Combination of a t cell therapy and continuous or intermittent dgk inhibitor dosing

Abstract

Provided herein are methods, compositions, and uses involving T cell therapies, such as adoptive T cell therapy, and an inhibitor of a Diacylglycerol kinase (DGK). The provided methods, compositions, and uses include those involving the administration or use of one or more DGK inhibitors (DGKi) in a combination therapy with a T cell therapy, such as a genetically engineered T cell therapy involving cells engineered with a recombinant receptor, such as chimeric antigen receptor (CAR) or T cell receptor (TCR).

Description

COMBINATION OF A T CELL THERAPY AND CONTINUOUS OR INTERMITTENT DGK INHIBITOR DOSING Cross-Reference to Related Applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 404,955, filed September 8, 2022, the contents of which are hereby incorporated by reference in their entirety for all purposes. Incorporation by Reference of Sequence Listing

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 735042026540SeqList.xml, created August 23, 2023, which is 358 kilobytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety. Field

[0003] The present disclosure relates in some aspects to methods, compositions, and uses involving T cell therapies, such as adoptive T cell therapy, and an inhibitor of a Diacylglycerol kinase (DGK). The provided methods, compositions, and uses include those involving the administration or use of one or more DGK inhibitors (DGKi) in a combination therapy with a T cell therapy, such as a genetically engineered T cell therapy involving cells engineered with a recombinant receptor, such as chimeric antigen receptor (CAR) or T cell receptor (TCR). Background

[0004] Various strategies are available for T cell therapies, for example administering engineered T cells for adoptive therapy. For example, strategies are available for engineering T cells expressing genetically engineered antigen receptors, such as CARs or TCRs, and administering compositions containing such cells to subjects. Improved strategies are needed to improve efficacy of the T cells of the cell therapy, for example improving the persistence, activity, and / or proliferation of the cells upon or following administration to subjects. Provided are methods, compositions, uses, and kits that meet such needs.Summary

[0005] Provided herein in some embodiments is a method of treatment, the method comprising administering to a subject having a cancer a combination therapy comprising: (a) a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein the T cell therapy is administered on Day 1 of the combination therapy; and (b) an inhibitor of DGKα and / or DGKζ, wherein the administration of the inhibitor is initiated on any of Days 1-8, inclusive, of the combination therapy, and the inhibitor is administered continuously at least until the number of engineered T cells of the T cell therapy has peaked in the subject following administration of the T cell therapy.

[0006] In some of any embodiments, the administration of the inhibitor is initiated subsequent to the administration of the T cell therapy.

[0007] Also provided herein in some embodiments is a method of treatment, the method comprising administering to a subject having a cancer an inhibitor of DGKα and / or DGKζ, wherein the inhibitor is administered as part of a combination therapy comprising the inhibitor and a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein: prior to initiation of administration of the inhibitor, the subject has been previously administered the T cell therapy, wherein the T cell therapy is administered on Day 1 of the combination therapy; the administration of the inhibitor is initiated on any of Days 1-8, inclusive, of the combination therapy; and the inhibitor is administered continuously at least until the number of engineered T cells of the T cell therapy has peaked in the subject following administration of the T cell therapy.

[0008] In some of any embodiments, the administration of the inhibitor is initiated on Day 1 of the combination therapy prior to the administration of the T cell therapy.

[0009] Also provided herein in some embodiments is a method of treatment, the method comprising administering to a subject having a cancer a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein the T cell therapy is administered as part of a combination therapy comprising the T cell therapy and an inhibitor of DGKα and / or DGKζ, wherein: the T cell therapy is administered on Day 1 of the combination therapy; the administration of the inhibitor is initiated on Day 1 of the combination therapy prior to the administration of the T cell therapy;and the inhibitor is administered continuously at least until the number of engineered T cells of the T cell therapy has peaked in the subject following administration of the T cell therapy.

[0010] In some of any embodiments, the inhibitor is administered daily, once every two days, or once every three days. In some of any embodiments, the inhibitor is administered daily.

[0011] In some of any embodiments, the inhibitor is administered once on each of the days that the inhibitor is administered.

[0012] In some of any embodiments, the inhibitor is administered until the number of engineered T cells of the T cell therapy has peaked in the subject following administration of the T cell therapy.

[0013] In some of any embodiments, the inhibitor is administered over a period of time between or between about 21 and 42 days, inclusive.

[0014] Also provided herein in some embodiments is a method of treatment, the method comprising administering to a subject having a cancer a combination therapy comprising: (a) a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein the T cell therapy is administered on Day 1 of the combination therapy; and (b) an inhibitor of DGKα and / or DGKζ, wherein the administration of the inhibitor is initiated on any of Days 1-8, inclusive, of the combination therapy, and the inhibitor is administered in a therapeutically effective dose for a period between or between about 21 and 42 days.

[0015] In some of any embodiments, the administration of the inhibitor is initiated subsequent to the administration of the T cell therapy.

[0016] Also provided herein in some embodiments is a method of treatment, the method comprising administering to a subject having a cancer an inhibitor of DGKα and / or DGKζ, wherein the inhibitor is administered as part of a combination therapy comprising the inhibitor and a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein: prior to initiation of administration of the inhibitor, the subject has been previously administered the T cell therapy, wherein the T cell therapy is administered on Day 1 of the combination therapy; the administration of the inhibitor is initiated on any of Days 1-8, inclusive, of the combination therapy; and the inhibitor is administered in a therapeutically effective dose for a period between or between about 21 and 42 days.

[0017] In some of any embodiments, the administration of the inhibitor is initiated on Day 1 of the combination therapy prior to the administration of the T cell therapy.

[0018] Also provided herein in some embodiments is a method of treatment, the method comprising administering to a subject having a cancer a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein the T cell therapy is administered as part of a combination therapy comprising the T cell therapy and an inhibitor of DGKα and / or DGKζ, wherein: the T cell therapy is administered on Day 1 of the combination therapy; the administration of the inhibitor is initiated on Day 1 of the combination therapy prior to the administration of the T cell therapy; and the inhibitor is administered in a therapeutically effective dose for a period between or between about 21 and 42 days.

[0019] In some of any embodiments, the therapeutically effective dose provides a dose of the inhibitor that is continuously therapeutically effective for the period between or between about 21 and 42 days.

[0020] In some of any embodiments, the inhibitor is administered every 2 days or 3 days.

[0021] Also provided herein in some embodiments is a method of treatment, the method comprising administering to a subject having a cancer a combination therapy comprising: (a) a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein the T cell therapy is administered on Day 1 of the combination therapy; and (b) an inhibitor of DGKα and / or DGKζ, wherein the administration of the inhibitor is initiated on any of Days 1-8, inclusive, of the combination therapy, and the inhibitor is administered in a plurality of cycles each comprising an administration period in which the inhibitor is administered followed by a rest period during which the inhibitor is not administered.

[0022] In some of any embodiments, the administration of the inhibitor is initiated subsequent to the administration of the T cell therapy.

[0023] Also provided herein in some embodiments is a method of treatment, the method comprising administering to a subject having a cancer an inhibitor of DGKα and / or DGKζ, wherein the inhibitor is administered as part of a combination therapy comprising the inhibitor and a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein: prior to initiation of administration of the inhibitor, the subject has been previously administered the T cell therapy,wherein the T cell therapy is administered on Day 1 of the combination therapy; the administration of the inhibitor is initiated on any of Days 1-8, inclusive, of the combination therapy; and the inhibitor is administered in a plurality of cycles each comprising an administration period in which the inhibitor is administered followed by a rest period during which the inhibitor is not administered.

[0024] In some of any embodiments, during the administration period, the inhibitor is administered daily, every two days, or every three days. In some of any embodiments, during the administration period, the inhibitor is administered daily.

[0025] In some of any embodiments, during the administration period, the inhibitor is administered once on each of the days that the inhibitor is administered.

[0026] In some of any embodiments, over the plurality of cycles, the inhibitor is administered until the number of engineered T cells of the T cell therapy has peaked in the subject following administration of the T cell therapy.

[0027] In some of any embodiments, over the plurality of cycles, the inhibitor is administered over a period of time between or between about 21 and 42 days, inclusive.

[0028] Also provided herein in some embodiments is a method of treatment, the method comprising administering to a subject having a cancer a combination therapy comprising: (a) a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein the T cell therapy is administered on Day 1 of the combination therapy; and (b) an inhibitor of DGKα and / or DGKζ, wherein the administration of the inhibitor is initiated on any of Days 1-8, inclusive, of the combination therapy, and the inhibitor is administered once daily for between or between about 21 and 42 consecutive days, inclusive.

[0029] In some of any embodiments, the administration of the inhibitor is initiated subsequent to the administration of the T cell therapy.

[0030] Also provided herein in some embodiments is a method of treatment, the method comprising administering to a subject having a cancer an inhibitor of DGKα and / or DGKζ, wherein the inhibitor is administered as part of a combination therapy comprising the inhibitor and a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein: prior to initiation of administration of the inhibitor, the subject has been previously administered the T cell therapy, wherein the T cell therapy is administered on Day 1 of the combination therapy; theadministration of the inhibitor is initiated on any of Days 1-8, inclusive, of the combination therapy; and the inhibitor is administered once daily for between or between about 21 and 42 consecutive days, inclusive.

[0031] In some of any embodiments, the administration of the inhibitor is initiated on any of Days 1-6, inclusive, of the combination therapy. In some of any embodiments, the administration of the inhibitor is initiated on any of Days 1-4, inclusive, of the combination therapy. In some of any embodiments, the administration of the inhibitor is initiated on Day 1 or Day 2 of the combination therapy. In some of any embodiments, the administration of the inhibitor is initiated on Day 1 of the combination therapy.

[0032] In some of any embodiments, the administration of the inhibitor is initiated on Day 1 of the combination therapy prior to the administration of the T cell therapy.

[0033] Also provided herein in some embodiments is a method of treatment, the method comprising administering to a subject having a cancer a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein the T cell therapy is administered as part of a combination therapy comprising the T cell therapy and an inhibitor of DGKα and / or DGKζ, wherein: the T cell therapy is administered on Day 1 of the combination therapy; the administration of the inhibitor is initiated on Day 1 of the combination therapy prior to the administration of the T cell therapy; and the inhibitor is administered once daily for between or between about 21 and 42 consecutive days, inclusive.

[0034] In some of any embodiments, the inhibitor is administered over a period of time between or between about 21 and 35 days, inclusive. In some of any embodiments, the inhibitor is administered over a period of time between or between about 21 and 28 days, inclusive. In some of any embodiments, the inhibitor is administered over a period of time between or between about 28 and 42 days, inclusive. In some of any embodiments, the inhibitor is administered over a period of time between or between about 28 and 35 days, inclusive. In some of any embodiments, the inhibitor is administered over a period of time that is or is about 28 days. In some of any embodiments, the inhibitor is administered over a period of time that is or is about 30 days.

[0035] In some of any embodiments, over the plurality of cycles, the inhibitor is administered over a period of time between or between about 21 and 35 days, inclusive. In some of any embodiments, over the plurality of cycles, the inhibitor is administered over a period oftime between or between about 21 and 28 days, inclusive. In some of any embodiments, over the plurality of cycles, the inhibitor is administered over a period of time between or between about 28 and 42 days, inclusive. In some of any embodiments, over the plurality of cycles, the inhibitor is administered over a period of time between or between about 28 and 35 days, inclusive. In some of any embodiments, over the plurality of cycles, the inhibitor is administered over a period of time that is or is about 28 days. In some of any embodiments, over the plurality of cycles, the inhibitor is administered over a period of time that is or is about 30 days.

[0036] In some of any embodiments, the inhibitor is administered once daily for between or between about 21 and 35 consecutive days, inclusive. In some of any embodiments, the inhibitor is administered once daily for between or between about 21 and 28 consecutive days, inclusive. In some of any embodiments, the inhibitor is administered once daily for between or between about 28 and 42 consecutive days, inclusive. In some of any embodiments, the inhibitor is administered once daily for between or between about 28 and 35 consecutive days, inclusive. In some of any embodiments, the inhibitor is administered once daily for or for about 28 consecutive days.

[0037] Also provided herein in some embodiments is amethod of treatment, the method comprising administering to a subject having a cancer a combination therapy comprising: (a) a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein the T cell therapy is administered on Day 1 of the combination therapy; and (b) an inhibitor of DGKα and / or DGKζ, wherein the administration of the inhibitor is initiated on Day 1 of the combination therapy, and the inhibitor is administered once daily on Days 1-28, inclusive, of the combination therapy.

[0038] In some of any embodiments, the administration of the inhibitor is initiated subsequent to the administration of the T cell therapy.

[0039] Also provided herein in some embodiments is a method of treatment, the method comprising administering to a subject having a cancer an inhibitor of DGKα and / or DGKζ, wherein the inhibitor is administered as part of a combination therapy comprising the inhibitor and a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein: prior to initiation of administration of the inhibitor, the subject has been previously administered the T cell therapy, wherein the T cell therapy is administered on Day 1 of the combination therapy; theadministration of the inhibitor is initiated on Day 1 of the combination therapy; and the inhibitor is administered once daily on Days 1-28, inclusive, of the combination therapy.

[0040] In some of any embodiments, the administration of the inhibitor is initiated prior to the administration of the T cell therapy.

[0041] Also provided herein in some embodiments is a method of treatment, the method comprising administering to a subject having a cancer a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein the T cell therapy is administered as part of a combination therapy comprising the T cell therapy and an inhibitor of DGKα and / or DGKζ, wherein: the T cell therapy is administered on Day 1 of the combination therapy; the administration of the inhibitor is initiated on Day 1 of the combination therapy prior to the administration of the T cell therapy; and the inhibitor is administered once daily on Days 1-28, inclusive, of the combination therapy.

[0042] In some of any embodiments, the inhibitor is administered once daily on Days 1-30, inclusive, of the combination therapy.

[0043] In some of any embodiments, the administration of the inhibitor is initiated within or within about 12 hours of the administration of the T cell therapy. In some of any embodiments, the administration of the inhibitor is initiated within or within about 6 hours of the administration of the T cell therapy. In some of any embodiments, the administration of the inhibitor is initiated within or within about 4 hours of the administration of the T cell therapy. In some of any embodiments, the administration of the inhibitor is initiated within or within about 2 hours of the administration of the T cell therapy. In some of any embodiments, the administration of the inhibitor is initiated within or within about 1 hour of the administration of the T cell therapy.

[0044] In some of any embodiments, the administration of the inhibitor is initiated on Day 1 of the combination therapy concurrently with the administration of the T cell therapy. In some of any embodiments, the administration of the inhibitor is initiated on Day 1 of the combination therapy during the administration of the T cell therapy.

[0045] In some of any embodiments, prior to the administration of the T cell therapy, the subject has been preconditioned with a lymphodepleting therapy comprising administration of fludarabine and / or cyclophosphamide. In some of any embodiments, prior to the administration of the T cell therapy, the subject has been preconditioned with a lymphodepleting therapycomprising administration of fludarabine and cyclophosphamide. In some of any embodiments, the method further comprises administering the lymphodepleting therapy to the subject.

[0046] In some of any embodiments, the lymphodepleting therapy comprises administration of: cyclophosphamide at between or between about 200 and 400 mg / m2, inclusive, daily for between or between about 2 and 4 days, inclusive; and / or fludarabine at between or between about 20 and 40 mg / m2, inclusive, daily for between or between about 2 and 4 days, inclusive. In some of any embodiments, the lymphodepleting therapy comprises administration of cyclophosphamide at between or between about 200 and 400 mg / m2, inclusive, daily for between or between about 2 and 4 days, inclusive. In some of any embodiments, the lymphodepleting therapy comprises administration of fludarabine at between or between about 20 and 40 mg / m2, inclusive, daily for between or between about 2 and 4 days, inclusive. In some of any embodiments, the lymphodepleting therapy comprises administration of cyclophosphamide at or at about 300 mg / m2and fludarabine at or at about 30 mg / m2each daily for or for about 3 days.

[0047] In some of any embodiments, the T cell therapy is administered between or between about 2 and 7 days, inclusive, after the administration of the lymphodepleting therapy.

[0048] In some of any embodiments, the inhibitor is an inhibitor of DGKα and not a significant inhibitor of DGKζ. In some of any embodiments, the inhibitor is an inhibitor of DGKζ and not a significant inhibitor of DGKα. In some of any embodiments, the inhibitor is an inhibitor of DGKα and DGKζ.

[0049] In some of any embodiments, the inhibitor is not a significant inhibitor of other DGKs.

[0050] In some of any embodiments, the inhibitor is a compound of Formula (I):

[0051]

[0052] or a pharmaceutically acceptable salt thereof, wherein:

[0053] R1is H, F, Cl, Br, -CN, C1-3alkyl substituted with zero to 4 R1a, C3-4cycloalkyl substituted with zero to 4 R1a, C1-3alkoxy substituted with zero to 4 R1a, -NRaRa, -S(O)nRe, or -P(O)ReRe;

[0054] each R1ais independently F, Cl, -CN, -OH, -OCH3, or -NRaRa;

[0055] each Rais independently H or C1-3alkyl;

[0056] each Reis independently C3-4cycloalkyl or C1-3alkyl substituted with zero to 4 R1a;

[0057] R2is H, C1-3alkyl substituted with zero to 4 R2a, or C3-4cycloalkyl substituted with zero to 4 R2a;

[0058] each R2ais independently F, Cl, -CN, -OH, -O(C1-2alkyl), C3-4cycloalkyl, C3-4alkenyl, or C3-4alkynyl;

[0059] R3is H, F, Cl, Br, -CN, C1-3alkyl, C1-2fluoroalkyl, C3-4cycloalkyl, C3-4fluorocycloalkyl, or -NO2;

[0060] R4is -CH2R4a, -CH2CH2R4a, -CH2CHR4aR4d, -CHR4aR4b, or -CR4aR4bR4c;

[0061] R4aand R4bare independently:

[0062] (i) C1-6alkyl substituted with zero to 4 substituents independently selected from F, Cl, -CN, -OH, -OCH3, -SCH3, C1-3fluoroalkoxy, -NRaRa, -S(O)2Re, or -NRaS(O)2Re;

[0063] (ii) C3-6cycloalkyl, heterocyclyl, phenyl, or heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, C1-4hydroxyalkyl, -(CH2)1-2O(C1-3alkyl), C1-4alkoxy, -O(C1-4hydroxyalkyl), -O(CH)1-3O(C1-3alkyl), C1-3fluoroalkoxy, -O(CH)1-3NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), -P(O)(C1-3alkyl)2, -S(O)2(C1-3alkyl), -O(CH2)1-2(C3-6cycloalkyl), -O(CH2)1-2(morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and Rd; or

[0064] (iii) C1-4alkyl substituted with one cyclic group selected from C3-6cycloalkyl, heterocyclyl, aryl, and heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-6cycloalkyl;

[0065] or R4aand R4btogether with the carbon atom to which they are attached form a C3-6cycloalkyl or a 3- to 6-membered heterocyclyl, each substituted with zero to 3 Rf;

[0066] each Rfis independently F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, or a cyclic group selected from C3-6cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, and -NRcRc;

[0067] R4cis C1-6alkyl or C3-6cycloalkyl, each substituted with zero to 4 substituents independently selected from F, Cl, -OH, C1-2alkoxy, C1-2fluoroalkoxy, and -CN;

[0068] R4dis -OCH3;

[0069] each Rcis independently H or C1-2alkyl;

[0070] Rdis phenyl substituted with zero to 1 substituent selected from F, Cl, -CN, -CH3, and -OCH3;

[0071] each R5is independently -CN, C1-6alkyl substituted with zero to 4 Rg, C2-4alkenyl substituted with zero to 4 Rg, C2-4alkynyl substituted with zero to 4 Rg, C3-4cycloalkyl substituted with zero to 4 Rg, phenyl substituted with zero to 4 Rg, oxadiazolyl substituted with zero to 3 Rg, pyridinyl substituted with zero to 4 Rg, -(CH2)1-2(heterocyclyl substituted with zero to 4 Rg), -(CH2)1-2NRcC(O)(C1-4alkyl), -(CH2)1-2NRcC(O)O(C1-4alkyl), -(CH2)1-2NRcS(O)2(C1-4alkyl), -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -C(O)O(C3-4cycloalkyl), -C(O)NRaRa, or -C(O)NRa(C3-4cycloalkyl);

[0072] each Rgis independently F, Cl, -CN, -OH, C1-3alkoxy, C1-3fluoroalkoxy, -O(CH2)1-2O(C1-2alkyl), or -NRcRc;

[0073] m is zero, 1, 2, or 3; and

[0074] n is zero, 1, or 2.

[0075] In some of any embodiments, the inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0076] R1is H, F, Cl, Br, -CN, C1-3alkyl substituted with zero to 4 R1a, cyclopropyl substituted with zero to 3 R1a, C1-3alkoxy substituted with zero to 3 R1a, -NRaRa, -S(O)nCH3, or -P(O)(CH3)2;

[0077] each R1ais independently F, Cl, or -CN;

[0078] each Rais independently H or C1-3alkyl;

[0079] R2is H or C1-2alkyl substituted with zero to 2 R2a;

[0080] each R2ais independently F, Cl, -CN, -OH, -O(C1-2alkyl), cyclopropyl, C3-4alkenyl, or C3-4alkynyl;

[0081] R3is H, F, Cl, Br, -CN, C1-2alkyl, -CF3, cyclopropyl, or -NO2;

[0082] R4aand R4bare independently:

[0083] (i) C1-4alkyl substituted with zero to 4 substituents independently selected from F, Cl, -CN, -OH, -OCH3, -SCH3, C1-3fluoroalkoxy, and -NRaRa;

[0084] (ii) C3-6cycloalkyl, heterocyclyl, phenyl, or heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, -CH2OH, -(CH2)1-2O(C1-2alkyl), C1-4alkoxy, -O(C1-4hydroxyalkyl), -O(CH)1-2O(C1-2alkyl), C1-3fluoroalkoxy, -O(CH)1-2NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), -P(O)(C1-2alkyl)2, -S(O)2(C1-3alkyl), -O(CH2)1-2(C3-4cycloalkyl), -O(CH2)1-2(morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and Rd; or

[0085] (iii) C1-3alkyl substituted with one cyclic group selected from C3-6cycloalkyl, heterocyclyl, phenyl, and heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-3alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-4cycloalkyl;

[0086] or R4aand R4btogether with the carbon atom to which they are attached, form a C3-6cycloalkyl or a 3- to 6-membered heterocyclyl, each substituted with zero to 3 Rf;

[0087] each Rfis independently F, Cl, Br, -OH, -CN, C1-4alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, or a cyclic group selected from C3-6cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each cyclic group substituted with zero to 3 substituents independentlyselected from F, Cl, Br, -OH, -CN, C1-4alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, and -NRcRc;

[0088] R4cis C1-4alkyl or C3-6cycloalkyl, each substituted with zero to 4 substituents independently selected from F, Cl, -OH, C1-2alkoxy, C1-2fluoroalkoxy, and -CN;

[0089] and each R5is independently -CN, C1-5alkyl substituted with zero to 4 Rg, C2-3alkenyl substituted with zero to 4 Rg, C2-3alkynyl substituted with zero to 4 Rg, C3-4cycloalkyl substituted with zero to 4 Rg, phenyl substituted with zero to 3 Rg, oxadiazolyl substituted with zero to 3 Rg, pyridinyl substituted with zero to 3 Rg, -(CH2)1-2(heterocyclyl substituted with zero to 4 Rg), -(CH2)1-2NRcC(O)(C1-4alkyl), -(CH2)1-2NRcC(O)O(C1-4alkyl), -(CH2)1-2NRcS(O)2(C1-4alkyl), -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -C(O)O(C3-4cycloalkyl), -C(O)NRaRa, or -C(O)NRa(C3-4cycloalkyl).

[0090] In some of any embodiments, the inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof having the structure:

[0091]

[0092] wherein:

[0093] R1is -CN;

[0094] R2is -CH3;

[0095] R3is H, F, or -CN;

[0096] R4is:

[0097]

[0098] In some of any embodiments, the inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof having the structure:

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112] In some of any embodiments, the inhibitor is a compound of Formula (II):

[0113]

[0114] or a salt thereof, wherein:

[0115] R1is H, F, Cl, Br, -CN, -OH, C1-3alkyl substituted with zero to 4 R1a, C3-4cycloalkyl substituted with zero to 4 R1a, C1-3alkoxy substituted with zero to 4 R1a, -NRaRa, -S(O)nRe, or -P(O)ReRe;

[0116] each R1ais independently F, Cl, -CN, -OH, -OCH3, or -NRaRa;

[0117] each Rais independently H or C1-3alkyl;

[0118] each Reis independently C3-4cycloalkyl or C1-3alkyl substituted with zero to 4 R1a;

[0119] R2is H, C1-3alkyl substituted with zero to 4 R2a, or C3-4cycloalkyl substituted with zero to 4 R2a;

[0120] each R2ais independently F, Cl, -CN, -OH, -O(C1-2alkyl), C3-4cycloalkyl, C3-4alkenyl, or C3-4alkynyl;

[0121] R4is -CH2R4a, -CH2CH2R4a, -CH2CHR4aR4d, -CHR4aR4b, or -CR4aR4bR4c;

[0122] R4aand R4bare independently:

[0123] (i) -CN or C1-6alkyl substituted with zero to 4 substituents independently selected from F, Cl, -CN, -OH, -OCH3, -SCH3, C1-3fluoroalkoxy, -NRaRa, -S(O)2Re, or -NRaS(O)2Re;

[0124] (ii) C3-6cycloalkyl, 4- to 10-membered heterocyclyl, phenyl, or 5-to 10-membered heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, C1-2bromoalkyl, C1-2cyanoalkyl, C1-4hydroxyalkyl, -(CH2)1-2O(C1-3alkyl), C1-4alkoxy, C1-3fluoroalkoxy, C1-3cyanoalkoxy, -O(C1-4hydroxyalkyl), -O(CRxRx)1-3O(C1-3alkyl), C1-3fluoroalkoxy, -O(CH2)1-3NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -CH2NRaRa, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -(CRxRx)0-2NRaC(O)O(C1-4alkyl), -P(O)(C1-3alkyl)2, -S(O)2(C1-3alkyl), -(CRxRx)1-2(C3-4cycloalkyl), -(CRxRx)1-2(morpholinyl), -(CRxRx)1-2(difluoromorpholinyl), -(CRxRx)1-2(dimethylmorpholinyl), -(CRxRx)1-2(oxaazabicyclo[2.2.1]heptanyl), (CRxRx)1-2(oxaazaspiro[3.3]heptanyl), -(CRxRx)1-2(methylpiperazinonyl), -(CRxRx)1-2(acetylpiperazinyl), -(CRxRx)1-2(piperidinyl), -(CRxRx)1-2(difluoropiperidinyl), -(CRxRx)1-2(methoxypiperidinyl), -(CRxRx)1-2(hydroxypiperidinyl), -O(CRxRx)0-2(C3-6cycloalkyl), -O(CRxRx)0-2(methylcyclopropyl), -O(CRxRx)0-2((ethoxycarbonyl)cyclopropyl), -O(CRxRx)0-2(oxetanyl), -O(CRxRx)0-2(methylazetidinyl), -O(CRxRx)0-2(tetrahydropyranyl), -O(CRxRx)1-2(morpholinyl), -O(CRxRx)0-2(thiazolyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, dioxolanyl, pyrrolidinonyl, and Rd; or

[0125] (iii) C1-4alkyl substituted with one cyclic group selected from C3-6cycloalkyl, 4- to 10-membered heterocyclyl, mono- or bicyclic aryl, or 5-to 10-membered heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH,-NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-6cycloalkyl;

[0126] or R4aand R4btogether with the carbon atom to which they are attached form a C3-6cycloalkyl or a 3- to 6-membered heterocyclyl, each substituted with zero to 3 Rf;

[0127] each Rfis independently F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, or a cyclic group selected from C3-6cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, and -NRcRc;

[0128] R4cis C1-6alkyl or C3-6cycloalkyl, each substituted with zero to 4 substituents independently selected from F, Cl, -OH, C1-2alkoxy, C1-2fluoroalkoxy, and -CN;

[0129] R4dis -OCH3;

[0130] each Rcis independently H or C1-2alkyl;

[0131] Rdis phenyl substituted with zero to 1 substituent selected from F, Cl, -CN, -CH3, and -OCH3;

[0132] each R5is independently -CN, C1-6alkyl substituted with zero to 4 Rg, C2-4alkenyl substituted with zero to 4 Rg, C2-4alkynyl substituted with zero to 4 Rg, C3-4cycloalkyl substituted with zero to 4 Rg, phenyl substituted with zero to 4 Rg, oxadiazolyl substituted with zero to 3 Rg, pyridinyl substituted with zero to 4 Rg, -(CH2)1-2(4- to 10-membered heterocyclyl substituted with zero to 4 Rg), -(CH2)1-2NRcC(O)(C1-4alkyl), -(CH2)1-2NRcC(O)O(C1-4alkyl), -(CH2)1-2NRcS(O)2(C1-4alkyl), -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -C(O)O(C3-4cycloalkyl), -C(O)NRaRa, or -C(O)NRa(C3-4cycloalkyl);

[0133] each Rgis independently F, Cl, -CN, -OH, C1-3alkoxy, C1-3fluoroalkoxy, -O(CH2)1-2O(C1-2alkyl), or -NRcRc;

[0134] m is zero, 1, 2, or 3; and

[0135] n is zero, 1, or 2.

[0136] In some of any embodiments, the inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0137] R1is H, F, Cl, Br, -CN, -OH, C1-3alkyl substituted with zero to 4 R1a, cyclopropyl substituted with zero to 3 R1a, C1-3alkoxy substituted with zero to 3 R1a, -NRaRa, -S(O)nCH3, or -P(O)(CH3)2;

[0138] R2is H or C1-2alkyl substituted with zero to 2 R2a;

[0139] each R2ais independently F, Cl, -CN, -OH, -O(C1-2alkyl), cyclopropyl, C3-4alkenyl, or C3-4alkynyl;

[0140] R4aand R4bare independently:

[0141] (i) -CN or C1-4alkyl substituted with zero to 4 substituents independently selected from F, Cl, -CN, -OH, -OCH3, -SCH3, C1-3fluoroalkoxy, and -NRaRa;

[0142] (ii) C3-6cycloalkyl, 4- to 10-membered heterocyclyl, phenyl, or 5-to 10-membered heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, C1-2bromoalkyl, C1-2cyanoalkyl, C1-2hydroxyalkyl, -CH2NRaRa, -(CH2)1-2O(C1-2alkyl), -(CH2)1-2NRxC(O)O(C1-2alkyl), C1-4alkoxy, -O(C1-4hydroxyalkyl), -O(CRxRx)1-2O(C1-2alkyl), C1-3fluoroalkoxy, C1-3cyanoalkoxy, -O(CH2)1-2NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), -P(O)(C1-2alkyl)2, -S(O)2(C1-3alkyl), -(CH2)1-2(C3-4cycloalkyl), -CRxRx(morpholinyl), -CRxRx(difluoromorpholinyl), -CRxRx(dimethylmorpholinyl), -CRxRx(oxaazabicyclo[2.2.1]heptanyl), -CRxRx(oxaazaspiro[3.3]heptanyl), -CRxRx(methylpiperazinonyl), -CRxRx(acetylpiperazinyl), -CRxRx(piperidinyl), -CRxRx(difluoropiperidinyl), -CRxRx(methoxypiperidinyl), -CRxRx(hydroxypiperidinyl), -O(CH2)0-2(C3-4cycloalkyl), -O(CH2)0-2(methylcyclopropyl), -O(CH2)0-2((ethoxycarbonyl)cyclopropyl), -O(CH2)0-2(oxetanyl), -O(CH2)0-2(methylazetidinyl), -O(CH2)1-2(morpholinyl), -O(CH2)0-2(tetrahydropyranyl), -O(CH2)0-2(thiazolyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert- butoxycarbonyl)azetidinyl, dioxolanyl, pyrrolidinonyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and Rd; or

[0143] (iii) C1-3alkyl substituted with one cyclic group selected from C3-6cycloalkyl, 4- to 10-membered heterocyclyl, mono- or bicyclic aryl, or 5-to 10-membered heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN,C1-3alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-4cycloalkyl;

[0144] or R4aand R4btogether with the carbon atom to which they are attached, form a C3-6cycloalkyl or a 3- to 6-membered heterocyclyl, each substituted with zero to 3 Rf;

[0145] each Rfis independently F, Cl, Br, -OH, -CN, C1-4alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, or a cyclic group selected from C3-6cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-4alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, and -NRcRc;

[0146] R4cis C1-4alkyl or C3-6cycloalkyl, each substituted with zero to 4 substituents independently selected from F, Cl, -OH, C1-2alkoxy, C1-2fluoroalkoxy, and -CN;

[0147] each R5is independently -CN, C1-5alkyl substituted with zero to 4 Rg, C2-3alkenyl substituted with zero to 4 Rg, C2-3alkynyl substituted with zero to 4 Rg, C3-4cycloalkyl substituted with zero to 4 Rg, phenyl substituted with zero to 3 Rg, oxadiazolyl substituted with zero to 3 Rg, pyridinyl substituted with zero to 3 Rg, -(CH2)1-2(4- to 10-membered heterocyclyl substituted with zero to 4 Rg), -(CH2)1-2NRcC(O)(C1-4alkyl), -(CH2)1-2NRcC(O)O(C1-4alkyl), -(CH2)1-2NRcS(O)2(C1-4alkyl), -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -C(O)O(C3-4cycloalkyl), -C(O)NRaRa, or -C(O)NRa(C3-4cycloalkyl);

[0148] each Rxis independently H or -CH3; and

[0149] m is 1, 2, or 3.

[0150] In some of any embodiments, the inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof having the structure:

[0151]

[0152] R1is -CN;

[0153] R2is -CH3;

[0154] R5ais -CH3or -CH2CH3; and

[0155] R5cis -CH3, -CH2CH3, or -CH2CH2CH3.

[0156] In some of any embodiments, the inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof having the structure:

[0158] In some of any embodiments, the inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof having the structure:

[0159] .

[0160] In some of any embodiments, the inhibitor is administered in a therapeutically effective amount. In some of any embodiments, the therapeutically effective dose provides a dose of the inhibitor that is continuously therapeutically effective for the period of time that the inhibitor is administered.

[0161] In some of any embodiments, the inhibitor is administered in a per day amount between or between about 0.25 and 250 mg, inclusive. In some of any embodiments, the inhibitor is administered in a per day amount between or between about 0.5 and 100 mg, inclusive.

[0162] In some of any embodiments, the inhibitor is administered in a once per day amount between or between about 0.25 and 250 mg, inclusive. In some of any embodiments, the inhibitor is administered in a once per day amount between or between about 0.5 and 100 mg, inclusive.

[0163] In some of any embodiments, the inhibitor is administered orally.

[0164] In some of any embodiments, the recombinant receptor is an engineered T cell receptor (eTCR).

[0165] In some of any embodiments, the recombinant receptor is a chimeric antigen receptor (CAR).

[0166] In some of any embodiments, the antigen is CD19, and the CAR is an anti-CD19 CAR. In some of any embodiments, the CAR is the CAR of BREYANZI® (lisocabtagene maraleucel), TECARTUS™ (brexucabtagene autoleucel), KYMRIAH™ (tisagenlecleucel), or YESCARTA™ (axicabtagene ciloleucel). In some of any embodiments, the T cell therapy is BREYANZI® (lisocabtagene maraleucel), TECARTUS™ (brexucabtagene autoleucel), KYMRIAH™ (tisagenlecleucel), or YESCARTA™ (axicabtagene ciloleucel).

[0167] In some of any embodiments, the antigen is BCMA, and the CAR is an anti-BCMA CAR. In some of any embodiments, the CAR is the CAR of ABECMA® (idecabtagene vicleucel) or CARVYKTI™ (ciltacabtagene autoleucel). In some of any embodiments, the T cell therapy is ABECMA® (idecabtagene vicleucel) or CARVYKTI™ (ciltacabtagene autoleucel).

[0168] In some of any embodiments, the cancer is a solid tumor. In some of any embodiments, the cancer is a hematological (liquid) tumor.

[0169] In some of any embodiments, the cancer is a B cell malignancy.

[0170] In some of any embodiments, the cancer is a leukemia. In some of any embodiments, the cancer is a lymphoma. In some of any embodiments, the cancer is a myeloma. In some of any embodiments, the myeloma is multiple myeloma.

[0171] In some of any embodiments, the cancer is relapsed or refractory.

[0172] In some of any embodiments, the T cell therapy comprises between or between about 0.1 x 106and 1,000 x 106total recombinant receptor-expressing T cells, inclusive. In some of any embodiments, the T cell therapy comprises between or between about 10 x 106and 1,000 x 106total recombinant receptor-expressing T cells, inclusive. In some of any embodiments, the T cell therapy comprises between or between about 10 x 106and 500 x 106total recombinant receptor-expressing T cells, inclusive.

[0173] In some of any embodiments, the recombinant receptor-expressing T cells are viable recombinant receptor-expressing T cells.

[0174] In some of any embodiments, the T cell therapy is administered intravenously.

[0175] In some of any embodiments, the T cells of the T cell therapy are autologous to the subject. In some of any embodiments, the T cells of the T cell therapy are allogeneic to the subject.

[0176] In some of any embodiments, the T cells of the T cell therapy are human T cells.

[0177] Also provided herein in some embodiments is a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of a cancer for use as part of a combination therapy comprising the T cell therapy and an inhibitor of DGKα and / or DGKζ, wherein the T cell therapy and the inhibitor are administered to a subject having the cancer according to any of the described methods.

[0178] Also provided herein in some embodiments is an inhibitor of DGKα and / or DGKζ for use as part of a combination therapy comprising the inhibitor and a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of a cancer, wherein the T cell therapy and the inhibitor are administered to a subject having the cancer according to any of the described methods.

[0179] Also provided herein in some embodiments is a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of a cancer and an inhibitor of DGKα and / or DGKζ for use as part of a combination therapy comprising the T cell therapy and the inhibitor, wherein the T cell therapy and the inhibitor are administered to a subject having the cancer according to any of the described methods.

[0180] Also provided herein in some embodiments is use of a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of a cancer as part of a combination therapy comprising the T cell therapy and an inhibitor of DGKα and / or DGKζ, wherein the T cell therapy and the inhibitor are administered to a subject having the cancer according to any of the described methods.

[0181] Also provided herein in some embodiments is use of an inhibitor of DGKα and / or DGKζ as part of a combination therapy comprising the inhibitor and a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigenexpressed by cells of a cancer, wherein the T cell therapy and the inhibitor are administered to a subject having the cancer according to any of the described methods.

[0182] Also provided herein in some embodiments is use of a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of a cancer and an inhibitor of DGKα and / or DGKζ as part of a combination therapy comprising the T cell therapy and the inhibitor, wherein the T cell therapy and the inhibitor are administered to a subject having the cancer according to any of the described methods.

[0183] Also provided herein in some embodiments is use of a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of a cancer in the manufacture of a medicament that is part of a combination therapy comprising the T cell therapy and an inhibitor of DGKα and / or DGKζ, wherein the T cell therapy and the inhibitor are administered to a subject having the cancer according to any of the described methods.

[0184] Also provided herein in some embodiments is use of an inhibitor of DGKα and / or DGKζ in the manufacture of a medicament that is part of a combination therapy comprising the inhibitor and a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of a cancer, wherein the T cell therapy and the inhibitor are administered to a subject having the cancer according to any of the described methods.

[0185] Also provided herein in some embodiments is use of a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of a cancer and an inhibitor of DGKα and / or DGKζ in the manufacture of a medicament that is a combination therapy comprising the T cell therapy and the inhibitor, wherein the T cell therapy and the inhibitor are administered to a subject having the cancer according to any of the described methods.

[0186] In some of any embodiments, the T cell therapy is any as described herein. In some embodiments, the inhibitor is any as described herein. In some embodiments, the subject is any as described herein. In some embodiments, the cancer is any as described herein.Brief Description of Drawings

[0187] FIG. 1A and 1B show expression of activation and differentiation markers in CAR- expressing T cells following stimulation with a CAR-specific anti-idiotypic antibody in the presence of an exemplary DGK inhibitor (Compound 17). FIG. 1A shows the mean across donors of the log2 fold change (presence vs. absence of Compound 17) in the % positive cells for the various activation and differentiation markers following stimulation with 3 µg / mL (left panel) or 30 µg / mL (right panel) of the CAR-specific anti-idiotypic antibody. FIG. 1B shows the mean across donors of the log2 fold change (presence vs. absence of Compound 17) in MFI of cells following stimulation with 3 µg / mL (left panel) or 30 µg / mL (right panel) of the CAR- specific anti-idiotypic antibody. In FIG. 1A and 1B, positive values are indicated with circles.

[0188] FIG. 2 shows growth curves (percent cellular confluence in well, as monitored using an Incucyte imaging system) of CAR-expressing cells stimulated with a CAR-specific anti- idiotypic antibody in the presence of Compound 17 or a control.

[0189] FIG. 3 shows the percent of specific lysis effected by CAR-expressing T cells co- cultured in the presence of Compound 17 (or a control) with CD19-antigen expressing target cells, K562.CD19 cells (high CD19 expression; left panel), Granta-519 cells (low CD19 expression; middle panel), and Raji cells (medium / high CD19 expression; right panel).

[0190] FIG. 4 shows the supernatant concentrations in pg / mL of IFNγ (left panel), IL-2 (middle panel), and TNFα (right panel) following co-culture of CAR-expressing T cells with K562.CD19 cells (circles), Granta-519 cells (squares), and Raji cells (triangles) in the presence of Compound 17.

[0191] FIG. 5A-5B and 6A-6B show cytolytic activity and cytokine production during re- challenge of CAR-expressing T cells chronically stimulated in the presence of Compound 17 (concurrent treatment). FIG. 5A shows tumor cell numbers of K562.CD19 (left panel), Granta- 519 (middle panel), and Raji cells (right panel) during 2D co-culture with CAR T cells that had been chronically stimulated in the presence of Compound 17. FIG. 5B shows the supernatant concentrations in pg / mL of IFNγ (left panel), IL-2 (middle panel), and TNFα (right panel) following 48 hours of 2D co-culture of CAR T cells with K562.CD19 cells (circles), Granta-519 cells (squares), and Raji cells (triangles). FIG. 6A shows normalized tumor volume of A549.CD19 (left panel) and Granta-519 tumor spheroids (right panel) at day 9 of co-culture with CAR T cells that had been concurrently treated with Compound 17 during chronic stimulation. FIG 6B shows the supernatant concentrations in pg / mL of IFNγ (left panel) IL 2 (middlepanel), and TNFα (right panel) following five days of 3D co-culture of CAR T cells with A549.CD19 (circles) and Granta-519 tumor spheroids (squares).

[0192] FIG. 7A-7B and 8A-8B show cytolytic activity and cytokine production during re- challenge in the presence of Compound 17 of chronically stimulated CAR-expressing T cells (rescue treatment). FIG. 7A shows tumor cell numbers of K562.CD19 (left panel), Granta-519 (middle panel), and Raji cells (right panel) during 2D co-culture with CAR T cells in the presence of Compound 17. FIG. 7B shows the supernatant concentrations in pg / mL of IFNγ (left panel), IL-2 (middle panel), and TNFα (right panel) following 48 hours of 2D co-culture of CAR T cells with K562.CD19 cells (circles), Granta-519 cells (squares), and Raji cells (triangles) in the presence of Compound 17. FIG. 8A shows normalized tumor volume of A549.CD19 (left panel) and Granta-519 tumor spheroids (right panel) at day 9 of co-culture with CAR T cells in the presence of Compound 17. FIG. 8B shows the supernatant concentrations in pg / mL of IFNγ (left panel), IL-2 (middle panel), and TNFα (right panel) following five days of 3D co-culture of CAR T cells with A549.CD19 (circles) and Granta-519 tumor spheroids (squares) in the presence of Compound 17.

[0193] FIG. 9 and 10 show cytolytic activity and proliferation of chronically stimulated T cells expressing an engineered T cell receptor (eTCR) following rescue treatment with Compound 17. FIG. 9 shows tumor cell numbers of CaSki cells monitored at various times during co-culture with chronically stimulated eTCR T cells in the presence of Compound 17 (left panel, eTCR T cells chronically stimulated with 10 µg / mL anti-Vbeta; right panel, eTCR T cells chronically stimulated with 20 µg / mL anti-Vbeta). FIG. 10 shows the cell counts for eTCR T cells for two donors, as shown from left to right: (1) chronically stimulated eTCR T cells with no compound treatment (control); (2) chronically stimulated eTCR T cells treated with Compound 17; or (3) fresh eTCR T cells that were not chronically stimulated.

[0194] FIG. 11 shows tumor burden in Raji cell-engrafted mice receiving three different dosing regimens (“Early”, “Delayed”, or “Continuous”) of the DGKi Compound 17 in combination with anti-CD19 CAR T cells. In FIG. 11, the shaded area indicates the period of time in which Compound 17 was administered orally once daily following CAR T cell administration in the Early, Delayed, or Continuous regimens.

[0195] FIG. 12 shows survival of the Raji cell-engrafted mice receiving the Early, Delayed, or Continuous Compound 17 regimen in combination with the anti-CD19 CAR T cells (n.s. [not significant]; * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001).

[0196] FIG. 13 shows tumor control index values for the Raji cell-engrafted mice receiving the Early, Delayed, or Continuous Compound 17 regimen in combination with the anti-CD19 CAR T cells (n.s. [not significant]; * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001).

[0197] FIG. 14 show tumor control index values with ANOVA results for tumor control index values for the Raji cell-engrafted mice receiving the Early, Delayed, or Continuous Compound 17 regimen in combination with the anti-CD19 CAR T cells (n.s. [not significant]; * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001). In FIG. 14 and for ANOVA testing, results from all groups of vehicle-treated mice were pooled into one group for statistical comparison.

[0198] FIG. 15 shows the number of circulating CAR-expressing cells and the CD4:CD8 ratio of circulating T cells on Day 15 in the Raji cell-engrafted mice receiving the Delayed or Continuous regimen (n.s. [not significant]; * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001).

[0199] FIG. 16 shows the total number of circulating CAR-expressing cells on Day 29 in the Raji cell-engrafted mice receiving the Early, Delayed, or Continuous Compound 17 regimen in combination with the anti-CD19 CAR T cells.

[0200] FIG. 17 shows tumor burden in Raji cell-engrafted mice receiving continuous dosing of the DGKi Compound 17 in combination with anti-CD19 CAR T cells. Compound 17 was administered orally once daily on Days 1-30 following CAR T cell administration on Day 1.

[0201] FIG. 18 shows survival of the Raji cell-engrafted mice receiving the continuous Compound 17 regimen in combination with the anti-CD19 CAR T cells.

[0202] FIG. 19 shows tumor control index values for the Raji cell-engrafted mice receiving the continuous Compound 17 regimen in combination with the anti-CD19 CAR T cells (n.s. [not significant]; * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001).

[0203] FIG. 20 shows the number of circulating CAR-expressing cells following CAR T cell administration in the Raji cell-engrafted mice receiving the continuous regimen (n.s. [not significant]; * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001).

[0204] FIG. 21 shows the number of circulating CAR-expressing cells from four healthy human donors following CAR T cell administration in the Raji cell-engrafted mice receiving DGKi administration on Days 1-7.

[0205] FIG. 22 shows tumor burden in Raji cell-engrafted mice receiving continuous dosing of the DGKi Compound 17 in combination with anti-CD19 CAR T cells or receiving DGKα / DGKζ single or double knock-out anti-CD19 CAR T cells.

[0206] FIG. 23 shows survival of the Raji cell-engrafted mice receiving the continuous Compound 17 regimen in combination with the anti-CD19 CAR T cells or receiving DGKα / DGKζ single or double knock-out anti-CD19 CAR T cells (n.s. [not significant]; * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001).

[0207] FIG. 24 shows tumor control index values for the Raji cell-engrafted mice receiving the continuous Compound 17 regimen in combination with the anti-CD19 CAR T cells or receiving DGKα / DGKζ single or double knock-out anti-CD19 CAR T cells (n.s. [not significant]; * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001).

[0208] FIG. 25 shows the number of circulating CAR-expressing cells following CAR T cell administration in the Raji cell-engrafted mice receiving the continuous regimen or in the Raji cell-engrafted mice receiving the DGKα / DGKζ single or double knock-out CAR T cells (n.s. [not significant]; * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001).

[0209] FIG. 26A-26B show tumor burden in Nalm6 cell-engrafted mice. FIG. 26A shows tumor burden in Nalm6 cell-engrafted mice receiving continuous dosing of the DGKi Compound 17 in combination with anti-CD19 CAR T cells. FIG. 26B shows historical tumor burden data in Nalm6 cell-engrafted mice receiving anti-CD19 CAR T cells.

[0210] FIG. 27 shows survival of the Nalm6 cell-engrafted mice receiving the continuous Compound 17 regimen in combination with the anti-CD19 CAR T cells (n.s. [not significant]; * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001).

[0211] FIG. 28 shows tumor control index values for the Nalm6 cell-engrafted mice receiving the continuous Compound 17 regimen in combination with the anti-CD19 CAR T cells (n.s. [not significant]; * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001).

[0212] FIG. 29 shows the number of circulating CAR-expressing cells following CAR T cell administration in the Nalm6 cell-engrafted mice receiving the continuous regimen (n.s. [not significant]; * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001).

[0213] FIG. 30 shows tumor burden following re-challenge of Nalm6 cell-engrafted mice that previously received continuous dosing of the DGKi Compound 17 in combination with anti- CD19 CAR T cells.

[0214] FIG. 31 shows survival following re-challenge of the Nalm6 cell-engrafted mice that previously received the continuous Compound 17 regimen in combination with the anti-CD19 CAR T cells (n.s. [not significant]; * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001). Detailed Description

[0215] Provided herein are combination therapies for use in treating a disease or condition involving administration of a T cell therapy directed against an antigen associated with the disease or condition, such as a chimeric antigen receptor (CAR)-T cell therapy or an engineered T cell receptor (eTCR)-T cell therapy, and a DGK inhibitor. In some embodiments, the T cell therapy is a composition including T cells for adoptive cell therapy in which the cells are engineered with a recombinant receptor targeting the antigen (e.g. a CAR or eTCR). In some embodiments, the disease or condition may be a cancer, infectious disease or autoimmune disease. In some embodiments, the DGKi is an inhibitor of DGKa, DGKz, or both DGKa and DGKz, such as a compound of Formula (I) or (II), such as a compound selected from compounds 1 to 34 or a pharmaceutically acceptable salt thereof. In some aspects, the provided methods and uses enhance or modulate proliferation and / or activity of T cells associated with administration of the T cell therapy (e.g. CAR-expressing T cells or eTCR-expressing T cells).

[0216] T cell-based therapies, such as adoptive T cell therapies (including those involving the administration of cells expressing recombinant antigen receptors specific for a disease or disorder of interest, such as CARs or eTCRs, can be effective in the treatment of cancer and other diseases and disorders. The engineered expression of recombinant receptors, such as CARs or eTCRs, on the surface of T cells enables the redirection of T-cell specificity. In clinical studies, CAR-T cells, for example anti-CD19 CAR-T cells, have produced durable, complete responses in both leukemia and lymphoma patients (Porter et al. (2015) Sci Transl Med., 7:303ra139; Kochenderfer (2015) J. Clin. Oncol., 33: 540-9; Lee et al. (2015) Lancet, 385:517-28; Maude et al. (2014) N Engl J Med, 371:1507-17).

[0217] In certain contexts, available approaches to adoptive cell therapy may not always be entirely satisfactory. For example, in certain cases, although CAR T cell persistence can be detected in many subjects with lymphoma, fewer complete responses (CRs) have been observed in subjects with NHL compared to subjects with ALL. More specifically, while higher overall response rates of up to 80 % (CR rate 47% to 60%) have been reported after CAR T cell infusion responses in some are transient and subjects have been shown to relapse in thepresence of persistent CAR T cells (Neelapu, 58th Annual Meeting of the American Society of Hematology (ASH): 2016; San Diego, CA, USA. Abstract No. LBA-6.2016; Abramson, Blood. 2016 Dec 01;128(22):4192). Another study reported a long term CR rate of 40% (Schuster, Ann Hematol. 2016 Oct;95(11):1805-10).

[0218] In some aspects, an explanation for this is the immunological exhaustion of circulating T cells of the T cell therapy, e.g., CAR-expressing T cells, and / or changes in T lymphocyte populations. In some contexts, optimal efficacy can depend on the ability of the administered cells to recognize and bind to a target, e.g., target antigen, to traffic, localize to and successfully enter appropriate sites within the subject, tumors, and environments thereof. In some contexts, optimal efficacy can depend on the ability of the administered cells to become activated, expand, to exert various effector functions, including cytotoxic killing and secretion of various factors such as cytokines, to persist, including long-term, to differentiate, transition or engage in reprogramming into certain phenotypic states (such as long-lived memory, less- differentiated, and effector states), to avoid or reduce immunosuppressive conditions in the local microenvironment of a disease, to provide effective and robust recall responses following clearance and re-exposure to target ligand or antigen, and avoid or reduce exhaustion, anergy, peripheral tolerance, terminal differentiation, and / or differentiation into a suppressive state.

[0219] In some embodiments, the exposure and persistence of engineered cells of a T cell therapy is reduced or declines after administration to the subject. Yet, observations indicate that, in some cases, increased exposure of the subject to administered cells expressing the recombinant receptors (e.g., increased number of cells or duration over time) may improve efficacy and therapeutic outcomes in adoptive cell therapy. Preliminary analysis conducted following the administration of different CD19-targeting CAR-expressing T cells to subjects with various CD19-expressing cancers in multiple clinical trials revealed a correlation between greater and / or longer degree of exposure to the CAR-expressing cells and treatment outcomes. Such outcomes included patient survival and remission, even in individuals with severe or significant tumor burden.

[0220] In some embodiments, following long-term stimulation or exposure to antigen and / or exposure under conditions in the tumor microenvironment, T cells can over time become hypofunctional and / or exhibit features associated with exhausted state. In some aspects, this reduces the persistence and efficacy of the T cells against antigen and limits their ability to be effective. There is a need for methods to improve the efficacy and function of T cells of a T celltherapy, e.g., CAR-expressing T cells or eTCR-expressing T cells, particularly to minimize, reduce, prevent or reverse hypofunctional or exhaustive states.

[0221] Diacylglycerol kinases (DGKs) are lipid kinases that mediate the conversion of diacylglycerol to phosphatidic acid thereby terminating T cell functions propagated through the TCR signaling pathway. Thus, DGKs serve as intracellular checkpoints and inhibition of DGKs are expected to enhance T cell signaling pathways and T cell activation. Supporting evidence include knock-out mouse models of either DGKa or DGKz 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 DGKa which resulted in inhibited T cell function (Prinz, P.U. et al., J Immunology (2012) 12:5990-6000). Thus, DGKa and DGKz 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.

[0222] The provided methods are based on observations that a DGKi, such as the exemplary Compound 17 as described, improves T cell function, including functions related to the ability to produce one or more cytokines, cytotoxicity, expansion, proliferation, and persistence of T cells. In some aspects, the provided methods enhance or modulate proliferation and / or activity of T cell activity associated with administration of the T cell therapy (e.g. CAR-expressing T cells). It is found that such methods and uses provide for or achieve improved or greater T cell functionality, and thereby improved anti-tumor efficacy.

[0223] It also is found herein that, in addition to potentiating T cell function, such DGKi, e.g., Compound 17, exhibit effects to reverse, delay, or prevent T cell exhaustion, including by increasing T cell signaling and / or altering one or more genes that are differentially regulated following chronic (long-term) stimulation. Thus, while in some cases agents that increase or potentiate T cell activity may drive the cells to an exhausted state, it is found herein that activity of such DGKi, e.g., Compound 17, to exert a potentiating effect on T cell activity is decoupled from T cell exhaustion. In some embodiments, the provided methods involving compoundadministration of such DGKi, e.g., Compound 17, is capable of potentiating activity of T cells and delaying, limiting, reducing, inhibiting or preventing exhaustion.

[0224] Moreover, observations herein show that the DGKi, e.g., Compound 17, exhibits activity to rescue T cells from T cell exhaustion, such as by restoring or partially restoring one or more T cell activities after a cell has shown features of exhaustion. Remarkably, results herein show that exposure of T cells, that have been chronically stimulated and exhibit features of exhausted T cells, to a DGKi described herein, such as Compound 17, are able to recover activity or have their activity restored or partially restored. The observations herein support that the provided methods may also achieve improved or more durable responses as compared to certain alternative methods, such as in particular groups of subjects treated.

[0225] These observations were made using a chronic stimulation assay to render T cells (e.g. CAR T cells) hypofunctional (e.g. reduced cytolysis and IL-2 secretion). Using this model, engineered T cells (e.g. CAR T cells or eTCR T cells) were examined to assess impact of DGKi, such as Compound 17, on function of the engineered T cells when present during (concurrent) or following (rescue) exposure to conditions leading to a hypofunctional, exhaustive state. Upon rechallenge with antigen, the findings provided herein demonstrate that concurrent treatment of engineered T cells (e.g. CAR T cells or eTCR T cells) during such conditions reversed activity and phenotypes associated with T cell hypofunctionality and preserved more effector function. Likewise, the results show that the later exposure of the DGKi, e.g., Compound 17, could rescue or restore T cell function, including cytokine production and cytolytic activity, of exhausted T cells. Further, the results were seen with different recombinant antigen receptors including and CARs and eTCRs.

[0226] It is also shown herein that administration of the DGKi, e.g., Compound 17, in a continuous dosing scheme, e.g., at least once daily for a plurality of consecutive days, such as for 28 consecutive days, improves in vivo anti-tumor effects following administration of engineered T cells for the T cell therapy, e.g., CAR T cells or eTCR T cells. As demonstrated herein, the continuous presence of the DGKi following T cell therapy administration, such as beginning on the same day as T cell therapy administration, can improve CAR T cell expansion and / or persistence, in particular that of CD4+ CAR T cells. Without wishing to be limited by a specific mechanism of action, the results shown herein are consistent with a finding that the continuous presence of the DGKi following T cell therapy administration may prevent or reduceexhaustion in T cells of the T cell therapy, thereby improving T cell anti-tumor activity and proliferative capacity following administration.

[0227] The provided findings indicate that combination therapy of a DGKi that is an inhibitor of DGKa, DGKz, or both DGKa and DGKz, such as a compound of Formula (I) or (II), such as a compound selected from compounds 1 to 34 or a pharmaceutically acceptable salt thereof, in methods involving a T cell therapy, such as involving administration of a composition of engineered T cells, achieves improved function of the T cell therapy, such as by potentiating T cell activity and reducing , preventing or delaying T cell exhaustion or rescuing cells from T cell exhaustion. In some embodiments, the combination therapy involves administration or use of a T cell therapy (e.g., CAR T cells or eTCR T cells) and a DGKi that is a compound of Formula (II). In some embodiments, the combination therapy involves administration or use of a T cell therapy (e.g., CAR T cells or eTCR T cells) and a DGKi that is a compound that is 4-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)propyl) piperazin-1- yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile or a stereoisomer thereof. In some embodiments, the combination therapy involves administration or use of a T cell therapy (e.g., CAR T cells or eTCR T cells) and a DGKi that is a compound that is 4-((2S,5R)- 2,5-diethyl-4-((S)-1-(4-(trifluoromethyl)phenyl) propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (Compound 17). In some embodiments, combination of the T cell therapy (e.g., administration of engineered T cells) with the DGKi, e.g., Compound 17, improves or enhances one or more functions and / or effects of the T cell therapy, such as persistence, expansion, cytotoxicity, and / or therapeutic outcomes, e.g., ability to kill or reduce the burden of tumor or other disease or target cell.

[0228] All publications, including patent documents, scientific articles and databases, referred to in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference. If a definition set forth herein is contrary to or otherwise inconsistent with a definition set forth in the patents, applications, published applications and other publications that are herein incorporated by reference, the definition set forth herein prevails over the definition that is incorporated herein by reference.

[0229] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.I. COMBINATION THERAPY

[0230] Provided herein in some embodiments are methods of treatment that include administering a cell therapy and an inhibitor of DGK to a subject having a disease or condition. In some embodiments, the inhibitor of DGK is an inhibitor of DGKα and / or DGKζ. In some embodiments, the cell therapy is a T cell therapy. In some embodiments, the T cell therapy includes engineered T cells. In some embodiments, the engineered T cells express a recombinant receptor. In some embodiments, the recombinant receptor is a chimeric antigen receptor (CAR). In some embodiments, the recombinant receptor is an engineered T cell receptor (TCR).

[0231] In some embodiments, the DGK inhibitor, e.g., the inhibitor of DGKα and / or DGKζ, is administered prior to the T cell therapy, e.g., the initiation of administration of the inhibitor is carried out, is performed, or occurs prior to initiation of administration of the T cell therapy. In some embodiments, the DGK inhibitor, e.g., the inhibitor of DGKα and / or DGKζ, is administered concurrently with the T cell therapy, e.g., the initiation of administration of the inhibitor is carried out, is performed, or occurs concurrently with administration of the T cell therapy. In some embodiments, the DGK inhibitor, e.g., the inhibitor of DGKα and / or DGKζ, is administered after the T cell therapy, e.g., the initiation of administration of the inhibitor is carried out, is performed, or occurs after initiation of administration of the T cell therapy.

[0232] Also provided herein in some embodiments are methods of treatment that include administering an inhibitor of DGK to a subject having a disease or condition. Also provided herein in some embodiments are methods of rescuing engineered cells of a cell therapy from exhaustion, e.g., rescuing engineered T cells of a T cell therapy from exhaustion, said methods including administering an inhibitor of DGK to a subject having a disease or condition. Also provided herein in some embodiments are methods of reducing or delaying the onset of T cell exhaustion of T cells of a T cell therapy, said methods including administering an inhibitor of DGK to a subject having a disease or condition. In some embodiments, the subject has previously been administered a cell therapy, e.g., T cell therapy, for treatment of the disease or condition.

[0233] The combination therapy, e.g., including engineered cells expressing a recombinant receptor, such as a chimeric antigen receptor (CAR), and the DGK inhibitor, or compositions including the engineered cells and / or the DGK inhibitor described herein, are useful in a variety of therapeutic, diagnostic, and prophylactic indications. For example, the combinations are useful in treating a variety of diseases and disorders in a subject Such methods and uses includetherapeutic methods and uses, for example involving administration of the engineered cells, the DGK inhibitor, and / or compositions containing one or both to a subject having a disease, condition, or disorder, such as a tumor or cancer. In some embodiments, the engineered cells, the DGK inhibitor, and / or compositions containing one or both are administered in an effective amount to effect treatment of the disease or disorder. Uses include uses of the engineered cells, the DGK inhibitor, and / or compositions containing one or both in such methods and treatments, and in the preparation of a medicament in order to carry out such therapeutic methods. In some embodiments, the methods are carried out by administering the engineered cells, the DGK inhibitor, and / or compositions containing one or both to the subject having or suspected of having the disease or condition. In some embodiments, the methods thereby treat the disease, condition, or disorder in the subject. In some embodiments, the DGK inhibitor is any as described in Section I-B. In some embodiments, the engineered cells are any as described in Sections I and II.

[0234] The disease or condition that is treated can be any in which expression of an antigen is associated with and / or involved in the etiology of the disease or condition, e.g., antigen expression causes, exacerbates, or otherwise is involved in such disease or condition. Exemplary diseases and conditions include diseases or conditions associated with malignancy or transformation of cells (e.g., cancer), autoimmune or inflammatory disease, or an infectious disease, e.g., caused by a bacterial, viral, or other pathogen. Exemplary antigens, which include antigens associated with various diseases and conditions that can be treated, are described herein. In particular embodiments, the antigen-binding domain of the recombinant receptor, e.g., CAR or TCR, expressed by the cell therapy, e.g., T cell therapy, administered as part of the methods provided herein, specifically binds to an antigen associated with the disease or condition.

[0235] In some embodiments, the disease or condition includes tumors, including solid tumors, hematologic malignancies, and melanomas, and including localized and metastatic tumors, infectious diseases, such as infection with a virus or other pathogen, e.g., HIV, HCV, HBV, CMV, HPV, and parasitic disease, and autoimmune and inflammatory diseases. In some embodiments, the disease or condition is a tumor, cancer, malignancy, neoplasm, or other proliferative disease or disorder. Such diseases include but are not limited to leukemia, lymphoma, e.g., acute myeloid (or myelogenous) leukemia (AML), chronic myeloid (or myelogenous) leukemia (CML), acute lymphocytic (or lymphoblastic) leukemia (ALL), chroniclymphocytic leukemia (CLL), hairy cell leukemia (HCL), small lymphocytic lymphoma (SLL), Mantle cell lymphoma (MCL), Marginal zone lymphoma, Burkitt lymphoma, Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), Anaplastic large cell lymphoma (ALCL), follicular lymphoma, refractory follicular lymphoma, diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM).

[0236] In some embodiments, the disease or condition is a B cell malignancy. In some embodiments, the B cell malignancy is selected from among acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin lymphoma (NHL), and Diffuse Large B-Cell Lymphoma (DLBCL). In some embodiments, the disease or condition is NHL. In some embodiments, the NHL is selected from the group consisting of aggressive NHL, diffuse large B cell lymphoma (DLBCL), NOS (de novo and transformed from indolent), primary mediastinal large B cell lymphoma (PMBCL), T cell / histocyte-rich large B cell lymphoma (TCHRBCL), Burkitt’s lymphoma, mantle cell lymphoma (MCL), and / or follicular lymphoma (FL), optionally, follicular lymphoma Grade 3B (FL3B).

[0237] In some embodiments, the disease or disorder is a B cell-related disorder. In some of any of the provided embodiments of the provided methods, the disease or disorder is an autoimmune disease or disorder. In some of any of the provided embodiments of the provided methods, the autoimmune disease or disorder is systemic lupus erythematosus (SLE), lupus nephritis, inflammatory bowel disease, rheumatoid arthritis, ANCA associated vasculitis, idiopathic thrombocytopenia purpura (ITP), thrombotic thrombocytopenia purpura (TTP), autoimmune thrombocytopenia, Chagas’ disease, Grave’s disease, Wegener’s granulomatosis, poly-arteritis nodosa, Sjogren’s syndrome, pemphigus vulgaris, scleroderma, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, vasculitis, diabetes mellitus, Reynaud’s syndrome, anti-phospholipid syndrome, Goodpasture’s disease, Kawasaki disease, autoimmune hemolytic anemia, myasthenia gravis, or progressive glomerulonephritis.

[0238] In some embodiments, the disease or condition is an infectious disease or condition, such as, but not limited to, viral, retroviral, bacterial, and protozoal infections, immunodeficiency, Cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, BK polyomavirus. In some embodiments, the disease or condition is an autoimmune or inflammatory disease or condition, such as arthritis, e.g., rheumatoid arthritis (RA), Type I diabetes, systemic lupus erythematosus (SLE), inflammatory bowel disease, psoriasis, scleroderma, autoimmune thyroid disease, Grave’s disease, Crohn’s disease, multiple sclerosis,asthma, and / or a disease or condition associated with transplant.

[0239] In some embodiments, the disease or disorder is a solid tumor, or a cancer associated with a non-hematological tumor. In some embodiments, the disease or disorder is a solid tumor, or a cancer associated with a solid tumor. In some embodiments, the disease or disorder is a pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, pancreatic cancer, rectal cancer, thyroid cancer, uterine cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancers, CNS cancers, brain tumors, bone cancer, or soft tissue sarcoma. In some embodiments, the disease or disorder is a bladder, lung, brain, melanoma (e.g. small-cell lung, melanoma), breast, cervical, ovarian, colorectal, pancreatic, endometrial, esophageal, kidney, liver, prostate, skin, thyroid, or uterine cancers. In some embodiments, the disease or disorder is a pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, pancreatic cancer, rectal cancer, thyroid cancer, uterine cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancers, CNS cancers, brain tumors, bone cancer, or soft tissue sarcoma.

[0240] In some embodiments, the antigen associated with the disease or condition is or includes αvβ6 integrin (avb6 integrin), B cell activating factor receptor (BAFF-R), B cell maturation antigen (BCMA), B7-H3, B7-H6, carbonic anhydrase 9 (CA9, also known as CAIX or G250), a cancer-testis antigen, cancer / testis antigen 1B (CTAG, also known as NY-ESO-1 and LAGE-2), carcinoembryonic antigen (CEA), a cyclin, cyclin A2, C-C Motif Chemokine Ligand 1 (CCL-1), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7 / 8, CD70, CD123, CD133, CD138, CD171, chondroitin sulfate proteoglycan 4 (CSPG4), delta-like ligand 3 (DLL3), epidermal growth factor protein (EGFR), type III epidermal growth factor receptor mutation (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrinB2, ephrin receptor A2 (EPHa2), estrogen receptor, Fc receptor like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), fetal acetylcholine receptor (fetal AchR), a folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O- acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gp100), glypican-3 (GPC3), G protein-coupled receptor class C group 5 member D (GPRC5D), Her2 / neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimers, Human high molecular weight- melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, Human leukocyteantigen A1 (HLA-A1), Human leukocyte antigen A2 (HLA-A2), IL-22 receptor alpha (IL- 22Rα), IL-13 receptor alpha 2 (IL-13Rα2), kinase insert domain receptor (kdr), kappa light chain, L1 cell adhesion molecule (L1-CAM), CE7 epitope of L1-CAM, Leucine Rich Repeat Containing 8 Family Member A (LRRC8A), Lewis Y, Melanoma-associated antigen (MAGE)- A1, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligands, melan A (MART-1), neural cell adhesion molecule (NCAM), oncofetal antigen, Preferentially expressed antigen of melanoma (PRAME), progesterone receptor, a prostate specific antigen, prostate stem cell antigen (PSCA), prostate specific membrane antigen (PSMA), Receptor Tyrosine Kinase Like Orphan Receptor 1 (ROR1), survivin, Trophoblast glycoprotein (TPBG also known as 5T4), tumor-associated glycoprotein 72 (TAG72), Tyrosinase related protein 1 (TRP1, also known as TYRP1 or gp75), Tyrosinase related protein 2 (TRP2, also known as dopachrome tautomerase, dopachrome delta-isomerase or DCT), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms Tumor 1 (WT-1), a pathogen-specific or pathogen-expressed antigen, or an antigen associated with a universal tag, and / or biotinylated molecules, and / or molecules expressed by HIV, HCV, HBV or other pathogens.

[0241] In some embodiments, the disease or condition is a B cell malignancy. In some embodiments, the disease or condition is large B cell lymphoma. In some embodiments, the B cell malignancy is selected from among acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), non-Hodgkin lymphoma (NHL), and Diffuse Large B- Cell Lymphoma (DLBCL). In some embodiments, the disease or condition is NHL. In some embodiments, the NHL is selected from the group consisting of aggressive NHL, diffuse large B cell lymphoma (DLBCL), NOS (de novo and transformed from indolent), primary mediastinal large B cell lymphoma (PMBCL), T cell / histocyte-rich large B cell lymphoma (TCHRBCL), Burkitt’s lymphoma, mantle cell lymphoma (MCL), and / or follicular lymphoma (FL), optionally, follicular lymphoma Grade 3B (FL3B). In any of such embodiments, the disease or condition has relapsed or is refractory to one or more previous treatments (relapsed or refractory disease; R / R). In some aspects, the recombinant receptor, e.g., CAR or TCR, specifically binds to an antigen associated with the disease or condition or expressed in cells of the environment of a lesion associated with the B cell malignancy. Antigens targeted by the receptors in some embodiments include antigens associated with a B cell malignancy, such as any of a number ofknown B cell marker. In some embodiments, the antigen targeted by the receptor is BAFF-R, CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Igkappa, Iglambda, CD79a, CD79b or CD30, or combinations thereof. For instance, the antigen in some embodiments is BAFF-R, and the CAR is as described in Qin et al., Science Translational Medicine 11 (511): eaaw9414 (2019). In some embodiments, the antigen targeted by the receptor is CD19. For instance, the recombinant receptor may be a CAR that is that of axicabtagene ciloleucel (Yescarta), tisagenlecleucel (Kymriah), or lisocabtagene maraleucel (Breyanzi). In some embodiments, the recombinant receptor may be a CAR that is that of TECARTUS™ (brexucabtagene autoleucel). In some embodiments, the T cell therapy, e.g., anti-CD19 CAR T cell therapy, is axicabtagene ciloleucel (Yescarta), tisagenlecleucel (Kymriah), lisocabtagene maraleucel (Breyanzi), or TECARTUS™ (brexucabtagene autoleucel).

[0242] In some embodiments, the disease or condition is a large B-cell lymphoma. In some embodiments, the large B-cell lymphoma is a relapsed or refractory large B-cell lymphoma. In some embodiments, the large B-cell lymphoma is a diffuse large B cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), a high-grade B-cell lymphoma, a primary mediastinal large B-cell lymphoma, or a follicular lymphoma grade 3B. In some embodiments, the target antigen bound by the recombinant receptor and associated with the large B-cell lymphoma is CD19. In some embodiments, the recombinant receptor is an anti- CD19 CAR. In some embodiments, the anti-CD19 CAR is that of lisocabtagene maraleucel (Breyanzi). In some embodiments, the T cell therapy is an anti-CD19 CAR T cell therapy. In some embodiments, the anti-CD19 CAR T cell therapy is lisocabtagene maraleucel (Breyanzi, see Sehgal et al., 2020, Journal of Clinical Oncology 38:15_suppl, 8040; Teoh et al., 2019, Blood 134(Supplement_1):593; and Abramson et al., 2020, The Lancet 396(10254): 839-852).

[0243] In some embodiments, the disease or condition is mantle cell lymphoma or B-cell precursor acute lymphoblastic leukemia (ALL). In some embodiments, the disease or condition is relapsed or refractory mantle cell lymphoma or relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). In some embodiments, the target antigen bound by the recombinant receptor and associated with the disease or condition is CD19. In some embodiments, the recombinant receptor is an anti-CD19 CAR. In some embodiments, the anti- CD19 CAR is that of TECARTUS™ (brexucabtagene autoleucel). In some embodiments, the T cell therapy is an anti-CD19 CAR T cell therapy. In some embodiments, the anti-CD19 CAR Tcell therapy is TECARTUS™ (brexucabtagene autoleucel, see Mian and Hill, 2021, Expert Opin Biol Ther; 21(4):435-441; and Wang et al., 2021, Blood 138(Supplement 1):744).

[0244] In some embodiments, the disease or condition is diffuse large B-cell lymphoma (DLBCL) or acute lymphoblastic leukemia (ALL). In some embodiments, the disease or condition is relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or relapsed or refractory acute lymphoblastic leukemia (ALL). In some embodiments, the target antigen bound by the recombinant receptor and associated with the disease or condition is CD19. In some embodiments, the recombinant receptor is an anti-CD19 CAR. In some embodiments, the anti- CD19 CAR is that of tisagenlecleucel (Kymriah). In some embodiments, the T cell therapy is an anti-CD19 CAR T cell therapy. In some embodiments, the anti-CD19 CAR T cell therapy is tisagenlecleucel (Kymriah, see Bishop et al., 2022, N Engl J Med 386:629:639; Schuster et al., 2019, N Engl J Med 380:45-56; Halford et al., 2021, Ann Pharmacother 55(4):466-479; Mueller et al., 2021, Blood Adv. 5(23):4980-4991; and Fowler et al., 2022, Nature Medicine 28:325- 332).

[0245] In some embodiments, the disease or condition is a B-cell lymphoma. In some embodiments, the B-cell lymphoma is a relapsed or refractory B-cell lymphoma. In some embodiments, the B-cell lymphoma is diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, high grade B-cell lymphoma, DLBCL that results from follicular lymphoma, or follicular lymphoma. In some embodiments, the target antigen bound by the recombinant receptor and associated with the B-cell lymphoma is CD19. In some embodiments, the recombinant receptor is an anti-CD19 CAR. In some embodiments, the anti-CD19 CAR is that of axicabtagene ciloleucel (Yescarta). In some embodiments, the T cell therapy is an anti- CD19 CAR T cell therapy. In some embodiments, the anti-CD19 CAR T cell therapy is axicabtagene ciloleucel (Yescarta, see Neelapu et al., 2017, N Engl J Med 377(26):2531-2544; Jacobson et al., 2021, The Lancet 23(1):P91-103; and Locke et al., 2022, N Engl J Med 386:640-654).

[0246] In some embodiments, the disease or condition is a myeloma, such as a multiple myeloma. Antigens targeted by the recombinant receptors in some embodiments include antigens associated with multiple myeloma. In some aspects, the antigen is expressed on multiple myeloma, such as B cell maturation antigen (BCMA), G protein-coupled receptor class C group 5 member D (GPRC5D), CD38 (cyclic ADP ribose hydrolase), CD138 (syndecan-1, syndecan, SYN-1), CS-1 (CS1, CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24), BAFF-R, TACI and / or FcRH5. Other exemplary multiple myeloma antigens include CD56, TIM-3, CD33, CD123, CD44, CD20, CD40, CD74, CD200, EGFR, β2-Microglobulin, HM1.24, IGF- 1R, IL-6R, TRAIL-R1, and the activin receptor type IIA (ActRIIA). See Benson and Byrd, J. Clin. Oncol. (2012) 30(16): 2013-15; Tao and Anderson, Bone Marrow Research (2011):924058; Chu et al., Leukemia (2013) 28(4):917-27; Garfall et al., Discov Med. (2014) 17(91):37-46. In some embodiments, the antigens include those present on lymphoid tumors, myeloma, AIDS-associated lymphoma, and / or post-transplant lymphoproliferations, such as CD38. Antibodies or antigen-binding fragments directed against such antigens are known and include, for example, those described in U.S. Patent No. 8,153,765; 8,603477, 8,008,450; U.S. Pub. No. US20120189622 or US20100260748; and / or International PCT Publication Nos. WO2006099875, WO2009080829 or WO2012092612 or WO2014210064. In some embodiments, such antibodies or antigen-binding fragments thereof (e.g. scFv) are contained in multispecific antibodies, multispecific chimeric receptors, such as multispecific CARs, and / or multispecific cells.

[0247] In some embodiments, the disease or disorder is a multiple myeloma (MM). In some embodiments, the disease or disorder is associated with expression of G protein-coupled receptor class C group 5 member D (GPRC5D) and / or expression of B cell maturation antigen (BCMA). In some embodiments, the subject has or is suspected of having a MM that is associated with expression of a tumor-associated antigen, such as a B cell maturation antigen (BCMA), G protein-coupled receptor class C group 5 member D (GPRC5D), or Fc receptor like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5). In some aspects, the recombinant receptor, e.g., CAR or TCR, specifically binds to an antigen associated with the MM, such as specifically binds to BCMA, GPRC5D, or FCRL5. In some embodiments, the target antigen associated with the disease or condition, e.g., with the MM, is BCMA. In some embodiments, the recombinant receptor is the CAR, e.g., anti-BCMA CAR, of ABECMA® (idecabtagene vicleucel) or CARVYKTI™ (ciltacabtagene autoleucel). In some embodiments, the T cell therapy, e.g., anti-BCMA CAR T cell therapy, is ABECMA® (idecabtagene vicleucel) or CARVYKTI™ (ciltacabtagene autoleucel).

[0248] In some embodiments, the disease or condition is a multiple myeloma. In some embodiments, the multiple myeloma is a relapsed or refractory multiple myeloma. In some embodiments, the target antigen bound by the recombinant receptor and associated with the multiple myeloma is BCMA. In some embodiments, the recombinant receptor is an anti-BCMACAR. In some embodiments, the anti-BCMA CAR is that of CARVYKTI™ (ciltacabtagene autoleucel). In some embodiments, the T cell therapy is an anti-BCMA CAR T cell therapy. In some embodiments, the anti-BCMA CAR T cell therapy is CARVYKTI™ (ciltacabtagene autoleucel, see Berdeja et al., Lancet. 2021 Jul 24;398(10297):314-324; and Martin, Abstract #549 [Oral], presented at 2021 American Society of Hematology (ASH) Annual Meeting & Exposition)).

[0249] In some embodiments, the disease or condition is a multiple myeloma. In some embodiments, the multiple myeloma is a relapsed or refractory multiple myeloma. In some embodiments, the target antigen bound by the recombinant receptor and associated with the multiple myeloma is BCMA. In some embodiments, the recombinant receptor is an anti-BCMA CAR. In some embodiments, the anti-BCMA CAR is that of ABECMA® (idecabtagene vicleucel). In some embodiments, the T cell therapy is an anti-BCMA CAR T cell therapy. In some embodiments, the anti-BCMA CAR T cell therapy is ABECMA® (idecabtagene vicleucel, see Raje et al., 2019, N Engl J Med 380:1726-1737; and Munshi et al., 2021, N Engl J Med 384:705-716).

[0250] In some embodiments, the disease or disorder is a chronic lymphocytic leukemia (CLL). In some embodiments, the subject has or is suspected of having a CLL that is associated with expression of a tumor-associated antigen, such as a Receptor Tyrosine Kinase Like Orphan Receptor 1 (ROR1). In some embodiments, the antigen is ROR1, and the disease or disorder is CLL. In some aspects, the recombinant receptor, e.g., CAR or TCR, specifically binds to an antigen associated with the CLL, such as specifically binds to ROR1.

[0251] In some embodiments, the disease or disorder is a non-small cell lung cancer (NSCLC). In some embodiments, the subject has or is suspected of having a NSCLC that is associated with expression of a tumor-associated antigen, such as a Receptor Tyrosine Kinase Like Orphan Receptor 1 (ROR1). In some embodiments, the antigen is ROR1, and the disease or disorder is NSCLC. In some aspects, the recombinant receptor, e.g., CAR or TCR, specifically binds to an antigen associated with the NSCLC, such as specifically binds to ROR1. In some embodiments, the CAR is as described in Specht et al., Cancer Res 79: 4 Supplement, Abstract P2-09-13.

[0252] In some embodiments, the disease or disorder is a triple negative breast cancer (TNBC). In some embodiments, the subject has or is suspected of having a TNBC that is associated with expression of a tumor-associated antigen, such as a Receptor Tyrosine KinaseLike Orphan Receptor 1 (ROR1). In some embodiments, the antigen is ROR1, and the disease or disorder is TNBC. In some aspects, the recombinant receptor, e.g., CAR or TCR, specifically binds to an antigen associated with the TNBC, such as specifically binds to ROR1. In some embodiments, the CAR is as described in Specht et al., Cancer Res 79: 4 Supplement, Abstract P2-09-13.

[0253] In some embodiments, the disease or disorder is a small cell lung cancer (SCLC), optionally a relapsed / refractory SCLC. In some embodiments, the subject has or is suspected of having a SCLC that is associated with expression of a tumor-associated antigen, such as DLL3. In some embodiments, the antigen is DLL3, and the disease or disorder is SCLC. In some aspects, the recombinant receptor, e.g., CAR or TCR, specifically binds to an antigen associated with the SCLC, such as specifically binds to DLL3. In some embodiments, the CAR is as described in Byers et al., Journal of Clinical Oncology 37, no. 15_suppl (2019).

[0254] In some embodiments, the disease or disorder is a renal cell carcinoma (RCC). In some embodiments, the subject has or is suspected of having an RCC that is associated with expression of a tumor-associated antigen, such as CD70. In some embodiments, the antigen is CD70, and the disease or disorder is RCC. In some aspects, the recombinant receptor, e.g., CAR or TCR, specifically binds to an antigen associated with the RCC, such as specifically binds to CD70. In some embodiments, the CAR is as described in Panowski et al., Cancer Res 79 (13 Supplement) 2326 (2019).

[0255] In some embodiments, the disease or disorder is an acute myeloid leukemia (AML). In some embodiments, the subject has or is suspected of having an AML that is associated with expression of a tumor-associated antigen, such as CD70. In some embodiments, the antigen is CD70, and the disease or disorder is AML. In some aspects, the recombinant receptor, e.g., CAR or TCR, specifically binds to an antigen associated with the AML, such as specifically binds to CD70. In some embodiments, the CAR is as described in Sauer et al., Blood 134 (Supplement_1): 1932 (2019).

[0256] In some embodiments, the antigen is or includes a pathogen-specific or pathogen- expressed antigen. In some embodiments, the antigen is a viral antigen (such as a viral antigen from HIV, HCV, HBV, etc.), bacterial antigens, and / or parasitic antigens.ADMINISTRATION OF A T CELL THERAPY

[0257] In some aspects, the methods provided herein include combination therapy by administering a cell therapy, e.g., T cell therapy, to a subject having a disease or condition, such as any disease or condition as described above, in combination with a DGK inhibitor. In some aspects, the methods provided herein include administering a DGK inhibitor to a subject in combination with (e.g., prior to, concurrently with, or subsequent to) administration of the cell therapy, e.g., T cell therapy. In some embodiments, provided methods include administering a DGK inhibitor to a subject that has previously been administered a cell therapy, e.g., T cell therapy, for treatment of a disease or condition. In some embodiments, the cell therapy, e.g., T cell therapy, is administered to the subject prior to administering the DGKi to the subject. In some embodiments, the cell therapy, e.g., T cell therapy, and the DGKi are administered concurrently.

[0258] In some embodiments, the cell therapy is a T cell therapy. The T cell therapy may include T cells engineered with a recombinant receptor, such as a CAR or an engineered TCR (e.g., eTCR). In some embodiments, the T cell therapy includes T cells (e.g., CD4+ and / or CD8+ T cells) that express a CAR that targets or binds an antigen associated with the disease or condition. In some embodiments, the T cell therapy includes T cells (e.g., CD4+ and / or CD8+ T cells) that express an eTCR that targets or binds an antigen associated with the disease or condition. A T cell therapy for use in the provided methods include any of a variety of CAR- expressing or eTCR-expressing T cells. It is within the level of a skilled artisan to choose the appropriate recombinant receptor (e.g., CAR or eTCR)-expressing T cell therapy for treating the disease or condition. Examples of T cell therapies, including CAR-expressing T cells and eTCR- expressing T cells, are described in Section II. In some embodiments, the T cells of the T cell therapy are allogenic to the subject being treated. In some embodiments, the T cells of the T cell therapy are autologous to the subject being treated.

[0259] Methods for administration of cells for adoptive cell therapy are known and may be used in connection with the provided methods, compositions and articles of manufacture and kits. For example, adoptive T cell therapy methods are described, e.g., in US Patent Application Publication No. 2003 / 0170238 to Gruenberg et al; US Patent No. 4,690,915 to Rosenberg; Rosenberg (2011) Nat Rev Clin Oncol. 8(10):577-85). See, e.g., Themeli et al. (2013) Nat Biotechnol. 31(10): 928-933; Tsukahara et al. (2013) Biochem Biophys Res Commun 438(1): 849; Davila et al (2013) PLoS ONE 8(4): e61338.

[0260] In some embodiments, the cell therapy, e.g., adoptive T cell therapy, is carried out by autologous transfer, in which the cells are isolated and / or otherwise prepared from the subject who is to receive the cell therapy, or from a sample derived from such a subject. Thus, in some aspects, the cells are derived from a subject, e.g., patient, in need of a treatment and the cells, following isolation and processing are administered to the same subject.

[0261] In some embodiments, the cell therapy, e.g., adoptive T cell therapy, is carried out by allogeneic transfer, in which the cells are isolated and / or otherwise prepared from a subject other than a subject who is to receive or who ultimately receives the cell therapy, e.g., a first subject. In such embodiments, the cells then are administered to a different subject, e.g., a second subject, of the same species. In some embodiments, the first and second subjects are genetically identical. In some embodiments, the first and second subjects are genetically similar. In some embodiments, the second subject expresses the same HLA class or supertype as the first subject.

[0262] The cells of the T cell therapy can be administered in a composition formulated for administration, or alternatively, in more than one composition (e.g., two compositions) formulated for separate administration. The dose(s) of the cells may include a particular number or relative number of cells or of the engineered cells, and / or a defined ratio or compositions of two or more sub-types within the composition, such as CD4 vs CD8 T cells.

[0263] The cells can be administered by any suitable means, for example, by bolus infusion, by injection, e.g., intravenous or subcutaneous injections, intraocular injection, periocular injection, subretinal injection, intravitreal injection, trans-septal injection, subscleral injection, intrachoroidal injection, intracameral injection, subconjectval injection, subconjuntival injection, sub-Tenon’s injection, retrobulbar injection, peribulbar injection, or posterior juxtascleral delivery. In some embodiments, they are administered by parenteral, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, a given dose is administered by a single bolus administration of the cells. In some embodiments, it is administered by multiple bolus administrations of the cells, for example, over a period of no more than 3 days, or by continuous infusion administration of the cells. In some embodiments, administration of the cell dose or any additional therapies, e.g., the lymphodepleting therapy, intervention therapy and / or combination therapy, is carried out via outpatient delivery.

[0264] For the treatment of disease, the appropriate dosage may depend on the type of disease to be treated, the type of cells or recombinant receptors, the severity and course of the disease, previous therapy, the subject’s clinical history and response to the cells, and the discretion of the attending physician. The compositions and cells are in some embodiments suitably administered to the subject at one time or over a series of treatments.

[0265] Following administration of the cells, the biological activity of the engineered cell populations in some embodiments is measured, e.g., by any of a number of known methods. Parameters to assess include specific binding of an engineered or natural T cell or other immune cell to antigen, in vivo, e.g., by imaging, or ex vivo, e.g., by ELISA or flow cytometry. In certain embodiments, the ability of the engineered cells to destroy target cells can be measured using any suitable known methods, such as cytotoxicity assays described in, for example, Kochenderfer et al., J. Immunotherapy, 32(7): 689-702 (2009), and Herman et al. J. Immunological Methods, 285(1): 25-40 (2004). In certain embodiments, the biological activity of the cells is measured by assaying expression and / or secretion of one or more cytokines, such as CD107a, IFNγ, IL-2, and TNF. In some aspects the biological activity is measured by assessing clinical outcome, such as reduction in tumor burden or load.

[0266] In some embodiments, the dose of cells of the T cell therapy, such a T cell therapy comprising cells engineered with a recombinant antigen receptor, e.g. CAR or TCR, is provided as a composition or formulation, such as a pharmaceutical composition or formulation. Such compositions can be used in accord with the provided methods, such as in the prevention or treatment of diseases, conditions, and disorders.

[0267] In some embodiments, the T cell therapy, such as engineered T cells (e.g. CAR or TCR T cells), are formulated with a pharmaceutically acceptable carrier. In some aspects, the choice of carrier is determined in part by the particular cell or agent and / or by the method of administration. Accordingly, there are a variety of suitable formulations. For example, the pharmaceutical composition can contain preservatives. Suitable preservatives may include, for example, methylparaben, propylparaben, sodium benzoate, and benzalkonium chloride. In some aspects, a mixture of two or more preservatives is used. The preservative or mixtures thereof are typically present in an amount of about 0.0001% to about 2% by weight of the total composition. Carriers are described, e.g., by Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such asphosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and / or non-ionic surfactants such as polyethylene glycol (PEG).

[0268] Buffering agents in some aspects are included in the compositions. Suitable buffering agents include, for example, citric acid, sodium citrate, phosphoric acid, potassium phosphate, and various other acids and salts. In some aspects, a mixture of two or more buffering agents is used. The buffering agent or mixtures thereof are typically present in an amount of about 0.001% to about 4% by weight of the total composition. Methods for preparing administrable pharmaceutical compositions are known. Exemplary methods are described in more detail in, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins; 21st ed. (May 1, 2005).

[0269] The formulations can include aqueous solutions. The formulation or composition may also contain more than one active ingredient useful for the particular indication, disease, or condition being prevented or treated with the cells or agents, where the respective activities do not adversely affect one another. Such active ingredients are suitably present in combination in amounts that are effective for the purpose intended. Thus, in some embodiments, the pharmaceutical composition further includes other pharmaceutically active agents or drugs, such as chemotherapeutic agents, e.g., asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine, vincristine, etc.

[0270] The pharmaceutical composition in some embodiments contains cells in amounts effective to treat or prevent the disease or condition, such as a therapeutically effective or prophylactically effective amount. Therapeutic or prophylactic efficacy in some embodiments is monitored by periodic assessment of treated subjects. For repeated administrations over severaldays or longer, depending on the condition, the treatment is repeated until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful and can be determined. The desired dosage can be delivered by a single bolus administration of the composition, by multiple bolus administrations of the composition, or by continuous infusion administration of the composition.

[0271] The cells may be administered using standard administration techniques, formulations, and / or devices. Provided are formulations and devices, such as syringes and vials, for storage and administration of the compositions. With respect to cells, administration can be autologous or heterologous. For example, immunoresponsive cells or progenitors can be obtained from one subject, and administered to the same subject or a different, compatible subject. Peripheral blood derived immunoresponsive cells or their progeny (e.g., in vivo, ex vivo or in vitro derived) can be administered via localized injection, including catheter administration, systemic injection, localized injection, intravenous injection, or parenteral administration. When administering a therapeutic composition (e.g., a pharmaceutical composition containing a genetically modified immunoresponsive cell), it will generally be formulated in a unit dosage injectable form (solution, suspension, emulsion).

[0272] Formulations include those for oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration. In some embodiments, the agent or cell populations are administered parenterally. The term “parenteral,” as used herein, includes intravenous, intramuscular, subcutaneous, rectal, vaginal, and intraperitoneal administration. In some embodiments, the agent or cell populations are administered to a subject using peripheral systemic delivery by intravenous, intraperitoneal, or subcutaneous injection.

[0273] Compositions in some embodiments are provided as sterile liquid preparations, e.g., isotonic aqueous solutions, suspensions, emulsions, dispersions, or viscous compositions, which may in some aspects be buffered to a selected pH. Liquid preparations are normally easier to prepare than gels, other viscous compositions, and solid compositions. Additionally, liquid compositions are somewhat more convenient to administer, especially by injection. Viscous compositions, on the other hand, can be formulated within the appropriate viscosity range to provide longer contact periods with specific tissues. Liquid or viscous compositions can comprise carriers, which can be a solvent or dispersing medium containing, for example, water,saline, phosphate buffered saline, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol) and suitable mixtures thereof.

[0274] Sterile injectable solutions can be prepared by incorporating the cells in a solvent, such as in admixture with a suitable carrier, diluent, or excipient such as sterile water, physiological saline, glucose, dextrose, or the like. The compositions can also be lyophilized. The compositions can contain auxiliary substances such as wetting, dispersing, or emulsifying agents (e.g., methylcellulose), pH buffering agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired. Standard texts may in some aspects be consulted to prepare suitable preparations.

[0275] Various additives which enhance the stability and sterility of the compositions, including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0276] The formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.

[0277] For the prevention or treatment of disease, the appropriate dosage may depend on the type of disease to be treated, the type of agent or agents, the type of cells or recombinant receptors, the severity and course of the disease, whether the agent or cells are administered for preventive or therapeutic purposes, previous therapy, the subject's clinical history and response to the agent or the cells, and the discretion of the attending physician. The compositions are in some embodiments suitably administered to the subject at one time or over a series of treatments.

[0278] In some cases, the cell therapy is administered as a single pharmaceutical composition comprising the cells. In some embodiments, a given dose is administered by a single bolus administration of the cells or agent. In some embodiments, it is administered by multiple bolus administrations of the cells or agent, for example, over a period of no more than 3 days, or by continuous infusion administration of the cells or agent.

[0279] In some embodiments, a dose of cells is administered to subjects in accord with the provided combination therapy methods. In some embodiments, the size or timing of the doses isdetermined as a function of the particular disease or condition in the subject. One may empirically determine the size or timing of the doses for a particular disease in view of the provided description.

[0280] In certain embodiments, the cells, or individual populations of sub-types of cells, are administered to the subject at a range of about 0.1 million to about 100 billion cells and / or that amount of cells per kilogram of body weight of the subject, such as, e.g., 0.1 million to about 50 billion cells (e.g., about 5 million cells, about 25 million cells, about 500 million cells, about 1 billion cells, about 5 billion cells, about 20 billion cells, about 30 billion cells, about 40 billion cells, or a range defined by any two of the foregoing values), 1 million to about 50 billion cells (e.g., about 5 million cells, about 25 million cells, about 500 million cells, about 1 billion cells, about 5 billion cells, about 20 billion cells, about 30 billion cells, about 40 billion cells, or a range defined by any two of the foregoing values), such as about 10 million to about 100 billion cells (e.g., about 20 million cells, about 30 million cells, about 40 million cells, about 60 million cells, about 70 million cells, about 80 million cells, about 90 million cells, about 10 billion cells, about 25 billion cells, about 50 billion cells, about 75 billion cells, about 90 billion cells, or a range defined by any two of the foregoing values), and in some cases about 100 million cells to about 50 billion cells (e.g., about 120 million cells, about 250 million cells, about 350 million cells, about 450 million cells, about 650 million cells, about 800 million cells, about 900 million cells, about 3 billion cells, about 30 billion cells, about 45 billion cells), about 10 million to about 600 million cells, about 100 million to about 600 million cells, about 100 million to about 450 million cells, about 150 million cells to about 300 or 450 million cells, or any value in between these ranges and / or per kilogram of body weight of the subject. Dosages may vary depending on attributes particular to the disease or disorder and / or patient and / or other treatments. In some embodiments, such values refer to numbers of recombinant receptor- expressing cells (e.g., CAR- or TCR-expressing cells); in other embodiments, they refer to number of T cells or PBMCs or total cells administered.

[0281] In some embodiments, the cell therapy comprises administration of a dose comprising a number of cell from or from about 1 x 105to 1 x 108total recombinant receptor- expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), from or from about 5 x 105to 1 x 107total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs) or from or from about 1 x 106to 1 x 107total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells(PBMCs), each inclusive. In some embodiments, the cell therapy comprises administration of a dose of cells comprising a number of cells at least or about at least 1 x 105total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), such at least or at least 1 x 106, at least or about at least 1 x 107, at least or about at least 1 x 108of such cells.

[0282] In some embodiments, for example, where the subject is a human, the dose includes fewer than about 5 x 108total recombinant receptor (e.g., TCR or CAR)-expressing cells, T cells, or peripheral blood mononuclear cells (PBMCs), e.g., in the range of about 1 x 106to 5 x 108such cells, such as 2 x 106, 5 x 106, 1 x 107, 5 x 107, 1 x 108, or 5 x 108total such cells, or the range between any two of the foregoing values.

[0283] In some embodiments, the number is with reference to the total number of CD3+ or CD8+, in some cases also recombinant receptor-expressing (e.g. TCR+ or CAR+) cells. In some embodiments, the cell therapy comprises administration of a dose comprising a number of cell from or from about 1 x 105to 1 x 108CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells, from or from about 5 x 105to 1 x 107CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells, or from or from about 1 x 106to 1 x 107CD3+ or CD8+ total T cells or CD3+ or CD8+recombinant receptor-expressing cells, each inclusive. In some embodiments, the cell therapy comprises administration of a dose comprising a number of cell from or from about 1 x 105to 1 x 108total CD3+ / CAR+ or CD8+ / CAR+ cells, from or from about 5 x 105to 1 x 107total CD3+ / CAR+ or CD8+ / CAR+ cells, or from or from about 1 x 106to 1 x 107total CD3+ / CAR+ or CD8+ / CAR+ cells, each inclusive.

[0284] In some embodiments, the dose of genetically engineered cells comprises from or from about 1 x 105to 5 x 108total recombinant receptor-expressing T cells, 1 x 105to 2.5 x 108total recombinant receptor-expressing T cells, 1 x 105to 1 x 108total recombinant receptor- expressing T cells, 1 x 105to 5 x 107total recombinant receptor-expressing T cells, 1 x 105to 2.5 x 107total recombinant receptor-expressing T cells, 1 x 105to 1 x 107total recombinant receptor-expressing T cells, 1 x 105to 5 x 106total recombinant receptor-expressing T cells, 1 x 105to 2.5 x 106total recombinant receptor-expressing T cells, 1 x 105to 1 x 106total recombinant receptor-expressing T cells, 1 x 106to 5 x 108total recombinant receptor- expressing T cells, 1 x 106to 2.5 x 108total recombinant receptor-expressing T cells, 1 x 106to 1 x 108total recombinant receptor-expressing T cells, 1 x 106to 5 x 107total recombinantreceptor-expressing T cells, 1 x 106to 2.5 x 107total recombinant receptor-expressing T cells, 1 x 106to 1 x 107total recombinant receptor-expressing T cells, 1 x 106to 5 x 106total recombinant receptor-expressing T cells, 1 x 106to 2.5 x 106total recombinant receptor- expressing T cells, 2.5 x 106to 5 x 108total recombinant receptor-expressing T cells, 2.5 x 106to 2.5 x 108total recombinant receptor-expressing T cells, 2.5 x 106to 1 x 108total recombinant receptor-expressing T cells, 2.5 x 106to 5 x 107total recombinant receptor- expressing T cells, 2.5 x 106to 2.5 x 107total recombinant receptor-expressing T cells, 2.5 x 106to 1 x 107total recombinant receptor-expressing T cells, 2.5 x 106to 5 x 106total recombinant receptor-expressing T cells, 5 x 106to 5 x 108total recombinant receptor- expressing T cells, 5 x 106to 2.5 x 108total recombinant receptor-expressing T cells, 5 x 106to 1 x 108total recombinant receptor-expressing T cells, 5 x 106to 5 x 107total recombinant receptor-expressing T cells, 5 x 106to 2.5 x 107total recombinant receptor-expressing T cells, 5 x 106to 1 x 107total recombinant receptor-expressing T cells, 1 x 107to 5 x 108total recombinant receptor-expressing T cells, 1 x 107to 2.5 x 108total recombinant receptor- expressing T cells, 1 x 107to 1 x 108total recombinant receptor-expressing T cells, 1 x 107to 5 x 107total recombinant receptor-expressing T cells, 1 x 107to 2.5 x 107total recombinant receptor-expressing T cells, 2.5 x 107to 5 x 108total recombinant receptor-expressing T cells, 2.5 x 107to 2.5 x 108total recombinant receptor-expressing T cells, 2.5 x 107to 1 x 108total recombinant receptor-expressing T cells, 2.5 x 107to 5 x 107total recombinant receptor- expressing T cells, 5 x 107to 5 x 108total recombinant receptor-expressing T cells, 5 x 107to 2.5 x 108total recombinant receptor-expressing T cells, 5 x 107to 1 x 108total recombinant receptor-expressing T cells, 1 x 108to 5 x 108total recombinant receptor-expressing T cells, 1 x 108to 2.5 x 108total recombinant receptor-expressing T cells, or 2.5 x 108to 5 x 108total recombinant receptor-expressing T cells.

[0285] In some embodiments, the dose of genetically engineered cells comprises at least or at least about 1 x 105TCR- or CAR-expressing cells, at least or at least about 2.5 x 105TCR- or CAR-expressing cells, at least or at least about 5 x 105TCR- or CAR-expressing cells, at least or at least about 1 x 106TCR- or CAR-expressing cells, at least or at least about 2.5 x 106TCR- or CAR-expressing cells, at least or at least about 5 x 106TCR- or CAR-expressing cells, at least or at least about 1 x 107TCR- or CAR-expressing cells, at least or at least about 2.5 x 107TCR- or CAR-expressing cells, at least or at least about 5 x 107TCR- or CAR-expressing cells, at least orat least about 1 x 108TCR- or CAR-expressing cells, at least or at least about 2.5 x 108TCR- or CAR-expressing cells, or at least or at least about 5 x 108TCR- or CAR-expressing cells.

[0286] In some embodiments, the dose of genetically engineered cells comprises from or from about 15 million to 1 billion total recombinant receptor-expressing T cells. In some embodiments, the dose of genetically engineered cells comprises from or from about 15 million to 600 million total recombinant receptor-expressing T cells. In some embodiments, the dose of genetically engineered cells comprises from or from about 150 million to 600 million total recombinant receptor-expressing T cells. In some embodiments, the dose of genetically engineered cells comprises from or from about 150 million to 450 million total recombinant receptor-expressing T cells.

[0287] In some embodiments, the dose of genetically engineered cells comprises at least or at least about 1 x 105recombinant receptor-expressing cells, at least or at least about 2.5 x 105recombinant receptor-expressing cells, at least or at least about 5 x 105recombinant receptor- expressing cells, at least or at least about 1 x 106recombinant receptor-expressing cells, at least or at least about 2.5 x 106recombinant receptor-expressing cells, at least or at least about 5 x 106recombinant receptor-expressing cells, at least or at least about 1 x 107recombinant receptor- expressing cells, at least or at least about 2.5 x 107recombinant receptor-expressing cells, at least or at least about 5 x 107recombinant receptor-expressing cells, at least or at least about 1 x 108recombinant receptor-expressing cells, at least or at least about 2.5 x 108recombinant receptor-expressing cells, or at least or at least about 5 x 108recombinant receptor-expressing cells.

[0288] In some embodiments, the cell therapy comprises administration of a dose comprising a number of cell from or from about 1 x 105to 1 x 108total recombinant receptor- expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), from or from about 5 x 105to 1 x 107total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs) or from or from about 1 x 106to 1 x 107total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), each inclusive. In some embodiments, the cell therapy comprises administration of a dose of cells comprising a number of cells at least or about at least 1 x 105total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), such at least or at least 1 x 106, at least or about at least 1 x 107, at least or about at least 1 x 108of such cells.

[0289] In some embodiments, for example, where the subject is a human, the dose includes fewer than about 5 x 108total recombinant receptor (e.g., CAR or TCR)-expressing cells, T cells, or peripheral blood mononuclear cells (PBMCs), e.g., in the range of about 1 x 106to 5 x 108such cells, such as 2 x 106, 5 x 106, 1 x 107, 5 x 107, 1 x 108, or 5 x 108total such cells, or the range between any two of the foregoing values.

[0290] In some embodiments, the number is with reference to the total number of CD3+ or CD8+, in some cases also recombinant receptor-expressing (e.g. CAR or TCR expressing) cells. In some embodiments, the cell therapy comprises administration of a dose comprising a number of cell from or from about 1 x 105to 1 x 108CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells, from or from about 5 x 105to 1 x 107CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells, or from or from about 1 x 106to 1 x 107CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells, each inclusive. In some embodiments, the cell therapy comprises administration of a dose comprising a number of cell from or from about 1 x 105to 1 x 108total CD3+ / recombinant receptor+ or CD8+ / recombinant receptor+ cells, from or from about 5 x 105to 1 x 107total CD3+ / recombinant receptor+ or CD8+ / recombinant receptor+ cells, or from or from about 1 x 106to 1 x 107total CD3+ / recombinant receptor+ or CD8+ / recombinant receptor+ cells, each inclusive.

[0291] In some embodiments, the cell therapy comprises administration of a dose comprising a number of cell from or from about 1 x 105to 5 x 108total recombinant receptor- expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), from or from about 5 x 105to 1 x 107total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs) or from or from about 1 x 106to 1 x 107total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), each inclusive. In some embodiments, the cell therapy comprises administration of a dose of cells comprising a number of cells at least or at least about 1 x 105total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), such at least or at least 1 x 106, at least or at least about 1 x 107, at least or at least about 1 x 108of such cells. In some embodiments, the number is with reference to the total number of CD3+ or CD8+, in some cases also recombinant receptor-expressing (e.g. CAR+ or TCR+) cells. In some embodiments, the cell therapy comprises administration of a dose comprising a number of cell from or from about 1 x 105to 5 x 108CD3+ or CD8+ total T cells or CD3+ or CD8+recombinant receptor-expressing cells, from or from about 5 x 105to 1 x 107CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells, or from or from about 1 x 106to 1 x 107CD3+ or CD8+ total T cells or CD3+ or CD8+recombinant receptor-expressing cells, each inclusive. In some embodiments, the cell therapy comprises administration of a dose comprising a number of cell from or from about 1 x 105to 5 x 108total CD3+ / recombinant receptor+ or CD8+ / recombinant receptor+ cells, from or from about 5 x 105to 1 x 107total CD3+ / recombinant receptor+ or CD8+ / recombinant receptor+ cells, or from or from about 1 x 106to 1 x 107total CD3+ / recombinant receptor+ or CD8+ / recombinant receptor+ cells, each inclusive.

[0292] In some embodiments, the T cells of the dose include CD4+ T cells, CD8+ T cells or CD4+ and CD8+ T cells.

[0293] In some embodiments, for example, where the subject is human, the CD8+ T cells of the dose, including in a dose including CD4+ and CD8+ T cells, includes between about 1 x 106and 5 x 108total recombinant receptor (e.g., CAR or TCR)-expressing CD8+cells, e.g., in the range of about 5 x 106to 1 x 108such cells, such cells 1 x 107, 2.5 x 107, 5 x 107, 7.5 x 107, 1 x 108, or 5 x 108total such cells, or the range between any two of the foregoing values. In some embodiments, the patient is administered multiple doses, and each of the doses or the total dose can be within any of the foregoing values. In some embodiments, the dose of cells comprises the administration of from or from about 1 x 107to 0.75 x 108total recombinant receptor-expressing CD8+ T cells, 1 x 107to 2.5 x 107total recombinant receptor-expressing CD8+ T cells, from or from about 1 x 107to 0.75 x 108total recombinant receptor-expressing CD8+ T cells, each inclusive. In some embodiments, the dose of cells comprises the administration of or about 1 x 107, 2.5 x 107, 5 x 1077.5 x 107, 1 x 108, or 5 x 108total recombinant receptor-expressing CD8+ T cells.

[0294] In some embodiments, the dose of cells, e.g., recombinant receptor-expressing T cells, is administered to the subject as a single dose or is administered only one time within a period of two weeks, one month, three months, six months, 1 year or more.

[0295] In some embodiments, the cell therapy comprises administration of a dose comprising a number of cells that is at least or at least about or is or is about 0.1 x 106cells / kg body weight of the subject, 0.2 x 106cells / kg, 0.3 x 106cells / kg, 0.4 x 106cells / kg, 0.5 x 106cells / kg, 1 x 106cell / kg, 2.0 x 106cells / kg, 3 x 106cells / kg or 5 x 106cells / kg.

[0296] In some embodiments, the cell therapy comprises administration of a dose comprising a number of cells is between or between about 0.1 x 106cells / kg body weight of the subject and 1.0 x 107cells / kg, between or between about 0.5 x 106cells / kg and 5 x 106cells / kg, between or between about 0.5 x 106cells / kg and 3 x 106cells / kg, between or between about 0.5 x 106cells / kg and 2 x 106cells / kg, between or between about 0.5 x 106cells / kg and 1 x 106cell / kg, between or between about 1.0 x 106cells / kg body weight of the subject and 5 x 106cells / kg, between or between about 1.0 x 106cells / kg and 3 x 106cells / kg, between or between about 1.0 x 106cells / kg and 2 x 106cells / kg, between or between about 2.0 x 106cells / kg body weight of the subject and 5 x 106cells / kg, between or between about 2.0 x 106cells / kg and 3 x 106cells / kg, or between or between about 3.0 x 106cells / kg body weight of the subject and 5 x 106cells / kg, each inclusive.

[0297] In some embodiments, the dose of cells comprises between at or about 2 x 105of the cells / kg and at or about 2 x 106of the cells / kg, such as between at or about 4 x 105of the cells / kg and at or about 1 x 106of the cells / kg or between at or about 6 x 105of the cells / kg and at or about 8 x 105of the cells / kg. In some embodiments, the dose of cells comprises no more than 2 x 105of the cells (e.g. antigen-expressing, such as CAR-expressing cells or TCR- expressing cells) per kilogram body weight of the subject (cells / kg), such as no more than at or about 3 x 105cells / kg, no more than at or about 4 x 105cells / kg, no more than at or about 5 x 105cells / kg, no more than at or about 6 x 105cells / kg, no more than at or about 7 x 105cells / kg, no more than at or about 8 x 105cells / kg, nor more than at or about 9 x 105cells / kg, no more than at or about 1 x 106cells / kg, or no more than at or about 2 x 106cells / kg. In some embodiments, the dose of cells comprises at least or at least about or at or about 2 x 105of the cells (e.g. antigen-expressing, such as CAR-expressing cells or TCR expressing cells) per kilogram body weight of the subject (cells / kg), such as at least or at least about or at or about 3 x 105cells / kg, at least or at least about or at or about 4 x 105cells / kg, at least or at least about or at or about 5 x 105cells / kg, at least or at least about or at or about 6 x 105cells / kg, at least or at least about or at or about 7 x 105cells / kg, at least or at least about or at or about 8 x 105cells / kg, at least or at least about or at or about 9 x 105cells / kg, at least or at least about or at or about 1 x 106cells / kg, or at least or at least about or at or about 2 x 106cells / kg.

[0298] In the context of adoptive cell therapy, administration of a given “dose” of cells encompasses administration of the given amount or number of cells as a single composition and / or single uninterrupted administration, e.g., as a single injection or continuous infusion, andalso encompasses administration of the given amount or number of cells as a split dose, provided in multiple individual compositions or infusions, over a specified period of time, which is no more than 3 days. Thus, in some contexts, the dose is a single or continuous administration of the specified number of cells, given or initiated at a single point in time. In some contexts, however, the dose is administered in multiple injections or infusions over a period of no more than three days, such as once a day for three days or for two days or by multiple infusions over a single day period.

[0299] Thus, in some aspects, the cells of the dose are administered in a single pharmaceutical composition. In some embodiments, the cells of the dose are administered in a plurality of compositions, collectively containing the cells of the dose.

[0300] The term “split dose” refers to a dose that is split so that it is administered over more than one day. This type of dosing is encompassed by the present methods and is considered to be a single dose. In some embodiments, the cells of a split dose are administered in a plurality of compositions, collectively comprising the cells of the dose, over a period of no more than three days.

[0301] Thus, the dose of cells may be administered as a split dose. For example, in some embodiments, the dose may be administered to the subject over 2 days or over 3 days. Exemplary methods for split dosing include administering 25% of the dose on the first day and administering the remaining 75% of the dose on the second day. In other embodiments, 33% of the dose may be administered on the first day and the remaining 67% administered on the second day. In some aspects, 10% of the dose is administered on the first day, 30% of the dose is administered on the second day, and 60% of the dose is administered on the third day. In some embodiments, the split dose is not spread over more than 3 days.

[0302] In some embodiments, the dose of cells is generally large enough to be effective in reducing disease burden.

[0303] In some embodiments, the cells are administered at a desired dosage, which in some aspects includes a desired dose or number of cells or cell type(s) and / or a desired ratio of cell types. Thus, the dosage of cells in some embodiments is based on a total number of cells (or number per kg body weight) and a desired ratio of the individual populations or sub-types, such as the CD4+ to CD8+ ratio. In some embodiments, the dosage of cells is based on a desired total number (or number per kg of body weight) of cells in the individual populations or of individual cell types. In some embodiments, the dosage is based on a combination of suchfeatures, such as a desired number of total cells, desired ratio, and desired total number of cells in the individual populations.

[0304] In some embodiments, the populations or sub-types of cells, such as CD8+and CD4+T cells, are administered at or within a tolerated difference of a desired dose of total cells, such as a desired dose of T cells. In some aspects, the desired dose is a desired number of cells or a desired number of cells per unit of body weight of the subject to whom the cells are administered, e.g., cells / kg. In some aspects, the desired dose is at or above a minimum number of cells or minimum number of cells per unit of body weight. In some aspects, among the total cells, administered at the desired dose, the individual populations or sub-types are present at or near a desired output ratio (such as CD4+to CD8+ratio), e.g., within a certain tolerated difference or error of such a ratio.

[0305] In some embodiments, the cells are administered at or within a tolerated difference of a desired dose of one or more of the individual populations or sub-types of cells, such as a desired dose of CD4+ cells and / or a desired dose of CD8+ cells. In some aspects, the desired dose is a desired number of cells of the sub-type or population, or a desired number of such cells per unit of body weight of the subject to whom the cells are administered, e.g., cells / kg. In some aspects, the desired dose is at or above a minimum number of cells of the population or sub- type, or minimum number of cells of the population or sub-type per unit of body weight.

[0306] Thus, in some embodiments, the dosage is based on a desired fixed dose of total cells and a desired ratio, and / or based on a desired fixed dose of one or more, e.g., each, of the individual sub-types or sub-populations. Thus, in some embodiments, the dosage is based on a desired fixed or minimum dose of T cells and a desired ratio of CD4+to CD8+cells, and / or is based on a desired fixed or minimum dose of CD4+and / or CD8+cells.

[0307] In some embodiments, the cells are administered at or within a tolerated range of a desired output ratio of multiple cell populations or sub-types, such as CD4+ and CD8+ cells or sub-types. In some aspects, the desired ratio can be a specific ratio or can be a range of ratios. for example, in some embodiments, the desired ratio (e.g., ratio of CD4+to CD8+cells) is between at or about 5:1 and at or about 5:1 (or greater than about 1:5 and less than about 5:1), or between at or about 1:3 and at or about 3:1 (or greater than about 1:3 and less than about 3:1), such as between at or about 2:1 and at or about 1:5 (or greater than about 1:5 and less than about 2:1, such as at or about 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.5:1, 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9: 1:2, 1:2.5,1:3, 1:3.5, 1:4, 1:4.5, or 1:5. In some aspects, the tolerated difference is within about 1%, about 2%, about 3%, about 4% about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% of the desired ratio, including any value in between these ranges.

[0308] In particular embodiments, the numbers and / or concentrations of cells refer to the number of recombinant receptor (e.g., CAR or TCR)-expressing cells. In other embodiments, the numbers and / or concentrations of cells refer to the number or concentration of all cells, T cells, or peripheral blood mononuclear cells (PBMCs) administered.

[0309] In some aspects, the size of the dose is determined based on one or more criteria such as response of the subject to prior treatment, e.g. chemotherapy, disease burden in the subject, such as tumor load, bulk, size, or degree, extent, or type of metastasis, stage, and / or likelihood or incidence of the subject developing toxic outcomes, e.g., CRS, macrophage activation syndrome, tumor lysis syndrome, neurotoxicity, and / or a host immune response against the cells and / or recombinant receptors being administered.

[0310] In some embodiments, administration of the DGK inhibitor in combination with the cells is able to significantly increase the expansion or proliferation of the cells, and thus a lower dose of cells can be administered to the subject. In some cases, the provided methods allow a lower dose of such cells to be administered, to achieve the same or better efficacy of treatment as the dose in a method in which the cell therapy is administered without administering the DGK inhibitor, such as at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold or 10-fold less than the dose in a method in which the cell therapy is administered without administering the DGK inhibitor.

[0311] In some embodiments, for example, the dose contains between or between about 5.0 x 106and 2.25 x 107, 5.0 x 106and 2.0 x 107, 5.0 x 106and 1.5 x 107, 5.0 x 106and 1.0 x 107, 5.0 x 106and 7.5 x 106, 7.5 x 106and 2.25 x 107, 7.5 x 106and 2.0 x 107, 7.5 x 106and 1.5 x 107, 7.5 x 106and 1.0 x 107, 1.0 x 107and 2.25 x 107, 1.0 x 107and 2.0 x 107, 1.0 x 107and 1.5 x 107, 1.5 x 107and 2.25 x 107, 1.5 x 107and 2.0 x 107, 2.0 x 107and 2.25 x 107. In some embodiments, the dose of cells contains a number of cells, that is between at least or at least about 5 x 106, 6 x 106, 7 x 106, 8 x 106, 9 x 106, 10 x 106and about 15 x 106recombinant- receptor expressing cells, such as recombinant-receptor expressing cells that are CD8+. In some embodiments, such dose, such as such target number of cells refers to the total recombinant-receptor expressing cells in the administered composition.

[0312] In some embodiments, for example, the lower dose contains less than about 5 x 106cells, recombinant receptor (e.g. TCR- or CAR)-expressing cells, T cells, and / or PBMCs per kilogram body weight of the subject, such as less than about 4.5 x 106, 4 x 106, 3.5 x 106, 3 x 106, 2.5 x 106, 2 x 106, 1.5 x 106, 1 x 106, 5 x 105, 2.5 x 105, or 1 x 105such cells per kilogram body weight of the subject. In some embodiments, the lower dose contains less than about 1 x 105, 2 x 105, 5 x 105, or 1 x 106of such cells per kilogram body weight of the subject, or a value within the range between any two of the foregoing values. In some embodiments, such values refer to numbers of recombinant receptor-expressing cells; in other embodiments, they refer to number of T cells or PBMCs or total cells administered.

[0313] In some embodiments, the subject receives multiple doses, e.g., two or more doses or multiple consecutive doses, of the cells. In some embodiments, two doses are administered to a subject. In some embodiments, the subject receives the consecutive dose, e.g., second dose, is administered approximately 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 days after the first dose. In some embodiments, multiple consecutive doses are administered following the first dose, such that an additional dose or doses are administered following administration of the consecutive dose. In some aspects, the number of cells administered to the subject in the additional dose is the same as or similar to the first dose and / or consecutive dose. In some embodiments, the additional dose or doses are larger than prior doses. In some embodiments, one or more subsequent dose of cells can be administered to the subject. In some embodiments, the subsequent dose of cells is administered greater than or greater than about 7 days, 14 days, 21 days, 28 days, or 35 days after initiation of administration of the first dose of cells. The subsequent dose of cells can be more than, approximately the same as, or less than the first dose. In some embodiments, administration of the T cell therapy, such as administration of the first and / or second dose of cells, can be repeated.

[0314] In some embodiments, initiation of administration of the cell therapy, e.g. the dose of cells or a first dose of a split dose of cells, is administered before (prior to), concurrently with or after (subsequently or subsequent to) the administration of the inhibitor of DGKα and / or DGKζ. In some embodiments, initiation of administration of the cell therapy relative to initiation of administration of the inhibitor of DGKα and / or DGKζ is as described in any of the embodiments described in Section I-B-2.

[0315] In some embodiments, the method involves, subsequent to administering the dose of cells of the T cell therapy, e.g., adoptive T cell therapy, but prior to administering the DGKinhibitor, assessing a sample from the subject for one or more function of T cells, such as expansion or persistence of the cells, e.g. as determined by level or amount in the blood, or other phenotypes or desired outcomes as described herein, e.g., such as those described in Section III. In some embodiments, the method involves, subsequent to administering the dose of cells of the T cell therapy, e.g., adoptive T cell therapy, but prior to administering the DGK inhibitor, assessing a sample from the subject for expression of one or more exhaustion markers. Various parameters for determining or assessing the regimen of the combination therapy are described in Section III. ADMINISTRATION OF DGKa AND / OR DGKz INHIBITORS

[0316] In some aspects, the methods provided herein include a combination thereapy by administering a DGK inhibitor in combination with a cell therapy, e.g., T cell therapy, to a subject having a disease or condition, such as any disease or condition as described above. The DGKi may be administered prior to, concurrently with, or subsequent to administration of a cell therapy, e.g. T cell therapy. In some aspects, the methods provided herein include administering a cell therapy, e.g., a T cell therapy, to a subject having a disease or condition, wherein the subject has previously been administered a DGK inhibitor. In some embodiments, the DGK inhibitor and cell therapy, e.g., T cell therapy, are administered to the subject concurrently.

[0317] In some embodiments, the inhibitor of DGK is an inhibitor of DGKa and / or DGKz. In certain embodiments, an inhibitor of DGKa and / or DGKz is an inhibitor of DGKa. In certain embodiments, an inhibitor of DGKa and / or DGKz is an inhibitor of DGKz. In certain embodiments, an inhibitor of DGKa and / or DGKz inhibits both enzymes. The level of enzyme inhibition may be measured as further described herein. In certain embodiments, an inhibitor of DGKa and / or DGKz is not a significant inhibitor of other DGK enzymes.

[0318] In certain embodiments, an inhibitor of DGKα and / or DGKζ increases an immune response, such as by increasing T cell activity. For example, an inhibitor of DGKα and / or DGKζ may increase primary T cell signaling, as evidenced, e.g., by an increase in pERK / pPKC signaling, which may be measured as further described herein. In certain embodiments, an inhibitor of DGKα and / or DGKζ has one or more of the following properties: (i) it lowers the threshold for antigen stimulation; (ii) increases CTL effector function; and (iii) enhances tumor cell killing. When an inhibitor of DGKα and / or DGKζ enhances tumor cell killing, this activity may be dependent on CD8+ T cells, as shown, e.g., in the CT26 animal model. When aninhibitor of DGKα and / or DGKζ enhances tumor cell killing, this activity may be dependent on NK cells, as shown, e.g., in the CT26 animal model. When an inhibitor of DGKα and / or DGKζ enhances tumor cell killing, this activity may be dependent on CD8+ T cells and NK cells, as shown, e.g., in the CT26 animal model. When an inhibitor of DGKα and / or DGKζ enhances tumor cell killing, this activity may be enhanced by CD4 cell depletion, e.g., in the CT-26 animal model. In certain embodiments, an inhibitor of DGKα and / or DGKζ enhances AH1+ Tetramer antigen presentation in the CT-26 animal model. An inhibitor of DGKα and / or DGKζ preferably includes one or more of the above cited properties, and may include all of them. 1. EXEMPLARY INHIBITORS OF DGKa AND / OR DGKz ENZYME ACTIVITY

[0319] Exemplary compounds, such as compounds of Formula I described herein and pharmaceutically acceptable salts thereof, are described in WO 2020 / 006018 and WO 2020 / 006016, the contents of both of which are specifically incorporated by reference herein. Exemplary compounds, such as compounds of Formula II described herein and pharmaceutically acceptable salts thereof, are described in PCT / US2020 / 048070, the contents of which are specifically incorporated by reference herein.

[0320] In some embodiments, the provided combination therapy of a T cell therapy and a DGK inhibitor involves administration or use of an inhibitor of DGKα and / or DGKζ that is a compound of Formula (I):

[0321]

[0322] or a pharmaceutically acceptable salt thereof, wherein:

[0323] R1is H, F, Cl, Br, -CN, C1-3alkyl substituted with zero to 4 R1a, C3-4cycloalkyl substituted with zero to 4 R1a, C1-3alkoxy substituted with zero to 4 R1a, -NRaRa, -S(O)nRe, or -P(O)ReRe;

[0324] each R1ais independently F, Cl, -CN, -OH, -OCH3, or -NRaRa;

[0325] each Rais independently H or C1-3alkyl;

[0326] each Reis independently C3-4cycloalkyl or C1-3alkyl substituted with zero to 4 R1a;

[0327] R2is H, C1-3alkyl substituted with zero to 4 R2a, or C3-4cycloalkyl substituted with zero to 4 R2a;

[0328] each R2ais independently F, Cl, -CN, -OH, -O(C1-2alkyl), C3-4cycloalkyl, C3-4alkenyl, or C3-4alkynyl;

[0329] R3is H, F, Cl, Br, -CN, C1-3alkyl, C1-2fluoroalkyl, C3-4cycloalkyl, C3-4fluorocycloalkyl, or -NO2;

[0330] R4is -CH2R4a, -CH2CH2R4a, -CH2CHR4aR4d, -CHR4aR4b, or -CR4aR4bR4c;

[0331] R4aand R4bare independently:

[0332] (i) C1-6alkyl substituted with zero to 4 substituents independently selected from F, Cl, -CN, -OH, -OCH3, -SCH3, C1-3fluoroalkoxy, -NRaRa, -S(O)2Re, or -NRaS(O)2Re;

[0333] (ii) C3-6cycloalkyl, heterocyclyl, phenyl, or heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, C1-4hydroxyalkyl, -(CH2)1-2O(C1-3alkyl), C1-4alkoxy, -O(C1-4hydroxyalkyl), -O(CH)1-3O(C1-3alkyl), C1-3fluoroalkoxy, -O(CH)1-3NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), -P(O)(C1-3alkyl)2, -S(O)2(C1-3alkyl), -O(CH2)1-2(C3-6cycloalkyl), -O(CH2)1-2(morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and Rd; or

[0334] (iii) C1-4alkyl substituted with one cyclic group selected from C3-6cycloalkyl, heterocyclyl, aryl, and heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-6cycloalkyl;

[0335] or R4aand R4btogether with the carbon atom to which they are attached form a C3-6cycloalkyl or a 3- to 6-membered heterocyclyl, each substituted with zero to 3 Rf;

[0336] each Rfis independently F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, or a cyclic group selected from C3-6cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, andbicyclic heteroaryl, each cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, and -NRcRc;

[0337] R4cis C1-6alkyl or C3-6cycloalkyl, each substituted with zero to 4 substituents independently selected from F, Cl, -OH, C1-2alkoxy, C1-2fluoroalkoxy, and -CN;

[0338] R4dis -OCH3;

[0339] each Rcis independently H or C1-2alkyl;

[0340] Rdis phenyl substituted with zero to 1 substituent selected from F, Cl, -CN, -CH3, and -OCH3;

[0341] each R5is independently -CN, C1-6alkyl substituted with zero to 4 Rg, C2-4alkenyl substituted with zero to 4 Rg, C2-4alkynyl substituted with zero to 4 Rg, C3-4cycloalkyl substituted with zero to 4 Rg, phenyl substituted with zero to 4 Rg, oxadiazolyl substituted with zero to 3 Rg, pyridinyl substituted with zero to 4 Rg, -(CH2)1-2(heterocyclyl substituted with zero to 4 Rg), -(CH2)1-2NRcC(O)(C1-4alkyl), -(CH2)1-2NRcC(O)O(C1-4alkyl), -(CH2)1-2NRcS(O)2(C1-4alkyl), -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -C(O)O(C3-4cycloalkyl), -C(O)NRaRa, or -C(O)NRa(C3-4cycloalkyl);

[0342] each Rgis independently F, Cl, -CN, -OH, C1-3alkoxy, C1-3fluoroalkoxy, -O(CH2)1-2O(C1-2alkyl), or -NRcRc;

[0343] m is zero, 1, 2, or 3; and

[0344] n is zero, 1, or 2.

[0345] In some embodiments, the provided combination therapy of a T cell therapy and a DGK inhibitor involves administration or use of an inhibitor of DGKα and / or DGKζ that is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0346] R1is H, F, Cl, Br, -CN, C1-3alkyl substituted with zero to 4 R1a, cyclopropyl substituted with zero to 3 R1a, C1-3alkoxy substituted with zero to 3 R1a, -NRaRa, -S(O)nCH3, or -P(O)(CH3)2;

[0347] each R1ais independently F, Cl, or -CN;

[0348] each Rais independently H or C1-3alkyl;

[0349] R2is H or C1-2alkyl substituted with zero to 2 R2a;

[0350] each R2ais independently F, Cl, -CN, -OH, -O(C1-2alkyl), cyclopropyl, C3-4alkenyl, or C3-4alkynyl;

[0351] R3is H, F, Cl, Br, -CN, C1-2alkyl, -CF3, cyclopropyl, or -NO2;

[0352] R4aand R4bare independently:

[0353] (i) C1-4alkyl substituted with zero to 4 substituents independently selected from F, Cl, -CN, -OH, -OCH3, -SCH3, C1-3fluoroalkoxy, and -NRaRa;

[0354] (ii) C3-6cycloalkyl, heterocyclyl, phenyl, or heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, -CH2OH, -(CH2)1-2O(C1-2alkyl), C1-4alkoxy, -O(C1-4hydroxyalkyl), -O(CH)1-2O(C1-2alkyl), C1-3fluoroalkoxy, -O(CH)1-2NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), -P(O)(C1-2alkyl)2, -S(O)2(C1-3alkyl), -O(CH2)1-2(C3-4cycloalkyl), -O(CH2)1-2(morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and Rd; or

[0355] (iii) C1-3alkyl substituted with one cyclic group selected from C3-6cycloalkyl, heterocyclyl, phenyl, and heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-3alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-4cycloalkyl;

[0356] or R4aand R4btogether with the carbon atom to which they are attached, form a C3-6cycloalkyl or a 3- to 6-membered heterocyclyl, each substituted with zero to 3 Rf;

[0357] each Rfis independently F, Cl, Br, -OH, -CN, C1-4alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, or a cyclic group selected from C3-6cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-4alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, and -NRcRc;

[0358] R4cis C1-4alkyl or C3-6cycloalkyl, each substituted with zero to 4 substituents independently selected from F, Cl, -OH, C1-2alkoxy, C1-2fluoroalkoxy, and -CN;

[0359] and each R5 is independently -CN, C1-5 alkyl substituted with zero to 4 Rg, C2-3alkenyl substituted with zero to 4 Rg, C2-3alkynyl substituted with zero to 4 Rg, C3-4cycloalkylsubstituted with zero to 4 Rg, phenyl substituted with zero to 3 Rg, oxadiazolyl substituted with zero to 3 Rg, pyridinyl substituted with zero to 3 Rg, -(CH2)1-2(heterocyclyl substituted with zero to 4 Rg), -(CH2)1-2NRcC(O)(C1-4alkyl), -(CH2)1-2NRcC(O)O(C1-4alkyl), -(CH2)1-2NRcS(O)2(C1-4alkyl), -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -C(O)O(C3-4cycloalkyl), -C(O)NRaRa, or -C(O)NRa(C3-4cycloalkyl).

[0360] In some embodiments, the provided combination therapy of a T cell therapy and a DGK inhibitor involves administration or use of an inhibitor of DGKα and / or DGKζ that is a compound of Formula (I) or a pharmaceutically acceptable salt thereof having the structure:wherein: R1is -CN; R2is -CH3; R3is H, F, or -CN; R4is:or

[0361] In some embodiments, the provided combination therapy of a T cell therapy and a DGK inhibitor involves administration or use of an inhibitor of DGKα and / or DGKζ that is a compound of Formula (I) or a pharmaceutically acceptable salt thereof having one the following structure or formula (or an isomer thereof): Methyl 1-(bis(4-fluorophenyl)methyl)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5- naphthyridin-4-yl)piperazine-2-carboxylate4-((2R,5S)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-6-bromo-1-methyl-2- oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile(R)-8-(4-(bis(4-fluorophenyl)methyl)-3-methylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydro- 1,5-naphthyridine-2,7-dicarbonitrile8-[(2S,5R)-4-[(4-chlorophenyl)(5-methylpyridin-2-yl)methyl]-2,5-dimethylpiperazin-1-yl]-5- methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile4-[(2S,5R)-4-[(4-chlorophenyl)(4-fluorophenyl)methyl]-2,5-dimethylpiperazin-1-yl]-6- methoxy-1-methyl-1,2-dihydro-1,5-naphthyridin-2-one8-[(2S,5R)-4-{[2-(difluoromethyl)-4-fluorophenyl]methyl}-2,5-dimethylpiperazin-1-yl]-5- methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile8-[(2S,5R)-4-[(4-fluorophenyl)(4-methylphenyl)methyl]-2,5-dimethylpiperazin-1-yl]-5- methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile8-[(2S,5R)-4-[1-(2,6-difluorophenyl)ethyl]-2,5-dimethylpiperazin-1-yl]-5-methyl-6-oxo-5,6- dihydro-1,5-naphthyridine-2-carbonitrile8-((3R)-4-((4-chlorophenyl)(5-fluoropyridin-2-yl)methyl)-3-methylpiperazin-1-yl)-5-methyl- 6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile8-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5- naphthyridine-2-carbonitrile8-[(2S,5R)-4-[bis(4-methylphenyl)methyl]-2,5-dimethylpiperazin-1-yl]-5-methyl-6-oxo-5,6- dihydro-1,5-naphthyridine-2-carbonitrile .

[0362] In some embodiments, the provided combination therapy of a T cell therapy and a DGK inhibitor involves administration or use of an inhibitor of DGKα and / or DGKζ that is a compound of Formula (II):I)

[0363] or a salt thereof, wherein:

[0364] R1is H, F, Cl, Br, -CN, -OH, C1-3alkyl substituted with zero to 4 R1a, C3-4cycloalkyl substituted with zero to 4 R1a, C1-3alkoxy substituted with zero to 4 R1a, -NRaRa, -S(O)nRe, or -P(O)ReRe;

[0365] each R1ais independently F, Cl, -CN, -OH, -OCH3, or -NRaRa;

[0366] each Rais independently H or C1-3alkyl;

[0367] each Re is independently C3-4cycloalkyl or C1-3alkyl substituted with zero to 4 R1a;

[0368] R2is H, C1-3alkyl substituted with zero to 4 R2a, or C3-4cycloalkyl substituted with zero to 4 R2a;

[0369] each R2ais independently F, Cl, -CN, -OH, -O(C1-2alkyl), C3-4cycloalkyl, C3-4alkenyl, or C3-4alkynyl;

[0370] R4is -CH2R4a, -CH2CH2R4a, -CH2CHR4aR4d, -CHR4aR4b, or -CR4aR4bR4c;

[0371] R4aand R4bare independently:

[0372] (i) -CN or C1-6alkyl substituted with zero to 4 substituents independently selected from F, Cl, -CN, -OH, -OCH3, -SCH3, C1-3fluoroalkoxy, -NRaRa, -S(O)2Re, or -NRaS(O)2Re;

[0373] (ii) C3-8carbocyclyl, 4- to 10-membered heterocyclyl, phenyl, or 5-to 10-membered heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, C1-2bromoalkyl, C1-2cyanoalkyl, C1-4hydroxyalkyl, -(CH2)1-2O(C1-3alkyl), C1-4alkoxy, C1-3fluoroalkoxy, C1-3cyanoalkoxy, -O(C1-4hydroxyalkyl), -O(CRxRx)1-3O(C1-3alkyl), C1-3fluoroalkoxy, -O(CH2)1-3NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -CH2NRaRa, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -(CRxRx)0-2NRaC(O)O(C1-4alkyl), -P(O)(C1-3alkyl)2, -S(O)2(C1-3alkyl), -(CRxRx)1-2(C3-4cycloalkyl), -(CRxRx)1-2(morpholinyl), -(CRxRx)1-2(difluoromorpholinyl),-(CRxRx)1-2(dimethylmorpholinyl), -(CRxRx)1-2(oxaazabicyclo[2.2.1]heptanyl), (CRxRx)1-2(oxaazaspiro[3.3]heptanyl), -(CRxRx)1-2(methylpiperazinonyl), -(CRxRx)1-2(acetylpiperazinyl), -(CRxRx)1-2(piperidinyl), -(CRxRx)1-2(difluoropiperidinyl), -(CRxRx)1-2(methoxypiperidinyl), -(CRxRx)1-2(hydroxypiperidinyl), -O(CRxRx)0-2(C3-6cycloalkyl), -O(CRxRx)0-2(methylcyclopropyl), -O(CRxRx)0-2((ethoxycarbonyl)cyclopropyl), -O(CRxRx)0-2(oxetanyl), -O(CRxRx)0-2(methylazetidinyl), -O(CRxRx)0-2(tetrahydropyranyl), -O(CRxRx)1-2(morpholinyl), -O(CRxRx)0-2(thiazolyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, dioxolanyl, pyrrolidinonyl, and Rd; or

[0374] (iii) C1-4alkyl substituted with one cyclic group selected from C3-6cycloalkyl, 4- to 10-membered heterocyclyl, mono- or bicyclic aryl, or 5-to 10-membered heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-6cycloalkyl;

[0375] or R4aand R4btogether with the carbon atom to which they are attached form a C3-6cycloalkyl or a 3- to 6-membered heterocyclyl, each substituted with zero to 3 Rf;

[0376] each Rfis independently F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, or a cyclic group selected from C3-6cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, and -NRcRc;

[0377] R4cis C1-6alkyl or C3-6cycloalkyl, each substituted with zero to 4 substituents independently selected from F, Cl, -OH, C1-2alkoxy, C1-2fluoroalkoxy, and -CN;

[0378] R4d is -OCH3;

[0379] each Rcis independently H or C1-2alkyl;

[0380] Rdis phenyl substituted with zero to 1 substituent selected from F, Cl, -CN, -CH3, and -OCH3;

[0381] each R5 is independently -CN, C1-6alkyl substituted with zero to 4 Rg, C2-4alkenyl substituted with zero to 4 Rg, C2-4alkynyl substituted with zero to 4 Rg, C3-4cycloalkyl substituted with zero to 4 Rg, phenyl substituted with zero to 4 Rg, oxadiazolyl substituted with zero to 3 Rg, pyridinyl substituted with zero to 4 Rg, -(CH2)1-2(4- to 10-membered heterocyclyl substituted with zero to 4 Rg), -(CH2)1-2NRcC(O)(C1-4alkyl), -(CH2)1-2NRcC(O)O(C1-4alkyl), -(CH2)1-2NRcS(O)2(C1-4alkyl), -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -C(O)O(C3-4cycloalkyl), -C(O)NRaRa, or -C(O)NRa(C3-4cycloalkyl);

[0382] each Rgis independently F, Cl, -CN, -OH, C1-3alkoxy, C1-3fluoroalkoxy, -O(CH2)1-2O(C1-2alkyl), or -NRcRc;

[0383] m is zero, 1, 2, or 3; and

[0384] n is zero, 1, or 2.

[0385] In some embodiments, the provided combination therapy of a T cell therapy and a DGK inhibitor involves administration or use of an inhibitor of DGKα and / or DGKζ that is a compound of Formula (II):

[0386] or a salt thereof, wherein:

[0387] R1is H, F, Cl, Br, -CN, C1-3alkyl substituted with zero to 4 R1a, C3-4cycloalkyl substituted with zero to 4 R1a, C1-3alkoxy substituted with zero to 4 R1a, -NRaRa, -S(O)nRe, or -P(O)ReRe;

[0388] each R1ais independently F, Cl, -CN, -OH, -OCH3, or -NRaRa;

[0389] each Rais independently H or C1-3alkyl;

[0390] each Reis independently C3-4cycloalkyl or C1-3alkyl substituted with zero to 4 R1a;

[0391] R2is H, C1-3alkyl substituted with zero to 4 R2a, or C3-4cycloalkyl substituted with zero to 4 R2a;

[0392] each R2ais independently F, Cl, -CN, -OH, -O(C1-2alkyl), C3-4cycloalkyl, C3-4alkenyl, or C3-4alkynyl;

[0393] R4is -CH2R4a, -CH2CH2R4a, -CH2CHR4aR4d, -CHR4aR4b, or -CR4aR4bR4c;

[0394] R4aand R4bare independently:

[0395] (i) C1-6alkyl substituted with zero to 4 substituents independently selected from F, Cl, -CN, -OH, -OCH3, -SCH3, C1-3fluoroalkoxy, -NRaRa, -S(O)2Re, or -NRaS(O)2Re;

[0396] (ii) C3-6cycloalkyl, heterocyclyl, phenyl, or heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, C1-4hydroxyalkyl, -(CH2)1-2O(C1-3alkyl), C1-4alkoxy, -O(C1-4hydroxyalkyl), -O(CH2)1-3O(C1-3alkyl), C1-3fluoroalkoxy, -O(CH2)1-3NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), -P(O)(C1-3alkyl)2, -S(O)2(C1-3alkyl), -O(CH2)1-2(C3-6cycloalkyl), -O(CH2)1-2(morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and Rd; or

[0397] (iii) C1-4alkyl substituted with one cyclic group selected from C3-6cycloalkyl, heterocyclyl, aryl, and heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-6cycloalkyl;

[0398] or R4aand R4btogether with the carbon atom to which they are attached form a C3-6cycloalkyl or a 3- to 6-membered heterocyclyl, each substituted with zero to 3 Rf;

[0399] each Rfis independently F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, or a cyclic group selected from C3-6cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, and -NRcRc;

[0400] R4cis C1-6alkyl or C3-6cycloalkyl, each substituted with zero to 4 substituents independently selected from F, Cl, -OH, C1-2alkoxy, C1-2fluoroalkoxy, and -CN;

[0401] R4d is -OCH3;

[0402] each Rcis independently H or C1-2alkyl;

[0403] Rdis phenyl substituted with zero to 1 substituent selected from F, Cl, -CN, -CH3, and -OCH3;

[0404] each R5 is independently -CN, C1-6alkyl substituted with zero to 4 Rg, C2-4alkenyl substituted with zero to 4 Rg, C2-4alkynyl substituted with zero to 4 Rg, C3-4cycloalkyl substituted with zero to 4 Rg, phenyl substituted with zero to 4 Rg, oxadiazolyl substituted with zero to 3 Rg, pyridinyl substituted with zero to 4 Rg, -(CH2)1-2(4- to 10-membered heterocyclyl substituted with zero to 4 Rg), -(CH2)1-2NRcC(O)(C1-4alkyl), -(CH2)1-2NRcC(O)O(C1-4alkyl), -(CH2)1-2NRcS(O)2(C1-4alkyl), -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -C(O)O(C3-4cycloalkyl), -C(O)NRaRa, or -C(O)NRa(C3-4cycloalkyl);

[0405] each Rgis independently F, Cl, -CN, -OH, C1-3alkoxy, C1-3fluoroalkoxy, -O(CH2)1-2O(C1-2alkyl), or -NRcRc;

[0406] m is zero, 1, 2, or 3; and

[0407] n is zero, 1, or 2.

[0408] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein: R1is H, F, Cl, Br, -CN, -OH, C1-3alkyl substituted with zero to 4 R1a, cyclopropyl substituted with zero to 3 R1a, C1-3alkoxy substituted with zero to 3 R1a, -NRaRa, -S(O)nCH3, or -P(O)(CH3)2; R2is H or C1-2alkyl substituted with zero to 2 R2a; each R2ais independently F, Cl, -CN, -OH, -O(C1-2alkyl), cyclopropyl, C3-4alkenyl, or C3-4alkynyl; R4aand R4bare independently: (i) -CN or C1-4alkyl substituted with zero to 4 substituents independently selected from F, Cl, -CN, -OH, -OCH3, -SCH3, C1-3fluoroalkoxy, and -NRaRa; (ii) C3-6carbocyclyl, 4- to 10-membered heterocyclyl, phenyl, or 5-to 10-membered heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, C1-2bromoalkyl, C1-2cyanoalkyl, C1-2hydroxyalkyl, -CH2NRaRa, -(CH2)1-2O(C1-2alkyl), -(CH2)1-2NRxC(O)O(C1-2alkyl), C1-4alkoxy, -O(C1-4hydroxyalkyl), -O(CRxRx)1-2O(C1-2alkyl), C1-3fluoroalkoxy, C1-3cyanoalkoxy, -O(CH2)1-2NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), -P(O)(C1-2alkyl)2, -S(O)2(C1-3alkyl), -(CH2)1-2(C3-4cycloalkyl), -CRxRx(morpholinyl), -CRxRx(difluoromorpholinyl), -CRxRx(dimethylmorpholinyl), -CRxRx(oxaazabicyclo[2.2.1]heptanyl), -CRxRx(oxaazaspiro[3.3]heptanyl),-CRxRx(methylpiperazinonyl), -CRxRx(acetylpiperazinyl), -CRxRx(piperidinyl), -CRxRx(difluoropiperidinyl), -CRxRx(methoxypiperidinyl), -CRxRx(hydroxypiperidinyl), -O(CH2)0-2(C3-4cycloalkyl), -O(CH2)0-2(methylcyclopropyl), -O(CH2)0-2((ethoxycarbonyl)cyclopropyl), -O(CH2)0-2(oxetanyl), -O(CH2)0-2(methylazetidinyl), -O(CH2)1-2(morpholinyl), -O(CH2)0-2(tetrahydropyranyl), -O(CH2)0-2(thiazolyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert- butoxycarbonyl)azetidinyl, dioxolanyl, pyrrolidinonyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and Rd; or (iii) C1-3alkyl substituted with one cyclic group selected from C3-6cycloalkyl, 4- to 10-membered heterocyclyl, phenyl, and heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-3alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-4cycloalkyl; or R4aand R4btogether with the carbon atom to which they are attached, form a C3-6cycloalkyl or a 3- to 6-membered heterocyclyl, each substituted with zero to 3 Rf; each Rfis independently F, Cl, Br, -OH, -CN, C1-4alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, or a cyclic group selected from C3-6cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-4alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, and -NRcRc; R4cis C1-4alkyl or C3-6cycloalkyl, each substituted with zero to 4 substituents independently selected from F, Cl, -OH, C1-2alkoxy, C1-2fluoroalkoxy, and -CN; each R5is independently -CN, C1-5 alkyl substituted with zero to 4 Rg, C2-3alkenyl substituted with zero to 4 Rg, C2-3alkynyl substituted with zero to 4 Rg, C3-4cycloalkyl substituted with zero to 4 Rg, phenyl substituted with zero to 3 Rg, oxadiazolyl substituted with zero to 3 Rg, pyridinyl substituted with zero to 3 Rg, -(CH2)1-2(4- to 10-membered heterocyclyl substituted with zero to 4 Rg), -(CH2)1-2NRcC(O)(C1-4alkyl), -(CH2)1-2NRcC(O)O(C1-4alkyl), -(CH2)1-2NRcS(O)2(C1-4alkyl), -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -C(O)O(C3-4cycloalkyl), -C(O)NRaRa, or -C(O)NRa(C3-4cycloalkyl);

[0409] each Rxis independently H or -CH3; and m is 1, 2, or 3.

[0410] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein: R1is H, F, Cl, Br, -CN, C1-3alkyl substituted with zero to 4 R1a, cyclopropyl substituted with zero to 3 R1a, C1-3alkoxy substituted with zero to 3 R1a, -NRaRa, -S(O)nCH3, or -P(O)(CH3)2; each R1ais independently F, Cl, or -CN; each Rais independently H or C1-3alkyl; R2is H or C1-2alkyl substituted with zero to 2 R2a; each R2ais independently F, Cl, -CN, -OH, -O(C1-2alkyl), cyclopropyl, C3-4alkenyl, or C3-4alkynyl; R4aand R4bare independently: (i) C1-4alkyl substituted with zero to 4 substituents independently selected from F, Cl, -CN, -OH, -OCH3, -SCH3, C1-3fluoroalkoxy, and -NRaRa; (ii) C3-6cycloalkyl, 4- to 10-membered heterocyclyl, phenyl, or 5-to 10-membered heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, -CH2OH, -(CH2)1-2O(C1-2alkyl), C1-4alkoxy, -O(C1-4hydroxyalkyl), -O(CH2)1-2O(C1-2alkyl), C1-3fluoroalkoxy, -O(CH2)1-2NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), -P(O)(C1-2alkyl)2, -S(O)2(C1-3alkyl), -O(CH2)1-2(C3-4cycloalkyl), -O(CH2)1-2(morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and Rd; or (iii) C1-3alkyl substituted with one cyclic group selected from C3-6cycloalkyl, heterocyclyl, phenyl, and heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-3alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-4cycloalkyl; or R4aand R4btogether with the carbon atom to which they are attached, form a C3-6cycloalkyl or a 3- to 6-membered heterocyclyl, each substituted with zero to 3 Rf; each Rfis independently F, Cl, Br, -OH, -CN, =O, C1-4alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, or a cyclic group selected from C3-6cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-4alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, and -NRcRc; R4cis C1-4alkyl or C3-6cycloalkyl, each substituted with zero to 4 substituents independently selected from F, Cl, -OH, C1-2alkoxy, C1-2fluoroalkoxy, and -CN; each R5is independently -CN, C1-5alkyl substitutedwith zero to 4 Rg, C2-3alkenyl substituted with zero to 4 Rg, C2-3alkynyl substituted with zero to 4 Rg, C3-4cycloalkyl substituted with zero to 4 Rg, phenyl substituted with zero to 3 Rg, oxadiazolyl substituted with zero to 3 Rg, pyridinyl substituted with zero to 3 Rg, -(CH2)1-2(heterocyclyl substituted with zero to 4 Rg), -(CH2)1-2NRcC(O)(C1-4alkyl), -(CH2)1-2NRcC(O)O(C1-4alkyl), -C(O)(C1-4alkyl), -(CH2)1-2NRcS(O)2(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -C(O)O(C3-4cycloalkyl), -C(O)NRaRa, or -C(O)NRa(C3-4cycloalkyl); and m is 1, 2, or 3.

[0411] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein: R1is Cl or -CN; R2is -CH3; R4is -CH2R4aor -CHR4aR4b; R4ais cyclopropyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, phenyl, pyridinyl, pyrimidinyl, oxadiazolyl, benzo[d][1,3]dioxolyl, or oxodihydrobenzo[d]oxazolyl, each substituted with zero to 3 substituents independently selected from F, Cl, -CN, -CH3, -CH(CH3)2, -CF3, -OCH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2(cyclopropyl), and cyclopropyl; R4bis: (i) -CH3and -CH2CH3; or (ii) phenyl, isoxazolyl, oxadiazolyl, or thiazolyl, each substituted with zero to 3substituents independently selected from F, Cl, -CH3, -C(CH3)3, -CF3, -OCF3, andcyclopropyl; each R5 is independently -CH3, -CH2CH3, -CH2OH, or -CH2OCH3; and m is 2.

[0412] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein: R1is Cl, -CN, -OH, -CHF2, -CH2OH, -CH2OCH3, -OCH3, -OCH2CH3, -OCHF2, -OCH2CH2OCH3, or -OCH2CH2N(CH3)2; R2is H, -CH3, or -CD3; R4is -CH2R4aor -CHR4aR4b; R4ais cyclohexyl, phenyl, pyridinyl, pyrimidinyl, oxadiazolyl, benzo[d][1,3]dioxolyl, or oxodihydrobenzo[d]oxazolyl, each substituted with zero to 3 substituents independently selected from F, Cl, Br, -CN, -CH3, -CH(CH3)2, -C(CH3)3, -CH2OH, -CHF2,-CF3, -CH2Br, -CH2NH2, -CH2NHC(O)OCH3, -C(CH3)2CN, -OCH3, -OCD3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2CH2CF3, -OC(CH3)2CN, -OC(CH3)2CH2OH, -OC(CH3)2CH2OCH3, -N(CH3)2, -C(O)OCH3, cyclopropyl, cyanocyclopropyl, methylcyclopropyl, -O(cyclopropyl), -O((ethoxycarbonyl)cyclopropyl), morpholinyl, pyrrolidinonyl, tetrahydropyranyl, dioxolanyl, -CH2(morpholinyl), -CH2(difluoromorpholinyl), -CH2(dimethylmorpholinyl), -CH2(oxaazabicyclo[2.2.1]heptanyl), -CH2(oxaazaspiro[3.3]heptanyl), -CH2(methylpiperazinonyl), -CH2(acetylpiperazinyl), -CH2(piperidinyl), -CH2(difluoropiperidinyl), -CH2(methoxypiperidinyl),-OCH2(methylcyclopropyl), -OCH2(methylazetidinyl), -OCH2(oxetanyl), -OCH2(tetrahydropyranyl), -OCH2(thiazolyl), or -OCH2CH2(cyclopropyl); R4bis: (i) -CN, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2; or (ii) phenyl, isoxazolyl, oxadiazolyl, thiazolyl, or triazolyl, each substituted with zero to 3 substituents independently selected from F, Cl, Br, -CH3, -C(CH3)3, -CF3, -OCF3, and cyclopropyl; each R5 is independently -CH3, -CH2CH3, -CH2CH2CH3, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CH2NH2, -CH2N3, or -CH2NHC(O)OCH3; and m is 2.

[0413] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R1is H, F, Cl, Br, -CN, -OH, C1-3alkyl substituted with zero to 4 R1a, cyclopropyl substituted with zero to 3 R1a, C1-3alkoxy substituted with zero to 3 R1a, -NRaRa, -S(O)nCH3, or -P(O)(CH3)2. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R1is Cl, -CN, -OH, -CHF2, -CH2OH, -CH2OCH3, -OCH3, -OCH2CH3, -OCHF2, -OCH2CH2OCH3, or -OCH2CH2N(CH3)2.

[0414] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R1is H, F, Cl, Br, -CN, C1-3alkyl substituted with zero to 4 R1a, cyclopropyl substituted with zero to 3 R1a, C1-3alkoxy substituted with zero to 3 R1a, -NRaRa, -S(O)nCH3, or -P(O)(CH3)2. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R1is H, F, Cl, Br, -CN, -CH3, cyclopropyl, -OCH3, or -NH2. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R1is Cl or -CN. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R1is -CN.

[0415] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R2is H, C1-2alkyl substituted with zero to 4 R2a, or C3-4cycloalkyl substituted with zero to 2 R2a. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R2is H or C1-2alkyl substituted with zero to 2 R2a. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R2is H or -CH3. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R1 is -CH3. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R2is H, -CH3, or -CD3.

[0416] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R2is H.

[0417] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R2is -CH3.

[0418] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R2is -CD3.

[0419] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CH2R4aor -CH2CH2R4a. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R4is -CH2R4aor -CD2R4a. AIn some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R4ais phenyl, pyridinyl, tetrahydropyranyl, benzoxazinyl, benzo[d][1,3]dioxolyl, benzoxazinonyl, indazolyl, indolyl, or quinolinyl, each substituted with zero to 3 substituents independently selected from F, Cl, Br, -CN, -OH, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CHF2, -CF3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -C(O)CH3, -C(O)OC(CH3)3, -N(CH3)2, cyanocyclopropyl, and phenyl. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R4ais phenyl, pyridinyl, or benzo[d][1,3]dioxolyl, each substituted with zero to 3 substituents independently selected from F, Cl, -CN, -CH3, -CH(CH3)2, -CF3, -OCH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2(cyclopropyl), and cyclopropyl.

[0420] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CH2R4a. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R4ais phenyl, pyridinyl, tetrahydropyranyl, benzoxazinyl, benzo[d][1,3]dioxolyl, benzoxazinonyl, indazolyl, indolyl, or quinolinyl, each substituted with zero to 3 substituents independently selected from F, Cl, Br, -CN, -OH, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CHF2, -CF3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -C(O)CH3, -C(O)OC(CH3)3, -N(CH3)2, cyanocyclopropyl, and phenyl. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R4ais phenyl, pyridinyl, or benzo[d][1,3]dioxolyl, each substituted with zero to 3 substituents independently selected from F, Cl, -CN, -CH3, -CH(CH3)2, -CF3, -OCH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2(cyclopropyl), and cyclopropyl.

[0421] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CH2R4a; and R4ais C3-8carbocyclyl, 4- to 10-membered heterocyclyl, phenyl, or 5-to 10-membered heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, C1-2bromoalkyl, C1-2cyanoalkyl, C1-4hydroxyalkyl, -(CH2)1-2O(C1-3alkyl), C1-4alkoxy, C1-3fluoroalkoxy, C1-3cyanoalkoxy, -O(C1-4hydroxyalkyl), -O(CRxRx)1-3O(C1-3alkyl), C1-3fluoroalkoxy, -O(CH2)1-3NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -CH2NRaRa, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -(CRxRx)0-2NRaC(O)O(C1-4alkyl), -P(O)(C1-3alkyl)2, -S(O)2(C1-3alkyl), -(CRxRx)1-2(C3-4cycloalkyl), -(CRxRx)1-2(morpholinyl), -(CRxRx)1-2(difluoromorpholinyl), -(CRxRx)1-2(dimethylmorpholinyl), -(CRxRx)1-2(oxaazabicyclo[2.2.1]heptanyl), (CRxRx)1-2(oxaazaspiro[3.3]heptanyl), -(CRxRx)1-2(methylpiperazinonyl), -(CRxRx)1-2(acetylpiperazinyl), -(CRxRx)1-2(piperidinyl), -(CRxRx)1-2(difluoropiperidinyl), -(CRxRx)1-2(methoxypiperidinyl), -(CRxRx)1-2(hydroxypiperidinyl), -O(CRxRx)0-2(C3-6cycloalkyl), -O(CRxRx)0-2(methylcyclopropyl), -O(CRxRx)0-2((ethoxycarbonyl)cyclopropyl), -O(CRxRx)0-2(oxetanyl), -O(CRxRx)0-2(methylazetidinyl), -O(CRxRx)0-2(tetrahydropyranyl), -O(CRxRx)1-2(morpholinyl), -O(CRxRx)0-2(thiazolyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, dioxolanyl, pyrrolidinonyl, and Rd.

[0422] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CH2R4a; and R4ais C3-6cycloalkyl, 4- to 10-membered heterocyclyl, phenyl, or 5-to 10-membered heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, C1-2bromoalkyl, C1-2cyanoalkyl, C1-2hydroxyalkyl, -CH2NRaRa, -(CH2)1-2O(C1-2alkyl), -(CH2)1-2NRxC(O)O(C1-2alkyl), C1-4alkoxy, -O(C1-4hydroxyalkyl), -O(CRxRx)1-2O(C1-2alkyl), C1-3fluoroalkoxy, C1-3cyanoalkoxy, -O(CH2)1-2NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), -P(O)(C1-2alkyl)2, -S(O)2(C1-3alkyl), -(CH2)1-2(C3-4cycloalkyl), -CRxRx(morpholinyl), -CRxRx(difluoromorpholinyl), -CRxRx(dimethylmorpholinyl), -CRxRx(oxaazabicyclo[2.2.1]heptanyl), -CRxRx(oxaazaspiro[3.3]heptanyl), -CRxRx(methylpiperazinonyl), -CRxRx(acetylpiperazinyl), -CRxRx(piperidinyl), -CRxRx(difluoropiperidinyl), -CRxRx(methoxypiperidinyl), -CRxRx(hydroxypiperidinyl), -O(CH2)0-2(C3-4cycloalkyl), -O(CH2)0-2(methylcyclopropyl), -O(CH2)0-2((ethoxycarbonyl)cyclopropyl), -O(CH2)0-2(oxetanyl),-O(CH2)0-2(methylazetidinyl), -O(CH2)1-2(morpholinyl), -O(CH2)0-2(tetrahydropyranyl), -O(CH2)0-2(thiazolyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert- butoxycarbonyl)azetidinyl, dioxolanyl, pyrrolidinonyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and Rd. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R4ais cyclohexyl, phenyl, or benzo[d][1,3]dioxolyl, each substituted with 1 to 3 substituents independently selected from F, Cl, -CH(CH3)2, -CF3, -OCH2CH3, -OCF3, cyclopropyl, and -OCH2(cyclopropyl).

[0423] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CHR4aR4b; R4ais: (i) C3-6cycloalkyl, heterocyclyl, phenyl, or heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, C1-4hydroxyalkyl, -(CH2)1-2O(C1-3alkyl), C1-4alkoxy, -O(C1-4hydroxyalkyl), -O(CH2)1-3O(C1-3alkyl), C1-3fluoroalkoxy, -O(CH2)1-3NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), -P(O)(C1-3alkyl)2, -S(O)2(C1-3alkyl), -O(CH2)1-2(C3-6cycloalkyl), -O(CH2)1-2(morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and Rd; or (ii) C1-4alkyl substituted with one cyclic group selected from C3-6cycloalkyl, heterocyclyl, aryl, and heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-6cycloalkyl; and R4bis phenyl or heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, C1-4hydroxyalkyl, -(CH2)1-2O(C1-3alkyl), C1-4alkoxy, -O(C1-4hydroxyalkyl), -O(CH2)1-3O(C1-3alkyl), C1-3fluoroalkoxy, -O(CH2)1-3NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), -P(O)(C1-3alkyl)2, -S(O)2(C1-3alkyl), -O(CH2)1-2(C3-6cycloalkyl), -O(CH2)1-2(morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, and methylpiperidinyl. In some embodiments, a compound of Formula(II) or a salt thereof is administered wherein R4ais (i) C3-6cycloalkyl, heterocyclyl, phenyl, or heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, -CH2OH, -(CH2)1-2O(C1-2alkyl), C1-4alkoxy, -O(C1-4hydroxyalkyl), -O(CH2)1-2O(C1-2alkyl), C1-3fluoroalkoxy, -O(CH2)1-2NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), -P(O)(C1-2alkyl)2, -S(O)2(C1-3alkyl), -O(CH2)1-2(C3-4cycloalkyl), -O(CH2)1-2(morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and Rd; or (ii) C1-3alkyl substituted with one cyclic group selected from C3-6cycloalkyl, heterocyclyl, phenyl, and heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-3alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-4cycloalkyl; and R4bis phenyl, isoxazolyl, oxadiazolyl, or thiazolyl, each substituted with zero to 3 substituents independently selected from F, Cl, -CH3, -C(CH3)3, -CF3, -OCF3, and cyclopropyl. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R4ais phenyl, pyridinyl, or benzo[d][1,3]dioxolyl, each substituted with zero to 3 substituents independently selected from F, Cl, -CN, -CH3, -CH(CH3)2, -CF3, -OCH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2(cyclopropyl), and cyclopropyl; and R4bis phenyl, isoxazolyl, oxadiazolyl, or thiazolyl, each substituted with zero to 3 substituents independently selected from F, Cl, -CH3, -C(CH3)3, -CF3, -OCF3, and cyclopropyl.

[0424] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CHR4aR4b; R4ais: (i) C3-6carbocyclyl, 4- to 10-membered heterocyclyl, phenyl, or 5-to 10-membered heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, C1-2bromoalkyl, C1-2cyanoalkyl, C1-4hydroxyalkyl, -(CH2)1-2O(C1-3alkyl), C1-4alkoxy, C1-3fluoroalkoxy, C1-3cyanoalkoxy, -O(C1-4hydroxyalkyl), -O(CRxRx)1-3O(C1-3alkyl), C1-3fluoroalkoxy, -O(CH2)1-3NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -CH2NRaRa, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl),-(CRxRx)0-2NRaC(O)O(C1-4alkyl), -P(O)(C1-3alkyl)2, -S(O)2(C1-3alkyl), -(CRxRx)1-2(C3-4cycloalkyl), -(CRxRx)1-2(morpholinyl), -(CRxRx)1-2(difluoromorpholinyl), -(CRxRx)1-2(dimethylmorpholinyl), -(CRxRx)1-2(oxaazabicyclo[2.2.1]heptanyl), (CRxRx)1-2(oxaazaspiro[3.3]heptanyl), -(CRxRx)1-2(methylpiperazinonyl), -(CRxRx)1-2(acetylpiperazinyl), -(CRxRx)1-2(piperidinyl), -(CRxRx)1-2(difluoropiperidinyl), -(CRxRx)1-2(methoxypiperidinyl), -(CRxRx)1-2(hydroxypiperidinyl), -O(CRxRx)0-2(C3-6cycloalkyl), -O(CRxRx)0-2(methylcyclopropyl), -O(CRxRx)0-2((ethoxycarbonyl)cyclopropyl), -O(CRxRx)0-2(oxetanyl), -O(CRxRx)0-2(methylazetidinyl), -O(CRxRx)0-2(tetrahydropyranyl), -O(CRxRx)1-2(morpholinyl), -O(CRxRx)0-2(thiazolyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, dioxolanyl, pyrrolidinonyl, and Rd; or (ii) C1-4alkyl substituted with one cyclic group selected from C3-6carbocyclyl, 4- to 10-membered heterocyclyl, 6- to 10-membered aryl, or 5-to 10-membered heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-6cycloalkyl; and R4bis phenyl, isoxazolyl, oxadiazolyl, thiazolyl, or triazolyl, each substituted with zero to 3 substituents independently selected from F, Cl, Br, -CH3, -C(CH3)3, -CF3, -OCF3, and cyclopropyl.

[0425] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CHR4aR4b; R4ais (i) C3-6cycloalkyl, heterocyclyl, phenyl, or heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, C1-4hydroxyalkyl, -(CH2)1-2O(C1-3alkyl), C1-4alkoxy, -O(C1-4hydroxyalkyl), -O(CH2)1-3O(C1-3alkyl), C1-3fluoroalkoxy, -O(CH2)1-3NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), -P(O)(C1-3alkyl)2, -S(O)2(C1-3alkyl), -O(CH2)1-2(C3-6cycloalkyl), -O(CH2)1-2(morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and Rd; or (ii) C1-4alkyl substituted with one cyclic group selected from C3-6cycloalkyl, heterocyclyl, mono- or bicyclicaryl, and heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-6cycloalkyl; and R4bis C1-6alkyl substituted with zero to 4 substituents independently selected from F, Cl, -CN, -OH, -OCH3, -SCH3, C1-3fluoroalkoxy, -NRaRa, -S(O)2Re, or -NRaS(O)2Re. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R4ais C3-6cycloalkyl, heterocyclyl, phenyl, or heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, -CH2OH, -(CH2)1-2O(C1-2alkyl), C1-4alkoxy, -O(C1-4hydroxyalkyl), -O(CH2)1-2O(C1-2alkyl), C1-3fluoroalkoxy, -O(CH2)1-2NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), -P(O)(C1-2alkyl)2, -S(O)2(C1-3alkyl), -O(CH2)1-2(C3-4cycloalkyl), -O(CH2)1-2(morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and Rd; or (ii) C1-3alkyl substituted with one cyclic group selected from C3-6cycloalkyl, heterocyclyl, phenyl, and heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-3alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-4cycloalkyl; and R4bis C1-4alkyl substituted with zero to 4 substituents independently selected from F, Cl, -CN, -OH, -OCH3, -SCH3, C1-3fluoroalkoxy, and -NRaRa. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R4ais phenyl, pyridinyl, or benzo[d][1,3]dioxolyl, each substituted with zero to 3 substituents independently selected from F, Cl, -CN, -CH3, -CH(CH3)2, -CF3, -OCH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2(cyclopropyl), and cyclopropyl; and R4bis -CH3and -CH2CH3.

[0426] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CHR4aR4b; R4ais (i) C3-8carbocyclyl, 4- to 10-membered heterocyclyl, phenyl, or 5-to 10-membered heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, C1-2bromoalkyl, C1-2cyanoalkyl, C1-4hydroxyalkyl, -(CH2)1-2O(C1-3alkyl), C1-4alkoxy, C1-3fluoroalkoxy, C1-3cyanoalkoxy, -O(C1-4hydroxyalkyl), -O(CRxRx)1-3O(C1-3alkyl), C1-3fluoroalkoxy, -O(CH2)1-3NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -CH2NRaRa, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -(CRxRx)0-2NRaC(O)O(C1-4alkyl), -P(O)(C1-3alkyl)2, -S(O)2(C1-3alkyl), -(CRxRx)1-2(C3-4cycloalkyl), -(CRxRx)1-2(morpholinyl), -(CRxRx)1-2(difluoromorpholinyl), -(CRxRx)1-2(dimethylmorpholinyl), -(CRxRx)1-2(oxaazabicyclo[2.2.1]heptanyl), (CRxRx)1-2(oxaazaspiro[3.3]heptanyl), -(CRxRx)1-2(methylpiperazinonyl), -(CRxRx)1-2(acetylpiperazinyl), -(CRxRx)1-2(piperidinyl), -(CRxRx)1-2(difluoropiperidinyl), -(CRxRx)1-2(methoxypiperidinyl), -(CRxRx)1-2(hydroxypiperidinyl), -O(CRxRx)0-2(C3-6cycloalkyl), -O(CRxRx)0-2(methylcyclopropyl), -O(CRxRx)0-2((ethoxycarbonyl)cyclopropyl), -O(CRxRx)0-2(oxetanyl), -O(CRxRx)0-2(methylazetidinyl), -O(CRxRx)0-2(tetrahydropyranyl), -O(CRxRx)1-2(morpholinyl), -O(CRxRx)0-2(thiazolyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, dioxolanyl, pyrrolidinonyl, and Rd; or (ii) C1-4alkyl substituted with one cyclic group selected from C3-6cycloalkyl, 4- to 10-membered heterocyclyl, mono- or bicyclic aryl, or 5-to 10-membered heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-6cycloalkyl; and R4bis -CN or C1-6alkyl substituted with zero to 4 substituents independently selected from F, Cl, -CN, -OH, -OCH3, -SCH3, C1-3fluoroalkoxy, -NRaRa, -S(O)2Re, or -NRaS(O)2Re. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R4ais (i) C3-6carbocyclyl, 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, C1-2bromoalkyl, C1-2cyanoalkyl, C1-2hydroxyalkyl, -CH2NRaRa, -(CH2)1-2O(C1-2alkyl), -(CH2)1-2NRxC(O)O(C1-2alkyl), C1-4alkoxy, -O(C1-4hydroxyalkyl), -O(CRxRx)1-2O(C1-2alkyl), C1-3fluoroalkoxy, C1-3cyanoalkoxy, -O(CH2)1-2NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), -P(O)(C1-2alkyl)2, -S(O)2(C1-3alkyl), -(CH2)1-2(C3-4cycloalkyl), -CRxRx(morpholinyl), -CRxRx(difluoromorpholinyl), -CRxRx(dimethylmorpholinyl), -CRxRx(oxaazabicyclo[2.2.1]heptanyl), -CRxRx(oxaazaspiro[3.3]heptanyl), -CRxRx(methylpiperazinonyl), -CRxRx(acetylpiperazinyl), -CRxRx(piperidinyl), -CRxRx(difluoropiperidinyl), -CRxRx(methoxypiperidinyl), -CRxRx(hydroxypiperidinyl), -O(CH2)0-2(C3-4cycloalkyl), -O(CH2)0-2(methylcyclopropyl), -O(CH2)0-2((ethoxycarbonyl)cyclopropyl), -O(CH2)0-2(oxetanyl), -O(CH2)0-2(methylazetidinyl), -O(CH2)1-2(morpholinyl), -O(CH2)0-2(tetrahydropyranyl), -O(CH2)0-2(thiazolyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert- butoxycarbonyl)azetidinyl, dioxolanyl, pyrrolidinonyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and Rd; or (ii) C1-3alkyl substituted with one cyclic group selected from C3-6cycloalkyl, 4- to 10-membered heterocyclyl, mono- or bicyclic aryl, or 5-to 10-membered heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-3alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-4cycloalkyl; and R4bis -CN or C1-4alkyl substituted with zero to 4 substituents independently selected from F, Cl, -CN, -OH, -OCH3, -SCH3, C1-3fluoroalkoxy, and -NRaRa.

[0427] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CHR4aR4b; and R4bis -CN, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2.

[0428] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CHR4aR4b; and R4bis -CN, -CH3, or -CH2CH3.

[0429] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CHR4aR4b; and R4bis -CN.

[0430] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CHR4aR4b; and R4bis -CH3or -CH2CH3.

[0431] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CHR4aR4b; and R4bis -CH3.

[0432] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CHR4aR4b; and R4bis -CH2CH3.

[0433] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein m is 1, 2, or 3; and each R5is independently -CN, C1-5alkyl substituted with zero to 4 Rg, C2-3alkenyl substituted with zero to 4 Rg, C2-3alkynyl substituted with zero to 4 Rg, C3-4cycloalkyl substituted with zero to 4 Rg, phenyl substituted with zero to 3 Rg, oxadiazolyl substituted with zero to 3 Rg, pyridinyl substituted with zero to 3 Rg, -(CH2)1-2(4- to 10- membered heterocyclyl substituted with zero to 4 Rg), -(CH2)1-2NRcC(O)(C1-4alkyl), -(CH2)1-2NRcC(O)O(C1-4alkyl), -(CH2)1-2NRcS(O)2(C1-4alkyl), -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -C(O)O(C3-4cycloalkyl), -C(O)NRaRa, or -C(O)NRa(C3-4cycloalkyl). In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein each R5is independently -CH3, -CH2CH3, -CH2OH, or -CH2OCH3.

[0434] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein m is zero.

[0435] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein m is 1, 2, or 3. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein m is 1 or 2. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein m is 1.

[0436] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein m is 2 or 3. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein m is 2.

[0437] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein m is 3.

[0438] In one embodiment, a compound of Formula (II) or a salt thereof is administered having the structure of Formula (III):I)

[0439] wherein one, two, or three of R5a, R5b, R5c, and R5dare each R5and the remainder of R5a, R5b, R5c, and R5dare each hydrogen. In some embodiments, a compound of Formula (III) or a salt thereof is administered wherein each R5 is independently -CN, -CH3, -CH2CH3,-CH(CH3)2, -CHC(CH3)2, -CH2F, -C(CH3)2F, -CF(CH3)CH(CH3)2, -CH2OH, -C(CH3)2OH, -C(CH3)(OH)CH(CH3)2, -CH2OCH3, -C(O)C(CH3)2, -C(O)OH, -C(O)OCH3, -C(O)OC(CH3)2, -C(O)NH2, -C(O)NH(cyclopropyl), -C(O)O(cyclopropyl), cyclopropyl, phenyl, methyloxadiazolyl, or methylpyridinyl. In some embodiments, a compound of Formula (III) or a salt thereof is administered wherein each R5 is independently -CH3, -CH2CH3, -CH2CH2CH3, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CH2NH2, -CH2N3, or -CH2NHC(O)OCH3.

[0440] In one embodiment, a compound of Formula (II) or a salt thereof is administered having the structure of Formula (IV):

[0441] wherein R5aand R5care each R5and R5band R5dare each hydrogen. In some embodiments, a compound of Formula (IV) or a salt thereof is administered wherein (i) R5ais -CH3or -CH2CH3and R5cis -CH3or -CH2CH3; or (ii) R5ais -CH3and R5cis -CH2OH or -CH2OCH3.

[0442] In one embodiment, a compound of Formula (IV) or a salt thereof is administered wherein R5ais -CH3and R5cis -CH3.

[0443] In one embodiment, a compound of Formula (IV) or a salt thereof is administered wherein R5ais -CH3and R5cis -CH2CH3.

[0444] In one embodiment, a compound of Formula (IV) or a salt thereof is administered wherein R5ais -CH2CH3and R5cis -CH3.

[0445] In one embodiment, a compound of Formula (IV) or a salt thereof is administered wherein R5ais -CH2CH3and R5cis -CH2CH3.

[0446] In one embodiment, a compound of Formula (IV) or a salt thereof is administered wherein R5ais -CH3and R5cis -CH2OH.

[0447] In one embodiment, a compound of Formula (IV) or a salt thereof is administered wherein R5ais -CH3and R5cis -CH2OCH3.

[0448] In one embodiment, a compound of Formula (IV) or a salt thereof is administered wherein R5ais -CH3and R5cis -CH2OCH2CH3.

[0449] In one embodiment, a compound of Formula (IV) or a salt thereof is administered wherein R5ais -CH3and R5cis -CH2CH2CH3.

[0450] In one embodiment, a compound of Formula (IV) or a salt thereof is administered wherein R5ais -CH3and R5cis -CH2N3.

[0451] In one embodiment, a compound of Formula (IV) or a salt thereof is administered wherein R5ais -CH3and R5cis -CH2NH2.

[0452] In one embodiment, a compound of Formula (IV) or a salt thereof is administered wherein R5ais -CH3and R5cis -CH2NHC(O)OCH3.

[0453] In one embodiment, a compound of Formula (IV) or a salt thereof is administered wherein R5ais -CH2OH and R5cis -CH3.

[0454] In one embodiment, a compound of Formula (IV) or a salt thereof is administered wherein R5ais -CH2OCH3and R5cis -CH3.

[0455] In one embodiment, a compound of Formula (II) or a salt thereof is administered having the structure:

[0456] In one embodiment, a compound of Formula (II) or a salt thereof is administered having the structure:

[0457] In one embodiment, a compound of Formula (II) or a salt thereof is administered having the structure:o

[0458] In one embodiment, a compound of Formula (II) or a salt thereof is administered having the structure:or

[0459] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is:In some embodiments, acompound of Formula (II) or a salt thereof is administered wherein R1is H, Br, -CN, or -OCH3; and R2is -CH3.

[0460] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is:. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R1is H, Br, -CN, or -OCH3; and R2is -CH3. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R1is -CN; and R2is -CH3.

[0461] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R1is -CN; and R2is -CH3.

[0462] In one embodiment, a compound of Formula (IV) or a salt thereof is administered wherein R1is -CN; and R2is -CH3.

[0463] In one embodiment, a compound of Formula (IV) or a salt thereof is administered wherein R1is -CN; R2is -CH3; R5ais -CH3; and R5cis -CH3.

[0464] In one embodiment, a compound of Formula (IV) or a salt thereof is administered wherein R1is -CN; R2is -CH3; R5ais -CH3; and R5cis -CH2CH3.

[0465] In one embodiment, a compound of Formula (IV) or a salt thereof is administered wherein R1is -CN; R2is -CH3; R5ais -CH3; and R5cis -CH2CH2CH3.

[0466] In one embodiment, a compound of Formula (IV) or a salt thereof is administered wherein R1is -CN; R2is -CH3; R5ais -CH2CH3; and R5cis -CH2CH3.

[0467] In one embodiment, a compound of Formula (IV) or a salt thereof is administered wherein R1is -CN; R2is -CH3; R5ais -CH3; and R5cis -CH3, -CH2CH3, or -CH2CH2CH3.

[0468] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R1is -CN; R2is -CH3; R4is -CHR4aR4b; and R4bis -CH3.

[0469] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R1is -CN; R2is -CH3; R4is -CHR4aR4b; and R4bis -CH2CH3.

[0470] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R1is -CN; R2is -CH3; R4is -CHR4aR4b; and R4bis -CH2CH2CH3.

[0471] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R1is -CN; R2is -CH3; R4is -CHR4aR4b; and R4bis -CH3, -CH2CH3, or -CH2CH2CH3.

[0472] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CHR4aR4b; and R4ais phenyl substituted with 1 to 2 substituents independentlyselected from F, Cl, -CF3-OCF3, or -OCH2(cyclopropyl). In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R1 is -CN; and R2is -CH3.

[0473] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CHR4aR4b; R4ais phenyl substituted -CF3or -OCF3; and R4bis -CH3, -CH2CH3, or -CH2CH2CH3. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R1 is -CN; and R2is -CH3.

[0474] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CHR4aR4b; R4ais phenyl substituted -CF3or -OCF3; and R4bis -CH3. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R1is -CN; and R2is -CH3.

[0475] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CHR4aR4b; R4ais phenyl substituted -CF3or -OCF3; and R4bis -CH2CH3. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R1is -CN; and R2is -CH3.

[0476] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4 is -CHR4aR4b; R4ais phenyl substituted -CF3or -OCF3; and R4bis -CH2CH2CH3. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R1 is -CN; and R2is -CH3.

[0477] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CHR4aR4b; R4ais phenyl substituted with 1 to 2 substituents independently selected from F, Cl, -CF3–OCF3, or –OCH2(cyclopropyl); and R4bis -CH3, -CH2CH3, or -CH2CH2CH3. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R1is -CN; and R2is -CH3.

[0478] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4 is -CHR4aR4b; and R4ais pyridinyl. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R1is -CN; and R2is -CH3.

[0479] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4 is -CHR4aR4b; and R4ais pyridinyl substituted with -CF3. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R1 is -CN; and R2is -CH3.

[0480] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CHR4aR4b; R4ais pyridinyl; and R4ais phenyl substituted with Cl. In someembodiments, a compound of Formula (II) or a salt thereof is administered wherein R1 is -CN; and R2is -CH3.

[0481] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4is -CHR4aR4b; R4ais pyridinyl substituted with -CF3; and R4bis phenyl substituted with F. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R1is -CN; and R2is -CH3.

[0482] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein R4 is -CHR4aR4b; one of R4aand R4bis phenyl substituted with F; and the other of R4aand R4bis oxadiazolyl substituted with cyclopropyl. In some embodiments, a compound of Formula (II) or a salt thereof is administered wherein R1 is -CN; and R2is -CH3.

[0483] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is: 4-((2S,5R)-4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-2,5- diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-2,5-diethyl-4-(2-fluoro-4-(trifluoromethoxy)benzyl) piperazin-1-yl)-1-methyl-2-oxo- 1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-2-methyl-4-(4- (trifluoromethoxy)benzyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine- 6-carbonitrile; 4-((2S,5R)-4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-5-ethyl-2- methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-5-ethyl-4-(2-fluoro-4-(trifluoromethoxy)benzyl)-2-methylpiperazin-1-yl)-1-methyl-2- oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-dimethyl-4-(3,4,5- trifluorobenzyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile; 4-((2S,5R)-4-(3,4-difluorobenzyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(2-chloro-4,5-difluorobenzyl)-2,5- dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-2,5-dimethylpiperazin-1-yl)-1- methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(2-chloro-4- fluorobenzyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(4-isopropylbenzyl)-2,5-dimethylpiperazin-1-yl)-1- methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(4- (cyclopropylmethoxy)benzyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(2-fluoro-4- (trifluoromethyl)benzyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(4-(trifluoromethyl)benzyl) piperazin-1-yl)-1-methyl-2- oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(4-cyclopropyl-2- fluorobenzyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile; 4-((2S,5R)-4-((4,4-difluorocyclohexyl)methyl)-2,5-diethylpiperazin-1-yl)-1- methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; or 4-((2S,5R)-4-(4- ethoxybenzyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile.

[0484] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is: 4-((2S,5R)-2,5-diethyl-4-((4-fluorophenyl)(5-(trifluoromethyl) pyridin-2-yl)methyl) piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6- carbonitrile; 4-((2S,5R)-2,5-diethyl-4-((4-fluorophenyl)(isoxazol-3-yl) methyl)piperazin-1-yl)-1- methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-((5- cyclopropylisoxazol-3-yl)(4-(trifluoromethoxy) phenyl)methyl)-2,5-diethylpiperazin-1-yl)-1- methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-4-((4- fluorophenyl)(5-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpiperazin-1-yl)-1-methyl-2-oxo- 1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (21-22); 4-((2S,5R)-4-((4-cyclopropylthiazol- 2-yl)(4-fluorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-4-((4-fluorophenyl)(6- (trifluoromethyl)pyridin-2-yl)methyl)-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-4-((4-fluorophenyl)(isoxazol- 3-yl)methyl)-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile; 4-((2S,5R)-4-((5-cyclopropylpyridin-2-yl)(4-fluorophenyl)methyl)-5-ethyl-2- methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-5-ethyl-4-((4-fluorophenyl)(pyridin-2-yl)methyl)-2-methylpiperazin-1-yl)-1-methyl-2- oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-2-methyl-4-(pyridin- 2-yl(4-(trifluoromethoxy)phenyl)methyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-((4-chlorophenyl) (pyridin-2-yl)methyl)-5-ethyl-2- methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (23- 24); 4-((2S,5R)-5-ethyl-4-((4-fluorophenyl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-2- methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-4-((5-cyclopropylisoxazol-3-yl)(4-(trifluoromethoxy)phenyl)methyl)-5-ethyl-2- methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-((5-cyclopropylisoxazol-3-yl)(4-fluorophenyl)methyl)-5-ethyl-2-methylpiperazin-1- yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-((2- cyclopropylthiazol-5-yl)(4-fluorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2- oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 6-chloro-4-((2S,5R)-4-((3-cyclopropyl- 1,2,4-oxadiazol-5-yl)(4-fluorophenyl) methyl)-2,5-dimethylpiperazin-1-yl)-1-methylpyrido[3,2- d]pyrimidin-2(1H)-one; 4-((2S,5R)-4-((3-cyclopropyl-1,2,4-oxadiazol-5-yl)(4- fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile (25-26); 4-((2S,5R)-4-((3-(tert-butyl)-1,2,4-oxadiazol-5-yl)(4- fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-((3-cyclopropyl-1,2,4-oxadiazol-5-yl)(4- fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile (25-26); 4-((2S,5R)-4-((3-cyclopropyl-1,2,4-oxadiazol-5-yl)(4- fluorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2-ethyl-4-((4-fluorophenyl)(5-(trifluoromethyl)pyridin- 2-yl)methyl)-5-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile; 4-((2S,5R)-2-ethyl-4-((4-fluorophenyl)(6-(trifluoromethyl)pyridin-2-yl) methyl)-5- methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-((4-fluorophenyl)(5- (trifluoromethyl)pyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (27-28); 4-((2S,5R)-4-((4-cyclopropylthiazol-2- yl)(4-fluorophenyl) methyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d] pyrimidine-6-carbonitrile; 4-((2S,5R)-4-((4-fluorophenyl)(isoxazol-3-yl) methyl)-2,5- dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6-carbonitrile; 4- ((2S,5R)-4-((5-cyclopropylisoxazol-3-yl)(4-(trifluoromethoxy)phenyl)methyl)-2,5- dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-4-((4-fluorophenyl) (2-(trifluoromethyl)thiazol-4-yl)methyl)-2,5-dimethylpiperazin-1- yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5S)-4-((4- fluorophenyl) (5-(trifluoromethyl)pyridin-2-yl)methyl)-5-(methoxymethyl)-2-methylpiperazin- 1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 6-chloro-4-((2S,5S)-4- ((4-fluorophenyl)(5-(trifluoromethyl)pyridin-2-yl)methyl)-5-(hydroxymethyl)-2- methylpiperazin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one; 4-((2S,5S)-4-((4-fluorophenyl)(5-(trifluoromethyl)pyridin-2-yl)methyl)-5-(hydroxymethyl)-2-methylpiperazin-1- yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl- 4-((4-fluorophenyl)(2-(trifluoromethyl) thiazol-4-yl)methyl)piperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-((6-(difluoromethyl)pyridin-2- yl)(4-fluorophenyl) methyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-((3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)(4- fluorophenyl)methyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-((3-cyclopropyl-1-methyl-1H-1,2,4-triazol-5-yl)(4- fluorophenyl)methyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-4-((4-fluorophenyl)(2-(trifluoromethyl)thiazol- 4-yl)methyl)-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile; 4-((2S,5R)-4-((6-(difluoromethyl)pyridin-2-yl)(4-fluorophenyl)methyl)-5-ethyl-2- methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 6- chloro-4-((2S,5R)-4-((5-cyclopropyl-1,2,4-oxadiazol-3-yl)(4-fluorophenyl)methyl)-2,5- diethylpiperazin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one; 4-((2S,5R)-4-((5- cyclopropyl-1,2,4-oxadiazol-3-yl)(4-fluorophenyl)methyl)-2,5-diethylpiperazin-1-yl)-1-methyl- 2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(bis(4- chlorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-((4-cyanophenyl)(4-fluorophenyl)methyl)-2,5- dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; or 4-((2S,5R)-4-((4-fluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2,5- dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile.

[0485] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is: 4-((2S,5R)-4-(1-(4-cyclopropylphenyl)ethyl)-2, 5-dimethylpiperazin- 1-yl)-1-methyl-2-oxo-1, 2-dihydropyrido[3, 2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5- diethyl-4-(1-(4-(trifluoromethyl)phenyl)propyl) piperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (17-18); 4-((2S,5R)-5-ethyl-2-methyl-4-(1-(4- (trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile (19-20); 4-((2S,5R)-2,5-diethyl-4-(1-(4- (trifluoromethoxy)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4- methoxyphenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-12-dihydropyrido[32-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-diethylpiperazin- 1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5- diethyl-4-(1-(4-methoxyphenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(4-isopropoxyphenyl)ethyl)piperazin-1- yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl- 4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(4-(trifluoromethoxy)benzyl) piperazin-1- yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4- (cyclopropylmethoxy)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4- (trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-cyclopropylphenyl)ethyl)-2,5-diethylpiperazin- 1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5- diethyl-4-(1-(3-fluoro-4-(trifluoromethoxy)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-(cyclopropylmethoxy)-2- fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(4- (trifluoromethoxy)phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4- (trifluoromethoxy)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-cyclopropyl-2-fluorophenyl)ethyl)-2,5- diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-2,5-diethyl-4-(1-(6-(trifluoromethyl) pyridin-3-yl)ethyl)piperazin-1-yl)-1-methyl-2- oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-2-methyl-4-(1-(4- (trifluoromethoxy)phenyl) ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-4-(1-(4-isopropoxyphenyl)ethyl)-2- methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-5-ethyl-4-(1-(4-methoxyphenyl)ethyl)-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-4-(1-(2-fluoro-4- (trifluoromethyl)phenyl)ethyl)-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-cyanophenyl) ethyl)-5-ethyl-2-methylpiperazin- 1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-cyclopropylphenyl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4- (cyclopropylmethoxy)phenyl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-(cyclopropylmethoxy)-2- fluorophenyl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)-5- ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile; 4-((2S,5R)-4-(1-(4-(difluoromethoxy)phenyl)propyl)-5-ethyl-2-methylpiperazin-1- yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)propyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-4-(1-(2-fluoro-4- (trifluoromethoxy)phenyl)ethyl)-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-2-methyl-4-(1-(4- (trifluoromethoxy)phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-4-(1-(2-fluoro-4- (trifluoromethoxy)phenyl)propyl)-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-2-methyl-4-(1-(4- (trifluoromethyl)phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-cyclopropyl-2-fluorophenyl)ethyl)-5-ethyl-2- methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-2-ethyl-5-methyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2- oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2-ethyl-4-(1-(2-fluoro-4- (trifluoromethyl)phenyl)ethyl)-5-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2-ethyl-5-methyl-4-(1-(4- (trifluoromethoxy)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1- yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5- dimethyl-4-(1-(4-(trifluoromethoxy)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-dimethyl-4-(1-(3,4,5- trifluorophenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6- carbonitrile; 4-((2S,5R)-2,5-dimethyl-4-(1-(4-(trifluoromethyl) phenyl)ethyl)piperazin-1-yl)-1- methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(2,4-difluorophenyl)ethyl)-2,5- dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-4-(1-(4-chloro-2-fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(3,4-difluorophenyl)ethyl)-2,5- dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-4-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methyl- 2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(2-fluoro-4- (trifluoromethoxy)phenyl)propyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-dimethyl-4-(1-(4- (trifluoromethoxy)phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-(difluoromethoxy)phenyl)ethyl)-2,5- dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-4-(1-(3-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1- methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-cyclopropyl-2- fluorophenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 6-chloro-4-((2S,5S)-5-(hydroxymethyl)-2-methyl-4-(1-(4- (trifluoromethyl)phenyl)ethyl) piperazin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one; 6- chloro-4-((2S,5S)-5-(methoxymethyl)-2-methyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl) piperazin-1-yl)-1-methylpyrido[3,2-d] pyrimidin-2(1H)-one; 4-((2S,5S)-5-(methoxymethyl)-2- methyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d] pyrimidine-6-carbonitrile; 4-((2S,5S)-5-(methoxymethyl)-2-methyl-4-(1- (4-(trifluoromethoxy)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6-carbonitrile; 4-((2S,5S)-5-(hydroxymethyl)-2-methyl-4-(1-(4- (trifluoromethoxy)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6-carbonitrile; 6-chloro-4-((2S,5R)-2,5-diethyl-4-(1-(4-((1-hydroxy-2- methylpropan-2-yl)oxy)phenyl)ethyl)piperazin-1-yl)-1-methylpyrido[3,2-d] pyrimidin-2(1H)- one; 6-chloro-4-((2S,5R)-2,5-diethyl-4-(1-(4-((1-methoxy-2-methylpropan-2- yl)oxy)phenyl)ethyl)piperazin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one; 6-chloro-4- ((2S,5R) 25 diethyl 4 (1 (4 ((1 methoxy 2 methylpropan 2 yl)oxy)phenyl)ethyl)piperazin 1yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one; 4-((2S,5R)-2,5-diethyl-4-(1-(4-(methoxy- d3)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile; 4-((2S,5R)-4-(1-(6-cyclopropylpyridin-3-yl)ethyl)-2,5-diethylpiperazin-1-yl)-1- methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1- (2-morpholino-4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-(2-cyanopropan-2- yl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-(cyclopropylmethoxy)-2-fluorophenyl)propyl)- 2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (29-30); 4-((2S,5R)-4-(1-(4-cyclopropylphenyl)propyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2- oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(3-methyl- 2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(2- morpholinopyrimidin-5-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(4-(methoxy-d3) phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(4-methoxyphenyl)propyl)piperazin-1-yl)-1-methyl-2- oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(6- methoxypyridin-2-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine- 6-carbonitrile; 4-((2S,5R)-4-(1-(4-(cyclopropylmethoxy)phenyl)propyl)-2,5-diethylpiperazin-1- yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl- 4-(1-(4-(1-methylcyclopropyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-cyanophenyl)propyl)-2,5- diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6-carbonitrile; 4- ((2S,5R)-4-(1-(4-(difluoromethoxy)phenyl) propyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo- 1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(6- (trifluoromethyl)pyridin-3-yl) propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl) piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-2,5-diethyl-4-(1-(6-methylpyridin-3-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(4-(2-oxopyrrolidin- 1-yl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-(difluoromethoxy)-2-fluorophenyl)propyl)-2,5-diethylpiperazin- 1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5- diethyl-4-(1-(4-isopropoxyphenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d] pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(p-tolyl)propyl) piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)- 4-(1-(4-chloro-2-fluorophenyl)propyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(6-(difluoromethoxy)pyridin-2- yl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)butyl)piperazin-1-yl)-1- methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (31-32); 4-((2S,5R)-2,5- diethyl-4-(1-(6-(trifluoromethoxy)pyridin-2-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(4-(2- morpholinopropan-2-yl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(4-methoxyphenyl)-2- methylpropyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile; 4-((2S,5R)-4-(1-(4-(2-cyanopropan-2-yl)phenyl) propyl)-2,5-diethylpiperazin-1- yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(2- cyclopropylbenzo[d]oxazol-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-cyclopropoxyphenyl)propyl)- 2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; ethyl (1S,2S)-2-(4-(1-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin- 4-yl)-2,5-diethylpiperazin-1-yl)ethyl)phenoxy)cyclopropane-1-carboxylate; 4-((2S,5R)-2,5- diethyl-4-(1-(4-isopropoxyphenyl)-2-methylpropyl)piperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-(1- cyanocyclopropyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; methyl 4-(1-((2R,5S)-4-(6-cyano-1-methyl-2- oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)ethyl)benzoate; 4- ((2S,5R)-2,5-diethyl-4-(1-(4-(morpholinomethyl)phenyl) propyl)piperazin-1-yl)-1-methyl-2- oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(4- (hydroxymethyl)phenyl)ethyl)piperazin-1-yl)- 1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-(bromomethyl)phenyl)ethyl)-2,5- diethylpiperazin-1-yl)-1-methyl-2-oxo-12-dihydropyrido[32-d]pyrimidine-6-carbonitrile; 4-((2S,5R) ,5-diethyl-4-(1-(4-((4-methoxypiperidin-1-yl)methyl)phenyl)ethyl)piperazin-1-yl)-1- methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-((2,2- dimethylmorpholino)methyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-((4,4-difluoropiperidin-1- yl)methyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-((2-oxa-6-azaspiro[3.3]heptan-6- yl)methyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(4-(piperidin-1- ylmethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile; 4-((2S,5R)-4-(1-(4-((4-acetylpiperazin-1-yl)methyl)phenyl)ethyl)-2,5- diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-2,5-diethyl-4-(1-(4-((4-hydroxypiperidin-1-yl)methyl)phenyl)ethyl)piperazin-1-yl)-1- methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1- (4-((4-methyl-3-oxopiperazin-1-yl)methyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(4-(((R)-3- hydroxypiperidin-1-yl)methyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-(((2S,6R)-2,6- dimethylmorpholino)methyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-2-methyl-4-(1-(3-methyl-2- oxo-2,3-dihydrobenzo[d]oxazol-5-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-cyclopropylphenyl)propyl)- 5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile; 4-((2S,5R)-4-(1-(4-cyclopropyl-2-fluorophenyl)propyl)-5-ethyl-2-methylpiperazin- 1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-4- (1-(4-methoxyphenyl)propyl)-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-ethoxyphenyl)propyl)-5-ethyl-2- methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-4-(1-(4-(cyclopropylmethoxy)phenyl)propyl)-5-ethyl-2-methylpiperazin-1-yl)-1- methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4- cyclopropoxyphenyl)propyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-4-(1-(4-methoxyphenyl)-2- methylpropyl)-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-(2-cyanopropan-2-yl)phenyl)propyl)-5-ethyl-2-methylpiperazin- 1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(3,4- difluorophenyl)propyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-bromophenyl)propyl)-5-ethyl-2- methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-5-ethyl-4-(1-(4-isopropoxyphenyl)-2-methylpropyl)-2-methylpiperazin-1-yl)-1-methyl- 2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-(1- cyanocyclopropyl)phenyl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-(cyclopropylmethoxy)-2,6- difluorophenyl)propyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-2-methyl-4-(1-(4-(tetrahydro-2H-pyran-4- yl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile; 4-((2S,5R)-4-(1-(4-(1,3-dioxolan-2-yl)phenyl)propyl)-5-ethyl-2-methylpiperazin-1- yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-4-(1- (4-isopropoxyphenyl)propyl)-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((^6^^5)-5-ethyl-2-methyl-4-(1-(4-(3,3,3- trifluoropropoxy)phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-2-methyl-4-(1-(4-((tetrahydro-2H-pyran-4- yl)methoxy)phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine- 6-carbonitrile; 4-((2S,5R)-4-(1-(4-(2-cyclopropylethoxy)phenyl)propyl)-5-ethyl-2- methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-5-ethyl-2-methyl-4-(1-(4-(oxetan-3-ylmethoxy)phenyl)propyl)piperazin-1-yl)-1- methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-2-methyl- 4-(1-(4-((1-methylazetidin-3-yl)methoxy)phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-2-methyl-4-(1-(4-((1- methylcyclopropyl)methoxy)phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-2-methyl-4-(1-(4-(thiazol-2- ylmethoxy)phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine- 6-carbonitrile; 4-((^6^^5)-4-(1-(3-bromo-4-(trifluoromethyl)phenyl)ethyl)-5-ethyl-2- methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((^6^^5)-5-ethyl-2-methyl-4-(1-(3-(morpholinomethyl)-4-(trifluoromethyl)phenyl) ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(3-((dimethylamino)methyl)-4-(trifluoromethyl)phenyl)ethyl)-5-ethyl-2- methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-5-ethyl-2-methyl-4-(1-(3-(piperidin-1-ylmethyl)-4-(trifluoromethyl)phenyl) ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-4-(1-(3-cyano-4-(trifluoromethyl)phenyl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-1- methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4- (aminomethyl)phenyl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; methyl (4-(1-((2R,5S)-4-(6-cyano-1-methyl-2- oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2-ethyl-5-methylpiperazin-1- yl)ethyl)benzyl)carbamate; 4-((2S,5R)-4-(1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-2,5- diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4- ((2S,5R)-4-(1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)propyl)-2,5-diethylpiperazin-1-yl)-1-methyl- 2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(3-cyclopropyl-1,2,4- oxadiazol-5-yl)-2-methylpropyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(5-cyclopropyl-1,3,4-oxadiazol- 2-yl)-2-methylpropyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 2-((2R,5S)-4-(6-chloro-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-2-(4-fluorophenyl)acetonitrile; 4-((2S,5R)-4-(1-(4- ((2-cyanopropan-2-yl)oxy)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-cyclopropylphenyl)propyl)- 2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-cyclopropyl-2-fluorophenyl)propyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2- oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 6-chloro-4-((2S,5R)-4-(1-(4- (hydroxymethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methylpyrido[3,2-d] pyrimidin- 2(1H)-one; 4-((2S,5R)-4-(1-(4-(hydroxymethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1- methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4- (bromomethyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-((2,2- dimethylmorpholino)methyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-(((1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)methyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-(((2S,6R)-2,6- dimethylmorpholino)methyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-((4,4-difluoropiperidin-1- yl)methyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(4-((2-oxa-6-azaspiro[3.3]heptan-6- yl)methyl)phenyl)ethyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 6-chloro-1-methyl-4-((2S,5R)-2-methyl-5-propyl-4-(1-(4- (trifluoromethyl)phenyl)ethyl)piperazin-1-yl) pyrido[3,2-d]pyrimidin-2(1H)-one; 1-methyl-4- ((2S,5R)-2-methyl-5-propyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-2-oxo-1,2- dihydropyrido[3,2-d] pyrimidine-6-carbonitrile (33-34); 6-chloro-4-((2S,5S)-5- (methoxymethyl)-2-methyl-4-(1-(4-(trifluoromethyl)phenyl) propyl)piperazin-1-yl)-1- methylpyrido[3,2-d]pyrimidin-2(1H)-one; 4-((2S,5S)-5-(methoxymethyl)-2-methyl-4-(1-(4- (trifluoromethyl) phenyl)propyl) piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2S,5S)-5-(ethoxymethyl)-2-methyl-4-(1-(4-(trifluoromethyl) phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile; 4-((2S,5S)-5-(azidomethyl)-2-methyl-4-(1-(4-(trifluoromethyl) phenyl)ethyl)piperazin-1-yl)-6-chloro-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one; 4-((2S,5R)- 5-(aminomethyl)-2-methyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-6-chloro-1- methylpyrido[3,2-d]pyrimidin-2(1H)-one; 4-((2S,5S)-5-(methoxymethyl)-2-methyl-4-(1-(4- (trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 4-((2R,5R)-2-(hydroxymethyl)-5-methyl-4-(1-(4- (trifluoromethyl)phenyl)ethyl) piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile; 6-chloro-4-((2R,5R)-2-(methoxymethyl)-5-methyl-4-(1-(4- (trifluoromethyl)phenyl)ethyl) piperazin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one; 4- ((2R,5R)-2-(methoxymethyl)-5-methyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl) piperazin-1-yl)-1- methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2R,5R)-5-ethyl-2- (hydroxymethyl)-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-5-ethyl-2-methyl-4-(1-(4- (trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-2- oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6-carbonitrile; 6-chloro-4-((2S,5R)-5-ethyl-2-methyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-(methyl-d3)pyrido[3,2-d]pyrimidin- 2(1H)-one; 4-((2S,5R)-5-ethyl-2-methyl-4-(1-(4-(trifluoromethyl)phenyl) ethyl)piperazin-1-yl)- 1-(methyl-d3)-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 6-chloro-4-((2S,5R)- 2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl) propyl)piperazin-1-yl)-1-methylpyrido[3,2- d]pyrimidin-2(1H)-one; 4-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin- 1-yl)-6-(hydroxymethyl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one; 4-((2S,5R)-2,5-diethyl-4- (1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-6-(methoxymethyl)-1-methylpyrido[3,2-d] pyrimidin-2(1H)-one; 6-chloro-4-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl) phenyl)ethyl)piperazin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one; 4-((2S,5R)-2,5- diethyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-6-methoxy-1-methylpyrido[3,2- d]pyrimidin-2(1H)-one; 4-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin- 1-yl)-6-ethoxy-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one; 4-((2S,5R)-2,5-diethyl-4-(1-(4- (trifluoromethyl)phenyl)ethyl) piperazin-1-yl)-6-(2-(dimethylamino)ethoxy)-1- methylpyrido[3,2-d]pyrimidin-2(1H)-one; 4-((2S,5R)-2,5-diethyl-4-(1-(4- (trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-6-(2-methoxyethoxy)-1-methylpyrido[3,2- d]pyrimidin-2(1H)-one; 4-((2S,5R)-2,5-diethyl-4-(1-(4- (trifluoromethyl)phenyl)propyl)piperazin-1-yl)-6-methoxy-1-methylpyrido[3,2-d]pyrimidin- 2(1H)-one; 4-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-6- ethoxy-1-methylpyrido[3,2-d] pyrimidin-2(1H)-one; 4-((2S,5R)-2,5-diethyl-4-(1-(4- (trifluoromethyl)phenyl) ethyl)piperazin-1-yl)-6-(difluoromethyl)-1-methylpyrido[3,2- d]pyrimidin-2(1H)-one; 6-(difluoromethyl)-4-((2S,5R)-5-ethyl-2-methyl-4-(1-(4- (trifluoromethyl) phenyl)ethyl)piperazin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one; 4- ((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-6-hydroxy-1- methylpyrido[3,2-d]pyrimidin-2(1H)-one; 4-((2S,5R)-2,5-diethyl-4-(1-(4- (trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-6-(difluoromethoxy)-1-methylpyrido[3,2-d] pyrimidin-2(1H)-one; 6-chloro-4-((2S,5R)-2,5-dimethyl-4-(1-(3- (trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)propyl)piperazin-1-yl)-1-methylpyrido[3,2-d] pyrimidin-2(1H)-one (diastereomeric mixture); 4-((2S,5R)-2,5-dimethyl-4-(1-(3- (trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)propyl) piperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-cyclopropylpropyl)-2,5- dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-4-(1-(3,3-difluorocyclobutyl)propyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2- dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; or 4-((2S,5R)-4-(1-(4,4- difluorocyclohexyl)propyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile.

[0486] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is:.

[0487] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)propyl) piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (17-18).

[0488] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-2,5-diethyl-4-((S)-1-(4-(trifluoromethyl)phenyl) propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile.

[0489] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-2,5-diethyl-4-((R)-1-(4-(trifluoromethyl)phenyl) propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile.

[0490] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is: .

[0491] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-5-ethyl-2-methyl-4-(1-(4-(trifluoromethyl)phenyl) ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (19- 20).

[0492] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-5-ethyl-2-methyl-4-((S)-1-(4-(trifluoromethyl) phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile.

[0493] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-5-ethyl-2-methyl-4-((R)-1-(4-(trifluoromethyl) phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile.

[0494] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is:.

[0495] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethoxy)phenyl) propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile.

[0496] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-2,5-diethyl-4-((S)-1-(4-(trifluoromethoxy)phenyl) propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile.

[0497] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-2,5-diethyl-4-((R)-1-(4-(trifluoromethoxy)phenyl) propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile.

[0498] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is:.

[0499] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-5-ethyl-4-((4-fluorophenyl)(5-(trifluoromethyl) pyridin-2- yl)methyl)-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile (21-22).

[0500] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-5-ethyl-4-((S)-(4-fluorophenyl)(5-(trifluoromethyl) pyridin-2-yl)methyl)-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6-carbonitrile.

[0501] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-5-ethyl-4-((R)-(4-fluorophenyl)(5-(trifluoromethyl) pyridin-2-yl)methyl)-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6-carbonitrile.

[0502] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is: .

[0503] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-5-ethyl-2-methyl-4-(1-(4-(trifluoromethoxy) phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile.

[0504] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-5-ethyl-2-methyl-4-((S)-1-(4-(trifluoromethoxy) phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile.

[0505] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-5-ethyl-2-methyl-4-((R)-1-(4-(trifluoromethoxy) phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile.

[0506] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is:.

[0507] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-5-ethyl-2-methyl-4-(1-(4-(trifluoromethoxy) phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile.

[0508] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-5-ethyl-2-methyl-4-((S)-1-(4-(trifluoromethoxy) phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile.

[0509] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-5-ethyl-2-methyl-4-((R)-1-(4-(trifluoromethoxy) phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile.

[0510] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is:.

[0511] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-5-ethyl-2-methyl-4-(1-(4-(trifluoromethyl)phenyl) propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile.

[0512] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-5-ethyl-2-methyl-4-((S)-1-(4-(trifluoromethyl) phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile.

[0513] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-5-ethyl-2-methyl-4-((R)-1-(4-(trifluoromethyl) phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile.

[0514] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is: .

[0515] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-4-((4-chlorophenyl)(pyridin-2-yl)methyl)-5-ethyl-2- methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (23- 24).

[0516] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-4-((R)-(4-chlorophenyl)(pyridin-2-yl)methyl)-5-ethyl-2- methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile.

[0517] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-4-((S)-(4-chlorophenyl)(pyridin-2-yl)methyl)-5-ethyl-2- methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile.

[0518] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is:.

[0519] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-4-((3-cyclopropyl-1,2,4-oxadiazol-5-yl)(4- fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile (25-26).

[0520] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-4-((R)-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)(4- fluorophenyl)methyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile.

[0521] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-4-((S)-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)(4- fluorophenyl)methyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile.

[0522] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is:.

[0523] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-4-((4-fluorophenyl)(5-(trifluoromethyl)pyridin-2- yl)methyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile (27-28).

[0524] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-4-((S)-(4-fluorophenyl)(5-(trifluoromethyl)pyridin-2- yl)methyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6- carbonitrile.

[0525] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-4-((R)-(4-fluorophenyl)(5-(trifluoromethyl)pyridin-2- yl)methyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6- carbonitrile.

[0526] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is: .

[0527] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-4-(1-(4-(cyclopropylmethoxy)-2-fluorophenyl) propyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (29-30).

[0528] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-4-((S)-1-(4-(cyclopropylmethoxy)-2-fluorophenyl) propyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile.

[0529] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-4-((R)-1-(4-(cyclopropylmethoxy)-2-fluorophenyl) propyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile.

[0530] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is:.

[0531] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl) butyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (31- 32).

[0532] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-2,5-diethyl-4-((S)-1-(4-(trifluoromethyl)phenyl) butyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile.

[0533] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 4-((2S,5R)-2,5-diethyl-4-((R)-1-(4-(trifluoromethyl)phenyl) butyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile.

[0534] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is:.

[0535] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 1-methyl-4-(2S,5R)-2-methyl-5-propyl-4-(1-(4- (trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile (33-34).

[0536] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 1-methyl-4-((2S,5R)-2-methyl-5-propyl-4-((S)-1-(4- (trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile.

[0537] In one embodiment, a compound of Formula (II) or a salt thereof is administered wherein said compound is 1-methyl-4-((2S,5R)-2-methyl-5-propyl-4-((R)-1-(4- (trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile. 2. COMPOSITIONS AND DOSING

[0538] Compounds described herein, e.g., in accordance with Formula (I) or (II), such as a compound selected from compounds 1 to 34, and / or pharmaceutically acceptable salts thereof, can be administered by any means suitable for the condition to be treated, which can depend on the need for site-specific treatment or quantity of the compound to be delivered.

[0539] Also embraced herein is a class of pharmaceutical compositions comprising a compound, e.g., a compound of Formula (I) or (II), such as a compound selected from compounds 1 to 34, and / or a pharmaceutically acceptable salt thereof; and one or more non- toxic, pharmaceutically-acceptable carriers and / or diluents and / or adjuvants (collectively referred to herein as “carrier” materials) and, if desired, other active ingredients. The compounds, e.g., the compounds of Formula (I) or (II), such as a compound selected fromcompounds 1 to 34, may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds and compositions described herein may, for example, be administered orally, mucosally, or parentally including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. For example, the pharmaceutical carrier may contain a mixture of mannitol or lactose and microcrystalline cellulose. The mixture may contain additional components such as a lubricating agent, e.g. magnesium stearate and a disintegrating agent such as crospovidone. The carrier mixture may be filled into a gelatin capsule or compressed as a tablet. The pharmaceutical composition may be administered as an oral dosage form or an infusion, for example.

[0540] The dosage regimen for the DGK inhibitor will vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration; and the renal and hepatic function of the patient.

[0541] In some embodiments, the inhibitor is administered in a therapeutically effective dose. In some embodiments, the therapeutically effective dose provides a dose of the inhibitor that is continuously therapeutically effective for a period of time.

[0542] By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to about 5000 mg per day, preferably between about 0.01 to about 1000 mg per day, and most preferably between about 0.1 to about 250 mg per day. Intravenously, the most preferred doses will range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion. A DGK inhibitor as described herein may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

[0543] The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices.

[0544] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 2000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.1-95% by weight based on the total weight of the composition.

[0545] A typical capsule for oral administration contains at least one DGK inhibitor (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. L gelatin capsule.

[0546] A typical injectable preparation is produced by aseptically placing at least one DGK inhibitor (250 mg) into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.

[0547] For oral administration, a pharmaceutical composition described herein may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. For example, the pharmaceutical composition may be provided as a tablet or capsule comprising an amount of active ingredient in the range of from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, and more preferably from about 0.5 to 100 mg. A suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, can be determined using routine methods.

[0548] Regardless of the route of administration selected, the DGK inhibitor for administration as described herein, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions containing same, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.

[0549] Actual dosage levels of the active ingredients in the pharmaceutical compositions containing the DGK inhibitor may be varied so as to obtain an amount of the active ingredient which is effective to achieve the therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0550] A physician having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician could start doses of the DGK inhibitor employed in the pharmaceutical composition at levels lower than that required in order to achieve the therapeutic effect and gradually increase the dosage until the effect is achieved.

[0551] In general, a suitable daily dose of a DGK inhibitor will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the DGK inhibitor for a patient will range from about 0.01 to about 50 mg per kilogram of body weight per day. If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain aspects, dosing is one administration per day.

[0552] Any pharmaceutical composition contemplated herein can, for example, be delivered orally via any acceptable and suitable oral preparations. Exemplary oral preparations, include, but are not limited to, for example, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any methods known in the art for manufacturing pharmaceutical compositions intended for oral administration. In order to provide pharmaceutically palatable preparations, a pharmaceutical composition can contain at least one agent selected from sweetening agents, flavoring agents, coloring agents, demulcents, antioxidants, and preserving agents.

[0553] A tablet can, for example, be prepared by admixing at least one compound, e.g., a compound of Formula (I) or (II), such as a compound selected from compounds 1 to 34, and / or at least one pharmaceutically acceptable salt thereof, with at least one non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets. Exemplary excipients include, but are not limited to, for example, inert diluents, such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, and alginic acid; binding agents, such as, for example, starch,gelatin, polyvinyl-pyrrolidone, and acacia; and lubricating agents, such as, for example, magnesium stearate, stearic acid, and talc. Additionally, a tablet can either be uncoated, or coated by known techniques to either mask the bad taste of an unpleasant tasting drug, or delay disintegration and absorption of the active ingredient in the gastrointestinal tract thereby sustaining the effects of the active ingredient for a longer period. Exemplary water soluble taste masking materials, include, but are not limited to, hydroxypropyl-methylcellulose and hydroxypropyl-cellulose. Exemplary time delay materials, include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[0554] Hard gelatin capsules can, for example, be prepared by mixing at least one compound, e.g., a compound of Formula (I) or (II), such as a compound selected from compounds 1 to 34, and / or at least one pharmaceutically acceptable salt thereof, with at least one inert solid diluent, such as, for example, calcium carbonate; calcium phosphate; and kaolin.

[0555] Soft gelatin capsules can, for example, be prepared by mixing at least one compound, e.g., a compound of Formula (I) or (II), such as a compound selected from compounds 1 to 34 and / or at least one pharmaceutically acceptable salt thereof, with at least one water soluble carrier, such as, for example, polyethylene glycol; and at least one oil medium, such as, for example, peanut oil, liquid paraffin, and olive oil.

[0556] An aqueous suspension can be prepared, for example, by admixing at least one compound, e.g., a compound of Formula (I) or (II), such as a compound selected from compounds 1 to 34, and / or at least one pharmaceutically acceptable salt thereof, with at least one excipient suitable for the manufacture of an aqueous suspension. Exemplary excipients suitable for the manufacture of an aqueous suspension, include, but are not limited to, for example, suspending agents, such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, alginic acid, polyvinyl-pyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as, for example, a naturally- occurring phosphatide, e.g., lecithin; condensation products of alkylene oxide with fatty acids, such as, for example, polyoxyethylene stearate; condensation products of ethylene oxide with long chain aliphatic alcohols, such as, for example heptadecaethylene-oxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as, for example, polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as, for example, polyethylene sorbitan monooleate. An aqueous suspension can also contain at least onepreservative, such as, for example, ethyl and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and / or at least one sweetening agent, including but not limited to, for example, sucrose, saccharin, and aspartame.

[0557] Oily suspensions can, for example, be prepared by suspending at least one compound, e.g., a compound of Formula (I) or (II), such as a compound selected from compounds 1 to 34, and / or at least one pharmaceutically acceptable salt thereof, in either a vegetable oil, such as, for example, arachis oil; olive oil; sesame oil; and coconut oil; or in mineral oil, such as, for example, liquid paraffin. An oily suspension can also contain at least one thickening agent, such as, for example, beeswax; hard paraffin; and cetyl alcohol. In order to provide a palatable oily suspension, at least one of the sweetening agents already described hereinabove, and / or at least one flavoring agent can be added to the oily suspension. An oily suspension can further contain at least one preservative, including, but not limited to, for example, an anti-oxidant, such as, for example, butylated hydroxyanisol, and alpha-tocopherol.

[0558] Dispersible powders and granules can, for example, be prepared by admixing at least one compound, e.g., a compound of Formula (I) or (II), such as a compound selected from compounds 1 to 34, and / or at least one pharmaceutically acceptable salt thereof, with at least one dispersing and / or wetting agent; at least one suspending agent; and / or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents are as already described above. Exemplary preservatives include, but are not limited to, for example, anti-oxidants, e.g., ascorbic acid. In addition, dispersible powders and granules can also contain at least one excipient, including, but not limited to, for example, sweetening agents; flavoring agents; and coloring agents.

[0559] An emulsion of at least one compound, e.g., a compound of Formula (I) or (II), such as a compound selected from compounds 1 to 34, and / or at least one pharmaceutically acceptable salt thereof, can, for example, be prepared as an oil-in-water emulsion. The oily phase of the emulsions comprising compounds of Formula (I) or (II), such as a compound selected from compounds 1 to 34 may be constituted from known ingredients in a known manner. The oil phase can be provided by, but is not limited to, for example, a vegetable oil, such as, for example, olive oil and arachis oil; a mineral oil, such as, for example, liquid paraffin; and mixtures thereof. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Suitable emulsifying agents include, but are not limited to, for example, naturally-occurringphosphatides, e.g., soy bean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as, for example, polyoxyethylene sorbitan monooleate. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. An emulsion can also contain a sweetening agent, a flavoring agent, a preservative, and / or an antioxidant. Emulsifiers and emulsion stabilizers suitable for use in the formulation for use in the treatment methods include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art.

[0560] The compounds, e.g., those of Formula (I) or (II), such as a compound selected from compounds 1 to 34, and / or at least one pharmaceutically acceptable salt thereof, can, for example, also be delivered intravenously, subcutaneously, and / or intramuscularly via any pharmaceutically acceptable and suitable injectable form. Exemplary injectable forms include, but are not limited to, for example, sterile aqueous solutions comprising acceptable vehicles and solvents, such as, for example, water, Ringer’s solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and aqueous or oleaginous suspensions.

[0561] Formulations for parenteral administration may be in the form of aqueous or non- aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and / or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin (i.e. Captisol), cosolvent solubilization (i.e. propylene glycol) or micellar solubilization (i.e. Tween 80).

[0562] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0563] A sterile injectable oil-in-water microemulsion can, for example, be prepared by 1) dissolving at least one compound, e.g., a compound of Formula (I) or (II), such as a compound selected from compounds 1 to 34, and / or a pharmaceutically acceptable salt thereof, in an oily phase, such as, for example, a mixture of soybean oil and lecithin; 2) combining a compound, e.g., a compound of Formula (I), and / or a pharmaceutically acceptable salt thereof, containing oil phase with a water and glycerol mixture; and 3) processing the combination to form a microemulsion.

[0564] A sterile aqueous or oleaginous suspension can be prepared in accordance with methods already known in the art. For example, a sterile aqueous solution or suspension can be prepared with a non-toxic parenterally-acceptable diluent or solvent, such as, for example, 1,3- butane diol; and a sterile oleaginous suspension can be prepared with a sterile non-toxic acceptable solvent or suspending medium, such as, for example, sterile fixed oils, e.g., synthetic mono- or diglycerides; and fatty acids, such as, for example, oleic acid.

[0565] Pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-alpha-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, polyethoxylated castor oil such as CREMOPHOR surfactant (BASF), or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as alpha-, beta-, and gamma- cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including2- and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.

[0566] The pharmaceutically active compounds described herein can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

[0567] The amounts of compounds that are administered and the dosage regimen for treating a disease condition with the compounds and / or compositions described herein depends on a variety of factors, including the age, weight, sex, the medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. A daily dose of about 0.001 to 100 mg / kg body weight, preferably between about 0.0025 and about 50 mg / kg body weight and most preferably between about 0.005 to 10 mg / kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day. Other dosing schedules include one dose per week and one dose per two day cycle.

[0568] For therapeutic purposes, the active compounds described herein are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered orally, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled- release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.

[0569] Pharmaceutical compositions described herein comprise at least one compound, e.g., a compound of Formula (I), and / or at least one pharmaceutically acceptable salt thereof, and optionally an additional agent selected from any pharmaceutically acceptable carrier, adjuvant,and vehicle. Alternate compositions described herein comprise a compound, such as a compound of the Formula (I) or (II), such as a compound selected from compounds 1 to 34 described herein, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0570] In some embodiments, the administration of the inhibitor of DGKα and / or DGKζ is initiated prior to, subsequently to, during, during the course of, simultaneously, near simultaneously, sequentially, and / or intermittently with the administration of the cell therapy, such as a T cell therapy. In some embodiments, the method involves initiating the administration of the inhibitor of DGKα and / or DGKζ prior to administration of the T cell therapy. In other embodiments, the method involves initiating the administration of the inhibitor of DGKα and / or DGKζ after administration of the T cell therapy. In some embodiments, the method involves initiating the administration of the inhibitor of DGKα and / or DGKζ on the same day of administration of the T cell therapy (e.g., on Day 1 of the combination therapy). In some embodiments, the method involves initiating the administration of the inhibitor of DGKα and / or DGKζ concurrently with the administration of the T cell therapy. In some embodiments, the administration of the inhibitor is initiated during the administration of the T cell therapy, e.g., the first dose of the inhibitor is administered while the T cell therapy is being infused.

[0571] In some embodiments, the inhibitor of DGKα and / or DGKζ is administered in an intermittent dosing regimen. In some embodiments, the intermittent dosing regimen involves non-daily administration of the inhibitor of DGKα and / or DGKζ. In some embodiments, the intermittent dosing regimen involves administration of the inhibitor of DGKα and / or DGKζ in a cycle.

[0572] In some embodiments, the inhibitor of DGKα and / or DGKζ is administered in a cycle. In some embodiments, the cycle comprises an administration period in which the inhibitor of DGKα and / or DGKζ is administered followed by a rest period during which the inhibitor of DGKα and / or DGKζ is not administered. In some embodiments, the total number of days of the cycle, e.g., from the beginning of initiating administration of the inhibitor of DGKα and / or DGKζ, is greater than or greater than about or is about 21 days, 28 days, 30 days, 40 days, 50 days, 60 days or more.

[0573] In some embodiments, the initiation of the administration of the inhibitor of DGKα and / or DGKζ and the initiation of administration of the T cell therapy are carried out on the same day in at least one cycle, optionally concurrently. In some embodiments, the initiation ofthe administration of the inhibitor of DGKα and / or DGKζ in at least one cycle is prior to initiation of administration of the T cell therapy. In some embodiments, the initiation of the administration of the inhibitor of DGKα and / or DGKζ in at least one cycle is concurrent with or on the same day as initiation of administration of the T cell therapy. In some embodiments, the method involves initiating the administration of the inhibitor of DGKα and / or DGKζ on the same day of administration of the T cell therapy (e.g., on Day 1 of the combination therapy). In some embodiments, the administration of the inhibitor is initiated on Day 1 of the combination therapy prior to the administration of the T cell therapy.

[0574] In some embodiments, the inhibitor of DGKα and / or DGKζ is administered from or from about 0 to 30 days, such as 0 to 15 days, 0 to 6 days, 0 to 96 hours, 0 to 24 hours, 0 to 12 hours, 0 to 6 hours, or 0 to 2 hours, 2 hours to 15 days, 2 hours to 6 days, 2 hours to 96 hours, 2 hours to 24 hours, 2 hours to 12 hours, 2 hours to 6 hours, 6 hours to 30 days, 6 hours to 15 days, 6 hours to 6 days, 6 hours to 96 hours, 6 hours to 24 hours, 6 hours to 12 hours, 12 hours to 30 days, 12 hours to 15 days, 12 hours to 6 days, 12 hours to 96 hours, 12 hours to 24 hours, 24 hours to 30 days, 24 hours to 15 days, 24 hours to 6 days, 24 hours to 96 hours, 96 hours to 30 days, 96 hours to 15 days, 96 hours to 6 days, 6 days to 30 days, 6 days to 15 days, or 15 days to 30 days prior to initiation of the T cell therapy. In some aspects, inhibitor of DGKα and / or DGKζ is administered no more than about 96 hours, 72 hours, 48 hours, 24 hours, 12 hours, 6 hours, 2 hours or 1 hour prior to initiation of the T cell therapy.

[0575] In some of any such embodiments in which the inhibitor of DGKα and / or DGKζ is given prior to the cell therapy (e.g. T cell therapy), the administration of the inhibitor of DGKα and / or DGKζ continues at regular intervals until the initiation of the cell therapy (e.g. T cell therapy)and / or for a time after the initiation of the cell therapy(e.g. T cell therapy).

[0576] In some embodiments, the inhibitor of DGKα and / or DGKζ is administered, or is further administered, after administration of the cell therapy (e.g. T cell therapy). In some embodiments, the inhibitor of DGKα and / or DGKζ is administered within or within about 1 hours, 2 hours, 6 hours, 12 hours, 24 hours, 48 hours, 96 hours, 4 days, 5 days, 6 days or 7 days, 14 days, 15 days, 21 days, 24 days, 28 days, 30 days, 36 days, 42 days, 60 days, 72 days or 90 days after initiation of administration of the cell therapy (e.g., T cell therapy). In some embodiments, the provided methods involve continued administration, such as at regular intervals, of the inhibitor of DGKα and / or DGKζ after initiation of administration of the cell therapy.

[0577] In some embodiments, the inhibitor of DGKα and / or DGKζ is administered up to or up to about 1 day, up to or up to about 2 days, up to or up to about 3 days, up to or up to about 4 days, up to or up to about 5 days, up to or up to about 6 days, up to or up to about 7 days, up to or up to about 12 days, up to or up to about 14 days, up to or up to about 21 days, up to or up to about 24 days, up to or up to about 28 days, up to or up to about 30 days, up to or up to about 35 days, up to or up to about 42 days, up to or up to about 60 days or up to or up to about 90 days, up to or up to about 120 days, up to or up to about 180 days, up to or up to about 240 days, up to or up about 360 days, or up to or up to about 720 days or more after the initiation of administration of the cell therapy (e.g., T cell therapy).

[0578] In some embodiments, the administration of the inhibitor is initiated on any of Days 1-6, inclusive, of the combination therapy. In some embodiments, the administration of the inhibitor is initiated on any of Days 1-4, inclusive, of the combination therapy. In some embodiments, the administration of the inhibitor is initiated on Day 1 or Day 2 of the combination therapy. In some embodiments, the administration of the inhibitor is initiated on Day 1 of the combination therapy. In some embodiments, Day 1 of the combination therapy is the day that the T cell therapy is administered.

[0579] In some embodiments, the administration of the inhibitor is initiated within or within about 12 hours of the administration of the T cell therapy. In some embodiments, the administration of the inhibitor is initiated within or within about 6 hours of the administration of the T cell therapy. In some embodiments, the administration of the inhibitor is initiated within or within about 4 hours of the administration of the T cell therapy. In some embodiments, the administration of the inhibitor is initiated within or within about 2 hours of the administration of the T cell therapy. In some embodiments, the administration of the inhibitor is initiated within or within about 1 hour of the administration of the T cell therapy.

[0580] In some of any such above embodiments, the inhibitor of DGKα and / or DGKζ is administered prior to and after initiation of administration of the cell therapy (e.g. T cell therapy).

[0581] In some embodiments, the initiation of the administration of the inhibitor of DGKα and / or DGKζ is carried out at or after, optionally immediately after or within 1 to 3 days after peak or maximum level of the cells of the T cell therapy are detectable in the blood of the subject. In some embodiments, the initiation of the administration of the inhibitor of DGKα and / or DGKζ is carried out at or after, optionally immediately after or within 1 to 3 days afterthe number of cells of the T cell therapy detectable in the blood, after having been detectable in the blood, is not detectable or is reduced, optionally reduced compared to a preceding time point after administration of the T cell therapy. In some embodiments, the initiation of the administration of the inhibitor of DGKα and / or DGKζ is carried out at or after, optionally immediately after or within 1 to 3 days after the number of cells of the T cell therapy detectable in the blood is decreased by or more than 1.5-fold, 2.0-fold, 3.0-fold, 4.0-fold, 5.0-fold, 10-fold or more the peak or maximum number cells of the T cell therapy detectable in the blood of the subject after initiation of administration of the T cell therapy. In some embodiments, the initiation of the administration of the inhibitor of DGKα and / or DGKζ is carried out at or after, optionally immediately after or within 1 to 3 days after at a time after a peak or maximum level of the cells of the T cell therapy are detectable in the blood of the subject, the number of cells of or derived from the T cells detectable in the blood from the subject is less than less than 10%, less than 5%, less than 1% or less than 0.1% of total peripheral blood mononuclear cells (PBMCs) in the blood of the subject. In some embodiments, the initiation of the administration of the inhibitor of DGKα and / or DGKζ is carried out at or after, optionally immediately after or within 1 to 3 days after the number of cells of the T cell therapy detectable in the blood that are exhausted is increased, e.g., by or more than 1.5-fold, 2.0-fold, 3.0-fold, 4.0-fold, 5.0-fold, 10- fold or more the peak or maximum number cells of the T cell therapy detectable in the blood of the subject that are not exhausted, after initiation of administration of the T cell therapy. In some embodiments, the initiation of the administration of the inhibitor of DGKα and / or DGKζ is carried out at or after, optionally immediately after or within 1 to 3 days after the subject exhibits disease progression and / or has relapsed following remission after treatment with the T cell therapy. In some embodiments, the initiation of the administration of the inhibitor of DGKα and / or DGKζ is carried out at or after, optionally immediately after or within 1 to 3 days after the subject exhibits increased tumor burden as compared to tumor burden at a time prior to or after administration of the T cells and prior to initiation of administration of the inhibitor of DGKα and / or DGKζ.

[0582] In some embodiments, the initiation of the administration of the inhibitor of DGKα and / or DGKζ in at least one cycle is after initiation of administration of the T cell therapy. In some embodiments, the initiation of the administration of the inhibitor of DGKα and / or DGKζ is at least or about at least 1 day, at least or about at least 2 days, at least or about at least 3 days, at least or about at least 4 days, at least or about at least 5 days, at least or about at least 6 days, atleast or about at least 7 days, at least or about at least 8 days, at least or about at least 9 days, at least or about at least 10 days, at least or at least about 12 days, at least or about at least 14 days, at least or at least about 15 days, at least or about at least 21 days, at least or at least about 24 days, at least or about at least 28 days, at least or about at least 30 days, at least or about at least 35 days or at least or about at least 42 days, at least or about at least 60 days, or at least or about at least 90 days after initiation of the administration of the T cell therapy. In some embodiments, the initiation of the administration of the inhibitor of DGKα and / or DGKζ is carried out at least 2 days after, at least 1 week after, at least 2 weeks after, at least 3 weeks after, or at least 4 weeks after, the initiation of the administration of the T cell therapy. In some embodiments, the initiation of administration of the inhibitor of DGKα and / or DGKζ is carried out 2 to 35 days after the initiation of administration of the T cell therapy. In some embodiments, the initiation of administration of the inhibitor of DGKα and / or DGKζ is carried out 2 to 28 days after the initiation of administration of the T cell therapy. In some embodiments, the initiation of administration of the inhibitor of DGKα and / or DGKζ is carried out 2 to 21 days after the initiation of administration of the T cell therapy. In some embodiments, the initiation of administration of the inhibitor of DGKα and / or DGKζ is carried out 2 to 14 days after the initiation of administration of the T cell therapy. In some embodiments, the initiation of administration of the inhibitor of DGKα and / or DGKζ is carried out 7 to 21 days after the initiation of administration of the T cell therapy. In some embodiments, the initiation of administration of the inhibitor of DGKα and / or DGKζ is carried out 7 to 14 days after the initiation of administration of the T cell therapy. In some embodiments, the initiation of the administration of the inhibitor of DGKα and / or DGKζ is carried out at a time that is greater than or greater than about 14 days, 15 days, 16 days, 17 days, 18 days, 19, days, 20 days, 21 days, 24 days, or 28 days after initiation of the administration of the T cell therapy.

[0583] In some embodiments, the inhibitor of DGKα and / or DGKζ is administered several times a day, twice a day, daily, every other day, three times a week, twice a week, or once a week after initiation of the cell therapy. In some embodiments, the inhibitor of DGKα and / or DGKζ is administered every three days. In some embodiments, the inhibitor of DGKα and / or DGKζ is administered every two days. In some embodiments, the inhibitor of DGKα and / or DGKζ is administered daily, such as in a continuous dosing regimen. In some embodiments the inhibitor of DGKα and / or DGKζ is administered twice a day. In some embodiments, theinhibitor of DGKα and / or DGKζ is administered three times a day. In other embodiments, the inhibitor of DGKα and / or DGKζ is administered every other day. In some embodiments, inhibitor of DGKα and / or DGKζ is administered during the administration period for a plurality of consecutive days, such as for up to about 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more than 30 consecutive days. In some embodiments, the inhibitor of DGKα and / or DGKζ is administered for greater than or greater than about 7 consecutive days, greater than or greater than about 14 consecutive days, greater than or greater than about 21 consecutive days, greater than or greater than about 21 consecutive days, or greater than or greater than about 28 consecutive days. In some embodiments, the inhibitor of DGKα and / or DGKζ is administered during the administration period for up to 21 consecutive days. In some embodiments, the inhibitor of DGKα and / or DGKζ is administered during the administration period for up to 21 consecutive days, wherein the cycle comprises greater than 30 days beginning upon initiation of the administration of the inhibitor of DGKα and / or DGKζ.

[0584] In some embodiments, the inhibitor of DGKα and / or DGKζ is administered at least until the number of engineered T cells of the T cell therapy has peaked in the subject following administration of the T cell therapy. In some embodiments, the inhibitor of DGKα and / or DGKζ is administered until the number of engineered T cells of the T cell therapy has peaked in th...

Claims

Claims 1. A method of treatment, the method comprising administering to a subject having a cancer a combination therapy comprising: (a) a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein the T cell therapy is administered on Day 1 of the combination therapy; and (b) an inhibitor of DGKα and / or DGKζ, wherein the administration of the inhibitor is initiated on any of Days 1-8, inclusive, of the combination therapy, and the inhibitor is administered once daily for between or between about 21 and 42 consecutive days, inclusive.

2. The method of claim 1, wherein the administration of the inhibitor is initiated subsequent to the administration of the T cell therapy.

3. A method of treatment, the method comprising administering to a subject having a cancer an inhibitor of DGKα and / or DGKζ, wherein the inhibitor is administered as part of a combination therapy comprising the inhibitor and a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein: prior to initiation of administration of the inhibitor, the subject has been previously administered the T cell therapy, wherein the T cell therapy is administered on Day 1 of the combination therapy; the administration of the inhibitor is initiated on any of Days 1-8, inclusive, of the combination therapy; and the inhibitor is administered once daily for between or between about 21 and 42 consecutive days, inclusive.

4. A method of treatment, the method comprising administering to a subject having a cancer a combination therapy comprising: (a) a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein the T cell therapy is administered on Day 1 of the combination therapy; and(b) an inhibitor of DGKα and / or DGKζ, wherein the administration of the inhibitor is initiated on any of Days 1-8, inclusive, of the combination therapy, and the inhibitor is administered continuously at least until the number of engineered T cells of the T cell therapy has peaked in the subject following administration of the T cell therapy.

5. The method of claim 4, wherein the administration of the inhibitor is initiated subsequent to the administration of the T cell therapy.

6. A method of treatment, the method comprising administering to a subject having a cancer an inhibitor of DGKα and / or DGKζ, wherein the inhibitor is administered as part of a combination therapy comprising the inhibitor and a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein: prior to initiation of administration of the inhibitor, the subject has been previously administered the T cell therapy, wherein the T cell therapy is administered on Day 1 of the combination therapy; the administration of the inhibitor is initiated on any of Days 1-8, inclusive, of the combination therapy; and the inhibitor is administered continuously at least until the number of engineered T cells of the T cell therapy has peaked in the subject following administration of the T cell therapy.

7. The method of claim 4, wherein the administration of the inhibitor is initiated on Day 1 of the combination therapy prior to the administration of the T cell therapy.

8. A method of treatment, the method comprising administering to a subject having a cancer a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein the T cell therapy is administered as part of a combination therapy comprising the T cell therapy and an inhibitor of DGKα and / or DGKζ, wherein: the T cell therapy is administered on Day 1 of the combination therapy; the administration of the inhibitor is initiated on Day 1 of the combination therapy prior to the administration of the T cell therapy; andthe inhibitor is administered continuously at least until the number of engineered T cells of the T cell therapy has peaked in the subject following administration of the T cell therapy.

9. The method of any one of claims 4-8, wherein the inhibitor is administered daily, every two days, or every three days.

10. The method of any one of claims 4-9, wherein the inhibitor is administered daily.

11. The method of any one of claims 4-10, wherein the inhibitor is administered once on each of the days that the inhibitor is administered.

12. The method of any one of claims 4-11, wherein the inhibitor is administered until the number of engineered T cells of the T cell therapy has peaked in the subject following administration of the T cell therapy.

13. The method of any one of claims 4-12, wherein the inhibitor is administered over a period of time between or between about 21 and 42 days, inclusive.

14. A method of treatment, the method comprising administering to a subject having a cancer a combination therapy comprising: (a) a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein the T cell therapy is administered on Day 1 of the combination therapy; and (b) an inhibitor of DGKα and / or DGKζ, wherein the administration of the inhibitor is initiated on any of Days 1-8, inclusive, of the combination therapy, and the inhibitor is administered in a therapeutically effective dose for a period between or between about 21 and 42 days.

15. The method of claim 14, wherein the administration of the inhibitor is initiated subsequent to the administration of the T cell therapy.

16. A method of treatment, the method comprising administering to a subject having a cancer an inhibitor of DGKα and / or DGKζ, wherein the inhibitor is administered as part of a combination therapy comprising the inhibitor and a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein: prior to initiation of administration of the inhibitor, the subject has been previously administered the T cell therapy, wherein the T cell therapy is administered on Day 1 of the combination therapy; the administration of the inhibitor is initiated on any of Days 1-8, inclusive, of the combination therapy; and the inhibitor is administered in a therapeutically effective dose for a period between or between about 21 and 42 days.

17. The method of claim 14, wherein the administration of the inhibitor is initiated on Day 1 of the combination therapy prior to the administration of the T cell therapy.

18. A method of treatment, the method comprising administering to a subject having a cancer a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein the T cell therapy is administered as part of a combination therapy comprising the T cell therapy and an inhibitor of DGKα and / or DGKζ, wherein: the T cell therapy is administered on Day 1 of the combination therapy; the administration of the inhibitor is initiated on Day 1 of the combination therapy prior to the administration of the T cell therapy; and the inhibitor is administered in a therapeutically effective dose for a period between or between about 21 and 42 days.

19. The method of any one of claims 14-18, wherein the therapeutically effective dose provides a dose of the inhibitor that is continuously therapeutically effective for the period between or between about 21 and 42 days.

20. The method of any one of claims 14-19, wherein the inhibitor is administered every 2 days or 3 days.

21. A method of treatment, the method comprising administering to a subject having a cancer a combination therapy comprising: (a) a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein the T cell therapy is administered on Day 1 of the combination therapy; and (b) an inhibitor of DGKα and / or DGKζ, wherein the administration of the inhibitor is initiated on any of Days 1-8, inclusive, of the combination therapy, and the inhibitor is administered in a plurality of cycles each comprising an administration period in which the inhibitor is administered followed by a rest period during which the inhibitor is not administered.

22. The method of claim 21, wherein the administration of the inhibitor is initiated subsequent to the administration of the T cell therapy.

23. A method of treatment, the method comprising administering to a subject having a cancer an inhibitor of DGKα and / or DGKζ, wherein the inhibitor is administered as part of a combination therapy comprising the inhibitor and a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein: prior to initiation of administration of the inhibitor, the subject has been previously administered the T cell therapy, wherein the T cell therapy is administered on Day 1 of the combination therapy; the administration of the inhibitor is initiated on any of Days 1-8, inclusive, of the combination therapy; and the inhibitor is administered in a plurality of cycles each comprising an administration period in which the inhibitor is administered followed by a rest period during which the inhibitor is not administered.

24. The method of any one of claims 21-23, wherein during the administration period, the inhibitor is administered daily, every two days, or every three days.

25. The method of any one of claims 21-24, wherein during the administration period, the inhibitor is administered daily.

26. The method of any one of claims 21-25, wherein during the administration period, the inhibitor is administered once on each of the days that the inhibitor is administered.

27. The method of any one of claims 21-26, wherein over the plurality of cycles, the inhibitor is administered until the number of engineered T cells of the T cell therapy has peaked in the subject following administration of the T cell therapy.

28. The method of any one of claims 21-27, wherein over the plurality of cycles, the inhibitor is administered over a period of time between or between about 21 and 42 days, inclusive.

29. The method of any one of claims 1-28, wherein the administration of the inhibitor is initiated on any of Days 1-6, inclusive, of the combination therapy, on any of Days 1-4, inclusive, of the combination therapy, on Day 1 or Day 2 of the combination therapy, and / or on Day 1 of the combination therapy.

30. The method of claim 1 or claim 29, wherein the administration of the inhibitor is initiated on Day 1 of the combination therapy prior to the administration of the T cell therapy.

31. A method of treatment, the method comprising administering to a subject having a cancer a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein the T cell therapy is administered as part of a combination therapy comprising the T cell therapy and an inhibitor of DGKα and / or DGKζ, wherein: the T cell therapy is administered on Day 1 of the combination therapy;the administration of the inhibitor is initiated on Day 1 of the combination therapy prior to the administration of the T cell therapy; and the inhibitor is administered once daily for between or between about 21 and 42 consecutive days, inclusive.

32. The method of any one of claims 1-31, wherein the inhibitor, optionally over the plurality of cycles, is administered over a period of time between or between about 21 and 35 days, inclusive, a period of time between or between about 21 and 28 days, inclusive; a period of time between or between about 28 and 42 days, inclusive; a period of time between or between about 28 and 35 days, inclusive; a period of time that is or is about 28 days; and / or a period of time that is or is about 30 days.

33. A method of treatment, the method comprising administering to a subject having a cancer a combination therapy comprising: (a) a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein the T cell therapy is administered on Day 1 of the combination therapy; and (b) an inhibitor of DGKα and / or DGKζ, wherein the administration of the inhibitor is initiated on Day 1 of the combination therapy, and the inhibitor is administered once daily on Days 1-28, inclusive, of the combination therapy.

34. The method of claim 33, wherein the administration of the inhibitor is initiated subsequent to the administration of the T cell therapy.

35. A method of treatment, the method comprising administering to a subject having a cancer an inhibitor of DGKα and / or DGKζ, wherein the inhibitor is administered as part of a combination therapy comprising the inhibitor and a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein: prior to initiation of administration of the inhibitor, the subject has been previously administered the T cell therapy, wherein the T cell therapy is administered on Day 1 of the combination therapy;the administration of the inhibitor is initiated on Day 1 of the combination therapy; and the inhibitor is administered once daily on Days 1-28, inclusive, of the combination therapy.

36. The method of claim 33, wherein the administration of the inhibitor is initiated prior to the administration of the T cell therapy.

37. A method of treatment, the method comprising administering to a subject having a cancer a T cell therapy comprising viable engineered T cells expressing a recombinant receptor directed against an antigen expressed by cells of the cancer, wherein the T cell therapy is administered as part of a combination therapy comprising the T cell therapy and an inhibitor of DGKα and / or DGKζ, wherein: the T cell therapy is administered on Day 1 of the combination therapy; the administration of the inhibitor is initiated on Day 1 of the combination therapy prior to the administration of the T cell therapy; and the inhibitor is administered once daily on Days 1-28, inclusive, of the combination therapy.

38. The method of any one of claims 33-37, wherein the inhibitor is administered once daily on Days 1-30, inclusive, of the combination therapy.

39. The method of any one of claims 1-38, wherein the administration of the inhibitor is initiated within or within about 12 hours of the administration of the T cell therapy, within or within about 6 hours of the administration of the T cell therapy, or within or within about 4 hours of the administration of the T cell therapy.

40. The method of any one of claims 1-39, wherein the administration of the inhibitor is initiated within or within about 2 hours of the administration of the T cell therapy.

41. The method of any one of claims 1-40, wherein the administration of the inhibitor is initiated within or within about 1 hour of the administration of the T cell therapy.

42. The method of any one of claims 1, 4, 9-14, 19-24, 27-32, and 37-41, wherein the administration of the inhibitor is initiated on Day 1 of the combination therapy concurrently with the administration of the T cell therapy.

43. The method of any one of claims 1, 4, 9-14, 19-24, 27-32, and 37-42, wherein the administration of the inhibitor is initiated on Day 1 of the combination therapy during the administration of the T cell therapy.

44. The method of any one of claims 1-43, wherein prior to the administration of the T cell therapy, the subject has been preconditioned with a lymphodepleting therapy comprising administration of fludarabine and / or cyclophosphamide.

45. The method of claim 44, wherein the method further comprises administering the lymphodepleting therapy to the subject.

46. The method of claim 44 or claim 45, wherein the lymphodepleting therapy comprises administration of: cyclophosphamide at between or between about 200 and 400 mg / m2, inclusive, daily for between or between about 2 and 4 days, inclusive; and / or fludarabine at between or between about 20 and 40 mg / m2, inclusive, daily for between or between about 2 and 4 days, inclusive.

47. The method of any one of claims 44-46, wherein the lymphodepleting therapy comprises administration of cyclophosphamide at or at about 300 mg / m2and fludarabine at or at about 30 mg / m2each daily for or for about 3 days.

48. The method of any one of claims 44-47, wherein the T cell therapy is administered between or between about 2 and 7 days, inclusive, after the administration of the lymphodepleting therapy.

49. The method of any one of claims 1-48, wherein the inhibitor is an inhibitor of DGKα and not a significant inhibitor of DGKζ.

50. The method of any one of claims 1-48, wherein the inhibitor is an inhibitor of DGKζ and not a significant inhibitor of DGKα.

51. The method of any one of claims 1-48, wherein the inhibitor is an inhibitor of DGKα and DGKζ.

52. The method of any one of claims 1-51, wherein the inhibitor is not a significant inhibitor of other DGKs.

53. The method of any one of claims 1-52, wherein the inhibitor is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: R1is H, F, Cl, Br, -CN, C1-3alkyl substituted with zero to 4 R1a, C3-4cycloalkyl substituted with zero to 4 R1a, C1-3alkoxy substituted with zero to 4 R1a, -NRaRa, -S(O)nRe, or -P(O)ReRe; each R1ais independently F, Cl, -CN, -OH, -OCH3, or -NRaRa; each Rais independently H or C1-3alkyl; each Reis independently C3-4cycloalkyl or C1-3alkyl substituted with zero to 4 R1a; R2is H, C1-3alkyl substituted with zero to 4 R2a, or C3-4cycloalkyl substituted with zero to 4 R2a; each R2ais independently F, Cl, -CN, -OH, -O(C1-2alkyl), C3-4cycloalkyl, C3-4alkenyl, or C3-4alkynyl; R3is H, F, Cl, Br, -CN, C1-3alkyl, C1-2fluoroalkyl, C3-4cycloalkyl, C3-4fluorocycloalkyl, or -NO2;R4is -CH2R4a, -CH2CH2R4a, -CH2CHR4aR4d, -CHR4aR4b, or -CR4aR4bR4c; R4aand R4bare independently: (i) C1-6alkyl substituted with zero to 4 substituents independently selected from F, Cl, -CN, -OH, -OCH3, -SCH3, C1-3fluoroalkoxy, -NRaRa, -S(O)2Re, or -NRaS(O)2Re; (ii) C3-6cycloalkyl, heterocyclyl, phenyl, or heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, C1-4hydroxyalkyl, -(CH2)1-2O(C1-3alkyl), C1-4alkoxy, -O(C1-4hydroxyalkyl), -O(CH)1-3O(C1-3alkyl), C1-3fluoroalkoxy, -O(CH)1-3NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), -P(O)(C1-3alkyl)2, -S(O)2(C1-3alkyl), -O(CH2)1-2(C3-6cycloalkyl), -O(CH2)1-2(morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and Rd; or (iii) C1-4alkyl substituted with one cyclic group selected from C3-6cycloalkyl, heterocyclyl, aryl, and heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-6cycloalkyl; or R4aand R4btogether with the carbon atom to which they are attached form a C3-6cycloalkyl or a 3- to 6-membered heterocyclyl, each substituted with zero to 3 Rf; each Rfis independently F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, or a cyclic group selected from C3-6cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, and -NRcRc; R4cis C1-6alkyl or C3-6cycloalkyl, each substituted with zero to 4 substituents independently selected from F, Cl, -OH, C1-2alkoxy, C1-2fluoroalkoxy, and -CN; R4dis -OCH3;each Rcis independently H or C1-2alkyl; Rdis phenyl substituted with zero to 1 substituent selected from F, Cl, -CN, -CH3, and -OCH3; each R5 is independently -CN, C1-6alkyl substituted with zero to 4 Rg, C2-4alkenyl substituted with zero to 4 Rg, C2-4alkynyl substituted with zero to 4 Rg, C3-4cycloalkyl substituted with zero to 4 Rg, phenyl substituted with zero to 4 Rg, oxadiazolyl substituted with zero to 3 Rg, pyridinyl substituted with zero to 4 Rg, -(CH2)1-2(heterocyclyl substituted with zero to 4 Rg), -(CH2)1-2NRcC(O)(C1-4alkyl), -(CH2)1-2NRcC(O)O(C1-4alkyl), -(CH2)1-2NRcS(O)2(C1-4alkyl), -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -C(O)O(C3-4cycloalkyl), -C(O)NRaRa, or -C(O)NRa(C3-4cycloalkyl); each Rgis independently F, Cl, -CN, -OH, C1-3alkoxy, C1-3fluoroalkoxy, -O(CH2)1-2O(C1-2alkyl), or -NRcRc; m is zero, 1, 2, or 3; and n is zero, 1, or 2.

54. The method of claim 53, wherein the inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: R1is H, F, Cl, Br, -CN, C1-3alkyl substituted with zero to 4 R1a, cyclopropyl substituted with zero to 3 R1a, C1-3alkoxy substituted with zero to 3 R1a, -NRaRa, -S(O)nCH3, or -P(O)(CH3)2; each R1ais independently F, Cl, or -CN; each Rais independently H or C1-3alkyl; R2is H or C1-2alkyl substituted with zero to 2 R2a; each R2ais independently F, Cl, -CN, -OH, -O(C1-2alkyl), cyclopropyl, C3-4alkenyl, or C3-4alkynyl; R3is H, F, Cl, Br, -CN, C1-2alkyl, -CF3, cyclopropyl, or -NO2; R4aand R4bare independently: (i) C1-4alkyl substituted with zero to 4 substituents independently selected from F, Cl, -CN, -OH, -OCH3, -SCH3, C1-3fluoroalkoxy, and -NRaRa; (ii) C3-6cycloalkyl, heterocyclyl, phenyl, or heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, -CH2OH, -(CH2)1-2O(C1-2alkyl), C1-4alkoxy, -O(C1-4hydroxyalkyl),-O(CH)1-2O(C1-2alkyl), C1-3fluoroalkoxy, -O(CH)1-2NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), -P(O)(C1-2alkyl)2, -S(O)2(C1-3alkyl), -O(CH2)1-2(C3-4cycloalkyl), -O(CH2)1-2(morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert- butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and Rd; or (iii) C1-3alkyl substituted with one cyclic group selected from C3-6cycloalkyl, heterocyclyl, phenyl, and heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-3alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-4cycloalkyl; or R4aand R4btogether with the carbon atom to which they are attached, form a C3-6cycloalkyl or a 3- to 6-membered heterocyclyl, each substituted with zero to 3 Rf; each Rfis independently F, Cl, Br, -OH, -CN, C1-4alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, or a cyclic group selected from C3-6cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-4alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, and -NRcRc; R4cis C1-4alkyl or C3-6cycloalkyl, each substituted with zero to 4 substituents independently selected from F, Cl, -OH, C1-2alkoxy, C1-2fluoroalkoxy, and -CN; and each R5is independently -CN, C1-5alkyl substituted with zero to 4 Rg, C2-3alkenyl substituted with zero to 4 Rg, C2-3alkynyl substituted with zero to 4 Rg, C3-4cycloalkyl substituted with zero to 4 Rg, phenyl substituted with zero to 3 Rg, oxadiazolyl substituted with zero to 3 Rg, pyridinyl substituted with zero to 3 Rg, -(CH2)1-2(heterocyclyl substituted with zero to 4 Rg), -(CH2)1-2NRcC(O)(C1-4alkyl), -(CH2)1-2NRcC(O)O(C1-4alkyl), -(CH2)1-2NRcS(O)2(C1-4alkyl), -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -C(O)O(C3-4cycloalkyl), -C(O)NRaRa, or -C(O)NRa(C3-4cycloalkyl).

55. The method of claim 54, wherein the inhibitor is a compound of Formula (I) or apharmaceutically acceptable salt thereof having the structure:wherein: R1is -CN; R2is -CH3; R3is H, F, or -CN; R4is:

56. The method of claim 53, wherein the inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof having the structure:.

57. The method of any one of claims 1-52, wherein the inhibitor is a compound of Formula (II):or a salt thereof, wherein: R1is H, F, Cl, Br, -CN, -OH, C1-3alkyl substituted with zero to 4 R1a, C3-4cycloalkyl substituted with zero to 4 R1a, C1-3alkoxy substituted with zero to 4 R1a, -NRaRa, -S(O)nRe, or -P(O)ReRe; each R1ais independently F, Cl, -CN, -OH, -OCH3, or -NRaRa; each Rais independently H or C1-3alkyl; each Reis independently C3-4cycloalkyl or C1-3alkyl substituted with zero to 4 R1a; R2is H, C1-3alkyl substituted with zero to 4 R2a, or C3-4cycloalkyl substituted with zero to 4 R2a; each R2ais independently F, Cl, -CN, -OH, -O(C1-2alkyl), C3-4cycloalkyl, C3-4alkenyl, or C3-4alkynyl; R4is -CH2R4a, -CH2CH2R4a, -CH2CHR4aR4d, -CHR4aR4b, or -CR4aR4bR4c; R4aand R4bare independently: (i) -CN or C1-6alkyl substituted with zero to 4 substituents independently selected from F, Cl, -CN -OH -OCH3-SCH3C1-3fluoroalkoxy -NRaRa-S(O)2Reor -NRaS(O)2Re;(ii) C3-6cycloalkyl, 4- to 10-membered heterocyclyl, phenyl, or 5-to 10-membered heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, C1-2bromoalkyl, C1-2cyanoalkyl, C1-4hydroxyalkyl, -(CH2)1-2O(C1-3alkyl), C1-4alkoxy, C1-3fluoroalkoxy, C1-3cyanoalkoxy, -O(C1-4hydroxyalkyl), -O(CRxRx)1-3O(C1-3alkyl), C1-3fluoroalkoxy, -O(CH2)1-3NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -CH2NRaRa, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -(CRxRx)0-2NRaC(O)O(C1-4alkyl), -P(O)(C1-3alkyl)2, -S(O)2(C1-3alkyl), -(CRxRx)1-2(C3-4cycloalkyl), -(CRxRx)1-2(morpholinyl), -(CRxRx)1-2(difluoromorpholinyl), -(CRxRx)1-2(dimethylmorpholinyl), -(CRxRx)1-2(oxaazabicyclo[2.2.1]heptanyl), (CRxRx)1-2(oxaazaspiro[3.3]heptanyl), -(CRxRx)1-2(methylpiperazinonyl), -(CRxRx)1-2(acetylpiperazinyl), -(CRxRx)1-2(piperidinyl), -(CRxRx)1-2(difluoropiperidinyl), -(CRxRx)1-2(methoxypiperidinyl), -(CRxRx)1-2(hydroxypiperidinyl), -O(CRxRx)0-2(C3-6cycloalkyl), -O(CRxRx)0-2(methylcyclopropyl), -O(CRxRx)0-2((ethoxycarbonyl)cyclopropyl), -O(CRxRx)0-2(oxetanyl), -O(CRxRx)0-2(methylazetidinyl), -O(CRxRx)0-2(tetrahydropyranyl), -O(CRxRx)1-2(morpholinyl), -O(CRxRx)0-2(thiazolyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, dioxolanyl, pyrrolidinonyl, and Rd; or (iii) C1-4alkyl substituted with one cyclic group selected from C3-6cycloalkyl, 4- to 10- membered heterocyclyl, mono- or bicyclic aryl, or 5-to 10-membered heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-6cycloalkyl; or R4aand R4btogether with the carbon atom to which they are attached form a C3-6cycloalkyl or a 3- to 6-membered heterocyclyl, each substituted with zero to 3 Rf; each Rfis independently F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, or a cyclic group selected from C3-6cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-6alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, and -NRcRc; R4cis C1-6alkyl or C3-6cycloalkyl, each substituted with zero to 4 substituents independently selected from F, Cl, -OH, C1-2alkoxy, C1-2fluoroalkoxy, and -CN; R4dis -OCH3; each Rcis independently H or C1-2alkyl; Rdis phenyl substituted with zero to 1 substituent selected from F, Cl, -CN, -CH3, and -OCH3; each R5is independently -CN, C1-6alkyl substituted with zero to 4 Rg, C2-4alkenyl substituted with zero to 4 Rg, C2-4alkynyl substituted with zero to 4 Rg, C3-4cycloalkyl substituted with zero to 4 Rg, phenyl substituted with zero to 4 Rg, oxadiazolyl substituted with zero to 3 Rg, pyridinyl substituted with zero to 4 Rg, -(CH2)1-2(4- to 10-membered heterocyclyl substituted with zero to 4 Rg), -(CH2)1-2NRcC(O)(C1-4alkyl), -(CH2)1-2NRcC(O)O(C1-4alkyl), -(CH2)1-2NRcS(O)2(C1-4alkyl), -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -C(O)O(C3-4cycloalkyl), -C(O)NRaRa, or -C(O)NRa(C3-4cycloalkyl); each Rgis independently F, Cl, -CN, -OH, C1-3alkoxy, C1-3fluoroalkoxy, -O(CH2)1-2O(C1-2alkyl), or -NRcRc; m is zero, 1, 2, or 3; and n is zero, 1, or 2.

58. The method of claim 57, wherein the inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof, wherein: R1 is H, F, Cl, Br, -CN, -OH, C1-3alkyl substituted with zero to 4 R1a, cyclopropyl substituted with zero to 3 R1a, C1-3alkoxy substituted with zero to 3 R1a, -NRaRa, -S(O)nCH3, or -P(O)(CH3)2; R2is H or C1-2alkyl substituted with zero to 2 R2a; each R2ais independently F, Cl, -CN, -OH, -O(C1-2alkyl), cyclopropyl, C3-4alkenyl, or C3-4alkynyl; R4aand R4bare independently:(i) -CN or C1-4alkyl substituted with zero to 4 substituents independently selected from F, Cl, -CN, -OH, -OCH3, -SCH3, C1-3fluoroalkoxy, and -NRaRa; (ii) C3-6cycloalkyl, 4- to 10-membered heterocyclyl, phenyl, or 5-to 10-membered heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, -CN, -OH, C1-6alkyl, C1-3fluoroalkyl, C1-2bromoalkyl, C1-2cyanoalkyl, C1-2hydroxyalkyl, -CH2NRaRa, -(CH2)1-2O(C1-2alkyl), -(CH2)1-2NRxC(O)O(C1-2alkyl), C1-4alkoxy, -O(C1-4hydroxyalkyl), -O(CRxRx)1-2O(C1-2alkyl), C1-3fluoroalkoxy, C1-3cyanoalkoxy, -O(CH2)1-2NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), -P(O)(C1-2alkyl)2, -S(O)2(C1-3alkyl), -(CH2)1-2(C3-4cycloalkyl), -CRxRx(morpholinyl), -CRxRx(difluoromorpholinyl), -CRxRx(dimethylmorpholinyl), -CRxRx(oxaazabicyclo[2.2.1]heptanyl), -CRxRx(oxaazaspiro[3.3]heptanyl), -CRxRx(methylpiperazinonyl), -CRxRx(acetylpiperazinyl), -CRxRx(piperidinyl), -CRxRx(difluoropiperidinyl), -CRxRx(methoxypiperidinyl), -CRxRx(hydroxypiperidinyl), -O(CH2)0-2(C3-4cycloalkyl), -O(CH2)0-2(methylcyclopropyl), -O(CH2)0-2((ethoxycarbonyl)cyclopropyl), -O(CH2)0-2(oxetanyl), -O(CH2)0-2(methylazetidinyl), -O(CH2)1-2(morpholinyl), -O(CH2)0-2(tetrahydropyranyl), -O(CH2)0-2(thiazolyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, dioxolanyl, pyrrolidinonyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and Rd; or (iii) C1-3alkyl substituted with one cyclic group selected from C3-6cycloalkyl, 4- to 10- membered heterocyclyl, mono- or bicyclic aryl, or 5-to 10-membered heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-3alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, -NRaS(O)2(C1-3alkyl), -NRaC(O)(C1-3alkyl), -NRaC(O)O(C1-4alkyl), and C3-4cycloalkyl; or R4aand R4btogether with the carbon atom to which they are attached, form a C3-6cycloalkyl or a 3- to 6-membered heterocyclyl, each substituted with zero to 3 Rf; each Rfis independently F, Cl, Br, -OH, -CN, C1-4alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRcRc, or a cyclic group selected from C3-6cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, -OH, -CN, C1-4alkyl, C1-2fluoroalkyl, C1-3alkoxy, C1-2fluoroalkoxy, and -NRcRc; R4cis C1-4alkyl or C3-6cycloalkyl, each substituted with zero to 4 substituents independently selected from F, Cl, -OH, C1-2alkoxy, C1-2fluoroalkoxy, and -CN; each R5is independently -CN, C1-5alkyl substituted with zero to 4 Rg, C2-3alkenyl substituted with zero to 4 Rg, C2-3alkynyl substituted with zero to 4 Rg, C3-4cycloalkyl substituted with zero to 4 Rg, phenyl substituted with zero to 3 Rg, oxadiazolyl substituted with zero to 3 Rg, pyridinyl substituted with zero to 3 Rg, -(CH2)1-2(4- to 10-membered heterocyclyl substituted with zero to 4 Rg), -(CH2)1-2NRcC(O)(C1-4alkyl), -(CH2)1-2NRcC(O)O(C1-4alkyl), -(CH2)1-2NRcS(O)2(C1-4alkyl), -C(O)(C1-4alkyl), -C(O)OH, -C(O)O(C1-4alkyl), -C(O)O(C3-4cycloalkyl), -C(O)NRaRa, or -C(O)NRa(C3-4cycloalkyl); each Rxis independently H or -CH3; and m is 1, 2, or 3.

59. The method of claim 58, wherein the inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof having the structure:R1is -CN; R2is -CH3; R5ais -CH3or -CH2CH3; and R5cis -CH3, -CH2CH3, or -CH2CH2CH3.

60. The method of claim 57, wherein the inhibitor is a compound of Formula (II) or apharmaceutically acceptable salt thereof having the structure:.

61. The method of claim 57, wherein the inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof having the structure:.

62. The method of any one of claims 1-13 and 21-61, wherein the inhibitor is administered in a therapeutically effective amount.

63. The method of claim 62, wherein the therapeutically effective dose provides a dose of the inhibitor that is continuously therapeutically effective for the period of time that the inhibitor is administered.

64. The method of any one of claims 1-63, wherein the inhibitor is administered in a per day amount between or between about 0.25 and 250 mg, inclusive.

65. The method of any one of claims 1-64, wherein the inhibitor is administered in a per day amount between or between about 0.5 and 100 mg, inclusive.

66. The method of any one of claims 1-65, wherein the inhibitor is administered orally.

67. The method of any one of claims 1-66, wherein the recombinant receptor is an engineered T cell receptor (eTCR).

68. The method of any one of claims 1-66, wherein the recombinant receptor is a chimeric antigen receptor (CAR).

69. The method of claim 68, wherein the antigen is CD19, and the CAR is an anti- CD19 CAR.

70. The method of claim 68 or claim 69, wherein the CAR is the CAR of BREYANZI® (lisocabtagene maraleucel), TECARTUS™ (brexucabtagene autoleucel), KYMRIAH™ (tisagenlecleucel), or YESCARTA™ (axicabtagene ciloleucel).

71. The method of any one of claims 68-70, wherein the T cell therapy is BREYANZI® (lisocabtagene maraleucel), TECARTUS™ (brexucabtagene autoleucel), KYMRIAH™ (tisagenlecleucel), or YESCARTA™ (axicabtagene ciloleucel).

72. The method of claim 68, wherein the antigen is BCMA, and the CAR is an anti- BCMA CAR.

73. The method of claim 68 or claim 72, wherein the CAR is the CAR of ABECMA® (idecabtagene vicleucel) or CARVYKTI™ (ciltacabtagene autoleucel).

74. The method of any one of claims 68, 72, and 73, wherein the T cell therapy is ABECMA® (idecabtagene vicleucel) or CARVYKTI™ (ciltacabtagene autoleucel).

75. The method of any one of claims 1-74, wherein the cancer is a solid tumor.

76. The method of any one of claims 1-74, wherein the cancer is a hematological (liquid) tumor.

77. The method of any one of claims 1-76, wherein the cancer is a B cell malignancy.

78. The method of any one of claims 1-74, 76, and 77, wherein the cancer is a leukemia.

79. The method of any one of claims 1-74, 76, and 77, wherein the cancer is a lymphoma.

80. The method of any one of claims 1-74, 76, and 77, wherein the cancer is a myeloma.

81. The method of claim 80, wherein the myeloma is multiple myeloma.

82. The method of any one of claims 1-81, wherein the cancer is relapsed or refractory.

83. The method of any one of claims 1-82, wherein the T cell therapy comprises between or between about 0.1 x 106and 1,000 x 106total recombinant receptor-expressing T cells, inclusive.

84. The method of any one of claims 1-83, wherein the T cell therapy comprises between or between about 10 x 106and 1,000 x 106total recombinant receptor-expressing T cells, inclusive.

85. The method of any one of claims 1-84, wherein the T cell therapy comprises between or between about 10 x 106and 500 x 106total recombinant receptor-expressing T cells, inclusive.

86. The method of any of claims 83-85, wherein the recombinant receptor-expressing T cells are viable recombinant receptor-expressing T cells.

87. The method of any one of claims 1-86, wherein the T cell therapy is administered intravenously.

88. The method of any one of claims 1-87, wherein the T cells of the T cell therapy are autologous to the subject.

89. The method of any one of claims 1-87, wherein the T cells of the T cell therapy are allogeneic to the subject.

90. The method of any one of claims 1-89, wherein the T cells of the T cell therapy are human T cells.

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