WO2023165528A1

WO2023165528A1 - Diacylglycerol kinase (dgk) alpha inhibitors and uses thereof

Info

Publication number: WO2023165528A1
Application number: PCT/CN2023/079066
Authority: WO
Inventors: Hongfu LU; Huaxing YU; Xiao DING; Feng Ren
Original assignee: Insilico Medicine Ip Limited
Priority date: 2022-03-01
Filing date: 2023-03-01
Publication date: 2023-09-07

Abstract

Described herein are DGKalpha inhibitors and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for the treatment of a disease or disorder associated with DGKalpha.

Description

DIACYLGLYCEROL KINASE (DGK) ALPHA INHIBITORS AND USES THEREOF

CROSS-REFERENCE

This patent application claims the benefit of International Application No. PCT/CN2022/078658, filed March 1, 2022; which is incorporated herein by reference in its entirety.

BACKGROUND

Diacylglycerol kinases (DGKs) represent a family of enzymes that catalyze phosphorylation of the membrane lipid sn-1, 2 diacylglycerol (DAG) to form phosphatidic acid (PA) . In T cells, DAG is formed downstream of the T cell receptor (TCR) after activation of the gamma 1 isoform of phospholipase C (PLCyl) and cleavage of phosphatidylinositol 4, 5-biphosphate (PIP2) into DAG and an additional second messenger, inositol 1, 4, 5-triphosphate (IP3) . Whereas, IP3 is important in facilitating release of calcium from the endoplasmic reticulum, DAG interacts with other proteins important in TCR signal transduction, such as Protein kinase CO and the Ras activating protein RasGRPI. Although, three isoforms of DGK are known to be present within T cells (DGKalpha, DGKdelta, and DGKzeta) , only two, DGKalpha and DGKzeta, are thought to play an important role in facilitating DAG metabolism downstream of the TCR.

Supporting evidence include knock-out mouse models of either DGKalpha or DGKzeta which show a hyper-responsive T cell phenotype and improved anti-tumor immune activity (Riese M. J. et al., Journal of Biological Chemistry, (2011) 7: 5254-5265; Zha Y et al., Nature Immunology, (2006) 12: 1343; Olenchock B.A. et al., (2006) 11: 1174-81) . Furthermore tumor infiltrating lymphocytes isolated from human renal cell carcinoma patients were observed to overexpress DGKalpha which resulted in inhibited T cell function (Prinz, P.U. et al., J Immunology (2012) 12: 5990-6000) . Thus, DGKalpha and DGKzeta are viewed as targets for cancer immunotherapy (Riese M.J. et al., Front Cell Dev Biol. (2016) 4: 108; Chen, S.S. 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 DGKalpha and DGKzeta, especially compounds that have selectivity over other diacylglycerol kinases, protein kinases, and/or other lipid kinases. There remains a need for compounds that are safe and effective in restoring T cell activation, lowering antigen threshold, enhancing antitumor functionality, and/or overcoming the suppressive effects of one or more endogenous immune checkpoints, such as PD-1, PD-L1, and CTLA-4, which would be an important addition for the treatment of patients with proliferative disorders, such as cancer, as well as a viral infections.

SUMMARY

Disclosed herein is a compound of Formula (I) , or a pharmaceutically acceptable salt thereof:

wherein:

W is N or CR^W;

R^W is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;

X is N or CR^X;

R^X is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;

Y is N or CR^Y;

R^Y is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;

Z is N or CR^Z;

R^Z is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;

R¹ is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;

U is N or CR^U;

R^U is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;

each R³ is independently halogen, -CN, -NO₂, -OH, -OR^a, -OC (=O) R^a, -OC (=O) OR^b, -OC (=O) NR^cR^d, -SH, -SR^a, -S (=O) R^a, -S (=O) ₂R^a, -S (=O) ₂NR^cR^d, -NR^cR^d, -NR^bC (=O) NR^cR^d, -NR^bC (=O) R^a, -NR^bC (=O) OR^b, -NR^bS (=O) ₂R^a, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;

or two R³ on the same atom are taken together to form an oxo;

or two R³ on the same or different carbons are taken together to form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R;

m is 0-8;

T is N or CR^T;

R^T is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;

L is absent, -O-, -S-, -NR⁴-, or -CR⁵R⁶-;

R⁴ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;

R⁵ and R⁶ are independently hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;

or R⁵ and R⁶ are taken together to form an oxo;

Ring Q is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R⁷ is independently halogen, -CN, -NO₂, -OH, -OR^a, -OC (=O) R^a, -OC (=O) OR^b, -OC (=O) NR^cR^d, -SH, -SR^a, -S (=O) R^a, -S (=O) ₂R^a, -S (=O) ₂NR^cR^d, -NR^cR^d, -NR^bC (=O) NR^cR^d, -NR^bC (=O) R^a, -NR^bC (=O) OR^b, -NR^bS (=O) ₂R^a, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;

or two R⁷ on the same atom are taken together to form an oxo;

p is 0-6;

each R^a is independently C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

or two R^a are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;

each R^b is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

or two R^b are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;

R^c and R^d are each independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (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 are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and

each R is independently halogen, -CN, -OH, -S (=O) CH₃, -S (=O) ₂CH₃, -S (=O) ₂NH₂, -S (=O) ₂NHCH₃, -S (=O) ₂N (CH₃) ₂, -NH₂, -NHCH₃, -N (CH₃) ₂, -C (=O) CH₃, -C (=O) OH, -C (=O) OCH₃, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, or C₃-C₆cycloalkyl;

or two R on the same atom form an oxo;

provided that the compound is not

In some embodiments of a compound of Formula (I) , the compound is of Formula (Ia) :

In some embodiments of a compound of Formula (I) , the compound is of Formula (Ib) :

In some embodiments of a compound of Formula (I) , the compound is of Formula (Ic) :

In some embodiments of a compound of Formula (I) , the compound is of Formula (Id) :

In some embodiments of a compound of Formula (I) , the compound is of Formula (Ie) :

Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Also disclosed herein is a method of inhibiting the activity of at least one of diacylglycerol kinase selected from diacylglycerol kinase alpha (DGKalpha) and diacylglycerol kinase zeta (DGKzeta) , in a subject in need thereof, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

Also disclosed herein is a method of inhibiting the activity of diacylglycerol kinase alpha (DGKalpha) , in a subject in need thereof, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

Also disclosed herein is a method of treating a disease associated with aberrant diacylglycerol kinase signaling, in a subject in need thereof, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

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.

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 INVENTION

Definitions

In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to. ” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the 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 content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.

The terms below, as used herein, have the following meanings, unless indicated otherwise:

“oxo” refers to =O.

“Carboxyl” refers to -COOH.

“Cyano” refers to -CN.

“Alkyl” refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C₁-C₆ alkyl” or “C_1-6alkyl” , means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C_1-10alkyl. In some embodiments, the alkyl is a C_1-6alkyl. In some embodiments, the alkyl is a C_1-5alkyl. In some embodiments, the alkyl is a C_1-4alkyl. In some embodiments, the alkyl is a C_1-3alkyl. Unless stated otherwise specifically in the specification, an alkyl group may 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, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

“Alkenyl” refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond (s) , and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH₂) , 1-propenyl (-CH₂CH=CH₂) , isopropenyl [-C (CH₃) =CH₂] , butenyl, 1, 3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C₂-C₆ alkenyl” or “C_2-6alkenyl” , means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may 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, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, - COOMe, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

“Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C₂-C₆ alkynyl” or “C_2-6alkynyl” , means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may 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, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

“Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may 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, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

“Alkoxy” refers to a radical of the formula -OR_a where R_a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may 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, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

“Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with 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 the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF₃, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF₃, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

“Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C₃-C₁₅ cycloalkyl or C₃-C₁₅ cycloalkenyl) , from three to ten carbon atoms (C₃-C₁₀ cycloalkyl or C₃-C₁₀ cycloalkenyl) , from three to eight carbon atoms (C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl) , from three to six carbon atoms (C₃-C₆ cycloalkyl or C₃-C₆ cycloalkenyl) , from three to five carbon atoms (C₃-C₅ cycloalkyl or C₃-C₅ cycloalkenyl) , or three to four carbon atoms (C₃-C₄ cycloalkyl or C₃-C₄ cycloalkenyl) . In some embodiments, the cycloalkyl is a 3-to 10-membered cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered cycloalkyl or a 5-to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, 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, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF₃, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF₃, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

“Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by 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.

“Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by 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 include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

“Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by 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 include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

“Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C₁-C₆ heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH₂OCH₃, -CH₂CH₂OCH₃, -CH₂CH₂OCH₂CH₂OCH₃, -CH (CH₃) OCH₃, -CH₂NHCH₃, -CH₂N (CH₃) ₂, -CH₂CH₂NHCH₃, or -CH₂CH₂N (CH₃) ₂. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF₃, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF₃, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

“Heterocycloalkyl” refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C₂-C₁₅ heterocycloalkyl or C₂-C₁₅ heterocycloalkenyl) , from two to ten carbon atoms (C₂-C₁₀ heterocycloalkyl or C₂-C₁₀ heterocycloalkenyl) , from two to eight carbon atoms (C₂-C₈ heterocycloalkyl or C₂-C₈ heterocycloalkenyl) , from two to seven carbon atoms (C₂-C₇ heterocycloalkyl or C₂-C₇ heterocycloalkenyl) , from two to six carbon atoms (C₂-C₆ heterocycloalkyl or C₂-C₆ heterocycloalkenyl) , from two to five carbon atoms (C₂-C₅ heterocycloalkyl or C₂-C₅ heterocycloalkenyl) , or two to four carbon atoms (C₂-C₄ heterocycloalkyl or C₂-C₄ heterocycloalkenyl) . Examples of such heterocycloalkyl radicals include, but are not limited to, 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, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1, 1-dioxo-thiomorpholinyl, 1, 3-dihydroisobenzofuran-1-yl, 3-oxo-1, 3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1, 3-dioxol-4-yl, and 2-oxo-1, 3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. 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-to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl may 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, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF₃, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF₃, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

“Heteroaryl” refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5-to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5-to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, 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, isoindolinyl, 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 may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF₃, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF₃, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH₂CH₃) , fully substituted (e.g., -CF₂CF₃) , mono-substituted (e.g., -CH₂CH₂F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH₂CHF₂, -CH₂CF₃, -CF₂CH₃, -CFHCHF₂, etc. ) . It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and/or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.

The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

The terms “treat, ” “treating” or “treatment, ” as used herein, include alleviating, abating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.

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, or a mutant thereof, is known or suspected to play a role.

As used herein, a “disease or disorder associated with DGKalpha” or, alternatively, “a DGKalpha-mediated disease or disorder” means any disease or other deleterious condition in which DGKalpha, or a mutant thereof, is known or suspected to play a role.

As used herein, a “disease or disorder associated with DGKzeta” or, alternatively, “a DGKzeta-mediated disease or disorder” means any disease or other deleterious condition in which DGKzeta, or a mutant thereof, is known or suspected to play a role.

Compounds

Described herein are compounds, or a pharmaceutically acceptable salt thereof useful in the treatment of a disease or disorder associated with DGK, especially DGKalpha.

wherein:

W is N or CR^W;

X is N or CR^X;

Y is N or CR^Y;

Z is N or CR^Z;

U is N or CR^U;

or two R³ on the same atom are taken together to form an oxo;

m is 0-8;

T is N or CR^T;

L is absent, -O-, -S-, -NR⁴-, or -CR⁵R⁶-;

or R⁵ and R⁶ are taken together to form an oxo;

Ring Q is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or two R⁷ on the same atom are taken together to form an oxo;

p is 0-6;

or two R on the same atom form an oxo;

provided that the compound is not

In some embodiments of a compound of Formula (I) , W is N. In some embodiments of a compound of Formula (I) , W is CR^W.

In some embodiments of a compound of Formula (I) , X is N. In some embodiments of a compound of Formula (I) , X is CR^X.

In some embodiments of a compound of Formula (I) , Y is N. In some embodiments of a compound of Formula (I) , Y is CR^Y.

In some embodiments of a compound of Formula (I) , Z is N. In some embodiments of a compound of Formula (I) , Z CR^Z.

In some embodiments of a compound of Formula (I) , (Ia) , or (Ic) - (Ie) , R^W is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , or (Ic) - (Ie) , R^W is hydrogen, halogen, -CN, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , or (Ic) - (Ie) , R^W is hydrogen, halogen, or -CN.

In some embodiments of a compound of Formula (I) , (Ia) , or (Ic) - (Ie) , R^W is hydrogen or halogen. In some embodiments of a compound of Formula (I) , (Ia) , or (Ic) - (Ie) , R^W is hydrogen.

In some embodiments of a compound of Formula (I) , (Ia) , (Ib) , Id) , or (Ie) , R^X is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ib) , Id) , or (Ie) , R^X is hydrogen, halogen, -CN, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) , (Ia) , (Ib) , Id) , or (Ie) , R^X is hydrogen, halogen, or -CN.

In some embodiments of a compound of Formula (I) , (Ia) , (Ib) , Id) , or (Ie) , R^X is hydrogen or halogen. In some embodiments of a compound of Formula (I) , (Ia) , (Ib) , Id) , or (Ie) , R^X is hydrogen.

In some embodiments of a compound of Formula (I) , (Ia) - (Ic) , or (Ie) , R^Y is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) , (Ia) - (Ic) , or (Ie) , R^Y is hydrogen, halogen, -CN, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) , (Ia) - (Ic) , or (Ie) , R^Y is hydrogen, halogen, or -CN.

In some embodiments of a compound of Formula (I) , (Ia) - (Ic) , or (Ie) , R^Y is halogen or -CN. In some embodiments of a compound of Formula (I) , (Ia) - (Ic) , or (Ie) , R^Y is halogen. In some embodiments of a compound of Formula (I) , (Ia) - (Ic) , or (Ie) , R^Y is fluorine or chlorine.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R^Z is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R^Z is hydrogen, halogen, -CN, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R^Z is hydrogen, halogen, or -CN. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R^Z is hydrogen or halogen. In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R^Z is hydrogen.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , R¹ is hydrogen, halogen, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R¹ is hydrogen.

In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , U is N. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , U is CR^U.

In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R^U is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R^U is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, -C (=O) NR^cR^d, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R^U is hydrogen, halogen, -CN, or -C (=O) NR^cR^d. In some embodiments of a compound of Formula (I) or (Ia) -(Ie) , R^U is -CN or -C (=O) NR^cR^d. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R^U is -CN.

In some embodiments of a compound of Formula (I) or (Ia) - (Id) , is

In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R³ is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R³ is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) -(Ie) , each R³ is independently halogen, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R³ is independently C₁-C₆alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R³ is independently methyl or ethyl.

In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , two R³ on different carbons are taken together to form a cycloalkyl optionally substituted with one or more R.

In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , two R³ on different carbons are taken together to form a heterocycloalkyl optionally substituted with one or more R.

In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 0-4. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 0-3. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 0-2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 1. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 0.

In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , T is N; and L is absent or -CR⁵R⁶-. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , T is CR^T; and L is absent, -O-, -S-, -NR⁴-, or -CR⁵R⁶-.

In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , T is N. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , T is CR^T.

In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R^T is hydrogen or C₁-C₆alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R^T is hydrogen.

In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is

In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , L is absent, -O-, or -CR⁵R⁶-. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , L is absent. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , L is -O-or -CR⁵R⁶-. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , L is -O-. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , L is -CR⁵R⁶-. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , L is -CH₂-. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , L is -CH (CH₃) -.

In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R⁵ and R⁶ are independently hydrogen, halogen, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R⁵ and R⁶ are independently hydrogen or C₁-C₆alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , R⁵ and R⁶ are hydrogen.

In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring Q is aryl or heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring Q is phenyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring Q is phenyl or 6-to 10-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring Q is heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring Q is 5-to 10-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring Q is 6-to 10-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring Q is 6-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring Q is 8-to 10-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring Q is 9-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring Q is monocyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring Q is bicyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring Q is 5-6 fused heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring Q is 6-5 fused heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring Q is 5-5 fused heteroaryl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring Q is 6-6 fused heteroaryl.

In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , Ring Q is

In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R⁷ is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R⁷ is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) -(Ie) , each R⁷ is independently halogen, -OR^a, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , each R⁷ is independently halogen, -O-C₁-C₆alkyl, -O-C₁-C₆haloalkyl, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , one or more R⁷ is -OR^a. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , one or more R⁷ is -O-C₁-C₆alkyl or -O-C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , one or more R⁷ is -OCF₃. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , one or more R⁷ is halogen. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , one or more R⁷ is fluorine. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , one or more R⁷ is C₁-C₆alkyl or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , one or more R⁷ is -CF₃ or methyl.

In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 0-6. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 0-5. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 0-4. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 0-3. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 0-2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 1-4. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 1-3. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 1. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , p is 0.

In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is

In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , is

In some embodiments of a compound disclosed herein, each R^a is independently C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R^a is independently C₁-C₆alkyl, C₁-C₆haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R^a is independently C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (heteroaryl) . In some embodiments of a compound disclosed herein, each R^a is independently C₁-C₆alkyl, C₁-C₆haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each R^a is independently C₁-C₆alkyl or C₁-C₆haloalkyl. In some embodiments of a compound disclosed herein, each R^a is independently C₁-C₆alkyl.

In some embodiments of a compound disclosed herein, each R^b is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R^b is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R^b is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (heteroaryl) . In some embodiments of a compound disclosed herein, each R^b is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each R^b is independently hydrogen, C₁-C₆alkyl or C₁-C₆haloalkyl. In some embodiments of a compound disclosed herein, each R^b is independently hydrogen or C₁-C₆alkyl. In some embodiments of a compound disclosed herein, each R^b is hydrogen. In some embodiments of a compound disclosed herein, each R^b is independently C₁-C₆alkyl.

In some embodiments of a compound disclosed herein, each R^c and R^d are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R^c and R^d are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R^c and R^d are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (heteroaryl) . In some embodiments of a compound disclosed herein, each R^c and R^d are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each R^c and R^d are independently hydrogen, C₁-C₆alkyl or C₁-C₆haloalkyl. In some embodiments of a compound disclosed herein, each R^c and R^d are independently hydrogen or C₁-C₆alkyl. In some embodiments of a compound disclosed herein, each R^c and R^d are hydrogen. In some embodiments of a compound disclosed herein, each R^c and R^d are independently C₁-C₆alkyl.

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

In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH₂, -NHCH₃, -N (CH₃) ₂, -C (=O) CH₃, -C (=O) OH, -C (=O) OCH₃, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, or C₃-C₆cycloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH₂, -NHCH₃, -N (CH₃) ₂, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, or C₃-C₆cycloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, C₁-C₆alkyl, C₁-C₆alkoxy, or C₁-C₆haloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, or C₁-C₆alkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -OH, or C₁-C₆alkyl. In some embodiments of a compound disclosed herein, each R is independently halogen or C₁-C₆alkyl. In some embodiments of a compound disclosed herein, each R is independently halogen.

In some embodiments of a compound disclosed herein, one or more of R, R¹, R³, R⁴, R⁵, R⁶, R⁷, R^U, R^T, R^X, R^Y, R^Z, R^W, R^a, R^b, R^c, and R^d groups comprise deuterium at a percentage higher than the natural abundance of deuterium.

In some embodiments of a compound disclosed herein, one or more ¹H are replaced with one or more deuteriums in one or more of the following groups R, R¹, R³, R⁴, R⁵, R⁶, R⁷, R^U, R^T, R^X, R^Y, R^Z, R^W, R^a, R^b, R^c, and R^d.

In some embodiments of a compound disclosed herein, the abundance of deuterium in each of R, R¹, R³, R⁴, R⁵, R⁶, R⁷, R^U, R^T, R^X, R^Y, R^Z, R^W, R^a, R^b, R^c, and R^d 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%of a total number of ¹H and deuterium.

In some embodiments of a compound disclosed herein, one or more ¹H of Ring Q are replaced with one or more deuteriums.

Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

In some embodiments the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is one of the compounds in Table 1.

TABLE 1

In some embodiments the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is one of the compounds in Table 2.

TABLE 2

Further Forms of Compounds Disclosed Herein

Isomers/Stereoisomers

In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess 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 situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the 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 enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.

Labeled compounds

In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as ²H (D) , ³H, ¹³C, ¹⁴C, ^l5N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability.

In some embodiments, the abundance of deuterium in each of the substituents disclosed herein 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%of a total number of ¹H and deuterium. In some embodiments, one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, one or more ¹H are replaced with one or more deuteriums in one or more of the substituents disclosed herein.

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

Pharmaceutically acceptable salts

In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

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

Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, 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.

Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4, 4’-methylenebis- (3-hydroxy-2-ene-1 -carboxylic acid) , 3-phenylpropionic acid, trimethylacetic acid, 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, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.

In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N⁺ (C_1-4 alkyl) ₄, and the like.

Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should 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.

Tautomers

In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.

Method of Treatment

Disclosed herein are methods of treating a disease modulated by DGK in a subject in need thereof, comprising administering to the subject a therapeutically affective amount of a compound, or a pharmaceutically acceptable salt thereof, disclosed herein.

Disclosed herein are methods of treating a disease modulated by DGKalpha in a subject in need thereof, comprising administering to the subject a therapeutically affective amount of a compound, or a pharmaceutically acceptable salt thereof, disclosed herein. In some embodiments, the disease is cancer or a viral infection.

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, renal cancer, thyroid cancer, or urinary track cancer.

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

Disclosed herein is a method of inhibiting the activity of at least one of diacylglycerol kinase comprising administering to the subject a therapeutically affective amount of a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, disclosed herein. In some embodiments, the diacylglycerol kinase is diacylglycerol kinase alpha (DGKalpha) . In some embodiments, the diacylglycerol kinase is diacylglycerol kinase zeta (DGKzeta) .

Dosing

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

In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms.

The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

In some embodiments, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In some embodiments, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg per body weight. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

Routes of Administration

Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.

Pharmaceutical Compositions/Formulations

The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary 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, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins1999) , herein incorporated by reference for such disclosure.

In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.

The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

Combination

Disclosed herein are methods of treating a disease or disorder associated with DGKalpha using a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with an additional therapeutic agent.

In some embodiments, the additional therapeutic agent is administered at the same time as 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 than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein.

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 death receptor 1) antibody, or an anti-PD-L1 (Programmed death ligand 1) antibody.

In some embodiments, the additional therapeutic agent is an anti-viral agent.

Examples

Example 1: 8-chloro-5- (4- (4- (trifluoromethoxy) phenoxy) piperidin-1-yl) - [1, 2, 4] triazolo [4, 3-a] quinazoline

To a mixture of compound 1-1 (5 g, 24.84 mmol) in DCM (50 mL) was added MsCl (2.88 mL, 37.26 mmol) and Et₃N (10.36 mL, 74.53 mmol) at 0 ℃. The mixture was stirred at room temperature for 12 h. The mixture was diluted with DCM (100 mL) , and then washed with H₂O (100 mL) and brine (120 mL) . The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give compound 1-2, which was directly used for the next step without further purification.

To a mixture of compound 1-2 (5.8 g, 20.76 mmol) in DMF (100 mL) was added compound 1-3 (3.509 mL, 26.99 mmol) and Cs₂CO₃ (20.29 g, 62.29 mmol) . The reaction mixture was stirred at 100 ℃ for 2 h. The reaction mixture was diluted with ethyl acetate and washed with saturated NaCl solution. The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 1-4, which was directly used in the next step without further purification.

A mixture of compound 1-4 (3.0 g, 8.30 mmol) in HCl (10 mL, 4 M in dioxane) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to give compound 1-5 as a white solid, which was used for the next step without further purification.

To the mixture of compound 1-6 (300 mg, 1.28 mmol) in MeCN (5 mL) was added compound 1-5 (381.06 mg, 1.28 mmol) and ethyldiisopropylamine (0.637 mL, 3.85 mmol) . The mixture was stirred at 60 ℃ for 1 h. The reaction mixture was diluted with H₂O and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give 1-7 as a yellow solid, which was used for the next step without further purification.

To a mixture of compound 1-7 (350 mg, 0.76 mmol) in EtOH (5 mL) was added hydrazine monohydrate (0.074 mL, 1.53 mmol) . The reaction mixture was stirred at 50 ℃ for 1 h. The reaction mixture was diluted with H₂O and extracted with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo to give compound 1-8. LCMS: MS (ESI) m/z [M+H] ⁺ = 453.9.

A mixture of compound 1-8 (150 mg, 0.33 mmol) in triethyl orthoformate (5 mL) was stirred at 110 ℃ for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC separation to give example 1. LCMS: MS (ESI) m/z [M+H] ⁺ = 464.1. ¹H NMR (400 MHz, DMSO) δ 9.59 (s, 1H) , 8.58 (d, J = 2.0 Hz, 1H) , 8.09 (d, J = 8.8 Hz, 1H) , 7.64 (dd, J = 8.8, 2.1 Hz, 1H) , 7.31 (d, J = 8.6 Hz, 2H) , 7.13 (d, J = 9.2 Hz, 2H) , 4.76 (s, 1H) , 3.84 (m, 2H) , 3.57 –3.42 (m, 2H) , 2.17 (m, 2H) , 1.90 (m, J = 9.3 Hz, 2H) .

Example 2: 7-chloro-5- (4- (1- (4-fluorophenyl) ethyl) piperazin-1-yl) - [1, 2, 4] triazolo [4, 3-a] [1, 5] naphthyridine-4-carbonitrile

A mixture of compound 2-1 (10 g, 60.18 mmol) and NBS (10.82 g, 60.78 mmol) in MeCN (120 mL) was stirred at room temperature for 1.5 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 X 100 mL) . The combined organic layer was collected, dried over Na₂SO₄, filtered, and the filtrate was concentrated in vacuum to give compound 2-2 as a yellow solid. LCMS: MS (ESI) m/z [M+H] ⁺ = 245.0.

To a mixture of compound 2-2 (12.1 g, 49.23 mmol) in DMF (100 mL) was added 2-cyanoacetic acid (5.86 g, 68.92 mmol) , DIEA (24.5 mL, 148.10 mmol) and T₃P (50%in EA, 62.9 g, 197.7 mmol) . The reaction was stirred at 25 ℃ for 16 h. The reaction mixture was quenched with water (400 mL) and the reaction mixture was diluted with ethyl acetate (300 mL) and washed with brine (3 X 300 mL) . The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give compound 2-3 as a yellow solid. LCMS: MS (ESI) m/z [M+H] ⁺ = 312.0.

To a mixture of compound 2-3 (3.8 g, 12.17 mmol) in THF (100 mL) was added KHMDS (14.2 mL, 1.0 M) at -78 ℃ under nitrogen. The mixture was allowed to warm to room temperature and stirred for 1.5 h. The mixture was quenched with saturated Na₂SO₄ solution (14 mL) . The mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 2-4 as a yellow solid. ¹HNMR (400 MHz, DMSO) δ 11.95 (s, 1H) , 7.85 (d, J = 8.7 Hz, 1H) , 7.63 (d, J = 8.7 Hz, 1H) .

To a mixture of compound 2-4 (1.5 g, 5.638 mmol) in POCl₃ (15 mL) were added DIEA (5.59 mL, 33.83 mmol) . The reaction mixture was stirred at 100 ℃ overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give compound 2-5 as a yellow solid. LCMS: MS (ESI) m/z [M+H] ⁺ = 258.1.

To a mixture of compound 2-5 (330 mg, 1.38 mmol) in i-PrOH (15 mL) were added 2-methylpropan-2-yl piperazine-1-carboxylate (256.05 mg, 1.38 mmol) and DIEA (1.14 mL, 6.87 mmol) . The reaction was stirred at 90 ℃ for 2 hr. The mixture was quenched with aq. NH₄Cl solution (20 mL) and extracted with EtOAc (2 X 20 mL) . The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give compound 2-6 as a yellow solid. LCMS: MS (ESI) m/z [M+H] ⁺ = 408.3.

To a mixture of compound 2-6 (200 mg, 0.49 mmol) in EtOH (2 mL) and THF (4 mL) was added hydrazine monohydrate (49.04 mg, 0.98 mmol) . The mixture was stirred at 50 ℃ for 0.5 h under N₂. The mixture was quenched with H₂O (15 mL) and extracted with EtOAc (2 X 15 mL) . The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give compound 2-7 as a yellow solid, which was used for the next step without further purification. LCMS: MS (ESI) m/z [M+H] ⁺ = 404.2.

A mixture of compound 2-7 (200 mg, 0.495 mmol) in triethyl orthoformate (2 mL) was stirred at 100 ℃ for 18 h under N₂. The mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give compound 2-8 as a yellow solid. LCMS: MS (ESI) m/z [M+H] ⁺ = 414.1.

A mixture of compound 2-8 (10 mg, 0.024 mmol) in HCl (1 mL, 4 M in dioxane) was stirred at 20 ℃ for 1 h. The reaction mixture was concentrated under reduced pressure to give compound 2-9 (10 mg) as a yellow solid, which was used for the next step without further purification. LCMS: MS (ESI) m/z [M+H] ⁺ = 314.1.

To a mixture of compound 2-9 (30 mg, 0.086 mmol) and 1- (1-bromoethyl) -4-fluorobenzene (26.09 mg, 0.128 mmol) in DMF (2 mL) was added K₂CO₃ (35.52 mg, 0.257 mmol) at 20 ℃ under N₂. The mixture was stirred at this temperature for 18 h. The reaction mixture was purified by prep-HPLC separation to give example 2. LCMS: MS (ESI) m/z [M+H] ⁺ = 436.3. ¹H NMR (400 MHz, DMSO) δ 9.81 (s, 1H) , 8.88 (d, J = 8.8 Hz, 1H) , 8.05 (d, J = 8.7 Hz, 1H) , 7.48 –7.32 (m, 2H) , 7.18 (t, J = 8.8 Hz, 2H) , 3.90 –3.75 (m, 4H) , 3.62 –3.53 (m, 1H) , 2.71 –2.54 (m, 4H) , 1.35 (d, J = 6.4 Hz, 3H) .

Example 3: 7-chloro-5- (4- (1- (4-fluorophenyl) ethyl) piperazin-1-yl) - [1, 2, 4] triazolo [4, 3-a] quinoline-4-carbonitrile

A mixture of compound 3-1 (10.0 g, 58.28 mmol) and trichloromethyl chloromethanoate (7 mL, 58.28 mmol) in dioxane (100 mL) was stirred at 110 ℃ for 18 h. After cooling to room temperature, the mixture was filtered and the filter cake was collected, dried under reduced pressure to afford compound 3-2 (10.9 g, 95%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H) , 7.87 (d, J = 2.3 Hz, 1H) , 7.78 (dd, J = 8.7, 2.4 Hz, 1H) , 7.17 (d, J = 8.7 Hz, 1H) .

A mixture of compound 3-2 (1.0 g, 4.81 mmol) , ethyl cyanoacetate (2.94 g, 25.97 mmol) and TEA (6.684 mL, 48.084 mmol) in THF (15 mL) was refluxed for 24 h. After cooling to room temperature, HCl (20 mL, 1 M) was added and the mixture was filtered. The filter cake was dried under reduced pressure to afford compound 3-3 as a light yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H) , 8.82 (br s, 1H) , 8.00 (d, J = 2.3 Hz, 1H) , 7.66 (dd, J = 8.8, 2.3 Hz, 1H) , 7.30 (d, J = 8.8 Hz, 1H) .

A mixture of compound 3-3 (500 mg, 1.36 mmol) and POCl₃ (1 mL) in MeCN (4 mL) was stirred at 80 ℃ for 3 h. The mixture was diluted with DCM (15 mL) and quenched with saturated NaHCO₃ (30 mL) . The mixture was extracted with DCM (20 mL X 3) . The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo to afford compound 3-4 as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J = 2.3 Hz, 1H) , 8.04 (d, J = 9.0 Hz, 1H) , 7.88 (dd, J = 9.0, 2.3 Hz, 1H) .

A mixture of compound 3-4 (330 mg, 1.27 mmol) , compound 3-5 (236.30 mg, 1.27 mmol) and DIEA (1.048 mL, 6.344 mmol) in i-PrOH (6 mL) was stirred at 90 ℃ for 3 h. After cooling to room temperature, the mixture was filtered and the filter cake was dried under reduced pressure to afford compound 3-6 as a white solid. LCMS: MS (ESI) m/z [M+H] ⁺ = 407.0.

To a mixture of compound 3-6 (100 mg, 0.246 mmol) in THF (4 mL) /EtOH (2 mL) was added hydrazine monohydrate (0.048 mL, 0.982 mmol) . The mixture was stirred at 50 ℃ for 2 h. After cooling to room temperature, the mixture was concentrated in vacuo to afford compound 3-7 as a yellow solid. LCMS: MS (ESI) m/z [M+H] ⁺ = 403.1.

A mixture of compound 3-7 (100 mg, 0.223 mmol) in triethyl orthoformate (10 mL) was stirred at 100 ℃ for 16 h. After cooling to room temperature, the mixture as concentrated in vacuo. The residue was purified by prep-TLC (PE/EA=1: 2, Rf = 0.3) to afford compound 3-8 as a light yellow solid. LCMS: MS (ESI) m/z [M+H] ⁺ = 413.3.

A mixture of compound 3-8 (70 mg, 0.119 mmol) in HCl (3 mL, 4 M in dioxane) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to afford compound 3-9 as a yellow solid, which was used for the next step directly without further purification. LCMS: MS (ESI) m/z [M+H] ⁺ = 313.0.

A mixture of compound 3-9 (60 mg, 0.125 mmol) , 1- (1-bromoethyl) -4-fluorobenzene (75.96 mg, 0.374 mmol) and K₂CO₃ (86.17 mg, 0.623 mmol) in DMF (3 mL) was stirred at room temperature for 4 h. The mixture was filtered and the filtrate was purified by prep-HPLC to afford example 3. LCMS: MS (ESI) m/z [M+H] ⁺ = 435.3. ¹H NMR (400 MHz, DMSO) δ 9.89 (s, 1H) , 8.46 (d, J = 8.8 Hz, 1H) , 8.00 (dd, J = 8.8, 1.5 Hz, 1H) , 7.93 (d, J = 1.5 Hz, 1H) , 7.43 (dd, J = 8.2, 5.8 Hz, 2H) , 7.19 (t, J = 8.8 Hz, 2H) , 3.63 –3.59 (m, 1H) , 3.56 –3.54 (m, 4H) , 2.71 m, 2H) , 2.64 –2.56 (m, 2H) , 1.36 (d, J = 6.6 Hz, 3H) .

Example 4: 7-fluoro-5- (4- (4- (trifluoromethoxy) phenoxy) piperidin-1-yl) - [1, 2, 4] triazolo [4, 3-a] quinoline-4-carbonitrile

To a mixture of compound 4-1 (3 g, 16.56 mmol) in THF (30 mL) was added ethyl cyanoacetate (10.12 g, 89.44 mmol) and Et₃N (23.02 mL, 165.64 mmol) at room temperature. The reaction mixture was refluxed for 12 h. The mixture was concentrated under reduced pressure. The residue was adjusted to pH= 3 and precipitate formed. The mixture was filtered and the filter cake was washed with H₂O (20 mL) . The filter cake was dried under reduced pressure to give compound 4-2 as a brown solid, which was used for the next step without further purification.

To a mixture of compound 4-2 (400 mg, 1.96 mmol) in CH₃CN (30 mL) was added POCl₃ (2.185 mL, 23.51 mmol) . The reaction mixture was stirred at 75 ℃ for 18 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give compound 4-3, which was used for the next step without further purification.

To a mixture of compound 4-3 (400 mg, 1.22 mmol) in i-PrOH (30 mL) was added compound 1-5 (318.67 mg, 1.22 mmol) and DIEA (0.20 mL, 1.22 mmol) . The reaction mixture was stirred at 85 ℃for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography to give compound 4-4 as a yellow solid. LCMS: MS (ESI) m/z [M+H] ⁺ = 466.2.

To a mixture of compound 4-4 (90 mg, 0.19 mmol) in EtOH (1 mL) and THF (2 mL) was added hydrazine monohydrate (116.06 mg, 2.32 mmol) . The mixture was stirred at 50 ℃ for 0.5 h under N₂. After cooling to room temperature, the mixture was quenched with H₂O (15 mL) and extracted with EtOAc (2 X 15 mL) . The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give compound 4-5 as a yellow solid, which was used for the next step without further purification. LCMS: MS (ESI) m/z [M+H] ⁺ = 462.1.

A mixture of compound 4-5 (90 mg, 0.195 mmol) in triethyl orthoformate (3 mL, 0.195 mmol) was stirred at 100 ℃ for 18 h under N₂. After cooling to room temperature, the mixture was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC separation to give example 4. LCMS: MS (ESI) m/z [M+H] ⁺ = 472.2; ¹H NMR (400 MHz, DMSO) δ 9.90 (s, 1H) , 8.53 (dd, J = 9.1, 4.8 Hz, 1H) , 7.96 –7.83 (m, 1H) , 7.78 (dd, J = 9.9, 2.8 Hz, 1H) , 7.32 (d, J = 8.5 Hz, 2H) , 7.20 –7.06 (m, 2H) , 4.85 –4.75 (m, 1H) , 3.80 –3.68 (m, 2H) , 3.62 –3.49 (m, 2H) , 2.30 –2.20 (m, 2H) , 2.05 –1.92 (m, 2H) .

Example 5: 5- ( (2S, 5R) -2-ethyl-5-methyl-4- (1- (4- (trifluoromethyl) phenyl) ethyl) piperazin-1-yl) pyrido [2, 3-e] [1, 2, 4] triazolo [4, 3-a] pyrimidine-7-carbonitrile

To a mixture of compound 5-1 (5.0 g, 27.24 mmol) in MeOH (60 mL) and conc. HCl (25 mL) was added Fe (1.07 g, 19.08 mmol) at 20 ℃. The reaction mixture was heated at 80 ℃ for 1 h. After cooling to room temperature, the mixture was poured into ice-water (100 mL) and filtered. The filter cake was washed with DCM (100 mL) . The filtrate was extracted with DCM (2 X 100 mL) . The combined organic layers were washed with brine (300 mL) , dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give compound 5-2 as a light yellow solid, which was used for the next step without further purification.

To a mixture of compound 5-2 (3.3 g, 21.49 mmol) in DMSO (60 mL) was added K₂CO₃ (5.94 g, 42.98 mmol) and H₂O₂ (4.87 g, 42.98 mmol) . The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (100 mL) and the precipitate formed. The mixture was filtered and the filter cake was washed with H₂O (50 mL) . The filter cake was dried under reduced pressure to give compound 5-3 as a brown solid, which was used for next step without further purification.

To a mixture of compound 5-3 (3.0 g, 17.5 mmol) in DMF (60 mL) were added Pd₂ (dba) ₃ (1.60 g, 1.74 mmol) , dppf (0.99 g, 1.74 mmol) , Zn (OAc) ₂ (0.32 mg, 1.74 mmol) and Zn (CN) ₂ (4.11 g, 34.98 mmol) . The mixture was stirred at 120 ℃ under microwave for 1 h in a sealed tube. The mixture was quenched with water (80 mL) and extracted with EtOAc (3 X 80 mL) . The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give compound 5-4 as a yellow solid. ¹H NMR (400 MHz, DMSO) δ 7.98 (s, 1H) , 7.71 (d, J = 8.8 Hz, 1H) , 7.54 (s, 2H) , 7.22 (d, J = 8.8 Hz, 1H) .

To a mixture of compound 5-4 (2.0 g, 12.33 mmol) in dioxane (80 mL) was added triphosgene (3.66 g, 12.33 mmol) at room temperature under N₂. The resulting mixture was stirred at 100 ℃ for 3 h. After cooling to room temperature, the reaction mixture was quenched with water (50 mL) and the precipitate formed. The mixture was filtered. The filter cake was washed with H₂O (50 mL) and dried under reduced pressure to afford 5-5 which was used for the next step without further purification.

To a suspension of compound 5-5 (325 mg, 1.73 mmol) in dry toluene (20 mL) were added POCl₃ (0.80 mL, 8.64 mmol) and DIEA (1.43 mL, 8.64 mmol) at room temperature. The reaction mixture was heated to 110 ℃ and stirred for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with saturated NaHCO₃ (40 mL) and brine (3 X 50 mL) . The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford compound 5-6 which was used for the next step without further purification.

To a solution of 5-10 (14.5 g, 103.88 mmol) in DCM (300 mL) were added benzaldehyde (9.52 mL, 94.23 mmol) and NaBH (OAc) ₃ (66.05 g, 311.64 mmol) at room temperature. The reaction was stirred at room temperature for 48 hr. The reaction was diluted with DCM (150 mL) and washed with water (150 mL) , saturated NaCl solution (150 mL) . The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give compound 5-11. LCMS: MS (ESI) m/z [M+H] ⁺ = 194.2.

To a mixture of compound 5-11 (7.57 g, 37.26 mmol) and methyl (2R) -2- (benzylamino) propanoate (6.0 g, 31.05 mmol) in DMF (100 mL) was added HATU (16.53 g, 43.47 mmol) and DIEA (10 g, 43.47 mmol) . The mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water (120 mL) and extracted with ethyl acetate (2 X 120 mL) . The combined organic layers were washed with water (200 mL) and brine (200 mL) , dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give compound 5-12 as a yellow liquid. LCMS: MS (ESI) m/z [M+H] ⁺ =379.4.

To a solution of compound 5-12 (4.7 g, 12.42 mmol) in DCM (240 mL) was added TFA (60 mL) . The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (100 mL) and washed with saturated NaHCO₃ solution (100 mL) . The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give compound 5-13. LCMS: MS (ESI) m/z [M+H] ⁺ =279.2.

A mixture of compound 5-13 (3.4 g, 12.22 mmol) in MeOH (100 mL) was stirred at 65℃overnight. The reaction mixture was concentrated under reduced pressure to give compound 5-14 as a yellow oil, which was used for the next step without further purification.

To a mixture of compound 5-14 (3.0 g, 12.18 mmol) in THF (50 mL) was added BH₃-THF (5.23 g, 60.90 mmol) dropwise under ice-bath temperature. The mixture was stirred at 70 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with MeOH (10 mL) and conc. HCl (2 mL) solution. Then the solution was heated at 70 ℃ with stirring for 3 h. The solvent was removed in vacuo, and the residue was partitioned between water (20 mL) and Et₂O (20 mL) . 1 M aqueous NaOH was added to adjust pH=12 and the mixture was extracted with DCM (3 X 50 mL) . The combined organic layers was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give compound 5-15 as a yellow liquid, which was used for the next step without further purification. LCMS: MS (ESI) m/z [M+H] ⁺ =219.2.

To a solution of compound 5-15 (2.6 g, 11.91 mmol) in DCM (60 mL) were added Boc₂O (4.10 mL, 17.86 mmol) and Et₃N (4.97 mL, 35.72 mmol) . The reaction mixture was stirred at 20 ℃ for 3 hr. The reaction mixture was washed with water (50 mL) , 1 M NaOH solution (40 mL) and saturated NaCl solution (3 X 40 mL) . The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give compound 5-16 as a yellow liquid, which was used for the next step without further purification. LCMS: MS (ESI) m/z [M+H] ⁺ =319.3.

To a solution of compound 5-16 (1.9 g, 5.97 mmol) in MeOH (25 mL) were added AcOH (0.342 mL, 5.97 mmol) and 10%Pd/C (1.90 g) . The reaction was stirred at 20 ℃ for overnight under H₂ (30 psi) . The mixture was filtered through a celite pad and the filter cake was rinsed with MeOH/EtOAc (1/1, 50 mL) . The filtrate was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford compound 5-17 as a yellow liquid. LCMS: MS (ESI) m/z [M+H] ⁺ = 229.3.

To a mixture of compound 5-18 (4.7 g, 24.72 mmol) in DCM (50 mL) was added SOCl₂ (2.69 mL, 37.07 mmol) dropwise under ice bath temperature. The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to give compound 5-19 as a yellow solid. LCMS: MS (ESI) m/z [M+H] ⁺ = 208.6.

To a solution of compound 5-17 (500 mg, 2.19 mmol) in DMSO (6 mL) were added compound 5-19 (913.59 mg, 4.38 mmol) and DIEA (1.09 mL, 6.57 mmol) . The reaction was stirred at 140 ℃ for 1 hr.The mixture was quenched with water (15 mL) and extracted with EtOAc (3 X 15 mL) . The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 5-20 as a yellow solid.

To a solution of compound 5-20 (350 mg, 0.87 mmol) in MeOH (5 mL) was added HCl (5 mL, 4 M in dioxane) . The reaction mixture was stirred at 20 ℃ for 1 hr. The mixture was concentrated under reduced pressure. The residue was adjusted to pH = 9 with aq. NaHCO₃ solution and extracted with ethyl acetate (3 X 15 mL) . The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give compound 5-7 as a yellow oil. LCMS: MS (ESI) m/z [M+H] ⁺ = 301.6.

To a suspension of compound 5-6 (100 mg, 0.44 mmol) in dry dioxane (8 mL) were added compound 5-7 (133.48 mg, 0.44 mmol) and DIEA (0.73 mL, 4.44 mmol) at room temperature. The reaction mixture was heated at 90 ℃ for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give compound 5-8 as a yellow solid. LCMS: MS (ESI) m/z [M+H] ⁺ = 489.2.

To a solution of compound 5-8 (70 mg, 0.143 mmol) in dry EtOH (4.0 mL) and THF (2.0 mL) was added hydrazine monohydrate (14.33 mg, 0.286 mmol) at room temperature. The reaction mixture was stirred at 50 ℃ for 3 h. The mixture was concentrated under reduced pressure to give compound 5-9 as a yellow solid. LCMS: MS (ESI) m/z [M+H] ⁺ = 485.3.

A mixture of compound 5-9 (33 mg, 0.068 mmol) in triethyl orthoformate (98%, 2.0 mL) was stirred at 120 ℃ for 4 h. The reaction mixture concentrated under reduced pressure. The residue was purified by prep-HPLC separation to obtain example 5. LCMS: MS (ESI) m/z [M+H] ⁺ = 495.4. ¹H NMR (400 MHz, DMSO) δ 9.59 (s, 1H) , 8.96 (d, J = 8.7 Hz, 1H) , 8.60 (d, J = 8.6 Hz, 1H) , 7.93 –7.60 (m, 4H) , 4.05 –3.55 (m, 3H) , 3.30 –3.10 (m, 2H) , 2.05 -1.85 (m, 2H) , 1.30 -1.20 (m, 6H) , 1.03 –0.93 (m, 2H) , 0.73 –0.63 (m, 2H) .

Example 6: 2- (1- (7-chloro- [1, 2, 4] triazolo [4, 3-a] quinazolin-5-yl) piperidin-4-yl) -5-methylbenzo [d] oxazole

To the mixture of compound 6-1 (5 g, 38.71 mmol) and 2-amino-4-methylphenol (5.01 g, 40.65 mmol) were added PPA (25 g, 73.98 mmol) , and the mixture was stirred at 180 ℃ for 2 h. After cooling to room temperature, the reaction mixture was quenched with water. The mixture was adjusted to pH=12 with 50%potassium hydroxide aqueous solution and then extracted with methylene chloride (2×200 mL) . The organic layer was washed with saturated brine and dried over Na₂SO₄, and evaporated under reduced pressure to afford compound 6-2. LCMS: MS (ESI) m/z [M+H] ⁺= 217.0

A mixture of compound 6-3 (300 mg, 1.29 mmol) , compound 6-2 (277.92 mg, 1.10 mmol) and DIEA (1.06 mL, 6.43 mmol) in IPA (5 mL) was stirred at 90 ℃ for 16 h. After cooling to room temperature, the mixture was filtered and the filter cake was dried under reduced pressure to afford compound 6-4 as an off-white solid. LCMS: MS (ESI) m/z [M+H] ⁺= 413.2.

A mixture of compound 6-4 (200 mg, 0.484 mmol) and hydrazinium hydroxide (0.24 mL, 4.84 mmol) in THF (6 mL) /EtOH (3 mL) was stirred at 50 ℃ for 16 h. The mixture was evaporated in vacuo to afford compound 6-5 as a yellow solid. LCMS: MS (ESI) m/z [M+H] ⁺= 409.2.

A mixture of compound 6-5 (200 mg, 0.44 mmol) in trimethyl orthoformate (15 mL) was stirred at 100 ℃ for 16 h. The mixture was concentrated in vacuo. MeOH (10 mL) was added to the residue. The mixture was filtered. The filter cake was dried under reduced pressure to afford the crude product (80 mg) as a yellow solid. 30 mg of crude product was purified by preparative HPLC separation to give example 6. LCMS: MS (ESI) m/z [M+H] ⁺ = 419.0. ¹H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H) , 8.39 (d, J = 8.7 Hz, 1H) , 8.07 –8.02 (m, 2H) , 7.57 (d, J = 8.2 Hz, 1H) , 7.51 (s, 1H) , 7.18 (dd, J =8.3, 0.7 Hz, 1H) , 4.08 (m, 2H) , 3.44 –3.30 (m, 3H) , 2.42 (s, 3H) , 2.29 –2.25 (m, 2H) , 2.19 –2.09 (m, 2H) .

Example 7: 5- (4- (5-methylbenzo [d] oxazol-2-yl) piperidin-1-yl) - [1, 2, 4] triazolo [4, 3-a] quinazoline-7-carbonitrile

A mixture of compound 6 (50 mg, 0.119 mmol) , zinc cyanide (42.05 mg, 0.358 mmol) , tris (dibenzylideneacetone) dipalladium chloroform complex (12.36 mg, 0.012 mmol) , 1, 1'-Bis (diphenylphosphino) ferrocene (13.48 mg, 0.024 mmol) , Zn (7.80 mg, 0.119 mmol) , Zinc acetate (2.19 mg, 0.012 mmol) and K₂CO₃ (49.49 mg, 0.358 mmol) in DMA (2.5 mL) was irradiated under nitrogen in microwave at 150 ℃ for 1 h. After cooling to room temperature, the reaction mixture was filtered through a celite pad and the filtrate was purified by prep-HPLC separation to afford example 7. LCMS: MS (ESI) m/z [M+H] ⁺ = 410.2. ¹H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H) , 8.54 (d, J = 1.5 Hz, 1H) , 8.50 (d, J = 8.6 Hz, 1H) , 8.38 (dd, J = 8.6, 1.6 Hz, 1H) , 7.57 (d, J = 8.3 Hz, 1H) , 7.51 (s, 1H) , 7.18 (dd, J = 8.2, 1.1 Hz, 1H) , 4.12 (d, J = 13.5 Hz, 2H) , 3.45 –3.36 (m, 8.6 Hz, 3H) , 2.42 (s, 3H) , 2.29 –2.13 (m, 4H) .

Example 8: 2- (1- (7-fluoro- [1, 2, 4] triazolo [4, 3-a] quinazolin-5-yl) piperidin-4-yl) -5-methylbenzo [d] oxazole

A mixture of compound 8-1 (300 mg, 1.38 mmol) , compound 6-2 (299 mg, 1.38 mmol) and IPEA (1.14 mL, 6.91 mmol) in IPA (10 mL) was stirred at 90 ℃ for 16 h. After cooling to room temperature, the mixture was filtered and the filtrate was dried under reduced pressure to afford compound 8-2 as a brown solid. LCMS: MS (ESI) m/z [M+H] ⁺ = 397.3

To a mixture of compound 8-2 (100 mg, 0.25 mmol) in EtOH (2 mL) /THF (4 mL) was added hydrazinium hydroxide (0.049 mL, 1.01 mmol) . The mixture was stirred at 50 ℃ for 4 h. The mixture was concentrated in vacuo to afford compound 8-3 as a yellow solid, which was used for the next step directly without further purification. LCMS: MS (ESI) m/z [M+H] ⁺ = 393.1

A mixture of compound 8-3 (100 mg, 0.166 mmol) in trimethyl orthoformate (15 mL) was stirred at 100 ℃ for 16 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC to afford example 8. LCMS: MS (ESI) m/z [M+H] ⁺ = 403.4. ¹H NMR (400 MHz, DMSO) δ 9.77 (d, J = 3.3 Hz, 1H) , 8.54 –8.45 (m, 1H) , 8.08 –8.02 (m, 2H) , 7.56 (d, J = 8.3 Hz, 1H) , 7.50 (s, 1H) , 7.18 (dd, J = 8.3, 0.9 Hz, 1H) , 4.41 –4.32 (m, 2H) , 3.69 –3.59 (m, 2H) , 3.55 –3.48 (m, 1H) , 2.42 (s, 3H) , 2.33 –2.27 (m, 2H) , 2.18 –2.08 (m, 2H) .

Example 9: 7-chloro-5- (4- (5-methylbenzo [d] oxazol-2-yl) piperidin-1-yl) - [1, 2, 4] triazolo [4, 3-a] quinoline-4-carbonitrile

A mixture of compound 3-4 (500 mg, 1.17 mmol) , compound 6-2 (252 mg, 1.15 mmol) and DIEA (0.96 mL, 5.83 mmol) in IPA (5 mL) was stirred at 90 ℃ for 16 h. After cooling to room temperature, the mixture was filtered and the filtrate was dried under reduced pressure to afford compound 9-1 as a white solid. LCMS: MS (ESI) m/z [M+H] ⁺ = 436.9.

To a mixture of compound 9-1 (100 mg, 0.23 mmol) in THF (6 mL) /DCE (15 mL) /EtOH (3 mL) was added hydrazinium hydroxide (0.049 mL, 0.98 mmol) . The mixture was stirred at 50 ℃ for 16 h. The mixture was concentrated in vacuo to afford compound 9-2 as a yellow solid, which was used for the next step directly without further purification. LCMS: MS (ESI) m/z [M+H] ⁺ = 432.9 A mixture of compound 9-2 (100 mg, 0.069 mmol) in trimethyl orthoformate (15 mL) was stirred at 100 ℃ for 16 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC to afford example 9. LCMS: MS (ESI) m/z [M+H] ⁺ = 443.3. ¹H NMR (400 MHz, DMSO) δ 9.91 (s, 1H) , 8.49 (d, J = 8.6 Hz, 1H) , 8.04 –8.02 (m, 2H) , 7.60 (d, J = 8.3 Hz, 1H) , 7.54 (s, 1H) , 7.20 (d, J = 8.4 Hz, 1H) , 3.86 –3.75 (m, 2H) , 3.63 (t, J = 11.3 Hz, 2H) , 3.49 –3.45 (m, 1H) , 2.44 (s, 3H) , 2.39 –2.35 (m, 2H) , 2.23 –2.12 (m, 2H) .

Example 10: 7-fluoro-5- (4- (5-methylbenzo [d] oxazol-2-yl) piperidin-1-yl) - [1, 2, 4] triazolo [4, 3-a] quinoline-4-carbonitrile

To a solution of compound 4-3 (300 mg, 1.05 mmol) in i-PrOH (30 mL) was added compound 6-2 (294 mg, 1.36mmol) and DIEA (1.73 mL, 10.45 mmol) . The reaction mixture was stirred at 90 ℃ for 2 h. The mixture was evaporated under reduced pressure and the resulting residue was purified by column chromatography on silica gel to give compound 10-1 as a yellow solid. LCMS: MS (ESI) m/z [M+H] ⁺ = 421.0.

To a solution of compound 10-1 (135 mg, 0.31 mmol) in THF (2 mL) and EtOH (10 mL) was added hydrazinium hydroxide solution (0.22 mL, 4.59 mmol) . The reaction mixture was stirred at 50 ℃for 3 h. After cooling to room temperature, the reaction mixture was diluted with DCM (70 mL) and washed with water (40 mL X 3) . The organic layers was dried over anhydrous Na₂SO₄, filtered, and evaporated to give compound 10-2 as a yellow solid. LCMS: MS (ESI) m/z [M+H] ⁺ = 417.1.

A mixture of trimethyl orthoformate (10 mL) and compound 10-2 (130 mg, 0.095 mmol) was stirred at 100 ℃ for 2 h. The reaction mixture was evaporated. The resulting residue was purified by prep-HPLC separation to give example 10. LCMS: MS (ESI) m/z [M+H] ⁺ = 427.1. ¹H NMR (400 MHz, DMSO) δ 9.90 (s, 1H) , 8.53 (dd, J = 9.1, 4.8 Hz, 1H) , 7.93 –7.85 (m, 1H) , 7.79 (dd, J = 10.0, 2.6 Hz, 1H) , 7.59 (d, J = 8.3 Hz, 1H) , 7.53 (s, 1H) , 7.20 (d, J = 8.2 Hz, 1H) , 3.79 (m, 2H) , 3.62 (m, 2H) , 2.43 (s, 3H) , 2.39 -2.31 (m, 3H) , 2.26 –2.15 (m, 2H) .

Example 11: 7-chloro-5- (4- (5-methylbenzo [d] oxazol-2-yl) piperidin-1-yl) - [1, 2, 4] triazolo [4, 3-a] [1, 5] naphthyridine-4-carbonitrile

To a mixture of 3-4 (50 mg, 0.19 mmol) and 6-2 (184 mg, 0.85 mmol) in i-PrOH (10 mL) was added DIEA (0.77 mL, 4.64 mmol) . The reaction was stirred at 90 ℃ for 2 h. The reaction mixture was diluted with EtOAc (30 mL) , washed with water (30 mL) , and sat. NaCl (30 mL) . The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo to give 11-1 (300 mg, 88.5%) . LCMS: MS (ESI) m/z [M+H] ⁺ = 438.5.

To a mixture of 11-1 (200 mg, 0.46 mmol) in EtOH (8 mL) and THF (4 mL) was added hydrazine monohydrate (58.5 mg, 1.83 mmol) . The reaction was stirred at 50 ℃ for 2 h. The reaction mixture was diluted with EtOAc (30 ml) and washed with water (20 mL) . The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo to give 11-2 (120 mg, 60.6%) . LCMS: MS (ESI) m/z [M+H] ⁺ = 433.6.

A mixture of 11-2 (120 mg, 0.28 mmol) in trimethoxymethane (15 mL) was stirred at 100 ℃for 12 h. The mixture was concentrated in vacuo and the resulting residue was purified by prep-HPLC separation to give example 11 (12.2 mg, 9.9%) . LCMS: MS (ESI) m/z [M+H] ⁺ = 444.1. ¹H NMR (400 MHz, DMSO) δ 9.84 (s, 1H) , 8.91 (d, J = 8.8 Hz, 1H) , 8.08 (d, J = 8.8 Hz, 1H) , 7.58 (d, J = 8.3 Hz, 1H) , 7.53 (s, 1H) , 7.19 (d, J = 8.4 Hz, 1H) , 4.22 (d, J = 12.4 Hz, 2H) , 3.69 (t, J = 11.2 Hz, 2H) , 3.55 –3.46 (m, 1H) , 2.42 (s, 3H) , 2.35 –2.28 (m, 2H) , 2.23 –2.14 (m, 2H) .

Example 12: 7-chloro-5- (4- (4- (trifluoromethoxy) phenoxy) piperidin-1-yl) - [1, 2, 4] triazolo [4, 3-a] [1, 5] naphthyridine-4-carbonitrile

To a mixture of 5-3 (100 mg, 0.58 mmol) in dioxane (5 mL) was added Triphosgene (173 mg, 0.58 mmol) . The mixture was stirred at 110 ℃ for 16 h under N₂. The mixture was quenched with H₂O (50 mL) and the precipitate formed. The mixture was filtered and the filter cake was washed with H₂O (20 mL) and dried under reduced pressure to give 12-1 (96 mg, 83.3%) . LCMS: MS (ESI) m/z [M+H] ⁺ =198.0.

To a mixture of 12-1 (95 mg, 0.48 mmol) in Toluene (5 mL) were added POCl₃ (0.22 mL, 2.40 mmol) and DIEA (0.40 mL, 2.40 mmol) . The mixture was stirred at 110 ℃ for 3 h under N₂. The mixture was concentrated under reduced pressure to give 12-2 (90 mg, 79.8%) , which was directly used in the next step without further purification.

To a mixture of 12-2 (100 mg, 0.43 mmol) in i-PrOH (5 mL) were added 6-2 (92.3 mg, 0.43 mmol) and DIEA (0.71 mL, 4.27 mmol) at 20 ℃ under N₂. The mixture was stirred at 90 ℃ for 16 h under N₂. The mixture was concentrated under reduced pressure to give 12-3 (150 mg, 84.8%) , which was directly used in the next step without further purification. LCMS: MS (ESI) m/z [M+H] ⁺ = 414.0.

To a mixture of 12-3 (20 mg, 0.048 mmol) in EtOH (5 mL) and THF (1 mL) was added Hydrazine monohydrate (12.0 mg, 0.24 mmol) at 20 ℃ under N₂. The mixture was stirred at 50 ℃ for 2 h under N₂. The mixture was concentrated under reduced pressure to give 12-4 (18 mg, 91.5%) , which was directly used in the next step without further purification. LCMS: MS (ESI) m/z [M+H] ⁺ = 410.0.

To a mixture of 12-4 (18 mg, 0.044 mmol) in Trimethoxymethane (5 mL) at 20 ℃ under N₂. The mixture was stirred at 100 ℃ for 16 h under N₂. The mixture was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC separation to give example 12 (7.7 mg, 2.6%) . LCMS: MS (ESI) m/z [M+H] ⁺ = 420.0. 1H NMR (400 MHz, DMSO) δ 9.51 (s, 1H) , 8.82 (d, J =8.8 Hz, 1H) , 8.12 (d, J = 8.8 Hz, 1H) , 7.55 (d, J = 8.3 Hz, 1H) , 7.49 (s, 1H) , 7.17 (d, J = 8.3 Hz, 1H) , 5.00 (d, J = 12.7 Hz, 2H) , 3.62 –3.42 (m, 3H) , 2.41 (s, 3H) , 2.30 –2.22 (m, 2H) , 2.10 –1.99 (m, 2H) .

Example 13: 2- ( (1R, 5S) -3- (7-chloropyrido [2, 3-e] [1, 2, 4] triazolo [4, 3-a] pyrimidin-5-yl) -3, 8-diazabicyclo [3.2.1] octan-8-yl) -5-methylbenzo [d] oxazole

A mixture of 13-1 (3.0 g, 18.2 mmol) in SOCl₂ (30 mL) was stirred at 80 ℃ for 18 h under N₂. The mixture was concentrated under reduced pressure to give 13-2 (2.5 g, 71.5%yield) . LCMS: MS (ESI) m/z [M+H] ⁺ = 168.0.

To a mixture of compound 13-2 (500 mg, 2.60 mmol) in DMSO (30 mL) was added DIEA (2.15 mL, 12.97 mmol) and tert-butyl 3, 8-diazabicyclo [3.2.1] octane-3-carboxylate (551 mg, 2.60 mmol) . The reaction mixture was stirred at 100 ℃ for 2 h. The mixture was poured into ice-water (100 mL) and extracted with DCM (3×50 mL) . The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude, which was purified by flash column chromatography to give compound 13-3. MS (ESI) m/z (M+H) ⁺= 344.2.

A mixture of compound 13-3 (900 mg, 2.53 mmol) in HCl (50 mL, 4 M in dioxane) was stirred at 25 ℃for 2 h. The mixture was concentrated under reduced pressure to give 13-4, which was directly used in the next step without further purification. MS (ESI) m/z (M+H) ⁺= 244.1.

To a mixture of 12-2 (110 mg, 0.47 mmol) in DMSO (5 mL) were added 13-4 (157 mg, 0.56 mmol) and DIEA (0.39 mL, 2.35 mmol) at 20 ℃ under N₂. The mixture was stirred at 90 ℃ for 16 h under N₂. The mixture was concentrated under reduced pressure to give 13-5 (80 mg, 38.7%) , which was directly used in the next step without further purification. MS (ESI) m/z (M+H) ⁺= 441.1.

To a mixture of 13-5 (40 mg, 0.091 mmol) in EtOH (5 mL) and THF (1 mL) was added Hydrazine monohydrate (22.7 mg, 0.45 mmol) at 20 ℃ under N₂. The mixture was stirred at 50 ℃ for 16 h under N₂. The mixture was concentrated under reduced pressure to afford 13-6 (30 mg, 75.5%) , which was directly used in the next step without further purification. MS (ESI) m/z (M+H) ⁺= 437.1.

To a mixture of 13-6 (30 mg, 0.069 mmol) in Trimethoxymethane (5 mL) at 20 ℃ under N₂. The mixture was stirred at 100 ℃ for 16 h under N₂. The mixture was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC separation to give example 13 (14.7 mg, 4.9%) . MS (ESI) m/z (M+H) ⁺= 447.0. 1H NMR (400 MHz, DMSO) δ 9.51 (s, 1H) , 8.84 (d, J = 8.8 Hz, 1H) , 8.15 (d, J = 8.8 Hz, 1H) , 7.27 (d, J = 8.1 Hz, 1H) , 7.10 (s, 1H) , 6.82 (d, J = 7.2 Hz, 1H) , 4.00 (d, J =12.1 Hz, 2H) , 3.70 –3.52 (m, 2H) , 3.31 –3.28 (m, 2H) , 2.33 (s, 3H) , 2.17 –2.05 (m, 2H) , 1.99 –1.91 (m, 2H) .

Example 14: 7-chloro-5- (4- (4- (trifluoromethoxy) phenoxy) piperidin-1-yl) - [1, 2, 4] triazolo [4, 3-a] [1, 5] naphthyridine-4-carbonitrile

To a mixture of 3-4 (200 mg, 0.77 mmol) and 1-5 (243 mg, 0.93 mmol) in i-PrOH (10 mL) was added DIEA (0.77 mL, 4.64 mmol) . The mixture was stirred at 90 ℃ for 2 h. The mixture was concentrated in vacuo and the residue was diluted with EtOAc (30 mL) and H₂O (20 mL) . The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo to give 14-1 (300 mg, 80.2%) . MS (ESI) m/z (M+H) ⁺= 483.0.

To a mixture of 14-1 (200 mg, 0.41 mmol) in THF (4 mL) and EtOH (8 mL) was added hydrazine monohydrate (0.082 mL, 1.66 mmol) . The reaction mixture was stirred at 50 ℃ for 1 h. The reaction mixture was diluted with EtOAc (10 ml) and washed with water (10 mL) . The organic layer was dried over Na₂SO₄ , filtered, and concentrated in vacuo to give 14-2 (100 mg, 50.5%) . MS (ESI) m/z (M+H) ⁺= 479.2.

A mixture of 14-2 (100 mg, 0.21 mmol) in Trimethoxymethane (10 mL) was stirred at 100 ℃for 12 h. The mixture was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC separation to give example 14 (14.6 mg, 14.3%) . MS (ESI) m/z (M+H) ⁺= 489.1. ¹H NMR (400 MHz, DMSO) δ 9.83 (s, 1H) , 8.91 (d, J = 8.8 Hz, 1H) , 8.08 (d, J = 8.8 Hz, 1H) , 7.31 (d, J = 8.8 Hz, 2H) , 7.16 (d, J = 9.2 Hz, 2H) , 4.88 –4.76 (m, 1H) , 4.11 –4.00 (m, 2H) , 3.79 –3.70 (m, 2H) , 2.28 –2.19 (m, 2H) , 2.00 –1.89 (m, 2H) .

Example A: DGKA inhibition ADP-Glo assay

The DGKA inhibition reactions were performed using ADP-Glo assay. The reactions were carried out in 50 mM HEPES, 100 mM NaCl, 10 mM MgCl₂, 1mM CaCl₂, 0.005%TritonX-100 and 1mM DTT as working solution (pH=7.5) . 30 nL DMSO solution of each test compound (Top concentration 0.4 μM with 10 point, 4-fold dilution series for each compound) were transferred to 384 well plate by Echo and 5 μL DGKA (SignalChem, D21-10BG) enzyme working solution at 2x final reaction concentration was added to each well. After incubated at 25℃ for 15 minutes, 5 μL substrate working solution contain 40 μM ATP (Promega, V915B) and 200 μM DLG (SignalChem, D430-59) were added to initiate reaction. After enzymatic reaction at 25℃ for 60 min, ADP Glo assay reagents (Promega, V9102) were added and luminescence was recorded using an EnVision following the instruction of manual. The percent inhibition was calculated from luminescence by no enzyme control reactions for 100%inhibition and DMSO only reactions for 0%inhibition. The IC₅₀ value was calculated via a regression analysis of the inhibition rate.

The data for Example A is shown in Table 3.

TABLE 3

IC₅₀ (nM) : 0<A≤1; 1<B≤10; 10<C≤100; 100<D≤1000; 1000<E

Claims

A compound of Formula (I) , or a pharmaceutically acceptable salt thereof:

wherein:

W is N or CR^W;

R^W is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;

X is N or CR^X;

R^X is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;

Y is N or CR^Y;

R^Y is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;

Z is N or CR^Z;

R^Z is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;

R¹ is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;

U is N or CR^U;

R^U is hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;

each R³ is independently halogen, -CN, -NO₂, -OH, -OR^a, -OC (=O) R^a, -OC (=O) OR^b, -OC (=O) NR^cR^d, -SH, -SR^a, -S (=O) R^a, -S (=O) ₂R^a, -S (=O) ₂NR^cR^d, -NR^cR^d, -NR^bC (=O) NR^cR^d, -NR^bC (=O) R^a, -NR^bC (=O) OR^b, -NR^bS (=O) ₂R^a, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;

or two R³ on the same atom are taken together to form an oxo;

or two R³ on the same or different carbons are taken together to form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R;

m is 0-8;

T is N or CR^T;

R^T is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;

L is absent, -O-, -S-, -NR⁴-, or -CR⁵R⁶-;

R⁴ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;

R⁵ and R⁶ are independently hydrogen, halogen, -CN, -OH, -OR^a, -NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;

or R⁵ and R⁶ are taken together to form an oxo;

Ring Q is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R⁷ is independently halogen, -CN, -NO₂, -OH, -OR^a, -OC (=O) R^a, -OC (=O) OR^b, -OC (=O) NR^cR^d, -SH, -SR^a, -S (=O) R^a, -S (=O) ₂R^a, -S (=O) ₂NR^cR^d, -NR^cR^d, -NR^bC (=O) NR^cR^d, -NR^bC (=O) R^a, -NR^bC (=O) OR^b, -NR^bS (=O) ₂R^a, -C (=O) R^a, -C (=O) OR^b, -C (=O) NR^cR^d, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;

or two R⁷ on the same atom are taken together to form an oxo;

p is 0-6;

each R^a is independently C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

or two R^a are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;

each R^b is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

or two R^b are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;

R^c and R^d are each independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene (cycloalkyl) , C₁-C₆alkylene (heterocycloalkyl) , C₁-C₆alkylene (aryl) , or C₁-C₆alkylene (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 are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and

each R is independently halogen, -CN, -OH, -S (=O) CH₃, -S (=O) ₂CH₃, -S (=O) ₂NH₂, -S (=O) ₂NHCH₃, -S (=O) ₂N (CH₃) ₂, -NH₂, -NHCH₃, -N (CH₃) ₂, -C (=O) CH₃, -C (=O) OH, -C (=O) OCH₃, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, or C₃-C₆cycloalkyl;

or two R on the same atom form an oxo;

provided that the compound is not
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (Ia) :
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (Ib) :
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (Ic) :
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (Id) :
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (Ie) :
The compound of any one of claims 1-4 and 6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R^Y is hydrogen, halogen, -CN, C₁-C₆alkyl, or C₁-C₆haloalkyl.
The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R³ on different carbons are taken together to form a heterocycloalkyl optionally substituted with one or more R.
The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 0-2.
The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R⁵ and R⁶ are independently hydrogen, C₁-C₆alkyl, or C₁-C₆haloalkyl.
The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring Q is phenyl or 6-to 10-membered heteroaryl.
The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein each R⁷ is independently halogen, -OR^a, C₁-C₆alkyl, or C₁-C₆haloalkyl.
The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, thereof, wherein p is 1 or 2.
The compound of claim 1, or a pharmaceutically acceptable salt, wherein the compound is selected from a compound found in table 1 or table 2.
A pharmaceutical composition comprising the compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
A method of inhibiting the activity of at least one of diacylglycerol kinase selected from diacylglycerol kinase alpha (DGKalpha) and diacylglycerol kinase zeta (DGKzeta) , in a subject in need thereof, the method comprising administering to the subject the compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the pharmaceutical composition of claim 15.
A method of inhibiting the activity of diacylglycerol kinase alpha (DGKalpha) , in a subject in need thereof, the method comprising administering to the subject the compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 15.
A method of treating a disease associated with aberrant diacylglycerol kinase signaling, in a subject in need thereof, the method comprising administering to the subject the compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 15.
The method of claim 18, wherein the diacylglycerol kinase is diacylglycerol kinase alpha.
The method of claim 18 or 19, wherein the disease is cancer or a viral infection.
The method of any one of claims 16-20, wherein the method further comprises administering an additional therapeutic agent.
The method of claim 21, wherein the additional therapeutic agent is an anti-cancer agent or an anti-viral agent.