Diacylglycerol kinase (DGK) alpha inhibitors and uses thereof

Abstract

Described herein are DGKα inhibitors, and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for treating diseases or disorders associated with DGKα.

Description

[Technical field]

[0001] REFERENCE TO RELATED APPLICATIONS This patent application claims the benefit of International Application No. PCT / CN2022 / 078655, filed March 1, 2022; International Application No. PCT / CN2022 / 091215, filed May 6, 2022; International Application No. PCT / CN2022 / 128282, filed October 28, 2022; and International Application No. PCT / CN2023 / 071962, filed January 12, 2023, which are incorporated by reference in their entireties. [Background technology]

[0002] Diacylglycerol kinases (DGKs) are a family of enzymes that catalyze the phosphorylation of the membrane lipid sn-1,2 diacylglycerol (DAG) to form phosphatidic acid (PA). In T cells, the γ1 isoform of phospholipase C (PLCyl) is activated and cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into DAG and an additional second messenger, inositol 1,4,5-triphosphate (IP3), which is formed downstream of the T cell receptor (TCR). IP3 is important in promoting calcium release from the endoplasmic reticulum, whereas DAG interacts with other proteins important for TCR signaling, such as protein kinase CO and the Ras activating protein RasGRPI. Three isoforms of DGKs (DGKα, DGKδ, and DGKζ) are known to exist in T cells, but only two, DGKα and DGKζ, are thought to play a key role in promoting DAG metabolism downstream of the TCR.

[0003] Supporting evidence includes knockout mouse models of either DGKα or DGKζ, which show a hyperresponsive T cell phenotype and enhanced antitumor immune activity (Riese MJ et al., Journal of Biological Chemistry, (2011) 7: 5254-5265; Zha Y et al., Nature Immunology, (2006) 12:1343; Olenchock BA et al., (2006) 11: 1174-81). Furthermore, it was observed that DGKα is overexpressed in tumor-infiltrating lymphocytes isolated from human renal cell carcinoma patients, resulting in inhibition of T cell function (Prinz, PU et al., J Immunology (2012) 12:5990-6000). Therefore, DGKα and DGKζ are considered targets for cancer immunotherapy (Riese MJ et al., Front Cell Dev Biol. (2016) 4: 108; Chen, SS et al., Front Cell Dev Biol. (2016) 4: 130; Avila-Flores, A. et al., Immunology and Cell Biology (2017) 95: 549-563; Noessner, E., Front Cell Dev Biol. (2017) 5: 16; Krishna, S., et al., Front Immunology (2013) 4:178; Jing, W. et al., Cancer Research (2017) 77: 5676-5686). There remains a need for compounds useful as inhibitors of one or both of DGKα and DGKζ, particularly compounds that have selectivity for them over other diacylglycerol kinases, protein kinases, and / or other lipid kinases. There remains a need for potent compounds that are safe and effective in restoring T cell activation, lowering the antigen threshold, enhancing antitumor function, and / or overcoming the suppressive effects of one or more endogenous immune checkpoints, such as PD-1, PD-L1, CTLA-4, to add to the treatment of patients with proliferative diseases such as cancer and viral infections. Summary of the Invention

[0004] Disclosed herein is a compound of formula (A): [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony, R 1a is halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; W is N or CR 1b and; Each R 1b are independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; R 2 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; U is N or CR U and; R U is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Ring B is heterocycloalkyl; Each R 3are independently halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; or two R on the same atom 3 come together to form oxo; or two R on the same or different carbons 3 taken together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; m is 0 to 6; X is N or CR X and; R X is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Y is N or CR Y and; R Y is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Z is N or CR Z and; R Z is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; R 5 is hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NRc R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, [ka] , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; R 4 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6Aminoalkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally selected from one or more R 4a Replaced with; Each R 4a are independently halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; or two R on the same atom 4a come together to form oxo; Each R a is independent, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or two R's a together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R b are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or two R's b together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R c and R d are each independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently halogen, -CN, -OH, -S(=O)CH 3 , -S(=O) 2 CH 3 , -S(=O) 2 NH 2 , -S(=O) 2 NHCH 3 , -S(=O) 2 N(CH 3 ) 2 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl or C 3 ~C 6 is cycloalkyl; Or two R on the same atom form an oxo.

[0005] In some embodiments of the compound of Formula (A) or a pharma- ceutically acceptable salt thereof, the compound has the formula (Aa): [ka] It is.

[0006] Further disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0007] Further disclosed herein is a method of inhibiting the activity of at least one diacylglycerol kinase selected from diacylglycerol kinase alpha (DGKα) and diacylglycerol kinase zeta (DGKζ) in a subject in need of such inhibition, the method comprising administering to the subject a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0008] Further disclosed herein is a method of inhibiting the activity of diacylglycerol kinase alpha (DGKα) in a subject in need of such inhibition, the method comprising administering to the subject a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0009] Further disclosed herein is a method of treating a disease associated with aberrant diacylglycerol kinase signaling in a subject in need of such treatment, the method comprising administering to the subject a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0010] In some embodiments, the diacylglycerol kinase is diacylglycerol kinase alpha. In some embodiments, the disease is cancer or a viral infection. In some embodiments, the method further comprises administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an anti-cancer agent or an anti-viral agent.

[0011] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Detailed Description of the Invention definition In the following description, certain specific details are set forth to enable a thorough understanding of various embodiments. However, one of ordinary skill in the art will appreciate that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout this specification and the claims that follow, the word "comprise" and variations thereof, such as "comprises" and "comprising," should be construed in an open and inclusive sense, i.e., "including, but not limited to." Additionally, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0013] References throughout this specification to "some embodiments" or "one embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the phrases "in one embodiment" or "in one embodiment" appear in various places throughout this specification, but not necessarily all are referring to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" is generally used in the sense of including "and / or" unless the context clearly dictates otherwise.

[0014] As used herein, the following terms have the following meanings unless otherwise indicated.

[0015] "Oxo" means =O.

[0016] "Carboxyl" means --COOH.

[0017] "Cyano" means -CN.

[0018] "Alkyl" refers to a straight or branched chain saturated hydrocarbon monoradical having from 1 to about 10 carbon atoms, more preferably from 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl. 1 ~C 6 Alkyl" or "C 1 ~ 6 Whenever a numerical range appears herein, such as "alkyl," it is meant that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, however, the definition also encompasses the occurrence of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is C 1 ~ 10 In some embodiments, alkyl is C 1 ~ 6 In some embodiments, alkyl is C 1 ~ 5 In some embodiments, alkyl is C 1 ~ 4 In some embodiments, alkyl is C 1 ~ 3Unless otherwise specifically stated in the specification, an alkyl group can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, the alkyl is optionally substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with a halogen.

[0019] "Alkenyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either the cis or trans conformation about the double bond, and should be understood to include both isomers. Examples include ethenyl (-CH=CH 2 ), 1-propenyl (-CH 2 CH=CH 2 ), isopropenyl (-C(CH 3 )=CH 2 ), butenyl, 1,3-butadienyl, and the like. 2 ~C 6 alkenyl" or "C 2 ~ 6Whenever a numerical range appears herein, such as "alkenyl," it is meant that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the definition also encompasses the occurrence of the term "alkenyl" where no numerical range is specified. Unless specifically stated otherwise in the specification, an alkenyl group can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, the alkenyl is optionally substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with a halogen.

[0020] "Alkynyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadinyl, and the like. 2 ~C 6 alkynyl" or "C 2 ~ 6Whenever a numerical range appears herein, such as "alkynyl," it is meant that the alkynyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the definition also encompasses the occurrence of the term "alkynyl" where no numerical range is specified. Unless specifically stated otherwise in the specification, alkynyl groups can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, the alkynyl is optionally substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with a halogen.

[0021] "Alkylene" means a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, the alkylene is optionally substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with a halogen.

[0022] "Alkoxy" means a group of the formula -OR a R means the radical of ais an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0023] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include fused ring systems (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, preadene, pyrene, and triphenylene hydrocarbon ring systems. Unless otherwise specifically stated in the specification, an aryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an aryl can be optionally substituted with, for example, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH2 , or -NO 2 In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH or -OMe. In some embodiments, the aryl is optionally substituted with a halogen.

[0024] "Cycloalkyl" means a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, cycloalkyls are fully saturated. Representative cycloalkyls include aryls and aryls having 3 to 15 carbon atoms (C 3 ~C 15 Fully saturated cycloalkyl or C 3 ~C 15 cycloalkenyl), 3 to 10 carbon atoms (C 3 ~C 10 Fully saturated cycloalkyl or C 3 ~C 10 cycloalkenyl), 3 to 8 carbon atoms (C 3 ~C 8 Fully saturated cycloalkyl or C 3 ~C 8 Cycloalkenyl), 3 to 6 carbon atoms (C 3 ~C 6 Fully saturated cycloalkyl or C 3 ~C 6 Cycloalkenyl), 3 to 5 carbon atoms (C 3 ~C 5 Fully saturated cycloalkyl or C 3 ~C 5 cycloalkenyl), or 3 to 4 carbon atoms (C 3 ~C 4 Fully saturated cycloalkyl or C 3 ~C 4Examples of monocyclic cycloalkyls include, but are not limited to, cycloalkyls having a cyclic aryl group (cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated in the specification, cycloalkyls can be optionally substituted with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, cycloalkyl is optionally selected from oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0025] "Halo" or "halogen" means bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0026] "Haloalkyl" means an alkyl radical, as defined above, substituted with one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0027] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0028] "Aminoalkyl" refers to an alkyl radical, as defined above, substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0029] "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, phosphorus, and combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one embodiment, the heteroalkyl is C1 ~C 6 Heteroalkyl is a heteroalkyl group consisting of 1 to 6 carbon atoms and one or more non-carbon atoms, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, which is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls include, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH(CH 3 )OCH 3 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N(CH 3 ) 2 Unless otherwise specifically stated in the specification, heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is optionally substituted with, for example, oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, heteroalkyl is optionally substituted with halogen.

[0030] "Heterocycloalkyl" means a 3-24 membered partially or fully saturated ring radical containing 2-23 carbon atoms and 1-8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heterocycloalkyl contains 1-3 nitrogens. In some embodiments, a heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, a heterocycloalkyl contains 1 nitrogen. In some embodiments, a heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless otherwise specifically stated in the specification, a heterocycloalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused ring systems (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom), spiro, or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical can be optionally oxidized; and the nitrogen atom can be optionally quaternized. Representative heterocycloalkyls include those having 2 to 15 carbon atoms (C 2 ~C 15 Fully saturated heterocycloalkyl or C 2 ~C 15 heterocycloalkenyl), 2 to 10 carbon atoms (C 2 ~C 10 Fully saturated heterocycloalkyl or C 2 ~C 10 heterocycloalkenyl), 2 to 8 carbon atoms (C 2 ~C 8 Fully saturated heterocycloalkyl or C 2 ~C 8 heterocycloalkenyl), 2 to 7 carbon atoms (C 2 ~C 7 Fully saturated heterocycloalkyl or C 2 ~C 7heterocycloalkenyl), 2 to 6 carbon atoms (C 2 ~C 6 Fully saturated heterocycloalkyl or C 2 ~C 6 heterocycloalkenyl), 2 to 5 carbon atoms (C 2 ~C 5 Fully saturated heterocycloalkyl or C 2 ~C 5 heterocycloalkenyl), or 2 to 4 carbon atoms (C 2 ~C 4 Fully saturated heterocycloalkyl or C 2 ~C 4Examples of such heterocycloalkyl radicals include, but are not limited to, heterocycloalkyl having a heterocycloalkenyl group. Examples of such heterocycloalkyl radicals include aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidin ... Examples of heterocycloalkyls include, but are not limited to, pyrazolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also encompasses all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In some embodiments, heterocycloalkyls have 2-10 carbons in the ring. When referring to the number of carbon atoms of a heterocycloalkyl, it is understood that the number of carbon atoms of the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl.In some embodiments, the heterocycloalkyl is a 3-7 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-6 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-6 membered heterocycloalkenyl. Unless otherwise specifically stated in the specification, the heterocycloalkyl can be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF. 3 , -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, heterocycloalkyl is optionally substituted with halogen.

[0031] "Heteroaryl" refers to a 5-14 membered ring system radical containing 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1-3 nitrogens. In some embodiments, the heteroaryl contains 1 or 2 nitrogens. In some embodiments, the heteroaryl contains 1 nitrogen. The heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused ring systems (when fused with a cycloalkyl or heterocycloalkyl ring, the heterocycloalkyl is bonded through an aromatic ring atom) or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a 5-6 membered heteroaryl. In some embodiments, the heteroaryl is a 6 membered heteroaryl. In some embodiments, the heteroaryl is a 5 membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolyl, These include, but are not limited to, dolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroaryl can be optionally substituted with, for example, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF. 3 , -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3 , -OH or -OMe. In some embodiments, the heteroaryl is optionally substituted with a halogen.

[0032] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where said event or circumstance occurs and cases where said event or circumstance does not occur. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined above. Additionally, an optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ), even if it is a complete substitution (e.g., -CF 2 CF 3 ), even if monosubstituted (e.g., -CH 2 CH 2 F), or may be substituted at any level between fully substituted and monosubstituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 (e.g., 1,2-dichlorophenyl)-1,2-dichlorophenyl (1,2,3-trifluoro ...

[0033] When referring to optional substituents, the term "one or more" means that the group in question is optionally substituted with one, two, three, or four substituents. In some embodiments, the group in question is optionally substituted with one, two, or three substituents. In some embodiments, the group in question is optionally substituted with one or two substituents. In some embodiments, the group in question is optionally substituted with one substituent. In some embodiments, the group in question is optionally substituted with two substituents.

[0034] By "effective amount" or "therapeutically effective amount" is meant an amount of a compound administered to a mammalian subject, either in a single dose or as part of a series, effective to produce the desired therapeutic effect.

[0035] The terms "treat", "treating" or "treatment" as used herein include alleviating, relieving or ameliorating at least one symptom of a disease or condition, preventing further symptoms, inhibiting a disease or condition, e.g., halting the progression of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or arresting a symptom of a disease or condition.

[0036] As used herein, a "disease or disorder associated with DGK" or alternatively a "DGK-mediated disease or disorder" means any disease or other deleterious condition in which DGK is known or suspected to play a role.

[0037] As used herein, "DGKα-associated disease or disorder" or alternatively "DGKα-mediated disease or disorder" means any disease or other deleterious condition in which DGKα is known or suspected to play a role.

[0038] As used herein, a "disease or disorder associated with DGKζ" or alternatively a "DGKζ-mediated disease or disorder" means any disease or other deleterious condition in which DGKζ is known or suspected to play a role.

[0039] compound Described herein are compounds or pharma- ceutically acceptable salts thereof that are useful in the treatment of diseases or disorders associated with DGK, particularly DGKα.

[0040] Disclosed herein is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony: Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 1 are independently halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c Rd , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; or two R on the same atom 1 come together to form oxo; n is 0 to 4; R 2 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; U is N or CR U and; R U is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Ring B is heterocycloalkyl; Each R 3 are independently halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; or two R on the same atom 3 come together to form oxo; or two R on the same or different carbons 3 taken together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; m is 0 to 6; X is N or CR X and; R X is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Y is N or CR Y and; R Y is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Z is N or CR Z and; R Z is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; R 4 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl may optionally be one or more R 4a Replaced with; Each R 4a are independently halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)Ra , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; or two R on the same atom 4a come together to form oxo; Each R a is independent, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or two R's a together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R b are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or two R's b together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R c and R dare each independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently halogen, -CN, -OH, -S(=O)CH 3 , -S(=O) 2 CH 3 , -S(=O) 2 NH 2 , -S(=O) 2 NHCH 3 , -S(=O) 2 N(CH 3 ) 2 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl or C 3 ~C 6 is cycloalkyl; Or two R on the same atom form an oxo.

[0041] Disclosed herein is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony: Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 1 are independently halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; or two R on the same atom 1 come together to form oxo; n is 0 to 4; R 2 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; U is N or CR U and; R U is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Ring B is heterocycloalkyl; Each R 3 are independently halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; or two R on the same atom 3 come together to form oxo; or two R on the same or different carbons 3 taken together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; m is 0 to 6; X is N or CR X and; R X is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Y is N or CR Y and; R Y is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Z is N or CR Z and; R Z is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; R 4 is C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally selected from one or more R 4a Replaced with; Each R 4a are independently halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)Ra , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; or two R on the same atom 4a come together to form oxo; Each R a is independent, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or two R's a together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R b are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or two R's b together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R c and R dare each independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently halogen, -CN, -OH, -S(=O)CH 3 , -S(=O) 2 CH 3 , -S(=O) 2 NH 2 , -S(=O) 2 NHCH 3 , -S(=O) 2 N(CH 3 ) 2 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl or C 3 ~C 6 is cycloalkyl; Or two R on the same atom form an oxo.

[0042] Disclosed herein is a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof. During the ceremony: Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 1 are independently halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; or two R on the same atom 1 come together to form oxo; n is 0 to 4; R 2 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; U is N or CR U and; R U is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Ring B is heterocycloalkyl; Each R 3 are independently halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; or two R on the same atom 3 come together to form oxo; or two R on the same or different carbons 3 taken together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; m is 0 to 6; X is N or CR X and; R X is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Y is N or CR Y and; R Y is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Z is N or CR Z and; R Z is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; R 5 is hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, [ka] , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; R 4 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally selected from one or more R 4a Replaced with; Each R 4a are independently halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR bC(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; or two R on the same atom 4a come together to form oxo; Each R a is independent, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or two R's a together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R b are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or two R's b together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R c and R d are each independently hydrogen, C 1 ~C6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently halogen, -CN, -OH, -S(=O)CH 3 , -S(=O) 2 CH 3 , -S(=O) 2 NH 2 , -S(=O) 2 NHCH 3 , -S(=O) 2 N(CH 3 ) 2 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 ~C 6Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl or C 3 ~C 6 is cycloalkyl; Or two R on the same atom form an oxo.

[0043] In some embodiments, the compound of formula (II) has the structure of formula (I).

[0044] In some embodiments of the compound of Formula (II), R 5 is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, [ka] , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R.

[0045] In some embodiments of the compound of Formula (II), R 5is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, [ka] , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R.

[0046] In some embodiments of the compound of Formula (II), R 5 is hydrogen, halogen, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, [ka] , cycloalkyl, or heterocycloalkyl; each of the alkyl, cycloalkyl, and heterocycloalkyl is optionally independently substituted with one or more R.

[0047] In some embodiments of the compound of Formula (II), R 5 is hydrogen, -OR a , C 1 ~C 6 Alkyl, [ka] , cycloalkyl, or heterocycloalkyl; each of the alkyl, cycloalkyl, and heterocycloalkyl is optionally independently substituted with one or more R.

[0048] In some embodiments of the compound of Formula (II), R 5 is hydrogen.

[0049] In some embodiments of the compound of Formula (II), R 5 -OR a In some embodiments of the compound of formula (II), R 5 Ha-OC 1 ~C 6 In some embodiments of the compound of formula (II), R 5 Ha-OC 1 ~C 6 In some embodiments of the compound of formula (II), R 5 is -O-cycloalkyl. In some embodiments of the compound of Formula (II), R 5 is -O-cycloalkyl, where cycloalkyl is a 3-6 membered ring and is optionally substituted with one or more R. In some embodiments of the compound of formula (II), R 5 is -O-heterocycloalkyl, where heterocycloalkyl is a 5-6 membered ring and is optionally substituted with one or more R.

[0050] In some embodiments of the compound of Formula (II), R 5 is C 1 ~C 6 It is an alkyl.

[0051] In some embodiments of the compound of Formula (II), R 5 is [ka] It is.

[0052] In some embodiments of the compound of Formula (II), R5 is cycloalkyl or heterocycloalkyl; each cycloalkyl and heterocycloalkyl is optionally independently substituted with one or more R.

[0053] In some embodiments of the compounds of formula (I) or (II), ring A is aryl or heteroaryl. In some embodiments of the compounds of formula (I) or (II), ring A is phenyl. In some embodiments of the compounds of formula (I) or (II), ring A is 6-membered heteroaryl. In some embodiments of the compounds of formula (I) or (II), ring A is pyridinyl. In some embodiments of the compounds of formula (I) or (II), ring A is 5-membered heteroaryl. In some embodiments of the compounds of formula (I) or (II), ring A is thiophenyl, furanyl, pyrrolyl, midazolyl, pyrazolyl, thiazolyl, oxazolyl, or triazolyl. In some embodiments of the compounds of formula (I) or (II), ring A is thiophenyl, furanyl, or pyrrolyl. In some embodiments of the compounds of formula (I) or (II), ring A is thiophenyl.

[0054] In some embodiments of the compound of Formula (I) or (II), the compound is a compound of Formula (Ia): [ka] It is.

[0055] In some embodiments of the compound of Formula (I) or (II), the compound is a compound of Formula (Ib): [ka] It is.

[0056] In some embodiments of the compound of Formula (I) or (II), the compound is a compound of Formula (Ic): [ka] It is.

[0057] In some embodiments of the compound of Formula (I) or (II), the compound is a compound of Formula (Id): [ka] It is.

[0058] In some embodiments of the compound of Formula (I) or (II), the compound is a compound of Formula (Ie): [ka] It is.

[0059] In some embodiments of the compound of Formula (I) or (II), the compound is a compound of Formula (If): [ka] It is.

[0060] In some embodiments of the compound of Formula (I) or (II), the compound is a compound of Formula (Ig): [ka] It is.

[0061] In some embodiments of the compounds of Formula (I), (Ia)-(Ig), or (II), each R 1 are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6In some embodiments of the compounds of Formula (I), (Ia)-(Ig), or (II), each R 1 are independently halogen, -CN, -OH, -OR a , -NR c R d In some embodiments of the compounds of Formula (I), (Ia)-(Ig), or (II), each R 1 are independently halogen, -CN, -OR a , -NR c R d In some embodiments, the heterocycloalkyl is a 5- or 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl contains 0-2 nitrogen atoms and 0-1 oxygen atoms. In some embodiments, the heterocycloalkyl contains 1 or 2 nitrogen atoms. In some embodiments, the heterocycloalkyl contains 1 oxygen atom. In some embodiments, the heterocycloalkyl contains 1 nitrogen atom and 1 oxygen atom. In some embodiments of a compound of Formula (I), (Ia)-(Ig), or (II), each R 1 are independently halogen, -CN, -OR a , or -NR c R d In some embodiments of the compound of Formula (I), (Ia)-(Ig), or (II), each R 1 are independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of Formula (I), (Ia)-(Ig), or (II), each R 1 are independently halogen, -CN, C 1 ~C 6 Alkyl or C 1 ~C6 In some embodiments of the compounds of Formula (I), (Ia)-(Ig), or (II), each R 1 is independently halogen or -CN. In some embodiments of the compound of Formula (I), (Ia)-(Ig), or (II), each R 1 is independently a halogen. In some embodiments of the compounds of Formula (I), (Ia)-(Ig), or (II), each R 1 is independently fluoro or chloro. In some embodiments of the compounds of Formula (I), (Ia)-(Ig), or (II), each R 1 In some embodiments of the compounds of Formula (I), (Ia)-(Ig), or (II), -OR a is -O-heterocycloalkyl, -OC 1 ~C 6 Alkyl, -OC 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Hydroxyl alkyl, -OC 1 ~C 6 In some embodiments of the compounds of Formula (I), (Ia)-(Ig), or (II), -OR a is -O-heterocycloalkyl, where heterocycloalkyl is a 5- or 6-membered ring. In some embodiments of the compound of Formula (I), (Ia)-(Ig), or (II), -OR a is [ka] In some embodiments of the compounds of Formula (I), (Ia)-(Ig), or (II), -OR a Ha-OC 1 ~C 6 In some embodiments of the compounds of Formula (I), (Ia)-(Ig), or (II), -OR a Ha-OC 1 ~C 6 In some embodiments of the compounds of Formula (I), (Ia)-(Ig), or (II), -ORa Ha-OC 1 ~C 6 In some embodiments of the compounds of Formula (I), (Ia)-(Ig), or (II), -OR a Ha-OC 1 ~C 6 It is an aminoalkyl.

[0062] In some embodiments of the compound of Formula (I), (Ia) or (II), n is 0 to 3. In some embodiments of the compound of Formula (I), (Ia) or (II), n is 0 to 2. In some embodiments of the compound of Formula (I), (Ia) or (II), n is 0 or 1. In some embodiments of the compound of Formula (I), (Ia) or (II), n is 0. In some embodiments of the compound of Formula (I), (Ia) or (II), n is 1. In some embodiments of the compound of Formula (I), (Ia) or (II), n is 2.

[0063] In some embodiments of the compounds of Formula (Ib)-(Ie), n' is 0 to 2. In some embodiments of the compounds of Formula (Ib)-(Ie), n' is 0 or 1. In some embodiments of the compounds of Formula (Ib)-(Ie), n' is 0. In some embodiments of the compounds of Formula (Ib)-(Ie), n' is 1. In some embodiments of the compounds of Formula (Ib)-(Ie), n' is 2.

[0064] In some embodiments of the compound of Formula (If) or (Ig), n" is 0 or 1. In some embodiments of the compound of Formula (If) or (Ig), n" is 0. In some embodiments of the compound of Formula (If) or (Ig), n" is 1. In some embodiments of the compound of Formula (If) or (Ig), n" is 2.

[0065] Disclosed herein is a compound of formula (A): [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony: R 1a is halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; W is N or CR 1b and; Each R 1b are independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; R 2 is hydrogen, C 1 ~C 6 Alkyl, C1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; U is N or CR U and; R U is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Ring B is heterocycloalkyl; Each R 3 are independently halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; or two R on the same atom 3 come together to form oxo; or two R on the same or different carbons 3 taken together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; m is 0 to 6; X is N or CR X and; R X is hydrogen, halogen, -CN, -OH, -ORa , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Y is N or CR Y and; R Y is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Z is N or CR Z and; R Z is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; R 5 is hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NRc R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, [ka] , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; R 4 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally selected from one or more R 4a Replaced with; Each R 4a are independently halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; or two R on the same atom 4a come together to form oxo; Each R a is independent, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or two R's a together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R b are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; Or two R's b together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R c and R d are each independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R; or R c and R dtogether with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently halogen, -CN, -OH, -S(=O)CH 3 , -S(=O) 2 CH 3 , -S(=O) 2 NH 2 , -S(=O) 2 NHCH 3 , -S(=O) 2 N(CH 3 ) 2 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl or C 3 ~C 6 is cycloalkyl; Or two R on the same atom form an oxo.

[0066] In some embodiments of the compounds of Formula (A), R 1a is halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 In some embodiments of the compounds of formula (A), R 1a is halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of formula (A), R 1a is halogen, -CN, C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of formula (A), R 1a are independently halogen, -CN, -OR a , or -NR c R d In some embodiments of the compound of Formula (A), R 1a -CN or -OR a In some embodiments of the compound of Formula (A), R 1a is -CN, -O-heterocycloalkyl, -OC 1 ~C 6 Alkyl, -OC 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Hydroxyl alkyl or -OC 1 ~C 6 In some embodiments of the compounds of Formula (A), R 1a is -CN, -O-heterocycloalkyl, -OC 1 ~C 3 Alkyl, -OC 1 ~C 3 Haloalkyl, -OC 1 ~C 3 Hydroxyl alkyl or -OC 1 ~C3 In some embodiments of the compounds of Formula (A), R 1a are independently -CN or -NR c R d In some embodiments of the compound of Formula (A), -OR a is -O-heterocycloalkyl, -OC 1 ~C 6 Alkyl, -OC 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Hydroxyl alkyl or -OC 1 ~C 6 In some embodiments of the compounds of formula (A), -OR a is -O-heterocycloalkyl, where heterocycloalkyl is a 5 or 6 membered ring. In some embodiments of the compound of Formula (A), -OR a is [ka] In some embodiments of the compound of formula (Aa), -OR a Ha-OC 1 ~C 6 In some embodiments of the compounds of formula (A), -OR a Ha-OC 1 ~C 6 In some embodiments of the compounds of formula (A), -OR a Ha-OC 1 ~C 6 In some embodiments of the compounds of formula (A), -OR a Ha-OC 1 ~C 3 In some embodiments of the compounds of formula (A), -OR a -O-CH 2 CH 2 In some embodiments of the compound of formula (A), -OR a Ha-OC 1 ~C 6 It is an aminoalkyl.

[0067] In some embodiments of the compounds of Formula (A), R 1a -OR a , -NR c R d or heterocycloalkyl. In some embodiments of the compounds of Formula (A), R 1a -OR a In some embodiments of the compound of Formula (A), R 1a is -O-heterocycloalkyl, -OC 1 ~C 6 Hydroxyl alkyl, -NH-C 1 ~C 6 Hydroxyl alkyl or -OC 1 ~C 6 In some embodiments of the compounds of Formula (A), R 1a is -O-heterocycloalkyl, -OC 1 ~C 6 Hydroxyl alkyl or -OC 1 ~C 6 In some embodiments of the compounds of Formula (A), R 1a is -O-heterocycloalkyl. In some embodiments of the compounds of Formula (A), R 1a is -O-5 to 6 membered heterocycloalkyl. In some embodiments of the compound of Formula (A), R 1a Ha-OC 1 ~C 6 In some embodiments of the compounds of Formula (A), R 1a Ha-OC 1 ~C 3 In some embodiments of the compounds of Formula (A), R 1a -O-CH 2 CH 2 In some embodiments of the compounds of formula (A), R 1a Ha-OC 1 ~C 6 It is an aminoalkyl.

[0068] In some embodiments of the compound of Formula (A), W is N. In some embodiments of the compound of Formula (A), W is CR 1b It is.

[0069] In some embodiments of the compound of Formula (A), each R 1b are independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 In some embodiments of the compounds of Formula (A), each R 1b are independently hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl or C 1 ~C 6 In some embodiments of the compound of Formula (A), each R 1b is independently hydrogen, halogen, or -CN. In some embodiments of the compound of Formula (A), each R 1b is independently hydrogen or halogen. In some embodiments of the compound of Formula (A), each R 1b are independently hydrogen or -CN.

[0070] In some embodiments of the compound of Formula (A) or a pharma- ceutically acceptable salt thereof, the compound is a compound of Formula (Aa): [ka] It is.

[0071] In some embodiments of the compound of Formula (A) or a pharma- ceutically acceptable salt thereof, the compound is a compound of Formula (Ab): [ka] It is.

[0072] In some embodiments of the compound of Formula (A) or a pharma- ceutically acceptable salt thereof, the compound is a compound of Formula (Ac): [ka] It is.

[0073] In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a is halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a is halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a is halogen, -CN, C 1 ~C 6 Alkyl or C1 ~C 6 In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a are independently halogen, -CN, -OR a , or -NR c R d In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a -CN or -OR a In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a is -CN, -O-heterocycloalkyl, -OC 1 ~C 6 Alkyl, -OC 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Hydroxyl alkyl or -OC 1 ~C 6 In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a is -CN, -O-heterocycloalkyl, -OC 1 ~C 3 Alkyl, -OC 1 ~C 3 Haloalkyl, -OC 1 ~C 3 Hydroxyl alkyl or -OC 1 ~C 3 In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a are independently -CN or -NR c R d In some embodiments of the compound of formula (Aa), (Ab), or (Ac), -OR a is -O-heterocycloalkyl, -OC 1 ~C 6 Alkyl, -OC 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Hydroxyl alkyl or -OC 1 ~C 6In some embodiments of the compound of formula (Aa), (Ab), or (Ac), -OR a is -O-heterocycloalkyl, where heterocycloalkyl is a 5- or 6-membered ring. In some embodiments of the compound of formula (Aa), (Ab), or (Ac), -OR a is [ka] In some embodiments of the compound of formula (Aa), (Ab), or (Ac), -OR a Ha-OC 1 ~C 6 In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), -OR a Ha-OC 1 ~C 6 In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), -OR a Ha-OC 1 ~C 6 In some embodiments of the compound of formula (Aa), (Ab), or (Ac), -OR a Ha-OC 1 ~C 6 It is an aminoalkyl.

[0074] In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a -OR a , -NR c R d In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a -OR a In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a is -O-heterocycloalkyl, -OC 1 ~C 6 Hydroxyl alkyl, -NH-C 1 ~C 6 Hydroxyl alkyl or -OC 1 ~C6 In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a is -O-heterocycloalkyl, -OC 1 ~C 6 Hydroxyl alkyl or -OC 1 ~C 6 In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a is -O-heterocycloalkyl. In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a Ha-OC 1 ~C 6 In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a Ha-OC 1 ~C 3 In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a -O-CH 2 CH 2 In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a Ha-OC 1 ~C 6 It is an aminoalkyl.

[0075] In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl or C 1 ~C 6 In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b is halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl or C 1 ~C 6 In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b is hydrogen, halogen, or -CN. In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b is halogen or -CN. In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b is hydrogen or -CN. In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b is hydrogen or halogen. In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b is halogen. In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b is Cl.

[0076] In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b is halogen, -CN, -OH, -OR a , -NRc R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b is halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b is halogen, -CN, C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of formula (Aa), R 1b is halogen or -CN. In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b is halogen. In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b is fluoro or chloro. In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b are independently halogen, -CN, -OR a , or -NR c R dIn some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b -CN or -OR a In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b is -CN, -O-heterocycloalkyl, -OC 1 ~C 6 Alkyl, -OC 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Hydroxyl alkyl or -OC 1 ~C 6 In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b is -CN, -O-heterocycloalkyl, -OC 1 ~C 3 Alkyl, -OC 1 ~C 3 Haloalkyl, -OC 1 ~C 3 Hydroxyl alkyl or -OC 1 ~C 3 In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1b are independently -CN or -NR c R d In some embodiments of the compound of formula (Aa), (Ab), or (Ac), -OR a is -O-heterocycloalkyl, -OC 1 ~C 6 Alkyl, -OC 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Hydroxyl alkyl or -OC 1 ~C 6 In some embodiments of the compound of formula (Aa), (Ab), or (Ac), -OR a is -O-heterocycloalkyl, where heterocycloalkyl is a 5- or 6-membered ring. In some embodiments of the compound of formula (Aa), (Ab), or (Ac), -ORa is [ka] In some embodiments of the compound of formula (Aa), (Ab), or (Ac), -OR a Ha-OC 1 ~C 6 In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), -OR a Ha-OC 1 ~C 6 In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), -OR a Ha-OC 1 ~C 6 In some embodiments of the compound of formula (Aa), (Ab), or (Ac), -OR a Ha-OC 1 ~C 6 It is an aminoalkyl.

[0077] In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a Ha-OC 1 ~C 6 hydroxylalkyl, R 1b In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a Ha-OC 1 ~C 3 hydroxylalkyl, R 1b In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a -O-CH 2 CH 2 OH and R 1b is CN.

[0078] In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a Ha-OC 1 ~C 6 hydroxylalkyl, R 1bis halogen. In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a Ha-OC 1 ~C 3 hydroxylalkyl, R 1b is halogen. In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a -O-CH 2 CH 2 OH and R 1b is a halogen.

[0079] In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a Ha-OC 1 ~C 6 hydroxylalkyl, R 1b In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a Ha-OC 1 ~C 3 hydroxylalkyl, R 1b In some embodiments of the compounds of formula (Aa), (Ab), or (Ac), R 1a -O-CH 2 CH 2 OH and R 1b is chloro.

[0080] In some embodiments of the compounds of Formula (A), (Aa), (Ab), or (Ac), R 5 is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6Aminoalkyl, C 1 ~C 6 Heteroalkyl, [ka] , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R.

[0081] In some embodiments of the compounds of Formula (A), (Aa), (Ab), or (Ac), R 5 is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, [ka] , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R.

[0082] In some embodiments of the compounds of Formula (A), (Aa), (Ab), or (Ac), R 5 is hydrogen, halogen, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, [ka] , cycloalkyl, or heterocycloalkyl; each of the alkyl, cycloalkyl, and heterocycloalkyl is optionally independently substituted with one or more R.

[0083] In some embodiments of the compounds of Formula (A), (Aa), (Ab), or (Ac), R 5 is hydrogen, -OR a , C 1 ~C 6 Alkyl, [ka] , 3- to 6-membered cycloalkyl, or 5- to 6-membered heterocycloalkyl; each of the alkyl, cycloalkyl, and heterocycloalkyl is optionally independently substituted with one or more R.

[0084] In some embodiments of the compounds of Formula (A), (Aa), (Ab), or (Ac), R 5 is hydrogen.

[0085] In some embodiments of the compounds of Formula (A), (Aa), (Ab), or (Ac), R 5 -OR a In some embodiments of the compound of Formula (A), (Aa), (Ab), or (Ac), R 5 Ha-OC 1 ~C 6 In some embodiments of the compound of Formula (A), (Aa), (Ab), or (Ac), R 5 Ha-OC 1 ~C 6 In some embodiments of the compounds of Formula (A), (Aa), (Ab), or (Ac), R 5 is -O-cycloalkyl. In some embodiments of the compounds of Formula (A), (Aa), (Ab), or (Ac), R 5is -O-cycloalkyl, where cycloalkyl is a 3-6 membered ring and is optionally substituted with one or more R. In some embodiments of a compound of Formula (A), (Aa), (Ab), or (Ac), R 5 is -O-heterocycloalkyl, where heterocycloalkyl is a 5-6 membered ring and is optionally substituted with one or more R.

[0086] In some embodiments of the compounds of Formula (A), (Aa), (Ab), or (Ac), R 5 is C 1 ~C 6 It is an alkyl.

[0087] In some embodiments of the compounds of Formula (A), (Aa), (Ab), or (Ac), R 5 is [ka] It is.

[0088] In some embodiments of the compounds of Formula (A), (Aa), (Ab), or (Ac), R 5 is a 3- to 6-membered cycloalkyl or a 5- to 6-membered heterocycloalkyl; each cycloalkyl and heterocycloalkyl is optionally independently substituted with one or more R.

[0089] In some embodiments of the compounds of Formula (A), (Aa), (Ab), (Ac)(I), (Ia)-(Ig), or (II), R 2 is hydrogen or C 1 ~C 6 In some embodiments of the compounds of Formula (A), (Aa), (Ab), (Ac)(I), (Ia)-(Ig), or (II), R 2 is C 1 ~C 6 In some embodiments of the compounds of Formula (A), (Aa), (Ab), (Ac)(I), (Ia)-(Ig), or (II), R 2 is C 1 ~C 3In some embodiments of the compounds of Formula (A), (Aa), (Ab), (Ac)(I), (Ia)-(Ig), or (II), R 2 is methyl.

[0090] In some embodiments of the compound of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), U is N. In some embodiments of the compound of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), U is CR U It is.

[0091] In some embodiments of the compounds of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), R U is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 In some embodiments of the compounds of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), R U is hydrogen, halogen, -CN, -C(=O)NR c R d , C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), R U is hydrogen, -CN, or -C(=O)NR cR d In some embodiments of the compounds of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), R U In some embodiments of the compounds of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), R U In some embodiments of the compound of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), R U is hydrogen.

[0092] In some embodiments of a compound of Formula (I), (II), (A), (Aa), or (Ab), [ka] It is.

[0093] In some embodiments of the compound of Formula (I), (II), (A), (Aa) or (Ab), [ka] It is.

[0094] In some embodiments of the compound of Formula (I), (II), (A), (Aa) or (Ab), [ka] It is.

[0095] In some embodiments of the compound of Formula (I), (II), (A), (Aa) or (Ab), [ka] It is.

[0096] In some embodiments of the compound of Formula (I), (II), (A), (Aa) or (Ab), [ka] In some embodiments of the compound of Formula (I), (II), (A), (Aa) or (Ab), [ka] In some embodiments of the compound of Formula (I), (II), (A), (Aa) or (Ab), [ka] In some embodiments of the compound of Formula (I), (II), (A), (Aa) or (Ab), [ka] In some embodiments of the compound of Formula (I), (II), (A), (Aa) or (Ab), [ka] In some embodiments of the compound of Formula (I), (II), (A), (Aa), or (Ab), [ka] It is.

[0097] In some embodiments of a compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), ring B is a 6-8 membered heterocycloalkyl. In some embodiments of a compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), ring B is a 6-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O, N, and S. In some embodiments of a compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), ring B is a 6-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O and N.

[0098] In some embodiments of a compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), ring B is a 6-7 membered heterocycloalkyl. In some embodiments of a compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), ring B is a 6-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O, N, and S. In some embodiments of a compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), ring B is a 6-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O and N.

[0099] In some embodiments of a compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), Ring B is a 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), Ring B is a 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O, N, and S. In some embodiments of a compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), Ring B is a 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O and N.

[0100] In some embodiments of a compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), Ring B is a 7-membered heterocycloalkyl. In some embodiments of a compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), Ring B is a 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O, N, and S. In some embodiments of a compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), Ring B is a 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O and N.

[0101] In some embodiments of a compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), [ka] In some embodiments of a compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), [ka] It is.

[0102] In some embodiments of the compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), each R 3 are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 In some embodiments of the compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), each R 3 are independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), each R 3 is independent, C 1 ~C 6 Alkyl or C 1 ~C 6 It is haloalkyl.

[0103] In some embodiments of the compounds of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), m is 0-6. In some embodiments of the compounds of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), m is 0-5. In some embodiments of the compounds of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), m is 0-4. In some embodiments of the compounds of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), m is 0-3. In some embodiments of the compounds of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), m is 0-2. In some embodiments of the compounds of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), m is 0 or 1. In some embodiments of the compounds of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), m is 1-6. In some embodiments of the compounds of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), m is 1-5. In some embodiments of the compounds of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), m is 1-4. In some embodiments of the compounds of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), m is 1-3. In some embodiments of the compounds of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), m is 1 or 2. In some embodiments of the compounds of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), m is 0. In some embodiments of the compounds of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), m is 1. In some embodiments of the compounds of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), m is 2. In some embodiments of the compounds of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), m is 3. In some embodiments of the compounds of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), m is 4. In some embodiments of the compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), m is 5. In some embodiments of the compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), m is 6.In some embodiments of the compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), m is 7. In some embodiments of the compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), m is 5-8.

[0104] In some embodiments of a compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), [ka] It is.

[0105] In some embodiments of the compound of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), X is N. In some embodiments of the compound of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), X is CR X It is.

[0106] In some embodiments of the compounds of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), R X is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 In some embodiments of the compounds of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), R X is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl or C 1 ~C 6In some embodiments of the compounds of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), R X is hydrogen, halogen, or C 1 ~C 6 In some embodiments of the compounds of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), R X is hydrogen.

[0107] In some embodiments of the compound of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), Y is N. In some embodiments of the compound of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), Y is CR Y It is.

[0108] In some embodiments of the compounds of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), R Y is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 In some embodiments of the compounds of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), R Y is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), R Y is hydrogen, halogen, or C 1 ~C6 In some embodiments of the compounds of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), R Y is hydrogen.

[0109] In some embodiments of the compound of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), Z is N. In some embodiments of the compound of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), Z is CR Z It is.

[0110] In some embodiments of the compounds of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), R Z is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 In some embodiments of the compounds of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), R Z is hydrogen, halogen, -CN, C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), R Z is hydrogen, halogen, or C 1 ~C 6 In some embodiments of the compounds of Formula (A), (Aa), (Ab), (I), (Ia)-(Ig), or (II), R Z is hydrogen.

[0111] In some embodiments of a compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), [ka] In some embodiments of a compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), [ka] In some embodiments of a compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), [ka] In some embodiments of a compound of Formula (A), (Aa), (I), (Ia)-(Ig), or (II), [ka] It is.

[0112] In some embodiments of the compound of Formula (A), (Aa), (Ab), (Ac), (I), (Ia)-(Ig), or (II), R 4 is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally selected from one or more R 4a In some embodiments of the compounds of Formula (A), (Aa), (Ab), (Ac), (I), (Ia)-(Ig), or (II), R 4 is cycloalkyl or heterocycloalkyl; cycloalkyl and heterocycloalkyl are optionally represented by one or more R 4a In some embodiments of the compounds of Formula (A), (Aa), (Ab), (Ac), (I), (Ia)-(Ig), or (II), R 4 is optionally one or more R 4aIn some embodiments of the compounds of Formula (A), (Aa), (Ab), (Ac), (I), (Ia)-(Ig), or (II), R 4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; each optionally being represented by one or more R 4a In some embodiments of the compounds of Formula (A), (Aa), (Ab), (Ac), (I), (Ia)-(Ig), or (II), R 4 is optionally one or more R 4a In some embodiments of the compounds of Formula (A), (Aa), (Ab), (Ac), (I), (Ia)-(Ig), or (II), R 4 is [ka] In some embodiments of the compound of Formula (A), (Aa), (Ab), (Ac), (I), (Ia)-(Ig), or (II), R 4 is [ka] In some embodiments of the compound of Formula (A), (Aa), (Ab), (Ac), (I), (Ia)-(Ig), or (II), R 4 is hydrogen. In some embodiments of the compounds of Formula (A), (Aa), (Ab), (Ac), (I), (Ia)-(Ig), or (II), R 4 is hydrogen or C 1 ~C 6 It is an alkyl.

[0113] In some embodiments of the compound of Formula (A), (Aa), (Ab), (Ac), (I), (Ia)-(Ig), or (II), R 4 is C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C1 ~C 6 Aminoalkyl, C 1 ~C 6 heteroalkyl, 3- to 6-membered cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally selected from one or more R 4a is replaced by.

[0114] In some embodiments of a compound of Formula (A), (Aa), (Ab), (Ac), (I), (Ia)-(Ig), or (II), each R 4a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; each of the alkyl, alkylene, cycloalkyl, and heterocycloalkyl is optionally independently substituted with one or more R.

[0115] In some embodiments of a compound of Formula (A), (Aa), (Ab), (Ac), (I), (Ia)-(Ig), or (II), each R 4a are independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 ~C6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 heteroalkyl, 3- to 6-membered cycloalkyl, or 5- to 6-membered heterocycloalkyl; each of the alkyl, cycloalkyl, and heterocycloalkyl is optionally independently substituted with one or more R.

[0116] In some embodiments of a compound of Formula (A), (Aa), (Ab), (Ac), (I), (Ia)-(Ig), or (II), each R 4a are independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl or C 1 ~C 6 haloalkyl; each alkyl is optionally independently substituted with one or more R. In some embodiments of a compound of Formula (A), (Aa), (Ab), (Ac), (I), (Ia)-(Ig), or (II), each R 4a are independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl or C 1 ~C 6 It is haloalkyl.

[0117] In some embodiments of a compound of Formula (A), (Aa), (Ab), (Ac), (I), (Ia)-(Ig), or (II), each R 4a is independent, C 1 ~C 6 Alkyl or C 1 ~C 6In some embodiments of a compound of Formula (A), (Aa), (Ab), (Ac), (I), (Ia)-(Ig), or (II), each R 4a is independent, C 1 ~C 6 In some embodiments of a compound of Formula (A), (Aa), (Ab), (Ac), (I), (Ia)-(Ig), or (II), each R 4a is independent, C 1 ~C 3 In some embodiments of a compound of Formula (A), (Aa), (Ab), (Ac), (I), (Ia)-(Ig), or (II), each R 4a is independent, CF 3 It is.

[0118] In some embodiments of the compounds disclosed herein, each R a is independent, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene (heteroaryl); each of the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independent, C 1 ~C 6 Alkyl, C 1 ~C6 haloalkyl, cycloalkyl, or heterocycloalkyl; each of the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independent, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 In some embodiments of the compounds disclosed herein, each R a is independent, C 1 ~C 6 Alkyl, C 1 ~C 6 In some embodiments of the compounds disclosed herein, each R a is independent, C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds disclosed herein, each R a is independent, C 1 ~C 6 It is an alkyl.

[0119] In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C 1 ~C 6 Alkyl, C1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene (heteroaryl); each of the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 haloalkyl, cycloalkyl, or heterocycloalkyl; each of the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1~C 6 Alkylene (aryl), or C 1 ~C 6 In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds disclosed herein, each R b are independently hydrogen or C 1 ~C 6 In some embodiments of the compounds disclosed herein, each R b is hydrogen. In some embodiments of the compounds disclosed herein, each R b is independent, C 1 ~C 6 It is an alkyl.

[0120] In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6Alkylene (aryl), or C 1 ~C 6 alkylene (heteroaryl); each of the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 haloalkyl, cycloalkyl, or heterocycloalkyl; each of the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds disclosed herein, R c and R d Each independently represents hydrogen or C 1 ~C 6 In some embodiments of the compounds disclosed herein, R c and R d Each is hydrogen. In some embodiments of the compounds disclosed herein, R c and R d are each independently 1 ~C 6 It is an alkyl.

[0121] In some embodiments of the compounds disclosed herein, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R.

[0122] In some embodiments of the compounds disclosed herein, each R is independently selected from halogen, —CN, —OH, —NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C6 Heteroalkyl or C 3 ~C 6 or two R on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently selected from halogen, -CN, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl or C 3 ~C 6 or two R on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently selected from halogen, -CN, -OH, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy or C 1 ~C 6 or two R on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, or C 1 ~C 6 or two R on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -OH, or C 1 ~C 6 In some embodiments of the compounds disclosed herein, each R is independently halogen or C 1 ~C 6 In some embodiments of the compounds disclosed herein, each R is independently halogen.

[0123] In some embodiments of the compounds disclosed herein, R, R 1 , R 2 , R 3 , R 4 , R 4a , R 5 , R X , R Y , R Z , R a , R b , R c , and R d One or more of the groups contains deuterium at a percentage higher than the natural abundance of deuterium.

[0124] In some embodiments of the compounds disclosed herein, one or more 1 H is one of the following groups: R, R 1 , R 2 , R 3 , R 4 , R 4a , R 5 , R X , R Y , R Z , R a , R b , R c , and R d is substituted with one or more deuterium atoms.

[0125] In some embodiments of the compounds disclosed herein, R, R 1 , R 2 , R 3 , R 4 , R 4a , R 5 , R X , R Y , R Z , R a , R b , R c , and R d The abundance of deuterium in each of is independently, on a molar basis, at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%.

[0126] In some embodiments of the compounds disclosed herein, one or more of rings A or B may be 1 H is replaced by one or more deuterium atoms.

[0127] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0128] In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is one of the compounds in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

[0129] In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is one of the compounds in Table 2. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0130] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as the corresponding mixtures thereof. In some cases, the compounds described herein have one or more chiral centers, each center being present in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as the corresponding mixtures thereof. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers resulting from a single preparation step, combination, or interchange are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomers are then recovered, along with the resolving agent, by any practical means that will not cause racemization.

[0131] isotopically enriched compounds Unless otherwise stated, the compounds described herein may exhibit natural isotopic abundance or may be artificially enriched in one or more atoms with a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes: 1 H (protium), 2 H (deuterium), and 3 H (tritium). Protium is the most abundant natural isotope of hydrogen. Enrichment with deuterium may provide several therapeutic advantages, such as increased in vivo half-life and / or exposure, or may yield compounds useful for investigating in vivo pathways of drug excretion and metabolism.

[0132] For example, the compounds described herein may be artificially enriched in one or more particular isotopes. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes that are not predominantly found in nature. In some embodiments, the compounds described herein may be artificially enriched in deuterium ( 2 H), tritium ( 3 H), Iodine-125( 125 I) and carbon-14 ( 14 C). In some embodiments, the compounds described herein may be artificially enriched with one or more isotopes selected from: 2 H, 11 C. 13 C. 14 C. 15 C. 12 N, 13 N, 15 N, 16 N, 16 O. 17 O. 14 F, 15 F, 16 F, 17 F, 18 F,33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 131 I, and 125 I. In some embodiments, the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%, by molar.

[0133] In some embodiments, the compounds are deuterated at at least one position. 1 Some or all of the H atoms 2 It is replaced by H atoms.

[0134] Methods for the synthesis of deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the procedures described in US Pat. Nos. 5,846,514 and 6,334,997, as well as the following synthetic methods. For example, deuterium substituted compounds can be synthesized using a variety of methods, such as those described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0135] Deuterated starting materials are readily available and are subject to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Many deuterium-containing reagents and building blocks are commercially available from chemical vendors such as Aldrich Chemical Co.

[0136] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0137] In some embodiments, the compounds described herein possess acidic or basic groups and thus react with any of a number of inorganic or organic bases, as well as inorganic and organic acids, to form pharma- ceutically acceptable salts, which in some embodiments are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting the purified compounds in free form with a suitable acid or base and isolating the salt thus formed.

[0138] Examples of pharma- ceutically acceptable salts include salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrophosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, Hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methyl benzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0139] Additionally, the compounds described herein can be prepared by dissolving the free base form of the compounds in various forms with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, and the like. , benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and other organic acids. In some embodiments, other acids, such as oxalic acid, are used in the preparation of salts that are not themselves pharma- ceutically acceptable but are useful as intermediates in obtaining the compounds disclosed herein and their pharma-ceutically acceptable acid addition salts.

[0140] In some embodiments, those compounds described herein that contain free acid groups are reacted with a suitable base, such as a pharma- ceutically acceptable metal cation hydroxide, carbonate, bicarbonate, sulfate, ammonia, or a pharma- ceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Exemplary salts include lithium, alkali or alkaline earth salts, such as sodium, potassium, calcium, magnesium, and aluminum salts. Illustrative bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1~4 Alkyl) 4 etc.

[0141] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It is to be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.

[0142] Tautomers In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can be interconverted by the migration of a hydrogen atom accompanied by the interchange of a single bond with an adjacent double bond. In bond configurations that allow tautomerization, chemical equilibrium of tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0143] Treatment methods Disclosed herein is a method of treating a disease modulated by DGK in a subject in need of such treatment, the method comprising administering to the subject a therapeutically affective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0144] Disclosed herein is a method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disease is cancer.

[0145] Disclosed herein is a method of treating a disease modulated by DGKα in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharma- ceutically acceptable salt thereof. In some embodiments, the disease is cancer or a viral infection.

[0146] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is breast cancer, cervical cancer, colon cancer, head and neck cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, thyroid cancer, or urinary tract cancer.

[0147] In some embodiments, the viral infection is an HIV infection, a hepatitis B virus infection, a hepatitis C virus infection, a human papillomavirus infection, a cytomegalovirus infection, a herpes simplex virus infection, an Epstein-Barr virus infection, or a varicella-zoster virus infection.

[0148] Disclosed herein is a method of inhibiting the activity of at least one diacylglycerol kinase, comprising administering to a subject a therapeutically effective amount of a compound disclosed herein or a pharma- ceutically acceptable salt thereof. In some embodiments, the diacylglycerol kinase is diacylglycerol kinase alpha (DGKα). In some embodiments, the diacylglycerol kinase is diacylglycerol kinase zeta (DGKζ). Disclosed herein is a method of modulating the activity of at least one diacylglycerol kinase selected from diacylglycerol kinase alpha (DGKα) and diacylglycerol kinase zeta (DGKζ) in a subject in need thereof, comprising administering to the subject a compound disclosed herein or a pharma- ceutically acceptable salt thereof. Disclosed herein is a method of modulating the activity of diacylglycerol kinase alpha (DGKα) in a subject in need thereof, comprising administering to the subject a compound disclosed herein or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject has a disease described herein. In some embodiments, the subject has cancer.

[0149] dosage In certain embodiments, compositions containing the compound(s) described herein are administered for therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially halt at least one symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight and response to drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose ranging trials.

[0150] In certain embodiments where the patient's condition does not improve, administration of the compound is administered chronically, i.e., for an extended period of time, including the entire lifespan of the patient, at the physician's discretion, to ameliorate or otherwise control or suppress the symptoms of the patient's disease or condition.

[0151] Once the patient's condition has improved, a maintenance dose is administered if necessary, after which, in certain embodiments, the dosage, or frequency of administration, or both, are reduced, depending on symptoms.

[0152] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the unique characteristics of the subject or host requiring treatment (e.g., weight, sex), but will nevertheless be determined by 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.

[0153] In some embodiments, dosages employed for adult human treatment typically range from 0.01 mg to 5000 mg per day. In some embodiments, suitable daily dosages for the compounds described herein or pharma- ceutically acceptable salts thereof are from about 0.01 to about 50 mg per kg of body weight. In various embodiments, daily dosages and unit doses will vary depending on many 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 judgement of the practitioner.

[0154] Route of Administration Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, intravaginal, intraaural, nasal, and topical administration.Further, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal injection, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0155] In certain embodiments, the compounds described herein are administered locally rather than systemically, for example, via injection of the compound directly into an organ, often in a depot or sustained release formulation. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, they are delivered in targeted drug delivery systems, for example, liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted to and selectively taken up by the organ. In still other embodiments, the compounds described herein are provided in the form of a fast release formulation, a sustained release formulation, or an intermediate release formulation.

[0156] Pharmaceutical Compositions / Formulations The compounds described herein are administered to a subject in need thereof, either alone or in combination with a pharma- ceutical acceptable carrier, excipient, or diluent, as a pharmaceutical composition, in accordance with standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0157] In another aspect, provided herein is a pharmaceutical composition comprising the compound described herein or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient.The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of active compound into pharmaceutically usable preparations.The choice of route of administration determines the appropriate formulation. Summary summaries of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosures.

[0158] In some embodiments, the pharma- ceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrants, dispersing agents, surfactants, lubricants, coloring agents, diluents, solubilizing agents, moistening agents, plasticizers, stabilizers, permeation enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, and any combination thereof.

[0159] Pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, solutions, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, oral solid dosage forms, powders, immediate release formulations, controlled release formulations, fast dissolve formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and combined immediate and controlled release formulations.

[0160] combination Disclosed herein are methods of treating diseases or disorders associated with DGKα using a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, in combination with an additional therapeutic agent.

[0161] In some embodiments, the additional therapeutic agent is administered simultaneously with the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior to administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound disclosed herein.

[0162] In some embodiments, the additional therapeutic agent is an anti-cancer agent. In some embodiments, the anti-cancer agent is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is an anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4) antibody, an anti-PD-1 (programmed cell death receptor 1) antibody, or an anti-PD-L1 (death ligand 1) antibody.

[0163] In some embodiments, the additional therapeutic agent is an antiviral agent. EXAMPLES

[0164] Example 1: 6-Chloro-1-methyl-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-1,5-naphthyridin-2(1H)-one [ka] [ka] A mixture of compound 1-1 (10 g, 60.18 mmol) in THF (100 mL) was added to AcOEt at room temperature. 2 O (55.29 g, 541.58 mmol) was added. The reaction mixture was cooled to 4° C. 2 The mixture was stirred at 60° C. for 18 h under reduced pressure. After cooling to room temperature, the mixture was concentrated under reduced pressure. Petroleum ether (500 mL) was added to the resulting residue and the suspension was stirred at 20° C. for 30 min. The mixture was filtered and the filter cake was washed with petroleum ether (500 mL). The filter cake was collected and dried under vacuum to give compound 1-2. LCMS: MS (ESI) m / z (M+H) + =209.0

[0165] To a mixture of compound 1-2 (10.7 g, 51.39 mmol) and cesium carbonate (25.11 g, 77.08 mmol) in DMF (200 mL) was added methyl iodide (10.94 g, 77.08 mmol) at 20° C. The mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water (500 mL) and extracted with DCM (3×200 mL). The combined organic layers were washed with brine (2×100 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. Petroleum ether (500 mL) was added to the resulting residue and the suspension was stirred at 20° C. for 30 min. The mixture was filtered and the filter cake was washed with petroleum ether (500 mL). The filter cake was collected and dried under reduced pressure to give compound 1-3. LCMS: MS (ESI) m / z (M+H) + = 223.1

[0166] To a mixture of compound 1-3 (4 g, 18.00 mmol) in DCM (200 mL) at 0-5 °C, urea hydrogen peroxide (2.54 g, 27.0 mmol) was added followed by the slow addition of trifluoroacetic anhydride (5.67 g, 27.00 mmol) over 40 min. The reaction mixture solidified during the addition of trifluoroacetic anhydride. After the addition was complete, the reaction mixture was stirred at 20 °C for 18 h. The reaction mixture was diluted with 10% NaHCO 3 The mixture was quenched with 100 mL of DCM and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (2×100 mL) and diluted with Na 2 SO 4 and concentrated under reduced pressure to give compound 1-4, which was used in the next step without further purification. LCMS: MS(ESI) m / z(M+H) + = 239.1

[0167] POCl 3 A mixture of 1-4 (2 g, 8.40 mmol) in (15 mL) was stirred at 65° C. for 2 h. The mixture was concentrated under reduced pressure. The residue was diluted with DCM (50 mL) and saturated NaHCO 3 The pH was adjusted to 8.0 with solution. The mixture was extracted with DCM (3×50 mL). The combined organic layers were washed with Na 2 SO4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography to give 1-5, which was confirmed by LCMS: MS m / z (ESI) [M+H] + = 257.2

[0168] A mixture of KHMDS (1M in THF) (6.68 mL, 6.68 mmol) in THF (100 mL) at -78 °C was 2 A solution of 1-5 (1.4 g, 4.45 mmol) in THF (10 mL) was added under reduced pressure. After the addition, the mixture was slowly warmed to 15° C. and stirred at that temperature for 2 h. The mixture was adjusted to pH=6.0 with 1N HCl. The mixture was evaporated to give the crude product, which was purified by flash column chromatography to give 1-6, which was confirmed by LCMS: MS m / z (ESI) [M+H] + = 211.2

[0169] POCl 3 A mixture of 1-6 (680 mg, 2.502 mmol) in (20 mL) was stirred at 100° C. for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with DCM (50 mL) and saturated NaHCO 3 The pH was adjusted to 8.0 with a solution of 100 ml of DCM. The resulting mixture was extracted with DCM (3×50 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography to give 1-7, which was confirmed by LCMS: MS m / z (ESI) [M+H] + = 229.1

[0170] To a mixture of 1-11 (8.0 g, 37.03 mmol) in anhydrous THF (200 mL) at 0° C. was added lithium aluminum hydride (51.8 mL, 1.0 M in THF) dropwise. After the addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with water (30 mL) followed by 15% NaOH solution (7.7 mL). The mixture was stirred for an additional hour and filtered. The filtrate was concentrated to give 1-12, which was confirmed by LCMS: LCMS:MS m / z (ESI) [M-17] + = 183.9

[0171] To a mixture of chloroacetyl chloride (3.07 g, 27.22 mmol) in dry DCM (200 mL) was added 1-12 (5.0 g, 24.75 mmol) at room temperature, followed by diisopropylethylamine (9.59 g, 74.24 mmol). The mixture was stirred at ambient temperature for 18 h. The mixture was quenched with saturated sodium bicarbonate. The organic layer was separated and washed with saturated NaHCO 3 The organic phase was washed with MgSO 4 The mixture was dried at 4° C., filtered, and the filtrate was evaporated to give 1-13, which was confirmed by LCMS: LCMS: MS m / z (ESI) [M-17] + = 260.0. 1 H NMR (400 MHz, CDCl 3 )δ 9.76(s, 1H), 7.98(d, J = 8.1 Hz, 1H), 7.39(dd, J = 8.1, 0.9 Hz, 1H), 7.19(t, J = 8.1 Hz, 1H), 4.97(s, 2H), 4.20(s, 2H)

[0172] A suspension of sodium tert-butoxide (2.42 g, 25.20 mmol) in t-BuOH (80 mL) was heated at 80° C. until a clear solution was obtained. Then 1-13 (3.90 g, 14.00 mmol) was added in one portion and the reaction was stirred at 80° C. for 2 h. The reaction mixture was cooled, poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by flash column chromatography to give 1-14, which was confirmed by LCMS: LCMS: MS m / z (ESI) [M+H] + = 241.9

[0173] To a mixture of 1-14 (3.3 g, 13.63 mmol) in anhydrous THF (200 mL) at 0 °C, BH 3 -Me 2 S (20.4 mL, 2.0 M) was added slowly. The reaction was refluxed for 2 h. The mixture was cooled to 0° C. and slowly quenched with water (200 mL). The mixture was extracted with ethyl acetate and the organic layer was concentrated. The resulting residue was purified by silica gel column chromatography to give 1-8, which was confirmed by LCMS: LCMS: MS m / z (ESI) [M+H] + = 229.9

[0174] To a mixture of 1-8 (226.31 mg, 0.992 mmol) in THF (8 mL), 2 LiHMDS (2.977 mL, 1 M) was added at room temperature under 2 The mixture was stirred at 20° C. for 10 min under reduced pressure. Then, 1-7 (250 mg, 1.091 mmol) was added to the mixture. The mixture was cooled to 37° C. under reduced pressure. 2 The mixture was stirred at room temperature for 1 h under reduced pressure. 4 The mixture was quenched with aqueous Cl (15 mL) and extracted with EtOAc (2×15 mL). 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give the crude product. The residue was purified by preparative TLC separation to give 1-9, which was confirmed by LCMS: MS m / z (ESI) [M+H+2] + = 422.0

[0175] N 2 To a mixture of 1-15 (10 g, 64.94 mmol) in DCM (200 mL) at room temperature under reduced pressure was added CDI (15.78 g, 97.44 mmol). The reaction mixture was stirred for 0.5 h. Then, Et 3 N (19.68 g, 194.82 mmol) and N,O-dimethylhydroxylamine hydrochloride (7.6 g, 77.93 mmol) were added to the above solution. The reaction mixture was stirred at room temperature for 48 h. The mixture was diluted with DCM (100 mL) and diluted with 1 M HCl (3×300 mL), saturated NaHCO 3 The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give 1-16, which was used in the next step without further purification.

[0176] To a mixture of 1-16 (5 g, 25.36 mmol) in dioxane (50 mL), 2 LiAlH at 0°C 4 (25.36 mL, 1M) was added. The mixture was stirred at 0-20° C. for 2 h. The mixture was diluted with H 2 O (1 mL), 15% NaOH (1 mL), and H 2 The mixture was purified by distillation at 95-97 °C under standard atmospheric pressure to give 1-17, which was used in the next step without further purification.

[0177] Dissolve 1-17 (10 g, 15.21 mmol) in MeOH (25 mL) and K 2 CO 3 (6.31 g, 45.62 mmol) was added to a mixture of N 2 Dimethyl (1-diazo-2-oxopropyl)phosphonate (5.84 g, 30.42 mmol) was added at 0° C. under reduced pressure. The mixture was stirred at 20° C. for 18 hours. The mixture was diluted with toluene (50 mL) and diluted with H 2 The mixture was purified by distillation under standard atmospheric pressure to give 1-10, which was used in the next step without further purification.

[0178] A mixture of 1-9 (260 mg, 0.309 mmol) and 1-10 (112.00 mg, 0.309 mmol) in DMF (0.5 mL) was diluted with N 2 Below, ZnBr 2 (347.94mg, 1.545mmol), Pd(dppf)Cl 2 (22.61 mg, 0.031 mmol) and TEA (0.859 mL, 6.180 mmol) were added. The mixture was stirred in a sealed tube at 100° C. for 15 min. The mixture was diluted with EtOAc (20 mL). The organic layer was washed with brine (3×20 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography to give the crude product.

[0179] 80 mg of the crude product was further purified by preparative HPLC separation to give Example 1. LCMS: MS m / z (ESI) [M+H] + = 474.1; 1 H NMR(400 MHz, DMSO)δ 7.99(d, J = 9.0 Hz, 1H), 7.60(d, J = 8.9 Hz, 1H), 7.31 - 7.21(m, 1H), 7.14(t, J = 7.8 Hz, 1H), 6.88(d, J = 8.0 Hz, 1H), 6.18(s, 1H), 4.90(s, 2H), 4.15 -3.95(m, 2H), 3.83 - 3.75(m, 2H), 3.54(s, 3H), 1.54 - 1.34(m, 4H)

[0180] Example 2: 5-Methyl-6-oxo-8-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] To a mixture of compound 1 (100 mg, 0.211 mmol) in DMF (2 mL), Pd 2 (dba) 3 CHCl 3 (21.84mg, 0.021mmol), Zn(CN) 2 (49.56 mg, 0.422 mmol), Zn (13.80 mg, 0.211 mmol), zinc bis(acetate) (3.87 mg, 0.021 mmol) and DPPF (23.82 mg, 0.042 mmol) were added. The mixture was stirred in a sealed tube under microwave at 150° C. for 1 h. The mixture was diluted with EtOAc (20 mL). The organic layer was washed with brine (3×20 mL) and diluted with Na 2 SO 4 The crude product was purified by silica gel column chromatography and preparative TLC separation to give Example 2. LCMS: MS m / z (ESI) [M+H] + = 465.0; 1 H NMR(400 MHz, DMSO)δ 8.07(s, 2H), 7.29(d, J = 7.6 Hz, 1H), 7.14(t, J = 7.8 Hz, 1H), 6.89(d, J = 8.1 Hz, 1H), 6.26(s, 1H), 4.91(s, 2H), 4.15 - 4.00(m, 2H), 3.85 - 3.75(m, 2H), 3.56(s, 3H), 1.50 - 1.41(m, 4H)

[0181] Example 3: 6-Chloro-1-methyl-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)quinolin-2(1H)-one [ka] To a solution of 3-1 (5 g, 35.31 mmol) in DCM (200 mL) was added 3-2 (5.77 g, 36.02 mmol) at 0° C., followed by the addition of EDCI (6.90 g, 36.02 mmol) in portions. The reaction mixture was stirred at 0° C. for 1 h. The mixture was washed with 1 M NaOH (50 mL×3) and then with 1 M HCl (50 mL×3). The organic layer was extracted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give 3-3, which was confirmed by LCMS: MS m / z (ESI) [M+H-57] + = 228.1

[0182] To a mixture of 3-3 (10 g, 32.72 mmol) in methanesulfonic acid (50 mL) was added phosphorus pentoxide (6.97 g, 49.08 mmol). The reaction mixture was stirred at 60° C. for 0.5 h and then at 110° C. for 0.5 h. The mixture was cooled to room temperature and poured into ice water (150 mL). The mixture was stirred for 0.5 h and then filtered. The filter cake was dried under reduced pressure to give 3-4, which was confirmed by LCMS: MS m / z (ESI) [M+H+CH 3 CN] + = 251.1

[0183] POCl 3 A mixture of 3-4 (2 g, 9.143 mmol) in 1,2-dichloromethane (30 mL) was stirred at 100° C. for 3 h. The mixture was evaporated and poured into ice water (20 mL). The mixture was adjusted to pH=8.0 with saturated sodium bicarbonate solution and extracted with DCM (100 mL×3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 4° C., filtered and concentrated under reduced pressure to give 3-5, which was confirmed by LCMS: MS m / z (ESI) [M+H] + = 228.1

[0184] To a mixture of 1-8 (150 mg, 0.658 mmol) in THF (5 mL), 2 LiHMDS (1.973 mL) was added at 20 °C under reduced pressure. The mixture was then cooled to 37 °C. 2The mixture was stirred at 20° C. for 0.5 h under reduced pressure. Then, 3-5 (180.08 mg, 0.790 mmol) was added to the mixture. The mixture was then subjected to N 2 The mixture was stirred at 20° C. for 1 h under reduced pressure. 4 The mixture was quenched with aqueous Cl (15 mL) and extracted with EtOAc (2×15 mL). 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography on silica gel to give 3-6, which was confirmed by LCMS: MS m / z (ESI) [M+H+2] + = 420.8

[0185] A mixture of 3-6 (170 mg, 0.405 mmol) and 1-10 (146.80 mg, 0.405 mmol) in DMF (1.5 mL) was diluted with N 2 Below, ZnBr 2 (456.07mg, 2.025mmol), Pd(dppf)Cl 2 (29.64 mg, 0.041 mmol) and TEA (1.126 mL, 8.101 mmol) were added. The mixture was stirred at 100° C. for 15 min in a sealed tube. The mixture was diluted with EtOAc (20 mL). The organic layer was washed with brine (3×20 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography on silica gel to give the crude product. 30 mg of the crude product was purified by preparative HPLC separation to give Example 3. MS m / z (ESI) [M+H] + 473.2; 1 H NMR(400 MHz, DMSO)δ 7.56(s, 2H), 7.20(d, J = 7.5 Hz, 1H), 7.11 - 6.98(m, 2H), 6.66 - 6.56(m, 2H), 5.05(s, 2H), 3.93 - 3.83(m, 2H), 3.80 - 3.62(m, 2H), 3.615(s, 3H), 1.53 - 1.43(m, 4H)

[0186] Example 4: 1-Methyl-2-oxo-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-1,2-dihydroquinoline-6-carbonitrile [ka] To a mixture of compound 3 (60 mg, 0.127 mmol) in DMA (2 mL), Pd 2 (dba) 3 CHCl 3 (13.13mg, 0.013mmol), Zn(CN) 2 (29.80 mg, 0.254 mmol), Zn (8.30 mg, 0.127 mmol), zinc bis(acetate) (2.33 mg, 0.013 mmol) and DPPF (14.32 mg, 0.025 mmol) were added. The mixture was stirred in a sealed tube under microwave at 150° C. for 1 h. The mixture was filtered and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC separation to give Example 4. MS m / z (ESI) [M+H] + 464.2; 1 H NMR(400 MHz, DMSO)δ 7.91(dd, J = 8.8, 1.8 Hz, 1H), 7.69(d, J = 8.9 Hz, 1H), 7.48(d, J = 1.8 Hz, 1H), 7.21(d, J = 6.9 Hz, 1H), 7.05(t, J = 7.9 Hz, 1H), 6.70 - 6.56(m, 2H), 5.10(s, 2H), 3.93 - 3.83(m, 2H), 3.80 - 3.66(m, 2H), 3.64(s, 3H), 1.53 - 1.51(m, 4H)

[0187] Example 5: 6-Chloro-1-methyl-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one [ka] To a mixture of 5-1 (10 g, 58.282 mmol) in dioxane (100 mL) was added trichloromethyl chloromethanoate (86.47 g, 437.114 mmol). The reaction mixture was stirred at 110° C. for 4 h. The reaction mixture was filtered and the filter cake was dried under reduced pressure to give 5-2. 1 H NMR(400 MHz, DMSO)δ 11.86(s, 1H), 7.87(d, J = 0.8 Hz, 1H), 7.78(dd, J = 8.8, 2.3 Hz, 1H), 7.16(d, J = 8.8 Hz, 1H)

[0188] To a mixture of 5-2 (10 g, 50.615 mmol) in DMF (100 mL), Na 2 CO 3 (6.44 g, 60.738 mmol) and CH 3 I (5 mL, 75.912 mmol) was added. The reaction mixture was cooled to 4° C. 2 The mixture was stirred at room temperature for 12 h under reduced pressure. The mixture was quenched with water (300 mL). The reaction mixture was filtered and the filter cake was dried under reduced pressure to give 5-3. 1 H NMR(400 MHz, DMSO)δ 7.96(d, J = 1.6 Hz, 1H), 7.93 - 7.87(m, 1H), 7.48(d, J = 8.8 Hz, 1H), 3.46(s, 3H)

[0189] To a mixture of 5-3 (1.5 g, 7.09 mmol) in THF (10 mL) was added ammonium hydroxide (0.546 mL, 14.18 mmol). The mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with ethyl acetate (30 mL). The organic layer was washed with water (30 mL) and saturated NaCl (2×30 mL) and diluted with Na 2 SO 4 Drying at 40° C., filtering and concentrating under reduced pressure gave 5-4. LCMS:MS m / z(ESI)[M+H] +185.2; 1H NMR(400 MHz, DMSO)δ 7.92(s, 1H), 7.65(d, J = 2.4 Hz, 1H), 7.30(dd, J = 8.9, 2.4 Hz, 1H), 6.64(d, J = 9.2 Hz, 1H), 2.77(s, 3H)

[0190] To a mixture of 5-4 (1.00 g, 5.42 mmol) in DMF (15 mL), 2 NaH (1.08 g, 27.08 mmol, 60% in mineral oil) was added at 0° C. under reduced pressure. The reaction mixture was warmed to room temperature and then cooled to 37° C. with N 2 The mixture was stirred under reduced pressure for 1 h. CDI (1.32 g, 8.13 mmol) was added to the mixture. The mixture was then heated under N 2 The mixture was stirred at 70° C. for 2 hours under reduced pressure. The mixture was diluted with DCM (15 ml) and adjusted to pH=4-5 with 1M HCl to form a precipitate. The mixture was filtered and the filter cake was washed with H 2 The filter cake was dried under reduced pressure to give the product 5-5. 1 H NMR(400 MHz, DMSO)δ 11.70(s, 1H), 7.92(t, J = 7.6 Hz, 1H), 7.80(dd, J = 8.8, 2.4 Hz, 1H), 7.46(d, J = 9.2 Hz, 1H), 3.43(s, 3H)

[0191] To a mixture of 5-5 (100 mg, 0.475 mmol) in toluene (5 mL), POCl 3 (0.221 mL, 2.374 mmol) and DIEA (0.392 mL, 2.374 mmol) were added. The reaction mixture was stirred at 110° C. for 3 h. The mixture was concentrated under reduced pressure to give 5-6, which was used in the next step without further purification.

[0192] To a mixture of 1-8 (99.58 mg, 0.437 mmol) in THF (5 mL), 2 LiHMDS (1.310 mL) was added at 20° C. under reduced pressure. The mixture was stirred for 0.5 h. Then 5-6 (100 mg, 0.437 mmol) was added to the mixture. The mixture was purged with N2 The mixture was stirred at 20° C. for 1 h under reduced pressure. 4 The mixture was quenched with aqueous Cl (15 mL) and extracted with EtOAc (2×15 mL). 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative TLC separation to give 5-7, which was confirmed by LCMS: MS m / z (ESI) [M+H] + 420.1

[0193] A mixture of 5-7 (34 mg, 0.081 mmol) and 1-10 (29.29 mg, 0.081 mmol) in DMF (0.2 mL) was diluted with N 2 Below, ZnBr 2 (91.00mg, 0.404mmol), Pd(dppf)Cl 2 (5.91 mg, 0.008 mmol) and TEA (0.225 mL, 1.616 mmol) were added. The mixture was stirred in a sealed tube at 100° C. for 15 min. The mixture was diluted with EtOAc (20 mL). The organic layer was washed with brine (3×20 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC separation to give Example 5. LCMS: MS m / z (ESI) [M+H] + 474.1; 1 H NMR(400 MHz, DMSO)δ 7.63(dd, J = 9.1, 2.3 Hz, 1H), 7.50 - 7.43(m, 2H), 7.24(t, J = 7.9 Hz, 1H), 7.04(d, J = 7.5 Hz, 1H), 6.57(d, J = 2.3 Hz, 1H), 5.05(s, 2H), 4.04 - 3.90(m, 4H), 3.52(s, 3H), 1.58 - 1.40(m, 4H)

[0194] Example 6: 1-Methyl-2-oxo-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-1,2-dihydroquinazoline-6-carbonitrile [ka] To a mixture of compound 5 (30 mg, 0.063 mmol) in DMA (2 mL), Pd 2 (dba) 3 CHCl 3 (6.55 mg, 0.006 mmol), Zn(CN) 2 (14.87 mg, 0.127 mmol), Zn (4.14 mg, 0.063 mmol), zinc bis(acetate) (1.16 mg, 0.006 mmol) and DPPF (7.15 mg, 0.013 mmol) were added. The mixture was stirred in a sealed tube under microwave at 150° C. for 1 h. The mixture was diluted with EtOAc (20 mL). The organic layer was washed with brine (3×20 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give the crude product. The residue was purified by preparative HPLC separation to give Example 6. LCMS: MS m / z (ESI) [M+H] + 465.2; 1 H NMR(400 MHz, DMSO)δ 7.95(dd, J = 8.9, 1.7 Hz, 1H), 7.57(d, J = 9.0 Hz, 1H), 7.49(d, J = 7.6 Hz, 1H), 7.23(t, J = 7.9 Hz, 1H), 7.05(d, J = 7.9 Hz, 1H), 6.97(d, J = 1.7 Hz, 1H), 5.05(s, 2H), 4.10 - 3.80(m, 2H), 3.54(s, 3H), 3.40 - 3.33(m, 2H), 1.60 - 1.40(m, 4H)

[0195] Example 7: 6-Chloro-1-methyl-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)pyrido[3,2-d]pyrimidin-2(1H)-one [ka] To a mixture of 7-1 (5.0 g, 27.2 mmol) in MeOH (60 mL) and HCl (25 mL, 37% wt / wt) was added Fe (1.07 g, 19.1 mmol) at 20° C. After stirring at 80° C. for 1 h, the reaction mixture was cooled to room temperature and poured into ice water (100 mL). The mixture was filtered and the filter cake was washed with DCM (100 mL). The filtrate was extracted with DCM (100 mL×2). The combined organic layers were washed with brine (300 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give 7-2, which was used directly in the next step without further purification.

[0196] To a suspension of 7-2 (3.3 g, 21.5 mmol) in THF (50 mL) was added DMAP (1.31 g, 10.75 mmol), pyridine (6.84 mL, 86 mmol) and TFAA (5.50 mL, 43 mmol). The mixture was stirred at 25° C. for 2 h. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The resulting residue was dissolved in DCM (80 mL) and the mixture was washed with water (80 mL). The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give 7-3, which was used directly in the next step without further purification.

[0197] To a mixture of 7-3 (2.5 g, 10.0 mmol) in DMF (15 mL), MeI (2.63 g, 18.5 mmol) and K 2 CO 3 (4.15 g, 30.1 mmol) was added. After stirring at 20° C. for 16 h, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with Na 2 SO4 The mixture was dried at 4° C., filtered and concentrated under reduced pressure to give 7-4, which was confirmed by LCMS: MS m / z (ESI) [M+H] + = 168.2 DMSO (20 mL) and H 2 To a mixture of 7-4 (1.4 g, 8.35 mmol) in 20O (5.0 mL), 2 CO 3 (2.31 g, 16.71 mmol) and H 2 O 2 (1.89 g, 16.71 mmol) was added. After stirring at 20° C. for 16 h, the reaction mixture was diluted with water (40 mL) and a precipitate formed. The mixture was filtered and the filter cake was dried under reduced pressure to give 7-5.

[0198] To a mixture of 7-5 (580 mg, 3.13 mmol) in DMF (5 mL), 2 NaH (375 mg, 9.37 mmol, 60% in mineral oil) was added at 0° C. under reduced pressure. After stirring at room temperature for 1 h, a solution of CDI (760.04 mg, 4.687 mmol) in DMF (3 mL) was added to the above solution. The reaction mixture was allowed to warm to 70° C. and stirred for an additional 2 h. After cooling to room temperature, a precipitate formed and the mixture was filtered. The filter cake was washed with water and dried under reduced pressure to give 7-6, which was confirmed by LCMS: MS m / z (ESI) [M+H] + = 212.0

[0199] A suspension of 7-6 (200 mg, 0.95 mmol) in dry toluene (8 mL) was added to POCl at room temperature. 3 (0.44 mL, 4.73 mmol) and DIEA (0.78 mL, 4.73 mmol) were added. The reaction mixture was then cooled to 5° C. 2 The mixture was heated at 110° C. for 2 h under reduced pressure. The reaction mixture was concentrated under reduced pressure to give 7-7, which was used directly in the next step without further purification.

[0200] To a mixture of 1-8 (130 mg, 0.57 mmol) in THF (5 mL), 2LiHMDS (1.71 mL) was added at 20° C. under reduced pressure. After stirring at 20° C. for 5 min, a solution of 7-7 (150 mg, 0.65 mmol) in DIEA (0.94 mL, 5.70 mmol) and THF (3 mL) was added to the mixture at −10° C. 2 After stirring at −10 °C for 1 h, the mixture was diluted with saturated NH 4 The mixture was quenched with Cl solution (15 mL) and extracted with DCM (15 mL x 2). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 7-8, which was confirmed by LCMS: MS m / z (ESI) [M+H] + = 422.9

[0201] A mixture of 7-8 (120 mg, 0.18 mmol) and 1-10 (98.13 mg, 0.18 mmol) in DMF (0.5 mL) was diluted with N 2 Below, ZnBr 2 (202mg, 0.90mmol), Pd(dppf)Cl 2 (13.1 mg, 0.018 mmol) and TEA (0.50 mL, 3.58 mmol) were added. After stirring at 100° C. for 15 min, the mixture was diluted with EtOAc (20 mL). The mixture was washed with brine (20 mL×3) and Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC separation to give Example 7. LCMS: MS m / z (ESI) [M+H] + 475.1. 1 H NMR(400 MHz, DMSO)δ 7.91(d, J = 9.0 Hz, 1H), 7.65(d, J = 9.0 Hz, 1H), 7.41(d, J = 7.7 Hz, 1H), 7.22(t, J = 7.8 Hz, 1H), 7.14(d, J = 7.5 Hz, 1H), 5.50 - 4.35(m, 3H), 4.22 - 3.75(m, 2H), 3.48(s, 3H), 3.46 - 3.25(m, 1H), 1.55 - 1.35(m, 4H)

[0202] Example 8: 2-Oxo-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile [ka] To a mixture of compound 7 (250 mg, 0.53 mmol) in DMF (5 mL), Pd 2 (dba) 3 (48.2 mg, 0.053 mmol), Zn(CN) 2 (309 mg, 2.63 mmol), Zn (34.4 mg, 0.53 mmol) and XPHOS (50.2 mg, 0.11 mmol) were added. The mixture was stirred in a sealed tube under microwave at 120° C. for 1 h. The mixture was diluted with EtOAc (20 mL) and the organic layer was washed with brine (20 mL×3) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC separation to give Example 8. LCMS: MS m / z (ESI) [M+H] + 466.2; 1 H NMR(400 MHz, DMSO)δ 8.09(d, J = 8.5 Hz, 1H), 7.99(d, J = 9.0 Hz, 1H), 7.43(d, J = 7.5 Hz, 1H), 7.27 - 7.11(m, 2H), 5.57 - 4.38(m, 3H), 4.15 - 3.77(m, 2H), 3.50(s, 3H), 3.40 - 2.96(m, 1H), 1.53 - 1.39(m, 4H)

[0203] Example 9: 6-Fluoro-1-methyl-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one [ka] To a mixture of compound 9-1 (3 g, 16.56 mmol) in DMF (20 mL), 2 CO 3 (6.87 g, 49.69 mmol) and MeI (3.53 g, 24.85 mmol) were added. The mixture was then heated to 400° C. for 24 hours. 2 The mixture was stirred at 20° C. for 2 hours under H 2 The mixture was quenched with 200 mL of H2O (50 mL) to form a precipitate. The mixture was filtered. The filter cake was washed with H2O. 2 O (20 mL) and dried under reduced pressure to give 9-2, which was used in the next step without further purification. 1 H NMR(400 MHz, DMSO)δ 7.85 - 7.68(m, 2H), 7.58 - 7.41(m, 1H), 3.47(s, 3H)

[0204] To a mixture of compound 9-2 (600 mg, 3.08 mmol) in THF (7 mL) was added ammonium hydroxide (3.5 mL, 25.44 mmol). The mixture was stirred at 15° C. for 30 min. The mixture was concentrated under reduced pressure. A solution of HCl (4 M) in MeOH was added to the residue and the mixture was stirred at 15° C. for 16 h. The mixture was concentrated under reduced pressure. The residue was diluted with NaHCO 3 The pH was adjusted to 8-9 with aqueous solution of DCM (50 mL) and extracted with DCM (50 mL). The organic layer was washed with brine (50 mL x 3) and then diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give compound 9-3, which was used in the next step without further purification. MS (ESI) m / z (M+H) + = 169.0

[0205] To a mixture of compound 9-3 (440 mg, 2.62 mmol) in THF (5 mL) was added NaH (313.92 mg, 13.08 mmol, 60% in mineral oil) and CDI (636.28 mg, 3.92 mmol). The mixture was purified by N 2 The mixture was stirred at 15° C. for 3 h under saturated NH 4The mixture was quenched with Cl solution (30 mL) to form a precipitate. The mixture was filtered. The filter cake was washed with DCM (30 mL) and dried under reduced pressure to give compound 9-4. MS (ESI) m / z (M+H) + = 195.0

[0206] A mixture of compound 9-4 (356 mg, 1.83 mmol) in toluene (5 mL) was diluted with DIEA (1.52 mL, 9.17 mmol) and POCl 3 (0.85 mL, 9.17 mmol) was added. The mixture was then rinsed with N 2 The mixture was stirred at 110 °C for 3 h under reduced pressure. The residue was dissolved in NaHCO 3 The pH was adjusted to 7-8 with aqueous solution of 1,000 ml of DCM (30 mL) and the organic layer was washed with brine (3×30 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give compound 9-5, which was used in the next step without further purification. MS (ESI) m / z (M+H) + = 212.9

[0207] To a mixture of 1-8 in THF (8 mL), 2 LiHMDS (2.37 mL) was added at 20° C. under reduced pressure. After stirring at 20° C. for 10 min, DIEA (1.30 mL, 7.89 mmol) and 9-5 (252 mg, 1.18 mmol) were added to the mixture at −10° C. The mixture was then immersed in N 2 The mixture was stirred at −10° C. for 1 h. 4 The mixture was quenched with aqueous Cl (15 mL) and extracted with EtOAc (15 mL x 2). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 9-6. MS(ESI)m / z(M+H) + = 404.0

[0208] A mixture of 9-6 (170 mg, 0.25 mmol) and 1-10 (166 mg, 0.30 mmol) in DMF (1 mL) was diluted with N 2 Below, ZnBr 2(284mg, 1.26mmol), Pd(dppf)Cl 2 (18.5 mg, 0.025 mmol) and TEA (0.70 mL, 5.05 mmol) were added. The mixture was stirred in a sealed tube at 100° C. for 15 min. The mixture was diluted with EtOAc (20 mL). The organic layer was washed with brine (20 mL×3) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC separation to give Example 9. MS (ESI) m / z (M+H) + = 458.2. 1 H NMR(400 MHz, DMSO)δ 7.60 - 7.40(m, 3H), 7.22(t, J = 7.9 Hz, 1H), 7.01(d, J = 7.9 Hz, 1H), 6.34(dd, J = 10.2, 2.7 Hz, 1H), 5.25 - 4.25(m, 4H), 4.03 - 3.80(m, 2H), 3.54(s, 3H), 1.56 - 1.40(m, 4H)

[0209] Example 10: 6-Fluoro-1-methyl-2-oxo-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-1,2-dihydroquinoline-3-carbonitrile [ka] To a mixture of 9-2 (100 mg, 0.51 mmol) in THF (5 mL) was added ethyl 2-cyanoacetate (0.295 mL, 2.77 mmol) and Et 3 N (0.71 mL, 5.12 mmol) was added. The reaction mixture was stirred at 90° C. for 72 h. The reaction was diluted with EtOAc (20 mL) and H 2 The organic layer was separated and then washed with brine and Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give 10-1. MS (ESI) m / z (M+H) + = 218.9. 1H NMR(400 MHz, DMSO)δ 7.82(dd, J = 9.3, 2.9 Hz, 1H), 7.71 - 7.51(m, 2H), 3.54(s, 3H)

[0210] POCl 3 A mixture of 10-1 (500 mg, 2.29 mmol) in hexane (2.5 mL) was stirred at 90° C. for 12 h. After cooling to room temperature, the reaction mixture was diluted with hexane and the resulting solid was collected by filtration. The filter cake was carefully added to saturated sodium bicarbonate solution. The solid was filtered and dried under reduced pressure to give 10-2. 1 H NMR (400 MHz, CDCl 3 )δ 7.80(dd, J = 8.6, 2.8 Hz, 1H), 7.53(tt, J = 20.0, 10.0 Hz, 1H), 7.44(dd, J = 9.3, 4.2 Hz, 1H), 3.76(s, 3H)

[0211] To a mixture of 1-8 (48.2 mg, 0.21 mmol) in THF (3 mL), 2 LiHMDS (0.63 mL) was added at room temperature under reduced pressure. After stirring for 10 min, 10-2 (50 mg, 0.21 mmol) was added to 2 The mixture was stirred at -10°C for 1 h. The mixture was diluted with NH 4 The mixture was quenched with aqueous Cl (15 mL) and extracted with EtOAc (15 mL x 2). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give 10-3, which was used directly in the next step without further purification. MS (ESI) m / z (M+H) + = 427.9

[0212] A mixture of 10-3 (110 mg, 0.26 mmol) and 1-10 (141 mg, 0.26 mmol) in DMF (0.5 mL) was diluted with N 2 Below, ZnBr 2 (289mg, 1.28mmol), Pd(dppf)Cl 2(18.8 mg, 0.026 mmol) and TEA (0.71 mL, 5.14 mmol) were added. The mixture was stirred in a sealed tube at 100° C. for 15 min. The mixture was diluted with EtOAc (20 mL). The organic layer was washed with brine (20 mL×3) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC separation to give Example 10. MS (ESI) m / z (M+H) + = 482.1. 1 H NMR(400 MHz, DMSO)δ 7.75 - 7.60(m, 2H), 7.34(dd, J = 9.5, 2.6 Hz, 1H), 7.20(d, J = 7.4 Hz, 1H), 7.09(t, J = 7.9 Hz, 1H), 6.79(d, J = 8.1 Hz, 1H), 5.17(d, J = 14.4 Hz, 1H), 5.04(d, J = 14.5 Hz, 1H), 4.17 - 4.07(m, 1H), 4.06 - 3.80(m, 3H), 3.66(s, 3H), 1.56 - 1.40(m, 4H)

[0213] Example 11: 6-Chloro-1-methyl-7-((tetrahydrofuran-3yl)oxy)-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one [ka] CHCl 3 A mixture of 11-1 (10.0 g, 55.2 mmol) in 100 mL of SO was added at ice bath temperature. 2 Cl 2 (8.94 g, 66.23 mmol) was added. The mixture was refluxed for 12 h. The reaction mixture was concentrated under reduced pressure to give 11-2. MS (ESI) m / z (M+H) + = 216.1 H 2To a mixture of NaOH (2.77 g, 69.3 mmol) in 2H2O (100 mL) and THF (100 mL) was added 11-2 (9.0 g, 34.64 mmol). The mixture was stirred at 105 °C overnight. The reaction mixture was acidified with HCl (2 M) to form a precipitate. The precipitate was collected by filtration. The filter cake was washed with water and dried under reduced pressure to give 11-3. MS (ESI) m / z (M+MeCN+H) + = 243.1 A mixture of 11-3 (6.0 g, 29.8 mmol) and CDI (4.83 g, 29.76 mmol) in THF (100 mL) was stirred at room temperature for 12 h. The mixture was quenched with water, resulting in the formation of a precipitate. The precipitate was collected by filtration, and the filter cake was washed with water and dried under reduced pressure to give 11-4. MS (ESI) m / z (M - H) + = 226.0

[0214] To a mixture of 11-4 (4.2 g, 18.5 mmol) in DMF (50 mL), DIEA (6.10 mL, 36.9 mmol) and CH 3 I (7.86 g, 55.4 mmol) was added. The reaction mixture was stirred at room temperature for 12 h. The reaction was quenched with ice, resulting in the formation of a precipitate. The precipitate was collected by filtration, and the filter cake was washed with water and dried under reduced pressure to give 11-5 as a brown-brown solid. MS (ESI) m / z (M + H) + = 242.1

[0215] To a mixture of 11-5 (3.0 g, 12.4 mmol) in THF (20 mL), NH 4 OH (0.96 mL, 24.8 mmol) was added. After stirring at 60° C. for 2 h, the reaction mixture was diluted with EtOAc (80 mL) and washed with water and brine. The organic layer was collected and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo to give 11-6. MS (ESI) m / z (M + H) + = 214.9

[0216] To a mixture of 11-6 (2.0 g, 9.32 mmol) in DMF (50 mL) was added NaH (1.86 g, 46.6 mmol, 60% in mineral oil) at 0 °C. After stirring at room temperature for 1 h, CDI (2.27 g, 13.98 mmol) was added to the mixture. The reaction mixture was stirred at 70 °C for 2 h. After cooling to room temperature, the mixture was diluted with water (30 mL) and filtered. The filter cake was washed with 1 M HCl solution and dried under reduced pressure to give 11-7. MS (ESI) m / z (M + H) + = 241.1

[0217] A suspension of 11-7 (1.0 g, 4.16 mmol) in dry toluene (30 mL) was added at room temperature to POCl 3 (1.93 mL, 20.8 mmol) and DIEA (3.43 mL, 20.8 mmol) were added. The reaction mixture was then cooled to 5° C. 2 The mixture was heated at 110° C. for 2 h under reduced pressure. The reaction mixture was concentrated under reduced pressure to give 11-8, which was used directly in the next step without further purification.

[0218] To a mixture of 1-8 (1.42 g, 6.23 mmol) in THF (30 mL), 2 LiHMDS (18.7 mL) was added at 20 °C under reduced pressure. The mixture was then rinsed with N 2 The mixture was stirred at 20° C. for 5 min under reduced pressure. Then, a solution of 11-8 (1.08 g, 4.15 mmol) in DIEA (6.86 mL, 41.53 mmol) and THF (10 mL) was added to the mixture. The mixture was then subjected to N 2 The mixture was stirred at 20° C. for 1 h under reduced pressure. 4 The mixture was quenched with aqueous Cl (50 mL) and extracted with DCM (50 mL x 2). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 11-9. MS(ESI)m / z(M+H) + = 450.0

[0219] To a mixture of 11-9 (200 mg, 0.44 mmol) in DMF (1 mL) was added LiCl (113 mg, 2.66 mmol). The mixture was stirred at 140° C. for 18 h. The mixture was concentrated under reduced pressure. The residue was diluted with DCM / MeOH (10 / 1, 15 mL) and filtered. The filtrate was concentrated under reduced pressure to give 11-10, which was used directly in the next step without further purification. MS (ESI) m / z (M + H) + = 436.0

[0220] To a mixture of 11-10 (110 mg, 0.25 mmol) in DMF (3 mL), Cs 2 CO 3 (410 mg, 1.26 mmol) and 3-bromotetrahydrofuran (114 mg, 0.76 mmol) were added. The mixture was diluted with N 2 The mixture was stirred at 100° C. for 4 h under reduced pressure. The mixture was diluted with EtOAc (30 mL). The organic layer was washed with brine (30 mL×3) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 11-11. MS(ESI)m / z(M+H) + = 506.0

[0221] A mixture of 11-11 (63 mg, 0.124 mmol) and 1-10 (68.0 mg, 0.124 mmol) in DMF (0.8 mL) was diluted with N 2 Below, ZnBr 2 (140mg, 0.622mmol), Pd(dppf)Cl 2 (9.10 mg, 0.012 mmol) and Et 3 N (0.35 mL, 2.49 mmol) was added. The mixture was stirred in a sealed tube at 100° C. for 15 min. The mixture was diluted with EtOAc (20 mL). The organic layer was washed with brine (20 mL×3) and Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC separation to give Example 11. MS (ESI) m / z (M + H) + = 560.2.1 H NMR(400 MHz, DMSO)δ 7.46(d, J = 7.8 Hz, 1H), 7.24(t, J = 7.9 Hz, 1H), 7.02(d, J = 7.4 Hz, 1H), 6.86(s, 1H), 6.57(s, 1H), 5.45 - 5.33(m, 1H), 5.15 - 4.75(m, 2H), 4.13 - 3.68(m, 6H), 3.55(s, 3H), 3.40 - 3.25(m, 2H), 2.40 - 2.24(m, 1H), 2.06 - 1.91(m, 1H), 1.55 - 1.40(m, 4H)

[0222] Example 12: 1-Methyl-2-oxo-7-((tetrahydrofuran-3yl)oxy)-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-1,2-dihydroquinazoline-6-carbonitrile [ka] To a mixture of compound 11 (90 mg, 0.153 mmol) in DMA (3 mL), Zn(CN) 2 (89.6 mg, 0.76 mmol), Zn (10 mg, 0.15 mmol), zinc bis(acetate) (28 mg, 0.15 mmol), dppf (25.9 mg, 0.046 mmol) and Pd 2 (dba) 3 . CHCl 3 (31.6 mg, 0.031 mmol) was added. The mixture was stirred in a sealed tube under microwave at 150° C. for 2 h. The mixture was filtered and the filtrate was purified by preparative HPLC separation to give Example 12. MS (ESI) m / z (M + H) + = 551.3. 1H NMR(400 MHz, DMSO)δ 7.48(d, J = 7.7 Hz, 1H), 7.24(t, J = 7.9 Hz, 1H), 7.04(d, J = 7.9 Hz, 1H), 6.87(s, 2H), 5.47 - 5.42(m, 1H), 5.16 - 4.82(m, 2H), 3.97 - 3.74(m, 6H), 3.56(s, 3H), 3.40 - 3.25(m, 2H), 2.38 - 2.29(m, 1H), 2.05 - 1.96(m, 1H), 1.53 - 1.46(m, 4H)

[0223] Example 13: 6-Chloro-7-(2-hydroxyethoxy)-1-methyl-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one [ka] A mixture of 11-10 (120 mg, 0.28 mmol) and 13-1 (197 mg, 0.82 mmol) in DMF (5 mL) was added to the solution of Cs 2 CO 3 (228 mg, 1.65 mmol) was added. The reaction was stirred at 60° C. for 16 h. The reaction mixture was diluted with EtOAc (10 ml) and washed with water and brine. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo to give 13-2. MS (ESI) m / z (M + H) + = 594.2

[0224] To a mixture of 13-2 (110 mg, 0.19 mmol) in DMF (1 mL), ZnBr 2 (208mg, 0.93mmol), Pd(dppf)Cl 2(13.5 mg, 0.019 mmol), TEA (0.51 mL, 3.70 mmol) and 1-10 (121 mg, 0.22 mmol) were added. The reaction mixture was stirred in a sealed tube at 100° C. for 15 min. The reaction mixture was diluted with EtOAc (30 mL) and washed with brine. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel to give Example 13-3. MS (ESI) m / z (M + H) + = 648.3

[0225] To a mixture of 13-3 (40 mg, 0.063 mmol) in THF (3 mL) was added TBAF (0.12 mL, 0.12 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC separation to give Example 13. MS (ESI) m / z (M + H) + = 534.1. 1 H NMR(400 MHz, DMSO)δ 7.46(d, J = 7.7 Hz, 1H), 7.24(t, J = 7.9 Hz, 1H), 7.00(d, J = 7.9 Hz, 1H), 6.94(s, 1H), 6.57(s, 1H), 5.25 - 4.75(m, 3H), 4.25(t, J = 4.6 Hz, 2H), 3.99 - 3.86(m, 2H), 3.80 - 3.74(m, 2H), 3.56(s, 3H), 3.50 - 3.24(m, 2H), 1.54 - 1.46(m, 4H)

[0226] Example 14: 7-(2-hydroxyethoxy)-1-methyl-2-oxo-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-1,2-dihydroquinazoline-6-carbonitrile [ka] 13-3 (70 mg, 0.11 mmol), Zn (7.06 mg, 0.11 mmol), Zn(OAc) in DMA (3 mL) 2 (2.0 mg, 0.011 mmol), Zn(CN) 2 (25.4 mg, 0.22 mmol) and DPPF (12.0 mg, 0.022 mmol) were added to a mixture of Pd 2 (dba) 3 . CHCl 3 (12 mg, 0.011 mmol) was added. The reaction was stirred in a sealed tube under microwave at 150° C. for 2 h. The reaction mixture was diluted with EtOAc (30 ml) and washed with brine. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give 14-1. MS(ESI)m / z(M+H) + = 639.4

[0227] To a mixture of 14-1 (60 mg, 0.094 mmol) in THF (5 mL) was added TBAF (0.094 mL, 0.188 mmol, 1M in THF). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC separation to give Example 14. MS (ESI) m / z (M + H) + = 525.2. 1 H NMR(400 MHz, DMSO)δ 7.48(d, J = 7.6 Hz, 1H), 7.24(t, J = 8.0 Hz, 1H), 7.03(d, J = 8.0 Hz, 1H), 6.94(s, 1H), 6.86(s, 1H), 5.20 - 4.90(m, 3H), 4.31(t, J = 4.4 Hz, 2H), 4.17 - 3.81(m, 2H), 3.79 - 3.69(m, 2H), 3.55(s, 3H), 3.34 - 3.25(m, 2H), 1.55 - 1.45(m, 4H)

[0228] Example 15: 6-chloro-7-((2-hydroxyethyl)amino)-1-methyl-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one [ka] A mixture of 11-10 (1.0 g, 2.29 mmol) and 1-10 (1.57 g, 1.15 mmol) in DMF (4 mL) was treated with ZnBr 2 (1.55g, 6.87mmol), Pd(dppf)Cl 2 (0.17 g, 0.23 mmol) and Et 3 N (3.82 mL, 27.48 mmol) was added to N 2 The mixture was stirred in a sealed tube at 100° C. for 15 min. The mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 15-1. MS(ESI)m / z(M+H) + = 490.1

[0229] To a mixture of 15-1 (50 mg, 0.097 mmol) in DMF (10 mL), Et 3 N (0.081 mL, 0.58 mmol) and 15-2 (52.0 mg, 0.15 mmol) were added. The mixture was diluted with N 2 The mixture was stirred at 25° C. for 18 h under reduced pressure. The mixture was poured into water (100 mL) and extracted with DCM (50 mL×3). The combined organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to give 15-3. MS(ESI)m / z(M+H) + = 622.0

[0230] A mixture of 15-3 (40 mg, 0.061 mmol) in dioxane (10 mL) was diluted with 15-4 (32.14 mg, 0.183 mmol), Pd 2 (dba) 3(5.60 mg, 0.006 mmol), Xantphos (3.54 mg, 0.006 mmol) and Cs 2 CO 3 (99.5 mg, 0.31 mmol) was added. The mixture was then diluted with N 2 The mixture was stirred at 100° C. for 5 h under reduced pressure. The mixture was poured into water (100 mL) and extracted with DCM (50 mL×3). The combined organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel to give 15-5. MS(ESI)m / z(M+H) + = 647.2

[0231] To a mixture of 15-5 (30 mg, 0.042 mmol) in THF (3 mL) was added a solution of TBAF (0.21 mL, 0.21 mmol). The mixture was diluted with N 2 The mixture was stirred at 25° C. for 18 h under reduced pressure. The mixture was poured into water (15 mL) and extracted with DCM (10 mL×3). The combined organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC separation to give Example 15. MS (ESI) m / z (M + H) + = 533.0. 1 H NMR(400 MHz, DMSO)δ 7.42(d, J = 7.7 Hz, 1H), 7.22(t, J = 7.8 Hz, 1H), 6.96(d, J = 8.0 Hz, 1H), 6.45(s, 1H), 6.38(s, 1H), 6.16(t, J = 5.4 Hz, 1H), 5.23 - 4.70(m, 3H), 3.96 - 3.80(m, 2H), 3.64 - 3.56(m, 2H), 3.49(s, 3H), 3.28 - 3.42(m, 4H), 1.52 - 1.46(m, 4H)

[0232] Example 16: 7-((2-hydroxyethyl)amino)-1-methyl-2-oxo-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-1,2-dihydroquinazoline-6-carbonitrile [ka] To a mixture of 15-5 (60 mg, 0.088 mmol) in DMA (1 mL), Zn(CN) 2 (51.7mg, 0.44mmol), Zn(5.8mg, 0.088mmol), Zn(OAc) 2 (17.0 mg, 0.093 mmol), Xantphos (26.8 mg, 0.046 mmol) and Pd 2 (dba) 3 . CHCl 3 (26.8 mg, 0.046 mmol) was added. The mixture was stirred in a sealed tube under microwave at 150° C. for 1 h. The mixture was poured into water (100 mL) and extracted with DCM (50 mL×3). The combined organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel to give 16-1. MS(ESI)m / z(M+H) + = 638.3

[0233] To a mixture of 16-1 (30 mg, 0.041 mmol) in THF (1 mL) was added a solution of TBAF (0.12 mL, 1 M). The mixture was diluted with N 2 The mixture was stirred at 25° C. for 16 h under reduced pressure. The mixture was poured into water (20 mL) and extracted with DCM (15 mL×3). The combined organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC separation to give Example 16. MS (ESI) m / z (M + H) + = 524.2. 1H NMR(400 MHz, DMSO)δ 7.45(dd, J = 7.7, 1.0 Hz, 1H), 7.24(t, J = 7.9 Hz, 1H), 7.06 - 6.97(m, 1H), 6.68(s, 1H), 6.60(t, J = 5.6 Hz, 1H), 6.35(s, 1H), 5.25 - 4.65(m, 3H), 4.25 - 3.70(m, 2H), 3.64 - 3.54(m, 2H), 3.47(s, 3H), 3.42 - 3.25(m, 4H), 1.53 - 1.44(m, 4H)

[0234] Example 17: 6-Chloro-7-(2-methoxyethoxy)-1-methyl-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one [ka] To a mixture of 11-10 (180 mg, 0.41 mmol) in DMF (2 mL), 2 CO 3 (285 mg, 2.06 mmol) and 1-bromo-2-methoxyethane (172 mg, 1.24 mmol) were added. The mixture was diluted with N 2 The mixture was stirred at 50° C. for 18 h under reduced pressure. The mixture was diluted with EtOAc (30 mL), washed with brine (30 mL×3), and added Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 17-1. MS(ESI)m / z(M+H) + = 494.0

[0235] A mixture of 17-1 (100 mg, 0.20 mmol) and 1-10 (111 mg, 0.20 mmol) in DMF (2 mL) was diluted with N 2 Below, ZnBr 2 (227mg, 1.01mmol), Pd(dppf)Cl 2 (14.8 mg, 0.020 mmol) and Et3 N (0.56 mL, 4.04 mmol) was added. The mixture was stirred in a sealed tube at 100° C. for 15 min. The mixture was diluted with EtOAc (20 mL), washed with brine (20 mL×3), and added with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC separation to give Example 17. MS (ESI) m / z (M + H) + = 548.2. 1 H NMR(400 MHz, DMSO)δ 7.45(d, J = 7.6 Hz, 1H), 7.23(t, J = 7.9 Hz, 1H), 7.00(d, J = 7.9 Hz, 1H), 6.93(s, 1H), 6.56(s, 1H), 5.22 - 4.73(m, 2H), 4.45 - 4.25(m, 2H), 4.03 - 3.83(m, 2H), 3.76 - 3.66(m, 2H), 3.55(s, 3H), 3.34 - 3.31(m, 5H), 1.57 - 1.40(m, 4H)

[0236] Example 18: 7-(2-Methoxyethoxy)-1-methyl-2-oxo-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-1,2-dihydroquinazoline-6-carbonitrile [ka] To a mixture of compound 17 (60 mg, 0.11 mmol) in DMA (1 mL), Pd 2 (dba) 3 . CHCl 3 (11.3 mg, 0.011 mmol), Zn(CN) 2 (25.7mg, 0.22mmol), Zn(7.2mg, 0.11mmol), Zn(OAc) 2(2.0 mg, 0.011 mmol) and dppf (12.4 mg, 0.022 mmol) were added. The mixture was stirred in a sealed tube under microwave at 150° C. for 2 h. The mixture was filtered and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC separation to give Example 18. MS (ESI) m / z (M + H) + = 539.3. 1 H NMR(400 MHz, DMSO)δ 7.48(d, J = 7.5 Hz, 1H), 7.23(t, J = 7.9 Hz, 1H), 7.03(d, J = 7.9 Hz, 1H), 6.94(s, 1H), 6.86(s, 1H), 5.16 - 4.90(m, 2H), 4.45 - 4.36(m, 2H), 4.02 - 3.83(m, 2H), 3.74 - 3.68(m, 2H), 3.55(s, 3H), 3.32(s, 3H), 3.29 - 3.28(m, 2H), 1.53 - 1.45(m, 4H)

[0237] Example 19: 6-Chloro-1-methyl-7-morpholino-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one [ka] A mixture of 15-3 (100 mg, 0.15 mmol) in dioxane (10 mL) was treated with morpholine (0.050 mL, 0.76 mmol), Brettphos-Pd-G3 (42 mg, 0.046 mmol), Brettphos (25 mg, 0.046 mmol) and Cs 2 CO 3 (248.8 mg, 0.76 mmol) was added. The mixture was then diluted with N 2 The mixture was stirred at 100° C. for 5 h under reduced pressure. The mixture was poured into water (20 mL) and extracted with DCM (30 mL×3). The combined organic layer was washed with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC separation to give Example 19. MS (ESI) m / z (M + H) + = 559.2. 1 H NMR (400 MHz, CD 3 OD)δ 7.51(d, J = 7.6 Hz, 1H), 7.28(t, J = 7.8 Hz, 1H), 7.00(d, J = 7.7 Hz, 1H), 6.91(s, 1H), 6.71(s, 1H), 5.26 - 4.75(m, 2H), 4.12 - 3.95(m, 2H), 3.92 - 3.78(m, 4H), 3.69(s, 3H), 3.40 - 3.14(m, 6H), 1.54 - 1.39(m, 4H)

[0238] Example 20: 7-(3-aminopropoxy)-6-chloro-1-methyl-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one [ka] To a mixture of 20-1 (5.0 g, 28.53 mmol) in DCM (50 mL) was added TEA (3.97 mL, 28.53 mmol), DMAP (0.35 g, 2.85 mmol) and TsCl (5.98 g, 31.39 mmol). The reaction mixture was stirred at 25 °C for 18 h. The mixture was poured into water (200 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel to give 20-2. MS (ESI) m / z (M+H-100) + = 229.9

[0239] A mixture of 11-10 (200 mg, 0.46 mmol) in DMF (10 mL) was diluted with N 2 At 25°C, 20-2 (754 mg, 2.29 mmol), Cs2 CO 3 (1.49 g, 4.58 mmol) and potassium iodide (38.0 mg, 0.23 mmol) were added. The reaction mixture was cooled to 4° C. 2 The mixture was stirred at 100° C. for 16 h under reduced pressure. The mixture was poured into water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel to give 20-3. MS (ESI) m / z (M+H) + = 593.0 To a mixture of 20-3 (200 mg, 0.34 mmol) in TEA (2 mL) and DMF (2 mL) at 25 °C, 1-10 (226 mg, 0.40 mmol), ZnBr 2 (379 mg, 1.68 mmol) and Pd(dppf)Cl 2 (24.6 mg, 0.034 mmol) was added. The mixture was then diluted with N 2 The mixture was stirred at 100° C. for 0.5 h under reduced pressure. The mixture was poured into water (100 mL) and extracted with DCM (50 mL×3). The combined organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel to give 20-4. MS (ESI) m / z (M+H) + = 647.2

[0240] To a mixture of 20-4 (170 mg, 0.26 mmol) in DCM (5 mL) was added TFA (0.5 mL). The mixture was purified by N 2 The mixture was stirred at room temperature for 2 h under reduced pressure. The mixture was poured into water (100 mL) and extracted with DCM (50 mL x 3). The combined organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC separation to give Example 20. MS (ESI) m / z (M+H) + = 547.1. 1H NMR(400 MHz, DMSO)δ 7.45(d, J = 7.2 Hz, 1H), 7.23(t, J = 7.9 Hz, 1H), 7.00(d, J = 7.6 Hz, 1H), 6.91(s, 1H), 6.57(s, 1H), 5.25 - 4.70(m, 2H), 4.35 - 4.19(m, 2H), 4.00 - 3.84(m, 2H), 3.55(s, 3H), 2.83 - 2.77(m, 2H), 2.63 - 2.58(m, 2H), 1.98 - 1.90(m, 2H), 1.51 - 1.49(m, 4H)

[0241] Example 21: (S)-6-chloro-1-methyl-7-((tetrahydrofuran-3yl)oxy)-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one [ka] To 21-1 (3.65 mL, 45.4 mmol) in THF (100 mL) was added TEA (8.20 mL, 59.0 mmol) at 0 °C, followed by MsCl (6.76 g, 59.0 mmol). 2 After stirring at 25° C. for 18 h under 2 The mixture was quenched with O (70 mL) and extracted with DCM (3×70 mL). 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give compound 21-2 (5.5 g, 69.3%), which was used in the next step without further purification.

[0242] A mixture of 11-10 (70 mg, 0.16 mmol) in DMF (10 mL) was treated with 21-2 (399 mg, 2.40 mmol), KI (13.3 mg, 0.080 mmol) and Cs 2 CO 3 (522 mg, 1.60 mmol) was added. 2After stirring at 100° C. for 3 h under reduced pressure, the mixture was poured into water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (3×50 mL) and extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 21-3 (60 mg, 73.9%). LCMS: MS(ESI) m / z(M+H) + = 505.8

[0243] To a mixture of 21-3 (60 mg, 0.12 mmol) in TEA (1 mL) and DMF (1 mL) was added 1-10 (119 mg, 0.14 mmol), ZnBr 2 (133 mg, 0.59 mmol) and Pd(dppf)Cl 2 (8.7 mg, 0.012 mmol) was added. After stirring in a sealed tube at 100° C. for 0.5 h, the mixture was poured into water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×50 mL) and extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give Example 21 (17.0 mg, 8.5%). LCMS: MS (ESI) m / z (M+H) + = 560.2. 1 H NMR(400 MHz, DMSO)δ 7.46(d, J = 7.8 Hz, 1H), 7.24(t, J = 7.8 Hz, 1H), 7.02(d, J = 7.9 Hz, 1H), 6.86(s, 1H), 6.57(s, 1H), 5.41 - 5.36(m, 1H), 5.25 - 4.80(m, 2H), 4.00 - 3.70(m, 6H), 3.55(s, 3H), 3.41 - 3.36(m, 2H), 2.35 - 2.25(m, 1H), 2.05 - 1.95(m, 1H), 1.57 - 1.43(m, 4H)

[0244] Example 22: (R)-6-chloro-1-methyl-7-((tetrahydrofuran-3yl)oxy)-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one [ka] Example 22 was prepared following a procedure similar to that of Example 21, but replacing reactant (R)-tetrahydrofuran-3-ol with (S)-tetrahydrofuran-3-ol. LCMS: MS (ESI) m / z (M+H) + = 560.2. 1 H NMR(400 MHz, DMSO)δ 7.46(d, J = 7.7 Hz, 1H), 7.24(t, J = 7.9 Hz, 1H), 7.02(d, J = 7.9 Hz, 1H), 6.86(s, 1H), 6.57(s, 1H), 5.41 - 5.35(m, 1H), 5.25 - 4.75(m, 2H), 3.98 - 3.71(m, 6H), 3.55(s, 3H), 3.31 - 3.25(m, 2H), 2.33 - 2.26(m, 1H), 2.05 - 1.93(m, 1H), 1.51 - 1.45(m, 4H)

[0245] Example 23: (S)-1-Methyl-2-oxo-7-((tetrahydrofuran-3yl)oxy)-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-1,2-dihydroquinazoline-6-carbonitrile [ka] The preparation of Example 23 followed the same procedure as Example 12, replacing reactant Example 11 with Example 21. LCMS: MS (ESI) m / z (M+H) + = 551.2. 1H NMR(400 MHz, DMSO)δ 7.48(dd, J = 7.8, 1.0 Hz, 1H), 7.24(t, J = 7.9 Hz, 1H), 7.04(dd, J = 8.0, 1.0 Hz, 1H), 6.87(s, 1H), 6.86(s, 1H), 5.48 - 5.42(m, 1H), 5.20 - 4.80(m, 2H), 3.99 - 3.71(m, 6H), 3.56(s, 3H), 3.38 - 3.32(m, 2H), 2.37 - 2.28(m, 1H), 2.05 - 1.96(m, 1H), 1.52 - 1.44(m, 4H)

[0246] Example 24: (R)-1-Methyl-2-oxo-7-((tetrahydrofuran-3yl)oxy)-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-1,2-dihydroquinazoline-6-carbonitrile [ka] The preparation of Example 24 followed the same procedure as Example 12, replacing reactant Example 11 with Example 22. LCMS: MS (ESI) m / z (M+H) + = 551.5. 1 H NMR(400 MHz, DMSO)δ 7.48(d, J = 7.6 Hz, 1H), 7.24(t, J = 7.9 Hz, 1H), 7.04(d, J = 7.8 Hz, 1H), 6.86(d, J = 2.1 Hz, 2H), 5.50 - 5.37(m, 1H), 5.25 - 4.80(m, 2H), 4.04 - 3.69(m, 6H), 3.56(s, 3H), 3.31 - 3.21(m, 2H), 2.39 - 2.28(m, 1H), 2.06 - 1.96(m, 1H), 1.51 - 1.46(m, 4H)

[0247] Example 25: 6-Chloro-1-methyl-7-((tetrahydro-2H-pyran-4yl)oxy)-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one [ka] Example 25 was prepared following a procedure similar to that of Example 11, but replacing reactant 3-bromotetrahydrofuran with 4-bromotetrahydropyran. LCMS: MS (ESI) m / z (M+H) + = 574.2. 1 H NMR δ 7.46(d, J = 7.6 Hz, 1H), 7.25(t, J = 7.6 Hz, 1H), 7.02(d, J = 8.0 Hz, 1H), 6.96(s, 1H), 6.58(s, 1H), 5.20 - 4.80(m, 3H), 4.05 - 3.75(m, 4H), 3.60 - 3.50(m, 5H), 3.43 - 3.38(m, 2H), 2.08 - 1.95(m, 2H), 1.69 - 1.58(m, 2H), 1.54 - 1.44(m, 4H)

[0248] Example 26: 1-Methyl-2-oxo-7-((tetrahydro-2H-pyran-4yl)oxy)-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-1,2-dihydroquinazoline-6-carbonitrile [ka] The preparation of Example 26 followed a similar procedure to Example 12, substituting reactant Example 11 with Example 25. LCMS: MS(ESI) m / z(M+H) + = 565.3 1H NMR(400 MHz, DMSO)δ 7.51 - 7.45(m, 1H), 7.25(t, J = 8.0 Hz, 1H), 7.05(d, J = 7.2 Hz, 1H), 6.97(s, 1H), 6.87(s, 1H), 5.15 - 4.87(m, 3H), 4.03 - 3.73(m, 4H), 3.60 - 3.50(m, 5H), 3.31 - 3.30(m, 2H), 2.08 - 1.97(m, 2H), 1.70 - 1.59(m, 2H), 1.52 - 1.46(m, 4H)

[0249] Example 27: 6-chloro-7-(3-hydroxypropoxy)-1-methyl-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one [ka] Example 27 was prepared following a procedure similar to that of Example 17, but replacing reactant 1-bromo-2-methoxyethane with 3-bromopropan-1-ol. LCMS: MS (ESI) m / z (M+H) + = 548.0. 1 H NMR(400 MHz, DMSO)δ 7.45(d, J = 7.6 Hz, 1H), 7.23(t, J = 7.9 Hz, 1H), 7.00(d, J = 7.8 Hz, 1H), 6.92(s, 1H), 6.56(s, 1H), 5.13 - 4.85(m, 2H), 4.63 - 4.55(m, 1H), 4.27(t, J = 6.0 Hz, 2H), 3.99 - 3.83(m, 2H), 3.59 - 3.52(m, 5H), 3.35 - 3.31(m, 2H), 1.94 - 1.86(m, 2H), 1.52 - 1.46(m, 4H)

[0250] Example 28: 7-(3-hydroxypropoxy)-1-methyl-2-oxo-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-1,2-dihydroquinazoline-6-carbonitrile [ka] The preparation of Example 28 followed the same procedure as Example 12, substituting reactant Example 11 with Example 27. LCMS: MS (ESI) m / z (M+H) + = 539.3. 1 H NMR(400 MHz, DMSO)δ 7.47(d, J = 7.6 Hz, 1H), 7.23(t, J = 8.0 Hz, 1H), 7.02(d, J = 8.0 Hz, 1H), 6.92(s, 1H), 6.86(s, 1H), 5.19 - 4.90(m, 2H), 4.67 - 4.59(m, 1H), 4.33(t, J = 6.0 Hz, 2H), 4.01 - 3.85(m, 2H), 3.59 - 3.52(m, 5H), 3.41 - 3.36(m, 2H), 1.95 - 1.84(m, 2H), 1.54 - 1.44(m, 4H)

[0251] Example 29: 6-chloro-7-(2-hydroxyethoxy)-1-methyl-4-(6-((1-methylcyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one [ka] Example 29 was prepared following a procedure similar to that of Example 13, replacing intermediate 1-ethynyl-1-(trifluoromethyl)cyclopropane (1-10) with 1-ethynyl-1-methylcyclopropane. LCMS: MS (ESI) m / z (M+H) + = 480.0. 1H NMR(400 MHz, DMSO)δ 7.36(d, J = 8.0 Hz, 1H), 7.21 - 7.15(m, 1H), 6.96 - 6.87(m, 2H), 6.56(s, 1H), 5.40 - 4.70(m, 3H), 4.33 - 4.17(m, 2H), 3.97 - 3.82(m, 2H), 3.80 - 3.72(m, 2H), 3.54(s, 3H), 3.49 - 3.45(m, 2H), 1.37(s, 3H), 1.05 - 0.97(m, 2H), 0.84 - 0.76(m, 2H)

[0252] Example 30: 6-chloro-7-(2-hydroxyethoxy)-1-methyl-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydropyrido[2,3-e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one [ka] To a mixture of 30-1 (27 g, 153.4 mmol) in THF (200 mL), 2 LDA (99.7 mL, 2 M in THF) was added dropwise at −78° C. The mixture was stirred at −78° C. for 30 min, and ethyl chloromethanoate (20 g, 184.3 mmol) was added in a 10 mL flask under reduced pressure. 2 The mixture was added to the above solution at −78° C. under reduced pressure. After stirring at 25° C. for 16 h, the mixture was poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with Na 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure gave crude compound 30-2, which was used directly in the next step without further purification. LCMS: MS(ESI) m / z(M+H) + = 247.9

[0253] To a mixture of 30-2 (36 g, 145.1 mmol) in DMSO (80 mL), NH 4OH (40 mL, 145.1 mmol) was added. After stirring at 100° C. for 3 h, the mixture was poured into water (100 mL) and extracted with EtOAc (3×100 mL). The mixture was concentrated under reduced pressure to give compound 30-3 (31 g, 87.2%). LCMS: MS (ESI) m / z (M+H) + = 245.0

[0254] To a mixture of 30-3 (31 g, 126.5 mmol) in THF (200 mL) at 0 °C, 2 Below, LiAlH 4 (7.2 g, 189.7 mmol) was added. The mixture was stirred at 0° C. for 5 min and then warmed to 25° C. for 3 h. The mixture was diluted with saturated Na 2 SO 4 The mixture was quenched with 1,2-dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 30-4 (7 g, 27.3%). LCMS: MS(ESI) m / z(M+H) + = 202.9

[0255] To a mixture of 30-4 (8.2 g, 40.4 mmol) in THF (150 mL) was added DIEA (33.4 mL) and chloroacetyl chloride (13.7 g, 121.2 mmol) at 0 °C. After stirring at room temperature for 16 h, the mixture was diluted with NaHCO 3 The mixture was quenched with aqueous solution of sodium hydroxide and extracted with DCM. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 30-5 (4.5 g, 31.3%). LCMS: MS (ESI) m / z (M+H) + = 354.5

[0256] A mixture of t-BuONa (4.2 g, 43.7 mmol) in t-BuOH (100 mL) was heated to 80° C. until all solids were dissolved, and 30-5 (7 g, 19.7 mmol) was added to the solution. After stirring at 80° C. for 2 h, the mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 30-6 (3.7 g, 77.4%). LCMS: MS (ESI) m / z (M+H) + = 242.8

[0257] A mixture of 30-6 (2.9 g, 11.9 mmol) in THF (100 mL) was added to BH 3 THF (60 mL, 1M in THF) was added. After stirring at 80 °C for 2 h, MeOH (10 mL) and 1N HCl (10 mL) were added to the mixture. The mixture was stirred at 80 °C for 2 h, then NaHCO 3 The mixture was quenched with aqueous solution (30 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 30-7 (1.1 g, 40.2%). LCMS: MS (ESI) m / z (M+H) + = 229.1

[0258] To a mixture of 30-7 (132 mg, 0.58 mmol) in THF (50 mL), N 2 LIHMDS (1.7 mL, 1 M in THF) was added at 20° C. under reduced pressure. 2 After stirring at 20 °C for 5 min under reduced pressure, a solution of 11-8 (100 mg, 0.39 mmol) in DIEA (0.64 mL, 3.86 mmol) and THF (10 mL) was added to the above mixture. The mixture was then cooled to 50 °C for 1 h. 2 The mixture was stirred at room temperature for 2 h under reduced pressure and then NH 4 The mixture was quenched with aqueous Cl (50 mL) and extracted with DCM (2×50 mL). 2 SO 4The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC to give 30-8 (83 mg, 47.7%). LCMS: MS(ESI) m / z(M+H) + = 450.7

[0259] To a mixture of 30-8 (50 mg, 0.11 mmol) in DMF (3 mL) was added LiCl (46.9 mg, 1.11 mmol). After stirring at 140 °C for 18 h, the mixture was concentrated under reduced pressure. The resulting residue was diluted with DCM / MeOH (10 / 1, 15 mL) and filtered. The filtrate was concentrated under reduced pressure to give the crude product 30-9, which was used in the next step without further purification. LCMS: MS (ESI) m / z (M+H) + = 437.0.

[0260] [ka] Example 30 was prepared following a similar procedure to Example 13, replacing intermediate 4-(6-bromo-2,3-dihydropyrido[2,3-e][1,4]oxazepin-1(5H)yl)-6-chloro-7-hydroxy-1-methylquinazolin-2(1H)-one (11-10) with intermediate 4-(6-bromo-2,3-dihydropyrido[2,3-e][1,4]oxazepin-1(5H)yl)-6-chloro-7-hydroxy-1-methylquinazolin-2(1H)-one (30-9). LCMS: MS(ESI) m / z(M+H) + = 535.2. 1 H NMR 1 H NMR(400 MHz, DMSO)δ 8.09(d, J = 5.2 Hz, 1H), 7.32(d, J = 5.2 Hz, 1H), 6.97(s, 1H), 6.65(s, 1H), 5.18 - 4.78(m, 3H), 4.27(t, J = 4.8 Hz, 2H), 3.98 - 3.89(m, 2H), 3.79 - 3.74(m, 2H), 3.59(s, 3H), 3.33 - 3.31(m, 2H), 1.57 - 1.52(m, 4H)

[0261] Example 31: 6-chloro-7-(2-hydroxyethoxy)-1-methyl-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydropyrido[3,4-e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one [ka] A mixture of LDA (20.1 g, 187.5 mmol) in THF (100 mL) was added to 2 31-1 (30.0 g, 170.5 mmol) was added at −78° C. under a vacuum. The reaction mixture was cooled to 100° C. with 2 The mixture was stirred at −78° C. for 1 hour under reduced pressure. Then, ethyl chloromethanoate (22.2 g, 204.6 mmol) was added. 2 After stirring at 0° C. for 1.5 h under reduced pressure, the mixture was poured into water (100 mL) and extracted with EtOAc (3×10 mL). 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 31-2 (32.4 g, 76.6%). LCMS: MS (ESI) m / z (M+H) + = 247.9

[0262] To a mixture of 31-2 (32.4 g, 130.6 mmol) in DMF (400 mL) was added (2,4-dimethoxyphenyl)methanamine (32.8 g, 195.9 mmol) and K at 20 °C. 2 CO 3 (54.2 g, 391.9 mmol) was added. 2 After stirring at 50° C. for 12 h under reduced pressure, the mixture was poured into water (100 mL) and extracted with EtOAc (3×100 mL). 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure, and the residue was purified by flash column chromatography to give 31-3 (50.8 g, 98.4%).

[0263] To a mixture of 31-3 (4.0 g, 10.1 mmol) in DCM (30 mL) was added TFA (30 mL). 2 The mixture was stirred at room temperature for 2 h under reduced pressure. The mixture was concentrated under reduced pressure to give the crude product, which was dissolved in DCM (100 mL) and saturated NaHCO 3 The pH was adjusted to 8.0 with (aqueous). The resulting mixture was extracted with DCM (3×50 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give the crude material, which was purified by silica gel column chromatography to give compound 31-4. LCMS: MS(ESI) m / z(M+H) + = 244.9

[0264] To a mixture of 31-4 (8.76 g, 35.7 mmol) in THF (100 mL), 2 LiAlH at 0°C 4 (53.6 mL, 1M in THF) was added. 2 After stirring at room temperature for 18 h under 2 SO 4 The mixture was quenched with a solution of 1,2-dichloromethane (HCl), ... + = 202.9

[0265] To a mixture of 31-5 (2.66 g, 13.1 mmol) in THF (35 mL) was added DIEA (6.49 mL, 39.3 mmol), and then chloroacetyl chloride (1.63 g, 14.4 mmol) was added to the mixture at 0 °C. 2 After stirring at room temperature for 16 h under reduced pressure, the mixture was poured into water (50 mL) and extracted with EtOAc (3×50 mL). 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give the crude material which was purified by flash column chromatography to give 31-6 (1.46 g, 39.9%). LCMS: MS(ESI) m / z(M+H) + = 278.8

[0266] To a mixture of t-BuONa (904 mg, 9.40 mmol) in t-BuOH (20 mL) was added 31-6 (1.46 g, 5.22 mmol). 2 After stirring at 80° C. for 2 h under reduced pressure, the mixture was concentrated under reduced pressure and 2 The mixture was quenched with 0 (30 mL) to form a precipitate. The mixture was filtered and the filter cake was lyophilized to give compound 31-7, which was used in the next step without further purification. LCMS: MS (ESI) m / z (M+H) + = 242.9.

[0267] [ka] Example 31 was prepared following a similar procedure to Example 30, replacing intermediate 6-bromo-1,5-dihydropyrido[2,3-e][1,4]oxazepin-2(3H)-one (30-6) with intermediate 6-bromo-1,5-dihydropyrido[3,4-e][1,4]oxazepin-2(3H)-one (31-7). LCMS: MS(ESI) m / z(M+H) + = 535.2. 1 H NMR(400 MHz, DMSO)δ 8.55(s, 1H), 8.14(s, 1H), 6.96(s, 1H), 6.61(s, 1H), 5.10 - 4.90(m, 3H), 4.30 - 4.22(m, 2H), 3.98 - 3.90(m, 2H), 3.81 - 3.73(m, 2H), 3.57(s, 3H), 3.47 - 3.41(m, 2H), 1.56 - 1.46(m, 4H)

[0268] Example 32: 7-(2-aminoethoxy)-6-chloro-1-methyl-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one [ka] A mixture of 11-10 (150 mg, 0.34 mmol) in DMF (15 mL) was treated with 32-1 (384 mg, 1.72 mmol), KI (57 mg, 0.34 mmol) and Cs 2 CO 3 (1.12 g, 3.43 mmol) was added. After stirring at 100° C. for 3 h, the reaction mixture was diluted with EtOAc (30 mL), washed with brine (3×30 mL), and added Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 32-2 (130 mg, 66.9%). LCMS: MS(ESI) m / z(M+H) + = 579.0

[0269] To a mixture of 32-2 (130 mg, 0.22 mmol) in DMF (1 mL), TEA (0.62 mL, 4.48 mmol), ZnBr 2 (252 mg, 1.12 mmol), 1-10 (36 mg, 0.27 mmol) and Pd(dppf)Cl 2 (16.4 mg, 0.022 mmol) was added. After stirring in a sealed tube at 100 °C for 15 min, the reaction was diluted with EtOAc (20 mL), washed with brine (3 x 20 mL), and added Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 32-3 (100 mg, 70.5%). LCMS: MS(ESI) m / z(M+H) + = 633.4

[0270] To a mixture of 32-3 (100 mg, 0.16 mmol) in DCM (3 mL) was added TFA (0.3 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the resulting residue was purified by preparative HPLC to give Example 32 (19.0 mg, 22.6%). LCMS: MS (ESI) m / z (M+H) + = 533.4. 1 H NMR (400 MHz, CD 3 OD)δ 7.48(dd, J = 7.8, 1.0 Hz, 1H), 7.26(t, J = 7.9 Hz, 1H), 7.03 - 6.97(m, 1H), 6.60(s, 1H), 6.51(s, 1H), 5.30 - 4.95(m, 2H), 4.00(s, 2H), 3.78(t, J = 5.6 Hz, 2H), 3.63(s, 3H), 3.45(t, J = 5.6 Hz, 2H), 3.36 - 3.32(m, 2H), 1.50 - 1.37(m, 4H)

[0271] Example 33: 7-(2-aminoethoxy)-1-methyl-2-oxo-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-1,2-dihydroquinazoline-6-carbonitrile [ka] To a mixture of 32-3 (40 mg, 0.063 mmol) in DMA (2 mL), Zn(CN) 2 (37mg, 0.32mmol), Zn(4.1mg, 0.063mmol), Zn(OAc) 2 (11.6 mg, 0.063 mmol), DPPF (17.8 mg, 0.032 mmol) and Pd 2 (dba) 3 CHCl 3(32.6 mg, 0.032 mmol) was added. The mixture was stirred at 160° C. for 1.5 h under microwave conditions. TFA (0.2 mL) was then added to the mixture and the mixture was stirred at room temperature for an additional 1 h. The mixture was concentrated under reduced pressure. The residue was diluted with DCM (20 mL) and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give Example 33 (1.8 mg, 4.8%). LCMS: MS (ESI) m / z (M+H) + = 524.3. 1 H NMR(400 MHz, d6-DMSO)δ 7.45(d, J = 7.7 Hz, 1H), 7.24(t, J = 7.9 Hz, 1H), 7.01(d, J = 7.9 Hz, 1H), 6.68(s, 1H), 6.36(s, 1H), 5.16 - 4.91(m, 2H), 3.99 - 3.81(m, 2H), 3.71 - 3.50(m, 4H), 3.47(s, 3H), 3.42 - 3.30(m, 2H), 1.52 - 1.46(m, 4H)

[0272] Example 34: 6-Chloro-1-methyl-7-(pyrrolidin-3-yloxy)-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one [ka] Example 34 was prepared following a similar procedure to Example 32, replacing intermediate tert-butyl (2-bromoethyl)carbamate (32-1) with intermediate tert-butyl 3-bromopyrrolidine-1-carboxylate. LCMS: MS (ESI) m / z (M+H) + = 559.2. 1H NMR(400 MHz, DMSO)δ 7.46(d, J = 7.7 Hz, 1H), 7.24(t, J = 7.8 Hz, 1H), 7.02(d, J = 7.9 Hz, 1H), 6.87(s, 1H), 6.57(s, 1H), 5.35 - 5.25(m, 1H), 5.15 - 4.70(m, 2H), 4.02 - 3.82(m, 2H), 3.55(s, 3H), 3.49 - 3.25(m, 3H), 3.07 - 2.97(m, 3H), 2.22 - 2.07(m, 1H), 2.00 - 1.82(m, 1H), 1.54 - 1.44(m, 4H)

[0273] Example 35: 6-chloro-1-methyl-7-((1-methylpyrrolidin-3yl)oxy)-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one [ka] Example 35 was prepared following a similar procedure to Example 21, replacing intermediate (R)-tetrahydrofuran-3-ol (21-1) with intermediate 1-methylpyrrolidin-3-ol. LCMS: MS (ESI) m / z (M+H) + = 573.2. 1 H NMR(400 MHz, DMSO)δ 7.46(d, J = 7.5 Hz, 1H), 7.24(t, J = 7.9 Hz, 1H), 7.02(d, J = 7.9 Hz, 1H), 6.78(s, 1H), 6.56(s, 1H), 5.30 - 4.80(m, 3H), 4.05 - 3.75(m, 2H), 3.54(s, 3H), 2.87 - 2.77(m, 1H), 2.72 - 2.63(m, 2H), 2.48 - 2.30(m, 4H), 2.26(s, 3H), 1.85 - 1.73(m, 1H), 1.53 - 1.45(m, 4H)

[0274] Examples 36 and 37: 6-chloro-4-(2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-7-(2-hydroxyethoxy)-1-methylquinazolin-2(1H)-one and 6-chloro-4-(6-cyclopropyl-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-7-(2-hydroxyethoxy)-1-methylquinazolin-2(1H)-one [ka] Dioxane (2 mL) and H 2 13-2 (100 mg, 0.17 mmol), cyclopropylboronic acid (20 mg, 0.23 mmol), K 2 CO 3 (69.65 mg, 0.504 mmol) and Pd(dppf)Cl 2 A mixture of (20 mg, 0.027 mmol) was dissolved in N 2 The mixture was stirred at 100° C. for 2 hours under reduced pressure. Water (10 mL) was added to the mixture, which was then extracted with EtOAc (10 mL×3). The combined organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a mixture of compound 36-1 and compound 37-1. LCMS: MS (ESI) m / z (M+H) + = 516.2, 556.2

[0275] To a mixture of 36-1 and 37-1 (120 mg) in THF (5 mL) was added a TBAF solution (0.4 mL, 1 M in THF) dropwise. After stirring at room temperature for 1 h, the mixture was added with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC to give Example 36 (12.4 mg) and Example 37 (24.8 mg).

[0276] Example 36: LCMS:MS(ESI)m / z(M+H) + = 402.0. 1H NMR(400 MHz, DMSO)δ 7.58(d, J = 6.5 Hz, 1H), 7.34(t, J = 7.4 Hz, 1H), 7.24(t, J = 7.6 Hz, 1H), 6.95(d, J = 7.6 Hz, 1H), 6.92(s, 1H), 6.52(s, 1H), 5.35 - 4.55(m, 3H), 4.24(t, J = 4.7 Hz, 2H), 4.05 - 3.82(m, 2H), 3.76(t, J = 4.7 Hz, 2H), 3.55(s, 3H), 3.41 - 3.35(m, 2H)

[0277] Example 37: LCMS:MS(ESI)m / z(M+H) + = 442.3. 1 H NMR(400 MHz, DMSO)δ 7.18 - 7.07(m, 2H), 6.90(s, 1H), 6.80(d, J = 7.3 Hz, 1H), 6.51(s, 1H), 5.55 - 4.65(m, 3H), 4.24(t, J = 4.7 Hz, 2H), 4.05 - 3.85(m, 2H), 3.75(q, J = 4.9 Hz, 2H), 3.54(s, 3H), 3.37 - 3.33(m, 2H), 2.24 - 2.14(m, 1H), 1.01(d, J = 7.2 Hz, 2H), 0.80 - 0.60(m, 2H)

[0278] Example 38: 6-chloro-7-(2-hydroxyethoxy)-1-methyl-4-(6-methyl-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one [ka] Example 38 was prepared following a procedure similar to that of Example 37, replacing the intermediate cyclopropylboronic acid with the intermediate methylboronic acid. LCMS: MS (ESI) m / z (M+H) + = 416.1. 1H NMR(400 MHz, DMSO)δ 7.23(d, J = 7.4 Hz, 1H), 7.13(t, J = 7.6 Hz, 1H), 6.90(s, 1H), 6.79(d, J = 7.7 Hz, 1H), 6.57(s, 1H), 5.10 - 4.70(m, 3H), 4.30 - 4.19(m, 2H), 3.98 - 3.82(m, 2H), 3.79 - 3.71(m, 2H), 3.54(s, 3H), 3.49 - 3.44(m, 2H), 2.46(s, 3H)

[0279] Example 39: 6-chloro-4-(6-ethynyl-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-7-(2-hydroxyethoxy)-1-methylquinazolin-2(1H)-one [ka] The preparation of Example 39 was carried out following a similar procedure to Example 13, but replacing the intermediate 1-ethynyl-1-(trifluoromethyl)cyclopropane (1-10) with the intermediate ethynyltrimethylsilanesilane. LCMS: MS (ESI) m / z (M+H) + = 426.0. 1 H NMR(400 MHz, DMSO)δ 7.50(d, J = 7.7 Hz, 1H), 7.24(t, J = 7.9 Hz, 1H), 7.01(d, J = 7.7 Hz, 1H), 6.93(s, 1H), 6.56(s, 1H), 5.26 - 4.80(m, 3H), 4.60(s, 1H), 4.24(t, J = 4.7 Hz, 2H), 4.01 - 3.82(m, 2H), 3.78 - 3.72(m, 2H), 3.55(s, 3H), 3.30 - 3.28(m, 2H)

[0280] Example 40: 6-chloro-7-(2-hydroxyethoxy)-1-methyl-4-(6-(prop-1-yn-1yl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one [ka] Example 40 was prepared following a procedure similar to that of Example 13, but replacing intermediate 1-ethynyl-1-(trifluoromethyl)cyclopropane (1-10) with intermediate prop-1-yne. LCMS: MS (ESI) m / z (M+H) + = 440.1. 1 H NMR(400 MHz, DMSO)δ 7.41(d, J = 7.8 Hz, 1H), 7.19(t, J = 7.9 Hz, 1H), 6.95- 6.89(m, 2H), 6.54(s, 1H), 5.35 - 4.65(m, 3H), 4.24(t, J = 4.8 Hz, 2H), 4.02 - 3.84(m, 2H), 3.79 - 3.70(m, 2H), 3.55(s, 3H), 3.31 - 3.26(m, 2H), 2.14(s, 3H)

[0281] Example 41: 6-chloro-4-(6-(cyclopropylethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-7-(2-hydroxyethoxy)-1-methylquinazolin-2(1H)-one [ka] Example 41 was prepared following a procedure similar to that of Example 13, but replacing intermediate 1-ethynyl-1-(trifluoromethyl)cyclopropane (1-10) with intermediate ethynylcyclopropane. LCMS: MS (ESI) m / z (M+H) + = 466.0. 1H NMR(400 MHz, DMSO)δ 7.38(d, J = 7.4 Hz, 1H), 7.18(t, J = 7.9 Hz, 1H), 6.94 - 6.88(m, 2H), 6.55(s, 1H), 5.20 - 4.70(m, 3H), 4.24(t, J = 4.6 Hz, 2H), 4.04 - 3.82(m, 2H), 3.79 - 3.72(m, 2H), 3.54(s, 3H), 3.31 - 3.24(m, 2H), 1.71 - 1.58(m, 1H), 1.01 - 0.90(m, 2H), 0.85 - 0.77(m, 2H)

[0282] Example 42: 6-chloro-7-(2-hydroxyethoxy)-4-(6-methoxy-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-1-methylquinazolin-2(1H)-one [ka] To a mixture of 13-2 (2.0 g, 3.36 mmol) in dioxane (20 mL), 2 (pin) 2 (1.7g, 6.72mmol), Pd(dppf)Cl 2 (0.20 g, 0.336 mmol) and KOAc (1.0 g, 10.1 mmol) were added. 2 After stirring at 100° C. for 3 h under reduced pressure, the mixture was diluted with ethyl acetate (90 mL). 2 Wash with O (50 mL × 2) and add Na 2 SO 4 and concentrated to give compound 42-1 (2.0 g). LCMS: MS (ESI) m / z (M+H) + = 642.0

[0283] To a mixture of 42-1 (2.0 g, 3.12 mmol) in ACN (20 mL) was added urea hydrogen peroxide (0.60 g, 6.23 mmol). After stirring at room temperature overnight, the mixture was 2The mixture was diluted with 200 mL of ethyl acetate (100 mL × 3) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (70 mL × 2), Na 2 SO 4 The mixture was dried at 47° C., filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 42-2 (1.1 g, 66.4%). LCMS: MS(ESI) m / z(M+H) + = 532.2

[0284] To a mixture of 42-2 (30 mg, 0.056 mmol) in DMF (2 mL), 2 NaH (3 mg, 60% in mineral oil) was added at 0° C. under reduced pressure. The mixture was stirred for 15 min, then iodomethane (41 mg, 0.29 mmol) was added. The reaction mixture was cooled to 5° C. and cooled to 5° C. 2 The mixture was stirred at room temperature overnight under reduced pressure. The mixture was diluted with ethyl acetate (15 mL) and diluted with H 2 Wash with O (10 mL × 2) and add Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give compound 42-3 (25 mg, 81.2%). LCMS: MS(ESI) m / z(M+H) + = 546.0

[0285] To a mixture of 42-3 (45 mg, 0.082 mmol) in THF (2 mL) was added TBAF (0.17 mL, 1 M in THF). After stirring at room temperature for 1 h, the mixture was diluted with ethyl acetate (20 mL) and diluted with H 2 Wash with O (3 × 20 mL) and add Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give Example 42 (14.1 mg, 39.6%). LCMS: MS (ESI) m / z (M+H) + = 432.1. 1H NMR(400 MHz, DMSO)δ 7.20(t, J = 8.1 Hz, 1H), 7.04(d, J = 8.2 Hz, 1H), 6.92(s, 1H), 6.68(s, 1H), 6.56(d, J = 8.0 Hz, 1H), 4.96(t, J = 5.1 Hz, 1H), 4.27 - 4.21(m, 2H), 3.90 - 3.85(m, 4H), 3.78 - 3.73(m, 2H), 3.56(s, 3H), 3.37 - 3.34(m, 2H), 3.31(s, 3H)

[0286] Example 43: 6-chloro-4-(6-cyclopropoxy-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-7-(2-hydroxyethoxy)-1-methylquinazolin-2(1H)-one [ka] Example 43 was prepared following a procedure similar to that of Example 42, but replacing the intermediate iodomethane with the intermediate cyclopropyl bromide. LCMS: MS (ESI) m / z (M+H) + = 458.0. 1 H NMR(400 MHz, DMSO)δ 7.32(d, J = 8.0 Hz, 1H), 7.21(t, J = 8.0 Hz, 1H), 6.90(s, 1H), 6.60(s, 1H), 6.56(d, J = 8.0 Hz, 1H), 5.20 - 4.75(m, 2H), 3.31 - 4.18(m, 2H), 4.02 -3.93(m, 1H), 3.88 - 3.82(m, 2H), 3.81 - 3.70(m, 2H), 3.53(s, 3H), 3.48 - 3.37(m, 2H), 3.88 - 3.80(m, 2H), 3.78 - 3.70(m, 2H)

[0287] Example 44: 4-(6-cyclopropyl-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-7-(2-hydroxyethoxy)-1-methyl-2-oxo-1,2-dihydroquinazoline-6-carbonitrile [ka] Example 44 was prepared following a procedure similar to that of Example 14, replacing intermediate 7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-chloro-1-methyl-4-(6-((1-(trifluoromethyl)cyclopropyl)ethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)quinazolin-2(1H)-one (13-3) with intermediate 7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-chloro-4-(6-cyclopropyl-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-1-methylquinazolin-2(1H)-one (37-1). LCMS: MS(ESI) m / z(M+H) + = 433.2. 1 H NMR(400 MHz, MeOD)δ 7.28 - 7.12(m, 2H), 6.96(s, 1H), 6.86 -6.79(m, 2H), 5.70 - 5.38(m, 2H), 4.38 - 4.26(m, 2H), 4.09 - 3.96(m, 2H), 3.65(s, 3H), 3.45 - 3.26(m, 2H), 2.24 - 2.08(m, 1H), 1.11 - 0.99(m, 2H), 0.90 - 0.62(m, 2H)

[0288] Example 45: 4-(6-ethyl-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-7-(2-hydroxyethoxy)-1-methyl-2-oxo-1,2-dihydroquinazoline-6-carbonitrile [ka] To a mixture of 13-2 (150 mg, 0.25 mmol) in dioxane (10 mL), ethylboronic acid (37 mg, 0.50 mmol), K 2 CO 3 (105 mg, 0.76 mmol) and PdCl 2 (dppf) (18 mg, 0.025 mmol) was added. 2 After stirring at 100° C. under reduced pressure overnight, the mixture was poured into water (30 mL) and extracted with EA (3×10 mL). 2 SO 4 The mixture was dried at 47° C., filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 45-1 (130 mg, 94.8%). LCMS: MS(ESI) m / z(M+H) + = 544.3

[0289] To a mixture of 45-1 (130 mg, 0.24 mmol) in DMA (3 mL), Zn(CN) 2 (56mg, 0.48mmol), Zn(16mg, 0.24mmol), Zn(OAc) 2 (44mg, 0.24mmol), Pd 2 (dba) 3 (22 mg, 0.024 mmol) and DPPF (41 mg, 0.072 mmol) were added. The mixture was stirred in a sealed tube under microwave at 150° C. for 1 h, then the mixture was filtered through a pad of Celite. The filtrate was poured into water (30 mL) and extracted with EA (3×10 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 45-2 (120 mg, 93.9%). LCMS: MS(ESI) m / z(M+H) + = 535.3

[0290] To a mixture of 45-2 (120 mg, 0.22 mmol) in THF (10 mL) was added TBAF (0.23 mL, 1M in THF). After stirring at room temperature for 2 h, the mixture was quenched with water (30 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with water (10 mL), filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give Example 45 (11.5 mg). LCMS: MS (ESI) m / z (M+H) + = 421.0. 1 H NMR(400 MHz, DMSO)δ 7.27(d, J = 7.2 Hz, 1H), 7.18(t, J = 7.6 Hz, 1H), 6.91(s, 1H), 6.84(d, J = 7.6 Hz, 1H), 6.69(s, 1H), 5.05 - 4.70(m, 3H), 4.33 - 4.25(m, 2H), 4.00 - 3.82(m, 2H), 3.77 - 3.72(m, 2H), 3.53(s, 3H), 3.34 - 3.33(m, 2H), 2.82(d, J = 7.6 Hz, 2H), 1.18(t, J = 7.6 Hz, 3H)

[0291] Example 46: 7-(2-hydroxyethoxy)-1-methyl-2-oxo-4-(6-(pyrrolidin-1yl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-1,2-dihydroquinazoline-6-carbonitrile [ka] 13-2 (110 mg, 0.19 mmol), pyrrolidine (0.04 mL, 0.46 mmol), Xphos (18 mg, 0.037 mmol), Cs in toluene (2 mL) 2 CO 3 (181 mg, 0.56 mmol) and Pd 2 (dba) 3 (17 mg, 0.018 mmol) in a sealed tube with N 2The mixture was stirred at 80° C. for 2 h under reduced pressure. Water (10 mL) was added to the mixture and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×20 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give compound 46-1 (100 mg, 92.4%). LCMS: MS (ESI) m / z (M+H) + = 585.4

[0292] To a solution of 46-1 (100 mg, 0.17 mmol) in DMA (3 mL), Zn (11 mg, 0.17 mmol), Zn(CN) 2 (40 mg, 0.34 mmol), Zn(OAc) 2 (31 mg, 0.17 mmol), dppf (19 mg, 0.034 mmol) and Pd 2 (dba) 3 -CHCl 3 (18 mg, 0.017 mmol) was added. After stirring in a sealed tube under microwave at 150° C. for 1 h, the mixture was diluted with EtOAc (10 mL) and filtered. The filtrate was washed with water (2×10 mL) and brine (10 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give compound 46-2 (50 mg, 50.8%). LCMS: MS (ESI) m / z (M+H) + = 576.1

[0293] To a mixture of 46-2 (50 mg, 0.087 mmol) in THF (2 mL) was added TBAF (0.17 mL THF, 1 M THF). After stirring at room temperature for 1 h, the mixture was diluted with EtOAc (15 mL). The mixture was diluted with H 2 Wash with O (3 × 20 mL) and add Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give Example 46 (13.6 mg, 33.8%). LCMS: MS (ESI) m / z (M+H) += 462.1. 1 H NMR(400 MHz, DMSO)δ 7.00(t, J = 7.9 Hz, 1H), 6.93 - 6.89(m, 2H), 6.88 - 6.85(m, 1H), 6.40(d, J = 7.7 Hz, 1H), 5.35 - 4.91(m, 3H), 4.33 - 4.27(m, 2H), 4.04 - 3.80(m, 2H), 3.79 - 3.70(m, 2H), 3.56(s, 3H), 3.51 - 3.33(m, 2H), 2.99 - 2.73(m, 4H), 1.97 - 1.84(m, 4H)

[0294] Example 47: 4-(6-(cyclopropylethynyl)-2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)yl)-7-(2-hydroxyethoxy)-1-methyl-2-oxo-1,2-dihydroquinazoline-6-carbonitrile [ka] The preparation of Example 47 was carried out following a similar procedure to Example 13 and Example 14, substituting intermediate 1-ethynyl-1-(trifluoromethyl)cyclopropane (1-10) with intermediate ethynylcyclopropane. LCMS: MS (ESI) m / z (M+H) + = 457.2. 1 H NMR(400 MHz, DMSO)δ 7.40(d, J = 8.0 Hz, 1H), 7.18(t, J = 8.0 Hz, 1H), 6.97 - 6.90(m, 2H), 6.81(s, 1H), 5.19 - 4.79(m, 3H), 4.30(t, J = 4.6 Hz, 2H), 4.01 - 3.80(m, 2H), 3.80 - 3.72(m, 2H), 3.54(s, 3H), 3.41 - 3.27(m, 2H), 1.72 - 1.57(m, 1H), 1.02 - 0.90(m, 2H), 0.87 - 0.77(m, 2H)

[0295] Example A: DGKA Inhibition ADP-Glo ​​Assay DGKA inhibition reactions were performed using the ADP-Glo ​​assay. 2 , 1 mM CaCl 2 Reactions were performed with 0.005% Triton X-100 and 1 mM DTT as working solution (pH = 7.5). 30 nL of each test compound in DMSO (maximum concentration 0.4 μM, 10-point 4-fold dilution series) was transferred to a 384-well plate with an Echo and 5 μL of DGKA (SignalChem, D21-10BG) enzyme working solution was added to each well at twice the final reaction concentration. After 15 min of incubation at 25 °C, the reaction was started by adding 5 μL of substrate working solution containing 40 μM ATP (Promega, V915B) and 200 μM DLG (SignalChem, D430-59). After 60 min of enzyme reaction at 25 °C, ADP Glo assay reagent (Promega, V9102) was added and luminescence was recorded using EnVision according to the manual instructions. Percent inhibition was calculated from the luminescence from control reactions without enzyme for 100% inhibition and from reactions with DMSO only for 0% inhibition. IC 50 Values ​​were calculated by regression analysis of inhibition rates.

[0296] The data for Example A are shown in Table 3. [Table 3]

[0297] Example B: IL-2 Release Detection Assay Isolate human pan-T cells from PBMCs according to the T cell isolation kit (Stemcell, 17951). T cells were suspended in RPMI1640 medium containing 10% FBS, 1% PS, and 55 μM β-Mer at a density of 3*10^6 cells / well / 3 ml and seeded in a 6-well plate and incubated at 37°C and 5% CO 2 The T cells were then harvested and suspended in fresh RPMI 1640 medium containing 10% FBS, 1% PS, and 55 μM β-Mer, and stained with anti-CD40. 3Seed 1*10^5 cells / well / 200μl in a pre-coated 96-well plate. Add compound dilutions to the cells and incubate at 37℃ and 5% CO 2 The cells were incubated at 4°C for 24 hours. IL-2 in the cell supernatant was detected using an ELISA kit (R&D, DY202). The EC 50 Fit a nonlinear regression equation: Y=Bottom+(Top-Bottom) / (1+10^((LogEC50-X)*HillSlope)), where X=compound concentration, Y=percent activation. Top and Bottom: Plateaus in the same units as Y. LogEC 50 : Logarithmic units the same as X. Activation fold: Top activation / DMSO control. Activation percentage at 100 nM: Nonlinear regression curve of activation at a concentration of 100 nM / DMSO control*100%. The data for Example B is shown in Table 4. [Table 4]

[0298] Example C: Pharmacokinetic profile evaluation Species and strain: SPF male CD-1 mice. Source: Sino-British SIPPR / BK Lab Animal Ltd, Shanghai. Three mice were orally gavage administrated with the given compound (formulation: 5% DMSO + 10% Solutol + 85% saline). After oral gavage administration, blood samples were collected via the cephalic vein (30 μL / time point) at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours. Blood samples were placed in tubes containing K2-EDTA and kept on ice until centrifugation. Blood samples were centrifuged at 6800g for 6 min at 2-8°C within 1 hour of collection and kept frozen at approximately -80°C. Aliquots of 10 μL plasma samples were protein precipitated with 200 μL MeOH containing 10 ng / mL verapamil (IS). The mixture was vortexed for 1 min and centrifuged at 18000g for 7 min. 180 μL of the supernatant was transferred to a 96-well plate. An aliquot of 6 μL of the supernatant was injected for LC-MS / MS analysis by an LC-MS / MS-04 (API4000) instrument. Quality control samples of intra-assay variability were used to confirm the analytical results. The precision of the quality control samples, >66.7%, should be 80-120% of the known value(s). A standard set of parameters, including area under the curve (AUC(0-t) and AUC(0-∞)), elimination half-life (T1 / 2), and maximum plasma concentration (Cmax), will be calculated using the noncompartmental analysis module of the FDA-approved pharmacokinetic program Phoenix WinNonlin7.0 (Pharsight, USA).

[0299] Species and strain: SPF male SD rats. Source: Sino-British SIPPR / BK Lab Animal Ltd, Shanghai. Three rats were gavaged with the given compound (formulation: 5% DMSO + 10% Solutol + 85% saline). After gavage, blood samples were collected via the submandibular vein or other suitable vein (0.15 mL / time point) at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours. Blood samples were placed in tubes containing K2-EDTA and kept on ice until centrifugation. Blood samples were centrifuged at 6800g, 2-8°C for 6 min within 1 h of collection and stored frozen at approximately -80°C. An aliquot of 30 μL of plasma sample was protein precipitated with 300 μL MeOH containing 100 ng / mL verapamil (IS). The mixture was vortexed for 1 min and centrifuged at 18000g for 7 min. Transfer 300 μL of the supernatant into a 96-well plate. An aliquot of 8 μL of the supernatant was injected for LC-MS / MS analysis by an LC-MS / MS-12 (TQ5500) instrument. Quality control samples of intra-assay variability were used to confirm the analytical results. The precision of the quality control samples, >66.7%, should be 80-120% of the known value(s). The area under the curve (AUC) was calculated using the noncompartmental analysis module of the FDA-approved pharmacokinetic program Phoenix WinNonlin 7.0 (Pharsight, USA). (0-t) and AUC (0-∞) ), elimination half-life (T 1 / 2 ), maximum plasma concentration (C max ) will be calculated.

[0300] The data for Example C are shown in Tables 5 and 6. [Table 5] [Table 6]

[0301] Based on both mouse and rat PK evaluation results, Examples 13 and 41 have longer T 1 / 2 , much higher C max and AUC are shown.

Claims

1. Compound of formula (A): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, During the ceremony: R １ａ is halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; W is N or CR １ｂ and Each R １ｂ are independently hydrogen, halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; R ２ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl; U is N or CR Ｕ and R Ｕ is hydrogen, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Ring B is heterocycloalkyl; Each R ３ are independently halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Or two R on the same atom ３ together to form oxo; or two R on the same or different carbons ３ taken together to form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; m is 0 to 6; X is N or CR Ｘ and R Ｘ is hydrogen, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Y is N or CR Ｙ and R Ｙ is hydrogen, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Z is N or CR Ｚ and R Ｚ is hydrogen, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; R ５ Hydrogen, halogens, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, 【Chemistry 2】 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; R ４ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally selected from one or more R ４ａ is replaced by; Each R ４ａ are independently halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Or two R on the same atom ４ａ together to form oxo; Each R ａ became independent and C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ alkylene(heteroaryl), wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently and optionally substituted with one or more R; Or two R's ａ together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R ｂ are independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ alkylene(heteroaryl), wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently and optionally substituted with one or more R; Or two R's ｂ together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R ｃ and R ｄ are each independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ alkylene(heteroaryl), wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently and optionally substituted with one or more R; and Or R ｃ and R ｄ together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently halogen, —CN, —OH, —S(═O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, or C ３ ~C ６ is cycloalkyl; or two R on the same atom form an oxo; A compound or a pharma- ceutically acceptable salt thereof.

2. The compound is a compound of formula (Aa): 【Chemistry 3】 2. The compound of claim 1, wherein:

3. R １ａ Ga-OR ａ 3. The compound according to claim 1 or 2, which is: or a pharma- ceutically acceptable salt thereof.

4. R １ｂ The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein is halogen or -CN.

5. R ２ is hydrogen or C １ ~C ６ The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

6. The compound according to any one of claims 1 to 5, wherein U is N, or a pharma- ceutically acceptable salt thereof.

7. The compound according to any one of claims 1 to 6, wherein Ring B is a 6-8 membered heterocycloalkyl, or a pharma- ceutically acceptable salt thereof.

8. A compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof.

9. The compound according to any one of claims 1 to 8, wherein m is 0, or a pharma- ceutically acceptable salt thereof.

10. R Ｘ The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

11. R Ｙ The compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

12. R Ｚ The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

13. R ５ But the following 【Chemistry 5】 13. The compound according to any one of claims 1 to 12, wherein:

14. R ４ But, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally selected from one or more R ４ａ 14. The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, substituted with:

15. R ４ is 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl; said cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally selected from one or more R ４ａ 15. The compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, substituted with:

16. R ４ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; each optionally being selected from one or more R ４ａ 16. The compound according to any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, substituted with:

17. Each R ４ａ are independently halogen, —CN, —OH, —OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ 17. The compound of any one of claims 1 to 16, wherein heteroalkyl, 3- to 6-membered cycloalkyl, or 5- to 6-membered heterocycloalkyl; and wherein alkyl, cycloalkyl, and heterocycloalkyl are each optionally and independently substituted with one or more R, or a pharma- ceutically acceptable salt thereof.

18. 2. The compound of claim 1, wherein the compound is selected from the compounds shown in Table 1 or Table 2, or a pharma- ceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

20. 20. A method of inhibiting the activity of at least one diacylglycerol kinase selected from diacylglycerol kinase alpha (DGKα) and diacylglycerol kinase zeta (DGKζ) in a subject in need of such inhibition, comprising administering to the subject a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof.

21. 20. A method of inhibiting the activity of diacylglycerol kinase alpha (DGKα) in a subject in need of such inhibition, comprising administering to the subject a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof.

22. 20. A method of modulating the activity of at least one diacylglycerol kinase selected from diacylglycerol kinase alpha (DGKα) and diacylglycerol kinase zeta (DGKζ) in a subject in need of said modulation, comprising administering to said subject a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof.

23. 20. A method of modulating diacylglycerol kinase alpha (DGKα) activity in a subject in need of said modulation, comprising administering to said subject a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof.

24. 20. A method of treatment of a disease associated with abnormalities in diacylglycerol kinase signaling in a subject in need of such treatment, comprising administering to the subject a compound according to any one of claims 1 to 18 or a pharma- ceutically acceptable salt thereof.

25. 25. The method of claim 24, wherein the diacylglycerol kinase is diacylglycerol kinase alpha.

26. 20. A method of treating a disease in a subject in need of such treatment, comprising administering to said subject a compound according to any one of claims 1 to 18 or a pharma- ceutically acceptable salt thereof.

27. 27. The method of claim 25 or 26, wherein the disease is cancer or a viral infection.

28. The method of any one of claims 20 to 27, further comprising administering an additional therapeutic agent.

29. 30. The method of claim 28, wherein the additional therapeutic agent is an anti-cancer agent or an anti-viral agent.

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