Combination of T-cell therapy and continuous or intermittent DGK inhibitor dosing

Abstract

Provided herein are methods, compositions, and uses relating to T cell therapy, such as adoptive T cell therapy, and inhibitors of diacylglycerol kinase (DGK). The provided methods, compositions, and uses include methods, compositions, and uses relating to the administration or use of one or more DGK inhibitors (DGKi) in combination therapy with T cell therapy, such as genetically engineered T cell therapy involving cells engineered with recombinant receptors, such as chimeric antigen receptors (CARs) or T cell receptors (TCRs).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 404,955, filed September 8, 2022, the entire contents of which are incorporated herein by reference for all purposes.

[0002] Incorporation by reference to sequence listing This application is being filed with an electronic Sequence Listing, which is provided as a file entitled 735042026540SeqList.xml, created on August 23, 2023, and which is 358 kilobytes in size. The information in the electronic Sequence Listing is incorporated by reference in its entirety.

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

[0004] For example, various strategies are available for T cell therapy, such as administering engineered T cells for adoptive therapy.For example, a strategy for engineering T cells is available, such as expressing engineered antigen receptors, such as CAR or TCR, and administering a composition containing such cells to a subject.There is a need for improved strategies for improving the effectiveness of T cells in cell therapy, for example, by improving the persistence, activity, and / or proliferation of cells during or after administration to a subject.Methods, compositions, uses, and kits that meet such needs are provided. Summary of the Invention

[0005] In some embodiments, provided herein are methods of treatment, comprising administering to a subject having cancer: (a) a T cell therapy comprising viable engineered T cells that express a recombinant receptor for 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 administration of the inhibitor begins on any of days 1-8, inclusive, of the combination therapy, and wherein the inhibitor is administered continuously until at least the number of engineered T cells of the T cell therapy peaks in the subject following administration of the T cell therapy.

[0006] In some of either embodiments, administration of the inhibitor begins subsequent to administration of the T cell therapy.

[0007] Also provided herein in some embodiments are methods of treatment, comprising administering to a subject having cancer an inhibitor of DGKα and / or DGKζ, where the inhibitor is administered as part of a combination therapy comprising the inhibitor and a T cell therapy comprising viable engineered T cells that express a recombinant receptor for an antigen expressed by cells of the cancer: the subject has previously been administered T cell therapy prior to initiation of administration of the inhibitor, and the T cell therapy is administered on day 1 of the combination therapy; administration of the inhibitor is initiated on any of days 1 to 8 (inclusive) of the combination therapy; and the inhibitor is continuously administered at least until the number of engineered T cells of the T cell therapy peaks in the subject after administration of the T cell therapy.

[0008] In some of either embodiment, administration of the inhibitor begins on day 1 of the combination therapy, prior to administration of the T cell therapy.

[0009] Also provided herein in some embodiments are methods of treatment, comprising administering to a subject having cancer a T cell therapy comprising viable engineered T cells that express a recombinant receptor for 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: the T cell therapy is administered on day 1 of the combination therapy; administration of the inhibitor is initiated on day 1 of the combination therapy, prior to administration of the T cell therapy; and the inhibitor is administered continuously until at least the number of engineered T cells of the T cell therapy peaks in the subject after administration of the T cell therapy.

[0010] In some of any of the embodiments, the inhibitor is administered daily, every other day, or every third day. In some of any of the embodiments, the inhibitor is administered daily.

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

[0012] In some of either embodiment, the inhibitor is administered until the number of engineered T cells of the T cell therapy peaks in the subject after administration of the T cell therapy.

[0013] In some of either embodiments, the inhibitor is administered for a period of 21 to 42 days or about 21 to 42 days, inclusive.

[0014] Also provided herein in some embodiments are methods of treatment, comprising administering to a subject having cancer: (a) a T cell therapy comprising viable engineered T cells that express a recombinant receptor for 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 administration of the inhibitor begins on any of days 1-8 (inclusive) of the combination therapy, and wherein the inhibitor is administered at a therapeutically effective dose for a period of 21-42 days or about 21-42 days.

[0015] In some of either embodiments, administration of the inhibitor begins subsequent to administration of the T cell therapy.

[0016] Also provided herein in some embodiments are methods of treatment, comprising administering to a subject having cancer an inhibitor of DGKα and / or DGKζ, where 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 for an antigen expressed by cells of the cancer: the subject has previously been administered T cell therapy prior to initiation of administration of the inhibitor, and the T cell therapy is administered on day 1 of the combination therapy; administration of the inhibitor is initiated on any of days 1 to 8 (inclusive) of the combination therapy; and the inhibitor is administered at a therapeutically effective dose for a period of 21 to 42 days or about 21 to 42 days.

[0017] In some of either embodiment, administration of the inhibitor begins on day 1 of the combination therapy, prior to administration of the T cell therapy.

[0018] Also provided herein in some embodiments are methods of treatment, comprising administering to a subject having cancer a T cell therapy comprising viable engineered T cells that express a recombinant receptor for 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: the T cell therapy is administered on day 1 of the combination therapy; administration of the inhibitor is initiated on day 1 of the combination therapy, prior to administration of the T cell therapy; and the inhibitor is administered at a therapeutically effective dose for a period of at or about 21 to 42 days.

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

[0020] In some of either embodiments, the inhibitor is administered every two or three days.

[0021] Also provided herein in some embodiments are methods of treatment, comprising administering to a subject having cancer: (a) a T cell therapy comprising viable engineered T cells that express a recombinant receptor for 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 administration of the inhibitor begins on any of days 1-8 (inclusive) of the combination therapy, and the inhibitor is administered in multiple cycles, each cycle comprising an administration period during which the inhibitor is administered followed by a rest period during which the inhibitor is not administered.

[0022] In some of either embodiments, administration of the inhibitor begins subsequent to administration of the T cell therapy.

[0023] Also provided herein in some embodiments are methods of treatment, comprising administering to a subject having cancer an inhibitor of DGKα and / or DGKζ, where 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 for an antigen expressed by cells of the cancer: where the subject has previously been administered T cell therapy prior to initiation of administration of the inhibitor, and the T cell therapy is administered on day 1 of the combination therapy; where administration of the inhibitor is initiated on any of days 1 to 8 (inclusive) of the combination therapy; or where the inhibitor is administered in multiple cycles, each cycle comprising an administration period during which the inhibitor is administered followed by a rest period during which the inhibitor is not administered.

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

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

[0026] In some of either embodiment, the inhibitor is administered over multiple cycles until the number of engineered T cells of the T cell therapy peaks in the subject after administration of the T cell therapy.

[0027] In some of either embodiments, the inhibitor is administered for a period of 21 to 42 days or about 21 to 42 days, inclusive, over multiple cycles.

[0028] Also provided herein in some embodiments are methods of treatment, comprising administering to a subject having cancer: (a) a T cell therapy comprising viable engineered T cells that express a recombinant receptor for 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 administration of the inhibitor begins on any of days 1-8, inclusive, of the combination therapy, and the inhibitor is administered once daily for 21-42 consecutive days or about 21-42 days, inclusive.

[0029] In some of either embodiments, administration of the inhibitor begins subsequent to administration of the T cell therapy.

[0030] Also provided herein in some embodiments are methods of treatment, comprising administering to a subject having cancer an inhibitor of DGKα and / or DGKζ, where 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 for an antigen expressed by cells of the cancer: where the subject has previously been administered T cell therapy prior to initiation of administration of the inhibitor, and the T cell therapy is administered on day 1 of the combination therapy; where administration of the inhibitor is initiated on any of days 1-8, inclusive, of the combination therapy; or where the inhibitor is administered once daily for 21-42 consecutive days or for about 21-42 days, inclusive.

[0031] In some of any of the embodiments, administration of the inhibitor begins on any of days 1-6 (inclusive) of combination therapy. In some of any of the embodiments, administration of the inhibitor begins on any of days 1-4 (inclusive) of combination therapy. In some of any of the embodiments, administration of the inhibitor begins on day 1 or day 2 of combination therapy. In some of any of the embodiments, administration of the inhibitor begins on day 1 of combination therapy.

[0032] In some of either embodiment, administration of the inhibitor begins on day 1 of the combination therapy, prior to administration of the T cell therapy.

[0033] Also provided herein in some embodiments are methods of treatment, comprising administering to a subject having cancer a T cell therapy comprising viable engineered T cells that express a recombinant receptor for 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: the T cell therapy is administered on day 1 of the combination therapy; administration of the inhibitor is initiated on day 1 of the combination therapy, prior to administration of the T cell therapy; and the inhibitor is administered once daily for 21 to 42 consecutive days or for about 21 to 42 days, inclusive.

[0034] In some of any of the embodiments, the inhibitor is administered for a period of 21 to 35 days or about 21 to 35 days, inclusive. In some of any of the embodiments, the inhibitor is administered for a period of 21 to 28 days or about 21 to 28 days, inclusive. In some of any of the embodiments, the inhibitor is administered for a period of 28 to 42 days or about 28 to 42 days, inclusive. In some of any of the embodiments, the inhibitor is administered for a period of 28 to 35 days or about 28 to 35 days, inclusive. In some of any of the embodiments, the inhibitor is administered for a period of 28 days or about 28 days. In some of any of the embodiments, the inhibitor is administered for a period of 30 days or about 30 days.

[0035] In some of any of the embodiments, over multiple cycles, the inhibitor is administered for a period of 21 to 35 days or about 21 to 35 days, inclusive. In some of any of the embodiments, over multiple cycles, the inhibitor is administered for a period of 21 to 28 days or about 21 to 28 days, inclusive. In some of any of the embodiments, over multiple cycles, the inhibitor is administered for a period of 28 to 42 days or about 28 to 42 days, inclusive. In some of any of the embodiments, over multiple cycles, the inhibitor is administered for a period of 28 to 35 days or about 28 to 35 days, inclusive. In some of any of the embodiments, over multiple cycles, the inhibitor is administered for a period of 28 days or about 28 days. In some of any of the embodiments, over multiple cycles, the inhibitor is administered for a period of 30 days or about 30 days.

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

[0037] Also provided herein in some embodiments are methods of treatment, comprising administering to a subject having cancer: (a) a T cell therapy comprising viable engineered T cells that express a recombinant receptor for 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 administration of the inhibitor begins on day 1 of the combination therapy and the inhibitor is administered once daily on days 1 through 28 (inclusive) of the combination therapy.

[0038] In some of either embodiments, administration of the inhibitor begins subsequent to administration of the T cell therapy.

[0039] Also provided herein in some embodiments are methods of treatment, comprising administering to a subject having cancer an inhibitor of DGKα and / or DGKζ, where 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 for an antigen expressed by cells of the cancer: prior to initiation of administration of the inhibitor, the subject has previously administered T cell therapy, where the T cell therapy is administered on day 1 of the combination therapy; administration of the inhibitor is initiated on day 1 of the combination therapy; or the inhibitor is administered once daily on days 1 through 28 (inclusive) of the combination therapy.

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

[0041] Also provided herein in some embodiments are methods of treatment, comprising administering to a subject having cancer a T cell therapy comprising viable engineered T cells that express a recombinant receptor for 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: the T cell therapy is administered on day 1 of the combination therapy; administration of the inhibitor is initiated on day 1 of the combination therapy, prior to administration of the T cell therapy; and the inhibitor is administered once daily on days 1 through 28 (inclusive) of the combination therapy.

[0042] In some of either embodiment, the inhibitor is administered once daily on days 1 through 30 (inclusive) of combination therapy.

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

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

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

[0046] In some of these embodiments, lymphodepletion therapy includes a daily dose of 200-400 mg / m for 2-4 days or about 2-4 days, inclusive. 2 or approximately 200-400 mg / m 2 cyclophosphamide (inclusive); and / or 20-40 mg / m daily for 2-4 days or about 2-4 days (inclusive)2 or approximately 20-40 mg / m 2 In some of the embodiments, the lymphodepletion therapy comprises administration of 200-400 mg / m2 fludarabine daily for 2-4 days or about 2-4 days (inclusive). 2 or approximately 200-400 mg / m 2 In some of the embodiments, the lymphodepletion therapy comprises administration of cyclophosphamide at 20-40 mg / m daily for 2-4 days or about 2-4 days (inclusive). 2 or approximately 20-40 mg / m 2 In some of the embodiments, the lymphodepletion therapy comprises administration of 300 mg / m fludarabine daily for at or about 3 days each. 2 or about 300 mg / m 2 of cyclophosphamide and 30 mg / m 2 of or about 30 mg / m 2 This includes administration of fludarabine.

[0047] In some of either embodiment, the T cell therapy is administered 2 to 7 days or about 2 to 7 days, inclusive, after administration of the lymphodepletion therapy.

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

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

[0050] In some of any of the embodiments, the inhibitor has the formula (I): [ka] (I) (In the formula, R1 is H, F, Cl, Br, -CN, or 0 to 4 R 1a C replaced with 1~3 Alkyl, 0 to 4 R 1a C replaced with 3~4 Cycloalkyl, 0 to 4 R 1a C replaced with 1~3 Alkoxy, -NR a R a , -S(O) n R e or -P(O)R e R e and; Each R 1a are independently F, Cl, -CN, -OH, -OCH3, or -NR a R a and; Each R a are independently H or C 1~3 is alkyl; Each R e independently, C 3~4 Cycloalkyl, or 0 to 4 R 1a C replaced with 1~3 is alkyl; R2 is H, 0 to 4 R 2a C replaced with 1~3 Alkyl or 0 to 4 R 2a C replaced with 3~4 is cycloalkyl; Each R 2a are independently F, Cl, -CN, -OH, -O(C 1~2 alkyl), C 3~4 Cycloalkyl, C 3~4 Alkenyl or C 3~4 is alkynyl; R3 is H, F, Cl, Br, -CN, C 1~3 Alkyl, C 1~2 Fluoroalkyl, C 3~4 Cycloalkyl, C 3~4 fluorocycloalkyl or -NO2; R4 is -CH2R 4a , -CH2CH2R 4a , -CH2CHR 4a R 4d, -CHR 4a R 4b or -CR 4a R 4b R 4c and; R 4a and R 4b is, independently, (i)F, Cl, -CN, -OH, -OCH3, -SCH3, C 1~3 Fluoroalkoxy, -NR a R a , -S(O)2R e or -NR a S(O)2R e C substituted with 0 to 4 substituents independently selected from 1~6 alkyl; (ii)F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~4 Hydroxyalkyl, -(CH2) 1~2 O(C 1~3 alkyl), C 1~4 Alkoxy, -O(C 1~4 hydroxyalkyl), -O(CH) 1~3 O(C 1~3 alkyl), C 1~3 Fluoroalkoxy, -O(CH) 1~3 NR c R c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl), -P(O)(C 1~3 alkyl)2, -S(O)2(C 1~3 alkyl), -O(CH2) 1~2 (C 3~6 cycloalkyl), -O(CH2) 1~2(morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and R d C, each substituted with 0 to 4 substituents independently selected from 3~6 cycloalkyl, heterocyclyl, phenyl, or heteroaryl; or (iii)C 3~6 C substituted with one cyclic group selected from cycloalkyl, heterocyclyl, aryl and heteroaryl 1~4 Alkyl, wherein the cyclic group is F, Cl, Br, —OH, —CN, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl) and C 3~6 substituted with 0 to 3 substituents independently selected from cycloalkyl, C 1~4 Is it alkyl? Or R 4a and R 4b These, together with the carbon atoms to which they are attached, form 0 to 3 R f C respectively substituted with 3~6 forming a cycloalkyl or a 3- to 6-membered heterocyclyl; Each R f are independently F, Cl, Br, -OH, -CN, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c Rc , or C 3~6 A cyclic group selected from cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each of which is selected from F, Cl, Br, —OH, —CN, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy and -NR c R c substituted with 0 to 3 substituents independently selected from: R 4c are F, Cl, -OH, C 1~2 Alkoxy, C 1~2 C, each substituted with 0 to 4 substituents independently selected from fluoroalkoxy and —CN; 1~6 Alkyl or C 3~6 is cycloalkyl; R 4d is -OCH3; Each R c are independently H or C 1~2 is alkyl; R d is phenyl substituted with 0-1 substituents selected from F, Cl, —CN, —CH3, and —OCH3; Each R5 is independently selected from -CN, 0 to 4 R g C replaced with 1~6 Alkyl, 0 to 4 R g C replaced with 2~4 Alkenyl, 0 to 4 R g C replaced with 2~4 Alkynyl, 0 to 4 R g C replaced with 3~4 Cycloalkyl, 0 to 4 R g phenyl substituted with 0 to 3 R g oxadiazolyl substituted with 0 to 4 R g Pyridinyl substituted with -(CH2) 1~2 (0 to 4 R g heterocyclyl substituted with -(CH2) 1~2 NR c C(O)(C1~4 alkyl), -(CH2) 1~2 NR c C(O)O(C 1~4 alkyl), -(CH2) 1~2 NR c S(O)2(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)O(C 3~4 cycloalkyl), -C(O)NR a R a or -C(O)NR a (C 3~4 cycloalkyl); Each R g are independently F, Cl, -CN, -OH, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy, -O(CH2) 1~2 O(C 1~2 alkyl) or -NR c R c and; m is 0, 1, 2 or 3; n is 0, 1 or 2) or a pharmaceutically acceptable salt thereof.

[0051] In some of the embodiments, the inhibitor is of formula (I): (In the formula, R1 is H, F, Cl, Br, -CN, or 0 to 4 R 1a C replaced with 1~3 Alkyl, 0 to 3 R 1a cyclopropyl substituted with 0-3 R 1a C replaced with 1~3 Alkoxy, -NR a R a , -S(O) n CH3 or -P(O)(CH3)2; Each R 1a are independently F, Cl, or —CN; Each R a are independently H or C 1~3 is alkyl; R2 is H or 0 to 2 R 2a C replaced with 1~2 is alkyl; Each R 2a are independently F, Cl, -CN, -OH, -O(C 1~2 alkyl), cyclopropyl, C 3~4 Alkenyl or C 3~4 is alkynyl; R3 is H, F, Cl, Br, -CN, C 1~2 alkyl, -CF3, cyclopropyl, or -NO2; R 4a and R 4b is, independently, (i)F, Cl, -CN, -OH, -OCH3, -SCH3, C 1~3 Fluoroalkoxy and -NR a R a C substituted with 0 to 4 substituents independently selected from 1~4 alkyl; (ii)F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3 Fluoroalkyl, -CH2OH, -(CH2) 1~2 O(C 1~2 alkyl), C 1~4 Alkoxy, -O(C 1~4 hydroxyalkyl), -O(CH) 1~2 O(C 1~2 alkyl), C 1~3 Fluoroalkoxy, -O(CH) 1~2 NR c R c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl), -P(O)(C 1~2alkyl)2, -S(O)2(C 1~3 alkyl), -O(CH2) 1~2 (C 3~4 cycloalkyl), -O(CH2) 1~2 (morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and R d C, each substituted with 0 to 4 substituents independently selected from 3~6 cycloalkyl, heterocyclyl, phenyl, or heteroaryl; or (iii)C 3~6 C substituted with one cyclic group selected from cycloalkyl, heterocyclyl, phenyl, and heteroaryl 1~3 Alkyl, wherein the cyclic group is F, Cl, Br, —OH, —CN, C 1~3 Alkyl, C 1~2 Fluoroalkyl, C 1~3 Alkoxy, C 1~2 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl) and C 3~4 substituted with 0 to 3 substituents independently selected from cycloalkyl, C 1~3 Is it alkyl? Or R 4a and R 4b These, together with the carbon atoms to which they are attached, form 0 to 3 R f C respectively substituted with 3~6 forming a cycloalkyl or a 3- to 6-membered heterocyclyl; Each R f are independently F, Cl, Br, -OH, -CN, C 1~4 Alkyl, C 1~2Fluoroalkyl, C 1~3 Alkoxy, C 1~2 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , or C 3~6 A cyclic group selected from cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each of which is selected from F, Cl, Br, —OH, —CN, C 1~4 Alkyl, C 1~2 Fluoroalkyl, C 1~3 Alkoxy, C 1~2 Fluoroalkoxy and -NR c R c substituted with 0 to 3 substituents independently selected from: R 4c are F, Cl, -OH, C 1~2 Alkoxy, C 1~2 C, each substituted with 0 to 4 substituents independently selected from fluoroalkoxy and —CN; 1~4 Alkyl or C 3~6 is cycloalkyl; Each R5 is independently selected from -CN, 0 to 4 R g C replaced with 1~5 Alkyl, 0 to 4 R g C replaced with 2~3 Alkenyl, 0 to 4 R g C replaced with 2~3 Alkynyl, 0 to 4 R g C replaced with 3~4 Cycloalkyl, 0 to 3 R g phenyl substituted with 0 to 3 R g oxadiazolyl substituted with 0-3 R g Pyridinyl substituted with -(CH2) 1~2 (0 to 4 R g heterocyclyl substituted with -(CH2) 1~2 NR c C(O)(C 1~4 alkyl), -(CH2) 1~2 NR c C(O)O(C 1~4 alkyl), -(CH2)1~2 NR c S(O)2(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)O(C 3~4 cycloalkyl), -C(O)NR a R a or -C(O)NR a (C 3~4 cycloalkyl) or a pharmaceutically acceptable salt thereof.

[0052] In some of any of the embodiments, the inhibitor has the structure: [ka] (In the formula, R1 is -CN; R2 is -CH3; R3 is H, F or -CN; R4 is [ka] [ka] is) or a pharmaceutically acceptable salt thereof.

[0053] In some of any of the embodiments, the inhibitor has the structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or [ka] or a pharmaceutically acceptable salt thereof.

[0054] In some of either embodiment, the inhibitor has the formula (II): [ka] (II) (In the formula, R1 is H, F, Cl, Br, -CN, -OH, or 0 to 4 R 1a C replaced with 1~3 Alkyl, 0 to 4 R 1a C replaced with 3~4 Cycloalkyl, 0 to 4 R 1a C replaced with 1~3 Alkoxy, -NR a R a , -S(O) n R e or -P(O)R e R e and; Each R 1a are independently F, Cl, -CN, -OH, -OCH3, or -NR a Ra and; Each R a are independently H or C 1~3 is alkyl; Each R e independently, C 3~4 Cycloalkyl or 0 to 4 R 1a C replaced with 1~3 is alkyl; R2 is H, 0 to 4 R 2a C replaced with 1~3 Alkyl or 0 to 4 R 2a C replaced with 3~4 is cycloalkyl; Each R 2a are independently F, Cl, -CN, -OH, -O(C 1~2 alkyl), C 3~4 Cycloalkyl, C 3~4 Alkenyl or C 3~4 is alkynyl; R4 is -CH2R 4a , -CH2CH2R 4a , -CH2CHR 4a R 4d , -CHR 4a R 4b or -CR 4a R 4b R 4c and; R 4a and R 4b is, independently, (i) -CN, or F, Cl, -CN, -OH, -OCH3, -SCH3, C 1~3 Fluoroalkoxy, -NR a R a , -S(O)2R e or -NR a S(O)2R e C substituted with 0 to 4 substituents independently selected from 1~6 alkyl; (ii)F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~2 Bromoalkyl, C 1~2 Cyanoalkyl, C 1~4Hydroxyalkyl, -(CH2) 1~2 O(C 1~3 alkyl), C 1~4 Alkoxy, C 1~3 Fluoroalkoxy, C 1~3 Cyanoalkoxy, -O(C 1~4 hydroxyalkyl), -O(CR x R x ) 1~3 O(C 1~3 alkyl), C 1~3 Fluoroalkoxy, -O(CH2) 1~3 NR c R c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -NR c R c , -CH2NR a R a , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -(CR x R x ) 0~2 NR a C(O)O(C 1~4 alkyl), -P(O)(C 1~3 alkyl)2, -S(O)2(C 1~3 alkyl), -(CR x R x ) 1~2 (C 3~4 cycloalkyl), -(CR x R x ) 1~2 (morpholinyl), -(CR x R x ) 1~2 (difluoromorpholinyl), -(CR x R x ) 1~2 (dimethylmorpholinyl), -(CR x R x ) 1~2 (oxazabicyclo[2.2.1]heptanyl), (CR x R x) 1~2 (oxazaspiro[3.3]heptanyl), -(CR x R x ) 1~2 (methylpiperazinonyl), -(CR x R x ) 1~2 (acetylpiperazinyl), -(CR x R x ) 1~2 (piperidinyl), -(CR x R x ) 1~2 (difluoropiperidinyl), -(CR x R x ) 1~2 (Methoxypiperidinyl), -(CR x R x ) 1~2 (hydroxypiperidinyl), -O(CR x R x ) 0~2 (C 3~6 cycloalkyl), -O(CR x R x ) 0~2 (methylcyclopropyl), -O(CR x R x ) 0~2 ((ethoxycarbonyl)cyclopropyl), -O(CR x R x ) 0~2 (oxetanyl), -O(CR x R x ) 0~2 (methylazetidinyl), -O(CR x R x ) 0~2 (tetrahydropyranyl), -O(CR x R x ) 1~2 (morpholinyl), -O(CR x R x ) 0~2 (thiazolyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, dioxolanyl, pyrrolidinonyl and R dC, each substituted with 0 to 4 substituents independently selected from 3~6 cycloalkyl, 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl; or (iii)C 3~6 C substituted with one cyclic group selected from cycloalkyl, 4- to 10-membered heterocyclyl, monocyclic or bicyclic aryl, or 5- to 10-membered heteroaryl 1~4 Alkyl, wherein the cyclic group is F, Cl, Br, —OH, —CN, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl) and C 3~6 substituted with 0 to 3 substituents independently selected from cycloalkyl, C 1~4 Is it alkyl? Or R 4a and R 4b These, together with the carbon atoms to which they are attached, form 0 to 3 R f C respectively substituted with 3~6 forming a cycloalkyl or a 3- to 6-membered heterocyclyl; Each R f are independently F, Cl, Br, -OH, -CN, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , or C 3~6A cyclic group selected from cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each of which is selected from F, Cl, Br, —OH, —CN, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy and -NR c R c substituted with 0 to 3 substituents independently selected from: R 4c are F, Cl, -OH, C 1~2 Alkoxy, C 1~2 C, each substituted with 0 to 4 substituents independently selected from fluoroalkoxy and —CN; 1~6 Alkyl or C 3~6 is cycloalkyl; R 4d is -OCH3; Each R c are independently H or C 1~2 is alkyl; R d is phenyl substituted with 0-1 substituents selected from F, Cl, —CN, —CH3, and —OCH3; Each R5 is independently selected from -CN, 0 to 4 R g C replaced with 1~6 Alkyl, 0 to 4 R g C replaced with 2~4 Alkenyl, 0 to 4 R g C replaced with 2~4 Alkynyl, 0 to 4 R g C replaced with 3~4 Cycloalkyl, 0 to 4 R g phenyl substituted with 0 to 3 R g oxadiazolyl substituted with 0 to 4 R g Pyridinyl substituted with -(CH2) 1~2 (0 to 4 R g 4-10 membered heterocyclyl substituted with -(CH2) 1~2 NR c C(O)(C 1~4 alkyl), -(CH2)1~2 NR c C(O)O(C 1~4 alkyl), -(CH2) 1~2 NR c S(O)2(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)O(C 3~4 cycloalkyl), -C(O)NR a R a or -C(O)NR a (C 3~4 cycloalkyl); Each R g are independently F, Cl, -CN, -OH, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy, -O(CH2) 1~2 O(C 1~2 alkyl) or -NR c R c and; m is 0, 1, 2 or 3; n is 0, 1 or 2) or a salt thereof.

[0055] In some of either embodiment, the inhibitor is of formula (II): (In the formula, R1 is H, F, Cl, Br, -CN, -OH, or 0 to 4 R 1a C replaced with 1~3 Alkyl, 0 to 3 R 1a cyclopropyl substituted with 0-3 R 1a C replaced with 1~3 Alkoxy, -NR a R a , -S(O) n CH3 or -P(O)(CH3)2; R2 is H or 0 to 2 R 2a C replaced with 1~2 is alkyl; Each R 2a are independently F, Cl, -CN, -OH, -O(C 1~2 alkyl), cyclopropyl, C3~4 Alkenyl or C 3~4 is alkynyl; R 4a and R 4b is, independently, (i) -CN, or F, Cl, -CN, -OH, -OCH3, -SCH3, C 1~3 Fluoroalkoxy and -NR a R a C substituted with 0 to 4 substituents independently selected from 1~4 alkyl; (ii)F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~2 Bromoalkyl, C 1~2 Cyanoalkyl, C 1~2 Hydroxyalkyl, -CHNR a R a , -(CH2) 1~2 O(C 1~2 alkyl), -(CH2) 1~2 NR x C(O)O(C 1~2 alkyl), C 1~4 Alkoxy, -O(C 1~4 hydroxyalkyl), -O(CR x R x ) 1~2 O(C 1~2 alkyl), C 1~3 Fluoroalkoxy, C 1~3 Cyanoalkoxy, -O(CH2) 1~2 NR c R c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl), -P(O)(C 1~2alkyl)2, -S(O)2(C 1~3 alkyl), -(CH2) 1~2 (C 3~4 cycloalkyl), -CR x R x (morpholinyl), -CR x R x (difluoromorpholinyl), -CR x R x (dimethylmorpholinyl), -CR x R x (oxazabicyclo[2.2.1]heptanyl), -CR x R x (oxazaspiro[3.3]heptanyl), -CR x R x (methylpiperazinonyl), -CR x R x (acetylpiperazinyl), -CR x R x (piperidinyl), -CR x R x (difluoropiperidinyl), -CR x R x (methoxypiperidinyl), -CR x R x (hydroxypiperidinyl), -O(CH2) 0~2 (C 3~4 cycloalkyl), -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 R dC, each substituted with 0 to 4 substituents independently selected from 3~6 cycloalkyl, 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl; or (iii)C 3~6 C substituted with one cyclic group selected from cycloalkyl, 4- to 10-membered heterocyclyl, monocyclic or bicyclic aryl, or 5- to 10-membered heteroaryl 1~3 Alkyl, wherein the cyclic group is F, Cl, Br, —OH, —CN, C 1~3 Alkyl, C 1~2 Fluoroalkyl, C 1~3 Alkoxy, C 1~2 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl) and C 3~4 substituted with 0 to 3 substituents independently selected from cycloalkyl, C 1~3 Is it alkyl? Or R 4a and R 4b These, together with the carbon atoms to which they are attached, form 0 to 3 R f C respectively substituted with 3~6 forming a cycloalkyl or a 3- to 6-membered heterocyclyl; Each R f are independently F, Cl, Br, -OH, -CN, C 1~4 Alkyl, C 1~2 Fluoroalkyl, C 1~3 Alkoxy, C 1~2 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , or C 3~6A cyclic group selected from cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each of which is selected from F, Cl, Br, —OH, —CN, C 1~4 Alkyl, C 1~2 Fluoroalkyl, C 1~3 Alkoxy, C 1~2 Fluoroalkoxy and -NR c R c substituted with 0 to 3 substituents independently selected from: R 4c are F, Cl, -OH, C 1~2 Alkoxy, C 1~2 C, each substituted with 0 to 4 substituents independently selected from fluoroalkoxy and —CN; 1~4 Alkyl or C 3~6 is cycloalkyl; Each R5 is independently selected from -CN, 0 to 4 R g C replaced with 1~5 Alkyl, 0 to 4 R g C replaced with 2~3 Alkenyl, 0 to 4 R g C replaced with 2~3 Alkynyl, 0 to 4 R g C replaced with 3~4 Cycloalkyl, 0 to 3 R g phenyl substituted with 0 to 3 R g oxadiazolyl substituted with 0-3 R g Pyridinyl substituted with -(CH2) 1~2 (0 to 4 R g 4-10 membered heterocyclyl substituted with -(CH2) 1~2 NR c C(O)(C 1~4 alkyl), -(CH2) 1~2 NR c C(O)O(C 1~4 alkyl), -(CH2) 1~2 NR c S(O)2(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4alkyl), -C(O)O(C 3~4 cycloalkyl), -C(O)NR a R a or -C(O)NR a (C 3~4 cycloalkyl); Each R x are independently H or -CH3; m is 1, 2, or 3) or a pharmaceutically acceptable salt thereof.

[0056] In some of any of the embodiments, the inhibitor has the structure: [ka] (In the formula, R1 is -CN; R2 is -CH3; R 5a is -CH3 or -CH2CH3; R 5c is -CH3, -CH2CH3 or -CH2CH2CH3) or a pharmaceutically acceptable salt thereof.

[0057] In some of any of the embodiments, the inhibitor has the structure: [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0058] In some of any of the embodiments, the inhibitor has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0059] In some of any of the embodiments, the inhibitor is administered in a therapeutically effective amount. In some of any of the embodiments, a therapeutically effective dose provides a dose of the inhibitor that is continuously therapeutically effective over the period of time that the inhibitor is administered.

[0060] In some of either embodiments, the inhibitor is administered in an amount of 0.25 to 250 mg or about 0.25 to 250 mg, inclusive, per day. In some of either embodiments, the inhibitor is administered in an amount of 0.5 to 100 mg or about 0.5 to 100 mg, inclusive, per day.

[0061] In some of any of the embodiments, the inhibitor is administered in a single daily amount of 0.25 to 250 mg or about 0.25 to 250 mg, inclusive. In some of any of the embodiments, the inhibitor is administered in a single daily amount of 0.5 to 100 mg or about 0.5 to 100 mg, inclusive.

[0062] In some of either embodiment, the inhibitor is administered orally.

[0063] In some of either embodiment, the recombinant receptor is an engineered T cell receptor (eTCR).

[0064] In some of either embodiment, the recombinant receptor is a chimeric antigen receptor (CAR).

[0065] In some of any of the embodiments, the antigen is CD19 and the CAR is an anti-CD19 CAR. In some of any of the embodiments, the CAR is a BREYANZI® (lysocabtagene-malaleucel), TECARTUS™ (brexcabtagene-autolucel), KYMRIAH™ (tisagenlecleucel), or YESCARTA™ (axicabtagene-siloleucel) CAR. In some of any of the embodiments, the T cell therapy is BREYANZI® (lysocabtagene-malaleucel), TECARTUS™ (brexcabtagene-autolucel), KYMRIAH™ (tisagenlecleucel), or YESCARTA™ (axicabtagene-siloleucel).

[0066] In some of any of the embodiments, the antigen is BCMA and the CAR is an anti-BCMA CAR. In some of any of the embodiments, the CAR is an ABECMA® (idecbutagen viculeucel) or CARVYKTI™ (siltacbutagen viculeucel) CAR. In some of any of the embodiments, the T cell therapy is ABECMA® (idecbutagen viculeucel) or CARVYKTI™ (siltacbutagen viculeucel).

[0067] In some of any of the embodiments, the cancer is a solid tumor. In some of any of the embodiments, the cancer is a hematological (liquid) tumor.

[0068] In some of any of the embodiments, the cancer is a B-cell malignancy.

[0069] In some of any of the embodiments, the cancer is leukemia. In some of any of the embodiments, the cancer is lymphoma. In some of any of the embodiments, the cancer is myeloma. In some of any of the embodiments, the myeloma is multiple myeloma.

[0070] In some of either embodiments, the cancer is relapsed or refractory.

[0071] In some of any of the embodiments, the T cell therapy comprises 0.1 x 10 6 ~1,000×10 6 pieces or approximately 0.1 x 10 6 ~1,000×10 6 In some of the embodiments, the T cell therapy comprises 10 x 10 total recombinant receptor-expressing T cells (inclusive). 6 ~1,000×10 6 pieces or approximately 10 x 10 6 ~1,000×10 6 In some of the embodiments, the T cell therapy comprises 10 x 10 total recombinant receptor-expressing T cells (inclusive). 6 ~500×10 6 pieces or approximately 10 x 10 6 ~500×10 6 Total recombinant receptor-expressing T cells (upper and lower limits included).

[0072] In some of either embodiment, the recombinant receptor-expressing T cells are viable recombinant receptor-expressing T cells.

[0073] In some of either embodiment, the T cell therapy is administered intravenously.

[0074] In some of any of the embodiments, the T cells of the T cell therapy are autologous to the subject. In some of any of the embodiments, the T cells of the T cell therapy are allogeneic to the subject.

[0075] In some of either embodiment, the T cells of the T cell therapy are human T cells.

[0076] Also provided herein, in some embodiments, is a T cell therapy comprising viable engineered T cells that express a recombinant receptor for an antigen expressed by cells of a cancer, for use as part of a combination therapy comprising a T cell therapy and an inhibitor of DGKα and / or DGKζ, wherein the T cell therapy and the inhibitor are administered to a subject with cancer according to any of the described methods.

[0077] Also provided herein, in some embodiments, are inhibitors 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 for an antigen expressed by cells of the cancer, wherein the T cell therapy and the inhibitor are administered to a subject with cancer according to any of the described methods.

[0078] Also provided herein, in some embodiments, is a T cell therapy comprising viable engineered T cells expressing a recombinant receptor for an antigen expressed by cells of the cancer, and an inhibitor of DGKα and / or DGKζ, for use as part of a combination therapy comprising a T cell therapy and an inhibitor, wherein the T cell therapy and the inhibitor are administered to a subject with cancer according to any of the described methods.

[0079] In some embodiments, also provided herein is the use of T cell therapy comprising viable engineered T cells expressing a recombinant receptor for an antigen expressed by cells of a cancer as part of a combination therapy comprising T cell therapy and an inhibitor of DGKα and / or DGKζ, wherein the T cell therapy and the inhibitor are administered to a subject with cancer according to any of the methods described.

[0080] In some embodiments, also provided herein is the 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 for an antigen expressed by cells of the cancer, wherein the T cell therapy and the inhibitor are administered to a subject with cancer according to any of the described methods.

[0081] In some embodiments, also provided herein is the use of a T cell therapy comprising viable engineered T cells expressing a recombinant receptor for an antigen expressed by cells of the cancer, and an inhibitor of DGKα and / or DGKζ, as part of a combination therapy comprising a T cell therapy and an inhibitor, wherein the T cell therapy and the inhibitor are administered to a subject with cancer according to any of the described methods.

[0082] In some embodiments, also provided herein is the use of a T cell therapy comprising viable engineered T cells expressing a recombinant receptor for an antigen expressed by cells of a cancer in the manufacture of a medicament that is part of a combination therapy comprising a T cell therapy and an inhibitor of DGKα and / or DGKζ, wherein the T cell therapy and the inhibitor are administered to a subject with cancer according to any of the methods described.

[0083] In some embodiments, also provided herein is the 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 that express a recombinant receptor for an antigen expressed by cells of the cancer, wherein the T cell therapy and the inhibitor are administered to a subject with cancer according to any of the methods described.

[0084] In some embodiments, also provided herein is the use of a T cell therapy comprising viable engineered T cells expressing a recombinant receptor for an antigen expressed by cells of the cancer, and an inhibitor of DGKα and / or DGKζ, in the manufacture of a medicament that is a combination therapy comprising a T cell therapy and an inhibitor, wherein the T cell therapy and the inhibitor are administered to a subject with cancer according to any of the described methods.

[0085] In some of any of the embodiments, the T cell therapy is any described herein. In some embodiments, the inhibitor is any described herein. In some embodiments, the subject is any described herein. In some embodiments, the cancer is any described herein. [Brief explanation of the drawings]

[0086] [Figure 1A] Figures 1A and 1B show the 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). Figure 1A shows the mean across donors of the log2 fold change in the % positive cells for various activation and differentiation markers (in the presence vs. absence of compound 17) following stimulation with a CAR-specific anti-idiotypic antibody at 3 μg / mL (left panel) or 30 μg / mL (right panel). Figure 1B shows the mean across donors of the log2 fold change in the MFI of cells (in the presence vs. absence of compound 17) following stimulation with a CAR-specific anti-idiotypic antibody at 3 μg / mL (left panel) or 30 μg / mL (right panel). In Figures 1A and 1B, positive values ​​are indicated by circles. [Figure 1B]Figures 1A and 1B show the 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). Figure 1A shows the mean across donors of the log2 fold change in the % positive cells for various activation and differentiation markers (in the presence vs. absence of compound 17) following stimulation with a CAR-specific anti-idiotypic antibody at 3 μg / mL (left panel) or 30 μg / mL (right panel). Figure 1B shows the mean across donors of the log2 fold change in the MFI of cells (in the presence vs. absence of compound 17) following stimulation with a CAR-specific anti-idiotypic antibody at 3 μg / mL (left panel) or 30 μg / mL (right panel). In Figures 1A and 1B, positive values ​​are indicated by circles. [Figure 2] Figure 2 shows the growth curves (percent cell confluence in the 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. [Figure 3] Figure 3 shows the percent specific lysis achieved by CAR-expressing T cells co-cultured with CD19 antigen-expressing target cells, K562.CD19 cells (high CD19 expression; left panel), Granta-519 cells (low CD19 expression; center panel), and Raji cells (medium / high CD19 expression; right panel) in the presence of Compound 17 (or control). [Figure 4] Figure 4 shows the supernatant concentrations in pg / mL of IFNγ (left panel), IL-2 (center panel), and TNFα (right panel) following coculture of CAR-expressing T cells with K562.CD19 cells (●), Granta-519 cells (■), and Raji cells (▲) in the presence of compound 17. [Figure 5A]Figures 5A-B and 6A-B show cytolytic activity and cytokine production during reloading of chronically stimulated CAR-expressing T cells in the presence of compound 17 (co-treatment). Figure 5A shows tumor cell counts of K562.CD19 cells (left panel), Granta-519 cells (middle panel), and Raji cells (right panel) in 2D co-culture with chronically stimulated CAR T cells in the presence of compound 17. [Figure 5B] Figure 5B shows the supernatant concentrations in pg / mL of IFNγ (left panel), IL-2 (middle panel), and TNFα (right panel) after 48 hours of 2D coculture of CAR T cells with K562.CD19 cells (●), Granta-519 cells (■), and Raji cells (▲). [Figure 6A] Figure 6A shows normalized tumor volumes of A549.CD19 (left panel) and Granta-519 tumor spheroids (right panel) at day 9 of co-culture with CAR T cells simultaneously treated with compound 17 during chronic stimulation. [Figure 6B] Figure 6B shows the supernatant concentrations in pg / mL of IFNγ (left panel), IL-2 (middle panel), and TNFα (right panel) after 5 days of 3D co-culture of CAR T cells with A549.CD19 (●) and Granta-519 tumor spheroids (■). [Figure 7A] Figures 7A-7B and 8A-8B show the cytolytic activity and cytokine production during reloading of chronically stimulated CAR-expressing T cells in the presence of compound 17 (rescue therapy). Figure 7A shows tumor cell counts of K562.CD19 cells (left panel), Granta-519 cells (middle panel), and Raji cells (right panel) in 2D co-culture with CAR T cells in the presence of compound 17. [Figure 7B] Figure 7B shows the supernatant concentrations in pg / mL of IFNγ (left panel), IL-2 (middle panel), and TNFα (right panel) after 48 hours of 2D co-culture of CAR T cells with K562.CD19 cells (●), Granta-519 cells (■), and Raji cells (▲) in the presence of compound 17. [Figure 8A]Figure 8A shows the normalized tumor volumes 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. [Figure 8B] Figure 8B shows the supernatant concentrations in pg / mL of IFNγ (left panel), IL-2 (middle panel), and TNFα (right panel) after 5 days of 3D co-culture of CAR T cells with A549.CD19 (●) and Granta-519 tumor spheroids (■). [Figure 9] Figures 9 and 10 show the cytolytic activity and proliferation of chronically stimulated T cells expressing an engineered T cell receptor (eTCR) following rescue treatment with compound 17. Figure 9 shows tumor cell counts 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-V beta; right panel, eTCR T cells chronically stimulated with 20 μg / mL anti-V beta). [Figure 10] FIG. 10 shows cell counts for eTCR T cells for two donors, as indicated from right to left: (1) chronically stimulated eTCR T cells without compound treatment (control); (2) chronically stimulated eTCR T cells treated with compound 17 (control); or (3) fresh eTCR T cells that were not chronically stimulated. [Figure 11] Figure 11 shows tumor burden in Raji cell-engrafted mice receiving three different dosing regimens ("early," "delayed," or "continuous") of DGKi Compound 17 in combination with anti-CD19 CAR T cells. In Figure 11, the shaded areas indicate the period during which Compound 17 was administered orally once daily after CAR T cell administration in the early, delayed, or continuous regimens. [Figure 12] Figure 12 shows survival of Raji cell-engrafted mice receiving early, delayed, or continuous Compound 17 regimens in combination with anti-CD19 CAR T cells (ns [non-significant]; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001). [Figure 13] Figure 13 shows the tumor control index values ​​for Raji cell-engrafted mice receiving early, delayed, or continuous Compound 17 regimens in combination with anti-CD19 CAR T cells (ns [non-significant]; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001). [Figure 14] Figure 14 shows the tumor control index values ​​along with the ANOVA results for Raji cell-engrafted mice receiving early, delayed, or continuous Compound 17 regimens in combination with anti-CD19 CAR T cells (ns [non-significant]; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001). In Figure 14, and for the ANOVA test, results from all groups of vehicle-treated mice were pooled into one group for statistical comparison. [Figure 15] Figure 15 shows the number of circulating CAR-expressing cells and the CD4:CD8 ratio of circulating T cells at day 15 in Raji cell-engrafted mice receiving delayed or continuous regimens (ns [non-significant]; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001). [Figure 16] Figure 16 shows the total number of circulating CAR-expressing cells at day 29 in Raji cell-engrafted mice receiving early, delayed or continuous Compound 17 regimens in combination with anti-CD19 CAR T cells. [Figure 17] Figure 17 shows tumor burden in Raji cell-engrafted mice receiving continuous dosing of DGKi compound 17 in combination with anti-CD19 CAR T cells. Following CAR T cell administration on day 1, compound 17 was administered orally once daily on days 1-30. [Figure 18] Figure 18 shows survival of Raji cell-engrafted mice receiving a continuous Compound 17 regimen in combination with anti-CD19 CAR T cells. [Figure 19]Figure 19 shows the tumor control index values ​​of Raji cell-engrafted mice receiving a continuous Compound 17 regimen in combination with anti-CD19 CAR T cells (ns [non-significant]; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001). [Figure 20] Figure 20 shows the number of circulating CAR-expressing cells after CAR T cell administration in Raji cell-engrafted mice undergoing continuous regimen (ns [non-significant]; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001). [Figure 21] Figure 21 shows the number of circulating CAR-expressing cells from four healthy human donors after CAR T cell administration in Raji cell-engrafted mice receiving DGKi administration on days 1-7. [Figure 22] Figure 22 shows tumor burden in Raji cell-engrafted mice receiving continuous dosing of DGKi compound 17 in combination with anti-CD19 CAR T cells or DGKα / DGKζ single or double knockout anti-CD19 CAR T cells. [Figure 23] Figure 23 shows survival of Raji cell-engrafted mice receiving a continuous Compound 17 regimen in combination with anti-CD19 CAR T cells or DGKα / DGKζ single or double knockout anti-CD19 CAR T cells (ns [non-significant]; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001). [Figure 24] Figure 24 shows the tumor control index values ​​of Raji cell-engrafted mice receiving a continuous Compound 17 regimen in combination with anti-CD19 CAR T cells or DGKα / DGKζ single or double knockout anti-CD19 CAR T cells (ns [non-significant]; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001). [Figure 25]Figure 25 shows the number of circulating CAR-expressing cells after CAR T-cell administration in Raji cell-engrafted mice receiving continuous regimens or DGKα / DGKζ single or double knockout CAR T cells (ns [non-significant]; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001). [Figure 26A] Figures 26A-26B show tumor burden in Nalm6 cell-engrafted mice. Figure 26A shows tumor burden in Nalm6 cell-engrafted mice receiving continuous dosing of DGKi compound 17 in combination with anti-CD19 CAR T cells. [Figure 26B] Figure 26B shows historical tumor burden data in Nalm6 cell-engrafted mice receiving anti-CD19 CAR T cells. [Figure 27] Figure 27 shows survival of Nalm6 cell-engrafted mice receiving a continuous Compound 17 regimen in combination with anti-CD19 CAR T cells (ns [non-significant]; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001). [Figure 28] Figure 28 shows the tumor control index values ​​of Nalm6 cell-engrafted mice receiving a continuous Compound 17 regimen in combination with anti-CD19 CAR T cells (ns [non-significant]; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001). [Figure 29] Figure 29 shows the number of circulating CAR-expressing cells after CAR T cell administration in Nalm6 cell-engrafted mice undergoing continuous regimen (ns [non-significant]; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001). [Figure 30] Figure 30 shows tumor burden after rechallenge of Nalm6 cell-engrafted mice previously receiving continuous dosing of DGKi compound 17 in combination with anti-CD19 CAR T cells. [Figure 31]Figure 31 shows survival after rechallenge of Nalm6 cell-engrafted mice that previously received a continuous Compound 17 regimen in combination with anti-CD19 CAR T cells (ns [non-significant]; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001). DETAILED DESCRIPTION OF THE INVENTION

[0087] Provided herein are combination therapies for use in treating a disease or condition, involving administration of a DGK inhibitor with T cell therapy directed against an antigen associated with the disease or condition, such as chimeric antigen receptor (CAR)-T cell therapy or engineered T cell receptor (eTCR)-T cell therapy. In some embodiments, the T cell therapy is a composition comprising T cells for adoptive cell therapy, in which the cells are engineered with a recombinant receptor (e.g., a CAR or eTCR) that targets the antigen. In some embodiments, the disease or condition may be cancer, an infectious disease, or an autoimmune disease. In some embodiments, the DGKi is an inhibitor of DGKα, DGKζ, or both DGKα and DGKζ, such as a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, such as a compound selected from Compounds 1-34. In some aspects, the provided methods and uses enhance or modulate the proliferation and / or activity of T cells (e.g., CAR-expressing T cells or eTCR-expressing T cells) associated with administration of the T cell therapy.

[0088] T cell-based therapies, such as adoptive T cell therapy (including therapies involving the administration of cells expressing recombinant antigen receptors specific for a disease or disorder of interest, such as CAR or eTCR), can be effective in the treatment of cancer and other diseases and disorders. The engineered expression of recombinant receptors, such as CAR or eTCR, on the surface of T cells allows for redirection of T cell specificity. In clinical studies, CAR-T cells, such as 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).

[0089] In certain situations, available approaches to adoptive cell therapy may not always be completely satisfactory. For example, in certain cases, CAR T cell persistence can be detected in many subjects with lymphoma, but fewer complete responses (CRs) have been observed in subjects with NHL compared to subjects with ALL. More specifically, higher overall response rates of up to 80% (CR rates of 47% to 60%) have been reported after CAR T cell infusion, but some responses were transient, and subjects were shown to relapse in the presence 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).

[0090] In some embodiments, this may be explained by the immunological exhaustion of circulating T cells (e.g., CAR-expressing T cells) of T cell therapy, and / or changes in T lymphocyte populations. In some situations, optimal efficacy may depend on the ability of the administered cells to recognize and bind to a target, e.g., a target antigen, transport to, localize, and successfully enter the appropriate site within the subject, tumor, and its environment. In some situations, optimal efficacy may depend on the ability of the administered cells to become activated, proliferate, exert various effector functions, including cytotoxic killing and secretion of various factors, such as cytokines, persist, including long-term, differentiate, transition to, or engage in reprogramming of a particular phenotypic state (such as long-lived memory, less differentiated, and effector state), avoid or reduce the immunosuppressive state in the local microenvironment of the disease, produce an effective and robust recall response after clearance and re-exposure to the target ligand or antigen, and avoid or reduce exhaustion, anergy, peripheral tolerance, terminal differentiation, and / or differentiation into a suppressive state.

[0091] In some embodiments, the exposure and persistence of engineered cells in T cell therapy are reduced or diminished after administration to a subject. Nevertheless, observations indicate that in some cases, increasing the subject's exposure to administered cells expressing recombinant receptors (e.g., increasing the number of cells or duration over time) can improve the efficacy and therapeutic outcome of adoptive cell therapy. Preliminary analyses conducted after administering different CD19-targeting CAR-expressing T cells to subjects with various CD19-expressing cancers in multiple clinical trials have revealed a correlation between greater and / or longer exposure to CAR-expressing cells and therapeutic outcome. Such outcomes include patient survival and remission, even in individuals with severe or significant tumor burden.

[0092] In some embodiments, after prolonged stimulation or exposure to an antigen and / or exposure under conditions in the tumor microenvironment, T cells can become hypofunctional and / or exhibit characteristics associated with an exhausted state over time. In some aspects, this reduces the persistence and effectiveness of the T cells against the antigen and limits their ability to be effective. In particular, there is a need for methods to improve the efficacy and function of T cells in T cell therapy, e.g., CAR-expressing T cells or eTCR-expressing T cells, to minimize, reduce, prevent, or reverse hypofunctional or exhausted states.

[0093] Diacylglycerol kinase (DGK) is a lipid kinase that mediates the conversion of diacylglycerol to phosphatidic acid, thereby terminating T cell function propagated via the TCR signaling pathway. Thus, DGK functions as an intracellular checkpoint, and inhibition of DGK is expected to enhance T cell signaling pathways and T cell activation. Supporting evidence includes knockout mouse models of either DGKα or DGKζ, which exhibit hyperresponsive T cell phenotypes and improved antitumor immune activity (Riese MJ et al., Journal of Biological Chemistry, (2011) 7: 5254-5265; Zha Y et al., Nature Immunology, (2006) 12: 1343; Olenchock BA et al., (2006) 11: 1174-81). Furthermore, tumor-infiltrating lymphocytes isolated from human renal cell carcinoma patients have been observed to overexpress DGKα, which resulted in inhibited T cell function (Prinz, PU et al., J Immunology (2012) 12:5990-6000). Therefore, DGKα and DGKζ are considered targets for cancer immunotherapy (Riese MJ et al., Front Cell Dev Biol. (2016) 4: 108; Chen, SS et al., Front Cell Dev Biol. (2016) 4: 130; Avila-Flores, A. et al., Immunology and Cell Biology (2017) 95: 549-563; Noessner, E., Front Cell Dev Biol. (2017) 5: 16; Krishna, S., et al., Front Immunology (2013) 4:178; Jing, W. et al., Cancer Research (2017) 77: 5676-5686).

[0094] The provided methods are based on the observation that DGKi, such as the described exemplary compound 17, improve T cell function, including functions related to the ability to produce one or more cytokines, T cell cytotoxicity, expansion, proliferation, and persistence. In some embodiments, the provided methods enhance or modulate the proliferation and / or activity of T cells (e.g., CAR-expressing T cells) associated with the administration of T cell therapy. Such methods and uses are found to provide or achieve improved or better T cell functionality and, thereby, improved anti-tumor efficacy.

[0095] In addition to enhancing T cell function, it is also found herein that such DGKis, e.g., Compound 17, exhibit the effect of reversing, delaying, or preventing T cell exhaustion, including by increasing T cell signaling and / or altering one or more genes that are differentially regulated after chronic (long-term) stimulation. Thus, while in some cases, agents that increase or enhance T cell activity can drive cells into an exhausted state, it is found herein that the activity of such DGKis, e.g., Compound 17, that exerts an enhancing effect on T cell activity is uncoupled from T cell exhaustion. In some embodiments, the provided methods involving the administration of such DGKis, e.g., Compound 17, can enhance T cell activity and delay, limit, reduce, inhibit, or prevent exhaustion.

[0096] Furthermore, observations herein indicate that DGKis, such as Compound 17, exhibit activity in rescuing T cells from T cell exhaustion, such as by restoring or partially restoring one or more T cell activities after the cells exhibit characteristics of exhaustion. Notably, the results herein indicate that exposure of chronically stimulated T cells exhibiting characteristics of exhausted T cells to a DGKi described herein, such as Compound 17, can revive, restore, or partially restore the activity. The observations herein support that the provided methods may also achieve improved or more durable responses compared to certain alternative methods, such as in certain groups of treated subjects.

[0097] These were observed by using a chronic stimulation assay to render T cells (e.g., CAR T cells) functionally impaired (e.g., reduced cytolysis and IL-2 secretion). Using this model, engineered T cells (e.g., CAR T cells or eTCR T cells) were tested to assess the impact of DGKi, such as Compound 17, on the function of the engineered T cells when present during (concurrent) or after (rescue) exposure to conditions that result in a functionally impaired, exhausted 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) in such conditions reversed the activity and phenotype associated with T cell hypofunction and preserved more effector function. Similarly, the results indicate that subsequent exposure to a DGKi, such as Compound 17, can rescue or restore T cell function, including cytokine production and cytolytic activity, of exhausted T cells. Furthermore, results were observed using different recombinant antigen receptors, including CAR and eTCR.

[0098] It has also been shown herein that administration of a DGKi, e.g., compound 17, in a continuous dosing scheme, e.g., at least once daily for multiple consecutive days, e.g., 28 consecutive days, improves in vivo antitumor efficacy after administration of engineered T cells for T cell therapy, e.g., CAR T cells or eTCR T cells. As demonstrated herein, the continuous presence of a DGKi after T cell therapy administration, e.g., starting on the same day as T cell therapy administration, can improve CAR T cell expansion and / or persistence, particularly that of CD4+ CAR T cells. While not wishing to be limited by a specific mechanism of action, the results presented herein are consistent with the finding that the continuous presence of a DGKi after T cell therapy administration can prevent or reduce exhaustion in T cells from T cell therapy, thereby improving T cell antitumor activity and proliferation capacity after administration.

[0099] The findings provided indicate that combination therapy of a DGKi that is an inhibitor of DGKα, DGKζ, or both DGKα and DGKζ, such as a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, such as a compound selected from Compounds 1-34, in methods involving T cell therapy, such as involving the administration of a composition of engineered T cells, achieves improved function of the T cell therapy, such as by enhancing T cell activity, reducing, preventing, or delaying T cell exhaustion, or rescuing cells from T cell exhaustion. In some embodiments, the combination therapy involves the 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 the administration or use of T cell therapy (e.g., CAR T cells or eTCR T cells) and a DGKi, 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 the administration or use of a T cell therapy (e.g., CAR T cells or eTCR T cells) and a DGKi that is the compound 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, the combination of T cell therapy (e.g., administration of engineered T cells) with a 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 outcome, e.g., ability to kill or reduce a tumor or other disease or target cell burden.

[0100] All publications, including patent documents, scientific articles, and databases, referenced in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication were incorporated herein by individual reference. To the extent that a definition set forth herein contradicts or is otherwise inconsistent with a definition set forth in a patent, application, published application, or other publication incorporated herein by reference, the definition set forth herein takes precedence over the definition incorporated herein by reference.

[0101] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0102] I. Combination Therapy In some embodiments, provided herein are therapeutic methods comprising administering to a subject having a disease or condition a cell therapy and an inhibitor of DGK. In some embodiments, the inhibitor of DGK is an inhibitor of DGKα and / or DGKζ. In some embodiments, the cell therapy is T cell therapy. In some embodiments, the T cell therapy comprises 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).

[0103] In some embodiments, the DGK inhibitor, e.g., an inhibitor of DGKα and / or DGKζ, is administered prior to T cell therapy, e.g., initiation of administration of the inhibitor is performed, accomplished, or occurs prior to initiation of administration of T cell therapy. In some embodiments, the DGK inhibitor, e.g., an inhibitor of DGKα and / or DGKζ, is administered simultaneously with T cell therapy, e.g., initiation of administration of the inhibitor is performed, accomplished, or occurs simultaneously with administration of T cell therapy. In some embodiments, the DGK inhibitor, e.g., an inhibitor of DGKα and / or DGKζ, is administered after T cell therapy, e.g., initiation of administration of the inhibitor is performed, accomplished, or occurs after initiation of administration of T cell therapy.

[0104] In some embodiments, also provided herein are therapeutic methods comprising administering an inhibitor of DGK to a subject having a disease or condition. In some embodiments, also provided herein are methods for rescuing engineered cells of cell therapy from exhaustion, e.g., rescuing engineered T cells of T cell therapy from exhaustion, comprising administering an inhibitor of DGK to a subject having a disease or condition. In some embodiments, also provided herein are methods for reducing or delaying the onset of T cell exhaustion of T cells of T cell therapy, comprising administering an inhibitor of DGK to a subject having a disease or condition. In some embodiments, the subject has previously received cell therapy, e.g., T cell therapy, for the treatment of the disease or condition.

[0105] Combination therapies, including engineered cells expressing a recombinant receptor, such as a chimeric antigen receptor (CAR), and a DGK inhibitor, or compositions comprising the engineered cells and / or DGK inhibitor described herein, are useful in a variety of therapeutic, diagnostic, and prophylactic indications. For example, the combinations are useful in treating various diseases and disorders in a subject. Such methods and uses include therapeutic methods and uses involving administration of the engineered cells, the DGK inhibitor, and / or a composition 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 a composition containing one or both are administered in an amount effective to provide treatment for the disease or disorder. Uses include the use of the engineered cells, the DGK inhibitor, and / or a composition containing one or both in such methods and treatments, and in the preparation of medicaments for carrying out such therapeutic methods. In some embodiments, the methods are carried out by administering the engineered cells, the DGK inhibitor, and / or a composition containing one or both to a subject having or suspected of having a disease or condition. In some embodiments, the method thereby treats a disease, condition, or disorder in a subject. In some embodiments, the DGK inhibitor is any of those described in Section IB. In some embodiments, the engineered cell is any of those described in Sections I and II.

[0106] The disease or condition to be treated may be one in which antigen expression is associated with and / or involved in the etiology of the disease or condition, e.g., antigen expression causes, exacerbates, or is otherwise involved in such disease or condition. Exemplary diseases and conditions include diseases or conditions associated with cellular malignancy or transformation (e.g., cancer), autoimmune or inflammatory diseases, or infectious diseases caused by, for example, bacteria, viruses, or other pathogens. Exemplary antigens, including antigens associated with various diseases and conditions that can be treated, are described herein. In certain embodiments, the antigen-binding domain of a recombinant receptor, e.g., a CAR or TCR, expressed by a cell therapy, e.g., a T cell therapy, administered as part of the methods provided herein specifically binds to an antigen associated with the disease or condition.

[0107] In some embodiments, the disease or condition includes tumors, including solid tumors, hematological malignancies and melanoma, and including localized and metastatic tumors, infectious diseases such as infections by viruses or other pathogens, e.g., HIV, HCV, HBV, CMV, HPV and parasitic diseases, 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, leukemias, lymphomas, such as acute myeloid (or myeloid) leukemia (AML), chronic myeloid (or myeloid) leukemia (CML), acute lymphocytic (or lymphoblastic) leukemia (ALL), chronic lymphocytic 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).

[0108] In some embodiments, the disease or condition is a B-cell malignancy. In some embodiments, the B-cell malignancy is selected from among acute lymphocytic leukemia (ALL), adult ALL, chronic lymphocytic leukemia (CLL), non-Hodgkin's 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 low-grade transformed), 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).

[0109] 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 thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), autoimmune thrombocytopenia, Chagas' disease, Graves' disease, Wegener's granulomatosis, polyarteritis nodosa, Sjogren's syndrome, pemphigus vulgaris, scleroderma, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathy, vasculitis, diabetes mellitus, Reynaud's syndrome, antiphospholipid syndrome, Goodpasture's disease, Kawasaki disease, autoimmune hemolytic anemia, myasthenia gravis, or progressive glomerulonephritis.

[0110] In some embodiments, the disease or condition is an infectious disease or condition, including, but not limited to, viral, retroviral, bacterial and protozoan infections, immunodeficiency, cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, BK polyomavirus, etc. In some embodiments, the disease or condition is an autoimmune or inflammatory disease or condition, such as arthritis, e.g., rheumatoid arthritis (RA), type 1 diabetes, systemic lupus erythematosus (SLE), inflammatory bowel disease, psoriasis, scleroderma, autoimmune thyroid disease, Graves' disease, Crohn's disease, multiple sclerosis, asthma, and / or a transplant-related disease or condition.

[0111] In some embodiments, the disease or disorder is a cancer associated with a solid tumor or a non-hematological tumor. In some embodiments, the disease or disorder is a cancer associated with a solid tumor. In some embodiments, the disease or disorder is a cancer associated with a solid tumor. In some embodiments, the disease or disorder is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, pancreatic cancer, rectal cancer, thyroid cancer, uterine cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain tumor, bone cancer, or soft tissue sarcoma. In some embodiments, the disease or disorder is bladder, lung, brain, melanoma (e.g., small cell lung melanoma), breast, cervical, ovarian, colorectal, pancreatic, endometrial, esophageal, kidney, liver, prostate, skin, thyroid, or uterine cancer. In some embodiments, the disease or disorder is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, pancreatic cancer, rectal cancer, thyroid cancer, uterine cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain tumor, bone cancer, or soft tissue sarcoma.

[0112] In some embodiments, the antigen associated with the disease or condition is 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), cancer testis antigen, cancer / testis antigen 1B (CTAG, also known as NY-ESO-1 and LAGE-2), carcinoembryonic antigen (CEA), cyclin D1, cyclin E1, cyclin B2, cyclin B3, cyclin B4, cyclin B5, cyclin B6, cyclin B7, cyclin B8, cyclin B9, cyclin B10, cyclin B11, cyclin B12, cyclin B13, cyclin B14, cyclin B15, cyclin B16, cyclin B17, cyclin B18, cyclin B19, cyclin B20, cyclin B21, cyclin B22, cyclin B23, cyclin B24, cyclin B25, cyclin B26, cyclin B27, cyclin B3, cyclin B45, cyclin B56, cyclin B6, cyclin B7, cyclin B87, cyclin B97, cyclin B19, cyclin B19, cyclin B19, cyclin B19, cyclin B22, cyclin B19, cyclin B23, cyclin B19, cyclin B24, cyclin B19, cyclin B25, cyclin B19, cyclin B26, cyclin B30, cyclin B45, cyclin B56, cyclin B19, cyclin B25, cyclin B19, cyclin B26, cyclin B30, , cyclin A2, CC 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 receptor (EGFR), type III epidermal growth factor receptor (EGFR) mutations vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrin B2, 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), 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 er b-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimer, human high molecular weight melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, human leukocyte antigen 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) ligand, melan-A (MART-1), neural cell adhesion molecule (NCAM), carcinoembryonic antigen, preferentially expressed antigen in melanoma (PRAME), progesterone receptor, prostate-specific antigen, prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), receptor tyrosine kinase-like orphan receptor 1 (ROR1), survivin, trophoblast glycoprotein G (TPBG, also known as 5T4), tumor-associated glycoprotein 72 (TAG) 72), 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), pathogen-specific or pathogen-expressed antigens, or antigens associated with universal tags and / or biotinylated molecules, and / or molecules expressed by HIV, HCV, HBV, or other pathogens.

[0113] 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 lymphocytic leukemia (ALL), adult ALL, chronic lymphocytic leukemia (CLL), non-Hodgkin's 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 low-grade transformed), primary mediastinal large B-cell lymphoma (PMBCL), T-cell / histiocyte-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 some 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., a CAR or TCR, specifically binds to an antigen associated with the disease or condition or an antigen expressed on cells in the environment of a lesion associated with a B cell malignancy. The antigen targeted by the receptor, in some embodiments, includes an antigen associated with a B cell malignancy, such as any of a number of known B cell markers. In some embodiments, the antigen targeted by the receptor is BAFF-R, CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Ig kappa, Ig lambda, CD79a, CD79b, or CD30, or a combination thereof. For example, in some embodiments, the antigen 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 example, the recombinant receptor can be a CAR that is axicabtagene ciloreucel (Yescarta), tisagenlecleucel (Kymriah), or lisocabtagene maraleucel (Breyanzi) CAR. In some embodiments, the recombinant receptor can be a CAR that is a TECARTUS™ (brexcabtagene autrucel) CAR. In some embodiments, the T cell therapy, e.g., anti-CD19 CAR T cell therapy, is axicabtagene ciloreucel (Yescarta), tisagenlecleucel (Kymriah), lisocabtagene maraleucel (Breyanzi), or TECARTUS™ (brexcabtagene autrucel).

[0114] In some embodiments, the disease or condition is large B-cell lymphoma. In some embodiments, the large B-cell lymphoma is relapsed or refractory large B-cell lymphoma. In some embodiments, the large B-cell lymphoma is diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from low-grade lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, or follicular lymphoma grade 3B. In some embodiments, the target antigen bound by the recombinant receptor and associated with 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 a CAR 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 lisocbutagen-malaleucel (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).

[0115] In some embodiments, the disease or condition is mantle cell lymphoma or precursor B-cell acute lymphoblastic leukemia (ALL). In some embodiments, the disease or condition is relapsed or refractory mantle cell lymphoma or relapsed or refractory precursor B-cell 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 TECARTUS™ (brexucabtagene autolucel) CAR. 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 TECARTUS™ (brexucabtagene-autolucel, see Mian and Hill, 2021, Expert Opin Biol Ther; 21(4):435-441; and Wang et al., 2021, Blood 138(Supplement 1):744).

[0116] 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 a tisagenlecleucel (Kymriah) CAR. 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).

[0117] In some embodiments, the disease or condition is B-cell lymphoma. In some embodiments, the B-cell lymphoma is 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 arising 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 axicabtagene ciloreucel (Yescarta) CAR. 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 ciloreucel (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).

[0118] In some embodiments, the disease or condition is a myeloma, such as multiple myeloma. The antigen targeted by the recombinant receptor, in some embodiments, comprises an antigen associated with multiple myeloma. In some aspects, the antigen is expressed in 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 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 antigen includes an antigen present in lymphoid tumors, myeloma, AIDS-related lymphoma, and / or post-transplant lymphoproliferation, such as CD38. Antibodies or antigen-binding fragments against such antigens are known and include those described in, for example, U.S. Patent Nos. 8,153,765; 8,603477; 8,008,450; U.S. Publication Nos. US20120189622 or US20100260748; and / or International PCT Publication Nos. WO2006099875, WO2009080829, WO2012092612, or WO2014210064. In some embodiments, such antibodies or antigen-binding fragments thereof (e.g., scFvs) are contained in multispecific antibodies, multispecific chimeric receptors, e.g., multispecific CARs, and / or multispecific cells.

[0119] In some embodiments, the disease or disorder is 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 MM associated with expression of a tumor-associated antigen such as 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., a CAR or TCR, specifically binds to an antigen associated with MM, e.g., specifically binds to BCMA, GPRC5D, or FCRL5. In some embodiments, the target antigen associated with the disease or condition, e.g., MM, is BCMA. In some embodiments, the recombinant receptor is an ABECMA® (idecbutagen-vicrucel) or CARVYKTI™ (siltacabtagene-autorucel) CAR, e.g., an anti-BCMA CAR. In some embodiments, the T cell therapy, e.g., anti-BCMA CAR T cell therapy, is ABECMA® (idecbutagen-viculucel) or CARVYKTI™ (siltacbutagen-autolucel).

[0120] In some embodiments, the disease or condition is multiple myeloma. In some embodiments, the multiple myeloma is relapsed or refractory multiple myeloma. In some embodiments, the target antigen bound by the recombinant receptor and associated with multiple myeloma is BCMA. In some embodiments, the recombinant receptor is an anti-BCMA CAR. In some embodiments, the anti-BCMA CAR is a CARVYKTI™ (siltacabtagene-autolucel) CAR. 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™ (siltacabtagene-autolucel, see Berdeja et al., Lancet. 2021 Jul 24;398(10297):314-324; and Martin, Abstract #549 [Oral], presented at the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition).

[0121] In some embodiments, the disease or condition is multiple myeloma. In some embodiments, the multiple myeloma is relapsed or refractory multiple myeloma. In some embodiments, the target antigen bound by the recombinant receptor and associated with multiple myeloma is BCMA. In some embodiments, the recombinant receptor is an anti-BCMA CAR. In some embodiments, the anti-BCMA CAR is an ABECMA® (idecbutagen-biclucel) CAR. 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® (idecbutagen-biclucel, see Raje et al., 2019, N Engl J Med 380:1726-1737; and Munshi et al., 2021, N Engl J Med 384:705-716).

[0122] In some embodiments, the disease or disorder is chronic lymphocytic leukemia (CLL). In some embodiments, the subject has or is suspected of having CLL associated with expression of a tumor-associated antigen, such as 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., a CAR or TCR, specifically binds to an antigen associated with CLL, e.g., specifically binds to ROR1.

[0123] In some embodiments, the disease or disorder is non-small cell lung cancer (NSCLC). In some embodiments, the subject has or is suspected of having NSCLC associated with expression of a tumor-associated antigen, such as 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., a CAR or TCR, specifically binds to an antigen associated with NSCLC, e.g., 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.

[0124] In some embodiments, the disease or disorder is triple-negative breast cancer (TNBC). In some embodiments, the subject has or is suspected of having TNBC associated with expression of a tumor-associated antigen, such as receptor tyrosine kinase-like 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., a CAR or TCR, specifically binds to an antigen associated with TNBC, e.g., 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.

[0125] In some embodiments, the disease or disorder is small cell lung cancer (SCLC), optionally relapsed / refractory SCLC. In some embodiments, the subject has or is suspected of having SCLC 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., a CAR or TCR, specifically binds to an antigen associated with SCLC, e.g., 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).

[0126] In some embodiments, the disease or disorder is renal cell carcinoma (RCC). In some embodiments, the subject has or is suspected of having RCC 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., a CAR or TCR, specifically binds to an antigen associated with RCC, e.g., specifically binds to CD70. In some embodiments, the CAR is as described in Panowski et al., Cancer Res 79 (13 Supplement) 2326 (2019).

[0127] In some embodiments, the disease or disorder is acute myeloid leukemia (AML). In some embodiments, the subject has or is suspected of having AML 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., a CAR or TCR, specifically binds to an antigen associated with AML, e.g., specifically binds to CD70. In some embodiments, the CAR is as described in Sauer et al., Blood 134 (Supplement_1): 1932 (2019).

[0128] In some embodiments, the antigen is or comprises a pathogen-specific or pathogen-expressed antigen, hi some embodiments, the antigen is a viral antigen (such as a viral antigen from HIV, HCV, HBV, etc.), a bacterial antigen, and / or a parasitic antigen.

[0129] Administration of AT cell therapy In some aspects, the methods provided herein include combination therapy by administering a cell therapy, e.g., T cell therapy, in combination with a DGK inhibitor to a subject having a disease or condition, such as any of the diseases or conditions described above. In some aspects, the methods provided herein include administering the DGK inhibitor to a subject in combination with (e.g., before, simultaneously with, or after) administration of the cell therapy, e.g., T cell therapy. In some embodiments, the methods provided include administering the DGK inhibitor to a subject who has previously been administered a cell therapy, e.g., T cell therapy, for the treatment of the disease or condition. In some embodiments, the cell therapy, e.g., T cell therapy, is administered to the subject before administration of the DGKi to the subject. In some embodiments, the cell therapy, e.g., T cell therapy and the DGKi are administered simultaneously.

[0130] In some embodiments, the cell therapy is T cell therapy. T cell therapy can include T cells engineered with a recombinant receptor, such as a CAR or an engineered TCR (e.g., eTCR). In some embodiments, T cell therapy includes T cells (e.g., CD4+ and / or CD8+ T cells) expressing a CAR that targets or binds to an antigen associated with a disease or condition. In some embodiments, T cell therapy includes T cells (e.g., CD4+ and / or CD8+ T cells) expressing an eTCR that targets or binds to an antigen associated with a disease or condition. T cell therapy for use in the provided methods includes any of a variety of CAR-expressing or eTCR-expressing T cells. Choosing an appropriate recombinant receptor (e.g., CAR or eTCR)-expressing T cell therapy to treat a disease or condition is within the level of skill of one of ordinary skill in the art. 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 allogeneic to the subject being treated. In some embodiments, the T cells of the T cell therapy are autologous to the subject being treated.

[0131] The method for administering cells for adoptive cell therapy is known, and can be used in connection with the provided methods, compositions, and products and kits.For example, the method of adoptive T cell therapy is described, for example, in U.S. Patent Application Publication No. 2003 / 0170238 to Gruenberg et al.; U.S. Patent No. 4,690,915 to Rosenberg; Rosenberg (2011) Nat Rev Clin Oncol. 8(10):577-85).For example, see Themeli et al. (2013) Nat Biotechnol. 31(10):928-933; Tsukahara et al. (2013) Biochem Biophys Res Commun 438(1):84-9; Davila et al. (2013) PLoS ONE 8(4):e61338.

[0132] In some embodiments, cell therapy, e.g., adoptive T cell therapy, is performed by autologous transfer, whereby cells are isolated and / or otherwise prepared from a subject to receive cell therapy or from a sample derived from such a subject. Thus, in some aspects, the cells are derived from a subject, e.g., a patient, in need of treatment, and the cells, after isolation and processing, are administered to the same subject.

[0133] In some embodiments, cell therapy, e.g., adoptive T cell therapy, is performed by allogeneic transfer, whereby cells are isolated and / or otherwise prepared from a subject other than the subject who is to receive or will ultimately receive cell therapy, e.g., a first subject. In such embodiments, the cells are then administered to a different subject of the same species, e.g., a second subject. 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.

[0134] The cells of the T cell therapy can be administered in a composition formulated for administration, or alternatively, in two or more compositions (e.g., two compositions) formulated for separate administration. A dose of cells can include a specific or relative number of cells or engineered cells, and / or two or more subtypes in a defined ratio or composition within the composition, such as CD4 vs. CD8 T cells.

[0135] The cells can be administered by any suitable means, for example, by bolus injection, injection, e.g., intravenous or subcutaneous injection, intraocular injection, periocular injection, subretinal injection, intravitreal injection, transseptal injection, subscleral injection, intrachoroidal injection, intracameral injection, subconjectval injection, subconjunctival injection, sub-Tenon injection, retrobulbar injection, peribulbar injection, or posterior juxtascleral delivery. In some embodiments, the cells are administered parenterally, intrapulmonary, intranasally, and, if desired for localized treatment, intralesionally. Parenteral injections include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, a predetermined dose is administered by a single bolus of cells. In some embodiments, a predetermined dose is administered by multiple boluses of cells over a period of, for example, three days or less, or by continuous infusion of cells. In some embodiments, administration of the cell dose or any additional therapy, eg, lymphodepleting therapy, interventional therapy, and / or combination therapy, is by exogenous delivery.

[0136] For treatment of disease, the appropriate dosage will depend on the type of disease being treated, the type of cells or recombinant receptor, the severity and course of the disease, previous therapy, the subject's clinical history and response to the cells, and the discretion of the treating physician. The compositions and cells, in some embodiments, are suitably administered to the subject at one time or over a series of treatments.

[0137] After administration of the cells, the biological activity of the engineered cell population is measured, in some embodiments, by any of a number of known methods. Parameters for evaluation include specific binding of engineered or natural T cells or other immune cells to antigens 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 method, such as the cytotoxicity assays described in 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 the expression and / or secretion of one or more cytokines, such as CD107a, IFNγ, IL-2, and TNF. In some aspects, biological activity is measured by assessing clinical outcomes, such as reduction in tumor burden or burden.

[0138] In some embodiments, the dose of cells of a T cell therapy, such as a T cell therapy comprising cells engineered with a recombinant antigen receptor, e.g., a CAR or TCR, is provided as a composition or formulation, such as a pharmaceutical composition or formulation. Such compositions can be used in accordance with the provided methods, such as in the prevention or treatment of diseases, conditions, and disorders.

[0139] In some embodiments, T cell therapies, 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, a variety of suitable formulations exist. For example, the pharmaceutical composition can contain a preservative. Suitable preservatives can 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, for example, in 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 may include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium 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) polymers; 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 counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as polyethylene glycol (PEG).

[0140] In some embodiments, a buffering agent is included in the composition. Suitable buffering agents include, for example, citric acid, sodium citrate, phosphoric acid, potassium phosphate, and various other acids and salts. In some embodiments, a mixture of two or more buffering agents is used. The buffering agent or mixture thereof is 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, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins; 21st ed. (May 1, 2005).

[0141] The formulation may comprise an aqueous solution. The formulation or composition may contain two or more active ingredients useful for the particular indication, disease, or condition being prevented or treated by the cells or agent, where the activities of each do not adversely affect each other. Such active ingredients are suitably present in combination in amounts effective for the intended purpose. Thus, in some embodiments, the pharmaceutical composition further comprises another pharmaceutically active agent or drug, such as a chemotherapeutic agent, e.g., asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine, vincristine, etc.

[0142] In some embodiments, the pharmaceutical composition contains cells in an amount effective for treating or preventing a disease or condition, such as a therapeutically or prophylactically effective amount. In some embodiments, therapeutic or prophylactic effectiveness is monitored by periodic evaluation of the treated subject. For repeated administration over several days or longer, depending on the condition, treatment is repeated until the 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 administration of the composition, or by continuous infusion administration of the composition.

[0143] Cells can be administered using standard administration techniques, formulations, and / or devices. Formulations and devices, such as syringes and vials, are provided for storing and administering the compositions. With respect to cells, administration can be autologous or xenogeneic. For example, immunoresponsive cells or precursors can be obtained from a subject and administered to the same subject or a different compatible subject. Peripheral blood-derived immunoresponsive cells or their progeny (e.g., derived in vivo, ex vivo, or in vitro) can be administered by 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 genetically modified immunoresponsive cells), it will generally be formulated in a unit-dosage injectable form (solution, suspension, emulsion).

[0144] Formulations include those for oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration. In some embodiments, the agent or cell population is administered parenterally. The term "parenteral," as used herein, includes intravenous, intramuscular, subcutaneous, rectal, vaginal, and intraperitoneal administration. In some embodiments, the agent or cell population is administered to a subject using peripheral systemic delivery via intravenous, intraperitoneal, or subcutaneous injection.

[0145] In some embodiments, the composition is provided as a sterile liquid preparation, such as an isotonic aqueous solution, suspension, emulsion, dispersion, or viscous composition, which may be buffered to a selected pH in some aspects. Liquid preparations are usually easier to prepare than gels, other viscous compositions, and solid compositions. Furthermore, liquid compositions are somewhat easier to administer, especially by injection. On the other hand, viscous compositions can be formulated within an appropriate viscosity range to provide a longer contact period with specific tissues. Liquid or viscous compositions can include, for example, a solvent or dispersion medium carrier, including water, saline, phosphate buffered saline, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol), and suitable mixtures thereof.

[0146] Sterile injectable solutions can be prepared by incorporating the cells in a solvent such as a mixture with a suitable carrier, diluent, or excipient, such as sterile water, saline, glucose, dextrose, or the like. The composition may also be lyophilized. The composition may contain auxiliary substances such as wetting, dispersing, or emulsifying agents (e.g., methylcellulose), pH buffering agents, gelling or viscosity-enhancing additives, preservatives, flavoring agents, coloring agents, and the like, depending on the desired route of administration and preparation. Standard texts can, in some embodiments, be consulted for preparing suitable preparations.

[0147] Various additives can be added to enhance the stability and sterility of the compositions, including antimicrobial preservatives, antioxidants, chelating agents, and buffers. Prevention of microbial action can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, etc. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0148] Formulations to be used for in vivo administration are generally sterile. Sterility is readily accomplished, for example, by filtration through sterile filtration membranes.

[0149] For the prevention or treatment of disease, the appropriate dosage will depend on the type of disease being treated, the type of agent(s), the type of cells or recombinant receptor, the severity and course of the disease, whether the agent or cells are being administered for prophylactic or therapeutic purposes, previous therapy, the subject's clinical history and response to the agent or cells, and the discretion of the attending physician. The compositions, in some embodiments, are suitably administered to the subject at one time or over a series of treatments.

[0150] In some cases, the cell therapy is administered as a single pharmaceutical composition containing cells. In some embodiments, a predetermined dose is administered by a single bolus of cells or agent. In some embodiments, it is administered by multiple bolus administration of cells or agent over a period of, for example, 3 days or less, or by continuous infusion of cells or agent.

[0151] In some embodiments, the dose of cells is administered to the subject in accordance with the provided combination therapy method.In some embodiments, the size or timing of the dose is determined as a function of the specific disease or condition in the subject.In consideration of the provided explanation, the size or timing of the dose for a specific disease can be empirically determined.

[0152] In certain embodiments, the cells, or individual populations or subtypes of cells, are in the range of about 100,000 to about 100 billion cells, and / or that amount of cells per kilogram of subject body weight, e.g., 100,000 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 any of the foregoing values). 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), for example, about 10 million to about 100 billion cells (e.g., about 20 million cells, about 30 million cells, about 40 million cells, 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 The subject may be administered approximately 450 million cells, approximately 650 million cells, approximately 800 million cells, approximately 900 million cells, approximately 3 billion cells, approximately 30 billion cells, approximately 45 billion cells, approximately 10 million to approximately 600 million cells, approximately 100 million to approximately 600 million cells, approximately 100 million to approximately 450 million cells, approximately 150 million to approximately 300 million or 450 million cells, or any value between these ranges, and / or per kilogram of subject body weight. Dosages may vary depending on the specific characteristics of the disease or disorder and / or patient and / or other treatments. In some embodiments, such values ​​refer to the number of recombinant receptor-expressing cells (e.g., CAR- or TCR-expressing cells); in other embodiments, it refers to the number of T cells or PBMCs or total cells administered.

[0153] In some embodiments, the cell therapy comprises 1 x 105 ~1×10 8 or approximately 1 x 10 5 ~Approx. 1×10 8 5 x 10 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs) 5 ~1×10 7 pieces or approximately 5 x 10 5 ~Approx. 1×10 7 1 x 10 total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs), or 1 x 10 6 ~1×10 7 or approximately 1 x 10 6 ~Approx. 1×10 7 In some embodiments, the cell therapy comprises administering a dose comprising at least 1 x 10 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), each inclusive of upper and lower limits. 5 or at least about 1 x 10 5 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), e.g., at least 1 x 10 6 or at least about 1 × 10 6 , at least 1 x 10 7 or at least about 1 × 10 7 , at least 1 x 10 8 or at least about 1 x 10 8 The method includes administering a dose of cells comprising a cell number of such cells.

[0154] In some embodiments, for example, when the subject is a human, the dose is about 5×10 8 Fewer than 10 total recombinant receptor (e.g., TCR or CAR)-expressing cells, T cells or peripheral blood mononuclear cells (PBMCs), e.g., about 1 x 10 6 ~Approx. 5×10 8 In the range of 2 x 10 such cells, e.g., 6 , 5×10 6 , 1×10 7 , 5×10 7 , 1×10 8 Or 5 x 10 8 all such cells, or a range between any two of the foregoing values.

[0155] In some embodiments, the number refers to the total number of CD3+ or CD8+, and in some cases, recombinant receptor-expressing (e.g., TCR+ or CAR+) cells. In some embodiments, cell therapy is administered in a volume of 1×10 5 ~1×10 8 pieces or approximately 1 x 10 5 ~Approx. 1×10 8 5 x 10 CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells 5 ~1×10 7 pieces or approximately 5 x 10 5 ~Approx. 1×10 7 1 x 10 CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells, or 1 x 10 6 ~1×10 7 pieces or approximately 1 x 10 6 ~Approx. 1×10 7 In some embodiments, the cell therapy comprises administering a dose comprising 1 x 10 total CD3+ or CD8+ T cells or CD3+ or CD8+ recombinant receptor-expressing cells, inclusive of the upper and lower cell limits. 5 ~1×10 8 or approximately 1 x 10 5 ~Approx. 1×10 8 5 x 10 total CD3+ / CAR+ or CD8+ / CAR+ cells 5 ~1×10 7 pieces or approximately 5 x 10 5 ~Approx. 1×10 7 total CD3+ / CAR+ or CD8+ / CAR+ cells, or 1 x 10 6 ~1×10 7 or approximately 1 x 10 6 ~Approx. 1×10 7 This includes administering a dose containing a cell count of 10 total CD3+ / CAR+ or CD8+ / CAR+ cells (including the upper and lower limits of each).

[0156] In some embodiments, the dose of genetically engineered cells is 1×10 5 ~5×10 8 1 x 10 total recombinant receptor-expressing T cells5 ~2.5×10 8 1 x 10 total recombinant receptor-expressing T cells 5 ~1×10 8 1 x 10 total recombinant receptor-expressing T cells 5 ~5×10 7 1 x 10 total recombinant receptor-expressing T cells 5 ~2.5×10 7 1 x 10 total recombinant receptor-expressing T cells 5 ~1×10 7 1 x 10 total recombinant receptor-expressing T cells 5 ~5×10 6 1 x 10 total recombinant receptor-expressing T cells 5 ~2.5×10 6 1 x 10 total recombinant receptor-expressing T cells 5 ~1×10 6 1 x 10 total recombinant receptor-expressing T cells 6 ~5×10 8 1 x 10 total recombinant receptor-expressing T cells 6 ~2.5×10 8 1 x 10 total recombinant receptor-expressing T cells 6 ~1×10 8 1 x 10 total recombinant receptor-expressing T cells 6 ~5×10 7 1 x 10 total recombinant receptor-expressing T cells 6 ~2.5×10 7 1 x 10 total recombinant receptor-expressing T cells 6 ~1×10 7 1 x 10 total recombinant receptor-expressing T cells 6 ~5×10 6 1 x 10 total recombinant receptor-expressing T cells 6 ~2.5×10 6 2.5 x 10 total recombinant receptor-expressing T cells 6 ~5×10 8 2.5 x 10 total recombinant receptor-expressing T cells 6 ~2.5×10 8 2.5 x 10 total recombinant receptor-expressing T cells 6 ~1×10 8 2.5 x 10 total recombinant receptor-expressing T cells 6 ~5×10 72.5 x 10 total recombinant receptor-expressing T cells 6 ~2.5×10 7 2.5 x 10 total recombinant receptor-expressing T cells 6 ~1×10 7 2.5 x 10 total recombinant receptor-expressing T cells 6 ~5×10 6 5 x 10 total recombinant receptor-expressing T cells 6 ~5×10 8 5 x 10 total recombinant receptor-expressing T cells 6 ~2.5×10 8 5 x 10 total recombinant receptor-expressing T cells 6 ~1×10 8 5 x 10 total recombinant receptor-expressing T cells 6 ~5×10 7 5 x 10 total recombinant receptor-expressing T cells 6 ~2.5×10 7 5 x 10 total recombinant receptor-expressing T cells 6 ~1×10 7 1 x 10 total recombinant receptor-expressing T cells 7 ~5×10 8 1 x 10 total recombinant receptor-expressing T cells 7 ~2.5×10 8 1 x 10 total recombinant receptor-expressing T cells 7 ~1×10 8 1 x 10 total recombinant receptor-expressing T cells 7 ~5×10 7 1 x 10 total recombinant receptor-expressing T cells 7 ~2.5×10 7 2.5 x 10 total recombinant receptor-expressing T cells 7 ~5×10 8 2.5 x 10 total recombinant receptor-expressing T cells 7 ~2.5×10 8 2.5 x 10 total recombinant receptor-expressing T cells 7 ~1×10 8 2.5 x 10 total recombinant receptor-expressing T cells 7 ~5×10 7 5 x 10 total recombinant receptor-expressing T cells 7 ~5×10 8 5 x 10 total recombinant receptor-expressing T cells7 ~2.5×10 8 5 x 10 total recombinant receptor-expressing T cells 7 ~1×10 8 1 x 10 total recombinant receptor-expressing T cells 8 ~5×10 8 1 x 10 total recombinant receptor-expressing T cells 8 ~2.5×10 8 total recombinant receptor-expressing T cells or 2.5 x 10 8 ~5×10 8 total recombinant receptor-expressing T cells, or their approximate number.

[0157] In some embodiments, the dose of genetically engineered cells is at least 1 x 10 5 or at least about 1×10 5 TCR- or CAR-expressing cells, at least 2.5 x 10 5 or at least about 2.5 × 10 5 TCR- or CAR-expressing cells, at least 5 x 10 5 or at least about 5×10 5 TCR- or CAR-expressing cells, at least 1 x 10 6 or at least about 1×10 6 TCR- or CAR-expressing cells, at least 2.5 x 10 6 or at least about 2.5 × 10 6 TCR- or CAR-expressing cells, at least 5 x 10 6 or at least about 5×10 6 TCR- or CAR-expressing cells, at least 1 x 10 7 or at least about 1×10 7 TCR- or CAR-expressing cells, at least 2.5 x 10 7 or at least about 2.5 × 10 7 TCR- or CAR-expressing cells, at least 5 x 10 7 or at least about 5×10 7 TCR- or CAR-expressing cells, at least 1 x 10 8 or at least about 1×10 8TCR- or CAR-expressing cells, at least 2.5 x 10 8 or at least about 2.5 × 10 8 TCR- or CAR-expressing cells, or at least 5 x 10 8 or at least about 5×10 8 It contains TCR- or CAR-expressing cells.

[0158] In some embodiments, the dose of engineered cells comprises 15 million to 1 billion or about 15 million to about 1 billion total recombinant receptor-expressing T cells. In some embodiments, the dose of engineered cells comprises 15 million to 600 million or about 15 million to about 600 million total recombinant receptor-expressing T cells. In some embodiments, the dose of engineered cells comprises 150 million to 600 million or about 150 million to about 600 million total recombinant receptor-expressing T cells. In some embodiments, the dose of engineered cells comprises 150 million to 450 million or about 150 million to about 450 million total recombinant receptor-expressing T cells.

[0159] In some embodiments, the dose of genetically engineered cells is at least 1 x 10 5 or at least about 1×10 5 At least 2.5 x 10 recombinant receptor-expressing cells 5 or at least about 2.5 × 10 5 recombinant receptor-expressing cells, at least 5 x 10 5 or at least about 5×10 5 recombinant receptor-expressing cells, at least 1 x 10 6 or at least about 1×10 6 At least 2.5 x 10 recombinant receptor-expressing cells 6 or at least about 2.5 × 10 6 recombinant receptor-expressing cells, at least 5 x 10 6 or at least about 5×10 6 recombinant receptor-expressing cells, at least 1 x 10 7 or at least about 1×10 7At least 2.5 x 10 recombinant receptor-expressing cells 7 or at least about 2.5 × 10 7 recombinant receptor-expressing cells, at least 5 x 10 7 or at least about 5×10 7 recombinant receptor-expressing cells, at least 1 x 10 8 or at least about 1×10 8 At least 2.5 x 10 recombinant receptor-expressing cells 8 or at least about 2.5 × 10 8 recombinant receptor-expressing cells or at least 5 x 10 8 or at least about 5×10 8 The recombinant receptor-expressing cells.

[0160] In some embodiments, the cell therapy comprises 1 x 10 5 ~1×10 8 5 x 10 or approximately 5 x 10 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs) 5 ~1×10 7 or approximately 1 x 10 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), or 1 x 10 6 ~1×10 7 In some embodiments, the cell therapy comprises administering a dose comprising at or about 1 x 10 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), each inclusive of upper and lower limits. 5 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), for example, at least or about at least 1 x 10 6 , at least or about at least 1 x 10 7 , at least or about at least 1 x 10 8 The method includes administering a dose of cells comprising a cell number of such cells.

[0161] In some embodiments, for example, when the subject is a human, the dose is about 5×10 8Fewer than 10 total recombinant receptor (e.g., CAR or TCR)-expressing cells, T cells or peripheral blood mononuclear cells (PBMCs), e.g., about 1 x 10 6 ~5×10 8 In the range of 2 x 10 such cells, e.g., 6 , 5×10 6 , 1×10 7 , 5×10 7 , 1×10 8 Or 5 x 10 8 all such cells, or a range between any two of the foregoing values.

[0162] In some embodiments, the number refers to the total number of CD3+ or CD8+, and in some cases, recombinant receptor-expressing (e.g., CAR- or TCR-expressing) cells. In some embodiments, cell therapy is administered in a cell line containing 1×10 5 ~1×10 8 pieces or approximately 1 x 10 5 ~Approx. 1×10 8 5 x 10 CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells 5 ~1×10 7 pieces or approximately 5 x 10 5 ~Approx. 1×10 7 1 x 10 CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells, or 1 x 10 6 ~1×10 7 pieces or approximately 1 x 10 6 ~Approx. 1×10 7 In some embodiments, the cell therapy comprises administering a dose comprising 1 x 10 total CD3+ or CD8+ T cells or CD3+ or CD8+ recombinant receptor-expressing cells, inclusive of the upper and lower cell limits. 5 ~1×10 8 or approximately 1 x 10 5 ~Approx. 1×10 8 5 x 10 total CD3+ / recombinant receptor+ or CD8+ / recombinant receptor+ cells 5 ~1×10 7 pieces or approximately 5 x 10 5 ~Approx. 1×10 7total CD3+ / recombinant receptor+ or CD8+ / recombinant receptor+ cells, or 1 x 10 6 ~1×10 7 or approximately 1 x 10 6 ~Approx. 1×10 7 This includes administering a dose containing a cell count of 10 total CD3+ / recombinant receptor+ or CD8+ / recombinant receptor+ cells (upper and lower limits of each).

[0163] In some embodiments, the cell therapy comprises 1 x 10 5 ~5×10 8 or approximately 1 x 10 5 ~Approx. 5×10 8 5 x 10 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs) 5 ~1×10 7 pieces or approximately 5 x 10 5 ~Approx. 1×10 7 1 x 10 total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs), or 1 x 10 6 ~1×10 7 or approximately 1 x 10 6 ~Approx. 1×10 7 In some embodiments, the cell therapy comprises administering a dose comprising at least about 1 x 10 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), each inclusive of upper and lower limits. 5 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), e.g., at least 1 x 10 6 or at least about 1 x 10 6 Pieces, at least 1 x 10 7 or at least about 1 x 10 7 Pieces, at least 1 x 10 8 or at least about 1 x 10 8 In some embodiments, the number refers to the total number of CD3+ or CD8+, and in some cases, recombinant receptor-expressing (e.g., CAR+ or TCR+) cells. In some embodiments, the cell therapy comprises administering a dose of cells comprising a cell number of 1×10 or more of such cells. In some embodiments, the number refers to the total number of CD3+ or CD8+, and in some cases, recombinant receptor-expressing (e.g., CAR+ or TCR+) cells. In some embodiments, the 5 ~5×10 8pieces or approximately 1 x 10 5 ~Approx. 5×10 8 5 x 10 CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells 5 ~1×10 7 pieces or approximately 5 x 10 5 ~Approx. 1×10 7 1 x 10 CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells, or 1 x 10 6 ~1×10 7 pieces or approximately 1 x 10 6 ~Approx. 1×10 7 In some embodiments, the cell therapy comprises administering a dose comprising 1 x 10 total CD3+ or CD8+ T cells or CD3+ or CD8+ recombinant receptor-expressing cells, inclusive of the upper and lower cell limits. 5 ~5×10 8 or approximately 1 x 10 5 ~Approx. 5×10 8 5 x 10 total CD3+ / recombinant receptor+ or CD8+ / recombinant receptor+ cells 5 ~1×10 7 pieces or approximately 5 x 10 5 ~Approx. 1×10 7 total CD3+ / recombinant receptor+ or CD8+ / recombinant receptor+ cells, or 1 x 10 6 ~1×10 7 or approximately 1 x 10 6 ~Approx. 1×10 7 This includes administering a dose containing a cell count of 10 total CD3+ / recombinant receptor+ or CD8+ / recombinant receptor+ cells (upper and lower limits of each).

[0164] In some embodiments, the dose of T cells comprises CD4+ T cells, CD8+ T cells, or CD4+ and CD8+ T cells.

[0165] In some embodiments, for example, when the subject is a human, the dose of CD8+ T cells, including in a dose comprising CD4+ and CD8+ T cells, is about 1 x 10 6 ~5×10 8Between about 5 x 10 total recombinant receptor (e.g., CAR or TCR)-expressing CD8+ cells, for example, about 5 x 10 6 ~Approx. 1×10 8 such cells in the range of 1 x 10 7 , 2.5×10 7 , 5×10 7 , 7.5×10 7 , 1×10 8 Or 5 x 10 8 In some embodiments, the patient is administered multiple doses, and each or the total dose can fall within any of the values ​​set forth above. In some embodiments, the dose of cells is 1 x 10 or more. 7 ~0.75×10 8 pieces or approximately 1 x 10 7 ~Approx. 0.75×10 8 1 x 10 total recombinant receptor-expressing CD8+ T cells 7 ~2.5×10 7 1 x 10 total recombinant receptor-expressing CD8+ T cells 7 ~0.75×10 8 pieces or approximately 1 x 10 7 ~Approx. 0.75×10 8 In some embodiments, the dose of cells comprises administering 1 x 10 total recombinant receptor-expressing CD8+ T cells (each inclusive). 7 , 2.5×10 7 , 5×10 7 , 7.5×10 7 , 1×10 8 Or 5 x 10 8 The method includes administering a total number of recombinant receptor-expressing CD8+ T cells.

[0166] In some embodiments, the dose of cells, e.g., recombinant receptor-expressing T cells, is administered to the subject as a single dose, or only once within a period of two weeks, one month, three months, six months, one year or more.

[0167] In some embodiments, the cell therapy comprises at least or at least about 0.1 x 10 6 Cells / kg (subject weight), 0.2 × 106 cells / kg, 0.3×10 6 cells / kg, 0.4×10 6 cells / kg, 0.5×10 6 cells / kg, 1×10 6 cells / kg, 2.0×10 6 cells / kg, 3×10 6 cells / kg or 5 x 10 6 It includes administering a dose containing a number of cells that is or is about cells / kg.

[0168] In some embodiments, the cell therapy comprises 0.1 x 10 6 Cells / kg (subject weight) ~ 1.0 x 10 7 Between cells / kg or approximately 0.1 x 10 6 Cells / kg (subject weight) ~ approx. 1.0 x 10 7 Between 0.5 x 10 cells / kg 6 cells / kg~5×10 6 Between 0.5 x 10 cells / kg or approximately 0.5 x 10 6 cells / kg ~ approx. 5×10 6 Between 0.5 x 10 cells / kg 6 cells / kg~3×10 6 Between 0.5 x 10 cells / kg or approximately 0.5 x 10 6 cells / kg ~ approx. 3×10 6 Between 0.5 x 10 cells / kg 6 cells / kg~2×10 6 Between 0.5 x 10 cells / kg or approximately 0.5 x 10 6 cells / kg ~ approx. 2×10 6 Between 0.5 x 10 cells / kg 6 cells / kg~1×10 6 Between 0.5 x 10 cells / kg or approximately 0.5 x 10 6 cells / kg ~ approx. 1×10 6 Between 1.0 x 10 cells / kg 6 ~5 x 10 cells / kg (subject weight) 6 Between 1.0 x 10 cells / kg or approximately 1.0 x 10 6 Cells / kg (subject weight) ~ approx. 5 x 10 6 Between 1.0 x 10 cells / kg 6 cells / kg~3×10 6Between 1.0 x 10 cells / kg or approximately 1.0 x 10 6 cells / kg ~ approx. 3×10 6 Between 1.0 x 10 cells / kg 6 cells / kg~2×10 6 Between 1.0 x 10 cells / kg or approximately 1.0 x 10 6 cells / kg ~ approx. 2×10 6 Between cells / kg, 2.0 x 10 6 ~5 x 10 cells / kg (subject weight) 6 Between 2.0 x 10 cells / kg or approximately 2.0 x 10 6 Cells / kg (subject weight) ~ approx. 5 x 10 6 Between cells / kg, 2.0 x 10 6 cells / kg~3×10 6 Between 2.0 x 10 cells / kg or approximately 2.0 x 10 6 cells / kg ~ approx. 3×10 6 cells / kg, or 3.0 x 10 6 ~5 x 10 cells / kg (subject weight) 6 Between 3.0 x 10 cells / kg or approximately 3.0 x 10 6 Cells / kg (subject weight) ~ approx. 5 x 10 6 This includes administering a dose containing a cell number between 100 and 100 cells / kg (inclusive).

[0169] In some embodiments, the dose of cells is 2×10 5 pieces or approximately 2 x 10 5 cells / kg ~ 2 x 10 6 pieces or approximately 2 x 10 6 Between 4 x 10 cells / kg, for example, 5 or approximately 4 x 10 5 cells / kg ~ 1 x 10 6 or approximately 1 x 10 6 Between 6 x 10 cells / kg or 6 x 10 5 pieces or approximately 6 x 10 5 cells / kg ~ 8 x 10 5 pieces or approximately 8 x 10 5 In some embodiments, the dose of cells comprises between 2 x 10 cells / kg of subject body weight. 5 3×10 or less cells (e.g., antigen-expressing, e.g., CAR-expressing or TCR-expressing cells) (cells / kg), e.g., 3×105 cells / kg or approximately 3 x 10 5 Cells / kg or less, 4×10 5 cells / kg or approximately 4 x 10 5 Cells / kg or less, 5×10 5 cells / kg or approximately 5 x 10 5 Cells / kg or less, 6×10 5 cells / kg or approximately 6 x 10 5 Cells / kg or less, 7×10 5 cells / kg or approximately 7 x 10 5 Cells / kg or less, 8×10 5 cells / kg or approximately 8 x 10 5 Cells / kg or less, 9×10 5 cells / kg or approximately 9 x 10 5 Cells / kg or less, 1×10 6 cells / kg or approximately 1 x 10 6 cells / kg or less, or 2 x 10 6 cells / kg or approximately 2 x 10 6 In some embodiments, the dose of cells comprises at least or at least about 2 x 10 cells / kg or less per kilogram of subject body weight. 5 pcs or 2 x 10 5 or approximately 2 x 10 5 cells (e.g., antigen-expressing, e.g., CAR-expressing or TCR-expressing cells) (cells / kg), e.g., at least 3 x 10 5 cells / kg or at least about 3 x 10 5 cells / kg or 3 x 10 5 cells / kg or approximately 3 x 10 5 cells / kg, at least 4 × 10 5 cells / kg or at least about 4 x 10 5 cells / kg or 4 x 10 5 cells / kg or approximately 4 x 10 5 cells / kg, at least 5 × 10 5 cells / kg or at least about 5 x 10 5 cells / kg or 5 x 10 5 cells / kg or approximately 5 x 10 5 cells / kg, at least 6 × 10 5 cells / kg or at least about 6 x 105 cells / kg or 6 x 10 5 cells / kg or approximately 6 x 10 5 cells / kg, at least 7 × 10 5 cells / kg or at least about 7 x 10 5 cells / kg or 7 x 10 5 cells / kg or approximately 7 x 10 5 cells / kg, at least 8 × 10 5 cells / kg or at least about 8 x 10 5 cells / kg or 8 x 10 5 cells / kg or approximately 8 x 10 5 cells / kg, at least 9 × 10 5 cells / kg or at least about 9 x 10 5 cells / kg or 9 x 10 5 cells / kg or approximately 9 x 10 5 cells / kg, at least 1 x 10 6 cells / kg or at least about 1 x 10 6 cells / kg or 1 x 10 6 cells / kg or approximately 1 x 10 6 cells / kg, or at least 2 × 10 6 cells / kg or at least about 2 x 10 6 cells / kg or 2 x 10 6 cells / kg or approximately 2 x 10 6 Contains cells / kg.

[0170] In the context of adoptive cell therapy, administration of a predetermined "dose" of cells encompasses administration of a predetermined amount or number of cells as a single composition and / or a single uninterrupted administration, e.g., as a single injection or continuous infusion, as well as administration of a predetermined amount or number of cells as divided doses provided in multiple individual compositions or infusions over a specified period of time, which is three days or less. Thus, in some situations, a dose is a single or continuous administration of a specified number of cells given or initiated at a single time point. However, in some situations, a dose is administered in multiple injections or infusions over a period of three days or less, such as once daily for three or two days, or by multiple infusions over a one-day period.

[0171] Thus, in some aspects, the dose of cells is administered in a single pharmaceutical composition, hi some embodiments, the dose of cells is administered in multiple compositions that collectively contain the dose of cells.

[0172] The term "split dose" refers to a dose that is divided so as to be administered over more than one day. This type of administration is encompassed by the present method and is considered to be a single dose. In some embodiments, the split dose cells are administered in multiple compositions that collectively comprise the dose cells over a period of 3 days or less.

[0173] Thus, the dose of cells can be administered as a split dose. For example, in some embodiments, the dose can be administered to a subject over two or three days. An exemplary method for split dosing includes administering 25% of the dose on day 1 and the remaining 75% of the dose on day 2. In other embodiments, 33% of the dose can be administered on day 1 and the remaining 67% on day 2. In some aspects, 10% of the dose is administered on day 1, 30% of the dose is administered on day 2, and 60% of the dose is administered on day 3. In some embodiments, the split dose does not extend for more than three days.

[0174] In some embodiments, the dose of cells is generally high enough to be effective in reducing disease burden.

[0175] In some embodiments, cells are administered at a desired dosage, which in some aspects includes a desired dose or number of cells or cell types and / or a desired ratio of cell types. Thus, the dosage of cells is, in some embodiments, based on the total number of cells (or number per kg body weight) and the desired ratio of individual populations or subtypes, for example, the ratio of CD4+ to CD8+. In some embodiments, the dosage of cells is based on the desired total number (or number per kg body weight) of cells in each population or of each cell type. In some embodiments, the dosage is based on a combination of such characteristics, such as the desired number of total cells, the desired ratio, and the desired total number of cells in each population.

[0176] In some embodiments, CD8 + and CD4 + A population or subtype of cells, such as T cells, is administered at a desired dose of total cells, such as a desired dose of T cells, or within an acceptable range of differences. In some embodiments, 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 embodiments, the desired dose is at or exceeds a minimum number of cells or a minimum number of cells per unit of body weight. In some embodiments, among the total cells administered at a desired dose, individual populations or subtypes are administered at a desired output ratio (e.g., CD4 + Against CD8 + ) within a certain acceptable difference or error of such ratio.

[0177] In some embodiments, cells are administered at a desired dose of one or more of the individual populations or subtypes of cells, such as a desired dose of CD4+ cells and / or a desired dose of CD8+ cells, or within an acceptable difference. In some aspects, the desired dose is the desired number of cells of a subtype or population, or the 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 exceeds the minimum number of cells of a population or subtype, or the minimum number of cells of a population or subtype per unit of body weight.

[0178] Thus, in some embodiments, dosage is based on a desired fixed dose and desired ratio of total cells and / or based on a desired fixed dose of one or more, e.g., each, of individual subtypes or subpopulations. Thus, in some embodiments, dosage is based on a desired fixed or minimum dose of T cells and CD4 + Against CD8 + Based on the desired ratio of cells and / or CD4 + and / or CD8 + Based on desired fixation or minimum dose of cells.

[0179] In some embodiments, cells are administered at a desired output ratio or within an acceptable range of multiple cell populations or subtypes, such as CD4+ and CD8+ cells or subtypes. In some aspects, the desired ratio can be a specific ratio or a range of ratios. For example, in some embodiments, the desired ratio (e.g., CD4 + Against CD8 + The ratio of cells is between 5:1 or about 5:1 and 5:1 or about 5:1 (or greater than about 1:5 and less than about 5:1), or between 1:3 or about 1:3 and 3:1 or about 3:1 (or greater than about 1:3 and less than about 3:1), for example, between 2:1 or about 2:1 and 1:5 or about 1:5 (or greater than about 1:5 and less than about 2:1), for example, 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 or an approximation thereof. In some embodiments, acceptable differences are 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.

[0180] In certain embodiments, the number and / or concentration of cells refers to the number of recombinant receptor (e.g., CAR or TCR)-expressing cells. In other embodiments, the number and / or concentration of cells refers to the number or concentration of administered total cells, T cells, or peripheral blood mononuclear cells (PBMCs).

[0181] In some embodiments, the size of the dose is determined based on one or more criteria such as the subject's response to previous treatment, e.g., chemotherapy; the disease burden in the subject, e.g., tumor burden, volume, size or extent, degree or type of metastasis, stage; and / or the likelihood or incidence that the subject will develop a toxic outcome, e.g., CRS, macrophage activation syndrome, tumor lysis syndrome, neurotoxicity, and / or host immune response, to the cells and / or recombinant receptor being administered.

[0182] In some embodiments, administration of a DGK inhibitor in combination with cells can significantly increase the expansion or proliferation of the cells, thereby allowing a lower dose of cells to be administered to a subject. In some cases, the provided methods allow for a lower dose of such cells to be administered, such as 1.5, 2, 3, 4, 5, or 10 times lower than the dose in methods in which the cell therapy is administered without the administration of a DGK inhibitor, to achieve the same or better therapeutic efficacy as the dose in methods in which the cell therapy is administered without the administration of a DGK inhibitor.

[0183] In some embodiments, for example, the dose is 5.0 x 10 6 ~2.25×10 7 , 5.0×10 6 ~2.0×10 7 , 5.0×10 6 ~1.5×10 7 , 5.0×10 6 ~1.0×10 7 , 5.0×10 6 ~7.5×10 6 , 7.5×10 6 ~2.25×10 7 , 7.5×10 6 ~2.0×10 7 , 7.5×10 6 ~1.5×10 7 , 7.5×10 6 ~1.0×10 7 , 1.0×10 7 ~2.25×10 7 , 1.0×10 7 ~2.0×107 , 1.0×10 7 ~1.5×10 7 , 1.5×10 7 ~2.25×10 7 , 1.5×10 7 ~2.0×10 7 , 2.0×10 7 ~2.25×10 7 In some embodiments, the dose of cells comprises at least or at least about 5 x 10 6 , about 6×10 6 , about 7×10 6 , about 8×10 6 , about 9×10 6 , about 10×10 6 ~Approx. 15×10 6 In some embodiments, such a dose, e.g., such a target number of cells, refers to the total recombinant receptor-expressing cells in the administered composition.

[0184] In some embodiments, for example, the lower dose is about 5×10 per kilogram of subject body weight. 6 Fewer than about 4.5 x 10 cells, recombinant receptor (e.g., TCR or CAR)-expressing cells, T cells and / or PBMCs, e.g., about 4.5 x 10 cells per kilogram of subject body weight 6 , about 4×10 6 , about 3.5×10 6 , about 3×10 6 , about 2.5×10 6 , about 2×10 6 , about 1.5×10 6 , about 1×10 6 , about 5×10 5 , about 2.5×10 5 or about 1 x 10 5 In some embodiments, the lower dose contains less than about 1 x 10 such cells per kilogram of subject body weight. 5 , about 2×10 5 , about 5×10 5 or about 1 x 10 6In some embodiments, such values ​​refer to the number of recombinant receptor-expressing cells; in other embodiments, they refer to the number of T cells or PBMCs or total cells administered.

[0185] In some embodiments, a subject receives multiple doses of cells, e.g., two or more consecutive doses. In some embodiments, two doses are administered to a subject. In some embodiments, a subject receives consecutive doses, e.g., a second dose is administered about 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, a first dose is followed by multiple consecutive doses, such that an additional dose is administered following administration of the consecutive doses. In some aspects, the number of cells administered to a subject in the additional doses is the same or similar to the first dose and / or the consecutive doses. In some embodiments, the additional dose is greater than the previous dose. In some embodiments, one or more subsequent doses of cells can be administered to a subject. In some embodiments, the subsequent dose of cells is administered more than or about 7, 14, 21, 28, or 35 days after the start of administration of the first dose of cells. Subsequent doses of cells can be greater than, about the same as, or less than the first dose. In some embodiments, the administration of T cell therapy may be repeated, such as administering the first and / or second doses of cells.

[0186] In some embodiments, the start of administration of the cell therapy, e.g., the first dose of a dose of cells or a sub-dose of cells, is administered prior to (before), simultaneously with, or after (subsequently or subsequently) the administration of the inhibitor of DGKα and / or DGKζ. In some embodiments, the start of administration of the cell therapy relative to the start of administration of the inhibitor of DGKα and / or DGKζ is as described in any of the embodiments described in Section IB-2.

[0187] In some embodiments, the methods involve evaluating a sample from the subject following administration of a dose of cells for T cell therapy, e.g., adoptive T cell therapy, but prior to administration of a DGK inhibitor, for one or more functions of T cells, such as expansion or persistence of cells as determined by, e.g., blood levels or amounts, or other phenotypes or desired outcomes described herein, such as, e.g., those described in Section III. In some embodiments, the methods involve evaluating a sample from the subject following administration of a dose of cells for T cell therapy, e.g., adoptive T cell therapy, but prior to administration of a DGK inhibitor, for expression of one or more exhaustion markers. Various parameters for determining or evaluating combination therapy regimens are described in Section III.

[0188] B. Administration of DGKα and / or DGKζ inhibitors In some aspects, the methods provided herein include combination therapy by administering a DGK inhibitor in combination with cell therapy, e.g., T cell therapy, to a subject having a disease or condition, such as any of the diseases or conditions described above. The DGKi can be administered before, simultaneously with, or after administration of the cell therapy, e.g., T cell therapy. In some aspects, the methods provided herein include administering cell therapy, e.g., T cell therapy, to a subject having a disease or condition, where the subject has previously been administered a DGK inhibitor. In some embodiments, the DGK inhibitor and the cell therapy, e.g., T cell therapy, are administered to the subject simultaneously.

[0189] In some embodiments, the inhibitor of DGK is an inhibitor of DGKα and / or DGKζ. In certain embodiments, the inhibitor of DGKα and / or DGKζ is an inhibitor of DGKα. In certain embodiments, the inhibitor of DGKα and / or DGKζ is an inhibitor of DGKζ. In certain embodiments, the inhibitor of DGKα and / or DGKζ inhibits both enzymes. The level of enzyme inhibition can be measured as further described herein. In certain embodiments, the inhibitor of DGKα and / or DGKζ is not a significant inhibitor of other DGK enzymes.

[0190] In certain embodiments, inhibitors of DGKα and / or DGKζ increase immune responses, such as by increasing T cell activity. For example, inhibitors of DGKα and / or DGKζ can increase primary T cell signaling, as evidenced by, for example, increased pERK / pPKC signaling, which can be measured as further described herein. In certain embodiments, inhibitors of DGKα and / or DGKζ have one or more of the following properties: (i) they lower the threshold for antigen stimulation; (ii) they increase CTL effector function; and (iii) they enhance tumor cell killing. When inhibitors of DGKα and / or DGKζ enhance tumor cell killing, this activity may depend on CD8+ T cells, as shown, for example, in the CT26 animal model. When inhibitors of DGKα and / or DGKζ enhance tumor cell killing, this activity may depend on NK cells, as shown, for example, in the CT26 animal model. When inhibitors of DGKα and / or DGKζ enhance tumor cell killing, this activity may depend on CD8+ T cells and NK cells, as shown, for example, in the CT26 animal model. When inhibitors of DGKα and / or DGKζ enhance tumor cell killing, this activity may be enhanced by CD4 cell depletion, for example, in the CT-26 animal model. In certain embodiments, inhibitors of DGKα and / or DGKζ enhance AH1+ tetramer antigen presentation in the CT-26 animal model. Inhibitors of DGKα and / or DGKζ preferably have one or more, and may include all, of the above-cited properties.

[0191] 1. Exemplary Inhibitors of DGKα and / or DGKζ Enzyme Activity Exemplary compounds, such as the compounds of Formula I described herein and pharmaceutically acceptable salts thereof, are described in WO2020 / 006018 and WO2020 / 006016, the contents of both of which are specifically incorporated herein by reference. Exemplary compounds, such as the compounds of Formula II described herein and pharmaceutically acceptable salts thereof, are described in PCT / US2020 / 048070, the contents of which are specifically incorporated herein by reference.

[0192] In some embodiments, the provided combination therapy of T cell therapy and DGK inhibitor comprises a compound of Formula (I): [ka] (I) (In the formula, R1 is H, F, Cl, Br, -CN, or 0 to 4 R 1a C replaced with 1~3 Alkyl, 0 to 4 R 1a C replaced with 3~4 Cycloalkyl, 0 to 4 R 1a C replaced with 1~3 Alkoxy, -NR a R a , -S(O) n R e or -P(O)R e R e and; Each R 1a are independently F, Cl, -CN, -OH, -OCH3, or -NR a R a and; Each R a are independently H or C 1~3 is alkyl; Each R e independently, C 3~4 Cycloalkyl or 0 to 4 R 1a C replaced with 1~3 is alkyl; R2 is H, 0 to 4 R 2a C replaced with 1~3 Alkyl or 0 to 4 R 2a C replaced with3~4 is cycloalkyl; Each R 2a are independently F, Cl, -CN, -OH, -O(C 1~2 alkyl), C 3~4 Cycloalkyl, C 3~4 Alkenyl or C 3~4 is alkynyl; R3 is H, F, Cl, Br, -CN, C 1~3 Alkyl, C 1~2 Fluoroalkyl, C 3~4 Cycloalkyl, C 3~4 fluorocycloalkyl or -NO2; R4 is -CH2R 4a , -CH2CH2R 4a , -CH2CHR 4a R 4d , -CHR 4a R 4b or -CR 4a R 4b R 4c and; R 4a and R 4b is, independently, (i)F, Cl, -CN, -OH, -OCH3, -SCH3, C 1~3 Fluoroalkoxy, -NR a R a , -S(O)2R e or -NR a S(O)2R e C substituted with 0 to 4 substituents independently selected from 1~6 alkyl; (ii)F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~4 Hydroxyalkyl, -(CH2) 1~2 O(C 1~3 alkyl), C 1~4 Alkoxy, -O(C 1~4 hydroxyalkyl), -O(CH) 1~3 O(C 1~3 alkyl), C 1~3 Fluoroalkoxy, -O(CH) 1~3 NR cR c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl), -P(O)(C 1~3 alkyl)2, -S(O)2(C 1~3 alkyl), -O(CH2) 1~2 (C 3~6 cycloalkyl), -O(CH2) 1~2 (morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and R d C, each substituted with 0 to 4 substituents independently selected from 3~6 cycloalkyl, heterocyclyl, phenyl, or heteroaryl; or (iii)C 3~6 C substituted with one cyclic group selected from cycloalkyl, heterocyclyl, aryl and heteroaryl 1~4 Alkyl, wherein the cyclic group is F, Cl, Br, —OH, —CN, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl) and C 3~6substituted with 0 to 3 substituents independently selected from cycloalkyl, C 1~4 Alkyl Is it; Or R 4a and R 4b These, together with the carbon atoms to which they are attached, form 0 to 3 R f C respectively substituted with 3~6 forming a cycloalkyl or a 3- to 6-membered heterocyclyl; Each R f are independently F, Cl, Br, -OH, -CN, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , or C 3~6 A cyclic group selected from cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each of which is selected from F, Cl, Br, —OH, —CN, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy and -NR c R c substituted with 0 to 3 substituents independently selected from: R 4c are F, Cl, -OH, C 1~2 Alkoxy, C 1~2 C, each substituted with 0 to 4 substituents independently selected from fluoroalkoxy and —CN; 1~6 Alkyl or C 3~6 is cycloalkyl; R 4d is -OCH3; Each R c are independently H or C 1~2 is alkyl; R d is phenyl substituted with 0-1 substituents selected from F, Cl, —CN, —CH3, and —OCH3; Each R5 is independently selected from -CN, 0 to 4 R g C replaced with 1~6 Alkyl, 0 to 4 R g C replaced with 2~4 Alkenyl, 0 to 4 R g C replaced with 2~4 Alkynyl, 0 to 4 R g C replaced with 3~4 Cycloalkyl, 0 to 4 R g phenyl substituted with 0 to 3 R g oxadiazolyl substituted with 0 to 4 R g Pyridinyl substituted with -(CH2) 1~2 (0 to 4 R g heterocyclyl substituted with -(CH2) 1~2 NR c C(O)(C 1~4 alkyl), -(CH2) 1~2 NR c C(O)O(C 1~4 alkyl), -(CH2) 1~2 NR c S(O)2(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)O(C 3~4 cycloalkyl), -C(O)NR a R a or -C(O)NR a (C 3~4 cycloalkyl); Each R g are independently F, Cl, -CN, -OH, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy, -O(CH2) 1~2 O(C 1~2 alkyl) or -NR c R c and; m is 0, 1, 2 or 3; n is 0, 1 or 2) or a pharmaceutically acceptable salt thereof.

[0193] In some embodiments, the provided combination therapy of T cell therapy and DGK inhibitor is a compound of formula (I), wherein: R1 is H, F, Cl, Br, -CN, or 0 to 4 R 1a C replaced with 1~3 Alkyl, 0 to 3 R 1a cyclopropyl substituted with 0-3 R 1a C replaced with 1~3 Alkoxy, -NR a R a , -S(O) n CH3 or -P(O)(CH3)2; Each R 1a are independently F, Cl, or —CN; Each R a are independently H or C 1~3 is alkyl; R2 is H or 0 to 2 R 2a C replaced with 1~2 is alkyl; Each R 2a are independently F, Cl, -CN, -OH, -O(C 1~2 alkyl), cyclopropyl, C 3~4 Alkenyl or C 3~4 is alkynyl; R3 is H, F, Cl, Br, -CN, C 1~2 alkyl, -CF3, cyclopropyl, or -NO2; R 4a and R 4b is, independently, (i)F, Cl, -CN, -OH, -OCH3, -SCH3, C 1~3 Fluoroalkoxy and -NR a R a C substituted with 0 to 4 substituents independently selected from 1~4 alkyl; (ii)F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3 Fluoroalkyl, -CH2OH, -(CH2) 1~2 O(C 1~2alkyl), C 1~4 Alkoxy, -O(C 1~4 hydroxyalkyl), -O(CH) 1~2 O(C 1~2 alkyl), C 1~3 Fluoroalkoxy, -O(CH) 1~2 NR c R c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl), -P(O)(C 1~2 alkyl)2, -S(O)2(C 1~3 alkyl), -O(CH2) 1~2 (C 3~4 cycloalkyl), -O(CH2) 1~2 (morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and R d C, each substituted with 0 to 4 substituents independently selected from 3~6 cycloalkyl, heterocyclyl, phenyl, or heteroaryl; or (iii)C 3~6 C substituted with one cyclic group selected from cycloalkyl, heterocyclyl, phenyl, and heteroaryl 1~3 Alkyl, wherein the cyclic group is F, Cl, Br, —OH, —CN, C 1~3 Alkyl, C 1~2 Fluoroalkyl, C 1~3 Alkoxy, C 1~2 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c, -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl) and C 3~4 substituted with 0 to 3 substituents independently selected from cycloalkyl, C 1~3 Alkyl Is it; Or R 4a and R 4b These, together with the carbon atoms to which they are attached, form 0 to 3 R f C respectively substituted with 3~6 forming a cycloalkyl or a 3- to 6-membered heterocyclyl; Each R f are independently F, Cl, Br, -OH, -CN, C 1~4 Alkyl, C 1~2 Fluoroalkyl, C 1~3 Alkoxy, C 1~2 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , or C 3~6 A cyclic group selected from cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each of which is selected from F, Cl, Br, —OH, —CN, C 1~4 Alkyl, C 1~2 Fluoroalkyl, C 1~3 Alkoxy, C 1~2 Fluoroalkoxy and -NR c R c substituted with 0 to 3 substituents independently selected from: R 4c are F, Cl, -OH, C 1~2 Alkoxy, C 1~2 C, each substituted with 0 to 4 substituents independently selected from fluoroalkoxy and —CN; 1~4 Alkyl or C 3~6 is cycloalkyl; Each R5 is independently selected from -CN, 0 to 4 R gC replaced with 1~5 Alkyl, 0 to 4 R g C replaced with 2~3 Alkenyl, 0 to 4 R g C replaced with 2~3 Alkynyl, 0 to 4 R g C replaced with 3~4 Cycloalkyl, 0 to 3 R g phenyl substituted with 0 to 3 R g oxadiazolyl substituted with 0-3 R g Pyridinyl substituted with -(CH2) 1~2 (0 to 4 R g heterocyclyl substituted with -(CH2) 1~2 NR c C(O)(C 1~4 alkyl), -(CH2) 1~2 NR c C(O)O(C 1~4 alkyl), -(CH2) 1~2 NR c S(O)2(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)O(C 3~4 cycloalkyl), -C(O)NR a R a or -C(O)NR a (C 3~4 cycloalkyl), The present invention relates to the administration or use of an inhibitor of DGKα and / or DGKζ, which is a compound or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments, the provided combination therapy of T cell therapy and DGK inhibitor has the structure: [ka] (In the formula, R1 is -CN; R2 is -CH3; R3 is H, F or -CN; R4 is [ka] is) The present invention relates to the administration or use of an inhibitor of DGKα and / or DGKζ, which is a compound of formula (I) having the formula:

[0195] In some embodiments, the provided combination therapy of T cell therapy and DGK inhibitor has 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-carboxylate; [ka] 4-((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; [ka] (R)-8-(4-(bis(4-fluorophenyl)methyl)-3-methylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile; [ka] 8-[(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-carbonitrile; [ka] 4-[(2S,5R)-4-[(4-chlorophenyl)(4-fluorophenyl)methyl]-2,5-dimethylpiperazin-1-yl]-6-methoxy-1-methyl-1,2-dihydro-1,5-naphthyridin-2-one; [ka] 8-[(2S,5R)-4-{[2-(difluoromethyl)-4-fluorophenyl]methyl}-2,5-dimethylpiperazin-1-yl]-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile; [ka] 8-[(2S,5R)-4-[(4-fluorophenyl)(4-methylphenyl)methyl]-2,5-dimethylpiperazin-1-yl]-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile; [ka] 8-[(2S,5R)-4-[1-(2,6-difluorophenyl)ethyl]-2,5-dimethylpiperazin-1-yl]-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile; [ka] 8-((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-dicarbonitrile; [ka] 8-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile; [ka] and 8-[(2S,5R)-4-[bis(4-methylphenyl)methyl]-2,5-dimethylpiperazin-1-yl]-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments, the provided combination therapy of T cell therapy and DGK inhibitor comprises a compound of formula (II): [ka] (II) (In the formula, R1 is H, F, Cl, Br, -CN, -OH, or 0 to 4 R 1a C replaced with 1~3 Alkyl, 0 to 4 R 1a C replaced with 3~4 Cycloalkyl, 0 to 4 R 1a C replaced with 1~3 Alkoxy, -NR a R a , -S(O) n R e or -P(O)R e R e and; Each R 1a are independently F, Cl, -CN, -OH, -OCH3, or -NR a R a and; Each R a are independently H or C 1~3 is alkyl; Each R e independently, C 3~4 Cycloalkyl, or 0 to 4 R 1a C replaced with 1~3 is alkyl; R2 is H, 0 to 4 R 2a C replaced with 1~3 Alkyl or 0 to 4 R 2a C replaced with 3~4 is cycloalkyl; Each R 2a are independently F, Cl, -CN, -OH, -O(C1~2 alkyl), C 3~4 Cycloalkyl, C 3~4 Alkenyl or C 3~4 is alkynyl; R4 is -CH2R 4a , -CH2CH2R 4a , -CH2CHR 4a R 4d , -CHR 4a R 4b or -CR 4a R 4b R 4c and; R 4a and R 4b is, independently, (i) -CN, or F, Cl, -CN, -OH, -OCH3, -SCH3, C 1~3 Fluoroalkoxy, -NR a R a , -S(O)2R e or -NR a S(O)2R e C substituted with 0 to 4 substituents independently selected from 1~6 alkyl; (ii)F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~2 Bromoalkyl, C 1~2 Cyanoalkyl, C 1~4 Hydroxyalkyl, -(CH2) 1~2 O(C 1~3 alkyl), C 1~4 Alkoxy, C 1~3 Fluoroalkoxy, C 1~3 Cyanoalkoxy, -O(C 1~4 hydroxyalkyl), -O(CR x R x ) 1~3 O(C 1~3 alkyl), C 1~3 Fluoroalkoxy, -O(CH2) 1~3 NR c R c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C1~4 alkyl), -NR c R c , -CH2NR a R a , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -(CR x R x ) 0~2 NR a C(O)O(C 1~4 alkyl), -P(O)(C 1~3 alkyl)2, -S(O)2(C 1~3 alkyl), -(CR x R x ) 1~2 (C 3~4 cycloalkyl), -(CR x R x ) 1~2 (morpholinyl), -(CR x R x ) 1~2 (difluoromorpholinyl), -(CR x R x ) 1~2 (dimethylmorpholinyl), -(CR x R x ) 1~2 (oxazabicyclo[2.2.1]heptanyl), (CR x R x ) 1~2 (oxazaspiro[3.3]heptanyl), -(CR x R x ) 1~2 (methylpiperazinonyl), -(CR x R x ) 1~2 (acetylpiperazinyl), -(CR x R x ) 1~2 (piperidinyl), -(CR x R x ) 1~2 (difluoropiperidinyl), -(CR x R x ) 1~2 (Methoxypiperidinyl), -(CR x R x )1~2 (hydroxypiperidinyl), -O(CR x R x ) 0~2 (C 3~6 cycloalkyl), -O(CR x R x ) 0~2 (methylcyclopropyl), -O(CR x R x ) 0~2 ((ethoxycarbonyl)cyclopropyl), -O(CR x R x ) 0~2 (oxetanyl), -O(CR x R x ) 0~2 (methylazetidinyl), -O(CR x R x ) 0~2 (tetrahydropyranyl), -O(CR x R x ) 1~2 (morpholinyl), -O(CR x R x ) 0~2 (thiazolyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, dioxolanyl, pyrrolidinonyl and R d C, each substituted with 0 to 4 substituents independently selected from 3~8 carbocyclyl, 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl; or (iii)C 3~6 C substituted with one cyclic group selected from cycloalkyl, 4- to 10-membered heterocyclyl, monocyclic or bicyclic aryl, or 5- to 10-membered heteroaryl 1~4 Alkyl, wherein the cyclic group is F, Cl, Br, —OH, —CN, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NRc R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl) and C 3~6 substituted with 0 to 3 substituents independently selected from cycloalkyl, C 1~4 Is it alkyl? Or R 4a and R 4b These, together with the carbon atoms to which they are attached, form 0 to 3 R f C respectively substituted with 3~6 forming a cycloalkyl or a 3- to 6-membered heterocyclyl; Each R f are independently F, Cl, Br, -OH, -CN, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , or C 3~6 A cyclic group selected from cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each of which is selected from F, Cl, Br, —OH, —CN, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy and -NR c R c substituted with 0 to 3 substituents independently selected from: R 4c are F, Cl, -OH, C 1~2 Alkoxy, C 1~2 C, each substituted with 0 to 4 substituents independently selected from fluoroalkoxy and —CN; 1~6 Alkyl or C 3~6 is cycloalkyl; R 4dis -OCH3; Each R c are independently H or C 1~2 is alkyl; R d is phenyl substituted with 0-1 substituents selected from F, Cl, —CN, —CH3, and —OCH3; Each R5 is independently selected from -CN, 0 to 4 R g C replaced with 1~6 Alkyl, 0 to 4 R g C replaced with 2~4 Alkenyl, 0 to 4 R g C replaced with 2~4 Alkynyl, 0 to 4 R g C replaced with 3~4 Cycloalkyl, 0 to 4 R g phenyl substituted with 0 to 3 R g oxadiazolyl substituted with 0 to 4 R g Pyridinyl substituted with -(CH2) 1~2 (0 to 4 R g 4-10 membered heterocyclyl substituted with -(CH2) 1~2 NR c C(O)(C 1~4 alkyl), -(CH2) 1~2 NR c C(O)O(C 1~4 alkyl), -(CH2) 1~2 NR c S(O)2(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)O(C 3~4 cycloalkyl), -C(O)NR a R a or -C(O)NR a (C 3~4 cycloalkyl); Each R g are independently F, Cl, -CN, -OH, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy, -O(CH2) 1~2 O(C 1~2alkyl) or -NR c R c and; m is 0, 1, 2 or 3; n is 0, 1 or 2) or a salt thereof.

[0197] In some embodiments, the provided combination therapy of T cell therapy and DGK inhibitor comprises a compound of formula (II): [ka] (II) (In the formula, R1 is H, F, Cl, Br, -CN, or 0 to 4 R 1a C replaced with 1~3 Alkyl, 0 to 4 R 1a C replaced with 3~4 Cycloalkyl, 0 to 4 R 1a C replaced with 1~3 Alkoxy, -NR a R a , -S(O) n R e or -P(O)R e R e and; Each R 1a are independently F, Cl, -CN, -OH, -OCH3, or -NR a R a and; Each R a are independently H or C 1~3 is alkyl; Each R e independently, C 3~4 Cycloalkyl, or 0 to 4 R 1a C replaced with 1~3 is alkyl; R2 is H, 0 to 4 R 2a C replaced with 1~3 Alkyl or 0 to 4 R 2a C replaced with 3~4 is cycloalkyl; Each R 2aare independently F, Cl, -CN, -OH, -O(C 1~2 alkyl), C 3~4 Cycloalkyl, C 3~4 Alkenyl or C 3~4 is alkynyl; R4 is -CH2R 4a , -CH2CH2R 4a , -CH2CHR 4a R 4d , -CHR 4a R 4b or -CR 4a R 4b R 4c and; R 4a and R 4b is, independently, (i)F, Cl, -CN, -OH, -OCH3, -SCH3, C 1~3 Fluoroalkoxy, -NR a R a , -S(O)2R e or -NR a S(O)2R e C substituted with 0 to 4 substituents independently selected from 1~6 alkyl; (ii)F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~4 Hydroxyalkyl, -(CH2) 1~2 O(C 1~3 alkyl), C 1~4 Alkoxy, -O(C 1~4 hydroxyalkyl), -O(CH2) 1~3 O(C 1~3 alkyl), C 1~3 Fluoroalkoxy, -O(CH2) 1~3 NR c R c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NRa C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl), -P(O)(C 1~3 alkyl)2, -S(O)2(C 1~3 alkyl), -O(CH2) 1~2 (C 3~6 cycloalkyl), -O(CH2) 1~2 (morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and R d C, each substituted with 0 to 4 substituents independently selected from 3~6 cycloalkyl, heterocyclyl, phenyl, or heteroaryl; or (iii)C 3~6 C substituted with one cyclic group selected from cycloalkyl, heterocyclyl, aryl and heteroaryl 1~4 Alkyl, wherein the cyclic group is F, Cl, Br, —OH, —CN, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl) and C 3~6 substituted with 0 to 3 substituents independently selected from cycloalkyl, C 1~4 Alkyl Is it; Or R 4a and R 4b These, together with the carbon atoms to which they are attached, form 0 to 3 R f C respectively substituted with 3~6forming a cycloalkyl or a 3- to 6-membered heterocyclyl; Each R f are independently F, Cl, Br, -OH, -CN, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , or C 3~6 A cyclic group selected from cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each of which is selected from F, Cl, Br, —OH, —CN, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy and -NR c R c substituted with 0 to 3 substituents independently selected from: R 4c are F, Cl, -OH, C 1~2 Alkoxy, C 1~2 C, each substituted with 0 to 4 substituents independently selected from fluoroalkoxy and —CN; 1~6 Alkyl or C 3~6 is cycloalkyl; R 4d is -OCH3; Each R c are independently H or C 1~2 is alkyl; R d is phenyl substituted with 0-1 substituents selected from F, Cl, —CN, —CH3, and —OCH3; Each R5 is independently selected from -CN, 0 to 4 R g C replaced with 1~6 Alkyl, 0 to 4 R g C replaced with 2~4 Alkenyl, 0 to 4 R g C replaced with 2~4 Alkynyl, 0 to 4 R g C replaced with3~4 Cycloalkyl, 0 to 4 R g phenyl substituted with 0 to 3 R g oxadiazolyl substituted with 0 to 4 R g Pyridinyl substituted with -(CH2) 1~2 (0 to 4 R g 4-10 membered heterocyclyl substituted with -(CH2) 1~2 NR c C(O)(C 1~4 alkyl), -(CH2) 1~2 NR c C(O)O(C 1~4 alkyl), -(CH2) 1~2 NR c S(O)2(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)O(C 3~4 cycloalkyl), -C(O)NR a R a or -C(O)NR a (C 3~4 cycloalkyl); Each R g are independently F, Cl, -CN, -OH, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy, -O(CH2) 1~2 O(C 1~2 alkyl) or -NR c R c and; m is 0, 1, 2 or 3; n is 0, 1 or 2) or a salt thereof.

[0198] In one embodiment, the compound of Formula (II) is provided, wherein R is H, F, Cl, Br, —CN, —OH, 0-4 R 1a C replaced with 1~3 Alkyl, 0 to 3 R 1a cyclopropyl substituted with 0-3 R 1a C replaced with1~3 Alkoxy, -NR a R a , -S(O) n CH3 or -P(O)(CH3)2; R2 is H or 0 to 2 R 2a C replaced with 1~2 alkyl; each R 2a are independently F, Cl, -CN, -OH, -O(C 1~2 alkyl), cyclopropyl, C 3~4 Alkenyl or C 3~4 alkynyl; R 4a and R 4b are independently (i) -CN, or F, Cl, -CN, -OH, -OCH3, -SCH3, C 1~3 Fluoroalkoxy and -NR a R a C substituted with 0 to 4 substituents independently selected from 1~4 Alkyl; (ii) F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~2 Bromoalkyl, C 1~2 Cyanoalkyl, C 1~2 Hydroxyalkyl, -CHNR a R a , -(CH2) 1~2 O(C 1~2 alkyl), -(CH2) 1~2 NR x C(O)O(C 1~2 alkyl), C 1~4 Alkoxy, -O(C 1~4 hydroxyalkyl), -O(CR x R x ) 1~2 O(C 1~2 alkyl), C 1~3 Fluoroalkoxy, C 1~3 Cyanoalkoxy, -O(CH2) 1~2 NR c R c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -NRc R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl), -P(O)(C 1~2 alkyl)2, -S(O)2(C 1~3 alkyl), -(CH2) 1~2 (C 3~4 cycloalkyl), -CR x R x (morpholinyl), -CR x R x (difluoromorpholinyl), -CR x R x (dimethylmorpholinyl), -CR x R x (oxazabicyclo[2.2.1]heptanyl), -CR x R x (oxazaspiro[3.3]heptanyl), -CR x R x (methylpiperazinonyl), -CR x R x (acetylpiperazinyl), -CR x R x (piperidinyl), -CR x R x (difluoropiperidinyl), -CR x R x (methoxypiperidinyl), -CR x R x (hydroxypiperidinyl), -O(CH2) 0~2 (C 3~4 cycloalkyl), -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 R d C, each substituted with 0 to 4 substituents independently selected from 3~6 carbocyclyl, 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl; or (iii) C 3~6 C substituted with one cyclic group selected from cycloalkyl, 4- to 10-membered heterocyclyl, phenyl, and heteroaryl 1~3 Alkyl, wherein the cyclic group is F, Cl, Br, —OH, —CN, C 1~3 Alkyl, C 1~2 Fluoroalkyl, C 1~3 Alkoxy, C 1~2 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl) and C 3~4 substituted with 0 to 3 substituents independently selected from cycloalkyl, C 1~3 alkyl; or R 4a and R 4b These, together with the carbon atoms to which they are attached, form 0 to 3 R f C respectively substituted with 3~6 form a cycloalkyl or 3- to 6-membered heterocyclyl; each R f are independently F, Cl, Br, -OH, -CN, C 1~4 Alkyl, C 1~2 Fluoroalkyl, C 1~3 Alkoxy, C 1~2 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c, or C 3~6 A cyclic group selected from cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each of which is selected from F, Cl, Br, —OH, —CN, C 1~4 Alkyl, C 1~2 Fluoroalkyl, C 1~3 Alkoxy, C 1~2 Fluoroalkoxy and -NR c R c and R is substituted with 0 to 3 substituents independently selected from 4c are F, Cl, -OH, C 1~2 Alkoxy, C 1~2 C, each substituted with 0 to 4 substituents independently selected from fluoroalkoxy and —CN; 1~4 Alkyl or C 3~6 cycloalkyl; each R5 is independently —CN, 0 to 4 R g C replaced with 1~5 Alkyl, 0 to 4 R g C replaced with 2~3 Alkenyl, 0 to 4 R g C replaced with 2~3 Alkynyl, 0 to 4 R g C replaced with 3~4 Cycloalkyl, 0 to 3 R g phenyl substituted with 0 to 3 R g oxadiazolyl substituted with 0-3 R g Pyridinyl substituted with -(CH2) 1~2 (0 to 4 R g 4-10 membered heterocyclyl substituted with -(CH2) 1~2 NR c C(O)(C 1~4 alkyl), -(CH2) 1~2 NR c C(O)O(C 1~4 alkyl), -(CH2) 1~2 NR c S(O)2(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)O(C3~4 cycloalkyl), -C(O)NR a R a or -C(O)NR a (C 3~4 cycloalkyl); Each R x is independently H or -CH3; m is 1, 2, or 3; or a salt thereof is administered.

[0199] In one embodiment, the compound of Formula (II) is provided, wherein R is H, F, Cl, Br, —CN, 0-4 R 1a C replaced with 1~3 Alkyl, 0 to 3 R 1a cyclopropyl substituted with 0-3 R 1a C replaced with 1~3 Alkoxy, -NR a R a , -S(O) n CH3 or -P(O)(CH3)2; each R 1a is independently F, Cl, or —CN; each R a are independently H or C 1~3 alkyl; R2 is H or 0 to 2 R 2a C replaced with 1~2 alkyl; each R 2a are independently F, Cl, -CN, -OH, -O(C 1~2 alkyl), cyclopropyl, C 3~4 Alkenyl or C 3~4 alkynyl; R 4a and R 4b are independently: (i) F, Cl, -CN, -OH, -OCH3, -SCH3, C 1~3 Fluoroalkoxy and -NR a R a C substituted with 0 to 4 substituents independently selected from 1~4 Alkyl; (ii) F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3 Fluoroalkyl, -CH2OH, -(CH2) 1~2 O(C 1~2 alkyl), C1~4 Alkoxy, -O(C 1~4 hydroxyalkyl), -O(CH2) 1~2 O(C 1~2 alkyl), C 1~3 Fluoroalkoxy, -O(CH2) 1~2 NR c R c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl), -P(O)(C 1~2 alkyl)2, -S(O)2(C 1~3 alkyl), -O(CH2) 1~2 (C 3~4 cycloalkyl), -O(CH2) 1~2 (morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and R d C, each substituted with 0 to 4 substituents independently selected from 3~6 cycloalkyl, 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl; or (iii) C 3~6 C substituted with one cyclic group selected from cycloalkyl, heterocyclyl, phenyl, and heteroaryl 1~3 Alkyl, wherein the cyclic group is F, Cl, Br, —OH, —CN, C 1~3 Alkyl, C 1~2 Fluoroalkyl, C 1~3 Alkoxy, C 1~2 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , -NRa S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl) and C 3~4 substituted with 0 to 3 substituents independently selected from cycloalkyl, C 1~3 alkyl; or R 4a and R 4b These, together with the carbon atoms to which they are attached, form 0 to 3 R f C respectively substituted with 3~6 form a cycloalkyl or 3- to 6-membered heterocyclyl; each R f are independently F, Cl, Br, -OH, -CN, =O, C 1~4 Alkyl, C 1~2 Fluoroalkyl, C 1~3 Alkoxy, C 1~2 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , or C 3~6 A cyclic group selected from cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each of which is selected from F, Cl, Br, —OH, —CN, C 1~4 Alkyl, C 1~2 Fluoroalkyl, C 1~3 Alkoxy, C 1~2 Fluoroalkoxy and -NR c R c and R is substituted with 0 to 3 substituents independently selected from 4c are F, Cl, -OH, C 1~2 Alkoxy, C 1~2 C, each substituted with 0 to 4 substituents independently selected from fluoroalkoxy and —CN; 1~4 Alkyl or C 3~6 cycloalkyl; each R5 is independently —CN, 0 to 4 R g C replaced with 1~5 Alkyl, 0 to 4 R g C replaced with 2~3Alkenyl, 0 to 4 R g C replaced with 2~3 Alkynyl, 0 to 4 R g C replaced with 3~4 Cycloalkyl, 0 to 3 R g phenyl substituted with 0 to 3 R g oxadiazolyl substituted with 0-3 R g Pyridinyl substituted with -(CH2) 1~2 (0 to 4 R g heterocyclyl substituted with -(CH2) 1~2 NR c C(O)(C 1~4 alkyl), -(CH2) 1~2 NR c C(O)O(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -(CH2) 1~2 NR c S(O)2(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)O(C 3~4 cycloalkyl), -C(O)NR a R a or -C(O)NR a (C 3~4 cycloalkyl); and m is 1, 2, or 3, or a salt thereof.

[0200] In one embodiment, there is provided a compound of Formula (II), wherein R1 is Cl or -CN; R2 is -CH3; and R4 is -CH2R 4a or -CHR 4a R 4b and;R 4ais cyclopropyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, phenyl, pyridinyl, pyrimidinyl, oxadiazolyl, benzo[d][1,3]dioxolyl, or oxodihydrobenzo[d]oxazolyl, each substituted with 0 to 3 substituents independently selected from F, Cl, —CN, —CH, —CH(CH), —CF, —OCH, —OCH(CH), —OCHF, —OCF, —OCH(cyclopropyl), and cyclopropyl; R 4b is (i) —CH3 and —CH2CH3; or (ii) phenyl, isoxazolyl, oxadiazolyl, or thiazolyl, each substituted with 0-3 substituents independently selected from F, Cl, —CH3, —C(CH3)3, —CF3, —OCF3, and cyclopropyl; each R5 is independently —CH3, —CH2CH3, —CH2OH, or —CHOCH3; and m is 2, or a salt thereof.

[0201] In one embodiment, there is provided a compound of Formula (II), wherein R1 is Cl, -CN, -OH, -CHF2, -CH2OH, -CH2OCH3, -OCH3, -OCH2CH3, -OCHF2, -OCH2CH2OCH3, or -OCH2CH2N(CH3)2; R2 is H, -CH3, or -CD3; and R4 is -CH2R 4a or -CHR 4a R 4b and;R 4ais F, Cl, Br, -CN, -CH3, -CH(CH3)2, -C(CH3)3, -CH2OH, -CHF2, -CF3, -CH2Br, -CH2NH2, -CH2NHC(O)OCH3, -C(CH3)2C N, -OCH3, -OCD3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2CH2CF3, -OC(CH3)2CN, -OC(CH3)2CH2OH, -OC(CH3)2 CH2OCH3, -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(oxazabicyclo[4.2.1.2 ... -chloro[2.2.1]heptanyl), -CH2(oxazaspiro[3.3]heptanyl), -CH2(methylpiperazinonyl), -CH2(acetylpiperazinyl), -CH2(piperidinyl), -CH2(difluoropiperidinyl), -CH2(methoxypiperidinyl), -CH2(hydroxypiperidinyl), -C(CH3)2(morpholinyl), -OCH2(cyclopropyl), -OCH2(methylcyclopropyl) ), -OCH2(methylazetidinyl), -OCH2(oxetanyl), -OCH2(tetrahydropyranyl), -OCH2(thiazolyl), or -OCH2CH2(cyclopropyl); R is cyclohexyl, phenyl, pyridinyl, pyrimidinyl, oxadiazolyl, benzo[d][1,3]dioxolyl, or oxodihydrobenzo[d]oxazolyl, each substituted with 0 to 3 substituents independently selected from -OCH2(methylazetidinyl), -OCH2(oxetanyl), -OCH2(tetrahydropyranyl), -OCH2(thiazolyl), or -OCH2CH2(cyclopropyl); R 4bis (i) -CN, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2; or (ii) phenyl, isoxazolyl, oxadiazolyl, thiazolyl, or triazolyl, each substituted with 0-3 substituents independently selected from F, Cl, Br, -CH3, -C(CH3)3, -CF3, -OCF3, and cyclopropyl; each R5 is independently -CH3, -CH2CH3, -CH2CH2CH3, -CH2OH, -CHOCH3, -CHOCH2CH3, -CH2NH2, -CH2N3, or -CH2NHC(O)OCH3; and m is 2, or a salt thereof.

[0202] In one embodiment, the compound of Formula (II) is provided, wherein R is H, F, Cl, Br, —CN, —OH, 0-4 R 1a C replaced with 1~3 Alkyl, 0 to 3 R 1a cyclopropyl substituted with 0-3 R 1a C replaced with 1~3 Alkoxy, -NR a R a , -S(O) n In some embodiments, a compound of formula (II) or a salt thereof is administered, wherein R is Cl, -CN, -OH, -CHF, -CHOH, -CHOCH, -OCH, -OCHCH, -OCHF, -OCHCHOCH, or -OCHCHN(CH).

[0203] In one embodiment, the compound of Formula (II) is provided, wherein R is H, F, Cl, Br, —CN, 0-4 R 1a C replaced with 1~3 Alkyl, 0 to 3 R 1a cyclopropyl substituted with 0-3 R 1a C replaced with 1~3 Alkoxy, -NR a R a , -S(O) nIn some embodiments, a compound of formula (II) wherein R is H, F, Cl, Br, -CN, -CH, cyclopropyl, -OCH, or -NH, or a salt thereof, is administered. In some embodiments, a compound of formula (II) wherein R is Cl or -CN, or a salt thereof, is administered. In some embodiments, a compound of formula (II) wherein R is -CN, or a salt thereof, is administered.

[0204] In one embodiment, the compound of Formula (II) is 2a C replaced with 1~2 Alkyl or 0 to 2 R 2a C replaced with 3~4 In some embodiments, a compound of formula (II) is administered, wherein R is H, or 0-2 R is cycloalkyl, or a salt thereof. 2a C replaced with 1~2 In some embodiments, a compound of formula (II) wherein R is H or -CH or a salt thereof is administered. In some embodiments, a compound of formula (II) wherein R is -CH or a salt thereof is administered. In some embodiments, a compound of formula (II) wherein R is H, -CH or -CD or a salt thereof is administered.

[0205] In one embodiment, a compound of formula (II), wherein R2 is H, or a salt thereof, is administered.

[0206] In one embodiment, a compound of formula (II), wherein R2 is -CH3, or a salt thereof, is administered.

[0207] In one embodiment, a compound of formula (II) or a salt thereof is administered, wherein R2 is -CD3.

[0208] In one embodiment, the compound of Formula (II) wherein R4 is -CH2R 4a or -CH2CH2R 4a In some embodiments, a compound of formula (II) is administered, wherein R is -CHR, or a salt thereof. 4a or -CD2R 4a In some embodiments, a compound of formula (II) is administered, wherein R 4a is 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, phenyl, pyridinyl, tetrahydropyranyl, benzoxazinyl, benzo[d][1,3]dioxolyl, benzoxazinonyl, indazolyl, indolyl, or quinolinyl, each substituted with 0-3 substituents independently selected from cyanocyclopropyl, and phenyl, or a salt thereof. In some embodiments, a compound of formula (II) is administered, wherein R 4a is phenyl, pyridinyl, or benzo[d][1,3]dioxolyl, each substituted with 0-3 substituents independently selected from F, Cl, -CN, -CH, -CH(CH), -CF, -OCH, -OCH(CH), -OCHF, -OCF, -OCH(cyclopropyl), and cyclopropyl; or a salt thereof.

[0209] In one embodiment, the compound of Formula (II) wherein R4 is -CH2R 4a In some embodiments, a compound of formula (II) is administered, wherein R 4ais 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, phenyl, pyridinyl, tetrahydropyranyl, benzoxazinyl, benzo[d][1,3]dioxolyl, benzoxazinonyl, indazolyl, indolyl, or quinolinyl, each substituted with 0-3 substituents independently selected from cyanocyclopropyl, and phenyl, or a salt thereof. In some embodiments, a compound of formula (II) is administered, wherein R 4a is phenyl, pyridinyl, or benzo[d][1,3]dioxolyl, each substituted with 0-3 substituents independently selected from F, Cl, -CN, -CH, -CH(CH), -CF, -OCH, -OCH(CH), -OCHF, -OCF, -OCH(cyclopropyl), and cyclopropyl; or a salt thereof.

[0210] In one embodiment, the compound of Formula (II) wherein R4 is -CH2R 4a and;R 4a are F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~2 Bromoalkyl, C 1~2 Cyanoalkyl, C 1~4 Hydroxyalkyl, -(CH2) 1~2 O(C 1~3 alkyl), C 1~4 Alkoxy, C 1~3 Fluoroalkoxy, C 1~3 Cyanoalkoxy, -O(C 1~4 hydroxyalkyl), -O(CR x R x ) 1~3 O(C 1~3 alkyl), C 1~3 Fluoroalkoxy, -O(CH2) 1~3 NR c R c, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -NR c R c , -CH2NR a R a , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -(CR x R x ) 0~2 NR a C(O)O(C 1~4 alkyl), -P(O)(C 1~3 alkyl)2, -S(O)2(C 1~3 alkyl), -(CR x R x ) 1~2 (C 3~4 cycloalkyl), -(CR x R x ) 1~2 (morpholinyl), -(CR x R x ) 1~2 (difluoromorpholinyl), -(CR x R x ) 1~2 (dimethylmorpholinyl), -(CR x R x ) 1~2 (oxazabicyclo[2.2.1]heptanyl), (CR x R x ) 1~2 (oxazaspiro[3.3]heptanyl), -(CR x R x ) 1~2 (methylpiperazinonyl), -(CR x R x ) 1~2 (acetylpiperazinyl), -(CR x R x ) 1~2 (piperidinyl), -(CR x R x ) 1~2 (difluoropiperidinyl), -(CR x Rx ) 1~2 (Methoxypiperidinyl), -(CR x R x ) 1~2 (hydroxypiperidinyl), -O(CR x R x ) 0~2 (C 3~6 cycloalkyl), -O(CR x R x ) 0~2 (methylcyclopropyl), -O(CR x R x ) 0~2 ((ethoxycarbonyl)cyclopropyl), -O(CR x R x ) 0~2 (oxetanyl), -O(CR x R x ) 0~2 (methylazetidinyl), -O(CR x R x ) 0~2 (tetrahydropyranyl), -O(CR x R x ) 1~2 (morpholinyl), -O(CR x R x ) 0~2 (thiazolyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, dioxolanyl, pyrrolidinonyl and R d C, each substituted with 0 to 4 substituents independently selected from 3~8 is carbocyclyl, 4-10 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl, or a salt thereof.

[0211] In one embodiment, the compound of Formula (II) wherein R4 is -CH2R 4a and;R 4a are F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~2Bromoalkyl, C 1~2 Cyanoalkyl, C 1~2 Hydroxyalkyl, -CHNR a R a , -(CH2) 1~2 O(C 1~2 alkyl), -(CH2) 1~2 NR x C(O)O(C 1~2 alkyl), C 1~4 Alkoxy, -O(C 1~4 hydroxyalkyl), -O(CR x R x ) 1~2 O(C 1~2 alkyl), C 1~3 Fluoroalkoxy, C 1~3 Cyanoalkoxy, -O(CH2) 1~2 NR c R c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl), -P(O)(C 1~2 alkyl)2, -S(O)2(C 1~3 alkyl), -(CH2) 1~2 (C 3~4 cycloalkyl), -CR x R x (morpholinyl), -CR x R x (difluoromorpholinyl), -CR x R x (dimethylmorpholinyl), -CR x R x (oxazabicyclo[2.2.1]heptanyl), -CR x R x (oxazaspiro[3.3]heptanyl), -CR x R x(methylpiperazinonyl), -CR x R x (acetylpiperazinyl), -CR x R x (piperidinyl), -CR x R x (difluoropiperidinyl), -CR x R x (methoxypiperidinyl), -CR x R x (hydroxypiperidinyl), -O(CH2) 0~2 (C 3~4 cycloalkyl), -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 R d C, each substituted with 0 to 4 substituents independently selected from 3~6 In some embodiments, a compound of formula (II), wherein R is cycloalkyl, 4-10 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl, or a salt thereof, is administered. 4a is 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), or a salt thereof.

[0212] In one embodiment, the compound of formula (II) wherein R4 is -CHR4a R 4b and;R 4a are (i) F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~4 Hydroxyalkyl, -(CH2) 1~2 O(C 1~3 alkyl), C 1~4 Alkoxy, -O(C 1~4 hydroxyalkyl), -O(CH2) 1~3 O(C 1~3 alkyl), C 1~3 Fluoroalkoxy, -O(CH2) 1~3 NR c R c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl), -P(O)(C 1~3 alkyl)2, -S(O)2(C 1~3 alkyl), -O(CH2) 1~2 (C 3~6 cycloalkyl), -O(CH2) 1~2 (morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and R d C, each substituted with 0 to 4 substituents independently selected from 3~6 cycloalkyl, heterocyclyl, phenyl, or heteroaryl; or (ii) C 3~6 C substituted with one cyclic group selected from cycloalkyl, heterocyclyl, aryl and heteroaryl 1~4Alkyl, wherein the cyclic group is F, Cl, Br, —OH, —CN, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl) and C 3~6 substituted with 0 to 3 substituents independently selected from cycloalkyl, C 1~4 alkyl; R 4b are F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~4 Hydroxyalkyl, -(CH2) 1~2 O(C 1~3 alkyl), C 1~4 Alkoxy, -O(C 1~4 hydroxyalkyl), -O(CH2) 1~3 O(C 1~3 alkyl), C 1~3 Fluoroalkoxy, -O(CH2) 1~3 NR c R c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl), -P(O)(C 1~3 alkyl)2, -S(O)2(C 1~3 alkyl), -O(CH2) 1~2 (C 3~6cycloalkyl), -O(CH2) 1~2 In some embodiments, a compound or salt thereof is administered, wherein R is phenyl or heteroaryl, each substituted with 0 to 4 substituents independently selected from (morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, and methylpiperidinyl. 4a are (i) F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3 Fluoroalkyl, -CH2OH, -(CH2) 1~2 O(C 1~2 alkyl), C 1~4 Alkoxy, -O(C 1~4 hydroxyalkyl), -O(CH2) 1~2 O(C 1~2 alkyl), C 1~3 Fluoroalkoxy, -O(CH2) 1~2 NR c R c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl), -P(O)(C 1~2 alkyl)2, -S(O)2(C 1~3 alkyl), -O(CH2) 1~2 (C 3~4 cycloalkyl), -O(CH2) 1~2(morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and R d C, each substituted with 0 to 4 substituents independently selected from 3~6 cycloalkyl, heterocyclyl, phenyl, or heteroaryl; or (ii) C 3~6 C substituted with one cyclic group selected from cycloalkyl, heterocyclyl, phenyl, and heteroaryl 1~3 Alkyl, wherein the cyclic group is F, Cl, Br, —OH, —CN, C 1~3 Alkyl, C 1~2 Fluoroalkyl, C 1~3 Alkoxy, C 1~2 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl) and C 3~4 substituted with 0 to 3 substituents independently selected from cycloalkyl, C 1~3 alkyl; R 4b is phenyl, isoxazolyl, oxadiazolyl, or thiazolyl, each substituted with 0-3 substituents independently selected from F, Cl, —CH3, —C(CH3)3, —CF3, —OCF3, and cyclopropyl. 4a is phenyl, pyridinyl, or benzo[d][1,3]dioxolyl, each substituted with 0 to 3 substituents independently selected from F, Cl, —CN, —CH, —CH(CH), —CF, —OCH, —OCH(CH), —OCHF, —OCF, —OCH(cyclopropyl), and cyclopropyl; R 4bis phenyl, isoxazolyl, oxadiazolyl, or thiazolyl, each substituted with 0-3 substituents independently selected from F, Cl, —CH3, —C(CH3)3, —CF3, —OCF3, and cyclopropyl, or a salt thereof.

[0213] In one embodiment, the compound of formula (II) wherein R4 is -CHR 4a R 4b and;R 4a are (i) F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~2 Bromoalkyl, C 1~2 Cyanoalkyl, C 1~4 Hydroxyalkyl, -(CH2) 1~2 O(C 1~3 alkyl), C 1~4 Alkoxy, C 1~3 Fluoroalkoxy, C 1~3 Cyanoalkoxy, -O(C 1~4 hydroxyalkyl), -O(CR x R x ) 1~3 O(C 1~3 alkyl), C 1~3 Fluoroalkoxy, -O(CH2) 1~3 NR c R c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -NR c R c , -CH2NR a R a , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -(CR x R x ) 0~2 NR a C(O)O(C 1~4 alkyl), -P(O)(C 1~3 alkyl)2, -S(O)2(C1~3 alkyl), -(CR x R x ) 1~2 (C 3~4 cycloalkyl), -(CR x R x ) 1~2 (morpholinyl), -(CR x R x ) 1~2 (difluoromorpholinyl), -(CR x R x ) 1~2 (dimethylmorpholinyl), -(CR x R x ) 1~2 (oxazabicyclo[2.2.1]heptanyl), (CR x R x ) 1~2 (oxazaspiro[3.3]heptanyl), -(CR x R x ) 1~2 (methylpiperazinonyl), -(CR x R x ) 1~2 (acetylpiperazinyl), -(CR x R x ) 1~2 (piperidinyl), -(CR x R x ) 1~2 (difluoropiperidinyl), -(CR x R x ) 1~2 (Methoxypiperidinyl), -(CR x R x ) 1~2 (hydroxypiperidinyl), -O(CR x R x ) 0~2 (C 3~6 cycloalkyl), -O(CR x R x ) 0~2 (methylcyclopropyl), -O(CR x R x ) 0~2 ((ethoxycarbonyl)cyclopropyl), -O(CR x R x ) 0~2 (oxetanyl), -O(CRx R x ) 0~2 (methylazetidinyl), -O(CR x R x ) 0~2 (tetrahydropyranyl), -O(CR x R x ) 1~2 (morpholinyl), -O(CR x R x ) 0~2 (thiazolyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, dioxolanyl, pyrrolidinonyl and R d C, each substituted with 0 to 4 substituents independently selected from 3~6 carbocyclyl, 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl; or (ii) C 3~6 C substituted with one cyclic group selected from carbocyclyl, 4- to 10-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl 1~4 Alkyl, wherein the cyclic group is F, Cl, Br, —OH, —CN, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl) and C 3~6 substituted with 0 to 3 substituents independently selected from cycloalkyl, C 1~4 alkyl; R 4bis phenyl, isoxazolyl, oxadiazolyl, thiazolyl, or triazolyl, each substituted with 0-3 substituents independently selected from F, Cl, Br, —CH3, —C(CH3)3, —CF3, —OCF3, and cyclopropyl, or a salt thereof.

[0214] In one embodiment, the compound of formula (II) wherein R4 is -CHR 4a R 4b and;R 4a are (i) F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~4 Hydroxyalkyl, -(CH2) 1~2 O(C 1~3 alkyl), C 1~4 Alkoxy, -O(C 1~4 hydroxyalkyl), -O(CH2) 1~3 O(C 1~3 alkyl), C 1~3 Fluoroalkoxy, -O(CH2) 1~3 NR c R c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl), -P(O)(C 1~3 alkyl)2, -S(O)2(C 1~3 alkyl), -O(CH2) 1~2 (C 3~6 cycloalkyl), -O(CH2) 1~2(morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and R d C, each substituted with 0 to 4 substituents independently selected from 3~6 cycloalkyl, heterocyclyl, phenyl, or heteroaryl; or (ii) C 3~6 C substituted with one cyclic group selected from cycloalkyl, heterocyclyl, monocyclic or bicyclic aryl and heteroaryl 1~4 Alkyl, wherein the cyclic group is F, Cl, Br, —OH, —CN, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl) and C 3~6 substituted with 0 to 3 substituents independently selected from cycloalkyl, C 1~4 alkyl; R 4b are F, Cl, -CN, -OH, -OCH3, -SCH3, C 1~3 Fluoroalkoxy, -NR a R a , -S(O)2R e or -NR a S(O)2R e C substituted with 0 to 4 substituents independently selected from 1~6 In some embodiments, a compound of formula (II), wherein R is alkyl, or a salt thereof, is administered. 4a are F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3Fluoroalkyl, -CH2OH, -(CH2) 1~2 O(C 1~2 alkyl), C 1~4 Alkoxy, -O(C 1~4 hydroxyalkyl), -O(CH2) 1~2 O(C 1~2 alkyl), C 1~3 Fluoroalkoxy, -O(CH2) 1~2 NR c R c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl), -P(O)(C 1~2 alkyl)2, -S(O)2(C 1~3 alkyl), -O(CH2) 1~2 (C 3~4 cycloalkyl), -O(CH2) 1~2 (morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and R d C, each substituted with 0 to 4 substituents independently selected from 3~6 cycloalkyl, heterocyclyl, phenyl, or heteroaryl; or (ii) C 3~6 C substituted with one cyclic group selected from cycloalkyl, heterocyclyl, phenyl, and heteroaryl 1~3 Alkyl, wherein the cyclic group is F, Cl, Br, —OH, —CN, C 1~3 Alkyl, C 1~2 Fluoroalkyl, C 1~3 Alkoxy, C 1~2Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl) and C 3~4 substituted with 0 to 3 substituents independently selected from cycloalkyl, C 1~3 alkyl; R 4b are F, Cl, -CN, -OH, -OCH3, -SCH3, C 1~3 Fluoroalkoxy and -NR a R a C substituted with 0 to 4 substituents independently selected from 1~4 In some embodiments, a compound of formula (II), wherein R is alkyl, or a salt thereof, is administered. 4a is phenyl, pyridinyl, or benzo[d][1,3]dioxolyl, each substituted with 0 to 3 substituents independently selected from F, Cl, —CN, —CH, —CH(CH), —CF, —OCH, —OCH(CH), —OCHF, —OCF, —OCH(cyclopropyl), and cyclopropyl; R 4b is -CH3 and -CH2CH3, or a salt thereof.

[0215] In one embodiment, the compound of formula (II) wherein R4 is -CHR 4a R 4b and;R 4a are (i) F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~2 Bromoalkyl, C 1~2 Cyanoalkyl, C 1~4 Hydroxyalkyl, -(CH2) 1~2 O(C 1~3 alkyl), C 1~4 Alkoxy, C 1~3 Fluoroalkoxy, C1~3 Cyanoalkoxy, -O(C 1~4 hydroxyalkyl), -O(CR x R x ) 1~3 O(C 1~3 alkyl), C 1~3 Fluoroalkoxy, -O(CH2) 1~3 NR c R c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -NR c R c , -CH2NR a R a , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -(CR x R x ) 0~2 NR a C(O)O(C 1~4 alkyl), -P(O)(C 1~3 alkyl)2, -S(O)2(C 1~3 alkyl), -(CR x R x ) 1~2 (C 3~4 cycloalkyl), -(CR x R x ) 1~2 (morpholinyl), -(CR x R x ) 1~2 (difluoromorpholinyl), -(CR x R x ) 1~2 (dimethylmorpholinyl), -(CR x R x ) 1~2 (oxazabicyclo[2.2.1]heptanyl), (CR x R x ) 1~2 (oxazaspiro[3.3]heptanyl), -(CR x R x ) 1~2 (methylpiperazinonyl), -(CRx R x ) 1~2 (acetylpiperazinyl), -(CR x R x ) 1~2 (piperidinyl), -(CR x R x ) 1~2 (difluoropiperidinyl), -(CR x R x ) 1~2 (Methoxypiperidinyl), -(CR x R x ) 1~2 (hydroxypiperidinyl), -O(CR x R x ) 0~2 (C 3~6 cycloalkyl), -O(CR x R x ) 0~2 (methylcyclopropyl), -O(CR x R x ) 0~2 ((ethoxycarbonyl)cyclopropyl), -O(CR x R x ) 0~2 (oxetanyl), -O(CR x R x ) 0~2 (methylazetidinyl), -O(CR x R x ) 0~2 (tetrahydropyranyl), -O(CR x R x ) 1~2 (morpholinyl), -O(CR x R x ) 0~2 (thiazolyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, dioxolanyl, pyrrolidinonyl and R d C, each substituted with 0 to 4 substituents independently selected from 3~8 carbocyclyl, 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl; or (ii) C3~6 C substituted with one cyclic group selected from cycloalkyl, 4- to 10-membered heterocyclyl, monocyclic or bicyclic aryl, or 5- to 10-membered heteroaryl 1~4 Alkyl, wherein the cyclic group is F, Cl, Br, —OH, —CN, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~3 Alkoxy, C 1~3 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl) and C 3~6 substituted with 0 to 3 substituents independently selected from cycloalkyl, C 1~4 alkyl; R 4b is -CN, or F, Cl, -CN, -OH, -OCH3, -SCH3, C 1~3 Fluoroalkoxy, -NR a R a , -S(O)2R e or -NR a S(O)2R e C substituted with 0 to 4 substituents independently selected from 1~6 In some embodiments, a compound of formula (II), wherein R is alkyl, or a salt thereof, is administered. 4a are (i) F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~2 Bromoalkyl, C 1~2 Cyanoalkyl, C 1~2 Hydroxyalkyl, -CHNR a R a , -(CH2) 1~2 O(C 1~2 alkyl), -(CH2) 1~2 NR x C(O)O(C 1~2 alkyl), C1~4 Alkoxy, -O(C 1~4 hydroxyalkyl), -O(CR x R x ) 1~2 O(C 1~2 alkyl), C 1~3 Fluoroalkoxy, C 1~3 Cyanoalkoxy, -O(CH2) 1~2 NR c R c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl), -P(O)(C 1~2 alkyl)2, -S(O)2(C 1~3 alkyl), -(CH2) 1~2 (C 3~4 cycloalkyl), -CR x R x (morpholinyl), -CR x R x (difluoromorpholinyl), -CR x R x (dimethylmorpholinyl), -CR x R x (oxazabicyclo[2.2.1]heptanyl), -CR x R x (oxazaspiro[3.3]heptanyl), -CR x R x (methylpiperazinonyl), -CR x R x (acetylpiperazinyl), -CR x R x (piperidinyl), -CR x R x (difluoropiperidinyl), -CR x R x (methoxypiperidinyl), -CRx R x (hydroxypiperidinyl), -O(CH2) 0~2 (C 3~4 cycloalkyl), -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 R d C, each substituted with 0 to 4 substituents independently selected from 3~6 carbocyclyl, 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl; or (ii) C 3~6 C substituted with one cyclic group selected from cycloalkyl, 4- to 10-membered heterocyclyl, monocyclic or bicyclic aryl, or 5- to 10-membered heteroaryl 1~3 Alkyl, wherein the cyclic group is F, Cl, Br, —OH, —C N.C. 1~3 Alkyl, C 1~2 Fluoroalkyl, C 1~3 Alkoxy, C 1~2 Fluoroalkoxy, -OCH2CH=CH2, -OCH2C≡CH, -NR c R c , -NR a S(O)2(C 1~3 alkyl), -NR a C(O)(C 1~3 alkyl), -NR a C(O)O(C 1~4 alkyl) and C 3~4substituted with 0 to 3 substituents independently selected from cycloalkyl, C 1~3 alkyl; R 4b is -CN, or F, Cl, -CN, -OH, -OCH3, -SCH3, C 1~3 Fluoroalkoxy and -NR a R a C substituted with 0 to 4 substituents independently selected from 1~4 The compound or salt thereof is administered.

[0216] In one embodiment, the compound of formula (II) wherein R4 is -CHR 4a R 4b and;R 4b is -CN, -CH3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)2, or a salt thereof.

[0217] In one embodiment, the compound of formula (II) wherein R4 is -CHR 4a R 4b and;R 4b is -CN, -CH3, or -CH2CH3, or a salt thereof is administered.

[0218] In one embodiment, the compound of formula (II) wherein R4 is -CHR 4a R 4b and;R 4b is -CN, or a salt thereof is administered.

[0219] In one embodiment, the compound of formula (II) wherein R4 is -CHR 4a R 4b and;R 4b is -CH3 or -CH2CH3, or a salt thereof.

[0220] In one embodiment, the compound of formula (II) wherein R4 is -CHR 4a R 4b and;R 4b is -CH3, or a salt thereof is administered.

[0221] In one embodiment, the compound of formula (II) wherein R4 is -CHR 4a R 4b and;R 4b is -CH2CH3, or a salt thereof is administered.

[0222] In one embodiment, the compound of Formula (II) is provided herein, wherein m is 1, 2, or 3; and each R is independently —CN, 0 to 4 R g C replaced with 1~5 Alkyl, 0 to 4 R g C replaced with 2~3 Alkenyl, 0 to 4 R g C replaced with 2~3 Alkynyl, 0 to 4 R g C replaced with 3~4 Cycloalkyl, 0 to 3 R g phenyl substituted with 0 to 3 R g oxadiazolyl substituted with 0-3 R g Pyridinyl substituted with -(CH2) 1~2 (0 to 4 R g 4-10 membered heterocyclyl substituted with -(CH2) 1~2 NR c C(O)(C 1~4 alkyl), -(CH2) 1~2 NR c C(O)O(C 1~4 alkyl), -(CH2) 1~2 NR c S(O)2(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)O(C 3~4 cycloalkyl), -C(O)NR a R a or -C(O)NR a (C 3~4In some embodiments, a compound of formula (II) or a salt thereof is administered, wherein each R is independently -CH, -CHCH, -CHOH, or -CHOCH.

[0223] In one embodiment, a compound of formula (II), wherein m is 0, or a salt thereof, is administered.

[0224] 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.

[0225] 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.

[0226] In one embodiment, a compound of formula (II), wherein m is 3, or a salt thereof, is administered.

[0227] In one embodiment, a compound of formula (III): [ka] (III) (In the formula, R 5a , R 5b , R 5c and R 5d 1, 2 or 3 of the R 5a , R 5b , R 5c and R 5d The remainder are hydrogen. In some embodiments, a compound of formula (II) having the structure: or a salt thereof is administered. In some embodiments, a compound of formula (III) or a salt thereof is administered, wherein each R is independently -CN, -CH, -CHCH, -CH(CH), -CHC(CH), -CHF, -C(CH)F, -CF(CH)CH(CH), -CHOH, -C(CH)OH, -C(CH)(OH)CH(CH), -CHOCH, -C(O)C(CH), -C(O)OH, -C(O)OCH, -C(O)OC(CH), -C(O)NH, -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.

[0228] In one embodiment, a compound of formula (IV): [ka] (IV) (In the formula, R 5a and R 5c are R5 and R 5b and R 5d are hydrogen atoms) In some embodiments, a compound of formula (II) having the structure: 5a is -CH3 or -CH2CH3, and R 5c is —CH or —CHCH; or (ii) R 5a is -CH3 and R 5c is -CH2OH or -CH2OCH3, or a salt thereof, is administered.

[0229] In one embodiment, there is provided a compound of formula (IV), wherein R 5ais -CH3 and R 5c is -CH3, a compound or a salt thereof is administered.

[0230] In one embodiment, there is provided a compound of formula (IV), wherein R 5a is -CH3 and R 5c is -CH2CH3, or a salt thereof is administered.

[0231] In one embodiment, there is provided a compound of formula (IV), wherein R 5a is -CH2CH3, and R 5c is -CH3, a compound or a salt thereof is administered.

[0232] In one embodiment, there is provided a compound of formula (IV), wherein R 5a is -CH2CH3, and R 5c is -CH2CH3, or a salt thereof is administered.

[0233] In one embodiment, there is provided a compound of formula (IV), wherein R 5a is -CH3 and R 5c is —CH 2 OH, or a salt thereof is administered.

[0234] In one embodiment, there is provided a compound of formula (IV), wherein R 5a is -CH3 and R 5c is —CH 2 OCH 3 , or a salt thereof is administered.

[0235] In one embodiment, there is provided a compound of formula (IV), wherein R 5a is -CH3 and R 5c is —CH 2 OCH 2 CH 3 , or a salt thereof is administered.

[0236] In one embodiment, there is provided a compound of formula (IV), wherein R 5a is -CH3 and R 5c is -CH2CH2CH3, or a salt thereof is administered.

[0237] In one embodiment, there is provided a compound of formula (IV), wherein R 5a is -CH3 and R 5c is -CH2N3, or a salt thereof is administered.

[0238] In one embodiment, there is provided a compound of formula (IV), wherein R 5a is -CH3 and R 5c is —CH 2 NH 2 , or a salt thereof is administered.

[0239] In one embodiment, there is provided a compound of formula (IV), wherein R 5a is -CH3 and R 5c is —CH 2 NHC(O)OCH 3 , or a salt thereof is administered.

[0240] In one embodiment, there is provided a compound of formula (IV), wherein R 5a is -CHOH, and R 5c is -CH3, a compound or a salt thereof is administered.

[0241] In one embodiment, there is provided a compound of formula (IV), wherein R 5a is -CH2OCH3, and R 5c is -CH3, a compound or a salt thereof is administered.

[0242] In one embodiment, the structure: [ka] or a salt thereof.

[0243] In one embodiment, the structure: [ka] or a salt thereof.

[0244] In one embodiment, the structure: [ka] or a salt thereof.

[0245] In one embodiment, the structure: [ka] or a salt thereof.

[0246] In one embodiment, the compound of formula (II) is (i); [ka] [ka] (ii); [ka] [ka] or (iii) [ka] In some embodiments, a compound of formula (II), or a salt thereof, is administered, wherein R1 is H, Br, -CN, or -OCH3; and R2 is -CH3.

[0247] In one embodiment, the compound of formula (II) is [ka] In some embodiments, a compound of formula (II) or a salt thereof is administered, wherein R1 is H, Br, -CN, or -OCH3; and R2 is -CH3. In some embodiments, a compound of formula (II) or a salt thereof is administered, wherein R1 is -CN; and R2 is -CH3.

[0248] In one embodiment, a compound of formula (II), or a salt thereof, is administered, wherein R1 is -CN; and R2 is -CH3.

[0249] In one embodiment, a compound of formula (IV), or a salt thereof, is administered, wherein R1 is -CN; and R2 is -CH3.

[0250] In one embodiment, there is provided a compound of formula (IV), wherein R1 is -CN; R2 is -CH3; and R 5a is -CH3; R 5c is -CH3, a compound or a salt thereof is administered.

[0251] In one embodiment, there is provided a compound of formula (IV), wherein R1 is -CN; R2 is -CH3; and R 5a is -CH3; R 5c is -CH2CH3, or a salt thereof is administered.

[0252] In one embodiment, there is provided a compound of formula (IV), wherein R1 is -CN; R2 is -CH3; and R 5a is -CH3; R 5c is -CH2CH2CH3, or a salt thereof is administered.

[0253] In one embodiment, there is provided a compound of formula (IV), wherein R1 is -CN; R2 is -CH3; and R 5a is -CH2CH3; R 5c is -CH2CH3, or a salt thereof is administered.

[0254] In one embodiment, there is provided a compound of formula (IV), wherein R1 is -CN; R2 is -CH3; and R 5a is -CH3; R 5c is -CH3, -CH2CH3 or -CH2CH2CH3, or a salt thereof.

[0255] In one embodiment, the compound of formula (II) is provided herein, wherein R1 is -CN; R2 is -CH3; and R4 is -CHR 4a R 4b and;R 4b is -CH3, a compound or a salt thereof is administered.

[0256] In one embodiment, the compound of formula (II) is provided herein, wherein R1 is -CN; R2 is -CH3; and R4 is -CHR 4a R 4b and;R 4b is -CH2CH3, or a salt thereof is administered.

[0257] In one embodiment, the compound of formula (II) is provided herein, wherein R1 is -CN; R2 is -CH3; and R4 is -CHR 4a R 4b and;R 4b is -CH2CH2CH3, or a salt thereof is administered.

[0258] In one embodiment, the compound of formula (II) is provided herein, wherein R1 is -CN; R2 is -CH3; and R4 is -CHR 4a R 4b and;R 4b is -CH3, -CH2CH3 or -CH2CH2CH3, or a salt thereof.

[0259] In one embodiment, there is provided a compound of Formula (II) wherein R4 is -CHR 4a R 4b and;R 4ais phenyl substituted with 1-2 substituents independently selected 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 R2 is —CH3.

[0260] In one embodiment, there is provided a compound of Formula (II) wherein R4 is -CHR 4a R 4b and;R 4a is phenyl substituted with -CF3 or -OCF3; R 4b is -CH3, -CH2CH3, or -CH2CH2CH3, or a salt thereof. In some embodiments, a compound of formula (II), wherein R1 is -CN; R2 is -CH3, or a salt thereof, is administered.

[0261] In one embodiment, there is provided a compound of Formula (II) wherein R4 is -CHR 4a R 4b and;R 4a is phenyl substituted with -CF3 or -OCF3; R 4b is -CH3, or a salt thereof. In some embodiments, a compound of formula (II), wherein R1 is -CN; R2 is -CH3, or a salt thereof, is administered.

[0262] In one embodiment, there is provided a compound of Formula (II) wherein R4 is -CHR 4a R 4b and;R 4a is phenyl substituted with -CF3 or -OCF3; R 4b is -CH2CH3, or a salt thereof. In some embodiments, a compound of formula (II), wherein R1 is -CN; R2 is -CH3, or a salt thereof, is administered.

[0263] In one embodiment, there is provided a compound of Formula (II) wherein R4 is -CHR 4a R4b and;R 4a is phenyl substituted with -CF3 or -OCF3; R 4b is -CH2CH2CH3, or a salt thereof, is administered. In some embodiments, a compound of formula (II), wherein R1 is -CN; R2 is -CH3, or a salt thereof, is administered.

[0264] In one embodiment, there is provided a compound of Formula (II) wherein R4 is -CHR 4a R 4b and;R 4a is phenyl substituted with 1 to 2 substituents independently selected from F, Cl, —CF3, —OCF3, or —OCH2 (cyclopropyl); R 4b is -CH3, -CH2CH3, or -CH2CH2CH3, or a salt thereof. In some embodiments, a compound of formula (II), wherein R1 is -CN; R2 is -CH3, or a salt thereof, is administered.

[0265] In one embodiment, there is provided a compound of Formula (II) wherein R4 is -CHR 4a R 4b and;R 4a is pyridinyl, or a salt thereof. In some embodiments, a compound of formula (II) is administered, wherein R is -CN; R is -CH, or a salt thereof.

[0266] In one embodiment, there is provided a compound of Formula (II) wherein R4 is -CHR 4a R 4b and;R 4a is pyridinyl substituted with -CF3, or a salt thereof, is administered. In some embodiments, a compound of formula (II), wherein R1 is -CN; R2 is -CH3, or a salt thereof, is administered.

[0267] In one embodiment, there is provided a compound of Formula (II) wherein R4 is -CHR 4a R 4b and;R4a is pyridinyl; R 4a is phenyl substituted with Cl, or a salt thereof, is administered. In some embodiments, a compound of formula (II) is administered, wherein R is -CN; R is -CH, or a salt thereof.

[0268] In one embodiment, there is provided a compound of Formula (II) wherein R4 is -CHR 4a R 4b and;R 4a is pyridinyl substituted with -CF; R 4b is phenyl substituted with F. In some embodiments, a compound of formula (II) or a salt thereof is administered, wherein R is -CN; R is -CH.

[0269] In one embodiment, there is provided a compound of Formula (II) wherein R4 is -CHR 4a R 4b and;R 4a and R 4b is phenyl substituted with F; 4a and R 4b and the other is oxadiazolyl substituted with cyclopropyl, or a salt thereof. In some embodiments, a compound of formula (II) is administered, wherein R is -CN; and R is -CH, or a salt thereof.

[0270] In one embodiment, a compound of Formula (II) or a salt thereof is administered, said compound being 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; -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 Pyrido[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-((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-(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-(2-fluoro-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-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-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;

[0271] In one embodiment, a compound of Formula (II) or a salt thereof is administered, said compound being 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 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 pyrido[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,5 R)-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 Do[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-(difluorophenyl)thiazol-4-yl)methyl)-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]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 do[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.

[0272] In one embodiment, a compound of Formula (II) or a salt thereof is administered, said compound being 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 Do[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-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-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile pyrido[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)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-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; ...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)-4-(1-(4-cyclopropylphenyl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile -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 [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-methylpiperazine- 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-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 Nitrile;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-dimethyl 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-(3,4,5-trifluorophenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile pyrido[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 Pyrido[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-di; 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)-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 )-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 pyrido[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]pyrimidine-6-carbonitrile;4-((2S,5R)-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]pyrimidine-6-carbonitrile 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)-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 Rimidin-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-(cyclo 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 (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-dihydro 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-(methoxy-d3)phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile 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- 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;4-((2S,5R)-2,5-diethyl-4-(1-(6-(difluoromethoxy)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-(trifluoromethyl)phenyl)butyl)piperazin-1-yl)-1-methyl-2-oxo- so-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 pyrido[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 ethyl(1S,2S)-2-(4-(1-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-4-yl)-2,5-diethylpiperazin-1-yl)ethyl)phenoxy)cyano; Chlopropane-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 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-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-2 ,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-((2 S,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) 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-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 Pyrido[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-((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-(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-((2S,5R)-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-((2S,5R)-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-((2S,5R)-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 Dropyrido[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-methylpiperazine-1-; 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;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-methylpiperazine-1- 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 Do[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-((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-aza Bicyclo[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[ ... Bonitrile (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]pyrimidin-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)-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)-6-(trifluoromethyl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one; )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 ]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-((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; 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-dimethyl4-(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-dimethyl4-(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)-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) ...) 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; 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.

[0273] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being [ka] is.

[0274] 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).

[0275] 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.

[0276] 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.

[0277] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being [ka] is.

[0278] 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).

[0279] 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.

[0280] 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.

[0281] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being [ka] is.

[0282] 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.

[0283] 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.

[0284] 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.

[0285] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being [ka] is.

[0286] In one embodiment, a compound of Formula (II) or a salt thereof is administered, wherein the 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).

[0287] 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.

[0288] 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.

[0289] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being [ka] is.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being [ka] is.

[0294] 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.

[0295] 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.

[0296] 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.

[0297] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being [ka] is.

[0298] 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.

[0299] 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.

[0300] 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.

[0301] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being [ka] is.

[0302] 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).

[0303] 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.

[0304] 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.

[0305] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being [ka] is.

[0306] In one embodiment, a compound of Formula (II) or a salt thereof is administered, wherein the 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).

[0307] 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.

[0308] 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.

[0309] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being [ka] is.

[0310] 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).

[0311] 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.

[0312] 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.

[0313] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being [ka] is.

[0314] 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).

[0315] 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.

[0316] 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.

[0317] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being [ka] is.

[0318] 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).

[0319] 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.

[0320] 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.

[0321] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being [ka] is.

[0322] 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).

[0323] 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.

[0324] 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.

[0325] 2. Composition and Dosage For example, a compound described herein according to Formula (I) or (II), e.g., a compound selected from Compounds 1-34, and / or a pharmaceutically acceptable salt thereof, can be administered by any means appropriate to the condition to be treated, which may depend on the need for site-specific treatment or the amount of compound to be delivered.

[0326] Also encompassed herein is a class of pharmaceutical compositions comprising a compound, e.g., a compound of Formula (I) or (II), e.g., a compound selected from Compounds 1-34, 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, optionally, other active ingredients. A compound, e.g., a compound of Formula (I) or (II), e.g., a compound selected from Compounds 1-34, can be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted for such a route, and in a dose effective for the intended treatment. The compounds and compositions described herein can be administered orally, mucosally, or parenterally, including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally, for example, in a dosage unit formulation containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. For example, the pharmaceutical carrier can contain mannitol or a mixture of lactose and microcrystalline cellulose. The mixture may contain additional components such as a lubricant, for example, magnesium stearate, and a disintegrant, for example, crospovidone. The carrier mixture may be filled into a gelatin capsule or compressed into a tablet. The pharmaceutical composition may be administered, for example, as an oral dosage form or an infusion solution.

[0327] Dosage regimens for DGK inhibitors will vary depending on known factors such as the pharmacodynamic characteristics of the particular agent and its mechanism and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of symptoms; type of concurrent therapy; frequency of treatment; route of administration; and the patient's renal and hepatic function.

[0328] In certain embodiments, the inhibitor is administered in a therapeutically effective amount, which in certain embodiments provides a dose of the inhibitor that is therapeutically effective over an extended period of time.

[0329] As a general guidance, the daily oral dosage of each active ingredient, when used for the indicated effect, will range from about 0.001 to about 5000 mg per day, preferably from about 0.01 to about 1000 mg per day, and most preferably from 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 in a constant rate infusion. The DGK inhibitors described herein can be administered in a single daily dose, or the total daily dosage can be administered in divided doses two, three, or four times daily.

[0330] The compounds are typically administered in admixture with a suitable pharmaceutical diluent, excipient, or carrier (collectively referred to herein as a pharmaceutical carrier) appropriately selected for the intended administration form, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practice.

[0331] Dosage forms (pharmaceutical compositions) suitable for administration can contain from about 1 milligram to about 2000 milligrams of active ingredient per dosage unit. In such pharmaceutical compositions, the active ingredient will usually be present in an amount of from about 0.1 to 95% by weight based on the total weight of the composition.

[0332] 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.

[0333] 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 saline to produce the injectable preparation.

[0334] For oral administration, the pharmaceutical compositions described herein may be in the form of, for example, tablets, capsules, liquid capsules, suspensions, or liquids. Pharmaceutical compositions are preferably prepared in the form of dosage units containing a specific amount of the active ingredient. For example, pharmaceutical compositions may be provided as tablets or capsules containing an amount of active ingredient ranging 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. Suitable daily doses for humans or other mammals may vary widely depending on the patient's condition and other factors, but can be determined using routine methods.

[0335] Regardless of the route of administration selected, the DGK inhibitors for administration described herein, which may be used in a suitable hydrated form, and / or pharmaceutical compositions containing the same, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0336] The actual dosage level of the active ingredient in the pharmaceutical composition containing DGK inhibitor can be varied to obtain an amount of the active ingredient that is effective for achieving a therapeutic response for a specific patient, composition and administration mechanism without causing toxicity to the patient.The selected dosage level will depend on various factors, including the activity of the specific compound used or its ester, salt or amide, the route of administration, the time of administration, the rate of excretion or metabolism of the specific compound used, the rate and extent of absorption, the duration of treatment, other drugs, compounds and / or materials used in combination with the specific compound used, the age, sex, weight, condition, overall health and previous medical history of the patient being treated, and similar factors well known in the medical field.

[0337] A physician having ordinary skill in the art can easily determine and prescribe the required effective amount of the pharmaceutical composition. For example, the physician can start the dose of the DGK inhibitor used in the pharmaceutical composition at a level lower than that required to achieve a therapeutic effect, and gradually increase the dosage until the effect is achieved.

[0338] Generally, a suitable daily dose of a DGK inhibitor will be that amount of the compound that is the lowest effective dose to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above. Generally, oral, intravenous, intracerebroventricular, and subcutaneous doses of a 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 can be administered as two, three, four, five, six, or more subdoses administered separately at appropriate intervals throughout the day, conveniently in a unit dosage form. In certain embodiments, dosing is a single administration per day.

[0339] Any pharmaceutical composition considered herein can be orally delivered, for example, through any acceptable and suitable oral preparation.Exemplary oral preparations include, but are not limited to, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs.The pharmaceutical composition intended for oral administration can be prepared according to any method known in the art for preparing pharmaceutical compositions intended for oral administration.In order to provide a pharmaceutically acceptable preparation, the pharmaceutical composition can contain at least one agent selected from sweeteners, flavoring agents, coloring agents, demulcents, antioxidants, and preservatives.

[0340] Tablets can be prepared, for example, by mixing at least one compound, e.g., a compound of Formula (I) or (II), e.g., a compound selected from Compounds 1-34, 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, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch, and alginic acid; binding agents such as starch, gelatin, polyvinylpyrrolidone, and acacia; and lubricants such as magnesium stearate, stearic acid, and talc. Furthermore, tablets may be uncoated or may be coated by any known technique to mask the unpleasant taste of unpleasant-tasting drugs or delay the disintegration and absorption of active ingredients in the gastrointestinal tract, thereby maintaining the effect of the active ingredients for a longer period of time.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, ethylcellulose and cellulose acetate butyrate.

[0341] Hard gelatin capsules can be prepared, for example, by mixing at least one compound, e.g., a compound of Formula (I) or (II), e.g., a compound selected from Compounds 1-34, 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.

[0342] Soft gelatin capsules can be prepared, for example, by mixing at least one compound, e.g., a compound of formula (I) or (II), e.g., a compound selected from compounds 1-34, and / or at least one pharmaceutically acceptable salt thereof, with at least one water-soluble carrier, e.g., polyethylene glycol; and at least one oil medium, e.g., peanut oil, liquid paraffin, and olive oil.

[0343] Aqueous suspensions can be prepared, for example, by mixing at least one compound, e.g., a compound of formula (I) or (II), e.g., a compound selected from compounds 1-34, and / or at least one pharmaceutically acceptable salt thereof, with at least one excipient suitable for the manufacture of aqueous suspensions. Exemplary excipients suitable for the manufacture of aqueous suspensions include, but are not limited to, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents such as naturally occurring phosphatides, e.g., lecithin; condensation products of alkylene oxides with fatty acids, such as, for example, polyoxyethylene stearates; 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 hexitols, 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. The aqueous suspensions may also contain at least one preservative, 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, for example, but not limited to, sucrose, saccharin, and aspartame.

[0344] Oily suspensions can be prepared, for example, by suspending at least one compound, such as a compound of formula (I) or (II), for example, a compound selected from compounds 1-34, and / or at least one pharmaceutically acceptable salt thereof, in a vegetable oil, such as peanut oil, olive oil, sesame oil, and coconut oil; or in a mineral oil, such as liquid paraffin. Oily suspensions can also contain at least one thickening agent, such as beeswax, hard paraffin, and cetyl alcohol. To provide acceptable oily suspensions, at least one sweetener and / or at least one flavoring agent, as described above, can be added to the oily suspension. Oily suspensions can further contain at least one preservative, including, but not limited to, an antioxidant, such as butylhydroxyanisole and alpha-tocopherol.

[0345] Dispersible powders and granules can be prepared, for example, by mixing at least one compound, such as a compound of formula (I) or (II), for example, a compound selected from Compounds 1-34, and / or at least one pharmaceutically acceptable salt thereof, with at least one dispersing agent 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 described above. Exemplary preservatives include, but are not limited to, antioxidants, such as ascorbic acid. In addition, dispersible powders and granules can also contain at least one excipient, including, but not limited to, sweeteners, flavoring agents, and coloring agents.

[0346] Emulsions of at least one compound, e.g., a compound of formula (I) or (II), e.g., a compound selected from compounds 1-34, and / or at least one pharmaceutically acceptable salt thereof, can be prepared, for example, as an oil-in-water emulsion. The oily phase of an emulsion containing a compound of formula (I) or (II), e.g., a compound selected from compounds 1-34, can be composed of known ingredients in a known manner. The oily phase can be provided, for example, by, but is not limited to, a vegetable oil, such as olive oil or peanut oil; a mineral oil, such as liquid paraffin; and mixtures thereof. The phase can simply comprise an emulsifier, or can comprise a mixture of at least one emulsifier with a fat or oil or both a fat and an oil. Suitable emulsifiers include, but are not limited to, naturally occurring phosphatides, such as soybean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer.It is also preferred to include both oil and fat.In summary, the emulsifier with or without stabilizer creates a so-called emulsifying wax, and the wax together with oil and fat creates a so-called emulsifying ointment base that forms the oily dispersed phase of cream formulations.Emulsions can also contain sweeteners, flavorings, preservatives and / or antioxidants. Emulsifiers and emulsion stabilizers suitable for use in formulations for use in therapeutic methods include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate, alone or in combination with waxes or other materials well known in the art.

[0347] The compounds, e.g., compounds of Formula (I) or (II), e.g., compounds selected from Compounds 1-34, and / or at least one pharmaceutically acceptable salt thereof, can also be delivered, for example, intravenously, subcutaneously, and / or intramuscularly via any pharmaceutically acceptable and suitable injectable form. Exemplary injectable forms include, but are not limited to, sterile aqueous solutions containing acceptable vehicles and solvents such as water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and aqueous or oleaginous suspensions.

[0348] Preparations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in preparations for oral administration, or by using other suitable dispersing or wetting agents and suspending agents. The compound can 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 arts. The active ingredient can also be administered by injection as a composition with a suitable carrier, including saline, dextrose, or water, or including cyclodextrins (i.e., Captisol), cosolvent solubilization (i.e., propylene glycol), or micelle solubilization (i.e., Tween 80).

[0349] Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used, water, Ringer's solution, and isotonic sodium chloride solution are particularly mentioned. In addition, sterile fixed oils have traditionally been used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectable solutions.

[0350] Sterile injectable oil-in-water microemulsions can be prepared, for example, by: 1) dissolving at least one compound, e.g., a compound of Formula (I) or (II), e.g., a compound selected from Compounds 1-34, and / or a pharmaceutically acceptable salt thereof, in an oily phase such as, for example, a mixture of soybean oil and lecithin; 2) combining the oily phase-containing compound, e.g., a compound of Formula (I) and / or a pharmaceutically acceptable salt thereof, with a water and glycerol mixture; and 3) processing the combination to form a microemulsion.

[0351] Sterile aqueous or fatty suspensions can be prepared according to methods already known in the art. For example, sterile aqueous solutions or suspensions can be prepared using non-toxic parenterally acceptable diluents or solvents, such as 1,3-butanediol; sterile fatty suspensions can be prepared using sterile non-toxic acceptable solvents or suspending media, such as sterile fixed oils, synthetic mono- or diglycerides, and fatty acids, such as oleic acid.

[0352] Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in pharmaceutical compositions include ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), such as d-alpha-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as Tween, polyethoxylated castor oil, such as CREMOPHOR surfactants (BASF), or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, etc. sorbate), a partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes, such as, but not limited to, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, 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 hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrin, or other solubilized derivatives, may also be advantageously used to enhance delivery of the compounds of the formulae described herein.

[0353] The pharmaceutically active compounds described herein can be processed according to conventional pharmaceutical methods to produce medicinal agents for administration to patients, including humans and other mammals. Pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and / or can contain conventional adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc. Tablets and pills can also be prepared with enteric coatings. Such compositions can also contain adjuvants such as wetting agents, sweeteners, flavorings, and fragrances.

[0354] The amount of compound and dosage regimen administered to treat a disease state with the compounds and / or compositions described herein will depend on a variety of factors, including the subject's age, weight, sex, medical condition, type of disease, severity of disease, route and frequency of administration, and the particular compound used. Thus, dosage regimens can vary widely but can be routinely determined using standard methods. A daily dose of about 0.001 to 100 mg / kg body weight, preferably about 0.0025 to about 50 mg / kg body weight, and most preferably 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.

[0355] For therapeutic purposes, the active compound described herein is usually combined with one or more adjuvants suitable for indicated administration route.When administered orally, the compound can be mixed with lactose, sucrose, starch powder, cellulose ester of alkanoic acid, cellulose alkyl ester, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphate and sulfate, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.Such capsule or tablet can contain controlled release formulation, such as can be provided in the dispersion of active compound in hydroxypropylmethylcellulose.

[0356] The 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. Other compositions described herein comprise a compound, e.g., a compound of Formula (I) or (II), e.g., a compound selected from Compounds 1-34 described herein, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0357] In some embodiments, administration of the DGKα and / or DGKζ inhibitor is initiated prior to, following, during, during the course of, simultaneously with, near-simultaneously with, sequentially with, and / or intermittently with administration of cell therapy, such as T cell therapy. In some embodiments, the method involves initiating administration of the DGKα and / or DGKζ inhibitor prior to administration of T cell therapy. In other embodiments, the method involves initiating administration of the DGKα and / or DGKζ inhibitor after administration of T cell therapy. In some embodiments, the method involves initiating administration of the DGKα and / or DGKζ inhibitor on the same day as administration of T cell therapy (e.g., day 1 of combination therapy). In some embodiments, the method involves initiating administration of the DGKα and / or DGKζ inhibitor concurrently with administration of T cell therapy. In some embodiments, administration of the inhibitor is initiated during administration of T cell therapy, e.g., the first dose of the inhibitor is administered while T cell therapy is being infused.

[0358] 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 cyclical administration of the inhibitor of DGKα and / or DGKζ.

[0359] In some embodiments, the inhibitor of DGKα and / or DGKζ is administered in cycles. In some embodiments, the cycle includes an administration period during 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 in the cycle, e.g., counted from the beginning of administration of the inhibitor of DGKα and / or DGKζ, is greater than or equal to or about 21 days, 28 days, 30 days, 40 days, 50 days, 60 days, or more.

[0360] In some embodiments, the initiation of administration of the inhibitor of DGKα and / or DGKζ and the initiation of administration of T cell therapy occur simultaneously, optionally on the same day, for at least one cycle. In some embodiments, the initiation of administration of the inhibitor of DGKα and / or DGKζ for at least one cycle occurs before the initiation of administration of T cell therapy. In some embodiments, the initiation of administration of the inhibitor of DGKα and / or DGKζ for at least one cycle occurs simultaneously with or on the same day as the initiation of administration of T cell therapy. In some embodiments, the method involves initiating administration of the inhibitor of DGKα and / or DGKζ on the same day as administration of T cell therapy (e.g., day 1 of combination therapy). In some embodiments, administration of the inhibitor begins on day 1 of combination therapy, prior to administration of T cell therapy.

[0361] In some embodiments, the initiation of administration of the inhibitor of DGKα and / or DGKζ and the initiation of administration of T cell therapy occur simultaneously, optionally on the same day, for at least one cycle. In some embodiments, the initiation of administration of the inhibitor of DGKα and / or DGKζ for at least one cycle occurs before the initiation of administration of T cell therapy. In some embodiments, the initiation of administration of the inhibitor of DGKα and / or DGKζ for at least one cycle occurs simultaneously with or on the same day as the initiation of administration of T cell therapy. In some embodiments, the inhibitor of DGKα and / or DGKζ is a...

Claims

1. A method of treatment comprising administering to a subject having cancer: (a) a T cell therapy comprising viable engineered T cells expressing a recombinant receptor for 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 administration of said inhibitor is initiated on any of days 1 to 8 (inclusive) of said combination therapy, and said inhibitor is administered once daily for 21 to 42 consecutive days or for about 21 to 42 days (inclusive); A method comprising administering a combination therapy comprising:

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

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

4. A method of treatment comprising administering to a subject having cancer: (a) a T cell therapy comprising viable engineered T cells expressing a recombinant receptor for 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 administration of said inhibitor begins on any of days 1 to 8 (inclusive) of said combination therapy, and said inhibitor is administered continuously until at least the number of engineered T cells of said T cell therapy peaks in said subject following administration of said T cell therapy. A method comprising administering a combination therapy comprising:

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

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

7. 5. The method of claim 4, wherein administration of the inhibitor begins on day 1 of the combination therapy and prior to administration of the T cell therapy.

8. 1. A method of treatment comprising administering to a subject having cancer a T cell therapy comprising viable engineered T cells that express a recombinant receptor for an antigen expressed by cells of the cancer, wherein the T cell therapy is administered as part of a combination therapy comprising T cell therapy and an inhibitor of DGKα and / or DGKζ: said T cell therapy is administered on day 1 of said combination therapy; administration of the inhibitor is initiated on day 1 of the combination therapy and prior to the administration of the T cell therapy; wherein the inhibitor is administered continuously at least until the number of engineered T cells of the T cell therapy peaks in the subject after administration of the T cell therapy.

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

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

11. 11. The method of any one of claims 4 to 10, wherein the inhibitor is administered once on each day the inhibitor is administered.

12. 12. The method of any one of claims 4 to 11, wherein the inhibitor is administered until the number of engineered T cells of the T cell therapy peaks in the subject after administration of the T cell therapy.

13. 13. The method of any one of claims 4 to 12, wherein the inhibitor is administered for a period of 21 to 42 days or about 21 to 42 days, inclusive.

14. A method of treatment comprising administering to a subject having cancer: (a) a T cell therapy comprising viable engineered T cells expressing a recombinant receptor for 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 administration of said inhibitor begins on any of days 1 to 8 (inclusive) of said combination therapy, and said inhibitor is administered at a therapeutically effective dose for a period of 21 to 42 days or about 21 to 42 days. A method comprising administering a combination therapy comprising:

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

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

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

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

19. 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 a period of at or about 21 to 42 days.

20. 20. The method of any one of claims 14 to 19, wherein the inhibitor is administered every two or three days.

21. A method of treatment comprising administering to a subject having cancer: (a) a T cell therapy comprising viable engineered T cells expressing a recombinant receptor for 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 administration of the inhibitor is initiated on any of days 1 to 8 (inclusive) of the combination therapy, and the inhibitor is administered in multiple cycles, each cycle comprising an administration period during which the inhibitor is administered followed by a rest period during which the inhibitor is not administered; A method comprising administering a combination therapy comprising:

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

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

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

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

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

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

28. 28. The method of any one of claims 21-27, wherein the inhibitor is administered for a period of 21 to 42 days or about 21 to 42 days, inclusive, over multiple cycles.

29. 29. The method of any one of claims 1 to 28, wherein administration of the inhibitor is initiated on any of days 1 to 6 (inclusive) of combination therapy, any of days 1 to 4 (inclusive) of combination therapy, on day 1 or 2 of combination therapy, and / or on day 1 of combination therapy.

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

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

32. 32. The method of any one of claims 1 to 31, wherein the inhibitor is administered for a period of at or about 21 to 35 days, inclusive; at or about 21 to 35 days, inclusive; at or about 21 to 28 days, inclusive; at or about 28 to 42 days, inclusive; at or about 28 to 35 days, inclusive; at or about 28 to 35 days, inclusive; at or about 28 days; and / or at or about 30 days, optionally over multiple cycles.

33. A method of treatment comprising administering to a subject having cancer: (a) a T cell therapy comprising viable engineered T cells expressing a recombinant receptor for 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 administration of the inhibitor begins on day 1 of the combination therapy and the inhibitor is administered once daily from days 1 to 28 (inclusive) of the combination therapy. A method comprising administering a combination therapy comprising:

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

35. 1. A method of treatment, comprising administering to a subject having cancer an inhibitor of DGKα and / or DGKζ, wherein said inhibitor is administered as part of a combination therapy comprising said inhibitor and a T cell therapy comprising viable engineered T cells expressing a recombinant receptor for an antigen expressed by cells of said cancer: the subject has previously been administered the T cell therapy prior to initiation of administration of the inhibitor, and the T cell therapy is administered on day 1 of the combination therapy; administration of said inhibitor begins on day 1 of said combination therapy; The method wherein said inhibitor is administered once daily on days 1 to 28 (inclusive) of said combination therapy.

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

37. 1. A method of treatment comprising administering to a subject having cancer a T cell therapy comprising viable engineered T cells that express a recombinant receptor for an antigen expressed by cells of the cancer, wherein the T cell therapy is administered as part of a combination therapy comprising T cell therapy and an inhibitor of DGKα and / or DGKζ: said T cell therapy is administered on day 1 of said combination therapy; administration of the inhibitor is initiated on day 1 of the combination therapy and prior to the administration of the T cell therapy; The method wherein said inhibitor is administered once daily on days 1 to 28 (inclusive) of said combination therapy.

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

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

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

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

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

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

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

45. 45. The method of claim 44, further comprising administering lymphodepletion therapy to the subject.

46. The lymphocyte depletion therapy 200-400 mg / m daily for 2-4 days or about 2-4 days (inclusive) ２ or about 200 to 400 mg / m ２ cyclophosphamide (inclusive); and / or 20-40 mg / m daily for 2-4 days or about 2-4 days (inclusive) ２ or about 20 to 40 mg / m ２ Fludarabine (inclusive) 46. ​​The method of claim 44 or claim 45, comprising administering:

47. The lymphodepletion therapy comprises administering 300 mg / m daily for 3 days or about 3 days each. ２ or about 300 mg / m ２ of cyclophosphamide and 30 mg / m ２ or about 30 mg / m ２ 47. The method of any one of claims 44 to 46, comprising administering fludarabine in an amount of 0.1 mg / kg or more.

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

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

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

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

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

53. The inhibitor has formula (I): 【Chemical 1】 (I) (In the formula, R １ is H, F, Cl, Br, —CN, 0 to 4 R １ａ C substituted with １～３ alkyl, 0 to 4 R １ａ C substituted with ３～４ cycloalkyl, 0 to 4 R １ａ C substituted with １～３ Alkoxy, —NR ａ R ａ , -S(O) ｎ R ｅ or -P(O)R ｅ R ｅ and Each R １ａ are independently F, Cl, —CN, —OH, —OCH ３ or -NR ａ R ａ and Each R ａ are independently H or C １～３ is alkyl; Each R ｅ are independently ３～４ cycloalkyl, or 0 to 4 R １ａ C substituted with １～３ is alkyl; R ２ is H, 0 to 4 R ２ａ C substituted with １～３ alkyl, or 0 to 4 R ２ａ C substituted with ３～４ is cycloalkyl; Each R ２ａ are independently F, Cl, —CN, —OH, —O(C １～２ alkyl), C ３～４ Cycloalkyl, C ３～４ alkenyl or C ３～４ is alkynyl; R ３ is H, F, Cl, Br, -CN, C １～３ Alkyl, C １～２ Fluoroalkyl, C ３～４ Cycloalkyl, C ３～４ Fluorocycloalkyl or —NO ２ and R ４ is -CH ２ R ４ａ , -CH ２ CH ２ R ４ａ , -CH ２ CHR ４ａ R ４ｄ , -CHR ４ａ R ４ｂ or -CR ４ａ R ４ｂ R ４ｃ and R ４ａ and R ４ｂ is, independently, (i) F, Cl, -CN, -OH, -OCH ３ , -SCH ３ , C １～３ Fluoroalkoxy, —NR ａ R ａ , -S(O) ２ R ｅ Or -NR ａ S (O) ２ R ｅ C substituted with 0 to 4 substituents independently selected from １～６ Alkyl; (ii) F, Cl, Br, -CN, -OH, C １～６ Alkyl, C １～３ Fluoroalkyl, C １～４ Hydroxyalkyl, -(CH ２ ) １～２ O (C １～３ alkyl), C １～４ Alkoxy, —O(C １～４ hydroxyalkyl), —O(CH) １～３ O (C １～３ alkyl), C １～３ Fluoroalkoxy, —O(CH) １～３ NR ｃ R ｃ , -OCH ２ CH=CH ２ , -OCH ２ C≡CH, -C(O)(C １～４ alkyl), —C(O)OH, —C(O)O(C １～４ alkyl), -NR ｃ R ｃ , -NR ａ S (O) ２ (C １～３ alkyl), -NR ａ C(O)(C １～３ alkyl), -NR ａ C(O)O(C １～４ alkyl), -P(O)(C １～３ alkyl) ２ , -S(O) ２ (C １～３ alkyl), —O(CH ２ ) １～２ (C ３～６ cycloalkyl), —O(CH ２ ) １～２ (morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl and R ｄ C, each substituted with 0 to 4 substituents independently selected from ３～６ cycloalkyl, heterocyclyl, phenyl, or heteroaryl; or (iii) C ３～６ C substituted with one cyclic group selected from cycloalkyl, heterocyclyl, aryl and heteroaryl １～４ alkyl, wherein the cyclic group is F, Cl, Br, —OH, —CN, C １～６ Alkyl, C １～３ Fluoroalkyl, C １～３ Alkoxy, C １～３ Fluoroalkoxy, —OCH ２ CH=CH ２ , -OCH ２ C≡CH, —NR ｃ R ｃ , -NR ａ S (O) ２ (C １～３ alkyl), -NR ａ C(O)(C １～３ alkyl), -NR ａ C(O)O(C １～４ alkyl) and C ３～６ substituted with 0 to 3 substituents independently selected from cycloalkyl; １～４ Alkyl Is it; Or R4 ａ and R4 ｂ together with the carbon atoms to which they are attached, represent 0 to 3 R ｆ C each substituted with ３～６ forming a cycloalkyl or a 3- to 6-membered heterocyclyl; Each R ｆ are independently F, Cl, Br, —OH, —CN, C １～６ Alkyl, C １～３ Fluoroalkyl, C １～３ Alkoxy, C １～３ Fluoroalkoxy, —OCH ２ CH=CH ２ , -OCH ２ C≡CH, —NR ｃ R ｃ , or C ３～６ A cyclic group selected from cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each of which is selected from F, Cl, Br, —OH, —CN, C １～６ Alkyl, C １～３ Fluoroalkyl, C １～３ Alkoxy, C １～３ Fluoroalkoxy and —NR ｃ R ｃ substituted with 0 to 3 substituents independently selected from R ４ｃ is F, Cl, -OH, C １～２ Alkoxy, C １～２ C, each substituted with 0 to 4 substituents independently selected from fluoroalkoxy and —CN; １～６ Alkyl or C ３～６ is cycloalkyl; R ４ｄ is -OCH ３ and Each R ｃ are independently H or C １～２ is alkyl; R ｄ is F, Cl, -CN, -CH ３ and -OCH ３ phenyl substituted with 0 to 1 substituents selected from Each R ５ are independently —CN, 0 to 4 R ｇ C substituted with １～６ alkyl, 0 to 4 R ｇ C substituted with ２～４ alkenyl, 0 to 4 R ｇ C substituted with ２～４ alkynyl, 0 to 4 R ｇ C substituted with ３～４ cycloalkyl, 0 to 4 R ｇ phenyl substituted with 0 to 3 R ｇ oxadiazolyl substituted with 0 to 4 R ｇ pyridinyl substituted with -(CH ２ ) １～２ (0 to 4 R ｇ heterocyclyl substituted with -(CH ２ ) １～２ NR ｃ C(O)(C １～４ alkyl), -(CH ２ ) １～２ NR ｃ C(O)O(C １～４ alkyl), -(CH ２ ) １～２ NR ｃ S (O) ２ (C １～４ alkyl), —C(O)(C １～４ alkyl), —C(O)OH, —C(O)O(C １～４ alkyl), —C(O)O(C ３～４ cycloalkyl), —C(O)NR ａ R ａ or -C(O)NR ａ (C ３～４ cycloalkyl); Each R ｇ are independently F, Cl, —CN, —OH, C １～３ Alkoxy, C １～３ Fluoroalkoxy, —O(CH ２ ) １～２ O (C １～２ alkyl) or -NR ｃ R ｃ and m is 0, 1, 2 or 3; n is 0, 1 or 2. or a pharmaceutically acceptable salt thereof.

54. The inhibitor is a compound of formula (I), wherein: R １ is H, F, Cl, Br, —CN, 0 to 4 R １ａ C substituted with １～３ alkyl, 0 to 3 R １ａ cyclopropyl substituted with 0 to 3 R １ａ C substituted with １～３ Alkoxy, —NR ａ R ａ , -S(O) ｎ CH ３ or -P(O)(CH ３ ) ２ and Each R １ａ is independently F, Cl, or —CN; Each R ａ are independently H or C １～３ is alkyl; R ２ is H or 0 to 2 R ２ａ C substituted with １～２ is alkyl; Each R ２ａ are independently F, Cl, —CN, —OH, —O(C １～２ alkyl), cyclopropyl, C ３～４ alkenyl or C ３～４ is alkynyl; R ３ H, F, Cl, Br, -CN, C １～２ Alkyl, —CF ３ , cyclopropyl or —NO ２ and R ４ａ and R ４ｂ But independently, (i) F, Cl, -CN, -OH, -OCH ３ , -SCH ３ , C １～３ Fluoroalkoxy and —NR ａ R ａ C substituted with 0 to 4 substituents independently selected from １～４ Alkyl; (ii) F, Cl, Br, -CN, -OH, C １～６ Alkyl, C １～３ Fluoroalkyl, —CH ２ OH, -(CH ２ ) １～２ O (C １～２ alkyl), C １～４ Alkoxy, —O(C １～４ hydroxyalkyl), —O(CH) １～２ O (C １～２ alkyl), C １～３ Fluoroalkoxy, —O(CH) １～２ NR ｃ R ｃ , -OCH ２ CH=CH ２ , -OCH ２ C≡CH, -C(O)(C １～４ alkyl), —C(O)OH, —C(O)O(C １～４ alkyl), -NR ｃ R ｃ , -NR ａ S (O) ２ (C １～３ alkyl), -NR ａ C(O)(C １～３ alkyl), -NR ａ C(O)O(C １～４ alkyl), -P(O)(C １～２ alkyl) ２ , -S(O) ２ (C １～３ alkyl), —O(CH ２ ) １～２ (C ３～４ cycloalkyl), —O(CH ２ ) １～２ (morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl and R ｄ C, each substituted with 0 to 4 substituents independently selected from ３～６ cycloalkyl, heterocyclyl, phenyl, or heteroaryl; or (iii) C ３～６ C substituted with one cyclic group selected from cycloalkyl, heterocyclyl, phenyl, and heteroaryl １～３ alkyl, wherein the cyclic group is F, Cl, Br, —OH, —CN, C １～３ Alkyl, C １～２ Fluoroalkyl, C １～３ Alkoxy, C １～２ Fluoroalkoxy, —OCH ２ CH=CH ２ , -OCH ２ C≡CH, —NR ｃ R ｃ , -NR ａ S (O) ２ (C １～３ alkyl), -NR ａ C(O)(C １～３ alkyl), -NR ａ C(O)O(C １～４ alkyl) and C ３～４ substituted with 0 to 3 substituents independently selected from cycloalkyl; １～３ Alkyl Is it; Or R ４ａ and R ４ｂ These, together with the carbon atoms to which they are attached, form 0 to 3 R ｆ C each substituted with ３～６ forming a cycloalkyl or a 3- to 6-membered heterocyclyl; Each R ｆ are independently F, Cl, Br, —OH, —CN, C １～４ Alkyl, C １～２ Fluoroalkyl, C １～３ Alkoxy, C １～２ Fluoroalkoxy, —OCH ２ CH=CH ２ , -OCH ２ C≡CH, —NR ｃ R ｃ , or C ３～６ A cyclic group selected from cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each of which is selected from F, Cl, Br, —OH, —CN, C １～４ Alkyl, C １～２ Fluoroalkyl, C １～３ Alkoxy, C １～２ Fluoroalkoxy and —NR ｃ R ｃ substituted with 0 to 3 substituents independently selected from R ４ｃ F, Cl, -OH, C １～２ Alkoxy, C １～２ C, each substituted with 0 to 4 substituents independently selected from fluoroalkoxy and —CN; １～４ Alkyl or C ３～６ is cycloalkyl; Each R ５ are independently —CN, 0 to 4 R ｇ C substituted with １～５ alkyl, 0 to 4 R ｇ C substituted with ２～３ alkenyl, 0 to 4 R ｇ C substituted with ２～３ alkynyl, 0 to 4 R ｇ C substituted with ３～４ cycloalkyl, 0 to 3 R ｇ phenyl substituted with 0 to 3 R ｇ oxadiazolyl substituted with 0 to 3 R ｇ pyridinyl substituted with -(CH ２ ) １～２ (0 to 4 R ｇ heterocyclyl substituted with -(CH ２ ) １～２ NR ｃ C(O)(C １～４ alkyl), -(CH ２ ) １～２ NR ｃ C(O)O(C １～４ alkyl), -(CH ２ ) １～２ NR ｃ S (O) ２ (C １～４ alkyl), —C(O)(C １～４ alkyl), —C(O)OH, —C(O)O(C １～４ alkyl), —C(O)O(C ３～４ cycloalkyl), —C(O)NR ａ R ａ or -C(O)NR ａ (C ３～４ 54. The method of claim 53, wherein the compound is cycloalkyl), or a pharmaceutically acceptable salt thereof.

55. 10. The inhibitor of claim 1, wherein the inhibitor has the structure: 【Chemistry 2】 (In the formula, R １ is —CN; R ２ is -CH ３ and R ３ is H, F or —CN; R ４ teeth, 【Chemistry 3】 is) 55. The method of claim 54, wherein the compound is a compound of formula (I) having the formula:

56. 10. The inhibitor of claim 1, wherein the inhibitor has the structure: 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 54. The method of claim 53, wherein the compound is a compound of formula (I) having the formula:

57. The inhibitor has the formula (II): 【Chemistry 8】 (In the formula, R １ is H, F, Cl, Br, —CN, —OH, 0 to 4 R １ａ C substituted with １～３ alkyl, 0 to 4 R １ａ C substituted with ３～４ cycloalkyl, 0 to 4 R １ａ C substituted with １～３ Alkoxy, —NR ａ R ａ , -S(O) ｎ R ｅ or -P(O)R ｅ R ｅ and Each R １ａ are independently F, Cl, —CN, —OH, —OCH ３ or -NR ａ R ａ and Each R ａ are independently H or C １～３ is alkyl; Each R ｅ are independently ３～４ cycloalkyl, or 0 to 4 R １ａ C substituted with １～３ is alkyl; R ２ is H, 0 to 4 R ２ａ C substituted with １～３ alkyl, or 0 to 4 R ２ａ C substituted with ３～４ is cycloalkyl; Each R ２ａ are independently F, Cl, —CN, —OH, —O(C １～２ alkyl), C ３～４ Cycloalkyl, C ３～４ alkenyl or C ３～４ is alkynyl; R ４ is -CH ２ R ４ａ , -CH ２ CH ２ R ４ａ , -CH ２ CHR ４ａ R ４ｄ , -CHR ４ａ R ４ｂ or -CR ４ａ R ４ｂ R ４ｃ and R ４ａ and R ４ｂ is, independently, (i) —CN, or F, Cl, —CN, —OH, —OCH ３ , -SCH ３ , C １～３ Fluoroalkoxy, —NR ａ R ａ , -S(O) ２ R ｅ Or -NR ａ S (O) ２ R ｅ C substituted with 0 to 4 substituents independently selected from １～６ Alkyl; (ii) F, Cl, Br, -CN, -OH, C １～６ Alkyl, C １～３ Fluoroalkyl, C １～２ Bromoalkyl, C １～２ Cyanoalkyl, C １～４ Hydroxyalkyl, -(CH ２ ) １～２ O (C １～３ alkyl), C １～４ Alkoxy, C １～３ Fluoroalkoxy, C １～３ Cyanoalkoxy, —O(C １～４ hydroxyalkyl), —O(CR ｘ R ｘ ) １～３ O (C １～３ alkyl), C １～３ Fluoroalkoxy, —O(CH ２ ) １～３ NR ｃ R ｃ , -OCH ２ CH=CH ２ , -OCH ２ C≡CH, -C(O)(C １～４ alkyl), —C(O)OH, —C(O)O(C １～４ alkyl), -NR ｃ R ｃ , -CH ２ NR ａ R ａ , -NR ａ S (O) ２ (C １～３ alkyl), -NR ａ C(O)(C １～３ alkyl), -(CR ｘ R ｘ ) ０～２ NR ａ C(O)O(C １～４ alkyl), -P(O)(C １～３ alkyl) ２ , -S(O) ２ (C １～３ alkyl), -(CR ｘ R ｘ ) １～２ (C ３～４ cycloalkyl), -(CR ｘ R ｘ ) １～２ (morpholinyl), -(CR ｘ R ｘ ) １～２ (difluoromorpholinyl), -(CR ｘ R ｘ ) １～２ (dimethylmorpholinyl), -(CR ｘ R ｘ ) １～２ (oxazabicyclo[2.2.1]heptanyl), (CR ｘ R ｘ ) １～２ (oxazaspiro[3.3]heptanyl), -(CR ｘ R ｘ ) １～２ (methylpiperazinonyl), -(CR ｘ R ｘ ) １～２ (acetylpiperazinyl), -(CR ｘ R ｘ ) １～２ (piperidinyl), -(CR ｘ R ｘ ) １～２ (difluoropiperidinyl), -(CR ｘ R ｘ ) １～２ (methoxypiperidinyl), -(CR ｘ R ｘ ) １～２ (hydroxypiperidinyl), —O(CR ｘ R ｘ ) ０～２ (C ３～６ cycloalkyl), —O(CR ｘ R ｘ ) ０～２ (methylcyclopropyl), —O(CR ｘ R ｘ ) ０～２ ((ethoxycarbonyl)cyclopropyl), —O(CR ｘ R ｘ ) ０～２ (oxetanyl), —O(CR ｘ R ｘ ) ０～２ (methylazetidinyl), —O(CR ｘ R ｘ ) ０～２ (tetrahydropyranyl), —O(CR ｘ R ｘ ) １～２ (morpholinyl), —O(CR ｘ R ｘ ) ０～２ (thiazolyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, dioxolanyl, pyrrolidinonyl and R ｄ C, each substituted with 0 to 4 substituents independently selected from ３～６ cycloalkyl, 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl; or (iii) C ３～６ C substituted with one cyclic group selected from cycloalkyl, 4- to 10-membered heterocyclyl, monocyclic or bicyclic aryl, or 5- to 10-membered heteroaryl １～４ alkyl, wherein the cyclic group is F, Cl, Br, —OH, —CN, C １～６ Alkyl, C １～３ Fluoroalkyl, C １～３ Alkoxy, C １～３ Fluoroalkoxy, —OCH ２ CH=CH ２ , -OCH ２ C≡CH, —NR ｃ R ｃ , -NR ａ S (O) ２ (C １～３ alkyl), -NR ａ C(O)(C １～３ alkyl), -NR ａ C(O)O(C １～４ alkyl) and C ３～６ substituted with 0 to 3 substituents independently selected from cycloalkyl; １～４ Is alkyl; Or R ４ａ and R ４ｂ together with the carbon atoms to which they are attached, represent 0 to 3 R ｆ C each substituted with ３～６ forming a cycloalkyl or a 3- to 6-membered heterocyclyl; Each R ｆ are independently F, Cl, Br, —OH, —CN, C １～６ Alkyl, C １～３ Fluoroalkyl, C １～３ Alkoxy, C １～３ Fluoroalkoxy, —OCH ２ CH=CH ２ , -OCH ２ C≡CH, —NR ｃ R ｃ , or C ３～６ A cyclic group selected from cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each of which is selected from F, Cl, Br, —OH, —CN, C １～６ Alkyl, C １～３ Fluoroalkyl, C １～３ Alkoxy, C １～３ Fluoroalkoxy and —NR ｃ R ｃ substituted with 0 to 3 substituents independently selected from R ４ｃ is F, Cl, -OH, C １～２ Alkoxy, C １～２ C, each substituted with 0 to 4 substituents independently selected from fluoroalkoxy and —CN; １～６ Alkyl or C ３～６ is cycloalkyl; R ４ｄ is -OCH ３ and Each R ｃ are independently H or C １～２ is alkyl; R ｄ is F, Cl, -CN, -CH ３ and -OCH ３ phenyl substituted with 0 to 1 substituents selected from Each R ５ are independently —CN, 0 to 4 R ｇ C substituted with １～６ alkyl, 0 to 4 R ｇ C substituted with ２～４ alkenyl, 0 to 4 R ｇ C substituted with ２～４ alkynyl, 0 to 4 R ｇ C substituted with ３～４ cycloalkyl, 0 to 4 R ｇ phenyl substituted with 0 to 3 R ｇ oxadiazolyl substituted with 0 to 4 R ｇ pyridinyl substituted with -(CH ２ ) １～２ (0 to 4 R ｇ 4- to 10-membered heterocyclyl substituted with -(CH ２ ) １～２ NR ｃ C(O)(C １～４ alkyl), -(CH ２ ) １～２ NR ｃ C(O)O(C １～４ alkyl), -(CH ２ ) １～２ NR ｃ S (O) ２ (C １～４ alkyl), —C(O)(C １～４ alkyl), —C(O)OH, —C(O)O(C １～４ alkyl), —C(O)O(C ３～４ cycloalkyl), —C(O)NR ａ R ａ or -C(O)NR ａ (C ３～４ cycloalkyl); Each R ｇ are independently F, Cl, —CN, —OH, C １～３ Alkoxy, C １～３ Fluoroalkoxy, —O(CH ２ ) １～２ O (C １～２ alkyl) or -NR ｃ R ｃ and m is 0, 1, 2 or 3; n is 0, 1 or 2. or a salt thereof.

58. The inhibitor is a compound of formula (II), wherein: R １ is H, F, Cl, Br, —CN, —OH, 0 to 4 R １ａ C substituted with １～３ alkyl, 0 to 3 R １ａ cyclopropyl substituted with 0 to 3 R １ａ C substituted with １～３ Alkoxy, —NR ａ R ａ , -S(O) ｎ CH ３ or -P(O)(CH ３ ) ２ and R ２ is H or 0 to 2 R ２ａ C substituted with １～２ is alkyl; Each R ２ａ are independently F, Cl, —CN, —OH, —O(C １～２ alkyl), cyclopropyl, C ３～４ alkenyl or C ３～４ is alkynyl; R ４ａ and R ４ｂ But independently, (i) —CN, or F, Cl, —CN, —OH, —OCH ３ , -SCH ３ , C １～３ Fluoroalkoxy and —NR ａ R ａ C substituted with 0 to 4 substituents independently selected from １～４ Alkyl; (ii) F, Cl, Br, -CN, -OH, C １～６ Alkyl, C １～３ Fluoroalkyl, C １～２ Bromoalkyl, C １～２ Cyanoalkyl, C １～２ Hydroxyalkyl, —CH ２ NR ａ R ａ , -(CH ２ ) １～２ O (C １～２ alkyl), -(CH ２ ) １～２ NR ｘ C(O)O(C １～２ alkyl), C １～４ Alkoxy, —O(C １～４ hydroxyalkyl), —O(CR ｘ R ｘ ) １～２ O (C １～２ alkyl), C １～３ Fluoroalkoxy, C １～３ Cyanoalkoxy, —O(CH ２ ) １～２ NR ｃ R ｃ , -OCH ２ CH=CH ２ , -OCH ２ C≡CH, -C(O)(C １～４ alkyl), —C(O)OH, —C(O)O(C １～４ alkyl), -NR ｃ R ｃ , -NR ａ S (O) ２ (C １～３ alkyl), -NR ａ C(O)(C １～３ alkyl), -NR ａ C(O)O(C １～４ alkyl), -P(O)(C １～２ alkyl) ２ , -S(O) ２ (C １～３ alkyl), -(CH ２ ) １～２ (C ３～４ cycloalkyl), -CR ｘ R ｘ (morpholinyl), -CR ｘ R ｘ (difluoromorpholinyl), -CR ｘ R ｘ (dimethylmorpholinyl), -CR ｘ R ｘ (oxazabicyclo[2.2.1]heptanyl), —CR ｘ R ｘ (oxazaspiro[3.3]heptanyl), -CR ｘ R ｘ (methylpiperazinonyl), -CR ｘ R ｘ (acetylpiperazinyl), -CR ｘ R ｘ (piperidinyl), -CR ｘ R ｘ (difluoropiperidinyl), -CR ｘ R ｘ (methoxypiperidinyl), -CR ｘ R ｘ (hydroxypiperidinyl), —O(CH ２ ) ０～２ (C ３～４ cycloalkyl), —O(CH ２ ) ０～２ (methylcyclopropyl), —O(CH ２ ) ０～２ ((ethoxycarbonyl)cyclopropyl), —O(CH ２ ) ０～２ (oxetanyl), —O(CH ２ ) ０～２ (methylazetidinyl), —O(CH ２ ) １～２ (morpholinyl), —O(CH ２ ) ０～２ (tetrahydropyranyl), —O(CH ２ ) ０～２ (thiazolyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, dioxolanyl, pyrrolidinonyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl and R ｄ C, each substituted with 0 to 4 substituents independently selected from ３～６ cycloalkyl, 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl; or (iii) C ３～６ C substituted with one cyclic group selected from cycloalkyl, 4- to 10-membered heterocyclyl, monocyclic or bicyclic aryl, or 5- to 10-membered heteroaryl １～３ alkyl, wherein the cyclic group is F, Cl, Br, —OH, —CN, C １～３ Alkyl, C １～２ Fluoroalkyl, C １～３ Alkoxy, C １～２ Fluoroalkoxy, —OCH ２ CH=CH ２ , -OCH ２ C≡CH, —NR ｃ R ｃ , -NR ａ S (O) ２ (C １～３ alkyl), -NR ａ C(O)(C １～３ alkyl), -NR ａ C(O)O(C １～４ alkyl) and C ３～４ substituted with 0 to 3 substituents independently selected from cycloalkyl; １～３ Alkyl Is it; Or R ４ａ and R ４ｂ These, together with the carbon atoms to which they are attached, form 0 to 3 R ｆ C each substituted with ３～６ forming a cycloalkyl or a 3- to 6-membered heterocyclyl; Each R ｆ are independently F, Cl, Br, —OH, —CN, C １～４ Alkyl, C １～２ Fluoroalkyl, C １～３ Alkoxy, C １～２ Fluoroalkoxy, —OCH ２ CH=CH ２ , -OCH ２ C≡CH, —NR ｃ R ｃ , or C ３～６ A cyclic group selected from cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each of which is selected from F, Cl, Br, —OH, —CN, C １～４ Alkyl, C １～２ Fluoroalkyl, C １～３ Alkoxy, C １～２ Fluoroalkoxy and —NR ｃ R ｃ substituted with 0 to 3 substituents independently selected from R ４ｃ F, Cl, -OH, C １～２ Alkoxy, C １～２ C, each substituted with 0 to 4 substituents independently selected from fluoroalkoxy and —CN; １～４ Alkyl or C ３～６ is cycloalkyl; Each R ５ are independently —CN, 0 to 4 R ｇ C substituted with １～５ alkyl, 0 to 4 R ｇ C substituted with ２～３ alkenyl, 0 to 4 R ｇ C substituted with ２～３ alkynyl, 0 to 4 R ｇ C substituted with ３～４ cycloalkyl, 0 to 3 R ｇ phenyl substituted with 0 to 3 R ｇ oxadiazolyl substituted with 0 to 3 R ｇ pyridinyl substituted with -(CH ２ ) １～２ (0 to 4 R ｇ 4- to 10-membered heterocyclyl substituted with -(CH ２ ) １～２ NR ｃ C(O)(C １～４ alkyl), -(CH ２ ) １～２ NR ｃ C(O)O(C １～４ alkyl), -(CH ２ ) １～２ NR ｃ S (O) ２ (C １～４ alkyl), —C(O)(C １～４ alkyl), —C(O)OH, —C(O)O(C １～４ alkyl), —C(O)O(C ３～４ cycloalkyl), —C(O)NR ａ R ａ or -C(O)NR ａ (C ３～４ cycloalkyl); Each R ｘ are independently H or —CH ３ and 58. The method of claim 57, wherein m is 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

59. 10. The inhibitor of claim 1, wherein the inhibitor has the structure: 【Chemistry 9】 (In the formula, R １ is —CN; R ２ is -CH ３ and R ５ａ is -CH ３ or -CH ２ CH ３ and R ５ｃ is -CH ３ , -CH ２ CH ３ or -CH ２ CH ２ CH ３ is) 59. The method of claim 58, wherein the compound is a compound of formula (II) having the formula:

60. 10. The inhibitor of claim 1, wherein the inhibitor has the structure: 【Chemistry 10】 【Chemistry 11】 58. The method of claim 57, wherein the compound is a compound of formula (II) having the formula:

61. 10. The inhibitor of claim 1, wherein the inhibitor has the structure: 【Chemistry 12】 58. The method of claim 57, wherein the compound is a compound of formula (II) having the formula:

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

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

64. 64. The method of any one of claims 1 to 63, wherein the inhibitor is administered in a daily amount of at or about 0.25 to 250 mg, inclusive.

65. 65. The method of any one of claims 1 to 64, wherein the inhibitor is administered in a daily amount of 0.5 to 100 mg or about 0.5 to 100 mg, inclusive.

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

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

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

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

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

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

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

73. 73. The method of claim 68 or claim 72, wherein the CAR is an ABECMA® (idecbutagen bileucel) or CARVYKTI™ (siltacbutagen autoleucel) CAR.

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

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

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

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

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

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

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

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

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

83. The T cell therapy ６ ~1,000 x 10 ６ or approximately 0.1 x 10 ６ ~1,000 x 10 ６ 83. The method of any one of claims 1 to 82, comprising total recombinant receptor-expressing T cells (upper and lower limits inclusive).

84. The T cell therapy ６ ~1,000 x 10 ６ pieces or about 10 x 10 ６ ~1,000 x 10 ６ 84. The method of any one of claims 1 to 83, comprising total recombinant receptor-expressing T cells (upper and lower limits inclusive).

85. The T cell therapy ６ ~500 x 10 ６ pieces or about 10 x 10 ６ ~500 x 10 ６ 85. The method of any one of claims 1 to 84, comprising total recombinant receptor-expressing T cells (upper and lower limits inclusive).

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

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

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

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

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