A is a C3-C6 heterocycloalkyl containing 1 to 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 cycloalkyl, 5-membered heteroaryl, or 6-membered heteroaryl; Each R a are 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, or substituted or unsubstituted monocyclic C3-C6 heterocycloalkyl; R 3 is H or C1-C4 alkyl; R 4 but, [ka] wherein u is 1 or 2 and v is 1 or 2; or Or R 4 But -L 2 -R 5 and L 2 does not exist or -CR 10 R 11 - and R 10 is -CH3, R 11 is H or -CH3, Or R 10 and R 11 together with the carbon atoms to which they are attached to form cyclopropyl-1,1-diyl, R 5 is unsubstituted or contains 1, 2, 3, or 4 R b and ring B is substituted with Ring B is a bridged C5-C 12 cycloalkyl, phenyl, naphthyl, or heteroaryl; Each R b are 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, 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 attached to the same carbon atom b together with the carbon atoms form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl; R 6 is unsubstituted or contains 1, 2, 3, or 4 R c and ring C is substituted with Ring C is phenyl, naphthyl, heteroaryl, C3-C 12 Cycloalkyl, or C2-C 10 heterocycloalkyl, or Or R 6 But 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 are 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 fused to ring C; R 7 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 is N and X 2 But, CR 8 or N, Or X 1But, CR 8 or N and X 2 is N, R 8 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 is 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 are 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, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

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

[0071] In some embodiments, R 3 is H or -CH3, and L 1 is absent, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, or cyclopropyl-1,1-diyl; X1 is N and X 2 is CR 8 or X 1 is CR 8 and X 2 is N.

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

[0073] In some embodiments, R 1 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 is as defined in some or any embodiment of formula (X).

[0075] In some embodiments, [ka] teeth, [ka] is.

[0076] In some embodiments, [ka] teeth [ka] is.

[0077] In some embodiments, each R b 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, or two R are bonded to the same carbon atom; b together with its carbon atom form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, thiomorpholinyl, or piperidinyl.

[0078] In some embodiments, [ka] teeth, [ka] is.

[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] Formula (XII) In the formula, X 1 , X 2 , L 1 , R 1 , R 2 , R 6 , and R 7 is as defined in some or any embodiment of formula (X), and n1, n2, and n3 are each independently 1, 2, or 3; Rd is 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 a 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 is as defined in some or any embodiment of formula (X).

[0081] In some embodiments, R 5 is unsubstituted or contains 1, 2, 3, or 4 R b and Ring B is phenyl or monocyclic heteroaryl.

[0082] In some embodiments, R 5 is unsubstituted or contains 1, 2, 3, or 4 R bor Ring B is 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 pyridazinyl.

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

[0085] In some embodiments, each R b are independently selected from the group consisting of F, Cl, Br, -CN, -OH, -NH, -NH(CH), -N(CH), -CH, -OCH, -CD, -OCD, -CFH, -CHF, -CF, -OCFH, -OCHF, and -OCF.

[0086] In some embodiments, L 1 is -CH2CH2- and R 2 is unsubstituted or contains 1, 2, 3, or 4 R a Ring A is a C3-C6 heterocycloalkyl containing 1-2 N atoms 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, and R 6 is unsubstituted or contains 1, 2, 3, or 4 R c Ring C is substituted with phenyl, naphthyl, heteroaryl, C3-C 12 Cycloalkyl, or C2-C 10 It is heterocycloalkyl.

[0087] In some embodiments, L 1 is -CH2CH2- and R 2 is unsubstituted or contains 1, 2, 3, or 4 R a and Ring A is 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 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 is as defined in some or any embodiment of formula (X), and n1, n2, and n3 are each independently 1, 2, or 3; R d is 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(R13 )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 a 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 is as defined in some or any embodiment of formula (X).

[0091] In some embodiments, R 6 is unsubstituted or contains 1, 2, 3, or 4 R c and Ring C is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 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] In some embodiments, each R care 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 )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] is.

[0095] In some embodiments, L 1 is -CH2-, -CH(CH3)-, -C(CH3)2-, or cyclopropyl-1,1-diyl, and R 2 is unsubstituted or contains 1, 2, 3, or 4 R 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 , R6 , and R 7 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 is as defined in some or any embodiment of formula (X), and n1, n2, and n3 are each independently 1, 2, or 3; R d is 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 a 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 , R6 , R 7 , R 10 , and R 11 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] is.

[0101] In some embodiments, each R a 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 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.

[0103] 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, -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 unsubstituted or contains 1, 2, 3, or 4 R c and ring C is substituted with Ring C is phenyl, naphthyl, heteroaryl, C3-C 12 Cycloalkyl, or C2-C 10 heterocycloalkyl, or Or R 6 is 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(R12 ), -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 are 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-C7 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, or a 1,4-dioxanyl ring fused to ring C.

[0105] In some embodiments, for any formula described herein, R 6 is unsubstituted or contains 1, 2, 3, or 4 R c and ring C is substituted with (R cis as defined herein), Ring C is phenyl, naphthyl, heteroaryl, C-C cycloalkyl, or C-C heterocycloalkyl, and R 4 teeth, [ka] and -L is a bridged cycloalkyl selected from 1 -R 2 is one of -L selected from Table 2 1 -R 2 In some such embodiments, R 1 is H. In some other such embodiments, R 1 is OH or O-C1-C3 alkyl.

[0106] In some embodiments, for any formula described herein, R 6 is the halo and R 4 teeth, [ka] and -L is a bridged cycloalkyl selected from 1 -R 2 is one of -L selected from Table 2 1 -R 2 In some such embodiments, R 1 is H. In some other such embodiments, R 1 is OH or O-C1-C3 alkyl.

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

[0108] In another aspect, described herein are compounds having one of the following structures in Table 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 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 is as defined herein for any of the preceding formulas, and R A is H, C1-C6 alkyl, or C1-C6 alkyl-aryl (aryl is substituted with C1-C3 alkyl, C1-C3 alkoxy, halo, or NO2).

[0110] Further forms of the compound In one aspect, the compounds described herein (compounds of Formula (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 the compounds having the same type of activity are also included within the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0111] As used herein, "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., the material may be administered to an individual without producing undesired biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0112] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent consisting of the cationic form of the therapeutically active agent in combination with a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are useful in solid dosage forms because they are typically more soluble and more rapidly soluble in gastric and intestinal fluids than non-ionic species. Furthermore, their solubility is often a function of pH, allowing for selective dissolution in one part of the gastrointestinal tract or another, an ability that can be manipulated as an aspect of delayed- and sustained-release behavior. Also, salt-forming molecules can be in equilibrium with their neutral forms, allowing for tailored passage through biological membranes.

[0113] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) with an acid. In some embodiments, a compound of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) (i.e., the free base form) is basic and is reacted with an organic or inorganic acid. 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, camphoric 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 sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), These include, but are 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 a compound of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) with a base. In some embodiments, a compound of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) is acidic and is reacted with a base. In such situations, the acidic protons of compounds of formula (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, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine, and the like. In other cases, the compounds described herein form salts with amino acids, such as, but not limited to, arginine, lysine, and the like. 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, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as sodium, calcium, potassium, magnesium, meglumine, N-methylglucamine, or ammonium salts.

[0115] It should be understood that a reference to a pharmaceutically acceptable salt includes solvent addition forms. In some embodiments, solvates contain stoichiometric or non-stoichiometric amounts of a solvent and are formed during the crystallization process with a pharmaceutically acceptable solvent, such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholic acid salts are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in 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 Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB), as well as active metabolites of these compounds that have the same type of activity.

[0117] In some embodiments, moieties (e.g., alkyl groups, aromatic rings) on the organic radicals of compounds of Formula (I), (II), (III), (IV), (X), ((XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) are susceptible to various metabolic reactions. Incorporation of appropriate substituents into the organic radical reduces, minimizes, or eliminates this metabolic pathway. In particular embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, halogen, deuterium, alkyl groups, haloalkyl groups, or deuteroalkyl groups.

[0118] In another embodiment, the compounds described herein are labeled isotopically (e.g., with a radioisotope) 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 isotopically labeled compounds identical to those listed in the various formulas and structures presented herein, but in which one or more atoms have been replaced by an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into the compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, and phosphorus, e.g., 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 In one aspect, the isotopically labeled compounds described herein, e.g., 3 H and 14 Compounds incorporating radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium offers certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogens in a compound of Formula (I) are replaced with deuterium.

[0120] In some embodiments, compounds of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) possess one or more stereocenters, and each stereocenter independently exists in either the R or S configuration. In some embodiments, compounds of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) exist in the R configuration. In some embodiments, compounds of Formula (I), (II), (III), (IV), (X), (XI), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) are present in the S configuration. The compounds provided herein include all diastereomeric, individual enantiomeric, atropisomeric, and epimeric forms, as well as appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and tsusamen (Z) isomers, as well as appropriate mixtures thereof.

[0121] Individual stereoisomers can be obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers on chiral chromatographic columns, or separation of diastereomers on non-chiral or chiral chromatographic columns, or crystallization and recrystallization in an appropriate solvent or mixture of solvents. In certain embodiments, compounds of Formula (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 diastereomeric compounds / salts, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In other embodiments, diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is accomplished by chromatography, or by formation of diastereomeric salts and separation by recrystallization or 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, stereoisomers are obtained by stereoselective synthesis.

[0122] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some cases, they are easier to administer than the parent drug. For example, they are bioavailable by oral administration, but the parent is not. Additionally or alternatively, prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, the prodrug's design increases effective water solubility. A non-limiting example of a prodrug is a compound described herein that is administered as an ester (the "prodrug") but is subsequently metabolically hydrolyzed to provide the active entity. A further example of a prodrug is a short peptide (polyamino acid) bonded to an acid group, where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.

[0123] 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 sulfonate esters. See, 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; "Design and Application of Prodrugs," in Bundgaard, H. A. Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, pp. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, pp. 1-38, each of which is incorporated herein by reference. In some embodiments, a hydroxyl group in a compound disclosed herein is used to form a prodrug, and the hydroxyl group is incorporated into an acyloxyalkyl ester, an alkoxycarbonyloxyalkyl ester, an alkyl ester, an aryl ester, a phosphate ester, a sugar ester, an ether, or the like. In some embodiments, the hydroxyl group of 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 the carboxylic acid group. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs.

[0124] Prodrug forms of the compounds described herein are included within the scope of the claims, where the prodrug is metabolized in vivo to produce a compound of formula (I), (II), (III), (IV), (X), (XIA), (XIB), (XII), (XIIA), (XIIB), (XIII), (XIIIA), and / or (XIIIB) as set forth herein. In some cases, some of the compounds described herein are prodrugs for another derivative or active compound.

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

[0126] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need thereof to produce metabolites, which are then used to produce a desired effect, including a desired therapeutic effect.

[0127] A "metabolite" of a compound disclosed herein is a derivative of that compound formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound formed when the compound is metabolized. As used herein, the term "metabolized" refers to the set of processes (including, but not limited to, hydrolysis reactions and enzyme-catalyzed reactions) by which a particular substance is transformed by an organism. Thus, enzymes can result in specific structural modifications to the compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase 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 are optionally identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound.

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

[0129] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[0130] The compounds are described, for example, in March's Advanced Organic Chemistry, 6 th The compounds are prepared using standard organic chemistry techniques, such as those described in The Journal of Organic Chemistry, Vol. 1, No. 1, pp. 111-115, 1997. Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be used, e.g., variations in solvents, reaction temperatures, reaction times, as well as different chemical reagents and other reaction conditions.

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

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

[0133] As used herein, C1-C x Includes C1-C2, C1-C3...C1-C xand the like. By way of example only, a group designated as "C1-C4" indicates that there are from 1 to 4 carbon atoms in the moiety, i.e., a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are from 1 to 4 carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0134] An "alkyl" group refers to an aliphatic hydrocarbon group. An alkyl group is branched or straight-chain. In some embodiments, an "alkyl" group has 1 to 10 carbon atoms, i.e., C1-C 10 It is alkyl. Numerical ranges such as "1 to 10," whenever they appear herein, refer to each integer within the given range. For example, "1 to 10 carbon atoms" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and so on, up to 10 carbon atoms, although this definition also covers occurrences of the term "alkyl" when no numerical range is specified. In some embodiments, alkyl is C1-C6 alkyl. In one aspect, alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0135] An "alkylene" group refers to a divalent alkyl radical. Any of the monovalent alkyl groups described above can be converted to an alkylene by abstracting a second hydrogen atom from the alkyl. In some embodiments, the alkylene is a C-C alkylene. In other embodiments, the alkylene is a C-C alkylene. Typical alkylene groups include, but are not limited to, -CH-, -CH(CH)-, -C(CH)-, -CHCH-, -CHCH(CH)-, -CHC(CH)-, -CHCHCH-, -CHCHCHCH-, and the like.

[0136] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR2, where R refers to the remaining portions 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 in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡CR, where R refers to the remainder 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] An "alkoxy" group refers to a (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 "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.

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

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

[0143] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic non-aromatic radical in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. A cycloalkyl can be saturated or partially saturated. In some embodiments, a cycloalkyl is a spirocyclic or bridged compound. In some embodiments, a cycloalkyl is optionally fused to an aromatic ring, and the point of attachment is at a carbon that is not an 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 bicyclo[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 decalinyl. In some embodiments, the cycloalkyl is C3-C6 cycloalkyl.

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

[0145] "1,4-dioxanyl ring fused to ring C" means [ka] Refers to...

[0146] "Deuteroalkyl" refers to an alkyl group in which at least one H is an isotope of hydrogen, i.e., deuterium ( 2 H) or tritium ( 3 H).

[0147] "Deuteroalkoxy" refers to an alkoxy group in which at least one H is an isotope of hydrogen, i.e., deuterium ( 2 H) or tritium ( 3 H).

[0148] The term "halo," or alternatively "halogen" or "halide," means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

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

[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 skeletal atoms of the alkyl are selected from atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl.

[0152] Examples of such heteroalkyls are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, and -CH2SCH3.

[0153] The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing 1 to 4 heteroatoms in 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 having 3 to 10 atoms in their ring system, and aromatic heterocyclic groups include rings having 5 to 10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, 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, dithiazole ... oranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolidinyl.Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C-linked) or N-attached where possible. For example, groups derived from pyrrole include both pyrrol-1-yl (N-linked) and pyrrol-3-yl (C-linked). Furthermore, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-linked), or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-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 term "heteroaryl" or, alternatively, "heteroaromatic" refers to an aryl group 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 furazanyl.Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, a heteroaryl contains 0 to 4 N atoms in the ring. In some embodiments, a heteroaryl contains 1 to 4 N atoms in the ring. In some embodiments, a heteroaryl contains 0 to 4 N atoms, 0 to 1 O atoms, and 0 to 1 S atoms in the ring. In some embodiments, a heteroaryl contains 1 to 4 N atoms, 0 to 1 O atoms, and 0 to 1 S atoms in the ring. In some embodiments, a heteroaryl is a C1-C9 heteroaryl. In some embodiments, a monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, a monocyclic heteroaryl is a 5- 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, a heterocycloalkyl is fused to an aryl or heteroaryl. In some embodiments, a heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. In some embodiments, the sulfur atom in a heterocycloalkyl is not oxidized. The term heteroalicyclic also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In one aspect, a heterocycloalkyl is a C2-C 10 In another embodiment, heterocycloalkyl is C-C10 Heterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0155] The term "bond" or "single bond" refers to a chemical bond between two atoms, or between two moieties when the atoms joined by the bond are considered to be part of a larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent and a bond is formed between the remaining specified groups.

[0156] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical substance embedded in or attached to a molecule.

[0157] The terms "optionally substituted" or "substituted" mean that the referenced group is optionally substituted with one or more additional groups independently selected from halogen, -CN, -NH, -NH(alkyl), -N(alkyl), -OH, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), 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 selected from halogen, —CN, —NH, —NH(CH), —N(CH), —OH, —COH, —CO(C-C alkyl), —C(═O)NH, —C(═O)NH(C-C alkyl), —C(═O)N(C-C alkyl), —S(═O)NH, —S(═O)NH(C-C alkyl), —S(═O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, —SC-C alkyl, —S(═O)C-C alkyl, and —S(═O)C-C alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -CH, -CHCH, -CF, -OCH, and -OCF. In some embodiments, substituents are substituted with one or two of the foregoing groups. In some embodiments, optional substituents on an aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0158] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means that there are no lasting adverse effects on the general health of the subject being treated.

[0159] The term "modulate," as used herein, means to interact with a target, directly or indirectly, to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target. In some embodiments, "modulate" means to interact with a target, directly or indirectly, to decrease or inhibit receptor activity.

[0160] The term "modulator," as used herein, refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, those of an agonist, partial agonist, inverse agonist, antagonist, or combinations thereof. In some embodiments, a modulator is an antagonist. A receptor antagonist is an inhibitor of receptor activity. An antagonist mimics a ligand that binds to a receptor and prevents receptor activation by the natural ligand. Preventing activity can have many effects. Where a natural agonist that binds to a receptor results in an increased cellular function, an antagonist that binds to and blocks this receptor reduces the function.

[0161] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable 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 of skill in the art are 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, the term "co-administration" and the like is meant to encompass the administration of selected therapeutic agents to a single patient and is intended to include therapeutic regimens in which agents are administered by the same or different routes of administration, or at the same or different times.

[0163] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient quantity of an agent or compound being administered that will relieve to some extent one or more of the symptoms of the disease or condition being treated. The results include reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to provide a clinically meaningful reduction in disease symptoms. An appropriate "effective" amount in any individual case is optionally determined using techniques such as a dose escalation study.

[0164] The terms "enhance" or "enhancing," as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0165] The terms "kit" and "article of manufacture" are used synonymously.

[0166] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans; non-human primates, e.g., chimpanzees, and other ape and monkey species; livestock, e.g., cows, horses, sheep, goats, pigs; domestic animals, e.g., rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0167] As used herein, the terms "treat," "treating," or "treatment" include alleviating, attenuating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, alleviating symptoms caused by the disease or condition, or arresting the symptoms of the disease or condition prophylactically and / or therapeutically.

[0168] Pharmaceutical Composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of the active compound into preparations for pharmaceutical use. Suitable formulations depend on the selected route of administration. Overviews of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for their disclosure.

[0169] In some embodiments, the compounds described herein are administered alone or in a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, excipient, or diluent. Administration of the compounds and compositions described herein can be by any method that allows 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 suppository, and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal, and topical (including epidermal, cutaneous, enema, eye drops, ear drops, intranasal, and intravaginal) administration, and the most suitable route can depend, for example, on the condition and disorder of the recipient. By way of example only, the compounds described herein can be administered locally to the area in need of treatment, for example, by local infusion during surgery, topical application such as a cream or ointment, injection, catheter, or implant. Administration can also be by direct injection at the site of the affected tissue or organ.

[0170] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous liquid or non-aqueous liquid, or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is provided as a bolus, electuary, or paste.

[0171] Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin ("gelcaps"), and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surfactant, or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, tablets are coated or scored and formulated so as to provide slow or controlled release of the active ingredient therein. All formulations intended for oral administration should be in dosages suitable for such administration. Push-fit capsules may contain the active ingredient in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. Dragee cores are provided with a suitable coating. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0172] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injectable formulations are presented in unit dosage form, e.g., in ampoules or multi-dose containers, with added preservatives. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing, and / or dispersing agents. The compositions may be presented in unit dosage or multi-dose containers, e.g., sealed ampoules and vials, and may be stored in powder form or freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, e.g., saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind described above.

[0173] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. 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 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, allowing for the preparation of highly concentrated solutions.

[0174] It will be understood that in addition to the ingredients specifically mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0175] Treatment method The compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are useful for modulating cannabinoid receptors. In some embodiments, the cannabinoid receptor modulated by the compounds and methods is the cannabinoid 2 receptor (CB2R).

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

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

[0178] In some embodiments, provided herein is a method for modulating cannabinoid 2 receptor (CB2R) activity in a mammal, comprising administering to the mammal a compound described herein, or any pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

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

[0180] In some embodiments, provided herein are methods for treating cancer in a mammal, comprising administering to the mammal a selective cannabinoid 2 receptor (CB2R) modulator. 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, provided herein are methods for treating cancer in a mammal, comprising administering to the mammal a CB2R antagonist or CB2R inverse agonist. 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-indol-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 any of the preceding embodiments, the cancer is a solid tumor.

[0185] In some or any of the preceding embodiments, the cancer is bladder cancer, colon cancer, brain cancer, breast cancer, endometrial cancer, heart cancer, kidney cancer, lung cancer, liver cancer, uterine cancer, blood and lymphatic cancer, 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, the cancer is a sarcoma, carcinoma, or lymphoma.

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

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

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

[0191] Anti-PD-1 / anti-PD-L1 agents In some embodiments, a compound described herein (i.e., a CB2R antagonist or inverse agonist) or a pharmaceutically acceptable salt thereof is administered in combination with an immune checkpoint inhibitor. Immune checkpoint inhibitors include, but are not limited to, anti-PD-1, anti-PD-L1, or programmed cell death protein 1 anti-ligand 2 (PD-L2) agents / inhibitors. In some embodiments, immune checkpoint inhibitors include, but are not limited to, anti-PD-1, anti-PD-L1, or programmed cell death protein 1 anti-ligand 2 (PD-L2) antibodies.

[0192] "PD-1" or "PD1" refers to the programmed death 1 (PD-1) receptor. Other names include programmed cell death protein 1 and CD279 (cluster of differentiation 279). PD-1 has two ligands, PD-L1 and PD-L2. In some embodiments, targeting 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, a compound described herein (i.e., a CB2R antagonist or inverse agonist), or a pharmaceutically acceptable salt thereof, is 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, the anti-PD-1 agent for use in combination with a compound described herein (i.e., a CB2R antagonist or inverse agonist) or a pharmaceutically acceptable salt thereof is nivolumab, pembrolizumab, atezolizumab, durvalumab, pidilizumab, avelumab, TSR-042, PDR-001, tislelizumab (BGB-A317), semipilimab (REGN2810), LY-3300054, 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, genolizumab (CBT-501), FAZ-053, CK-301, AK 104, or GLS-010, BGB-108, SHR-1210, PDR-001, PF-06801591, STI-1110, mDX-400, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalizumab (JS 001), dostalizumab (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 against programmed cell death protein 1 (PD1). In some embodiments, the anti-PD-1 antibody binds to an epitope on PD-1 that blocks PD-1 from binding to any one or more of its putative ligands. In some embodiments, the anti-PD-1 antibody binds to an epitope on the PD-1 protein that blocks PD-1 from binding to PD-L1 and / or PD-L2.

[0200] Exemplary anti-PD-1 antibodies include, but are not limited to, nivolumab / MDX-1106 / BMS-9300 / ONO1152, a fully human lgG4 anti-PD-1 monoclonal antibody; pidilizumab (MDV9300 / CT-011), a humanized lgG1 monoclonal antibody; pembrolizumab (MK-3475 / pembrolizumab / lambrolizumab), a 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), semipilimab (Libtayo), ravlolizumab (Merck), or BGB-A317.

[0202] In some embodiments, the anti-PD1 antibody is an antibody set forth 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 terms "antibody" (singular and plural) include all types of immunoglobulins or fragments thereof, including IgG, IgM, IgA, IgD, and IgE, that may be suitable for the medical uses disclosed herein. Antibodies may be monoclonal or polyclonal and may be of any species of origin, including, for example, mouse, rat, rabbit, horse, or human. Antibody fragments that retain specific binding to the protein or epitope bound by an antibody, e.g., PD-L1 or PD-1, as used in this disclosure are included within the scope of the term "antibody." Antibodies may also be chimeric or humanized, particularly when used for therapeutic purposes. Antibodies and antibody fragments can be obtained or prepared using a variety of methods.

[0204] In some embodiments, the anti-PD-1 agent for use in combination with a compound described herein (i.e., a CB2R antagonist or inverse agonist) or a pharmaceutically acceptable salt thereof is 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 directed against programmed 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 pharmaceutically acceptable salts thereof 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 exemplary antibodies include, but are not limited to, those set forth 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 from Aurigene and Laboratoires Pierre Fabre), CA-170 (Aurigene / Curis), and BMS-986189 (a macrocyclic peptide from 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, US20180044304, US20180044303, US 20180044350, US20180057455, US20180057486, US20180045142, WO20180044963, WO2018044783, W O2018009505, WO20180044329, WO2017066227, WO2017087777, US20170145025, WO2017079669, W02 017070089, US2017107216, WO2017222976, US20170262253, WO2017205464, US20170320875, WO201 7192961, WO2017112730, US20170174679, WO2017106634, WO2017202744, WO2017202275, WO201720 2273, WO2017202274, WO2017202276, WO2017180769, WO2017118762, WO2016041511, 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 at about 400 mg to about 1000 mg.

[0212] Medication and Treatment Regimen In one embodiment, the compounds described herein, or pharmaceutically acceptable salts thereof, are used in the preparation of a medicament for treating a disease or condition in a mammal that would benefit from inhibiting or reducing CB2R activity. Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment involve administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof.

[0213] In certain embodiments, compositions containing the compounds described herein are administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a mammal already suffering from a disease or condition in an amount sufficient to cure or at least partially prevent at least one symptom of the disease or condition. The effective amount for this use will depend on the severity and course of the disease or condition, previous therapy, the mammal's health status, weight, and response to the drug, as well as the judgment of a medical professional. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0214] In prophylactic applications, compositions containing the compounds described herein are administered to a mammal susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." For this use, the precise amount will also depend on the mammal's health, weight, and the like. When used in a mammal, 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 drugs, as well as the judgment of a medical professional. In one aspect, prophylactic treatment involves administering a pharmaceutical composition containing a compound described herein or a pharmaceutically acceptable salt thereof to a mammal that has previously experienced at least one symptom of the disease being treated and is now in remission, to prevent the recurrence of symptoms of the disease or condition.

[0215] In certain embodiments where the mammal's condition does not improve, at the discretion of a medical professional, administration of the compound is administered chronically, i.e., for an extended period of time, including the entire lifespan of the mammal, to ameliorate or otherwise control or limit the symptoms of the mammal's 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 period of time (i.e., a "drug holiday"). In certain embodiments, the length of the drug holiday is between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. Dose reductions during the drug holiday are, by way of example only, between 10% and 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0217] After improvement of the patient's condition occurs, maintenance doses are administered as needed. In certain embodiments, the dosage or frequency of administration, or both, are then reduced as a function of symptoms, to a level at which the improved disease, disorder, or condition is maintained. In certain embodiments, however, the mammal requires intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0218] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the condition and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0219] In general, however, doses used in adult treatment typically range from 0.01 mg to 5000 mg per day. In one aspect, doses used in adult treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented as a single dose or as divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four or more sub-doses per day.

[0220] In one embodiment, a suitable daily dose for a compound described herein or a pharmaceutically acceptable salt thereof is about 0.01 to about 50 mg per kg of body weight. In some embodiments, the amount of active ingredient in the daily dose or dosage form will be lower or higher than the ranges set forth herein, depending on a number of variables related to the particular treatment regimen. In various embodiments, the daily dose and unit dose will vary 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 efficacy of such treatment regimens are 50 and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, and is known as the LD 50 / ED 50 In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating a therapeutically effective daily dose range and / or therapeutically effective unit dose for use in mammals, including humans. In some embodiments, the daily dose of the compounds described herein is at least 100 mg / kg / day at a dose that is consistent with minimal toxicity and / or ED4. 50 In certain embodiments, the daily dose varies within this range depending upon the dosage form employed and the route of administration utilized.

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

[0223] In any of the foregoing aspects, further embodiments include a single administration of an effective amount of the compound, including further embodiments in which (i) the compound is administered once daily, or (ii) the compound is administered multiple times throughout the day to the mammal.

[0224] In any of the foregoing aspects, further embodiments include multiple administrations of an effective amount of the compound, including further embodiments where (i) the compound is administered as a single dose, continuously or intermittently, (ii) the time between multiple administrations is every 6 hours, (iii) the compound is administered to the mammal every 8 hours, (iv) the compound is administered to the mammal every 12 hours, or (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method includes a drug holiday during which administration of the compound is temporarily withheld or the dose of the administered compound is temporarily reduced, at the end of which dosing of the compound is resumed. In one embodiment, the length of the drug holiday ranges from 2 days to 1 year.

[0225] In certain cases, it may be 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 anti-cancer agents.

[0226] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., the adjuvant itself has minimal therapeutic benefit, but when combined with another therapeutic agent, 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 with another agent (including a treatment regimen) that also has a therapeutic benefit.

[0227] In one particular embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein 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 event, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient is simply the additive 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 formulating pharmaceutical compositions and / or in therapeutic regimens in which the compounds disclosed herein are administered in combination with one or more additional agents, e.g., additional therapeutically effective drugs, adjuvants, etc. The therapeutically effective dosages of drugs and other agents for use in combination therapeutic regimens are optionally determined by means similar to those described above for the active ingredients themselves. Additionally, the prevention / treatment methods described herein encompass the use of metronomic dosing, i.e., providing lower doses more frequently to minimize toxic side effects. In some embodiments, combination therapeutic regimens encompass therapeutic regimens in which administration of a compound described herein or a pharmaceutically acceptable salt thereof is initiated before, during, or after treatment with a second agent described herein, and continues until any time during or after treatment with the second agent. This also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt thereof, and a second agent used in combination are administered simultaneously or at different times and / or at increasing or decreasing intervals during the treatment period. Combination treatments also include periodic treatments that are started and stopped at different times to aid in the clinical management of the patient.

[0230] Dosage regimens to treat, prevent, or ameliorate the condition for which relief is sought are modified according to various factors (e.g., the disease or disorder from which the subject suffers, the subject's age, weight, sex, diet, medical condition), etc. Thus, in some cases, the dosage regimen actually employed will vary and, in some embodiments, will deviate from the dosage regimens set forth herein.

[0231] In the combination therapies described herein, the dosage of the co-administered compounds varies depending on the type of co-drug used, the particular drug used, the disease or condition being treated, etc. In additional embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered simultaneously or sequentially with the 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 administration is simultaneous, the multiple therapeutic agents may, by way of example only, be provided in a single, unified form or in multiple forms (e.g., as a single pill or as two separate pills).

[0233] The compounds described herein, or pharmaceutically acceptable salts thereof, and combination therapies may be administered before, during, or after the onset of a disease or condition, and the timing of administering a composition containing the compound may vary. Thus, in one embodiment, the compounds described herein are used as prophylactics and are administered continuously to a subject prone to developing a condition or disease to prevent the onset of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of symptoms. In certain embodiments, the compounds described herein are administered as soon as practicable after the onset of a disease or condition is detected or suspected, for the period necessary to treat the disease. In some embodiments, the length of treatment required may vary, and the length of treatment may be tailored to meet the specific needs of each subject. For example, in certain embodiments, the compounds described herein or formulations containing the compounds are administered for at least two weeks, from about one month to about five years.

[0234] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is administered in combination with chemotherapy, radiation therapy, a monoclonal antibody, or a combination thereof.

[0235] Chemotherapy involves the use of anti-cancer drugs.

[0236] In addition to the CB2R antagonists or inverse agonists described above, the following CB2R antagonists or inverse agonists are contemplated in the combination therapies described herein for use in treating 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-indol-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 any one of the CB2R antagonists or inverse agonists described in V. Lucchesi et al., J. Med. Chem. 2014, 57, 8777-8791. Abbreviation [Table 2]

[0237] General synthesis method Compounds of formula (I) and / or (X) are prepared as described in the following schemes.

[0238] Scheme 1 illustrates an embodiment for preparing compounds of Formula (I) and / or Formula (X). [ka]

[0239] Compound 1-1(X 1 and X 2where R is as defined herein and R is H, a halo, or a triflate group, or any other suitable leaving group, is reacted with ethyl 3-chloro-3-oxopropanoate to give compound 1-2, which can be cyclized in the presence of a base and a protic solvent to give compound 1-3, which can be converted to compounds of formula (I) and / or formula (X). Examples of suitable bases for cyclization include sodium methoxide, sodium ethoxide, and the like. Suitable solvents include methanol, ethanol, and the like.

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

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

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

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

[0244] Scheme 4 shows the R 1 is H or OH, and compounds 1-3 and / or 2-3 and / or 3-3 shown above (collectively summarized as compound 4-1) can be converted to compounds of formula (I) and / or formula (X). [ka]

[0245] Compound 4-1 and collectively summarized compounds 1-3, 2-3, or 3-3 (X 1 and X 2 is as defined herein, R may be H, halo, or triflate group, or any other suitable leaving group, and R' is C1-C3 alkyl or benzyl, compound 4-1 is reacted with compound 4-2 to give compound 4-3. Any suitable base can be used in this reaction (e.g., K2CO3, Cs2CO3). R of compound 4-2 2 is as defined herein, and LG is any suitable leaving group (e.g., halo). The ester of compound 4-3 is hydrolyzed to give compound 4-4. Compound 4-4 is coupled with compound 4-5 under any suitable amide coupling conditions (e.g., HATU, EDCI) to give compound 4-6. R of compound 4-5 4 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" together with the atoms to which they are attached form a dioxaborolane ring. Compound 4-7 is coupled with a suitable compound 4-8 to give a compound of formula (I) or formula (X). In compound 4-8, R 6 is as defined herein, and LG″ is any suitable leaving group (e.g., halo). The coupling reaction between compounds 4-7 and 4-8 may be mediated by any suitable palladium catalyst, or by any other similar organometallic coupling method known to those skilled in the art.

[0246] Scheme 5 shows the R 1 is H or OH, and compounds 1-3 and / or 2-3 and / or 3-3 shown above (collectively summarized as compound 4-1) can be converted to compounds of formula (I) and / or formula (X). [ka]

[0247] Compound 4-1 and collectively summarized compounds 1-3, 2-3, or 3-3 (X 1 and X 2 is as defined herein, R may be H, halo, or triflate group, or any other suitable leaving group, and R' is C1-C3 alkyl or benzyl, compound 4-1 is reacted with compound 4-2 to give compound 4-3. Any suitable base can be used in this reaction (e.g., K2CO3, Cs2CO3). R of compound 4-2 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 atoms to which they are attached form a dioxaborolane ring. Compound 5-1 is coupled with a suitable compound 4-8 to give compound 5-2. The coupling reaction between compound 5-1 and compound 4-8 may be mediated by any suitable palladium catalyst or 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). The ester of compound 5-2 is hydrolyzed to provide compound 5-3. Compound 5-3 is coupled with compound 4-5 under any suitable amide coupling conditions (e.g., HATU, EDCI) to provide compounds of Formula (I) and / or Formula (X).

[0248] Scheme 6 shows the R1 is H or OH, and compounds 1-3 and / or 2-3 and / or 3-3 shown above (collectively summarized as compound 4-1) can be converted to compounds of formula (I) and / or formula (X). [ka]

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

[0250] Scheme 7 shows the R 1

[0033] An embodiment is provided for the preparation of compounds of formula (I) and / or (X) where is alkyl. [ka]

[0251] Compound 7-1(X 1 and X 2 Starting with 7-(CH 2 ) (where R is as defined herein and R can be H, a halo, or a triflate group, or any other suitable leaving group), conversion to the Weinreb amide provides compound 7-2. Reaction with a suitable Grignard reagent provides compound 7-3, which is converted to compound 7-4 by reaction with ethyl 3-chloro-3-oxopropanoate. Cyclization of compound 7-4 in the presence of a base provides compound 7-5, which is converted to compounds of Formula (I) and / or (X) using the methods described in Scheme 4-6.

[0252] Scheme 8 shows the R 1

[0033] An embodiment is provided for the preparation of compounds of formula (I) and / or (X) where is alkoxy. [ka]

[0253] Compound 8-1(X 1 and X 2 is as defined herein, R is H, halo, or triflate group, or any other suitable leaving group, and R' is C-C alkyl or benzyl) is reacted with an alkylating agent to give compound 8-2 (R''' is C-C alkyl), which can be converted to compounds of formula (I) and / or (X) using methods described in Schemes 4-6. As an example, reacting compound 8-1 with DMSO gives R''' methyl, and reacting compound 8-1 with propyl iodide gives R''' isopropyl.

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

[0255] The compounds of the present 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 temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, it will be understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, although such conditions can be determined by one skilled in the art by routine optimization procedures.

[0256] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting particular functional groups, are well known in the art. For example, numerous protecting groups are described in T.W. Greene and G.M.Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and the references cited therein.

[0257] Additionally, compounds of the present disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. Unless otherwise specified, all such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure. Pure stereoisomers (or enriched 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 using, for example, chiral column chromatography, chiral resolving agents, and the like.

[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 These compounds can be prepared by procedures described in standard reference texts such as "The Organic Synthesis of Benzyl Alcohols" (VCH Publishers Inc., 1989), "The Organic Synthesis of Benzyl Alcohols," and "The Organic Synthesis of Benzyl Alcohols," or obvious modifications thereof. [Example]

[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 - Synthesis of 6-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 ethyl 5-bromo-2-(3-ethoxy-3-oxopropanamido)nicotinate [ka]

[0261] To a solution of methyl 2-amino-5-bromo-pyridine-3-carboxylate (0.5 g, 2.16 mmol, 1 equiv) in DCM (10 mL) was added a solution of ethyl 3-chloro-3-oxo-propanoate (390.99 mg, 2.60 mmol, 325.82 μL, 1.2 equiv) in DCM (10 mL) at 0 °C. The mixture was stirred at 20 °C for 2 h. TLC showed complete consumption of the starting material and the formation of a new spot. The mixture was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were 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 give ethyl 5-bromo-2-(3-ethoxy-3-oxopropanamido)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 equiv) in MeOH (10 mL) was added NaOMe (469.57 mg, 8.69 mmol, 6 equiv) at 20° C. The reaction was stirred at 70° C. for 1 h. TLC showed complete consumption of the starting material and the formation of a new spot.

[0266] The reaction mixture was acidified to pH=5 by dropwise addition of 2 N hydrochloric acid at 0° C. The mixture was filtered and the resulting solid was washed with water (5 mL) to give 6-bromo-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-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 ethyl 6-bromo-1-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate [ka]

[0269] To a mixture of ethyl 6-bromo-4-hydroxy-2-oxo-1H-1,8-naphthyridine-3-carboxylate (480 mg, 1.53 mmol, 1 equiv.) and 1-(bromomethyl)-4-fluoro-benzene (318.76 mg, 1.69 mmol, 208.34 μL, 1.1 equiv.) in DMF (5 mL) was added CsCO (1.50 g, 4.60 mmol, 3 equiv.). The mixture was stirred at 90 °C for 12 h. LCMS showed complete consumption of the starting material and the formation of a new peak by TLC.

[0270] The mixture was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (petroleum ether / ethyl acetate = 50:1 to 10:1) to give ethyl 6-bromo-1-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate (600 mg) 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) (Gradient: 5 to 95% B in 2.20 min, 0.5% B in 0.01 min, 5 to 95% B in 1.81 min (0.01-1.00 min), 95 to 100% B (1.00-1.80 min), 5% B, 0.40 min hold at 5% B). 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 a 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-naphthyridine-3-carboxamide [ka]

[0274] To 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 equiv.) and 1-(4-fluorophenyl)ethanamine (39.65 mg, 284.89 μmol, 37.40 μL, 1.2 equiv.) in toluene (1 mL) was added DIEA (92.05 mg, 712.22 μmol, 124.06 μL, 3 equiv.). The mixture was stirred at 120° C. for 1 hour. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0275] The mixture was concentrated, and the residue was purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 60% to 85%, 10 min) to give 6-bromo-1-(4-fluorobenzyl)-N-(1-(4-fluorophenyl)ethyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-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). LCMS (ESI+) for product: m / z 514.0,516.0[M+H] + ,Rt:3.419 minutes.

[0277] LCMS method 5-95 AB-HPLC:LCMS (positive electrospray ionization) (Gradient: 5% B at 0.40 min, and 5 to 95% B from 0.40 to 3.00 min, hold at 95% B for 1.00 min, 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 x 2.1 mm column (5 μm particles). Detection methods were diode array (DAD), evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0278] Example 2 - Synthesis 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 (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-naphthyridine-3-carboxylate (100 mg, 237.41 μmol, 1 equiv.) and spiro[3.3]heptan-2-amine (42.06 mg, 284.89 μmol, 1.2 equiv., HCl) in toluene (1 mL) was added DIEA (92.05 mg, 712.22 μmol, 124.06 μL, 3 equiv.). The mixture was stirred at 120° C. for 1 hour. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0280] The solid that formed was collected by filtration and air-dried to give 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). LCMS (ESI+) for product: m / z 486.0, 488.0 [M+H] + ,Rt:2.989 minutes.

[0282] LCMS method 50-50 AB-HPLC:LCMS (positive electrospray ionization) (gradient: 50% B in 0.40 min, and 50 to 100% B from 0.40 to 3.00 min, hold at 100% B for 1.00 min, then 100 to 50% B in 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 x 2.1 mm column (5 μm particles). The detection methods were diode array (DAD), evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0283] Example 3 - Synthesis of 6-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] To 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 equiv.) and 4-(1-aminoethyl)benzonitrile (38.18 mg, 261.15 μmol, 1.1 equiv.) in toluene (1 mL) was added DIEA (92.05 mg, 712.22 μmol, 124.05 μL, 3 equiv.). The mixture was stirred at 120° C. for 1 hour. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0285] The mixture was filtered, and the filtrate was 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 give 6-bromo-N-(1-(4-cyanophenyl)ethyl)-1-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-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 in 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. 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 x 2.1 mm column (5 μm particles). The detection method was a diode array (DAD).

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

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

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

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

[0292] 5-95AB-2 min: The column used for chromatography was a 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 100–1000. 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 in 2.00 min, 5% B in 0.01 min, 5 to 95% B (0.01–1.00 min), 95 to 100% B (1.00–1.80 min), 5% B in 1.81 min, and a 0.19 min hold at 5% B. The flow rates were 1.0 mL / min (0.00–1.80 min) and 1.2 mL / min (1.81–2.00 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 equiv.) and 4-(2-chloroethyl)morpholine (653.74 mg, 3.51 mmol, 1.1 equiv., HCl) in DMF (20 mL) was added CsCO (8.32 g, 25.55 mmol, 8 equiv.) under N. The mixture was stirred at 50 °C for 5 h. LCMS showed complete consumption of the starting material and the formation of a new peak. The mixture was purified by preparative HPLC (neutral conditions) to give the desired product (0.85 g) as a yellow solid, which was used without further purification.

[0294] LCMS (ESI+) for 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 100–1000. 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 in 2.20 min, 5% B in 0.01 min, 5 to 95% B (0.01–1.00 min), 95 to 100% B (1.00–1.80 min), 5% B in 1.81 min, and a 0.40 min hold at 5% B. 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 equiv.) and spiro[3.3]heptan-2-amine (7.83 mg, 70.38 μmol, 1 equiv.) in toluene (1 mL) was added DIEA (9.10 mg, 70.38 μmol, 12.26 μL, 1 equiv.). The mixture was stirred at 120° C. for 2 hours. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0298] The mixture was filtered and concentrated under reduced pressure, and the residue was purified by preparative HPLC (HCl) to give 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). LCMS (ESI+) for 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, then 95 to 5% B at 0.01 min. 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 x 2.1 mm column (5 µm particles). Detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0301] Example 5 - Synthesis of 6-(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 ethyl 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate [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 equiv.), KCO (194.54 mg, 1.41 mmol, 3 equiv.), and (4-fluorophenyl)boronic acid (78.78 mg, 563.04 μmol, 1.2 equiv.) in dioxane (0.2 mL) and HO (0.02 mL) was added Pd(PPh) (54.22 mg, 46.92 μmol, 0.1 equiv.) under N. The mixture was stirred at 100 °C for 1 h. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0303] The mixture was filtered, and the filtrate was purified by preparative HPLC (column: Luna Omega 5u Polar C18 100A; mobile phase: [water (0.04% HCl)-ACN]; B%: 25% to 55%, 7 min) to give ethyl 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate (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). LCMS (ESI+) for product: m / z 442.3 [M+H] + ,Rt:1.877 minutes.

[0305] 5-95AB: 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 100–1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC-grade acetonitrile. The gradient was 5–95% B in 2.20 min, 5% B in 0.01 min, 5–95% B (0.01–1.00 min), 95–100% B (1.00–1.80 min), 5% B in 1.81 min, and a 0.40 min hold at 5% B. 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-naphthyridine-3-carboxamide [ka]

[0307] To 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 equiv.) and 4-methylcyclohexanamine (6.15 mg, 54.37 μmol, 7.20 μL, 1.2 equiv.) in toluene (0.5 mL) was added DIEA (5.86 mg, 45.31 μmol, 7.89 μL, 1 equiv.). The mixture was stirred at 120° C. for 1 hour. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0308] The mixture was filtered and concentrated under reduced pressure, and the residue was triturated with MeOH (0.3 mL) and filtered to give 6-(4-fluorophenyl)-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-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 in 0.40 min, 5 to 95% B from 0.40 to 3.40 min, held at 95% B for 0.45 min, then 95 to 5% B in 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 Xbridge Shield RP18 2.1 x 50 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization. The MS range was 100–1000.

[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 equiv.) and spiro[3.3]heptan-2-amine (20.07 mg, 135.92 μmol, 1.2 equiv., HCl) in toluene (0.5 mL) was added DIEA (14.64 mg, 113.26 μmol, 19.73 μL, 1 equiv.) at 20° C. The mixture was stirred at 120° C. for 1 h. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0313] The mixture was filtered and concentrated, and the residue was triturated with MeOH (0.5 mL) and filtered to give 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 in 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. 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 x 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and 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] 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 equiv.) and 4,4-difluorocyclohexanamine (2.33 mg, 13.59 μmol, 1.2 equiv., HCl) in toluene (0.2 mL) was added DIEA (1.46 mg, 11.33 μmol, 1.97 μL, 1 equiv.) at 20° C. The mixture was stirred at 120° C. for 1 h. LCMS 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 give N-(4,4-difluorocyclohexyl)-6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-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 in 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. 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 x 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and 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 equiv) and [1.1.1]pentan-1-amine HCl (1.63 mg, 13.59 μmol, 1.2 equiv, HCl) in toluene (0.3 mL) was added DIEA (1.46 mg, 11.33 μmol, 1.97 μL, 1 equiv) at 20° C. The mixture was stirred at 120° C. for 1 h. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0323] The mixture was filtered and concentrated, and the residue was triturated with MeOH (0.5 mL) and filtered to give 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 (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 in 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. 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 x 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and 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] To 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 equiv.) and 1-(4-fluorophenyl)ethanamine (14.75 mg, 106.01 μmol, 13.92 μL, 1.2 equiv.) in toluene (1 mL) was added DIEA (11.42 mg, 88.34 μmol, 15.39 μL, 1 equiv.). The mixture was stirred at 120° C. for 1 hour. LCMS 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 give 6-(4-fluorophenyl)-N-(1-(4-fluorophenyl)ethyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-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). LCMS (ESI+) for product: m / z 535.2 [M+H] + ,Rt:2.510 minutes.

[0329] LCMS method The gradient was 5% B in 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. 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 x 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and 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 ethyl 4-hydroxy-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate [ka]

[0331] 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 equiv.), KCO (97.27 mg, 703.79 μmol, 3 equiv.), and (4-methoxyphenyl)boronic acid (53.47 mg, 351.90 μmol, 1.5 equiv.) in dioxane (10 mL) and HO (1 mL) was added Pd(PPh) (27.11 mg, 23.46 μmol, 0.1 equiv.) under N. The mixture was stirred at 100 °C for 1 h. LCMS 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 × 25 mm × 5 μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 15% to 35%, 10 min) to give ethyl 4-hydroxy-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-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] To a mixture of ethyl 4-hydroxy-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate (15 mg, 33.08 μmol, 1 equiv) and spiro[3.3]heptan-2-amine (5.86 mg, 39.69 μmol, 1.2 equiv, HCl) in toluene (1 mL) was added DIEA (4.27 mg, 33.08 μmol, 5.76 μL, 1 equiv) at 20° C. The mixture was stirred at 120° C. for 1 h. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0336] The mixture was filtered, concentrated, and the residue was triturated with MeOH, filtered (0.5 mL), and purified by filtration to give -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). LCMS (ESI+) for product: m / z 519.3 [M+H] + ,Rt:2.570 minutes.

[0338] LCMS method The gradient was 5% B in 0.40 min, 5 to 95% B from 0.40 to 3.40 min, held at 95% B for 0.45 min, then 95 to 5% B in 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 Xbridge Shield RP18 2.1 x 50 mm column (5 μm particles). Detection methods included diode array (DAD) and 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: Ethyl 6-(4-chlorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate [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 equiv.), KCO (97.27 mg, 703.79 μmol, 3 equiv.), and (4-chlorophenyl)boronic acid (44.02 mg, 281.52 μmol, 1.2 equiv.) in dioxane (1 mL) and HO (0.1 mL) was added Pd(PPh) (27.11 mg, 23.46 μmol, 0.1 equiv.) under N. The mixture was stirred at 100 °C for 1 h. LCMS showed complete consumption of the starting material and the formation of a new peak.

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

[0342] LCMS (ESI+) for 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 100–1000. 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 in 2.20 min, 5% B in 0.01 min, 5 to 95% B (0.01–1.00 min), 95 to 100% B (1.00–1.80 min), 5% B in 1.81 min, and a 0.40 min hold at 5% B. 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 equiv.) and spiro[3.3]heptan-2-amine (12.38 mg, 83.86 μmol, 1.2 equiv., HCl) in toluene (1 mL) was added DIEA (9.03 mg, 69.88 μmol, 12.17 μL, 1 equiv.). The mixture was stirred at 120° C. for 1 hour. TLC showed the completion of the reaction and the formation of a new spot.

[0346] The mixture was filtered, concentrated in vacuo, and the residue was triturated with MeOH (0.5 mL) and filtered to give 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 in 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. 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 x 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0349] Example 12 - Synthesis 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 (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 equiv.) and bicyclo[1.1.1]pentan-3-amine (61.72 mg, 516.12 μmol, 1.1 equiv., HCl) in toluene (1 mL) was added DIEA (60.64 mg, 469.20 μmol, 81.73 μL, 1 equiv.). The mixture was stirred at 120° C. for 12 hours. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0351] The mixture was concentrated to give 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] LCMS (ESI+) for product: m / z 465.3, 463.3 [M+H]+, Rt: 0.687 min.

[0353] LCMS method The gradient was 5 to 95% B in 0.7 min, 95 to 95% B in 0.45 min, 95 to 5% B in 0.01 min, and then held at 0% B for 0.44 min (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, and 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-naphthyridine-3-carboxamide (120 mg, 259.00 μmol, 1 equiv.) and [4-(difluoromethoxy)phenyl]boronic acid (58.41 mg, 310.80 μmol, 1.2 equiv.) in dioxane (1 mL) and HO (0.25 mL) was added KCO (107.39 mg, 776.99 μmol, 3 equiv.) and Pd(PPh) (29.93 mg, 25.90 μmol, 0.1 equiv.). The mixture was stirred at 80 °C for 2 h under N. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0356] The mixture was concentrated, and the residue was purified by preparative HPLC (neutral conditions; column: mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 75% to 95%, 10 min) to give 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 in 0.40 min, then 5 to 95% B from 0.40 to 3.40 min, held at 95% B for 0.45 min, then 95 to 5% B in 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 Xbridge Shield RP18 2.1 x 50 mm column (5 μm particles). Detection was by 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-naphthyridine-3-carboxamide (60 mg, 129.50 μmol, 1 equiv.) and (4-methoxyphenyl)boronic acid (23.61 mg, 155.40 μmol, 1.2 equiv.) in dioxane (1 mL) and HO (0.25 mL) was added KCO (53.69 mg, 388.50 μmol, 3 equiv.) and Pd(PPh) (14.96 mg, 12.95 μmol, 0.1 equiv.). The mixture was stirred at 80 °C for 2 h under N. LCMS 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 give 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 in 0.40 min, then 5 to 95% B from 0.40 to 3.40 min, held at 95% B for 0.45 min, then 95 to 5% B in 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 Xbridge Shield RP18 2.1 x 50 mm column (5 μm particles). Detection was by 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: Ethyl 4-hydroxy-1-(2-morpholinoethyl)-2-oxo-6-phenyl-1,2-dihydro-1,8-naphthyridine-3-carboxylate [ka]

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

[0366] The mixture was filtered and concentrated under reduced pressure, and the residue was purified by preparative HPLC (neutral conditions) to give ethyl 4-hydroxy-1-(2-morpholinoethyl)-2-oxo-6-phenyl-1,2-dihydro-1,8-naphthyridine-3-carboxylate (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 5-95% B_2 min: The column used for chromatography was a 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 100–1000. 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 in 2.00 min, 5% B in 0.01 min, 5 to 95% B (0.01–1.00 min), 95 to 100% B (1.00–1.80 min), 5% B in 1.81 min, and a 0.19 min hold at 5% B. The flow rates were 1.0 mL / min (0.00–1.80 min) and 1.2 mL / min (1.81–2.00 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 equiv.) and ethyl 4-hydroxy-1-(2-morpholinoethyl)-2-oxo-6-phenyl-1,8-naphthyridine-3-carboxylate (90 mg, 212.53 μmol, 1 equiv.) in toluene (1 mL) was added DIEA (54.94 mg, 425.07 μmol, 74.04 μL, 2 equiv.). The mixture was stirred at 120° C. for 2 hours. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0371] The mixture was filtered and concentrated under reduced pressure, and the residue was purified by preparative HPLC (HCl conditions) to give 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_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, then 95 to 5% B at 0.01 min. 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 x 2.1 mm column (5 μm particles). Detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection, and 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 1-phenylethyl 2-[[4-(3-isoquinolylmethyl)pyrazolo[1,5-a]pyridine-3-carbonyl]amino]spiro[3.3]heptane-6-carboxylate [ka]

[0375] 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 equiv.), [4-(difluoromethoxy)phenyl]boronic acid (41.14 mg, 218.89 μmol, 1.2 equiv.), Pd(dppf)Cl.CHCl (14.90 mg, 18.24 μmol, 0.1 equiv.), NaCO (29.00 mg, 273.62 μmol, 1.5 equiv.) in dioxane (2 mL) and water (0.2 mL) was stirred at 90 °C for 2 h under N. LCMS 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 × 30 mm × 3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 70% to 90%, 6 min) to give 1-phenylethyl 2-[[4-(3-isoquinolylmethyl)pyrazolo[1,5-a]pyridine-3-carbonyl]amino]spiro[3.3]heptane-6-carboxylate (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+) for product: m / z 557.3 [M+H]+, Rt: 3.903 min.

[0378] LCMS method The gradient was 0 to 80% B in 3.4 min, 80 to 100% B in 0.45 min, 100 to 0% B in 0.01 min, and then held at 0% B for 0.65 min (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, and 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-naphthyridine-3-carboxamide (90 mg, 182.41 μmol, 1 equiv), (4-cyanophenyl)boronic acid (32.16 mg, 218.89 μmol, 1.2 equiv), Pd(dppf)Cl.CHCl (14.90 mg, 18.24 μmol, 0.1 equiv), NaCO (29.00 mg, 273.62 μmol, 1.5 equiv) in dioxane (2 mL) and water (0.2 mL) was stirred under N at 90 °C for 2 h. LCMS showed complete consumption of starting material and formation of a new peak.

[0381] The mixture was concentrated, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 70% to 98%, 8 min) to give 6-(4-cyanophenyl)-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-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). LCMS (ESI+) for product: m / z 516.3 [M+H]+, Rt: 3.753 min.

[0383] LCMS method The gradient was 0 to 80% B in 3.4 min, 80 to 100% B in 0.45 min, 100 to 0% B in 0.01 min, and then held at 0% B for 0.65 min (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, and 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] 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 equiv), (4-cyclopropylphenyl)boronic acid (35.46 mg, 218.89 μmol, 1.2 equiv), Pd(dppf)Cl.CHCl (14.90 mg, 18.24 μmol, 0.1 equiv), NaCO (29.00 mg, 273.62 μmol, 1.5 equiv) in dioxane (2 mL) and water (0.2 mL) was stirred under N at 90 °C for 2 h. LCMS showed complete consumption of starting material and formation of a new peak.

[0386] The mixture was concentrated, and the residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 85% to 98%, 10 min) to give 6-(4-cyclopropylphenyl)-4-hydroxy-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-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, 17.3 Hz, 3H), 0.94 (br d, J=5.1 Hz, 2H), 0.77 (br s, 2H). LCMS (ESI+) for product: m / z 531.3 [M+H]+, Rt: 4.174 min.

[0388] LCMS method The gradient was 0 to 80% B in 3.4 min, 80 to 100% B in 0.45 min, 100 to 0% B in 0.01 min, and then held at 0% B for 0.65 min (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, and 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-naphthyridine-3-carboxamide (150 mg, 304.02 μmol, 1 equiv), (4-isopropoxyphenyl)boronic acid (65.67 mg, 364.82 μmol, 1.2 equiv), Pd(dppf)Cl.CHCl (24.83 mg, 30.40 μmol, 0.1 equiv), NaCO (48.33 mg, 456.03 μmol, 1.5 equiv) in dioxane (1 mL) and water (0.2 mL) was stirred at 90 °C for 2 h under N. LCMS 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 × 25 mm × 5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 70% to 95%, 10 min) to give 4-hydroxy-6-(4-isopropoxyphenyl)-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-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, 13.3 Hz, 1H), 1.92-1.76 (m, 2H), 1.73-1.63 (m, 2H), 1.39 (d, J=6.0 Hz, 9H), 1.19-1.05 (m, 1H), 1.04-0.91 (m, 3H). LCMS (ESI+) for product: m / z 549.3 [M+H]+, Rt: 4.085 min.

[0393] LCMS method The gradient was 0 to 80% B in 3.4 min, 80 to 100% B in 0.45 min, 100 to 0% B in 0.01 min, and then held at 0% B for 0.65 min (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, and 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 equiv), 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (39.39 mg, 218.89 μmol, 1.2 equiv), Pd(dppf)Cl.CHCl (14.90 mg, 18.24 μmol, 0.1 equiv), NaCO (29.00 mg, 273.62 μmol, 1.5 equiv) in dioxane (1 mL) and water (0.1 mL) was stirred under N at 90 °C for 2 h. LCMS showed complete consumption of 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 × 30 mm × 3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 75% to 99%, 6 min) to give 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 (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+) for product: m / z 549.3 [M+H]+, Rt: 3.898 min.

[0398] LCMS method The gradient was 0 to 80% B in 3.4 min, 80 to 100% B in 0.45 min, 100 to 0% B in 0.01 min, and then held at 0% B for 0.65 min (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, and 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-naphthyridine-3-carboxamide (56 mg, 113.50 μmol, 1 equiv), (4-methoxyphenyl)boronic acid (20.70 mg, 136.20 μmol, 1.2 equiv), Pd(dppf)Cl.CHCl (9.27 mg, 11.35 μmol, 0.1 equiv), NaCO (18.04 mg, 170.25 μmol, 1.5 equiv) in dioxane (2 mL) and water (0.2 mL) was stirred under N at 90 °C for 2 h. LCMS showed that the starting material had been 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 × 25 mm × 5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 70% to 95%, 10 min) to give 4-hydroxy-6-(4-methoxyphenyl)-N-(4-methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (11.1 mg, 21.24 μmol) as a white solid.

[0402] 1 H 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). LCMS (ESI+) for product: m / z 521.3 [M+H]+, Rt: 3.948 min.

[0403] LCMS method The gradient was 0 to 80% B in 3.4 min, 80 to 100% B in 0.45 min, 100 to 0% B in 0.01 min, and then held at 0% B for 0.65 min (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, and positive electrospray ionization (MS).

[0404] Example 21 - Synthesis of 6-(5-cyanopyridin-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: Ethyl 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 [ka]

[0405] To a mixture of ethyl 6-bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate (800 mg, 1.88 mmol, 1 equiv.), KOAc (552.58 mg, 5.63 mmol, 3 equiv.), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.77 g, 18.77 mmol, 10 equiv.) in DMSO (20 mL) was added Pd(PPh3)2Cl2 (131.73 mg, 187.68 μmol, 0.1 equiv.) under N2. The mixture was stirred at 80 °C for 1 h. LCMS showed 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 × 50 mm × 10 μm; phase: [water (0.05% HCl)-ACN]; B%: 0% to 30%, 20 min) to give ethyl 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 (400 mg) as a yellow oil, which was used in the next step without further purification.

[0407] LCMS (ESI+) for 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 100–1000. 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 in 2.20 min, 5% B in 0.01 min, 5 to 95% B (0.01–1.00 min), 95 to 100% B (1.00–1.80 min), 5% B in 1.81 min, and a 0.40 min hold at 5% B. The flow rate was 1.0 mL / min.

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

[0410] To a mixture of ethyl 4-hydroxy-1-(2-morpholinoethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,8-naphthyridine-3-carboxylate (270 mg, 570.43 μmol, 1 equiv.), KCO (473.02 mg, 3.42 mmol, 6 equiv.), and 6-bromopyridine-3-carbonitrile (125.27 mg, 684.52 μmol, 1.2 equiv.) in dioxane (4 mL) and HO (0.4 mL) was added Pd(PPh) (65.92 mg, 57.04 μmol, 0.1 equiv.) under N. The mixture was stirred at 100 °C for 1 h. LCMS 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 purified by preparative HPLC (column: Phenomenex luna C18 250 × 50 mm × 10 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 5% to 35%, 10 min) to give ethyl 6-(5-cyanopyridin-2-yl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate (120 mg, 266.99 μmol) as a white solid.

[0412] 1 H NMR (ET26059-546-P1C, 400 MHz, DMSO-d6) δ = 9.48 (d, J = 2.5 Hz, 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 = 7.0 Hz, 4H), 4.04-4.00 (m, 2H), 3.52 (br s, 4H), 1.31 (s, 3H). LCMS (ESI+) for 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 100–1000. 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 in 2.20 min, 5% B in 0.01 min, 5 to 95% B (0.01–1.00 min), 95 to 100% B (1.00–1.80 min), 5% B in 1.81 min, and a 0.40 min hold at 5% B. The flow rate was 1.0 mL / min.

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

[0415] To a mixture of ethyl 6-(5-cyano-2-pyridyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate (30 mg, 66.75 μmol, 1 equiv.) and 1-(4-fluorophenyl)ethanamine (11.15 mg, 80.10 μmol, 10.52 μL, 1.2 equiv.) in toluene (0.5 mL) was added DIEA (8.63 mg, 66.75 μmol, 11.63 μL, 1 equiv.). The mixture was stirred at 120° C. for 1 hour. LCMS 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 × 30 mm × 3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 50% to 80%, 10 min) to give 6-(5-cyanopyridin-2-yl)-N-(1-(4-fluorophenyl)ethyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (11.5 mg, 20.77 μmol) as a white solid.

[0417] 1H 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+) for product: m / z 543.2 [M+H]+, Rt: 2.366 min.

[0418] LCMS method The gradient was 5% B in 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. 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 x 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0419] Example 22 - Synthesis of 6-(5-cyanopyridin-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-cyanopyridin-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] To a mixture of ethyl 6-(5-cyano-2-pyridyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate (30 mg, 66.75 μmol, 1 equiv.) and spiro[3.3]heptan-2-amine (8.91 mg, 80.10 μmol, 1.2 equiv.) in toluene (0.5 mL) was added DIEA (8.63 mg, 66.75 μmol, 11.63 μL, 1 equiv.). The mixture was stirred at 120° C. for 1 hour. LCMS 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 × 30 mm × 3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 55% to 85%, 10 min) to give 6-(5-cyanopyridin-2-yl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3.3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-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). LCMS (ESI+) for product: m / z 515.3 [M+H] + ,Rt:2.436 minutes.

[0423] LCMS method The gradient was 5% B in 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. 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 x 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and 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 equiv) in DCM (3 mL) was added 2-morpholinoethanol (195.11 mg, 1.49 mmol, 182.35 μL, 1.2 equiv), PPh3 (487.67 mg, 1.86 mmol, 1.5 equiv), and DIAD (375.97 mg, 1.86 mmol, 361.51 μL, 1.5 equiv). The mixture was stirred at 25 °C for 2 h. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0426] The mixture was washed with water (2 × 5 mL), and the organic layer was washed with brine (5 mL) and dried over NaSO. The mixture was concentrated to give 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: Ethyl 6-bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydroquinoline-3-carboxylate [ka]

[0428] To a mixture of NaH (78.82 mg, 1.97 mmol, 60% purity, 2 equiv.) in DMF (3 mL) was added diethyl propanedionate (789.15 mg, 4.93 mmol, 744.48 μL, 5 equiv.) and a solution of 6-bromo-1-(2-morpholinoethyl)-3,1-benzoxazine-2,4-dione (350 mg, 985.41 μmol, 1 equiv.) in DMF (2 mL) at 0° C. The mixture was stirred at 90° C. for 2 h. LCMS 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 EtOAc (2×20 mL).

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

[0430] 1H 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=9.1Hz,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+) for product: m / z 425.0,427.0[M+H]+, Rt: 0.902 min.

[0431] LCMS method The gradient was 5 to 95% B in 0.7 min, 95 to 95% B in 0.45 min, 95 to 5% B in 0.01 min, and then held at 0% B for 0.44 min (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, and positive electrospray ionization (MS).

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

[0433] A mixture of (4-fluorophenyl)boronic acid (151.35 mg, 1.08 mmol, 2 equiv.), ethyl 6-bromo-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-quinoline-3-carboxylate (230 mg, 540.83 μmol, 1 equiv.), NaCO (114.64 mg, 1.08 mmol, 2 equiv.), and Pd(dppf)Cl.CHCl (44.17 mg, 54.08 μmol, 0.1 equiv.) in dioxane (2.5 mL) and HO (0.5 mL) was degassed and purged with N three times. The mixture was then stirred at 100 °C for 2 h under N. LCMS indicated 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 EtOAc (3 × 20 mL). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4.

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

[0435] LCMS (ESI+) for product: m / z 441.1 [M+H]+, Rt: 1.00 min.

[0436] LCMS method The gradient was 5 to 95% B in 0.7 min, 95 to 95% B in 0.45 min, 95 to 5% B in 0.01 min, and then held at 0% B for 0.44 min (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, and 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 equiv.) in toluene (2 mL) was added spiro[3.3]heptan-2-amine (40.13 mg, 271.83 μmol, 1.2 equiv., HCl). The mixture was stirred at 110° C. for 6 hours. LCMS 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 give 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). LCMS (ESI+) for product: m / z 506.3 [M+H]+, Rt: 3.906 min.

[0441] LCMS method The gradient was 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, then 95 to 5% B in 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 Xbridge Shield RP18 2.1 x 50 mm column (5 μm particles). Detection was by diode array (DAD) and positive electrospray ionization.

[0442] Example 24 - Synthesis of N-(1-(4-cyanophenyl)ethyl)-6-(5-cyanopyridin-2-yl)-1-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (Compound 24) [ka] Preparation of N-(1-(4-cyanophenyl)ethyl)-6-(5-cyanopyridin-2-yl)-1-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

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

[0444] The mixture was filtered, and the filtrate was purified by preparative HPLC (column: Luna Omega 5u Polar C18 100A; mobile phase: [water (0.04% HCl)-ACN]; B%: 70% to 90%, 7 min) to give N-(1-(4-cyanophenyl)ethyl)-6-(5-cyanopyridin-2-yl)-1-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-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). LCMS (ESI+) for product: m / z 545.2 [M+H] + ,Rt:3.138 minutes.

[0446] LCMS method The gradient was 5% B in 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. 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 x 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0447] Example 25 - Synthesis of 6-(5-(difluoromethoxy)pyridin-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] To a mixture of 6-bromopyridin-3-ol (400 mg, 2.30 mmol, 1 equiv.) and (2-chloro-2,2-difluoro-acetyl)oxysodium (700.98 mg, 4.60 mmol, 2 equiv.) in DMF (4 mL) was added potassium carbonate (476.59 mg, 3.45 mmol, 1.5 equiv.) under N2. The mixture was stirred at 80 °C for 12 h. LCMS 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 min. 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 give 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: Ethyl 6-(5-(difluoromethoxy)pyridin-2-yl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate [ka]

[0452] To a mixture of ethyl 4-hydroxy-1-(2-morpholinoethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,8-naphthyridine-3-carboxylate (100 mg, 211.27 μmol, 1 equiv.), KCO (175.20 mg, 1.27 mmol, 6 equiv.), and 2-bromo-5-(difluoromethoxy)pyridine (70.99 mg, 316.91 μmol, 1.5 equiv.) in dioxane (1 mL) and HO (0.1 mL) was added Pd(PPh) (24.41 mg, 21.13 μmol, 0.1 equiv.) under N. The mixture was stirred at 100 °C for 1 h. LCMS 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 × 50 mm × 10 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 10% to 40%, 10 min) to give ethyl 6-(5-(difluoromethoxy)pyridin-2-yl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate (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). LCMS (ESI+) for 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 100–1000. 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 in 2.20 min, 5% B in 0.01 min, 5 to 95% B (0.01–1.00 min), 95 to 100% B (1.00–1.80 min), 5% B in 1.81 min, and a 0.40 min hold at 5% B. The flow rate was 1.0 mL / min.

[0456] Step 3: Preparation of 6-(5-(difluoromethoxy)pyridin-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-naphthyridine-3-carboxylate (39 mg, 79.52 μmol, 1 equiv.) and spiro[3.3]heptan-2-amine (10.61 mg, 95.42 μmol, 1.2 equiv.) in toluene (1 mL) was added DIEA (10.28 mg, 79.52 μmol, 13.85 μL, 1 equiv.). The mixture was stirred at 120° C. for 1 hour. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0458] The reaction mixture was concentrated, and the residue was triturated with MeOH (0.5 mL) to give 6-(5-(difluoromethoxy)pyridin-2-yl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3.3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-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 = 2.8 Hz, 2H), 2.09-2.01 (m, 4H), 1.99-1.93 (m, 2H), 1.85-1.77 (m, 2H). LCMS (ESI+) for product: m / z 556.3 [M+H] + ,Rt:2.535 minutes.

[0460] LCMS method The gradient was 5% B in 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. 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 x 2.1 mm column (5 μm particles). Detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization. The MS range was 100–1000.

[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: Ethyl 6-bromo-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate [ka]

[0462] To a solution of ethyl 6-bromo-2-oxo-1H-1,8-naphthyridine-3-carboxylate (2 g, 6.73 mmol, 1 equiv.) in DMF (15 mL) was added CsCO (6.14 g, 18.85 mmol, 2.8 equiv.) at 20 °C. The mixture was stirred at 20 °C for 1 h, and 4-(2-chloroethyl)morpholine (2.51 g, 13.46 mmol, 2 equiv., HCl) was added to the mixture at 20 °C, and the mixture was stirred at 50 °C for 14 h. TLC showed that all starting material had been consumed and 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 phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate=0:1) to give ethyl 6-bromo-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate (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 equiv.), ethyl 6-bromo-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylate (1.7 g, 4.14 mmol, 1 equiv.) in HO (5 mL) and dioxane (20 mL) was added NaCO (878.38 mg, 8.29 mmol, 2 equiv.), Pd(dppf)Cl.CHCl (338.39 mg, 414.37 μmol, 0.1 equiv.) at 20 °C under N. The mixture was stirred at 100 °C for 15 h. LCMS showed all starting material was consumed and a major peak was formed.

[0466] The mixture was filtered, and the filtrate was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 30 mm × 5 μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 20% to 32%, 10 min) to give 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 in 0.7 min, 95 to 95% B in 0.45 min, 95 to 5% B in 0.01 min, and then held at 0% B for 0.44 min (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, and 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-naphthyridine-3-carboxylic acid (70 mg, 170.97 μmol, 1 equiv) in DMF (1 mL) was added HATU (130.01 mg, 341.94 μmol, 2 equiv), DIEA (66.29 mg, 512.90 μmol, 89.34 μL, 3 equiv) at 20° C. 4,4-Dimethylcyclohexanamine (26.10 mg, 205.16 μmol, 1.2 equiv) was added to the mixture at 20° C., and the mixture was stirred at 20° C. for 1 h. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0471] The mixture was filtered, and the filtrate was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 50% to 85%, 8 min) to give N-(4,4-dimethylcyclohexyl)-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-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). LCMS (ESI+) for product: m / z 519.2 [M+H]+, Rt: 2.341 min.

[0473] LCMS method The gradient was 5% B in 0.40 min, 5 to 95% B from 0.4 to 3.0 min, held at 95% B for 1.00 min, then 95 to 5% B in 0.01 min. 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 x 2.1 mm column (5 μm particles). Detection was by 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-naphthyridine-3-carboxylic acid (70 mg, 170.97 μmol, 1 equiv) in DMF (1 mL) was added HATU (130.01 mg, 341.94 μmol, 2 equiv), DIEA (66.29 mg, 512.90 μmol, 89.34 μL, 3 equiv) at 20° C. 4,4-Difluorocyclohexanamine (35.21 mg, 205.16 μmol, 1.2 equiv, HCl) was added to the mixture at 20° C., and the mixture was stirred at 20° C. for 1 h. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0476] The mixture was filtered, and the filtrate was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 50% to 85%, 8 min) to give N-(4,4-difluorocyclohexyl)-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-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). LCMS (ESI+) for product: m / z 527.1 [M+H]+, Rt: 2.141 min.

[0478] LCMS method The gradient was 5% B in 0.40 min, 5 to 95% B from 0.4 to 3.0 min, held at 95% B for 1.00 min, then 95 to 5% B in 0.01 min. 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 x 2.1 mm column (5 μm particles). Detection was by 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: tert-Butyl (4-methylenecyclohexyl)carbamate (F2) [ka]

[0480] To a solution of methyltriphenylphosphonium bromide (16.75 g, 46.89 mmol, 2 equiv.) in THF (40 mL) was added potassium 2-methylpropan-2-olate (1 M, 47.0 mL, 2 equiv.) at -20 °C under N2. The mixture was stirred at -20 °C for 0.5 h, and tert-butyl N-(4-oxocyclohexyl)carbamate (5 g, 23.44 mmol, 5.00 mL, 1 equiv.) was added to the mixture at 0 °C. The mixture was stirred at 20 °C for 14.5 h. LCMS showed complete consumption of the starting material and the formation of a new peak. TLC showed that all starting material had been consumed, and the 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 phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, petroleum ether:ethyl acetate = 10:1 to 0:1) to give tert-butyl (4-methylenecyclohexyl)carbamate (4 g, 18.93 mmol) as a white solid.

[0482] Step 2: tert-Butyl spiro[2.5]octan-6-ylcarbamate (F3) [ka]

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

[0484] LCMS, formation of desired product, 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 give tert-butyl spiro[2.5]octan-6-ylcarbamate (6 mg, 26.63 μmol, 2.81% yield) 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]octan-6-amine (F) [ka]

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

[0488] LCMS showed complete consumption of the starting material and the formation of a new peak. The mixture was concentrated to give spiro[2.5]octan-6-amine (2.5 mg) as a yellow oil, which was used without further purification.

[0489] LCMS (ESI+) for product: m / z 126.4 [M+1]+, Rt: 0.161 min.

[0490] LCMS method The gradient was 10 to 90% B in 1.15 min, held at 90% B for 0.4 min, 90 to 10% B in 0.01 min, then held at 10% B for 0.54 min (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 a 2.1 x 30 mm Phenomenex Luna-C18 column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and 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-naphthyridine-3-carboxylic acid (8 mg, 19.54 μmol, 1 equiv) in DMF (0.5 mL) was added HATU (14.86 mg, 39.08 μmol, 2 equiv), DIEA (7.58 mg, 58.62 μmol, 89.34 μL, 3 equiv) at 20° C. (4-Fluorophenyl)methanamine (25.67 mg, 205.16 μmol, 10.21 μL, 3 equiv) was added to the mixture at 20° C., and the mixture was stirred at 20° C. for 1 h. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0493] The mixture was filtered, and the filtrate was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 50% to 85%, 8 min) to give 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[2.5]octan-6-yl)-1,2-dihydro-1,8-naphthyridine-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 = 8.6 Hz, 2H), 1.80-1.71 (m, 2H), 1.65-1.62 (m, 2H), 1.13 (br d, J = 13.5 Hz, 2H), 0.36-0.31 (m, 2H), 0.30-0.24 (m, 2H). LCMS (ESI+) for product: m / z 517.3 [M+H]+, Rt: 2.282 min.

[0495] LCMS method The gradient was 5% B in 0.40 min, 5 to 95% B from 0.4 to 3.0 min, held at 95% B for 1.00 min, then 95 to 5% B in 0.01 min. 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 x 2.1 mm column (5 μm particles). Detection was by diode array (DAD) 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-naphthyridine-3-carboxylic acid (75 mg, 183.18 μmol, 1 equiv) in DMF (1 mL) was added HATU (139.30 mg, 366.36 μmol, 2 equiv), DIEA (71.02 mg, 549.54 μmol, 95.72 μL, 3 equiv) at 20° C. Spiro[3.3]heptan-2-amine (24.44 mg, 219.82 μmol, 1.2 equiv) was added to the mixture at 20° C., and the mixture was stirred at 20° C. for 1 h. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0498] The mixture was filtered, and the filtrate was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 50% to 85%, 8 min) to give 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+) for product: m / z 503.3 [M+H]+, Rt: 2.236 min.

[0500] LCMS method The gradient was 5% B in 0.40 min, 5 to 95% B from 0.4 to 3.0 min, held at 95% B for 1.00 min, then 95 to 5% B in 0.01 min. 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 x 2.1 mm column (5 μm particles). Detection was by 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-naphthyridine-3-carboxylic acid (70 mg, 170.97 μmol, 1 equiv) in DMF (1 mL) was added HATU (130.01 mg, 341.94 μmol, 2 equiv), DIEA (66.29 mg, 512.90 μmol, 89.34 μL, 3 equiv) at 20° C. 1-(4-Fluorophenyl)ethanamine (26.17 mg, 188.06 μmol, 24.69 μL, 1.1 equiv) was added to the mixture at 20° C., and the mixture was stirred at 20° C. for 1 h. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0503] The mixture was filtered, and the filtrate was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 50% to 85%, 8 min) to give N-(1-(4-fluorophenyl)ethyl)-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (12.1 mg, 22.35 μmol) 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). LCMS (ESI+) for product: m / z 531.3 [M+H]+, Rt: 2.226 min.

[0505] LCMS method The gradient was 5% B in 0.40 min, 5 to 95% B from 0.4 to 3.0 min, held at 95% B for 1.00 min, then 95 to 5% B in 0.01 min. 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 x 2.1 mm column (5 μm particles). Detection was by 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] To a solution of 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylic acid (70 mg, 170.97 μmol, 1 equiv) in DMF (1 mL) was added HATU (130.01 mg, 341.94 μmol, 2 equiv), DIEA (66.29 mg, 512.90 μmol, 89.34 μL, 3 equiv) at 20° C. 2-Oxaspiro[3.3]heptan-6-amine (28.14 mg, 188.06 μmol, 1.1 equiv, HCl) was added to the mixture at 20° C., and the mixture was stirred at 20° C. for 1 h. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0508] The mixture was filtered, and the filtrate was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 50% to 85%, 8 min) to give 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_6min-220: The gradient was 5% B in 0.40 min, then 5 to 95% B from 0.4 to 3.0 min, held at 95% B for 1.00 min, then 95 to 5% B in 0.01 min. 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 x 2.1 mm column (5 µm particles). The detection method was 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: tert-Butyl (4-methylenecyclohexyl)carbamate [ka]

[0512] A solution of 2-amino-5-bromo-pyridine-3-carbaldehyde (6 g, 29.9 mmol, 1 equiv), diethyl propanedionate (47.8 g, 298 mmol, 45 mL, 10 equiv), and piperidine (12.7 g, 149 mmol, 14.7 mL, 5.0 equiv) was heated at 100° C. for 12 hours.

[0513] TLC (petroleum ether / ethyl acetate=1 / 1) showed that the starting material was consumed and a new spot was 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 give tert-butyl (4-methylenecyclohexyl)carbamate (6 g, 20.2 mmol) as a white solid, which 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: Ethyl 6-bromo-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate [ka]

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

[0517] The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was washed with methyl tert-butyl ether (30 mL) to give ethyl 6-bromo-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate (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 equiv.) was dissolved in THF (5 mL), MeOH (5 mL), and HO (5 mL). LiOH.HO (409 mg, 9.75 mmol, 4.0 equiv.) was added to the reaction solution. The solution was stirred at 30 °C for 12 h. LCMS 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 min.

[0521] The resulting solid was collected by filtration and dried in vacuo to give 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 equiv.), spiro[3.3]heptan-2-amine (270 mg, 1.83 mmol, 1.0 equiv., HCl), EDCI (702 mg, 3.66 mmol, 2.0 equiv.), and HOBt (495 mg, 3.66 mmol, 2.0 equiv.) were dissolved in DMF (10 mL). The solution was stirred at 30 °C for 5 min. TEA (927 mg, 9.16 mmol, 1.27 mL, 5.0 equiv.) was then added to the reaction solution. The solution was stirred at 30 °C for 12 h. LCMS showed complete consumption of the starting material 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 min, and the resulting solid was collected by filtration, washed with HO (10 mL), and dried under vacuum to give 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, which 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 equiv.), (4-fluorophenyl)boronic acid (4.42 mg, 31.6 μmol, 1.5 equiv.), Pd(PPh3)4 (2.43 mg, 2.10 μmol, 0.1 equiv.), and K2CO3 (7.27 mg, 52.6 μmol, 2.5 equiv.) were dissolved in dioxane (0.5 mL) and HO (0.1 mL). The suspension was stirred at 90 °C for 12 h. LCMS indicated complete consumption of the starting material and the formation of a new peak. An additional vial was set up as above, and the reaction mixtures were combined.

[0529] The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 30 mm × 5 μm; mobile phase: [water (0.04% HCl)—CHCN]; B%: 35% to 63%, 10 min) to give 6-(4-fluorophenyl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3.3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-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 in 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. 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 x 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and 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 equiv.), 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (11.4 mg, 63.1 μmol, 1 equiv.), Pd(PPh3)4 (7.29 mg, 6.31 μmol, 0.1 equiv.), and K2CO3 (21.8 mg, 158 μmol, 2.5 equiv.) were dissolved in dioxane (1 mL) and HO (0.5 mL). The suspension was stirred at 90 °C for 2 h. LCMS indicated complete consumption of the starting material and the formation of a new peak. An additional vial was set up as above, and the reaction mixtures were combined.

[0534] The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 30 mm × 5 μm; mobile phase: [water (0.04% HCl)—CHCN]; B%: 35% to 65%, 10 min) to give 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 (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 in 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. 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 x 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0537] Example 34 - Synthesis of 1-(2-morpholinoethyl)-2-oxo-6-(pyridin-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-(pyridin-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 equiv.), tributyl(2-pyridyl)stannane (11.6 mg, 31.6 μmol, 1.5 equiv.), and Pd(PPh3)4 (2.43 mg, 2.10 μmol, 0.1 equiv.) were dissolved in toluene (0.5 mL). The suspension was stirred at 120 °C for 2 h. LCMS indicated complete consumption of starting material and the formation of a new peak. An additional vial was set up as above, and all two reaction mixtures were combined. An additional vial was set up as above, and all two reaction mixtures were combined.

[0539] The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 30 mm × 5 μm; mobile phase: [water (0.04% HCl)—CHCN]; B%: 25% to 55%, 10 min) to give 1-(2-morpholinoethyl)-2-oxo-6-(pyridin-2-yl)-N-(spiro[3.3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-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 = 5.9 Hz, 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 = 7.8 Hz, 2H). LCMS (ESI+) for product: m / z 474.2 (M+H) + ,Rt:2.003 minutes.

[0541] LCMS method The gradient was 5% B in 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. 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 x 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0542] Example 35 - Synthesis of 1-(2-morpholinoethyl)-2-oxo-6-(pyrimidin-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-(pyrimidin-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 equiv.), tributyl(pyrimidin-4-yl)stannane (11.7 mg, 31.6 μmol, 1.5 equiv.), and Pd(PPh3)4 (2.43 mg, 2.10 μmol, 0.1 equiv.) were dissolved in toluene (0.5 mL). The suspension was stirred at 120 °C for 12 h. LCMS indicated complete consumption of the starting material and the formation of a new peak. An additional vial was set up as above, and the reaction mixtures were combined.

[0544] The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [water (0.04% HCl)—CHCN]; B%: 15% to 40%, 10 min) to give 1-(2-morpholinoethyl)-2-oxo-6-(pyrimidin-4-yl)-N-(spiro[3.3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-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=5.9 Hz, 2H), 4.38 (t, J=7.8 Hz, 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+) for product: m / z 475.3 (M+H) + ,Rt:1.915 minutes.

[0546] LCMS method The gradient was 5% B in 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. 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 x 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0547] Example 36 - Synthesis of 6-(5-cyanopyridin-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 equiv.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (200 mg, 789 μmol, 1.5 equiv.), KOAc (155 mg, 1.58 mmol, 3 equiv.), and Pd(PPh3)2Cl2 (36.9 mg, 52.6 μmol, 0.1 equiv.) were dissolved in dioxane (10 mL). The suspension was heated to 80 °C for 12 h. LCMS showed complete consumption of the starting material and the formation of a new peak. 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 phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated to give 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, which was used in the next step without further purification.

[0550] LCMS (ESI+) for product: m / z 441.2 (M-82) + ,Rt:1.024 minutes.

[0551] LCMS method The gradient was 5 to 95% B in 0.7 min, 95 to 95% B in 0.45 min, 95 to 5% B in 0.01 min, and then held at 0% B for 0.44 min (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, and positive electrospray ionization (MS).

[0552] Step 2: Preparation of 6-(5-isocyanopyridin-2-yl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3.3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-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-naphthyridine-3-carboxamide (50 mg, 95.7 μmol, 1 equiv.), 6-bromopyridine-3-carbonitrile (26.3 mg, 144 μmol, 1.5 equiv.), Pd(PPh3)4 (11.1 mg, 9.57 μmol, 0.1 equiv.), and K2CO3 (26.5 mg, 191 μmol, 2.0 equiv.) were dissolved in dioxane (2 mL) and HO (0.5 mL). The suspension was heated to 80 °C for 3 h. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0554] The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC (Gilson Auto-Purification System) to give 6-(5-isocyanopyridin-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:2.095 minutes.

[0556] LCMS method The gradient was 5% B in 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. 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 x 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0557] Example 37 - Synthesis of 6-(5-fluoropyridin-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-fluoropyridin-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 equiv.), 2-bromo-5-fluoro-pyridine (25.3 mg, 143 μmol, 1.5 equiv.), Pd(PPh3)4 (11.1 mg, 9.57 μmol, 0.1 equiv.), and K2CO3 (26.5 mg, 191 μmol, 2.0 equiv.) were dissolved in dioxane (2 mL) and HO (0.5 mL). The suspension was heated to 80 °C for 12 h. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0559] The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC (Gilson Auto-Purification System) to give 6-(5-fluoropyridin-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.

[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 = 3.4 Hz, 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+) for product: m / z 492.2 (M+H) + ,Rt:2.100 minutes.

[0561] LCMS method The gradient was 5% B in 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. 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 x 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0562] Example 38 - Synthesis of 1-(2-morpholinoethyl)-2-oxo-6-(pyrimidin-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-(pyrimidin-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]heptan-2-yl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,8-naphthyridine-3-carboxamide (70 mg, 134 μmol, 1 equiv.), 2-bromopyrimidine (32.0 mg, 201 μmol, 1.5 equiv.), Pd(PPh3)4 (15.5 mg, 13.4 μmol, 0.1 equiv.), and K2CO3 (37.0 mg, 268 μmol, 2.0 equiv.) were dissolved in dioxane (5 mL) and HO (1 mL). The suspension was heated to 80 °C for 12 h. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0564] The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [water (0.04% HCl)—CH3CN]; B%: 20% to 45%, 10 min) to give 1-(2-morpholinoethyl)-2-oxo-6-(pyrimidin-2-yl)-N-(spiro[3.3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (9 mg, 19.0 μmol) as a white solid.

[0565] 1H NMR(400MHz,METHANOL-d4)δ=9.77(d,J=2.0Hz,1H),9.32(d,J=2.0Hz,1H),9.03(s,1H),8.94(d,J=4.9Hz,2H),7.48(t,J=4.9Hz,1H),5.07(br t,J=6.1Hz,2H),4.37(t,J=7.8Hz,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 product: m / z 475.3(M+H) + ,Rt:1.954 minutes.

[0566] LCMS method The gradient was 5% B in 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. 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 x 2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0567] Example 39 - Synthesis of N-(4,4-dimethylcyclohexyl)-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (Compound 39) [ka] Step 1: Diethyl 2-(5-bromo-2-nitrobenzylidene)malonate [ka]

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

[0569] The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=50:1 to 1:1) to give diethyl 2-(5-bromo-2-nitrobenzylidene)malonate (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 a HALO AQ-C18 2.1 x 30 mm (2.7 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100-1000. 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 in 4.30 min, 5% B in 0.01 min, 5 to 95% B (0.01-3.00 min), hold at 95% B for 0.50 min, 95 to 5% B (3.50-3.51 min), 5% B at 3.51 min, hold at 5% B for 0.79 min. The flow rate was 1.0 mL / min.

[0572] Step 2: Ethyl 6-bromo-2-oxo-1,2-dihydroquinoline-3-carboxylate [ka]

[0573] To a solution of diethyl 2-[(5-bromo-2-nitro-phenyl)methylene]propanedioate (3.3 g, 8.87 mmol, 1 equiv) in AcOH (20 mL) was added Fe (1.24 g, 22.17 mmol, 2.5 equiv) at 25° C. The mixture was stirred at 85° C. for 2 h. LCMS showed 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] 1H NMR (400 MHz, 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 = 3.1 Hz, 2H), 1.51-1.22 (m, 3H). LCMS (ESI+) for 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 100–1000. 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 in 4.30 min, 5% B in 0.01 min, 5 to 95% B (0.01–3.00 min), hold at 95% B for 0.50 min, 95 to 5% B (3.50–3.51 min), 5% B at 3.51 min, hold at 5% B for 0.79 min. The flow rate was 1.0 mL / min.

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

[0578] To a solution of ethyl 6-bromo-2-oxo-1H-quinoline-3-carboxylate (1 g, 3.38 mmol, 1 equiv) in DMF (20 mL) was added CsCO (4.95 g, 15.20 mmol, 4.5 equiv) at 25 °C. The mixture was stirred at 50 °C for 1 h. 4-(2-Chloroethyl)morpholine (2.51 g, 13.51 mmol, 4 equiv, HCl) was added to the mixture at 50 °C, and the mixture was stirred at 50 °C for 11 h. LCMS 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) and extracted with ethyl acetate (3 × 50 mL). The organic layer was washed with brine (30 mL), dried over NaSO (50 g), and concentrated.

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

[0580] 1 H NMR (400 MHz, CDCl) δ = 8.30 (s, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.73 (dd, J = 2.3 Hz, 9.1 Hz, 1H), 7.33 (d, J = 9.1 Hz, 1H), 4.43 (q, J = 7.2 Hz, 4H), 3.78-3.66 (m, 4H), 2.74-2.48 (m, 6H), 1.42 (t, J = 7.1 Hz, 3H). LCMS (ESI+) for 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 100–1000. 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), hold at 95% B within 0.5 min, 95 to 5% B (3.50–3.51 min), hold at 5% B for 0.79 min. The flow rate was 1.0 mL / min (0.01–4.30 min).

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

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

[0584] The mixture was poured into NH4Cl (15 mL) and extracted with ethyl acetate (3 × 5 mL), and the organic layer was washed with brine (3 mL), dried over Na2SO4 (5 g), and 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, which was used without further purification.

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

[0586] 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 100–1000. 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), hold at 95% B within 0.5 min, 95 to 5% B (3.50–3.51 min), hold 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 [ka]

[0588] To a solution of ethyl 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-quinoline-3-carboxylate (99.77 mg, 228.58 μmol, 1 equiv) in dioxane (2 mL) was added NaOH (2 M, 0.8 mL, 7.00 equiv) at 25 °C. The mixture was stirred at 80 °C for 2 h. LCMS 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) and extracted with ethyl acetate (3 × 50 mL). The organic layer was washed with brine (30 mL), dried over NaSO (20 g), and concentrated to give the desired product (93 mg, 227.69 μmol) as a brown oil.

[0589] The mixture was poured into NH4Cl (15 mL) and extracted with ethyl acetate (3 × 5 mL), and the organic layer was washed with brine (3 mL), dried over Na2SO4 (5 g), and 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, 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 100–1000. 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), hold at 95% B within 0.5 min, 95 to 5% B (3.50–3.51 min), hold at 5% B for 0.79 min. The flow rate was 1.0 mL / min (0.01–4.30 min).

[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 equiv) in DMF (1 mL) was added HATU (125.67 mg, 330.52 μmol, 1.5 equiv), DIEA (56.96 mg, 440.69 μmol, 76 μL, 2 equiv), and 4,4-dimethylcyclohexanamine (33.64 mg, 264.42 μmol, 1.2 equiv) at 25° C. The mixture was stirred at 25° C. for 2 h. LCMS showed complete consumption of the starting material and the formation of a new peak.

[0594] The mixture was filtered, and the filtrate was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 45% to 75%, 10 min) to give N-(4,4-dimethylcyclohexyl)-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (20 mg, 38.17 μmol, 17.32% yield, 98.8% purity) 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+) for 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 100–1000. 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), hold at 95% B within 0.5 min, 95 to 5% B (3.50–3.51 min), hold at 5% B for 0.79 min. The flow rate was 1.0 mL / min (0.01–4.30 min).

[0597] Example 40 - Synthesis of 6-(5-cyanopyridin-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-naphthyridine-3-carboxylic acid (350 mg, 915.73 μmol, 1 equiv), BPD (1.86 g, 7.33 mmol, 8 equiv), Pd(PPh3)2Cl2 (64.27 mg, 91.57 μmol, 0.1 equiv), and KOAc (269.62 mg, 2.75 mmol, 3 equiv) in dioxane (3 mL) was stirred at 80 °C for 2 h.

[0599] LCMS showed 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 x 3 mL).

[0600] The combined aqueous layers were washed with 2M HCl (3 mL) and the resulting solid was filtered and concentrated under reduced pressure to give 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] LCMS (ESI+) for product: m / z 348.2 [M+H] + ,Rt:0.454 minutes.

[0602] LCMS method The column used for chromatography was a 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 100–1000. 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 in 4.50 min, 5% B in 0.25 min, 5 to 95% B (0.25–2.25 min), 95 to 100% B (2.25–4.05 min), 5% B in 1.81 min, and a 0.43 min hold at 5% B. The flow rates were 1.0 mL / min (0.00–4.05 min) and 1.2 mL / min (4.05–4.5 min).

[0603] Method 2: A mixture of 6-bromo-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylic acid (120 mg, 313.96 μmol, 1 equiv), BPD (637.82 mg, 2.51 mmol, 8 equiv), KOAc (92.44 mg, 941.89 μmol, 3 equiv), and Pd(PPh)Cl (22.04 mg, 31.40 μmol, 0.1 equiv) in dioxane (7 mL) was degassed and purged with N three times, after which the mixture was stirred at 80 °C for 2 h under a N atmosphere. LCMS showed complete consumption of the starting material 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 give 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 (80 mg, 186.36 μmol) as a white solid, which was used without further purification.

[0605] LCMS (ESI+) for product: m / z 348.2 [M+H] +,Rt:0.532 minutes.

[0606] LCMS method The column used for chromatography was a 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 100–1000. 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 in 2.00 min, 5% B in 0.01 min, 5 to 95% B (0.01–1.00 min), 95 to 100% B (1.00–1.80 min), 5% B in 1.81 min, and a 0.19-min hold at 5% B. The flow rates were 1.0 mL / min (0.00–1.80 min) and 1.2 mL / min (1.81–2.00 min).

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

[0608] Method 1: A mixture of 6-bromopyridine-3-carbonitrile (63.95 mg, 349.43 μmol, 1 equiv.), 1-(2-morpholinoethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,8-naphthyridine-3-carboxylic acid (150 mg, 349.43 μmol, 1 equiv.), KCO (144.88 mg, 1.05 mmol, 3 equiv.), and Pd(PPh) (40.38 mg, 34.94 μmol, 0.1 equiv.) in dioxane (1 mL) and water (0.25 mL) was degassed and purged with N three times. The mixture was then stirred at 80° C. for 2 h under a N atmosphere. LCMS indicated 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 give 6-(5-cyanopyridin-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] LCMS (ESI+) for product: m / z 406.2 [M+H] + ,Rt:0.878 minutes.

[0611] LCMS method The column used for chromatography was a 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 100–1000. 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 in 4.50 min, 5% B in 0.25 min, 5 to 95% B (0.25–2.25 min), 95 to 100% B (2.25–4.05 min), 5% B in 1.81 min, and a 0.43 min hold at 5% B. The flow rates were 1.0 mL / min (0.00–4.05 min) and 1.2 mL / min (4.05–4.5 min).

[0612] Method 2: A mixture of 6-bromopyridine-3-carbonitrile (42.63 mg, 232.95 μmol, 1 equiv.), 1-(2-morpholinoethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,8-naphthyridine-3-carboxylic acid (100 mg, 232.95 μmol, 1 equiv.), KCO (96.59 mg, 698.86 μmol, 3 equiv.), and Pd(PPh) (26.92 mg, 23.30 μmol, 0.1 equiv.) in dioxane (1 mL) and water (0.25 mL) was degassed and purged with N three times. The mixture was then stirred at 80° C. for 2 h under a N atmosphere. LCMS indicated complete consumption of the starting material and the formation of a new peak at the desired mass.

[0613] The mixture was filtered and concentrated under reduced pressure, and the residue was purified by preparative HPLC (HCl condition) to give 6-(5-cyanopyridin-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] LCMS (ESI+) for product: m / z 406.2 [M+H] + ,Rt:1.038 minutes.

[0615] LCMS method The column used for chromatography was a 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 100–1000. 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 in 2.00 min, 5% B in 0.01 min, 5 to 95% B (0.01–1.00 min), 95 to 100% B (1.00–1.80 min), 5% B in 1.81 min, and a 0.19-min hold at 5% B. The flow rates were 1.0 mL / min (0.00–1.80 min) and 1.2 mL / min (1.81–2.00 min).

[0616] Step 3: Preparation of 6-(5-cyanopyridin-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 equiv), 6-(5-cyano-2-pyridyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylic acid (40 mg, 98.67 μmol, 1 equiv), DIEA (76.51 mg, 592.00 μmol, 103.12 μL, 6 equiv), T3P (251.15 mg, 394.67 μmol, 234.72 μL, 50% purity, 4 equiv) in DMF (0.5 mL) was stirred for 2 h at 20° C. LCMS showed complete consumption of the starting material and formation of a new peak at the desired mass.

[0618] The reaction mixture was filtered and concentrated under reduced pressure, and the filtrate was purified by preparative HPLC (neutral conditions) to give 6-(5-cyanopyridin-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] 1 H 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 in 0.40 min, 5 to 95% B from 0.40 to 3.40 min, held at 95% B for 0.45 min, then 95 to 5% B in 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 xbridge shield RP18 2.1 x 50 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization. The MS range was 100–1000.

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

[0622] To a solution of 6-(5-cyano-2-pyridyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylic acid (40 mg, 98.67 μmol, 1 equiv.) and 4-(1-aminoethyl)benzonitrile (21.64 mg, 148.00 μmol, 1.5 equiv.) in DMF (1 mL) was added DIEA (76.51 mg, 592.00 μmol, 103.12 μL, 6 equiv.) and T3P (125.58 mg, 197.33 μmol, 117.36 μL, 50% purity, 2 equiv.). The mixture was stirred at 25° C. for 1 h. LCMS 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 give N-(1-(4-cyanophenyl)ethyl)-6-(5-cyanopyridin-2-yl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-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=7.1 Hz, 3H). LCMS (ESI+) for product: m / z 534.3 [M+H] + ,Rt:2.919 minutes.

[0625] LCMS method The gradient was 5% B at 0.40 min, 5 to 95% B from 0.40 to 3.40 min, held at 95% B for 0.45 min, then 95 to 5% B at 0.01 min. The flow rate was 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 x 50 mm column (5 μm particles). Detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization.

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

[0627] A mixture of 1-(4-fluorophenyl)cyclopropanamine (29.83 mg, 197.34 μmol, 2 equiv.), 6-(5-cyano-2-pyridyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylic acid (40 mg, 98.67 μmol, 1 equiv.), DIEA (76.51 mg, 592.02 μmol, 103.12 μL, 6 equiv.), and T3P (125.58 mg, 197.34 μmol, 117.36 μL, 50% purity, 2 equiv.) in DMF (1 mL) was stirred for 2 h at 20° C. LCMS indicated 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 give 6-(5-cyanopyridin-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] 1H 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 in 0.40 min, 5 to 95% B from 0.40 to 3.40 min, held at 95% B for 0.45 min, then 95 to 5% B in 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 xbridge Shield RP18 2.1 x 50 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0631] Example 43 - Synthesis of 6-(5-(difluoromethoxy)pyridin-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 ethyl 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 [ka]

[0632] To a mixture of ethyl 6-bromo-1-[(4-fluorophenyl)methyl]-2-oxo-1,8-naphthyridine-3-carboxylate (150 mg, 370.17 μmol, 1 equiv.), KOAc (363.29 mg, 3.70 mmol, 10 equiv.), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (940.01 mg, 3.70 mmol, 10 equiv.) in DMSO (2 mL) was added Pd(PPh3)4 (42.78 mg, 37.02 μmol, 0.1 equiv.) under N2. The mixture was stirred at 80 °C for 1 h. LCMS 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 combined organic phases were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give ethyl 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 (120 mg, 265.32 μmol), which was used without further purification.

[0634] LCMS (ESI+) for 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 100–1000. 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 in 2.20 min, 5% B in 0.01 min, 5 to 95% B (0.01–1.00 min), 95 to 100% B (1.00–1.80 min), 5% B in 1.81 min, and a 0.40 min hold at 5% B. The flow rate was 1.0 mL / min.

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

[0637] To a mixture of ethyl 1-[(4-fluorophenyl)methyl]-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,8-naphthyridine-3-carboxylate (120 mg, 265.32 μmol, 1 equiv.), KCO (110.01 mg, 795.96 μmol, 3 equiv.), and 2-bromo-5-(difluoromethoxy)pyridine (71.32 mg, 318.39 μmol, 1.2 equiv.) in dioxane (1 mL) and HO (0.1 mL) was added Pd(PPh) (30.66 mg, 26.53 μmol, 0.1 equiv.) under N. The mixture was stirred at 100 °C for 1 h. LCMS 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) and the aqueous phase was extracted with ethyl acetate (3 x 5 mL).

[0638] The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give ethyl 6-(5-(difluoromethoxy)pyridin-2-yl)-1-(4-fluorobenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate (90 mg), which was used without further purification.

[0639] LCMS (ESI+) for 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 100–1000. 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 in 2.20 min, 5% B in 0.01 min, 5 to 95% B (0.01–1.00 min), 95 to 100% B (1.00–1.80 min), 5% B in 1.81 min, and a 0.40 min hold at 5% B. The flow rate was 1.0 mL / min.

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

[0642] To a mixture of ethyl 6-[5-(difluoromethoxy)-2-pyridyl]-1-[(4-fluorophenyl)methyl]-2-oxo-1,8-naphthyridine-3-carboxylate (90 mg, 191.73 μmol, 1 equiv.) in DMSO (5 mL) was added NaOH (2 M, 958.65 μL, 10 equiv.). The mixture was stirred at 50° C. for 2 hours. LCMS 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 NaSO, filtered, and concentrated in vacuo to give 6-(5-(difluoromethoxy)pyridin-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] LCMS (ESI+) for 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 100–1000. 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 in 2.20 min, 5% B in 0.01 min, 5 to 95% B (0.01–1.00 min), 95 to 100% B (1.00–1.80 min), 5% B in 1.81 min, and a 0.40 min hold at 5% B. The flow rate was 1.0 mL / min.

[0646] Step 4: Preparation of 6-(5-(difluoromethoxy)pyridin-2-yl)-1-(4-fluorobenzyl)-2-oxo-N-(spiro[3.3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0647] To a mixture of 6-[5-(difluoromethoxy)-2-pyridyl]-1-[(4-fluorophenyl)methyl]-2-oxo-1,8-naphthyridine-3-carboxylic acid (32 mg, 72.50 μmol, 1 equiv.) and spiro[3.3]heptan-2-amine (12.85 mg, 87.00 μmol, 1.2 equiv., HCl) in DMF (1 mL) was added DIEA (56.22 mg, 435.02 μmol, 75.77 μL, 6 equiv.) and T3P (92.28 mg, 145.01 μmol, 86.24 μL, 50% purity, 2 equiv.). The mixture was stirred at 20 °C for 1 h. LCMS 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 purified by preparative HPLC (column: Phenomenex Gemini-NX 150 × 30 mm × 5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 55% to 85%, 8 min) to give 6-(5-(difluoromethoxy)pyridin-2-yl)-1-(4-fluorobenzyl)-2-oxo-N-(spiro[3.3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-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, 8.6 Hz, 2H), 6.99 (t, J = 8.7 Hz, 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 = 7.4 Hz, 2H), 2.05-1.96 (m, 4H), 1.92-1.82 (m, 2H). LCMS (ESI-) for product: m / z 535.2 [M+H] + ,Rt:3.680 minutes.

[0650] LCMS method The gradient was 5% B in 0.40 min, 5 to 95% B from 0.40 to 3.40 min, held at 95% B for 0.45 min, then 95 to 5% B in 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 Xbridge Shield RP18 2.1 x 50 mm column (5 μm particles). Detection methods included diode array (DAD) and 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-naphthyridine-3-carboxylic acid (190 mg, 497.11 μmol, 1 equiv.) in dioxane (2 mL) and water (0.2 mL) was added (4-cyanophenyl)boronic acid (87.65 mg, 596.53 μmol, 1.2 equiv.), KCO (206.11 mg, 1.49 mmol, 3 equiv.), and Pd(PPh) (57.44 mg, 49.71 μmol, 0.1 equiv.). The mixture was stirred at 80 °C for 2 h under N. LCMS indicated 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 give 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] LCMS (ESI+) for 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 100–1000. 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 in 2.20 min, 5% B in 0.01 min, 5 to 95% B (0.01–1.00 min), 95 to 100% B (1.00–1.80 min), 5% B in 1.81 min, and a 0.39 min hold at 5% B. The flow rate was 1.0 mL / min.

[0656] Step 2: Preparation of 6-(4-cyanophenyl)-1-(2-morpholinoethyl)-2-oxo-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-naphthyridine-3-carboxylic acid (25 mg, 61.82 μmol, 1 equiv) in DMF (0.5 mL) was added spiro[3.3]heptan-2-amine (10.95 mg, 74.18 μmol, 1.2 equiv, HCl), T3P (39.34 mg, 123.63 μmol, 36.76 μL, 2 equiv), and DIEA (47.94 mg, 370.90 μmol, 64.60 μL, 6 equiv).

[0658] The mixture was stirred 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. The mixture was purified by preparative HPLC (neutral conditions) to give 6-(4-cyanophenyl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3.3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (9 mg, 18.09 μmol) as a white solid.

[0659] 1 H 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). LCMS (ESI+) for product: m / z 498.3 [M+H]+ ,Rt:3.283 minutes.

[0660] LCMS method The gradient was 5% B in 0.40 min, 5 to 95% B from 0.40 to 3.40 min, held at 95% B for 0.45 min, then 95 to 5% B in 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 Xbridge Shield RP18 2.1 x 50 mm column (5 μm particles). Detection methods included diode array (DAD) and 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-naphthyridine-3-carboxylic acid (20 mg, 49.45 μmol, 1 equiv) in DMF (0.5 mL) was added 1-(4-fluorophenyl)ethanamine (10.42 mg, 59.34 μmol, 9.83 μL, 1.2 equiv, HCl), T3P (31.47 mg, 98.91 μmol, 29.41 μL, 2 equiv), and DIEA (38.35 mg, 296.72 μmol, 51.68 μL, 6 equiv). The mixture was stirred at 25 °C for 1 h. LCMS 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 give 6-(4-cyanophenyl)-N-(1-(4-fluorophenyl)ethyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-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). LCMS (ESI+) for product: m / z 526.3 [M+H] + ,Rt:3.184 minutes.

[0665] LCMS method The gradient was 5% B in 0.40 min, 5 to 95% B from 0.40 to 3.40 min, held at 95% B for 0.45 min, then 95 to 5% B in 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 Xbridge Shield RP18 2.1 x 50 mm column (5 μm particles). Detection methods included diode array (DAD) and 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-(pyridin-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 equiv.) in DMF (0.5 mL) was added bicyclo[1.1.1]pentan-3-amine (8.87 mg, 74.18 μmol, 2.46 μL, 1.2 equiv., HCl), T3P (39.34 mg, 123.63 μmol, 36.76 μL, 2 equiv.), and DIEA (47.94 mg, 370.90 μmol, 64.60 μL, 6 equiv.). The mixture was stirred at 25 °C for 1 h. LCMS 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 give 1-(2-morpholinoethyl)-2-oxo-6-(pyridin-2-yl)-N-(spiro[3.3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-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+) for product: m / z 470.3[M+H] + ,Rt:3.092 minutes.

[0670] LCMS method The gradient was 5% B in 0.40 min, 5 to 95% B from 0.40 to 3.40 min, held at 95% B for 0.45 min, then 95 to 5% B in 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 Xbridge Shield RP18 2.1 x 50 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0671] Example 47 - Synthesis of 6-(5-(difluoromethoxy)pyridin-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)pyridin-2-yl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid [ka]

[0672] To a mixture of 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 equiv.) in dioxane (2 mL) and HO (0.2 mL), 2-bromo-5-(difluoromethoxy)pyridine (5.22 mg, 23.30 μmol, 1 equiv.), Pd(PPh3)4 (2.69 mg, 2.33 μmol, 0.1 equiv.), and K2CO3 (9.66 mg, 69.89 μmol, 3 equiv.) were added under N2. The mixture was stirred at 80 °C for 2 h under N2. 16 additional vials were set up as above. LCMS showed complete consumption of the starting material and the formation of a new peak at the desired mass. All 17 reaction mixtures were combined.

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

[0674] LCMS (ESI+) for 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 100–1000. 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 in 2.20 min, 5% B in 0.01 min, 5 to 95% B (0.01–1.00 min), 95 to 100% B (1.00–1.80 min), 5% B in 1.81 min, and a 0.39 min hold at 5% B. The flow rate was 1.0 mL / min.

[0676] Step 2: Preparation of 6-(5-(difluoromethoxy)pyridin-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-naphthyridine-3-carboxylic acid (30 mg, 67.20 μmol, 1 equiv) in DMF (0.5 mL) was added spiro[3.3]heptan-2-amine (11.91 mg, 80.64 μmol, 1.2 equiv, HCl), DIEA (52.11 mg, 403.22 μmol, 70.23 μL, 6 equiv), and T3P (42.77 mg, 134.41 μmol, 39.97 μL, 2 equiv) under N2. The mixture was stirred at 25 °C for 1 h under N2. 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 give 6-(5-(difluoromethoxy)pyridin-2-yl)-1-(2-morpholinoethyl)-2-oxo-N-(spiro[3.3]heptan-2-yl)-1,2-dihydro-1,8-naphthyridine-3-carboxamide (25 mg, 46.33 μmol) as a white solid.

[0679] 1 H NMR(400MHz,DMSO-d6)δ=9.70(d,J=7.6Hz,1H),9.44(d,J=2.3Hz,1H),9.10(d,J=2.3Hz,1H),8.94(s,1H) ),8.64(d,J=2.8Hz,1H),8.21(d,J=8.7Hz,1H),7.87(dd,J=2.8,8.7Hz,1H),7.60-7.21(m,1H),4.67(br t,J=7.1Hz,2H),4.36-4.25(m,1H),3.53(t,J=4.4Hz,4H),2.65-2.61(m,2H),2.44(br d,J=2.7Hz,4H),2.41(br dd, J = 2.3, 9.4 Hz, 2H), 2.09-2.03 (m, 2H), 2.00-1.93 (m, 4H), 1.85-1.77 (m, 2H). LCMS (ESI+) for product: m / z 540.3 [M+H] + ,Rt:3.284 minutes.

[0680] LCMS method The gradient was 5% B in 0.40 min, 5 to 95% B from 0.40 to 3.40 min, held at 95% B for 0.45 min, then 95 to 5% B in 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 Xbridge Shield RP18 2.1 x 50 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0681] Example 48 Synthesis of (R)-6-(5-(difluoromethoxy)pyridin-2-yl)-N-(1-(4-fluorophenyl)ethyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (Compound 48) [ka] Preparation of (R)-6-(5-(difluoromethoxy)pyridin-2-yl)-N-(1-(4-fluorophenyl)ethyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0682] To a mixture of 6-[5-(difluoromethoxy)-2-pyridyl]-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylic acid (35 mg, 78.40 μmol, 1 equiv.) in DMF (0.5 mL) was added (1R)-1-(4-fluorophenyl)ethanamine (16.52 mg, 94.09 μmol, 1.2 equiv., HCl), DIEA (60.80 mg, 470.43 μmol, 81.94 μL, 6 equiv.), and T3P (49.89 mg, 156.81 μmol, 46.63 μL, 2 equiv.) under N2. The mixture was stirred at 25 °C for 1 h under N2. LCMS showed complete consumption of the starting material and the formation of a new peak at the desired mass.

[0683] The mixture was filtered, and the filtrate was purified by preparative HPLC (neutral conditions) to give (R)-6-(5-(difluoromethoxy)pyridin-2-yl)-N-(1-(4-fluorophenyl)ethyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (29 mg, 51.10 μmol) as a white solid.

[0684] 1H NMR(400MHz,DMSO-d6)δ=9.98(d,J=7.6Hz,1H),9.45(d,J=2.4Hz,1H),9.11(d,J=2.4Hz,1H),8.96(s,1H),8.64(d,J=2.9Hz,1H ),8.21(d,J=8.8Hz,1H),7.87(dd,J=2.8,8.8Hz,1H),7.61-7.16(m,5H),5.19(quin,J=7.0Hz,1H),4.72-4.64(m,2H),3.53(br t,J=4.3Hz,4H),2.63(br t,J=7.2Hz,2H),2.52(br s, 4H), 1.52 (d, J=6.9 Hz, 3H). LCMS (ESI+) for product: m / z 568.3 [M+H] + ,Rt:3.181 minutes.

[0685] LCMS method The gradient was 5% B in 0.40 min, 5 to 95% B from 0.40 to 3.40 min, held at 95% B for 0.45 min, then 95 to 5% B in 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 Xbridge Shield RP18 2.1 x 50 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0686] Example 49 Synthesis of (S)-6-(5-(difluoromethoxy)pyridin-2-yl)-N-(1-(4-fluorophenyl)ethyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (Compound 49) [ka] Preparation of (S)-6-(5-(difluoromethoxy)pyridin-2-yl)-N-(1-(4-fluorophenyl)ethyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0687] To a mixture of 6-[5-(difluoromethoxy)-2-pyridyl]-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylic acid (30 mg, 67.20 μmol, 1 equiv.) in DMF (0.5 mL) was added (1S)-1-(4-fluorophenyl)ethanamine (14.16 mg, 80.64 μmol, 1.2 equiv., HCl), DIEA (52.11 mg, 403.22 μmol, 70.23 μL, 6 equiv.), and T3P (42.77 mg, 134.41 μmol, 39.97 μL, 2 equiv.) under N2. The mixture was stirred at 25 °C for 1 h under N2. LCMS showed complete consumption of the starting material and the formation of a new peak at the desired mass.

[0688] The mixture was filtered, and the filtrate was purified by preparative HPLC (neutral conditions) to give (S)-6-(5-(difluoromethoxy)pyridin-2-yl)-N-(1-(4-fluorophenyl)ethyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (25 mg, 44.05 μmol) as a white solid.

[0689] 1 H NMR(400MHz,DMSO-d6)δ=9.97(d,J=7.6Hz,1H),9.45(d,J=2.3Hz,1H),9.10(d,J=2.4Hz,1H),8.95(s,1H),8.64(d,J=2.8Hz,1H ),8.21(d,J=8.8Hz,1H),7.86(dd,J=2.8,8.7Hz,1H),7.60-7.16(m,5H),5.19(quin,J=7.0Hz,1H),4.72-4.64(m,2H),3.53(br t,J=4.3Hz,4H),2.64(br t, J = 7.1 Hz, 2H), 2.53-2.51 (m, 4H), 1.52 (d, J = 7.0 Hz, 3H). LCMS (ESI+) for product: m / z 568.3 [M+H] + ,Rt:3.136 minutes.

[0690] LCMS method The gradient was 5% B in 0.40 min, 5 to 95% B from 0.40 to 3.40 min, held at 95% B for 0.45 min, then 95 to 5% B in 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 Xbridge Shield RP18 2.1 x 50 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization.

[0691] Example 50 Synthesis of N-(bicyclo[1.1.1]pentan-1-yl)-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (Compound 50) [ka] Step 1: Preparation of 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid [ka]

[0692] To a mixture of 6-bromo-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylic acid (50 mg, 130.82 μmol, 1 equiv) in dioxane (0.5 mL) and HO (0.05 mL) was added (4-methoxyphenyl)boronic acid (23.85 mg, 156.98 μmol, 1.2 equiv), KCO (54.24 mg, 392.46 μmol, 3 equiv), and Pd(PPh) (15.12 mg, 13.08 μmol, 0.1 equiv) under N. The mixture was stirred at 80 °C for 2 h under N. LCMS showed complete consumption of the starting material and the formation of a new peak at the desired mass.

[0693] The mixture was concentrated, and the residue was triturated with petroleum ether:ethyl acetate (4:1), filtered, and the solid was air-dried to give 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid (50 mg, 122.12 μmol) as a yellow solid.

[0694] LCMS (ESI+) for product: m / z 410.2 [M+H] + ,Rt:1.082 minutes.

[0695] 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 100–1000. 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 in 2.20 min, 5% B in 0.01 min, 5 to 95% B (0.01–1.00 min), 95 to 100% B (1.00–1.80 min), 5% B in 1.81 min, and a 0.39 min hold at 5% B. The flow rate was 1.0 mL / min.

[0696] Step 2: Preparation of N-(bicyclo[1.1.1]pentan-1-yl)-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide [ka]

[0697] To a mixture of 6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,8-naphthyridine-3-carboxylic acid (5 mg, 12.21 μmol, 1 equiv.) in DMF (0.5 mL) was added bicyclo[1.1.1]pentan-3-amine (1.75 mg, 14.65 μmol, 1.2 equiv., HCl), DIEA (9.56 mg, 74.00 μmol, 12.89 μL, 6 equiv.), and T3P (15.54 mg, 24.42 μmol, 14.53 μL, 50% purity, 2 equiv.). The mixture was stirred at 25 °C for 1 h. LCMS showed complete consumption of the starting material and the formation of a new peak at the desired mass.

[0698] The mixture was filtered, and the filtrate was purified by preparative HPLC (neutral conditions) to give N-(bicyclo[1.1.1]pentan-1-yl)-6-(4-methoxyphenyl)-1-(2-morpholinoethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide (6.3 mg, 13.21 μmol) as a pale yellow solid.

[0699] 1 H NMR(400MHz,DMSO-d6)δ=10.01(s,1H),9.11(d,J=2.4Hz,1H),8.90(s,1H),8.75(d,J=2.4Hz,1H),7.78(d,J=8.8Hz,2H),7.10(d,J=8.8Hz,2H),4.65(br t,J=7.1Hz,2H),3.83(s,3H),3.54(br t,J=4.4Hz,4H),2.62(br t,J=7.1Hz,2H),2.53-2.52(m,4H),2.47-2.46(m,2H),2.13(s,6H). LCMS (ESI+) for product: m / z 475.3[M+H] + ,Rt:3.239 minutes.

[0700] LCMS method The gradient was 5% B in 0.40 min, 5 to 95% B from 0.40 to 3.40 min, held at 95% B for 0.45 min, then 95 to 5% B in 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 Xbridge Shield RP18 2.1 x 50 mm column (5 μm particles). Detection methods included diode array (DAD) and evaporative light sc...

Claims

1. A compound having the structure of formula (X), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chem.499】 During the ceremony, R １ is —OH, L １ But it doesn't exist, or C １ -C ４ Alkylene, or C ３ -C ５ is cycloalkylene, R ２ is unsubstituted or contains 1, 2, 3, or 4 R ａ Ring A is substituted with Ring A is a C ring containing 1 to 2 N atoms and 0 or 1 O or S atom ３ -C ６ Heterocycloalkyl, C containing 0 or 1 N atom and 1 O or S atom ３ -C ６ Heterocycloalkyl, phenyl, C ３ -C １０ cycloalkyl, 5-membered heteroaryl, or 6-membered heteroaryl; Each R ａ are independently halogen, —CN, —OH, —OR １２ , -SR １２ , -S(=O)R １２ , -S(=O) ２ R １２ , -S(=O) ２ N (R １３ ) ２ , -NR １３ S (= O) ２ R １２ , -N(R １３ ) ２ , -OC(=O)(R １２ ), -CO ２ R 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 , C １ -C ４ Alkyl, C ２ -C ４ Alkenyl, C ２ -C ４ Alkynyl, C １ -C ４ Deuteroalkyl, C １ -C ４ Fluoroalkyl, C １ -C ４ Heteroalkyl or substituted or unsubstituted monocyclic C ３ -C ６ heterocycloalkyl; R ３ is H or C １ -C ４ is alkyl, R ４ but, [500] wherein u is 1 or 2 and v is 1 or 2; or Or R ４ But, -L ２ -R ５ and L ２ is not present or -CR １０ R １１ - and R １０ But -CH ３ and R １１ is H or -CH ３ Or Or R １０ and R １１ together with the carbon atoms to which they are attached form cyclopropyl-1,1-diyl, R ５ is unsubstituted or contains 1, 2, 3, or 4 R ｂ Ring B is substituted with Ring B is bridged C ５ -C １２ cycloalkyl, phenyl, naphthyl, or heteroaryl; Each R ｂ are independently selected from halogen, —CN, —OH, —N(R １３ ) ２ , -OC(=O)(R １２ ), -CO ２ R 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 , C １ -C ４ Alkyl, C ２ -C ４ Alkenyl, C ２ -C ４ Alkynyl, C １ -C ４ Alkoxy, C １ -C ４ Deuteroalkyl, C １ -C ４ Deuteroalkoxy, C １ -C ４ Fluoroalkyl, C １ -C ４ Fluoroalkoxy, C １ -C ４ Heteroalkyl or substituted or unsubstituted monocyclic C ３ -C ６ heterocycloalkyl; Or two R bonded to the same carbon atom ｂ together with the carbon atom, C ３ -C ６ Cycloalkyl or C ３ -C ６ forming a heterocycloalkyl, R ６ is unsubstituted or contains 1, 2, 3, or 4 R ｃ Ring C is substituted with Ring C is phenyl, naphthyl, heteroaryl, C ３ -C １２ cycloalkyl, or C ２ -C １０ is heterocycloalkyl, Each R ｃ are independently halogen, —CN, —OH, —OR １２ , -SR １２ , -S(=O)R １２ , -S(=O) ２ R １２ , -S(=O) ２ N (R １３ ) ２ , -NR １３ S (= O) ２ R １２ , -N(R １３ ) ２ , -OC(=O)(R １２ ), -CO ２ R 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 , C １ -C ４ Alkyl, C ２ -C ４ Alkenyl, C ２ -C ４ Alkynyl, C １ -C ４ Deuteroalkyl, C １ -C ４ Fluoroalkyl, C １ -C ４ Heteroalkyl, substituted or unsubstituted C ３ -C ６ Cycloalkyl, substituted or unsubstituted C ３ -C ６ selected from the group consisting of heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, or a 1,4-dioxanyl ring fused to Ring C; R ７ is H, X １ is N and X ２ But, CR ８ or N, Or X １ But, CR ８ or N, and X ２ is N, R ８ is H, halogen, -CN, -OH, -N(R １３ ) ２ , C １ -C ４ Alkyl, C ２ -C ４ Alkenyl, C ２ -C ４ Alkynyl, C １ -C ４ Alkoxy, C １ -C ４ Deuteroalkyl, C １ -C ４ Deuteroalkoxy, C １ -C ４ Fluoroalkyl, C １ -C ４ Fluoroalkoxy, or C １ -C ４ is heteroalkyl, Each R １２ But independently, C １ -C ４ Alkyl, C １ -C ４ Deuteroalkyl, C １ -C ４ Fluoroalkyl, C １ -C ４ Heteroalkyl, substituted or unsubstituted C ３ -C ６ Cycloalkyl, substituted or unsubstituted C ３ -C ６ is selected from the group consisting of heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; and Each R １３ are independently hydrogen, C １ -C ４ Alkyl, C １ -C ４ Deuteroalkyl, C １ -C ４ Fluoroalkyl, C １ -C ４ Heteroalkyl, substituted or unsubstituted C ３ -C ６ Cycloalkyl, substituted or unsubstituted C ３ -C ６ selected from the group consisting of heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. R ３ is H or -CH ３ and L １ does not exist or -CH ２ -, -CH ２ CH ２ -, -CH ２ CH ２ CH ２ -, -CH(CH ３ ) -, -C(CH ３ ) ２ - or cyclopropyl-1,1-diyl, X １ is N and X ２ But, CR ８ Or Or X １ But, CR ８ and X ２ is N, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

3. 3. The compound of claim 1 or claim 2, wherein the compound of formula (X) has the following structure of formula (XI): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemical 501】 【Request Item 4】 【Chemical 502】 but, 【Chemical 503】 4. The compound of claim 1, wherein: 【Request Item 5】 【Chemical 504】 but, 【Chemical 505】 4. The compound of claim 1, wherein:

6. Each R ｂ are independently F, Cl, Br, —CN, —OH, —NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , -CH ３ , -OCH ３ , -CD ３ , -OCD ３ , -CFH ２ , -CHF ２ , -CF ３ , -OCFH ２ , -OCHF ２ , and -OCF ３ or selected from the group consisting of Or two R bonded to the same carbon atom ｂ is taken together with said carbon atom to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, thiomorpholinyl, or piperidinyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 【Request Item 7】 【Chemistry 506】 but, 【Chemical 507】 4. The compound of claim 1, wherein:

8. The compound of formula (X) has the following structure of formula (XII): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemical 508】 During the ceremony, n1, n2, and n3 are each independently 1, 2, or 3; R ｄ is halogen, -CN, -OH, -N(R １３ ) ２ , -OC(=O)(R １２ ), -CO ２ R 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 , C １ -C ４ Alkyl, C ２ -C ４ Alkenyl, C ２ -C ４ Alkynyl, C １ -C ４ Alkoxy, C １ -C ４ Deuteroalkyl, C １ -C ４ Deuteroalkoxy, C １ -C ４ Fluoroalkyl, C １ -C ４ Fluoroalkoxy, C １ -C ４ Heteroalkyl or substituted or unsubstituted monocyclic C ３ -C ６ 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is heterocycloalkyl.

9. 3. The compound of claim 1 or claim 2, wherein the compound of formula (X) has the following structure of formula (XIII): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemical 509】

10. R ５ is unsubstituted or contains 1, 2, 3, or 4 R ｂ Ring B is substituted with 10. The compound of claim 9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is phenyl or monocyclic heteroaryl.

11. R ５ is unsubstituted or contains 1, 2, 3, or 4 R ｂ Ring B is substituted with Alternatively, the compound of claim 9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.

12. 10. The compound of claim 9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

13. R ５ but, 【Chemical 510】 and 10. The compound of claim 9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 0, 1, or 2.

14. Each R ｂ are independently F, Cl, Br, —CN, —OH, —NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , -CH ３ , -OCH ３ , -CD ３ , -OCD ３ , -CFH ２ , -CHF ２ , -CF ３ , -OCFH ２ , -OCHF ２ , and -OCF ３ 14. The compound of any one of claims 9 to 13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

15. L １ But -CH ２ CH ２ - and R ２ is unsubstituted or contains 1, 2, 3, or 4 R ａ and ring A is substituted with Ring A is a C ring containing 1 to 2 N atoms and 0 or 1 O or S atom ３ -C ６ Heterocycloalkyl or C containing 0 or 1 N atom and 1 O or S atom ３ -C ６ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is heterocycloalkyl.

16. L １ But -CH ２ CH ２ - and R ２ is unsubstituted or contains 1, 2, 3, or 4 R ａ Ring A is substituted with 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, or piperazinyl.

17. 8. The compound of any one of claims 1 to 7, wherein the compound of formula (X) has the following structure of formula (XIA): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemical 511】

18. The compound of formula (X) has the following structure of formula (XIIA): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemical 512】 During the ceremony, n1, n2, and n3 are each independently 1, 2, or 3; R ｄ is halogen, -CN, -OH, -N(R １３ ) ２ , -OC(=O)(R １２ ), -CO ２ R 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 , C １ -C ４ Alkyl, C ２ -C ４ Alkenyl, C ２ -C ４ Alkynyl, C １ -C ４ Alkoxy, C １ -C ４ Deuteroalkyl, C １ -C ４ Deuteroalkoxy, C １ -C ４ Fluoroalkyl, C １ -C ４ Fluoroalkoxy, C １ -C ４ Heteroalkyl or substituted or unsubstituted monocyclic C ３ -C ６ 10. The compound of any one of claims 1, 2 and 8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is heterocycloalkyl.

19. 10. The compound of any one of claims 1, 2 and 9, wherein the compound of formula (X) has the following structure of formula (XIIIA), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemical 513】

20. R ６ is unsubstituted or contains 1, 2, 3, or 4 R ｃ Ring C is substituted with 20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring C is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, thiomorpholinyl, or piperidinyl.

21. R ６ but, 【Chemical 514】 and 20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0, 1, or 2.

22. Each R ｃ is independently F, Cl, Br, -CN, -OH, -OCH ３ , -OCD ３ , -OCFH ２ , -OCHF ２ , -OCF ３ , -O-cyclopropyl, -S(=O) ２ CH ３ , -S(=O) ２ NH ２ , -S(=O) ２ NH(CH ３ ), -S(=O) ２ N(CH ３ ) ２ , -NHS(=O) ２ CH ３ , -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , -OC(=O)CH ３ , -CO ２ H, -CO ２ CH ３ , -CO ２ CH ２ CH ３ , -C(=O)N(R １５ ) ２ , -C(=O)-NH ２ , -C(=O)NH(CH ３ ), -C(=O)N(CH ３ ) ２ , -NHC(=O)CH ３ , -CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -C(CH ３ ) ３ , -CD ３ , -CFH ２ , -CHF ２ , -CF ３ , -CH=CH ２ , -C(CH ３ )=CH ２ , -CH≡CH, -CH≡CCH ３ 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is selected from the group consisting of cyclopropyl, cyclopropyl, or oxetanyl.

23. R ６ but, 【Chemical 515】 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

24. L １ But -CH ２ -, -CH(CH ３ ) -, -C(CH ３ ) ２ - or cyclopropyl-1,1-diyl, R ２ is unsubstituted or contains 1, 2, 3, or 4 R ａ Ring A is substituted with Ring A is phenyl, C ３ -C １０ 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is cycloalkyl, 5-membered heteroaryl, or 6-membered heteroaryl.

25. 8. The compound of any one of claims 1 to 7, wherein the compound of formula (X) has the following structure of formula (XIB): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemical 516】

26. The compound of formula (X) has the following structure of formula (XIIB): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemical 517】 During the ceremony, n1, n2, and n3 are each independently 1, 2, or 3; R ｄ is halogen, -CN, -OH, -N(R １３ ) ２ , -OC(=O)(R １２ ), -CO ２ R 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 , C １ -C ４ Alkyl, C ２ -C ４ Alkenyl, C ２ -C ４ Alkynyl, C １ -C ４ Alkoxy, C １ -C ４ Deuteroalkyl, C １ -C ４ Deuteroalkoxy, C １ -C ４ Fluoroalkyl, C １ -C ４ Fluoroalkoxy, C １ -C ４ Heteroalkyl or substituted or unsubstituted monocyclic C ３ -C ６ 10. The compound of any one of claims 1, 2 and 8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is heterocycloalkyl.

27. 10. The compound of any one of claims 1, 2 and 9, wherein the compound of formula (X) has the following structure of formula (XIIIB): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemical 518】

28. R ２ but, 【Chemical 519】 and 28. The compound of any one of claims 25 to 27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 0, 1, or 2.

29. R ２ but, 【Chemical 520】 28. The compound of any one of claims 25 to 27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

30. Each R ａ are independently F, Cl, Br, —CN, —OH, —OCH ３ , -OCD ３ , -OCFH ２ , -OCHF ２ , -OCF ３ , —O-cyclopropyl, —S(═O) ２ CH ３ , -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , -CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -C(CH ３ ) ３ , -CD ３ , -CFH ２ , -CHF ２ , -CF ３ 30. The compound of claim 28 or claim 29, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is selected from the group consisting of cyclopropyl, cyclopropyl, or oxetanyl.

31. The following structure: 【Chem.521】 【Chemical 522】 【Chemical 523】 【Chemical Formula 524】 【Chemical Formula 525】 【Chemical 526】 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

32. 32. A pharmaceutical composition comprising a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

33. 33. The pharmaceutical composition of claim 32, wherein the pharmaceutical composition is formulated for administration to a mammal by oral, intravenous, or subcutaneous administration.

34. 33. The pharmaceutical composition of claim 32, wherein the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, dispersion, solution, or emulsion.

35. Cannabinoid 2 receptor (CB ２ 32. A composition for modulating the activity of a compound of formula (I) or (II) in a mammal, comprising the compound of formula (I) or (II) or any pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

36. Cannabinoid 2 receptor (CB ２ 32. A composition for treating a disease or disorder in a mammal mediated by the action of a compound of formula (I) or (II), comprising the compound of formula (I) or (II), or any pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

37. 32. A composition for treating cancer in a mammal, comprising a compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

38. 38. The composition of claim 37, wherein the cancer is a solid tumor.

39. 38. The composition of claim 37, wherein the cancer is bladder cancer, colon cancer, brain cancer, breast cancer, endometrial cancer, heart cancer, kidney cancer, lung cancer, liver cancer, uterine cancer, blood and lymphatic cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, or skin cancer.

40. 38. The composition of claim 37, wherein the cancer is prostate cancer, breast cancer, colon cancer, or lung cancer.

41. 38. The composition of claim 37, wherein the cancer is a sarcoma, carcinoma, or lymphoma.

42. The composition of any one of claims 35 to 41, characterized in that it is administered to the mammal in combination with at least one additional therapy.

43. The composition according to any one of claims 35 to 41, characterized in that it is administered to the mammal in combination with at least one immune checkpoint inhibitor.

44. 44. The composition of claim 43, wherein the immune checkpoint inhibitor is an anti-PD-1 agent or an anti-PD-L1 agent.

45. 45. The composition of claim 44, wherein the anti-PD-1 or anti-PD-L1 agent is nivolumab, pembrolizumab, semipilimab, ravlolizumab, avelumab, durvalumab, or atezolizumab.

46. The composition of any one of claims 35 to 45, wherein the mammal is a human.

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