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 / 078653, filed March 1, 2022; International Application No. PCT / CN2022 / 091497, filed May 7, 2022; International Application No. PCT / CN2022 / 127020, filed October 24, 2022; and International Application No. PCT / CN2023 / 071857, 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 (I): [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony: Ring A is phenyl or 6-membered 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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; 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, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , 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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; 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 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 adjacent carbons3 together form an alkenylene; 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 8; T is N or CR T and; R T is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, or C 1 ~C 6 is heteroalkyl; Each R 4 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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; p is 0 to 4; Each R a is independently 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 each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Or two R's atogether 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 each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 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 ~C6 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 each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 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; and 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 6Heteroalkyl, or C 3 ~C 6 is cycloalkyl; or two R on the same atom form an oxo; or a pharma- ceutically acceptable salt thereof.

[0005] In some embodiments of the compound of Formula (I), the compound has the formula (Ia): [ka] It is.

[0006] In some embodiments of the compound of Formula (I), the compound has the formula (Ib): [ka] It is.

[0007] In some embodiments of the compound of Formula (I), the compound has the formula (Ic): [ka] It is.

[0008] In some embodiments of the compound of Formula (I), the compound has the formula (Id): [ka] It is.

[0009] In some embodiments of the compound of Formula (I), the compound has the formula (Ie): [ka] It is.

[0010] In some embodiments of the compound of Formula (I), the compound has the formula (If): [ka] and In the formula, each R 1a and R 1b are independently 1 is selected from.

[0011] In some embodiments of the compound of Formula (I), the compound has the formula (Ig): [ka] and In the formula, each R 1a and R 1b are independently 1 is selected from.

[0012] Disclosed herein is a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony: Ring A is phenyl or 6-membered 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)Ra , -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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; 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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Ring B is a bicyclic ring; 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 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; m is 0 to 8; Each R 4 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 6Hydroxyalkyl, 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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; p is 0 to 4; Each R a is independently 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 each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 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 bare 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 each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 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, C1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 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; and 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; or a pharma- ceutically acceptable salt thereof.

[0013] In some embodiments of the compound of Formula (II), the compound has the formula (IIa): [ka] It is.

[0014] In some embodiments of the compound of Formula (II), the compound has the formula (IIb): [ka] It is.

[0015] In some embodiments of the compound of Formula (II), the compound has the formula (IIc): [ka] It is.

[0016] In some embodiments of the compound of Formula (II), the compound has the formula (IId): [ka] It is.

[0017] In some embodiments of the compound of Formula (II), the compound has the formula (IIe): [ka] It is.

[0018] 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.

[0019] 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.

[0020] 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.

[0021] Further disclosed herein is a method of treating a disease associated with abnormalities in diacylglycerol kinase signaling in a subject in need thereof, the method comprising administering to the subject a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0022] 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.

[0023] 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

[0024] 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.

[0025] 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.

[0026] As used herein, the following terms have the following meanings unless otherwise indicated.

[0027] "Oxo" means =O.

[0028] "Carboxyl" means --COOH.

[0029] "Cyano" means --CN.

[0030] "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.

[0031] "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.

[0032] "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.

[0033] "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.

[0034] "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, an alkoxy is optionally substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with a halogen.

[0035] "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.

[0036] "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.

[0037] "Halo" or "halogen" means bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0038] "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.

[0039] "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.

[0040] "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.

[0041] "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.

[0042] "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.

[0043] "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.

[0044] 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 ...

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] Disclosed herein is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony: Ring A is phenyl or 6-membered 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 , C1 ~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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; 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, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , 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 ~C6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; 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 6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each 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 adjacent carbons 3 together form an alkenylene; 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 8; T is N or CR T and; R T is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, or C 1 ~C 6 is heteroalkyl; Each R 4 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 , -NRb 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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; p is 0 to 4; Each R a is independently 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), C1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 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 each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 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, C1 ~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 each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 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; and 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; or a pharma- ceutically acceptable salt thereof.

[0053] Disclosed herein is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, In the above formula (I): Ring A is phenyl or 6-membered 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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; 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, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , 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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; 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, C1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each 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 8; T is N or CR T and; R T is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, or C 1 ~C 6 is heteroalkyl; Each R 4 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 bC(=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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; p is 0 to 4; Each R a is independently 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), C1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 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 each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 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; Rc 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 each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 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; and 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; or a pharma- ceutically acceptable salt thereof.

[0054] In some embodiments of the compound of formula (I), ring A is phenyl. In some embodiments of the compound of formula (I), ring A is 6-membered heteroaryl. In some embodiments of the compound of formula (I), ring A is pyridinyl.

[0055] In some embodiments of the compound of Formula (I), the compound has the formula (Ia): [ka] It is.

[0056] In some embodiments of the compound of Formula (I), the compound has the formula (Ib): [ka] It is.

[0057] In some embodiments of the compound of formula (Ib), the compound has formula (Ic): [ka] It is.

[0058] In some embodiments of the compound of Formula (I), the compound has the formula (Id): [ka] It is.

[0059] In some embodiments of the compound of Formula (I), the compound has the formula (Ie): [ka] It is.

[0060] In some embodiments of the compound of Formula (I), the compound has the formula (If): [ka] and In the formula, each R 1a and R 1b are independently 1 is selected from.

[0061] In some embodiments of the compound of Formula (I), the compound has the formula (Ig): [ka] and In the formula, each R 1a and R 1b are independently 1 is selected from.

[0062] In some embodiments of the compound of Formula (Ib), n is 1 or 2; 1 are independently -CN, -O-heterocycloalkyl, -OC 1 ~C 6 Alkyl, -OC 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Hydroxyl alkyl or -OC 1 ~C 6 R is an aminoalkyl; 2 is C 1 ~C6 alkyl; T is CH; U is N or CH; p is 1 or 2; and each R 4 are independently halogen or C 1 ~C 6 In some embodiments of the compound of Formula (Ib), p is 1. In some embodiments of the compound of Formula (Ib), p is 2. In some embodiments, R 4 is a halogen, such as F. In some embodiments, R 4 is C 1 ~C 6 In some embodiments of the compound of formula (Ib), R 4 is C 1 ~C 3 In some embodiments of the compound of formula (Ib), R 4 is methyl. In some embodiments, R 2 is C 1 ~C 3 In some embodiments of the compound of formula (Ib), R 2 In some embodiments of the compound of Formula (Ib), U is N. In some embodiments, U is CH. In some embodiments of the compound of Formula (Ib), each R 1 are independently -CN, -O-heterocycloalkyl, -OC 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Hydroxyl alkyl or -OC 1 ~C 6 In some embodiments of the compound of Formula (Ib), each R 1 is independently -CN or -O-heterocycloalkyl. In some embodiments of the compound of Formula (Ib), each R 1 are independently -CN or -OC 1 ~C 6 In some embodiments of the compound of Formula (Ib), each R 1 are independently -CN or -OC 1 ~C 6In some embodiments of the compound of Formula (Ib), each R 1 are independently -CN or -OC 1 ~C 3 In some embodiments of the compound of Formula (Ib), each R 1 are independently -CN or -OC 1 ~C 6 In some embodiments of the compound of Formula (Ib), each R 1 are independently -CN or -O-CH 2 CH 2 In some embodiments of the compound of formula (Ib), at least one R 1 is CN. In some embodiments of the compound of Formula (Ib), n' is 1. In some embodiments of the compound of Formula (Ib), n' is 2.

[0063] In some embodiments of the compound of Formula (If), each R 1a and R 1b are independently -CN, -O-heterocycloalkyl, -OC 1 ~C 6 Alkyl, -OC 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Hydroxyl alkyl or -OC 1 ~C 6 R is an aminoalkyl; 2 is C 1 ~C 6 alkyl; T is CH; U is N or CH; p is 1 or 2; and R 4 are independently halogen or C 1 ~C 6 In some embodiments of the compound of formula (If), p is 1. In some embodiments of the compound of formula (If), p is 2. In some embodiments of the compound of formula (If), R 4 is a halogen, such as F. In some embodiments of the compound of formula (If), R 4 is C 1 ~C6 In some embodiments of the compound of formula (If), R 4 is C 1 ~C 3 In some embodiments of the compound of formula (If), R 4 is methyl. In some embodiments of the compound of formula (If), R 2 is C 1 ~C 3 In some embodiments of the compound of formula (If), R 2 is methyl. In some embodiments of the compound of formula (If), U is N. In some embodiments of the compound of formula (If), U is CH. In some embodiments of the compound of formula (If), each R 1a and R 1b are independently -CN, -O-heterocycloalkyl, -OC 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Hydroxyl alkyl or -OC 1 ~C 6 In some embodiments of the compound of formula (If), each R 1a and R 1b is independently -CN or -O-heterocycloalkyl. In some embodiments of the compound of Formula (If), each R 1a and R 1b are independently -CN or -OC 1 ~C 6 In some embodiments of the compound of formula (If), each R 1a and R 1b are independently -CN or -OC 1 ~C 6 In some embodiments of the compound of formula (If), each R 1a and R 1b are independently -CN or -OC 1 ~C 6 In some embodiments of the compound of formula (If), R 1a is C 1 ~C 6hydroxylalkyl, R 1b In some embodiments of the compound of formula (If), R 1a is C 1 ~C 3 hydroxylalkyl, R 1b In some embodiments of the compound of formula (If), R 1a is -O-CH 2 CH 2 OH and R 1b is CN.

[0064] In some embodiments of the compound of Formula (If), each R 1a and R 1b are independently -CN, -O-heterocycloalkyl, -OC 1 ~C 6 Alkyl, -OC 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Hydroxyl alkyl or -OC 1 ~C 6 R is an aminoalkyl; 2 is C 1 ~C 6 alkyl; T is CH; U is N or CH; and R 4 is halogen or C 1 ~C 6 In some embodiments of the compounds of formula (Ig), R 4 is a halogen, such as F. In some embodiments of the compounds of Formula (Ig), R 4 is C 1 ~C 6 In some embodiments of the compounds of formula (Ig), R 4 is C 1 ~C 3 In some embodiments of the compounds of formula (Ig), R 4 is methyl. In some embodiments of the compound of Formula (Ig), R 2 is C 1 ~C 3 In some embodiments of the compounds of formula (Ig), R2 is methyl. In some embodiments of the compound of Formula (Ig), U is N. In some embodiments of the compound of Formula (Ig), U is CH. In some embodiments of the compound of Formula (Ig), each R 1a and R 1b are independently -CN, -O-heterocycloalkyl, -OC 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Hydroxyl alkyl or -OC 1 ~C 6 In some embodiments of the compound of Formula (Ig), each R 1a and R 1b is independently -CN or -O-heterocycloalkyl. In some embodiments of the compound of Formula (Ig), each R 1a and R 1b are independently -CN or -OC 1 ~C 6 In some embodiments of the compound of Formula (Ig), each R 1a and R 1b are independently -CN or -OC 1 ~C 6 In some embodiments of the compound of Formula (Ig), each R 1a and R 1b are independently -CN or -OC 1 ~C 6 In some embodiments of the compounds of formula (Ig), R 1a is C 1 ~C 6 hydroxylalkyl, R 1b In some embodiments of the compound of formula (Ig), R 1a is C 1 ~C 3 hydroxylalkyl, R 1b In some embodiments of the compound of formula (Ig), R 1a is -O-CH 2 CH 2 OH and R 1b is CN.

[0065] In some embodiments of the compound of formula (If) or (Ig), 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 (If) or (Ig), 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 (If) or (Ig), R 1a is halogen, -CN, C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of formula (If) or (Ig), R 1a is halogen or -CN. In some embodiments of the compound of formula (If) or (Ig), R 1a is halogen. In some embodiments of the compound of formula (If) or (Ig), R 1a is fluoro or chloro. In some embodiments of the compounds of formula (If) or (Ig), R 1a In some embodiments of the compound of formula (If) or (Ig), R 1aare independently halogen, -CN, -OR a , or -NR c R d In some embodiments of the compound of formula (If) or (Ig), R 1a -CN or -OR a In some embodiments of the compound of formula (If) or (Ig), 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 compound of formula (If) or (Ig), 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 compound of formula (If) or (Ig), R 1a are independently -CN or -NR c R d In some embodiments of the compound of formula (If) or (Ig), -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 (If) or (Ig), -OR aIn some embodiments of the compound of formula (If) or (Ig), -OR a is [ka] In some embodiments of the compound of formula (If) or (Ig), -OR a -OC 1 ~C 6 In some embodiments of the compound of formula (If) or (Ig), -OR a -OC 1 ~C 6 In some embodiments of the compound of formula (If) or (Ig), -OR a -OC 1 ~C 6 In some embodiments of the compound of formula (If) or (Ig), -OR a -OC 1 ~C 6 It is an aminoalkyl.

[0066] In some embodiments of the compound of formula (If) or (Ig), R 1b 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 (If) or (Ig), R 1bis 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 (If) or (Ig), R 1b is halogen, -CN, C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of formula (If) or (Ig), R 1b is halogen or -CN. In some embodiments of the compound of formula (If) or (Ig), R 1b is halogen. In some embodiments of the compound of formula (If) or (Ig), R 1b is fluoro or chloro. In some embodiments of the compounds of formula (If) or (Ig), R 1b In some embodiments of the compound of formula (If) or (Ig), R 1b are independently halogen, -CN, -OR a , or -NR c R d In some embodiments of the compound of formula (If) or (Ig), R 1b -CN or -OR a In some embodiments of the compound of formula (If) or (Ig), 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 compound of formula (If) or (Ig), R 1b is -CN, -O-heterocycloalkyl, -OC 1 ~C 3 Alkyl, -OC1 ~C 3 Haloalkyl, -OC 1 ~C 3 Hydroxyl alkyl or -OC 1 ~C 3 In some embodiments of the compound of formula (If) or (Ig), R 1b are independently -CN or -NR c R d In some embodiments of the compound of formula (If) or (Ig), -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 (If) or (Ig), -OR a In some embodiments of the compound of formula (If) or (Ig), -OR a is [ka] In some embodiments of the compound of formula (If) or (Ig), -OR a -OC 1 ~C 6 In some embodiments of the compound of formula (If) or (Ig), -OR a -OC 1 ~C 6 In some embodiments of the compound of formula (If) or (Ig), -OR a -OC 1 ~C 6 In some embodiments of the compound of formula (If) or (Ig), -OR a -OC 1 ~C 6 It is an aminoalkyl.

[0067] In some embodiments of the compound of Formula (I) or (Ia), n is 0, 1, 2, 3, or 4. In some embodiments of the compound of Formula (I) or (Ia), n is 0 to 2. In some embodiments of the compound of Formula (I) or (Ia), n is 0 or 1. In some embodiments of the compound of Formula (I) or (Ia), n is 2. In some embodiments of the compound of Formula (I) or (Ia), n is 1. In some embodiments of the compound of Formula (I) or (Ia), n is 0.

[0068] In some embodiments of the compounds of Formula (Ib)-(Ie), n' is 0, 1, 2, or 3. 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 2. 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 0.

[0069] In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), 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) or (Ia)-(Ig), 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) or (Ia)-(Ig), each R 1 are independently halogen, -CN, C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), each R 1 is independently halogen or -CN. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), each R 1 is independently a halogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), each R 1 is independently fluoro or chloro. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), each R 1 is independently -CN. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), each R 1 are independently halogen, -CN, -OR a , or -NR c R d In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), each R 1 are independently -CN or -OR a In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), each R 1 are independently -CN, -O-heterocycloalkyl, -OC 1 ~C 6 Alkyl, -OC 1 ~C 6 Haloalkyl, -OC 1 ~C 6Hydroxyl alkyl or -OC 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), each R 1 are independently -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 (I) or (Ia)-(Ig), each R 1 are independently -CN or -NR c R d In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), -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 (I) or (Ia)-(Ig), -OR a In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), -OR is -O-heterocycloalkyl, wherein the heterocycloalkyl is a 5- or 6-membered ring. a is [ka] In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), -OR a -OC 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), -OR a -OC 1 ~C 6In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), -OR a -OC 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), -OR a -OC 1 ~C 6 In some embodiments, each R 1 are independently -CN, -O-heterocycloalkyl, -OC 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Hydroxyl alkyl or -OC 1 ~C 6 In some embodiments, each R 1 is independently -CN or -O-heterocycloalkyl. In some embodiments, each R 1 are independently -CN or -OC 1 ~C 6 In some embodiments, each R 1 are independently -CN or -OC 1 ~C 6 In some embodiments, each R 1 are independently -CN or -OC 1 ~C 3 In some embodiments, each R 1 are independently -CN or -O-CH 2 CH 2 In some embodiments, each R 1 are independently -CN or -OC 1 ~C 6 In some embodiments, at least one R 1 is -CN.

[0070] In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), R 2 is hydrogen or C 1 ~C6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), R 2 is C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), R 2 is C 1 ~C 3 In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), R 2 is methyl.

[0071] In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), U is N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), U is CR U It is.

[0072] In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), R U is hydrogen, halogen, -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 (I) or (Ia)-(Ig), R U is hydrogen, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), R U is hydrogen.

[0073] In some embodiments of the compounds of formula (I), [ka] teeth, [ka] It is.

[0074] In some embodiments of the compounds of formula (I), [ka] teeth, [ka] It is.

[0075] In some embodiments of the compounds of formula (I), [ka] teeth, [ka] It is.

[0076] In some embodiments of the compounds of formula (I), [ka] teeth, [ka] It is.

[0077] In some embodiments of the compounds of formula (I), [ka] teeth, [ka] In some embodiments of the compound of formula (I), [ka] teeth, [ka] In some embodiments of the compound of formula (I), [ka] teeth, [ka] In some embodiments of the compound of formula (I), [ka] teeth, [ka] In some embodiments of the compound of formula (I), [ka] teeth, [ka] It is.

[0078] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), each R 3 are independently 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 (I) or (Ia)-(Ie), each R 3 is independently 1~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), each R 3 is independently 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), two R on the same or different carbons are alkyl. 3 taken together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), two R on different carbons are 3 taken together form a cycloalkyl optionally substituted with one or more R.

[0079] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), m is 0-4. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), m is 0-3. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), m is 0-2. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), m is 0. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), m is 1. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), m is 2. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), m is 3. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), m is 4. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), m is 3. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), m is 5-8.

[0080] In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), T is N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), T is CR T It is.

[0081] In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), R T is hydrogen or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), R T is hydrogen.

[0082] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), [ka] teeth, [ka] It is.

[0083] In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), each R 4 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 compounds of Formula (I) or (Ia)-(Ig), each R 4 are independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl or C 1 ~C 6In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), each R 4 are independently halogen, -C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), each R 4 are independently halogen or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), each R 4 is independently 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), each R 4 In some embodiments of the compounds of Formula (I) or (Ia)-(Ig), R 4 is F.

[0084] In some embodiments of the compounds of Formula (I) or (Ia)-(If), p is 0 to 2. In some embodiments of the compounds of Formula (I) or (Ia)-(If), p is 1 or 2. In some embodiments of the compounds of Formula (I) or (Ia)-(If), p is 0. In some embodiments of the compounds of Formula (I) or (Ia)-(If), p is 1. In some embodiments of the compounds of Formula (I) or (Ia)-(If), p is 2.

[0085] In some embodiments of the compounds of Formula (I) or (Ia)-(If), [ka] teeth, [ka] It is.

[0086] Disclosed herein is a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony: Ring A is phenyl or 6-membered 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 6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; 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 ~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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; Ring B is a bicyclic ring; 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 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; m is 0 to 8; Each R 4 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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally independently substituted with one or more R; p is 0 to 4; Each R ais independently 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 each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 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 6Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 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), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is 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; and 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; or a pharma- ceutically acceptable salt thereof.

[0087] In some embodiments of the compound of formula (II), ring A is phenyl. In some embodiments of the compound of formula (II), ring A is 6-membered heteroaryl. In some embodiments of the compound of formula (II), ring A is pyridinyl.

[0088] In some embodiments of the compound of Formula (II), the compound has the formula (IIa): [ka] It is.

[0089] In some embodiments of the compound of Formula (II), the compound has the formula (IIb): [ka] It is.

[0090] In some embodiments of the compound of Formula (II), the compound has the formula (IIc): [ka] It is.

[0091] In some embodiments of the compound of Formula (II), the compound has the formula (IId): [ka] It is.

[0092] In some embodiments of the compound of Formula (II), the compound has the formula (IIe): [ka] It is.

[0093] In some embodiments of the compound of formula (II), the compound has the formula (IIf): [ka] and In the formula, each R 1a and R 1b are independently 1 is selected from.

[0094] In some embodiments of the compound of Formula (II) or (IIa), n is 0, 1, 2, 3, or 4. In some embodiments of the compound of Formula (II) or (IIa), n is 0 to 2. In some embodiments of the compound of Formula (II) or (IIa), n is 0 or 1. In some embodiments of the compound of Formula (II) or (IIa), n is 2. In some embodiments of the compound of Formula (II) or (IIa), n is 1. In some embodiments of the compound of Formula (II) or (IIa), n is 0. In some embodiments of the compound of Formula (IIb)-(IIe), n' is 0 to 2. In some embodiments of the compound of Formula (IIb)-(IIe), n' is 0 or 1. In some embodiments of the compound of Formula (IIb)-(IIe), n' is 2. In some embodiments of the compound of Formula (IIb)-(IIe), n' is 1. In some embodiments of the compounds of Formulae (IIb)-(IIe), n' is 0.

[0095] In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), 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 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), each R 1 are independently halogen, -CN, -OH, -OR a , -NR c R d , C1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), each R 1 are independently halogen, -CN, C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), each R 1 is independently halogen or -CN. In some embodiments of the compound of Formula (II) or (IIa)-(IIf), each R 1 is independently a halogen. In some embodiments of the compound of Formula (II) or (IIa)-(IIf), each R 1 is independently fluoro or chloro. In some embodiments of the compound of Formula (II) or (IIa)-(IIf), each R 1 is independently -CN. In some embodiments of the compound of Formula (II) or (IIa)-(IIf), each R 1 are independently halogen, -CN, -OR a , or -NR c R d In some embodiments of the compound of Formula (II) or (IIa)-(IIf), each R 1 are independently -CN or -OR a In some embodiments of the compound of Formula (II) or (IIa)-(IIf), each R 1 are independently -CN or -NR c R d In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), -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 compounds of Formula (II) or (IIa)-(IIf), -OR a In some embodiments of the compound of Formula (II) or (IIa) through (IIf), -OR is -O-heterocycloalkyl, wherein the heterocycloalkyl is a 5- or 6-membered ring. a is [ka] In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), -OR a -OC 1 ~C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), -OR a -OC 1 ~C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), -OR a -OC 1 ~C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), -OR a -OC 1 ~C 6 In some embodiments, each R 1 are independently -CN, -O-heterocycloalkyl, -OC 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Hydroxyl alkyl or -OC 1 ~C 6 In some embodiments, each R 1 is independently -CN or -O-heterocycloalkyl. In some embodiments, each R 1 are independently -CN or -OC 1 ~C 6 In some embodiments, each R 1 are independently -CN or -OC 1 ~C6 In some embodiments, each R 1 are independently -CN or -OC 1 ~C 6 In some embodiments, at least one R 1 is -CN.

[0096] In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), R 2 is hydrogen or C 1 ~C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), R 2 is C 1 ~C 6 It is an alkyl.

[0097] In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), U is N. In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), U is CR U It is.

[0098] In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), 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 (II) or (IIa)-(IIf), R Uis 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 (II) or (IIa)-(IIf), R U is hydrogen, -CN, or -C(=O)NR c R d In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), R U is hydrogen or -CN. In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), R U is -CN.

[0099] In some embodiments of the compound of Formula (II), [ka] teeth, [ka] It is.

[0100] In some embodiments of the compound of Formula (II), [ka] teeth, [ka] It is.

[0101] In some embodiments of the compound of Formula (II), [ka] teeth, [ka] It is.

[0102] In some embodiments of the compound of Formula (II), [ka] teeth, [ka] It is.

[0103] In some embodiments of the compound of Formula (II), [ka] teeth, [ka] In some embodiments of the compound of formula (II), [ka] teeth, [ka] In some embodiments of the compound of formula (II), [ka] teeth, [ka] In some embodiments of the compound of formula (II), [ka] teeth, [ka] In some embodiments of the compound of formula (II), [ka] teeth, [ka] It is.

[0104] In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), ring B is a bicyclic heterocycloalkyl. In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), ring B is a bicyclic 6- to 10-membered heterocycloalkyl. In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), ring B is a bicyclic 6- to 10-membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), ring B is a bicyclic 6- to 10-membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), ring B is a bridged bicyclic ring. In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), Ring B is 3,8-diazabicyclo[3.2.1]octane or 2,5-diazabicyclo[2.2.2]octane. In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), Ring B is [ka] It is.

[0105] In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), each R 3 are independently 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 (II) or (IIa)-(IIf), each R 3 is independently 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), each R 3 is independently 1 ~C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), each R 3 is independently methyl or ethyl.

[0106] In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), m is 0-4. In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), m is 0-3. In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), m is 0-2. In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), m is 2. In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), m is 1. In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), m is 2. In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), m is 3. In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), m is 4. In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), m is 5-8.

[0107] In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), each R 4 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 , C1 ~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 (II) or (IIa)-(IIf), each R 4 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 (II) or (IIa)-(IIf), each R 4 are independently halogen, C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), each R 4 are independently halogen or C 1 ~C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), each R 4 is independently 1 ~C 6 In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), each R 4 In some embodiments of the compounds of Formula (II) or (IIa)-(IIf), R 4 is F.

[0108] In some embodiments of the compound of Formula (II) or (IIa)-(IIf), p is 0 to 2. In some embodiments of the compound of Formula (II) or (IIa)-(IIf), p is 1 or 2. In some embodiments of the compound of Formula (II) or (IIa)-(IIf), p is 2. In some embodiments of the compound of Formula (II) or (IIa)-(IIf), p is 1. In some embodiments of the compound of Formula (II) or (IIa)-(IIf), p is 0.

[0109] In some embodiments of the compound of Formula (II) or (IIa)-(IIf), [ka] teeth, [ka] It is.

[0110] 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 6alkylene (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 ~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 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 6In some embodiments of the compounds disclosed herein, each R a is independent, C 1 ~C 6 It is an alkyl.

[0111] 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 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 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 6Hydroxyalkyl, 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.

[0112] 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, C1 ~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, 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 C1 ~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 6 In 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.

[0113] 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.

[0114] 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 ~C6 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, -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 C1 ~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.

[0115] In some embodiments of the compounds disclosed herein, R, R 1 , R 2 , R 3 , R 4 , R U , R T , R a , R b , R c , and R d One or more of the groups contains a percentage of deuterium that is greater than the natural abundance of deuterium.

[0116] In some embodiments of the compounds disclosed herein, one or more 1 H is the following group: R, R 1 , R 2 , R 3 , R 4 , R U , R T , R a , R b , R c , and R d is substituted with one or more deuterium atoms.

[0117] In some embodiments of the compounds disclosed herein, R, R 1 , R 2 , R 3 , R 4 , R U , R T , R a , R b , R c , and R dThe abundance of deuterium in each of is independently at least 1 mol%, at least 10 mol%, at least 20 mol%, at least 30 mol%, at least 40 mol%, at least 50 mol%, at least 60 mol%, at least 70 mol%, at least 80 mol%, at least 90 mol%, or 100 mol%.

[0118] In some embodiments of the compounds disclosed herein, one or more of ring A or ring B may be 1 H is replaced by one or more deuterium atoms.

[0119] 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.

[0120] 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]

[0121] In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is one of the compounds in Table 2. [Table 2]

[0122] 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, with 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 interconversion 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.

[0123] 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.

[0124] 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, 35S, 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.

[0125] 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.

[0126] 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. 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.

[0127] 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.

[0128] 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.

[0129] 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, bromide, etc. Hydrogen chloride, 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.

[0130] 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 with 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, and muconic acid. 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.

[0131] In some embodiments, those compounds described herein that contain free acid groups are reacted with a suitable base, such as hydroxides, carbonates, bicarbonates, sulfates of pharma- ceutically acceptable metal cations, with ammonia, or with pharma-ceutically acceptable organic primary, secondary, tertiary, or quaternary amines. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, and aluminum salts. Illustrative bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C 1~4 Alkyl) 4 etc.

[0132] 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.

[0133] 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.

[0134] Treatment methods Disclosed herein is a method of treating a disease modulated by DGK in a subject in need of such treatment, comprising administering to the subject a therapeutically affective amount of a compound disclosed herein or a pharma- ceutically acceptable salt thereof. Disclosed herein is a method of treating a disease in a subject in need of such treatment, comprising administering to the subject a therapeutically affective amount of a compound disclosed herein or a pharma- ceutically acceptable salt thereof. In some embodiments, the disease is cancer.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] dosage In certain embodiments, compositions containing a 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 arrest at least one symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous 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.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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, and intramedullary injections, as well as intrathecal injections, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] In some embodiments, the additional therapeutic agent is an antiviral agent. EXAMPLES

[0154] Example 1: 5-Methyl-8-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] To a mixture of compound 1-1 (10 g, 60.18 mmol) in THF (100 mL), Ac 2 O (55.29 g, 541.58 mmol) was added at room temperature. The reaction mixture was cooled to 5° C. 2 The mixture was stirred at 60° C. for 18 hours 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 minutes. The mixture was filtered, and the filter cake was rinsed with petroleum ether (500 mL). The filter cake was collected and dried under vacuum to give compound 1-2. MS (ESI) m / z (M+H) + =209.0.

[0155] 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 reaction 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 extracted with Na 2 SO 4The 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 minutes. The mixture was filtered, and the filter cake was rinsed with petroleum ether (500 mL). The filter cake was collected and dried under reduced pressure to give compound 1-3. MS (ESI) m / z (M+H) + =223.1.

[0156] To a mixture of compound 1-3 (4 g, 18.00 mmol) in DCM (200 mL) at 0-5° C., urea peroxide (2.54 g, 27.0 mmol) was slowly added followed by 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 The mixture was dried at 40° C. and concentrated under reduced pressure to give compound 1-4, which was used in the next step without further purification. MS (ESI) m / z (M+H) + =239.1.

[0157] To a mixture of compound 1-4 (1.8 g, 7.56 mmol) in DCM (150 mL) at 20° C., trimethylsilyl cyanide (1.23 g, 11.33 mmol) was added. The reaction mixture was stirred for 10 min and cooled to −10° C. Benzoyl chloride (1.59 g, 11.33 mmol) was then added from a 10 mL dropping funnel over 15 min, followed by slow addition of TEA (1.15 g, 11.33 mmol) from a 10 mL dropping funnel over 20 min. The reaction mixture was stirred at room temperature 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 4The mixture was dried at 40° C., filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain compound 1-5. MS (ESI) m / z (M+H) + =248.1.

[0158] To a mixture of compound 1-5 (1.6 g, 6.47 mmol) in tetrahydrofuran (100 mL), KHMDS (7.76 mL, 7.76 mmol, 1 M) was added in a 20 mL flask. 2 The mixture was added over 10 min at -78°C. The reaction mixture was stirred for 15 min. The reaction mixture was slowly warmed to 20°C over 30 min and then stirred for an additional 18 h. The reaction mixture was cooled to 0°C. The reaction was quenched with saturated sodium bicarbonate solution (70 mL). The mixture was washed with ethyl acetate (2 x 100 mL). The aqueous layer was collected and acidified with 1.5 N HCl to pH 3.0. The mixture was stirred for 15 min to form a precipitate. The precipitate was collected by filtration to give compound 1-6. MS (ESI) m / z (M+H) + =202.1.

[0159] To a solution of compound 1-6 (920 mg, 4.57 mmol) in DMF (50 mL) was added Et 3 N (1388 mg, 5.49 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.96 g, 5.49 mmol) were added. The mixture was diluted with N 2 The mixture was stirred at 20° C. for 18 hours. The mixture was poured into water (100 mL), extracted with DCM (30 mL×3), and 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography to give compound 1-7. MS(ESI) m / z(M+H) + =334.2.

[0160] To a mixture of compound 1-8 (5 g, 38.71 mmol) and compound 1-9 (5.01 g, 40.65 mmol), PPA (25 g, 73.98 mmol) was added and the mixture was stirred at 180° C. for 2 h. After cooling to 20° C., the reaction was quenched with water. The mixture was adjusted to pH=12 with 50% aqueous potassium hydroxide, then extracted with methylene chloride (2×200 mL). The organic layer was washed with saturated brine and diluted with Na 2 SO 4 The mixture was dried at 40° C. and evaporated under reduced pressure to give compound 1-10. MS(ESI) m / z(M+H) + =217.0.

[0161] To a solution of compound 1-7 (80 mg, 0.230 mmol) in DMSO (10 mL), compound 1-10 (59.56 mg, 0.275 mmol) and ethyldiisopropylamine (0.190 mL, 1.148 mmol) were added. The reaction mixture was stirred at 130° C. for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give Example 1. MS (ESI) m / z (M+H) + = 400.2. 1 H NMR (400 MHz, DMSO) δ 8.17 (d, J = 8.8 Hz, 1H), 8.08 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.50 (s, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.16 (s, 1H), 4.05 (d, J = 12.7 Hz, 2H), 3.54 (s, 3H), 3.40 - 3.35 (m, 1H), 3.15 (t, J = 11.1 Hz, 2H), 2.41 (s, 3H), 2.27 - 2.17 (m, 2H), 2.10 - 1.98 (m, 2H).

[0162] Example 2: 6-Chloro-1-methyl-4-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)quinolin-2(1H)-one [ka] To a solution of compound 2-1 (5 g, 35.31 mmol) in DCM (200 mL) was added compound 2-2 (5.77 g, 36.02 mmol) at 0° C., and then EDCI (6.90 g, 36.02 mmol) was added in portions. The reaction mixture was stirred at 0° C. for 1 h. The mixture was washed with 1M NaOH (50 mL×3) and then with 1M HCl (50 mL×3). 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 compound 2-3, which was used in the next step without further purification. MS (ESI) m / z (M-56+H) + = 228.1.

[0163] To a solution of compound 2-3 (10 g, 37.72 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 an additional 0.5 h. The mixture was cooled to 20° C. 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 compound 2-4, which was used in the next step without further purification. MS (ESI) m / z (M+CH 3 CN+H) + = 251.1.

[0164] POCl 3 A mixture of compound 2-4 (2 g, 9.14 mmol) in 10 mL of ethyl acetate 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 40° C., filtered and concentrated under reduced pressure to give compound 2-5, which was used in the next step without further purification. MS (ESI) m / z (M+H) + = 228.1.

[0165] To a mixture of compound 2-5 (100 mg, 0.438 mmol) and compound 1-10 (142.25 mg, 0.658 mmol) in DMSO (4 mL) was added DIEA (0.362 mL, 2.192 mmol). The mixture was diluted with N 2 The mixture was stirred at 130° C. for 5 hours. 2 The mixture was quenched with 2×O (15 mL) and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine (3×30 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by preparative HPLC to give Example 2. MS (ESI) m / z (M+H) + = 408.1. 1 H NMR (400 MHz, DMSO) δ 7.71 - 7.62 (m, 2H), 7.60 - 7.48 (m, 3H), 7.19 (d, J = 8.3 Hz, 1H), 6.13 (s, 1H), 3.56 (s, 3H), 3.46 - 3.38 (m, 2H), 3.31 - 3.22 (m, 1H), 3.01 - 2.87 (m, 2H), 2.43 (s, 3H), 2.32 - 2.24 (m, 2H), 2.18 - 2.06 (m, 2H).

[0166] Example 3: 1-Methyl-4-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-2-oxo-1,2-dihydroquinoline-6-carbonitrile [ka] To a mixture of compound 3-1 (Example 2) (30 mg, 0.057 mmol) in DMA (1 mL) was added Zn(CN) 2 (13.44mg, 0.114mmol), Zn (3.74mg, 0.057mmol), Pd 2 (dba) 3 (10.48mg, 0.011mmol), Zn(OAc) 2(2.10 mg, 0.011 mmol) and DPPF (6.35 mg, 0.011 mmol) were added. The reaction mixture was stirred in a sealed tube under microwave at 150° C. for 1 h. The mixture was diluted with DCM (50 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give Example 3. MS (ESI) m / z (M+H) + = 399.3. 1 H NMR (400 MHz, DMSO) δ 8.14 (d, J = 1.6 Hz, 1H), 8.00 (dd, J = 8.8, 1.7 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.52 (s, 1H), 7.19 (d, J = 8.3 Hz, 1H), 6.16 (s, 1H), 3.58 (s, 3H), 3.44 (d, J = 12.3 Hz, 2H), 2.95 (t, J = 10.8 Hz, 2H), 2.42 (s, 3H), 2.37 - 2.10 (m, 5H).

[0167] Example 4: 6-Chloro-1-methyl-4-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)quinazolin-2(1H)-one [ka] To a mixture of compound 4-1 (10 g, 58.28 mmol) in dioxane (100 mL) was added trichloromethyl chloromethanoate (86.47 g, 437.11 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 compound 4-2, which was used in the next step without further purification. 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).

[0168] To a mixture of compound 4-2 (10 g, 50.62 mmol) in DMF (100 mL), Na 2 CO 3 (6.44 g, 60.74 mmol) and CH 3 I (5 mL, 75.91 mmol) was added. The reaction mixture was then cooled to 5° C. 2 The mixture was stirred at 20° C. for 12 h. The mixture was quenched with water (300 mL). The reaction mixture was filtered and the filter cake was dried under reduced pressure to give compound 4-3, which was used in the next step without further purification. 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).

[0169] To a mixture of compound 4-3 (1500 mg, 7.09 mmol) in THF (10 mL) was added ammonium hydroxide (0.546 mL, 14.178 mmol). The mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EA (30 mL). The organic layer was washed with water (30 mL) and saturated brine (2×30 mL) and concentrated with Na 2 SO 4 The mixture was dried at 4° C., filtered and concentrated under reduced pressure to give compound 4-4, which was used in the next step without further purification. MS (ESI) m / z (M+H) + = 185.2. 1 H 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).

[0170] To a mixture of compound 4-4 (1000 mg, 5.417 mmol) in DMF (15 mL), NaH (1083.31 mg, 27.08 mmol, 60% in mineral oil) was added 2 The reaction mixture was cooled to 0° C. 2The mixture was stirred at 0°C to 20°C for 1 hour. CDI (1317.44 mg, 8.125 mmol) was added to the mixture. The mixture was diluted with N 2 The mixture was stirred at 70° C. for 2 h. The mixture was diluted with DCM (15 mL) and adjusted to pH=4-5 with 1M HCl to produce a precipitate. The mixture was filtered and the filter cake was washed with H 2 O (20 mL) and dried under reduced pressure to give compound 4-5, which was used in the next step without further purification. 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).

[0171] A mixture of compound 4-5 (100 mg, 0.475 mmol) in toluene (5 mL) was added to 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 compound 4-6, which was used in the next step without further purification. MS (ESI) m / z (M+H) + = 228.9.

[0172] To a mixture of compound 4-6 (100 mg, 0.437 mmol) and compound 1-10 in dioxane (5 mL) was added DIEA (0.072 mL, 0.437 mmol). The mixture was diluted with N 2 The mixture was stirred at 90° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain Example 4. MS (ESI) m / z (M+H) + =409.1. 1H NMR (400 MHz, DMSO) δ 7.80 - 7.73 (m, 2H), 7.56 (d, J = 8.4 Hz, 1H), 7.53 - 7.42 (m, 2H), 7.18 (d, J = 8.4 Hz, 1H), 4.21 (d, J = 13.2Hz, 2H), 3.46 (s, 3H), 3.44 - 3.37 (m, 3H), 2.41 (s, 3H), 2.28 - 2.16 (m, 2H), 2.08 - 1.92 (m, 2H).

[0173] Example 5: 1-Methyl-4-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile [ka] To a mixture of compound 5-1 (Example 4) (100 mg, 0.245 mmol) and Zn (15.99 mg, 0.245 mmol) in DMF (5 mL), zinc bis(acetate) (4.49 mg, 0.024 mmol), Zn(CN) 2 (57.43 mg, 0.489 mmol), DPPF (40.82 mg, 0.049 mmol) and Pd 2 (dba) 3 (22.40 mg, 0.024 mmol) was added. The mixture was stirred in a sealed tube under microwave at 120° C. for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (flow rate 20 ml / min; mobile phase: 0.1% FA solution, acetonitrile; gradient: 43% to 53% acetonitrile, column: C18) to give Example 5. MS (ESI) m / z (M+H) + = 400.2. 1 H NMR (400 MHz, CDCl 3) δ 8.02 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.52 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 4.42 (d, J = 12.4 Hz, 2H), 3.63 (s, 3H), 3.54 (s, 2H), 3.45 (s, 1H), 2.48 (s, 3H), 2.37 (s, 2H), 2.27 (s, 2H).

[0174] Example 6: 6-Fluoro-1-methyl-4-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)quinolin-2(1H)-one [ka] To a mixture of compound 6-1 (3 g, 16.56 mmol) in DMF (20 mL), 2 CO 3 (6.867 g, 49.69 mmol) and MeI (3.53 g, 24.85 mmol) were added. This mixture was then treated with N 2 The mixture was stirred at 20° C. for 2 hours. 2 The mixture was quenched with 200 mL of H2O (50 mL) and a precipitate formed. The mixture was filtered. The filter cake was washed with H2O. 2 O (20 mL) and dried under reduced pressure to give compound 6-2, 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).

[0175] To a mixture of compound 6-2 (500 mg, 2.562 mmol) in NMP (10 mL) was added diethyl malonate (451.41 mg, 2.818 mmol) and NaH (122.98 mg, 3.075 mmol, 60% in mineral oil). The mixture was diluted with N 2The mixture was stirred at 120° C. for 2 h. The mixture was diluted with PE / EtOAc (150 mL / 30 mL) and washed with brine (3×150 mL). 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 compound 6-3, which was used in the next step without further purification. MS (ESI) m / z (MH) + = 264.0.

[0176] Dioxane (4 mL) and H 2 To a mixture of compound 6-3 (286 mg, 1.078 mmol) in O (2 mL) was added NaOH (431.31 mg, 10.783 mmol). The mixture was diluted with N 2 The mixture was stirred at 120° C. for 16 hours under reduced pressure. The mixture was concentrated under reduced pressure. The pH of the residue was adjusted to 4-5 with an aqueous HCl solution (1M), and a precipitate was formed. The mixture was filtered. The filter cake was washed with H 2 Rinsing with O (20 mL) and drying under reduced pressure gave compound 6-4, which was used in the next step without further purification. MS (ESI) m / z (M+H) + = 194.0.

[0177] POCl 3 A mixture of compound 6-4 (193 mg, 0.999 mmol) in 2 mL of N 2 The mixture was stirred at 90° C. for 2 hours. The residue was dissolved in NaHCO 3 The pH was adjusted to 7-8 using aqueous hexanes and extracted with DCM (150 mL). The organic layer was washed with brine (3×150 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give compound 6-5, which was used in the next step without further purification. MS (ESI) m / z (M+H) + = 211.9.

[0178] To a mixture of compound 6-5 (146 mg, 0.69 mmol) in IPA (10 mL) was added compound 1-10 (149.23 mg, 0.69 mmol) and DIEA (445.86 mg, 3.45 mmol). The mixture was immersed in N 2The mixture was stirred at 90° C. for 16 hours. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give Example 6. MS (ESI) m / z (M+H) + = 392.3. 1 H NMR (400 MHz, DMSO) δ 7.67 - 7.39 (m, 5H), 7.19 (d, J = 8.3 Hz, 1H), 6.13 (s, 1H), 3.57 (s, 3H), 3.48 - 3.38 (m, 2H), 3.29 - 3.23 (m, 1H), 3.00 - 2.87 (m, 2H), 2.43 (s, 3H), 2.34 - 2.05 (m, 4H).

[0179] Example 7: 6-Fluoro-1-methyl-4-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)quinazolin-2(1H)-one [ka] To a mixture of compound 6-2 (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 purified by distillation with NaHCO 3 The pH was adjusted to 8-9 using aqueous hexanes and extracted with DCM (50 mL). The organic layer was washed with brine (3×50 mL) and then extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give compound 7-1, which was used in the next step without further purification. MS (ESI) m / z (M+H) + = 169.0.

[0180] To a mixture of compound 7-1 (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). 2The mixture was stirred at 15° C. for 3 hours. 4 Quenching with saturated Cl solution (30 mL) produced a precipitate. The mixture was filtered. The filter cake was rinsed with DCM (30 mL) and dried under reduced pressure to give compound 7-2. MS (ESI) m / z (M+H) + = 195.0.

[0181] A mixture of compound 7-2 (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. This mixture was then cooled to 100° C. 2 The mixture was stirred at 110° C. for 3 hours. The residue was dissolved in NaHCO 3 The pH was adjusted to 7-8 using aqueous hexanes and extracted with DCM (30 mL). 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 7-3, which was used in the next step without further purification. MS (ESI) m / z (M+H) + = 212.9.

[0182] To a mixture of compound 7-3 (200 mg, 0.94 mmol) in IPA (5 mL) was added compound 1-10 (122.07 mg, 0.56 mmol) and DIEA (607.92 mg, 4.70 mmol). 2 The mixture was stirred at 90° C. for 16 hours. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give Example 7. MS (ESI) m / z (M+H) + = 393.0. 1 H NMR (400 MHz, DMSO) δ 7.71 - 7.53 (m, 3H), 7.52 - 7.45 (m, 2H), 7.18 (d, J = 8.0 Hz, 1H), 4.27 - 4.14 (m, 2H), 3.47 (s, 3H), 3.43 - 3.35 (m, 3H), 2.41 (s, 3H), 2.25 - 2.16 (m, 2H), 2.07 - 1.95 (m, 2H).

[0183] Example 8: 6-Fluoro-1-methyl-4-((1R,5S))-8-(5-methylbenzo[d]oxazol-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile [ka] To a mixture of compound 8-2 (500 mg, 2.596 mmol) in DMSO (30 mL) was added DIEA (2.145 mL, 12.97 mmol) and compound 8-3 (551.02 mg, 2.596 mmol). The reaction mixture was stirred at 100° C. for 2 h. The mixture was poured into ice water (100 mL) and 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 eluting with petroleum ether / ethyl acetate=1 / 1 to give compound 8-4. MS (ESI) m / z (M+H) + = 344.2.

[0184] A mixture of compound 8-4 (900 mg, 2.530 mmol) in HCl / dioxane (50 mL, 4 M) was stirred at 25° C. for 2 h. The mixture was concentrated under reduced pressure to give compound 8-5, which was used in the next step without further purification. MS (ESI) m / z (M+H) + = 244.1.

[0185] To a mixture of compound 8-6 (150 mg, 0.628 mmol) in DMSO (20 mL) was added DIEA (1.037 mL, 6.276 mmol) and compound 8-5 (240.15 mg, 0.816 mmol). The reaction mixture was stirred at 130° C. for 2 h. The mixture was poured into ice water (100 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give the crude product which was purified by preparative HPLC to give Example 8. MS (ESI) m / z (M+H) + = 444.4. 1 H NMR (400 MHz, MeOD) δ 7.88 (dd, J = 9.6, 2.9 Hz, 1H), 7.69 (dd, J = 9.4, 4.6 Hz, 1H), 7.63 - 7.56 (m, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.19 (s, 1H), 6.98 (d, J = 7.2 Hz, 1H), 4.75 - 4.70 (m, 2H), 3.97 (d, J = 11.1 Hz, 2H), 3.71 (s, 3H), 3.53 (d, J = 10.0 Hz, 2H), 2.46 - 2.39 (m, 5H), 2.37 - 2.25 (m, 2H).

[0186] Example 9: 6-Chloro-1-methyl-4-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka] A mixture of compound 1-1 (10 g, 60.18 mmol) and NBS (10.82 g, 60.78 mmol) in ACN (120 mL) was stirred at 20° C. for 1.5 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give compound 9-1. MS (ESI) m / z (M+H) + = 245.

[0187] To a mixture of compound 9-1 (12.065 g, 49.23 mmol) in DMF (100 mL) was added 2-cyanoacetic acid (5.86 g, 68.92 mmol), DIEA (24.476 mL, 148.10 mmol) and T 3P (50% in EA, 62.9 g, 197.69 mmol) was added. The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with EtOAc (300 mL) and washed with brine (3×300 mL). 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 compound 9-2. MS (ESI) m / z (M+H) + = 313.

[0188] To a mixture of compound 9-2 (3.8 g, 12.17 mmol) in THF (100 mL), KHMDS (14.2 mL, 14.19 mmol, 1 M) was added 2 The reaction mixture was warmed to 20° C. and N 2 The mixture was stirred at 20° C. for 1.5 hours. 2 SO 4 It was quenched with saturated solution (14 mL). The mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 9-3. 1 H NMR (400 MHz, DMSO) δ 11.95 (s, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H).

[0189] To a mixture of compound 9-3 (1000 mg, 3.76 mmol) in DMF (20 mL) was added NaH (601.39 mg, 15.03 mmol, 60% in mineral oil) at 0° C., and the mixture was then rinsed with N 2 The mixture was stirred at 0°C for 0.5 hours. 3 I (0.936 mL, 15.03 mmol) was added to the mixture. The reaction mixture was then rinsed with N 2 The mixture was stirred at room temperature for 12 hours under reduced pressure. 2 The mixture was diluted with 200 mL of HO (15 mL) and adjusted to pH = 3 with 1 M HCl solution, producing a precipitate. The mixture was filtered and the filter cake was washed with H 2 The filter cake was collected and dried under reduced pressure to give compound 9-4, which was used in the next step without further purification. MS (ESI) m / z (M+H) + = 279.9.

[0190] POCl 3 To a mixture of compound 9-4 (500 mg, 1.79 mmol) in DIEA (10 mL) was added DIEA (1.770 mL, 10.71 mmol). The reaction mixture was cooled to 37° C. for 1 hour and then cooled to 37° C. 2 The mixture was stirred at 120° C. for 4 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 9-4. MS (ESI) m / z (M+H) + = 299.9. 1 H NMR (400 MHz, DMSO) δ 8.22 (dd, J = 47.4, 9.0 Hz, 1H), 8.04 (dd, J = 37.2, 9.0 Hz, 1H), 3.65 (d, J = 4.6 Hz, 3H).

[0191] To a mixture of compound 9-5 (100 mg, 0.335 mmol) and compound 1-10 (21.54 mg, 0.087 mmol) in IPA (5 mL) was added DIEA (0.332 mL, 2.010 mmol). The reaction mixture was stirred at 90° C. for 2 h. 2 The mixture was quenched with O and extracted with EtOAc. The organic layer was washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give compound 9-6. MS (ESI) m / z (M+H) + = 478.2.

[0192] A mixture of compound 9-6 (50 mg, 0.108 mmol) in HCl / dioxane (5 mL, 4 M) was stirred at 85° C. for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give Example 9. MS (ESI) m / z (M+H) + = 434.1. 1H NMR: (400 MHz, MeOD) δ 8.54 (s, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.50 - 7.45 (m, 2H), 7.21 (d, J = 8.3 Hz, 1H), 4.45 (d, J = 13.0 Hz, 2H), 3.73 (t, J = 10.5 Hz, 2H), 3.65 (s, 3H), 3.47 - 3.43 (m, 1H), 2.46 (s, 3H), 2.42 - 2.26 (m, 4H).

[0193] Example 10: 6-Chloro-1-methyl-4-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one [ka] POCl 3 A mixture of 1-4 (2.0 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 NaHCO 3 The pH was adjusted to 8.0 using saturated aqueous solution. The mixture was extracted with DCM (3×50 mL). The combined organic layers were washed with 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 flash column chromatography to give 10-1. LCMS: MS m / z (ESI) [M+H] + = 257.2.

[0194] A solution of KHMDS (1 M in THF) (6.68 mL, 6.68 mmol) in THF (100 mL) was diluted with 10-1 (1.4 g, 4.45 mmol) in THF (10 mL) at -78 °C and N 2After the addition, the mixture was slowly warmed to 15° C. and stirred at this temperature for 2 h. The mixture was adjusted to pH=6.0 with 1N HCl. The mixture was concentrated in vacuo. The resulting residue was purified by flash column chromatography to give 10-2. LCMS: MS m / z (ESI) [M+H] + = 211.2.

[0195] POCl 3 A mixture of 10-2 (680 mg, 2.50 mmol) in DCM (20 mL) was stirred at 100 °C for 2 h. The mixture was concentrated under reduced pressure. The resulting residue was diluted with DCM (50 mL) and NaHCO 3 The pH was adjusted to 8.0 using saturated aqueous solution. The mixture was extracted with DCM (3×50 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to give 10-3. LCMS: MS m / z (ESI) [M+H] + = 229.1.

[0196] A mixture of 10-3 (40 mg, 0.18 mmol), 1-10 (41.6 mg, 0.19 mmol) and DIEA (0.14 mL, 0.87 mmol) in isopropyl alcohol (3 mL) was stirred at 90° C. for 18 h. The mixture was concentrated in vacuo and the resulting residue was purified by preparative HPLC to give Example 10. LCMS: MS m / z (ESI) [M+H] + = 409.1. 1 H NMR (400 MHz, DMSO-d 6) δ 8.01 (d, J = 9.0 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.51 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.10 (s, 1H), 4.06 (d, J = 12.3 Hz, 2H), 3.53 (s, 3H), 3.44 - 3.07 (m, 3H), 2.42 (s, 3H), 2.27 - 2.18 (m, 2H), 2.08 - 1.98 (m, 2H).

[0197] Example 11: 6-chloro-1-4-(4-(5-fluorobenzo[d]oxazol-2-yl)piperidin-1-yl)-1-methyl-1,5-naphthyridin-2(1H)-one [ka] To a mixture of 11-2 (9.0 g, 39.25 mmol) in polyphosphoric acid (100 mL) was added 11-1 (4.99 g, 39.25 mmol). The mixture was stirred at 200° C. for 4 h. The mixture was cooled to room temperature and quenched with ice water (200 mL). The mixture was basified with aqueous NaOH (50% w / w), resulting in the formation of a precipitate. The precipitate was collected by filtration, the filter cake was rinsed with water, and dried under reduced pressure to give 11-3. LCMS: MS m / z (ESI) [M+H] + = 221.0.

[0198] A mixture of 10-3 (50 mg, 0.22 mmol), 11-3 (57.7 mg, 0.26 mmol) and DIEA (0.18 mL, 1.09 mmol) in isopropyl alcohol (3 mL) was stirred at 90° C. for 36 h. The mixture was concentrated in vacuo and the resulting residue was purified by preparative HPLC to give Example 11. LCMS: MS m / z (ESI) [M+H] + = 413.1. 1 H NMR (400 MHz, DMSO-d 6) δ 8.01 (d, J = 8.9 Hz, 1H), 7.78 - 7.68 (m, 2H), 7.63 - 7.57 (m, 1H), 7.27 - 7.20 (m, 1H), 6.11 (s, 1H), 4.06 (d, J = 12.3 Hz, 2H), 3.53 (s, 3H), 3.36 - 3.28 (m, 1H), 3.12 (t, J = 11.6 Hz, 2H), 2.26 - 2.20 (m, 2H), 2.09 - 2.00 (m, 2H).

[0199] Example 12: 8-(4-(5-fluorobenzo[d]oxazol-2-yl)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] POCl 3 A mixture of 1-6 (900 mg, 4.47 mmol) in (10 mL) was stirred at 85° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by ethanol with NaHCO 3 It was quenched with saturated aqueous solution (50 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give 12-1. LCMS: MS m / z (ESI) [M+H] + = 220.1.

[0200] To a mixture of 12-1 (100 mg, 0.45 mmol) in DMSO (10 mL) was added 11-3 (239 mg, 0.90 mmol) and DIEA (0.75 mL, 4.51 mmol). The reaction mixture was stirred at 130° C. for 16 h. The mixture was cooled to room temperature and poured into water (100 mL). The resulting mixture was extracted with DCM (3×50 mL). The combined organic layers were washed with Na 2 SO 4The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure. To the resulting residue was added MeOH (5 mL) and THF (5 mL). After stirring for 16 h, the mixture was filtered. The filter cake was collected and dried to give Example 12. LCMS: MS m / z (ESI) [M+H] + = 404.1. 1 H NMR (400 MHz, DMSO) δ 8.18 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.74 (dd, J = 8.9, 4.4 Hz, 1H), 7.60 (dd, J = 8.8, 2.6 Hz, 1H), 7.24 (td, J = 9.6, 2.6 Hz, 1H), 6.17 (s, 1H), 4.06 (d, J = 12.8 Hz, 2H), 3.55 (s, 3H), 3.43 - 3.33 (m, 1H), 3.21 - 3.11 (m, 2H), 2.29 - 2.20 (m, 2H), 2.11 - 1.99 (m, 2H).

[0201] Example 13: 6-Chloro-1-methyl-4-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)pyrido[3,2-d]pyrimidin-2(1H)-one [ka] To a mixture of 13-1 (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 layer was 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 13-2, which was used directly in the next step without further purification.

[0202] To a suspension of 13-2 (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 13-3, which was used directly in the next step without further purification.

[0203] To a solution of 13-3 (2.5 g, 10.0 mmol) in DMF (15 mL) was added 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 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give 13-4. LCMS: MS m / z (ESI) [M+H] + = 168.2.

[0204] DMSO (20 mL) and H 2 To a solution of 13-4 (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 13-5.

[0205] To a solution of 13-5 (580 mg, 3.13 mmol) in DMF (5 mL), NaH (375 mg, 9.37 mmol, 60% in mineral oil) was added 2After 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 warmed to 70° C. and stirred for another 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 13-6, which was checked by LCMS: MS m / z (ESI) [M+H] + = 212.0.

[0206] A suspension of 13-6 (200 mg, 0.95 mmol) in anhydrous toluene (8 mL) was added to POCl 3 (0.44 mL, 4.73 mmol) and DIEA (0.78 mL, 4.73 mmol) were added at room temperature. The reaction mixture was diluted with N 2 The mixture was heated under reduced pressure at 110° C. for 2 h. The mixture was concentrated under reduced pressure to give 13-7, which was used directly in the next step without further purification.

[0207] CH 3 To a mixture of 13-7 (100 mg, 0.44 mmol) in CN (5 mL) was added 1-10 (188 mg, 0.87 mmol) and DIEA (0.72 mL, 4.35 mmol). The mixture was stirred at 90° C. for 2 h. The mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give Example 13. LCMS: MS m / z (ESI) [M+H] + = 410.1. 1 H NMR (400 MHz, DMSO) δ 7.95 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.49 (s, 1H), 7.17 (d, J = 8.3 Hz, 1H), 3.70 - 3.25 (m, 8H), 2.41 (s, 3H), 2.28-2.18 (m, 2H), 2.02-1.89 (m, 2H).

[0208] Example 14: 1-Methyl-4-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile [ka] A mixture of compound 13 (50 mg, 0.12 mmol) in DMA (2 mL) was diluted with Zn (8.0 mg, 0.12 mmol), Zn(OAc) 2 (2.7 mg, 0.012 mmol), Zn(CN) 2 (28.7 mg, 0.24 mmol), DPPF (13.8 mg, 0.024 mmol) and Pd 2 (dba) 3 -CHCl 3 (11.2 mg, 0.012 mmol) was added. The mixture was stirred at 150° C. in microwave for 1 h. The mixture was filtered through a Celite pad and the filtrate was purified by preparative HPLC separation to give Example 14. LCMS: MS m / z (ESI) [M+H] + = 401.1. 1 H NMR (400 MHz, DMSO) δ 8.25 (d, J = 8.9 Hz, 1H), 8.00 (d, J = 8.9 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.48 (s, 1H), 7.17 (d, J = 8.3 Hz, 1H), 3.75-3.25 (m, 8H), 2.41 (s, 3H), 2.31 - 2.20 (m, 2H), 2.04 - 1.90 (m, 2H).

[0209] Example 15: 6-chloro-7-(2-methoxyethoxy)-1-methyl-4-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one [ka] To a mixture of 15-1 (10.0 g, 43.28 mmol) in DCM (300 mL) was added pyridine (10.45 mL, 129.84 mmol). The mixture was cooled to 0° C. and AcCl (4.62 mL, 64.92 mmol) was added. The mixture was cooled to 0° C. and 10 mL of N 2 The mixture was stirred at 15° C. for 18 h. The mixture was poured into water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with 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 flash column chromatography to give 15-2. LCMS: MS m / z (ESI) [M+H] + = 272.9.

[0210] To a mixture of 15-2 (11.0 g, 40.26 mmol) in DMF (150 mL), Cs 2 CO 3 (26.23 g, 80.52 mmol) and MeI (8.57 g, 60.39 mmol) were added to the mixture. 2 The mixture was stirred at 25° C. for 18 h. The mixture was poured into water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with 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 flash column chromatography to give 15-3. LCMS: MS m / z (ESI) [M+H] + = 287.1.

[0211] To a mixture of 15-3 (3.2 g, 10.59 mmol) in dioxane (150 mL), 2 (pin) 2 (4.03g, 15.88mmol), Pd(dppf)Cl 2 (1.55 g, 2.12 mmol), KOAc (3.12 g, 31.77 mmol) were added to the mixture. 2 The mixture was stirred at 100° C. for 3 h. The mixture was poured into water (100 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with Na 2 SO 4The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give 15-4. LCMS: MS m / z (ESI) [M+H] + = 252.5.

[0212] CH 3 To a mixture of 15-4 (3.0 g, 11.31 mmol) in CN (300 mL) was added CO(NH 2 ) 2 H 2 O 2 (2.13 g, 22.62 mmol) was added to the mixture. 2 The mixture was stirred at 25° C. for 18 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to give 15-5. LCMS: MS m / z (ESI) [M+H] + = 225.0.

[0213] A solution of 15-5 (830 mg, 3.30 mmol) in DMF (20 mL) was diluted with 1-bromo-2-methoxyethane (1.37 g, 9.89 mmol) and K 2 CO 3 (2.73 g, 19.78 mmol) was added to the mixture. 2 The mixture was stirred at 60° C. for 18 h. The mixture was poured into water (30 mL) and extracted with DCM (3×30 mL). The combined organic layers were washed with 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 flash column chromatography to give 15-6. LCMS: MS m / z (ESI) [M+H] + = 283.0.

[0214] A solution of 15-6 (500 mg, 1.77 mmol) in DCE (50 mL) was added to CO(NH 2 ) 2 H 2 O 2 (1.58 g, 16.83 mmol) and TFAA (3.53 g, 16.8 mmol) were added to the mixture. 2 The mixture was stirred at 70° C. for 2 hours. 3The pH was adjusted to 8.0 using a saturated aqueous solution. 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 over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give 15-7. LCMS: MS m / z (ESI) [M+H] + = 299.0.

[0215] CH 3 To a solution of 15-7 (370 mg, 1.18 mmol) in CN (50 mL) was added POCl 3 (1.10 mL, 11.79 mmol) was added. This mixture was then cooled to 100° C. 2 The mixture was stirred at 70° C. for 2 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in NaHCO 3 The pH was adjusted to 8.0 using saturated aqueous solution of 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 flash column chromatography to give 15-8. LCMS: MS m / z (ESI) [M+H] + = 316.9. To a solution of 15-8 (300 mg, 0.88 mmol) in THF (50 mL), KHMDS (1.32 mL) was added 2 The mixture was added at −78° C. 2 The mixture was stirred at −78° C. for 1 hour. 2 The mixture was stirred at 25° C. for 3 h. The pH of the mixture was adjusted to 5.0, and the resulting mixture was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to give 15-9. LCMS:MS m / z(ESI) [M+H] + =284.9.

[0216] POCl 3 A mixture of 15-9 (180 mg, 0.60 mmol) in (5 mL) of N 2 The mixture was stirred at 80° C. for 2 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in NaHCO 3The pH was adjusted to 8.0 using a saturated aqueous solution. 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 over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give 15-10. LCMS: MS m / z (ESI) [M+H] + = 302.9.

[0217] To a solution of 15-10 (170 mg, 0.54 mmol) in isopropyl alcohol (3 mL) was added 1-10 (129 mg, 0.60 mmol) and DIEA (0.90 mL, 5.44 mmol). This mixture was diluted with N 2 The mixture was stirred at 100° C. for 30 h. The mixture was poured into water (100 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with 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 separation to give Example 15. LCMS: MS m / z (ESI) [M+H] + = 483.1. 1 H NMR (400 MHz, DMSO) δ 7.56 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 10.1 Hz, 2H), 7.18 (d, J = 7.9 Hz, 1H), 5.95 (s, 1H), 4.47 - 4.40 (m, 2H), 4.10 - 4.01 (m, 2H), 3.80 - 3.74 (m, 2H), 3.56 (s, 3H), 3.36 (s, 3H), 3.10 (t, 2H), 2.49 - 2.45 (m, 1H), 2.42 (s, 3H), 2.25 - 2.16 (m, 2H), 2.09 - 1.95 (m, 2H).

[0218] Example 16: 3-(2-Methoxyethoxy)-5-methyl-8-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] To a mixture of compound 15 (30 mg, 0.062 mmol) in DMA (1 mL), Zn(CN) 2 (36.5mg, 0.31mmol), Zn(4.1mg, 0.062mmol), Zn(OAc) 2 (11.4 mg, 0.062 mmol), Pd 2 (dba) 3 CHCl 3 (32.2 mg, 0.031 mmol) and DPPF (17.5 mg, 0.031 mmol) were added. The mixture was stirred in a sealed tube under microwave at 160° C. for 2 h. The mixture was poured into water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with 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 separation to give Example 16. LCMS: MS m / z (ESI) [M+H] + = 474.2. 1 H NMR (400 MHz, DMSO) δ 7.57 - 7.53 (m, 2H), 7.50 (s, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.01 (s, 1H), 4.54 - 4.48 (m, 2H), 4.08 - 4.00 (m, 2H), 3.80 - 3.75 (m, 2H), 3.55 (s, 3H), 3.36 (s, 3H), 3.31 - 3.27 (m, 1H), 3.14 (t, J = 11.0 Hz, 2H), 2.41 (s, 3H), 2.25 - 2.17 (m, 2H), 2.08 - 1.96 (m, 2H).

[0219] Example 17: 6-Chloro-7-((2-hydroxyethyl)amino)-1-methyl-4-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one [ka] To a mixture of 15-3 (2.0 g, 6.97 mmol) in DCM (20 mL) was added TFAA (2.19 g, 10.45 mmol) and urea peroxide (0.98 g, 10.45 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was then cooled to 0° C. with NaHCO 3 The organic layer was poured into saturated aqueous solution (150 mL) and extracted with DCM (150 mL x 3). 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated in vacuo to give 17-1. LCMS: MS m / z (ESI) [M+H] + = 303.1. CH 3 To a mixture of 17-1 (1.10 g, 3.63 mmol) in CN (10 mL) was added POCl 3 (1 mL, 10.76 mmol) was added. The mixture was stirred at 80 °C for 18 h. The mixture was diluted with DCM (30 mL) and NaHCO 3 The mixture was poured into saturated aqueous solution (100 mL). The mixture was extracted with DCM (100 mL x 3). The organic layer was extracted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated in vacuo to give 17-2. LCMS: MS m / z (ESI) [M+H] + = 321.1.

[0220] To a mixture of 17-2 (1.00 g, 3.11 mmol) in THF (20 mL), KHMDS (3.73 mL, 1 M in THF) was added 2 The mixture was stirred at -78°C for 2 h, then warmed to room temperature and added with N 2 The mixture was stirred for another 2 h under reduced pressure. The mixture was poured into water (100 mL) and acidified with HCl (1 M, aq.) to pH 4. The mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of 17-3, filtered and concentrated in vacuo to give 17-3. LCMS: MS m / z (ESI) [M+H] + = 288.8.

[0221] CH 3To a mixture of 17-3 (400 mg, 1.38 mmol) in CN (5 mL), POCl 3 (1 mL, 10.76 mmol) was added. This mixture was then cooled to 100° C. 2 The mixture was stirred at 60 °C for 18 h. The mixture was diluted with DCM (30 mL) and added NaHCO 3 The mixture was poured into saturated aqueous solution (100 mL). The mixture was extracted with DCM (100 mL x 3). The combined organic layers were washed with Na 2 SO 4 Drying at 40° C., filtration and concentration in vacuo gave 17-4. LCMS: MS m / z (ESI) [M+MeCN+H] + = 347.8.

[0222] A mixture of 17-4 (200 mg, 0.65 mmol), 1-10 (182.6 mg, 0.84 mmol) and DIEA (0.54 mL, 3.25 mmol) in isopropyl alcohol (5 mL) was stirred at 90° C. for 18 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give 17-5. LCMS: MS m / z (ESI) [M+H] + = 486.9.

[0223] 17-5 (180 mg, 0.37 mmol), 17-6 (64.7 mg, 0.37 mmol), Pd 2 (dba) 3 (16.9 mg, 0.018 mmol), Xantphos (21.4 mg, 0.037 mmol) and Cs 2 CO 3 (360.7 mg, 1.11 mmol) was dissolved in N 2 The mixture was stirred at 80° C. for 18 hours. The mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The resulting residue was purified by preparative TLC to give 17-7. LCMS: MS m / z (ESI) [M+H] + = 582.4.

[0224] To a mixture of 17-7 (60 mg, 0.10 mmol) in THF (3 mL) was added a TBAF solution (0.21 mL, 1 M THF solution). The mixture was stirred at room temperature for 4 h. The mixture was diluted with EtOAc (20 mL) and diluted with H 2 The organic layer was washed with NaO (3 × 20 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 HPLC to give Example 17. LCMS: MS m / z (ESI) [M+H] + = 468.2. 1 H NMR (400 MHz, DMSO) δ 7.56 (d, J = 8.3 Hz, 1H), 7.50 (s, 1H), 7.24 - 7.10 (m, 1H), 6.89 (s, 1H), 6.05 (t, J = 5.6 Hz, 1H), 5.77 (s, 1H), 4.99 - 4.83 (m, 1H), 4.14 - 3.96 (m, 2H), 3.70 - 3.63 (m, 2H), 3.50 (s, 3H), 3.39 - 3.35 (m, 2H), 3.30 - 3.25 (m, 1H), 3.14 - 3.09 (m, 2H), 2.42 (s, 3H), 2.23 - 2.14 (m, 2H), 2.07 - 1.94 (m, 2H).

[0225] Example 18: 3-((2-hydroxyethyl)amino)-5-methyl-8-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] A mixture of 17-7 (100 mg, 0.17 mmol) in DMF (5 mL) was added to X-phos (16.4 mg, 0.034 mmol), Zn(CN) 2 (40.3 mg, 0.34 mmol), Zn (11 mg, 0.17 mmol) and Pd 2 (dba) 3(15.7 mg, 0.017 mmol) was added. The reaction mixture was stirred at 120° C. for 1 h in a microwave. The mixture was diluted with EtOAc (15 mL) and H 2 The organic layer was washed with NaO (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 silica gel column chromatography to give 18-1. LCMS: MS m / z (ESI) [M+H] + = 573.3.

[0226] To a solution of 18-1 (100 mg, 0.17 mmol) in THF (10 mL) was added TBAF (0.83 mL, 1.0 M in THF). 2 The mixture was stirred at 25° C. for 18 h. The mixture was poured into water (100 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with 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 separation to give Example 18. LCMS: MS m / z (ESI) [M+H] + = 459.3. 1 H NMR (400 MHz, DMSO) δ 7.55 (d, J = 8.3 Hz, 1H), 7.50 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.94 (s, 1H), 6.60 (t, J = 5.6 Hz, 1H), 5.82 (s, 1H), 4.90 (t, J = 5.5 Hz, 1H), 4.03 (d, J = 12.6 Hz, 2H), 3.64 (q, J = 5.6 Hz, 2H), 3.47 (s, 3H), 3.40 (q, J = 5.6 Hz, 2H), 3.30 - 3.26 (m, 1H), 3.10 (t, J = 11.2 Hz, 2H), 2.41 (s, 3H), 2.19 (m, 2H), 2.00 (m, 2H).

[0227] Example 19: 7-((2-hydroxyethyl)amino)-1-methyl-4-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one [ka] To a mixture of 15-3 (2.0 g, 6.97 mmol) in THF (20 mL) was added KHMDS (8.36 mL, 1 M THF solution) at -78 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with NH 4 The mixture was quenched with saturated Cl solution (30 mL) and extracted with EtOAc (40 mL). 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated in vacuo to give 19-1. LCMS: MS m / z (ESI) [M+MeCN+H] + = 295.9.

[0228] POCl 3 A mixture of 19-1 (1.2 g, 4.71 mmol) in 15 mL of N 2 The mixture was stirred at 85° C. for 2 h. The mixture was concentrated in vacuo. The residue was dissolved in NaHCO 3 The pH was adjusted to 8-9 using saturated aqueous solution (30 mL) and extracted with DCM (30 mL). 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated in vacuo to give 19-2. LCMS: MS m / z (ESI) [M+H] + = 273.0.

[0229] To a mixture of 19-2 (500 mg, 1.83 mmol) and 1-10 (474.5 mg, 2.19 mmol) in DMSO (10 mL) was added DIEA (1.81 mL, 10.97 mmol). The reaction mixture was stirred at 130° C. for 2 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with brine (20 mL). The organic layer was extracted with Na 2 SO 4The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give 19-3. LCMS: MS m / z (ESI) [M+H] + = 453.2.

[0230] 19-3 (240 mg, 0.53 mmol), 17-6 (185.7 mg, 1.06 mmol) and Cs in dioxane (10 mL) 2 CO 3 (517.5 mg, 1.59 mmol) with Xantphos (61.3 mg, 0.11 mmol) and Pd 2 (dba) 3 (97.0 mg, 0.11 mmol) was added. The reaction was stirred at 100° C. for 16 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with brine (20 mL). The organic layer was extracted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give 19-4. LCMS: MS m / z (ESI) [M+H] + = 548.4.

[0231] To a mixture of 19-4 (50 mg, 0.091 mmol) in THF (3 mL) was added TBAF (0.18 mL, 1 M THF solution). The mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (20 mL) and washed with water (3×20 mL). The organic layer was extracted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated in vacuo. The resulting residue was purified by preparative HPLC separation to give Example 19. LCMS: MS m / z (ESI) [M+H] + = 434.2. 1H NMR (400 MHz, DMSO) δ 8.00 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.72 (s, 1H), 6.59 (t, J = 5.6 Hz, 1H), 5.71 (s, 1H), 4.80 (t, J = 5.6 Hz, 1H), 4.10 (d, J = 12.4 Hz, 2H), 3.65 - 3.58 (m, 2H), 3.45 (s, 3H), 3.30 - 3.24 (m, 3H), 3.11 - 2.98 (m, 2H), 2.41 (s, 3H), 2.22 - 2.12 (m, 2H), 2.09 - 1.89 (m, 2H).

[0232] Example 20: 6-Chloro-1-methyl-4-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-7-((tetrahydrofuran-3-yl)oxy)-1,5-naphthyridin-2(1H)-one [ka] The preparation of Example 20 was performed following a similar procedure to Example 15, where the intermediate 1-bromo-2-methoxyethane was replaced by 3-bromotetrahydrofuran. LCMS: MS m / z (ESI) [M+H] + = 495.1. 1 H NMR (400 MHz, DMSO) δ 7.56 (d, J = 8.3 Hz, 1H), 7.50 (s, 1H), 7.42 (s, 1H), 7.17 (d, J = 8.8 Hz, 1H), 5.96 (s, 1H), 5.48 - 5.42 (m, 1H), 4.08 - 4.00 (m, 2H), 3.98 - 3.76 (m, 5H), 3.56 (s, 3H), 3.15 - 3.06 (m, 2H), 2.41 (s, 3H), 2.38 - 2.28 (m, 1H), 2.25 - 2.16 (m, 2H), 2.12 - 1.95 (m, 3H).

[0233] Example 21: 5-Methyl-8-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-6-oxo-3-((tetrahydrofuran-3-yl)oxy)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] The preparation of Example 21 was performed according to the same procedure as Example 16, where the reactant (Example 15) was replaced by Example 20. LCMS: MS m / z (ESI) [M+H] + = 486.3. 1 H NMR (400 MHz, DMSO) δ 7.55 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 9.8 Hz, 2H), 7.17 (d, J = 8.3 Hz, 1H), 6.01 (s, 1H), 5.58 - 5.50 (m, 1H), 4.08 - 4.00 (m, 2H), 3.99 - 3.88 (m, 3H), 3.86 - 3.78 (m, 1H), 3.56 (s, 3H), 3.38 - 3.33 (m, 1H), 3.14 (m, 2H), 2.41 (s, 3H), 2.37 - 2.29 (m, 1H), 2.25 - 2.16 (m, 2H), 2.13 - 1.98 (m, 3H).

[0234] Example 22: 6-chloro-7-(2-hydroxyethoxy)-1-methyl-4-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one [ka] To a solution of 15-5 (7.0 g, 29.34 mmol) in DMF (100 mL), benzyl bromide (15.06 g, 88.04 mmol), K 2 CO 3 (40.56 g, 293.46 mmol) was added to the mixture. 2The mixture was stirred at 60° C. for 3 h. The mixture was poured into water (80 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 22-1 (9.0 g, 97.6%). LCMS: MS m / z (ESI) [M+H] + = 315.2.

[0235] To a solution of 22-1 (9 g, 27.200 mmol) in DCE (200 mL) was added urea peroxide (17.91 g, 190.4 mmol) and TFAA (39.99 g, 190.4 mmol). 2 The mixture was stirred at 70° C. for 2 h. After cooling to room temperature, the mixture was diluted with NaHCO 3 The pH was adjusted to 8.0 using saturated aqueous solution of Na and extracted with DCM (3×100 mL). 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 22-2 (8.0 g, 84.6%). LCMS: MS m / z (ESI) [M+H] + = 331.1.

[0236] CH 3 To a solution of 22-2 (8.0 g, 23.01 mmol) in CN (100 mL) was added POCl 3 (10.69 mL, 115.03 mmol) was added. This mixture was then cooled to room temperature. 2 The mixture was stirred at 60° C. for 3 hours. The mixture was concentrated under reduced pressure and added NaHCO 3 The pH was adjusted to 8.0 using saturated aqueous solution of Na and extracted with DCM (3×50 mL). 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give 22-3 (7.0 g, 78.5%). LCMS: MS m / z (ESI) [M+H] + = 349.0.

[0237] To a solution of 22-3 (1.1 g, 3.00 mmol) in THF (30 mL) was added KHMDS (0.72 g, 3.60 mmol) at 80 °C. The reaction mixture was diluted with N 2 The mixture was stirred at 80° C. for 10 min. The mixture was adjusted to pH=6.0 with 1N HCl and concentrated under reduced pressure to give 22-4 (950 mg, 95.1%). LCMS: MS m / z (ESI) [M+H] + = 317.0.

[0238] POCl 3 A mixture of 22-4 (950 mg, 2.85 mmol) in (10 mL) was stirred at 85 °C for 3 h. The mixture was poured into ice water (100 mL) and added NaHCO 3 The pH was adjusted to 8.0 using a saturated aqueous solution. The resulting mixture was extracted with DCM (50 mL x 3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 cc, filtered and concentrated under reduced pressure to give 22-5 (600 mg, 59.7%). LCMS: MS m / z (ESI) [M+H] + = 334.8.

[0239] To a solution of 22-5 (600 mg, 1.70 mmol) in i-PrOH (10 mL) was added 1-10 (735.6 mg, 3.40 mmol) and DIPEA (2.81 mL, 17.01 mmol). This mixture was diluted with N 2 The mixture was stirred at 110° C. for 32 h. The mixture was poured into water (100 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 22-6 (440 mg, 47.7%). LCMS: MS m / z (ESI) [M+H] + = 515.0.

[0240] To a solution of 22-6 (550 mg, 1.03 mmol) in DCM (5 mL) at -78 °C, 3 (5.13 mL, 5.13 mmol) was added. 2After stirring at room temperature for 18 h, the mixture was quenched with MeOH (10 mL) and NH 3 H 2 The pH was adjusted to 8-9 with O (0.5 mL). The resulting mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give compound 22-7 (300 mg, 66.8%). LCMS: MS m / z (ESI) [M+H] + = 425.0.

[0241] A mixture of 22-7 (100 mg, 0.24 mmol) in DMF (10 mL) was treated with (2-bromoethoxy)(tert-butyl)dimethylsilane (169 mg, 0.72 mmol) and Cs 2 CO 3 (383 mg, 1.18 mmol) was added. After stirring at 100° C. for 3 h, the mixture was quenched with water (20 mL) and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine (3×30 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 22-8 (50 mg, 36.4%). LCMS: MS m / z (ESI) [M+H] + = 583.2.

[0242] To a mixture of 22-8 (40 mg, 0.069 mmol) in THF (0.5 mL) was added TBAF (0.34 mL, 0.34 mmol). 2 After stirring at room temperature for 1 h, the mixture was diluted with EtOAc (15 mL) and washed with water (3×20 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 HPLC to give Example 22 (2.37 mg). LCMS: MS m / z (ESI) [M+H] + = 469.1. 1H NMR (400 MHz, DMSO) δ 7.65 - 7.40 (m, 3H), 7.23 - 7.13 (m, 1H), 5.95 (s, 1H), 5.04 (br s, 1H), 4.33 (m, 2H), 4.06 (m, 2H), 3.83 (m, 2H), 3.56 (s, 3H), 3.19 - 3.02 (m, 3H), 2.42 (s, 3H), 2.25 - 2.15 (m, 2H), 2.09 - 1.97 (m, 2H).

[0243] Example 23: 3-(2-hydroxyethoxy)-5-methyl-8-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] To a mixture of 22-8 (50 mg, 0.086 mmol) in DMA (1 mL), Zn(CN) 2 (50.5 mg, 0.43 mmol), Zn (5.61 mg, 0.086 mmol), zinc bis(acetate) (15.7 mg, 0.086 mmol), dppf (23.8 mg, 0.043 mmol) and Pd(dba). 3 CHCl 3 (34.8 mg, 0.043 mmol) was added. The mixture was stirred at 160° C. for 1.5 h under microwave conditions. The mixture was diluted with ethyl acetate (20 mL) and filtered through a pad of Celite. The filtrate was washed with brine (3×20 mL) and concentrated with 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 silica gel column chromatography to give compound 23-1. LCMS: MS m / z (ESI) [M+H] + = 574.0.

[0244] To a mixture of 23-1 (100 mg, 0.17 mmol) in THF (4 mL) was added TBAF (0.35 mL, 0.35 mmol). After stirring at room temperature for 1 h, the mixture was diluted with EtOAc (15 mL) and washed with water (3×20 mL). 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. The resulting residue was purified by preparative HPLC to give Example 23 (10.6 mg). LCMS: MS m / z (ESI) [M+H] + = 460.0. 1 H NMR (400 MHz, DMSO) δ 7.58 - 7.52 (m, 2H), 7.50 (s, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.01 (s, 1H), 5.06 (t, J = 5.2 Hz, 1H), 4.40 (t, J = 4.7 Hz, 2H), 4.08 - 3.98 (m, 2H), 3.88 - 3.78 (m, 2H), 3.55 (s, 3H), 3.29 - 3.24 (m, 1H), 3.18 - 3.08 (m, 2H), 2.41 (s, 3H), 2.25 - 2.16 (m, 2H), 2.09 - 1.94 (m, 2H).

[0245] Example 24: 3-(3-hydroxypropoxy)-5-methyl-8-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] The preparation of Example 24 was carried out according to a similar procedure to Example 23, where the reactant 1-(2-bromoethoxy)(tert-butyl)dimethylsilane was replaced by (3-bromopropoxy)(tert-butyl)dimethylsilane. LCMS: MS m / z (ESI) [M+H] + = 474.1. 1H NMR (400 MHz, DMSO) δ 7.55 (d, J = 8.3 Hz, 1H), 7.52 (s, 1H), 7.50 (s, 1H), 7.20 - 7.15 (m, 1H), 6.01 (s, 1H), 4.67 (t, J = 5.1 Hz, 1H), 4.42 (t, J = 6.2 Hz, 2H), 4.04 (d, J = 12.7 Hz, 2H), 3.62 (m, 2H), 3.56 (s, 3H), 3.34 (m, 1H), 3.14 (t, J = 11.0 Hz, 2H), 2.41 (s, 3H), 2.26 - 2.16 (m, 2H), 2.08 - 1.92 (m, 4H).

[0246] Example 25: 5-Methyl-8-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-6-oxo-3-((tetrahydro-2H-pyran-4-yl)oxy)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] The preparation of Example 25 was carried out according to a similar procedure to Example 23, where the reactant 1-(2-bromoethoxy)(tert-butyl)dimethylsilane was replaced by 4-bromotetrahydro-2H-pyran. LCMS: MS m / z (ESI) [M+H] + = 500.4. 1H NMR (400 MHz, DMSO) δ 7.59 - 7.54 (m, 2H), 7.50 (s, 1H), 7.17 (dd, J = 8.3, 1.1 Hz, 1H), 6.01 (s, 1H), 5.21 - 5.12 (m, 1H), 4.04 (d, J = 12.7 Hz, 2H), 3.92 - 3.84 (m, 2H), 3.67 - 3.56 (m, 2H), 3.55 (s, 3H), 3.31 - 3.26 (m, 1H), 3.14 (t, J = 10.9 Hz, 2H), 2.42 (s, 3H), 2.26 - 2.17 (m, 2H), 2.11 - 1.95 (m, 4H), 1.78 - 1.66 (m, 2H).

[0247] Example 26: 3-(2-aminoethoxy)-5-methyl-8-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] A solution of 22-2 (100 mg, 0.22 mmol) in DMF (15 mL) was diluted with tert-butyl (2-bromoethyl)carbamate (245 mg, 1.09 mmol) and Cs 2 CO 3 (428 mg, 1.31 mmol) was added. 2 After stirring at 100° C. for 2 h, the mixture was diluted with EtOAc (20 mL) and 2 The organic layer was washed with NaO (3 × 20 mL). 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 26-1 (80 mg, 62.4%). LCMS: MS m / z (ESI) [M+H] + = 568.2.

[0248] To a mixture of 26-2 (70 mg, 0.12 mmol) in DMA (2 mL), Zn(CN) 2(68.7mg, 0.59mmol), Zn (1.53mg, 0.023mmol), Pd 2 (dba) 3 CHCl 3 (24.23mg, 0.023mmol), Zn(OAc) 2 (4.30 mg, 0.023 mmol) and DPPF (13.22 mg, 0.023 mmol) were added. 2 After stirring at 120° C. for 1 h, the mixture was diluted with EtOAc (20 mL) and 2 The organic layer was washed with NaO (3 × 20 mL). 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 26-2 (30 mg, 41.3%). LCMS: MS m / z (ESI) [M+H] + = 559.3.

[0249] To a solution of 26-2 (30 mg, 0.051 mmol) in DCM (1 mL) was added TFA (116 mg). After stirring at 25 °C for 18 h, the mixture was diluted with NaHCO 3 The pH was adjusted to 8.0 using saturated aqueous solution and extracted with DCM (3×15 mL). The combined organic layers were washed with 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 26 (7.7 mg). LCMS: MS m / z (ESI) [M+H] + = 459.2. 1H NMR (400 MHz, DMSO) δ 7.56 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 7.3 Hz, 2H), 7.17 (d, J = 8.2 Hz, 1H), 6.01 (s, 1H), 4.37 - 4.30 (m, 2H), 4.08 - 3.99 (m, 2H), 3.56 (s, 3H), 3.27 - 3.21 (m, 2H), 3.18 - 3.09 (m, 3H), 3.06 - 2.98 (m, 2H), 2.41 (s, 3H), 2.24 - 2.17 (m, 2H), 2.06 - 1.97 (m, 2H).

[0250] Example 27: 5-Methyl-8-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-6-oxo-3-(pyrrolidin-3-yloxy)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] Example 27 was prepared following a similar procedure to Example 26, where the reactant tert-butyl (2-bromoethyl)carbamate was replaced by tert-butyl 3-bromopyrrolidine-1-carboxylate. LCMS: MS m / z (ESI) [M+H] + = 485.2. 1 H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.49 - 7.40 (m, 2H), 7.16 (d, J = 8.2 Hz, 1H), 6.04 - 5.91 (m, 1H), 5.52 - 5.34 (m, 1H), 4.02 (d, J = 12.3 Hz, 2H), 3.54 (s, 3H), 3.45 - 3.41 (m, 1H), 3.34 - 3.22 (m, 2H), 3.19 - 3.04 (m, 4H), 2.39 (s, 3H), 2.26 - 2.15 (m, 3H), 2.14 - 1.92 (m, 3H).

[0251] Example 28: (R)-5-Methyl-8-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-6-oxo-3-((tetrahydrofuran-3-yl)oxy)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] To a solution of 28-1 (500 mg, 5.68 mmol) in anhydrous DCM (15 mL) was added Et 3 N (1.72 g, 2.37 mL, 17.0 mmol) and MsCl (975 mg, 8.51 mmol) were dissolved in N 2 After stirring at room temperature for 16 h, the mixture was added to DCM (20 mL) and washed with water (20 mL x 2) and brine (15 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 compound 28-2 (900 mg), which was used in the next step without further purification.

[0252] A solution of 22-2 (100 mg, 0.24 mmol) and 28-2 (117 mg, 0.71 mmol) in DMF (5 mL) was added with Cs 2 CO 3 (460 mg, 1.41 mmol) was added. After stirring at 100° C. for 3 h, the mixture was diluted with EtOAc (20 mL) and washed with water (20 mL×3) and brine (20 mL). 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. The residue was purified by silica gel column chromatography to give compound 28-3 (65 mg, 55.8%). LCMS: MS m / z (ESI) [M+H] + = 495.3.

[0253] 28-3 (70 mg, 0.14 mmol), Zn (9.25 mg, 0.14 mmol), Zn(CN) in DMA (2 mL) 2 (16.5 mg, 0.14 mmol), Zn(OAc) 2 (25.9 mg, 0.14 mmol), dppf (77.9 mg, 0.14 mmol) and Pd2 dba 3 CHCl 3 A mixture of (146.2 mg, 0.14 mmol) was stirred at 150° C. for 1 h under microwave. The mixture was quenched with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL). The organic layer was washed with 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 28 (26.5 mg, 38.6%). LCMS: MS m / z (ESI) [M+H] + = 486.2. 1 H NMR (400 MHz, DMSO) δ 7.55 (d, J = 8.0 Hz, 1H), 7.50-7.48 (m, 2H), 7.17 (d, J = 8.0 Hz, 1H), 6.02 (s, 1H), 5.57 - 5.48 (m, 1H), 4.05-4.02 (m, 2H), 3.97-3.96 (m, 2H), 3.95-3.93 (m, 1H), 3.83-3.81 (m, 1H), 3.56 (s, 3H), 3.32 - 3.25 (m, 1H), 3.19 - 3.10 (m, 2H), 2.42 (s, 3H), 2.37-2.33 (m, 1H), 2.22-2.20 (m, 2H), 2.12-2.00 (m, 3H).

[0254] Example 29: (S)-5-Methyl-8-(4-(5-methylbenzo[d]oxazol-2-yl)piperidin-1-yl)-6-oxo-3-((tetrahydrofuran-3-yl)oxy)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] The preparation of Example 29 was performed following a similar procedure to Example 28, where the reactant (S)-tetrahydrofuran-3-ol was replaced by (R)-tetrahydrofuran-3-ol. LCMS: MS m / z (ESI) [M+H] + = 486.2. 1H NMR (400 MHz, DMSO) δ 7.55 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 9.4 Hz, 2H), 7.17 (d, J = 8.2 Hz, 1H), 6.02 (s, 1H), 5.59 - 5.49 (m, 1H), 4.09 - 3.98 (m, 2H), 3.97 - 3.88 (m, 3H), 3.85 - 3.75 (m, 1H), 3.56 (s, 3H), 3.33 - 3.25 (m, 1H), 3.20 - 3.09 (m, 2H), 2.42 (s, 3H), 2.40 - 2.27 (m, 1H), 2.26 - 2.14 (m, 2H), 2.13 - 1.95 (m, 3H).

[0255] Example 30: 3-(2-hydroxyethoxy)-5-methyl-8-(1-(5-methylbenzo[d]oxazol-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] The preparation of intermediate 30-3 followed a similar procedure to intermediate 15-10, where 1-bromo-2-methoxyethane was replaced by benzyl bromide.

[0256] SOCl 2 To a solution of 30-1 (2.0 g, 12.1 mmol) in DMF (12 mL, 165.4 mmol) was added dropwise at 0° C. DMF (0.9 mL, 12.1 mmol). After stirring at room temperature for 0.5 h, the mixture was concentrated under reduced pressure. The residue was dissolved in DCM (30 mL) and washed with saturated Na 2 CO 3 The organic layer was washed with water (10 mL) and brine (10 mL), and then diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product, which was purified by silica gel column chromatography to give 30-2 (1.2 g, 59.2%). LCMS: MS m / z (ESI) [M+H] += 168.0.

[0257] 30-3 (500 mg, 1.49 mmol), 30-4 (369 mg, 1.19 mmol), K 2 CO 3 (618 mg, 4.48 mmol) and Pd(dppf)Cl 2 (54.6 mg, 0.075 mmol) and H 2 A mixture of N2O (0.8 mL) and 2 The reaction mixture was stirred at 80° C. for 2 hours. 2 The mixture was added with 200 mL of ethyl acetate (10 mL×10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (30 mL×2) and then with Na 2 SO 4 The mixture was dried over 1000 ml, filtered, and concentrated under reduced pressure. The resulting residue was purified by C18 reverse phase column chromatography to give compound 30-5 (200 mg, 27.8%). LCMS: MS m / z (ESI) [M+H] + = 482.2. 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 - 7.26 (m, 5H), 7.00 (d, J = 8.3 Hz, 1H), 6.56 (d, J = 4.1 Hz, 1H), 6.07 (s, 1H), 5.23 (s, 2H), 4.07 - 4.01 (m, 2H), 3.58 (t, J = 5.5 Hz, 2H), 3.51 (s, 3H), 2.62 - 2.50 (m, 2H), 1.48 - 1.37 (s, 9H).

[0258] To a solution of 30-5 (170 mg, 0.35 mmol) in DCM (2.5 mL) was added TFA (0.5 mL). After stirring at room temperature for 1 h, the mixture was concentrated under reduced pressure to give compound 30-6 (170 mg), which was used in the next step without further purification. LCMS: MS m / z (ESI) [M+H] + = 382.0.

[0259] To a mixture of 30-6 (170 mg, 0.31 mmol) and 30-2 (105 mg, 0.63 mmol) in DMF (3 mL) was added DIEA (0.52 mL, 3.12 mmol). After stirring at 70 °C for 2 h, the mixture was added with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with water (10 mL x 2) and brine (10 mL) and extracted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 30-7 (120 mg, 75.1%). LCMS: MS m / z (ESI) [M+H] + = 513.3.

[0260] To a solution of 30-7 (195 mg, 0.38 mmol) in DCM (5 mL) was added BBr 3 (1.0 mL, 1M in DCM) was added dropwise at 0° C. After stirring at room temperature for 1 h, the mixture was diluted in DCM (20 mL) and quenched by the dropwise addition of MeOH (1 mL) at −78° C. The mixture was washed with water (2×10 mL) and brine (10 mL) and then diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 30-8 (120 mg, 74.7%). LCMS: MS m / z (ESI) [M+H] + = 423.0.

[0261] To a solution of 30-8 (100 mg, 0.24 mmol) in DMF (8 mL), 2 CO 3 (462 mg, 1.42 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (170 mg, 0.71 mmol) were added. After stirring at 100° C. for 3 h, the reaction mixture was diluted with EtOAc (20 mL), washed with water (10 mL×3) and brine (10 mL), and then diluted with Na 2 SO 4The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 30-9 (55 mg, 40.0%). LCMS: MS m / z (ESI) [M+H] + = 581.3.

[0262] 30-9 (50 mg, 0.086 mmol), Zn (6 mg, 0.092 mmol), Zn(CN) in DMA (1 mL) 2 (20 mg, 0.171 mmol), Zn(OAc) 2 (15 mg, 0.082 mmol), dppf (40 mg, 0.087 mmol) and Pd 2 (dba) 3 A mixture of (25 mg, 0.027 mmol) was stirred at 150 °C for 1 h in a sealed tube under microwave conditions. The mixture was diluted with EtOAc (15 mL) and washed with water (10 mL x 2) and brine (10 mL), and added with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give the crude product 30-10, which was used in the next step without further purification. LCMS: MS m / z (ESI) [M+H] + = 515.4.

[0263] To a solution of 30-10 (50 mg, 0.052 mmol) in THF (2 mL) was added TBAF (0.15 mL, 1 M THF solution). After stirring at room temperature for 1 h, the reaction mixture was diluted with EtOAc (15 mL) and then diluted with H 2 Wash with 2×O (10 mL) and brine (10 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 HPLC to give Example 30 (6.9 mg). LCMS: MS m / z (ESI) [M+H] + = 458.1. 1H NMR (400 MHz, DMSO) δ 7.63 (s, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.12 (s, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.67 (s, 1H), 6.26 (s, 1H), 5.12 - 5.00 (m, 1H), 4.42 (t, J = 4.6 Hz, 2H), 4.34 - 4.23 (m, 2H), 3.91 - 3.76 (m, 4H), 3.63 (s, 3H), 2.76 - 2.65 (m, 2H), 2.34 (s, 3H).

[0264] Example A: DGKA Inhibition ADP-Glo ​​Assay The DGKA inhibition reaction was performed using the ADP-Glo ​​assay. The standard solution (pH = 7.5) was 50 mM HEPES, 100 mM NaCl, 10 mM MgCl 2 , 1 mM CaCl 2 Reactions were performed with 0.005% TritonX-100 and 1 mM DTT. 30 nL DMSO solution of each test compound (10 points with a top concentration of 0.4 μM, 4-fold dilution series for each compound) was transferred to a 384-well plate by Echo and 5 μL DGKA (SignalChem, D21-10BG) enzyme standard solution at 2× final reaction concentration was added to each well. After incubation at 25° C. for 15 min, 5 μL standard solution contained 40 μM ATP (Promega, V915B) and 200 μM DLG (SignalChem, D430-59) was added to start the reaction. 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 manufacturer's instructions. % inhibition was calculated from luminescence from control reaction without enzyme as 100% inhibition and reaction with DMSO only as 0% inhibition. IC 50 Values ​​were calculated by regression analysis of the inhibition rates.

[0265] The data for Example A are shown in Table 3. [Table 3]

[0266] Example B: IL-2 Release Detection Assay Isolate human pan T cells from PBMCs by T cell isolation kit (Stemcell, 17951). 3×10 6 Suspension T cells in RPMI 1640 medium containing 10% FBS, 1% PS and 55 μM β-Mer at a density of cells / well / 3 ml were seeded into 6-well plates and incubated at 37°C and 5% CO. 2 The overnight-recovered T cells were harvested, suspended in fresh RPMI 1640 medium containing 10% FBS, 1% PS, and 55 μM β-Mer, and incubated with anti-CD40. 3 Add 1 x 10 of the antibody to a pre-coated 96-well plate. 5 200 μl cells were seeded per well. Compound dilutions were added to the cells and incubated at 37° C. and 5% CO 2 The cells were incubated with 500 mM NaCl for 24 hours. IL-2 in the cell supernatant was detected by ELISA kit (R&D, DY202). Compound EC 50 The nonlinear regression equation is: Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X) × HillSlope), where X = compound concentration and Y = activity %. Top and Bottom: Plateaus in the same units as Y. LogEC 50 : Same log unit as X. Activity fold: Top activity / DMSO control. % activity at 100 nM: Nonlinear regression curve activity at a concentration of 100 nM / DMSO control x 100%.

[0267] The data for Example B is shown in Table 4. [Table 4]

[0268] Example C: Pharmacokinetic profile evaluation Species and strain: SPF CD-1 mice Source: Sino-British SIPPR / BK Lab Animal Ltd, Shanghai. Three mice were administered the given compound (formulation: 5% DMSO + 10% Solutol + 85% saline) intravenously or the given compound (formulation: 5% DMSO + 10% Solutol + 85% saline) by gavage. Blood samples were collected from the cephalic vein at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after intravenous administration or at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours after gavage, at 30 μL / time point. Blood samples were placed in tubes containing K2-EDTA and stored on ice until centrifugation. Blood samples were centrifuged at 6800g for 6 minutes at 2-8°C within 1 hour after collection and frozen at approximately -80°C. Aliquots of 10 μL plasma samples were protein precipitated using 200 μL MeOH containing 10 ng / mL verapamil (IS). The mixture was vortexed for 1 min and centrifuged at 18000 g for 7 min. 180 μL supernatant was transferred to a 96-well plate. An aliquot of 6 μL supernatant was injected for LC-MS / MS analysis by an LC-MS / MS-04 (API4000) instrument. Analytical results were confirmed using quality control samples for intra-assay variation. The precision of >66.7% of the quality control samples should be 80-120% of the known value. 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) are calculated using the noncompartmental analysis module of the FDA-approved pharmacokinetic program Phoenix WinNonlin 7.0 (Pharsight, USA).

[0269] The data for Example C are shown in Table 5. [Table 5]

[0270] The mouse PK data for the compounds disclosed herein, particularly in comparison to the following existing compound (Example 570, WO 2021 / 105117), shows AUC 0~t and AUC 0~∞ showed a much improved PK profile for [ka] Example 570, International Publication No. 2021 / 105117

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, During the ceremony: Ring A is phenyl or 6-membered 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 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; 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, -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , 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; 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 adjacent carbons ３ together form an alkenylene; 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 8; T is N or CR Ｔ and R Ｔ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ is heteroalkyl; Each R ４ 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; p is 0 to 4; 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 alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each 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 alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each 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), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each 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; and 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. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Ring A is a 6-membered heteroaryl.

3. 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein Ring A is pyridinyl.

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

5. The compound is a compound of formula (If): 【Chemistry 3】 and In the formula, R １ａ and R １ｂ Each independently represents R １ Selected from:

2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

6. The compound according to any one of claims 1 to 3, wherein n is 0 to 2, or a pharma- ceutically acceptable salt thereof.

7. 5. The compound of claim 4, or a pharma- ceutically acceptable salt thereof, wherein n' is 2.

8. 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 ６ 8. The compound of any one of claims 1 to 7, which is heteroalkyl, cycloalkyl, or heterocycloalkyl, or a pharma- ceutically acceptable salt thereof.

9. Each R １ are independently -CN or -OR ａ 9. The compound according to any one of claims 1 to 8, wherein:

10. R ２ is hydrogen or C １ ~C ６ 10. The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

11. U is CR Ｕ 11. The compound according to any one of claims 1 to 10, wherein:

12. R Ｕ is hydrogen, halogen, -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 12. The compound of any one of claims 1 to 11, which is heteroalkyl, cycloalkyl, or heterocycloalkyl, or a pharma- ceutically acceptable salt thereof.

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

14. Each R ３ are independently 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 14. The compound of any one of claims 1 to 13, which is heteroalkyl, cycloalkyl, or heterocycloalkyl, or a pharma- ceutically acceptable salt thereof.

15. Two R on the same or different carbons ３ or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 1 to 13, wherein R is substituted with R, or ...

16. 16. The compound according to any one of claims 1 to 4 or 6 to 15, wherein m is 2, or a pharma- ceutically acceptable salt thereof.

17. T is CR Ｔ 17. The compound according to any one of claims 1 to 16, wherein:

18. R Ｔ is hydrogen or C １ ~C ６ 18. The compound of any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

19. Each R ４ 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 19. The compound of any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof, which is heteroalkyl, cycloalkyl, or heterocycloalkyl.

20. Each R ４ became independent and C １ ~C ６ 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

21. 21. The compound according to any one of claims 1 to 20, wherein p is 1 or 2, or a pharma- ceutically acceptable salt thereof.

22. Compound of formula (II): 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof, During the ceremony: Ring A is phenyl or 6-membered 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 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; 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 ~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 a bicyclic ring; 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; m is 0 to 8; Each R ４ 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; p is 0 to 4; 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 alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each 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 alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each 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), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each 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; and 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.

23. 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 ６ 23. The compound of claim 22, or a pharma- ceutically acceptable salt thereof, which is heteroalkyl, cycloalkyl, or heterocycloalkyl.

24. R ２ is hydrogen or C １ ~C ６ 24. The compound of claim 22 or 23, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

25. R Ｕ is hydrogen, -CN, or -C(=O)NR ｃ R ｄ 25. The compound according to any one of claims 22 to 24, wherein:

26. The compound according to any one of claims 22 to 25, wherein Ring B is a bicyclic 6-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from the group consisting of N and O, or a pharma- ceutically acceptable salt thereof.

27. The compound according to any one of claims 22 to 26, wherein ring B is 3,8-diazabicyclo[3.2.1]octane or 2,5-diazabicyclo[2.2.2]octane, or a pharma- ceutically acceptable salt thereof.

28. Ring B is one of the following 【Chemistry 5】 28. The compound according to any one of claims 22 to 27, wherein:

29. Each R ４ are independently halogen, C １ ~C ６ Alkyl, or C １ ~C ６ 29. The compound of any one of claims 22 to 28, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

30. 23. The compound of claim 1 or 22, wherein the compound is selected from the compounds shown in Table 1 or Table 2, or a pharma- ceutically acceptable salt thereof.

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

32. 31. 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 inhibition, comprising administering to the subject a compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof.

33. 31. 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 30, or a pharma- ceutically acceptable salt thereof.

34. 31. 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 30, or a pharma- ceutically acceptable salt thereof.

35. 31. A method of modulating the activity of diacylglycerol kinase alpha (DGKα) in a subject in need of said modulation, comprising administering to said subject a compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof.

36. 31. A method of treating a disease associated with abnormalities in diacylglycerol kinase signaling in a subject in need thereof, comprising administering to said subject a compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof.

37. 36. The method of claim 35, wherein the diacylglycerol kinase is diacylglycerol kinase alpha.

38. 37. The method of claim 35 or 36, wherein the disease is cancer or a viral infection.

39. The method of any one of claims 31 to 38, further comprising administering an additional therapeutic agent.

40. 40. The method of claim 39, wherein the additional therapeutic agent is an anti-cancer agent or an anti-viral agent.

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