Combination of T cell therapy and DGK inhibitors

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 / 156,342, filed March 3, 2021, the entire contents of which are incorporated by reference herein for all purposes.

[0002] INCORPORATION BY REFERENCE TO SEQUENCE LISTING This application is being filed with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 735042024440SeqList.txt, created on February 28, 2022, which is 388 kilobytes in size. The information in the electronic Sequence Listing is incorporated by reference in its entirety.

[0003] Field 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 methods, compositions and uses provided 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, 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, administering engineered T cells for adoptive therapy.For example, strategies are available for engineering T cells, such as expressing engineered antigen receptors, such as CAR or TCR, and administering compositions containing such cells to subjects.Improved strategies are needed to improve the efficacy of T cells in cell therapy, such as improving the persistence, activity and / or proliferation of cells during or after administration to subjects.Methods, compositions, kits and systems that meet such needs are provided. Summary of the Invention

[0005] Provided herein is a method of treatment comprising: (a) administering a T cell therapy to a subject having a disease or condition, where the T cell therapy comprises engineered T cells that express a recombinant receptor; and then (b) administering to the subject an inhibitor of DGKα and / or DGKζ.

[0006] Provided herein is a T cell therapy and an inhibitor of DGKα and / or DGKζ for use in a method of treating a disease or condition, the method comprising: (a) administering T cell therapy to a subject having the disease or condition, where the T cell therapy comprises engineered T cells that express a recombinant receptor; and then (b) administering an inhibitor of DGKα and / or DGKζ to the subject.

[0007] Provided herein is the use of a combination of T cell therapy and an inhibitor of DGKα and / or DGKζ in a method for treating a disease or condition, the method comprising: (a) administering T cell therapy to a subject having the disease or condition, where the T cell therapy comprises engineered T cells that express a recombinant receptor; and then (b) administering an inhibitor of DGKα and / or DGKζ to the subject.

[0008] Provided herein is the use of a combination of T cell therapy and an inhibitor of DGKα and / or DGKζ in the manufacture of a medicament for treating a disease or condition in a subject, wherein the T cell therapy comprises engineered T cells expressing a recombinant receptor.

[0009] Provided herein are methods of treatment comprising administering an inhibitor of DGKα and / or DGKζ to a subject having a disease or condition, wherein at the start of administration of the inhibitor, the subject has previously been administered T cell therapy comprising engineered T cells expressing a recombinant receptor for treatment of the disease or condition.

[0010] Provided herein is an inhibitor of DGKα and / or DGKζ for use in a method of treating a disease or condition in a subject, the method comprising administering an inhibitor of DGKα and / or DGKζ to the subject, wherein at the start of administration of the inhibitor, the subject has previously been administered T cell therapy comprising engineered T cells expressing a recombinant receptor, for the treatment of the disease or condition.

[0011] Provided herein is the use of an inhibitor of DGKα and / or DGKζ in a method for treating a disease or condition, the method comprising administering an inhibitor of DGKα and / or DGKζ to a subject, wherein at the start of administration of the inhibitor, the subject has previously been administered T cell therapy comprising engineered T cells expressing a recombinant receptor for the treatment of the disease or condition.

[0012] Provided herein is the use of an inhibitor of DGKα and / or DGKζ in the manufacture of a medicament for treating a disease or condition in a subject, wherein at the start of administration of the inhibitor, the subject has previously been administered T cell therapy comprising engineered T cells expressing a recombinant receptor for the treatment of the disease or condition.

[0013] Provided herein is a method of rescuing engineered T cells of a T cell therapy from exhaustion, comprising administering to a subject an inhibitor of DGKα and / or DGKζ, where at the start of administration of the inhibitor, the subject has previously been administered a T cell therapy comprising engineered T cells expressing a recombinant receptor for the treatment of a disease or condition.

[0014] Provided herein is a method for reducing or delaying the onset of T cell exhaustion in T cells of a T cell therapy, comprising administering to a subject an inhibitor of DGKα and / or DGKζ, where at the start of administration of the inhibitor, the subject has previously been administered a T cell therapy comprising engineered T cells expressing a recombinant receptor for the treatment of a disease or condition.

[0015] In some of any of the embodiments provided, the inhibitors of human DGKα and / or DGKζ are inhibitors of DGKα and are not significant inhibitors of DGKζ. In some of any of the embodiments provided, the inhibitors of DGKα and / or DGKζ are inhibitors of DGKζ and are not significant inhibitors of DGKα. In some of any of the embodiments provided, the inhibitors of DGKα and / or DGKζ are inhibitors of DGKα and DGKζ. In some of any of the embodiments provided, the inhibitors of DGKα and / or DGKζ are not significant inhibitors of other DGKs.

[0016] In some of any of the provided embodiments, the recombinant receptor is a chimeric antigen receptor (CAR).

[0017] In some of any of the provided embodiments, the recombinant receptor is an engineered T cell receptor (eTCR).

[0018] In some of any of the provided embodiments, the T cells of the T cell therapy are autologous to the subject. In some of the provided embodiments, the T cells of the T cell therapy are allogeneic to the subject.

[0019] Provided herein is a method of treatment comprising: (a) administering a T cell therapy to a subject having a disease or condition, where the T cell therapy comprises engineered T cells that express a recombinant receptor; and then (b) administering to the subject an inhibitor of DGKα and / or DGKζ.

[0020] In some embodiments, initiation of administration of the inhibitor of DGKα and / or DGKζ occurs after initiation of administration of T cell therapy.

[0021] Provided herein are methods of treatment comprising administering an inhibitor of DGKα and / or DGKζ to a subject having a disease or condition, wherein at the start of administration of the inhibitor of DGKα and / or DGKζ, the subject has previously been administered T cell therapy comprising engineered T cells expressing a recombinant receptor for treatment of the disease or condition.

[0022] Provided herein is a method of rescuing engineered T cells of a T cell therapy from exhaustion, comprising administering to a subject an inhibitor of DGKα and / or DGKζ, wherein at the start of administration of the inhibitor of DGKα and / or DGKζ, the subject has previously been administered a T cell therapy comprising engineered T cells expressing a recombinant receptor for the treatment of a disease or condition.

[0023] Provided herein is a method for reducing or delaying the onset of T cell exhaustion in T cells of a T cell therapy, comprising administering to a subject an inhibitor of DGKα and / or DGKζ, wherein at the start of administration of the inhibitor of DGKα and / or DGKζ, the subject has previously been administered a T cell therapy comprising engineered T cells expressing a recombinant receptor for the treatment of a disease or condition.

[0024] In some of any of the provided embodiments, initiation of administration of the DGKα and / or DGKζ inhibitor occurs 1-28 days after initiation of administration of the T cell therapy. In some of any of the provided embodiments, initiation of administration of the DGKα and / or DGKζ inhibitor occurs 1 day or about 1 day, 2 days or about 2 days, 3 days or about 3 days, 4 days or about 4 days, 5 days or about 5 days, or 6 days or about 6 days after initiation of administration of the T cell therapy.

[0025] In some of any of the provided embodiments, upon administration of an inhibitor of DGKα and / or DGKζ, at least or about 10%, at least or about 20%, at least or about 30%, at least or about 40%, or at least or about 50% of the total recombinant receptor-expressing T cells in a biological sample from the subject have an exhausted phenotype.

[0026] In some of any of the provided embodiments, administration of the inhibitor of DGKα and / or DGKζ is initiated at or about the time or within about one week of when peak or maximum levels of cells of the T cell therapy are detected or detectable in the subject's blood.

[0027] In some of any of the provided embodiments, initiation of administration of the inhibitor of DGKα and / or DGKζ occurs 7 to 21 days after initiation of administration of the T cell therapy.

[0028] In some of any of the provided embodiments, initiation of administration of the DGKα and / or DGKζ inhibitor occurs 7 to 14 days after initiation of administration of the T cell therapy. In some of any of the provided embodiments, initiation of administration of the DGKα and / or DGKζ inhibitor occurs 7 or about 7 days, 8 or about 8 days, 9 or about 9 days, 10 or about 10 days, 11 or about 11 days, 12 or about 12 days, 13 or about 13 days, or 14 or about 14 days after initiation of administration of the T cell therapy.

[0029] In some of any of the provided embodiments, initiation of administration of the DGKα and / or DGKζ inhibitor occurs 15 to 21 days after initiation of administration of the T cell therapy. In some of any of the provided embodiments, initiation of administration of the DGKα and / or DGKζ inhibitor occurs 15 or about 15 days, 16 or about 16 days, 17 or about 17 days, 18 or about 18 days, 19 or about 19 days, 20 or about 20 days, or 21 or about 21 days after initiation of administration of the T cell therapy.

[0030] In some of any of the provided embodiments, initiation of administration of the inhibitor of DGKα and / or DGKζ occurs simultaneously with administration of the T cell therapy.

[0031] In some of any of the provided embodiments, initiation of administration of the inhibitor of DGKα and / or DGKζ occurs prior to initiation of administration of the T cell therapy.

[0032] Provided herein is a method of treatment comprising administering to a subject having a disease or condition a T cell therapy comprising engineered T cells expressing a recombinant receptor for treatment of the disease or condition, wherein at the initiation of administration of the T cell therapy, the subject has previously been administered an inhibitor of DGKα and / or DGKζ.

[0033] Provided herein is a T cell therapy for use in a method of treating a disease or condition, the method comprising administering the T cell therapy to a subject having the disease or condition, the T cell therapy comprising engineered T cells that express a recombinant receptor, and wherein at the initiation of administration of the T cell therapy, the subject has previously been administered an inhibitor of DGKα and / or DGKζ.

[0034] Provided herein is the use of T cell therapy in a method of treating a disease or condition, the method comprising administering T cell therapy to a subject having the disease or condition, the T cell therapy comprising engineered T cells expressing a recombinant receptor, and wherein at the initiation of administration of the T cell therapy, the subject has previously been administered an inhibitor of DGKα and / or DGKζ.

[0035] Provided herein is the use of T cell therapy in the manufacture of a medicament for treating a disease or condition in a subject, wherein the T cell therapy comprises engineered T cells expressing a recombinant receptor, and wherein, at the initiation of administration of the T cell therapy, the subject has previously been administered an inhibitor of DGKα and / or DGKζ.

[0036] In some of the provided embodiments, prior to administration of the inhibitor of DGKα and / or DGKζ, the subject is preconditioned with lymphodepleting therapy comprising administration of fludarabine and / or cyclophosphamide. In some of the provided embodiments, prior to administration of the inhibitor of DGKα and / or DGKζ, the subject is preconditioned with lymphodepleting therapy comprising administration of fludarabine and cyclophosphamide.

[0037] In some of any of the provided embodiments, the inhibitor of DGKα and / or DGKζ is administered 1 day or about 1 day or less than 1 day, 2 days or about 2 days or less than 2 days, or 3 days or about 3 days or less than 3 days prior to the initiation of administration of the T cell therapy.

[0038] In some of the provided 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 the provided embodiments, prior to administration of the T cell therapy, the subject is preconditioned with lymphodepleting therapy comprising administration of fludarabine and cyclophosphamide.

[0039] In some of any of the provided embodiments, the lymphodepletion therapy comprises about 200-400 mg / m daily for 2-4 days, optionally 3 days. 2 (including upper and lower limits), as appropriate, 300 mg / m 2 or about 300 mg / m 2 of cyclophosphamide and / or approximately 20-40 mg / m 2 , as appropriate, 30mg / m 2 or about 30 mg / m 2 or lymphodepleting therapy includes administration of fludarabine at a dose of about 500 mg / m 2 In some of any of the provided embodiments, the lymphodepletion therapy includes administration of 300 mg / m cyclophosphamide daily for three days. 2or about 300 mg / m 2 of cyclophosphamide and 30 mg / m 2 or about 30 mg / m 2 This includes administration of fludarabine.

[0040] In some of any of the provided embodiments, the T cell therapy is administered to the subject 2-7 days after the lymphodepletion therapy.

[0041] In some of any of the embodiments provided, the inhibitors of DGKα and / or DGKζ are inhibitors of DGKα and are not critical inhibitors of DGKζ. In some of any of the embodiments provided, the inhibitors of DGKα and / or DGKζ are inhibitors of DGKζ and are not critical inhibitors of DGKα. In some of any of the embodiments provided, the inhibitors of DGKα and / or DGKζ are inhibitors of DGKα and DGKζ. In some of any of the embodiments provided, the inhibitors of DGKα and / or DGKζ are not critical inhibitors of other DGKs.

[0042] In some of any of the provided embodiments, the inhibitor of DGKα and / or DGKζ has formula (I): [ka] (I) (In the formula, R 1 is H, F, Cl, Br, -CN, 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, -OCH 3 or -NR a Ra and each R a are independently H or C 1~3 alkyl; each R e is independently 3~4 Cycloalkyl or 0 to 4 R 1a C replaced with 1~3 R is alkyl; 2 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 Alkynyl; R 3 are H, F, Cl, Br, -CN, C 1~3 Alkyl, C 1~2 Fluoroalkyl, C 3~4 Cycloalkyl, C 3~4 Fluorocycloalkyl or -NO 2 ;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 ;R 4a and R 4b are 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 eC 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 each substituted with 0 to 4 substituents independently selected from 3~6cycloalkyl, 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; or R 4a and R 4b Together with the carbon atom to which they are attached, they form 0 to 3 R f C, each replaced by 3~6 cycloalkyl or 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, C1~3 Fluoroalkyl, C 1~3 Alkoxy, C 1~3 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; 1~6 Alkyl or C 3~6 Cycloalkyl; R 4d -OCH 3 and each R c are independently H or C 1~2 R is alkyl; d are F, Cl, -CN, -CH 3 and -OCH 3 and each R 5 are independently -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 0-3 R g oxadiazolyl substituted with 0 to 4 R g Pyridinyl substituted with -(CH 2 ) 1~2 (0 to 4 R g -(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 NRc 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 m is 0, 1, 2 or 3; n is 0, 1 or 2). or a pharma- ceutically acceptable salt thereof.

[0043] In some embodiments, the inhibitor of DGKα and / or DGKζ is a compound of formula (I), wherein R 1 is H, F, Cl, Br, -CN, 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 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 R is alkyl; 2 is H or 0 to 2 R 2a C replaced with 1~2 alkyl; each R 2a are independently F, Cl, -CN, -OH, -O(C1~2 Alkyl), cyclopropyl, C 3~4 Alkenyl or C 3~4 Alkynyl; R 3 are H, F, Cl, Br, -CN, C 1~2 Alkyl, -CF 3 , cyclopropyl or -NO 2 ;R 4a and R 4b are 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 (C1~3 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 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; or R 4a and R 4b Together with the carbon atom to which they are attached, they form 0 to 3 R f C, each replaced by 3~6 cycloalkyl or 3- to 6-membered heterocyclyl; each R f are independently F, Cl, Br, -OH, -CN, C 1~4 Alkyl, C1~2 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 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 is cycloalkyl; each R 5 are 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 0-3 R g oxadiazolyl substituted with 0-3 R g Pyridinyl substituted with -(CH 2 ) 1~2 (0 to 4 R g -(CH 2 ) 1~2 NR c C(O)(C 1~4 alkyl), -(CH2 ) 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), or a pharma- ceutically acceptable salt thereof.

[0044] In some embodiments, the inhibitor of DGKα and / or DGKζ has the structure: [ka] [In the formula, R 1 is -CN; R 2 is -CH 3 ;R 3 is H, F or -CN; R 4 teeth, [ka] is] or a pharma- ceutically acceptable salt thereof.

[0045] In some embodiments, the inhibitor of DGKα and / or DGKζ has the structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0046] In some of any of the provided embodiments, the inhibitor of DGKα and / or DGKζ has formula (II): [ka] (II) (In the formula, R 1 is H, F, Cl, Br, -CN, -OH, 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 R1a are independently F, Cl, -CN, -OH, -OCH 3 or -NR a R a and each R a are independently H or C 1~3 alkyl; each R e is independently 3~4 Cycloalkyl or 0 to 4 R 1a C replaced with 1~3 R is alkyl; 2 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 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 ;R 4a and R 4b are 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 1~6Alkyl, 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 Rx ) 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 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, 4-10 membered heterocyclyl, monocyclic or bicyclic aryl, or 5-10 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 alkyl; or R 4a and R 4b Together with the carbon atom to which they are attached, they form 0 to 3 R f C, each replaced by 3~6 cycloalkyl or 3- to 6-membered heterocyclyl; each R f are independently F, Cl, Br, -OH, -CN, C 1~6 Alkyl, C1~3 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 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; 1~6 Alkyl or C 3~6 Cycloalkyl; R 4d -OCH 3 and each R c are independently H or C 1~2 R is alkyl; d are F, Cl, -CN, -CH 3 and -OCH 3 and each R 5 are independently -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 0-3 R goxadiazolyl substituted with 0-4 R g Pyridinyl substituted with -(CH 2 ) 1~2 (0 to 4 R g 4-10 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 m is 0, 1, 2 or 3; n is 0, 1 or 2). or a salt thereof.

[0047] In some embodiments, the inhibitor of DGKα and / or DGKζ is a compound of formula (II), wherein R 1 is H, F, Cl, Br, -CN, -OH, 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 1~3Alkoxy, -NR a R a , -S(O) n CH 3 or -P(O)(CH 3 ) 2 ;R 2 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, -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 Rc , -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 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, 4-10 membered heterocyclyl, monocyclic or bicyclic aryl, or 5-10 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 3~4substituted with 0 to 3 substituents independently selected from cycloalkyl; 1~3 alkyl; or R 4a and R 4b Together with the carbon atom to which they are attached, they form 0 to 3 R f C, each replaced by 3~6 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, -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 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 is cycloalkyl; each R 5 are 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 3~4Cycloalkyl, 0 to 3 R g Phenyl substituted with 0-3 R g oxadiazolyl substituted with 0-3 R g Pyridinyl substituted with -(CH 2 ) 1~2 (0 to 4 R g 4-10 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 m is 1, 2 or 3, or a pharma- ceutically acceptable salt thereof.

[0048] In some embodiments, the inhibitor of DGKα and / or DGKζ has the structure: [ka] (In the formula, R 1 is -CN; R 2 is -CH 3 ;R 5a is -CH 3 or -CH 2 CH 3 ;R 5c is -CH 3 , -CH 2 CH 3or -CH 2 CH 2 CH 3 is) or a pharma- ceutically acceptable salt thereof.

[0049] In some embodiments, the inhibitor of DGKα and / or DGKζ has the structure: [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0050] In some of any of the provided embodiments, the inhibitor of DGKα and / or DGKζ has the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0051] In some of any of the provided embodiments, an inhibitor of DGKα and / or DGKζ is administered in an amount, at a time, for a duration and / or at a frequency effective to result in increased antigen-specific or antigen receptor-driven activity of the engineered T cells.

[0052] In some of any of the provided embodiments, an inhibitor of DGKα and / or DGKζ is administered in an amount, at a time, for a duration and / or at a frequency effective to prevent, inhibit or delay the development of an exhausted phenotype in the engineered T cells.

[0053] In some of any of the provided embodiments, an inhibitor of DGKα and / or DGKζ is administered in an amount, at a time point, for a duration and / or at a frequency effective to at least partially reverse the exhaustion phenotype in the engineered T cells.

[0054] In some of any of the provided embodiments, the level of exhaustion of the engineered T cells expressing the recombinant receptor is determined by measuring the level of one or more exhaustion markers on the cell surface of the engineered T cells expressing the recombinant receptor.

[0055] In some of the embodiments provided, the inhibitor of DGKα and / or DGKζ is administered in an amount of 0.25 mg to 250 mg or about 0.25 mg to about 250 mg. In some of the embodiments provided, the inhibitor of DGKα and / or DGKζ is administered in an amount of 0.5 mg to 100 mg or about 0.5 mg to about 100 mg.

[0056] In some of the embodiments provided, the recombinant receptor is an engineered T cell receptor (eTCR). In some of the embodiments provided, the recombinant receptor is a chimeric antigen receptor (CAR).

[0057] In some of any of the provided embodiments, the CAR is the CAR of BREYANZI® (lisocabtagene maraleucel), TECARTUS™ (brexucabtagene autoleucel), KYMRIAH™ (tisagenleucel), YESCARTA™ (axicabtagene ciloleucel), ABECMA® (idecabtagene biculeucel), or CARVYKTI™ (ciltacabtagene autoleucel). In some of any of the provided embodiments, the CAR is the CAR of BREYANZI® (lisocabtagene maraleucel). In some of any of the provided embodiments, the CAR is the CAR of TECARTUS™ (brexucabtagene autoleucel). In some of the embodiments provided, the CAR is KYMRIAH™ (tisagenlecleucel). In some of the embodiments provided, the CAR is YESCARTA™ (axicabtagene siloleucel). In some of the embodiments provided, the CAR is CARVYKTI™ (siltacabtagene autreucel).

[0058] In some of the embodiments provided, the T cell therapy is BREYANZI® (lysocabtagene maralelucel), TECARTUS™ (brexcabtagene autreucel), KYMRIAH™ (tisagenlecleucel), YESCARTA™ (axicabtagene siloleucel), ABECMA® (idecabtagene biculeucel) or CARVYKTI™ (siltacabtagene autreucel). In some of the embodiments provided, the T cell therapy is BREYANZI® (lysocabtagene maralelucel). In some of the embodiments provided, the T cell therapy is TECARTUS™ (brexcabtagene autreucel). In some of the embodiments provided, the T cell therapy is KYMRIAH™ (tisagenlecleucel). In some of the embodiments provided, the T cell therapy is YESCARTA™ (axicabtagene siloleucel). In some of the embodiments provided, the T cell therapy is CARVYKTI™ (siltacabtagene siloleucel).

[0059] In some of the embodiments provided, the recombinant receptor binds to a target antigen associated with, specific for, and / or expressed in cells or tissues of a disease or condition. In some of the embodiments provided, the disease or condition is cancer, an autoimmune or inflammatory disease, or an infectious disease. In some of the embodiments provided, the disease or condition is cancer. In some of the embodiments provided, the disease or condition is a cancer that is a B-cell malignancy. In some embodiments, the B-cell malignancy is a leukemia, lymphoma, or myeloma. In some of the embodiments provided, the cancer is a solid tumor. In some of the embodiments provided, the cancer is a hematological (liquid) tumor.

[0060] In some of any of the provided embodiments, the dose of cells of the T cell therapy is 1×10 5 ~1×10 9 pcs or approx. 1×105 ~Approx. 1×10 9 In some of the provided embodiments, the dose of cells in the T cell therapy comprises 1×10 total recombinant receptor-expressing T cells (inclusive). 5 ~5×10 8 pcs or approx. 1×10 5 ~Approx. 5×10 8 Total recombinant receptor-expressing T cells, 1 x 10 6 ~2.5×10 8 pcs or approx. 1×10 6 ~Approx. 2.5×10 8 Total recombinant receptor-expressing T cells, 5 x 10 6 ~1×10 8 Pieces or about 5 x 10 6 ~Approx. 1×10 8 Total recombinant receptor-expressing T cells, 1 x 10 7 ~2.5×10 8 pcs or approx. 1×10 7 ~Approx. 2.5×10 8 total recombinant receptor-expressing T cells or 5 x 10 7 ~1×10 8 Pieces or about 5 x 10 7 ~Approx. 1×10 8 In some of the provided embodiments, the dose of cells in the T cell therapy is 1.5×10 7 ~6×10 8 pcs or approx. 1.5 x 10 7 ~Approx. 6×10 8 Total recombinant receptor-expressing T cells, 1.5 x 10 8 ~6×10 8 pcs or approx. 1.5 x 10 8 ~Approx. 6×10 8 total recombinant receptor-expressing T cells or 1.5 x 10 8 ~4.5×10 8 pcs or approx. 1.5 x 10 8 ~Approx. 4.5×10 8 total recombinant receptor-expressing T cells (upper and lower limits included).

[0061] In some of any of the provided embodiments, the dose of T cell therapy cells is administered parenterally, optionally intravenously. In some of any of the provided embodiments, the dose of T cell therapy cells is administered intravenously.

[0062] In some of any of the provided embodiments, the T cell therapy includes primary T cells obtained from the subject. In some of any of the provided embodiments, the T cells of the T cell therapy are autologous to the subject. In some of the provided embodiments, the T cells of the T cell therapy are allogeneic to the subject.

[0063] In some of any of the provided embodiments, the T cell therapy includes T cells that are CD4+ or CD8+. In some of any of the provided embodiments, the T cell therapy includes T cells that are CD4+ and CD8+. In some of any of the provided embodiments, the T cell therapy includes T cells that are CD4+ and T cells that are CD8+.

[0064] In some of any of the provided embodiments, the method further comprises administering to the subject a checkpoint antagonist. In some of any of the provided embodiments, the checkpoint antagonist is an antagonist of the PD1 / PD-L1 axis. In some of the provided embodiments, the checkpoint antagonist is an antagonist of CTLA4.

[0065] In some of any of the provided embodiments, the methods further include administering to the subject an antagonist of the PD1 / PD-L1 axis and an antagonist of CTLA4.

[0066] In some of any of the provided embodiments, the antagonist of the PD1 / PD-L1 axis is an antagonist of human PD1. In some of any of the provided embodiments, the antagonist of human PD-1 is nivolumab, pembrolizumab, or any other PD-1 antagonist described herein. In some of any of the provided embodiments, the antagonist of human PD-1 is nivolumab or a variant thereof.

[0067] In some of any of the provided embodiments, the antagonist of the PD1 / PD-L1 axis is an antagonist of human PD-L1. In some of any of the provided embodiments, the antagonist of human PD-L1 is atezolizumab or any other PD-L1 antagonist described herein.

[0068] In some of the embodiments provided, the antagonist of CTLA4 is an antagonist of human CTLA4. In some of the embodiments provided, the antagonist of human CTLA4 is ipilimumab or any other CTLA4 antagonist described herein. In some of the embodiments provided, the antagonist of human CTLA4 is ipilimumab or a variant thereof, optionally a variant with reduced toxicity compared to ipilimumab. In some of the embodiments provided, the antagonist of human CTLA4 is a variant of ipilimumab with reduced toxicity compared to ipilimumab.

[0069] In some of any of the provided embodiments, administration of the checkpoint antagonist is initiated on the same day as administration of the inhibitor of DGKα and / or DGKζ.

[0070] In some of any of the provided embodiments, the inhibitor of DGKα and / or DGKζ and optionally the checkpoint antagonist are administered for a period of up to 3 months after initiation of administration of T cell therapy. In some of any of the provided embodiments, the inhibitor of DGKα and / or DGKζ and optionally the checkpoint antagonist are administered for a period of up to 6 months after initiation of administration of T cell therapy.

[0071] In some of any of the provided embodiments, the inhibitor of DGKα and / or DGKζ and the checkpoint antagonist are administered for a period of up to 3 months after initiation of administration of T cell therapy. In some of any of the provided embodiments, the inhibitor of DGKα and / or DGKζ and the checkpoint antagonist are administered for a period of up to 6 months after initiation of administration of T cell therapy.

[0072] In some of any of the provided embodiments, at the end of the period, if the subject exhibits a complete response (CR) after treatment or the disease or condition progresses or relapses following remission after treatment, the inhibitor of DGKα and / or DGKζ and, optionally, the checkpoint antagonist are discontinued. In some of any of the provided embodiments, at the end of the period, if the subject exhibits a complete response (CR) after treatment or the disease or condition progresses or relapses following remission after treatment, the inhibitor of DGKα and / or DGKζ and the checkpoint antagonist are discontinued.

[0073] In some of any of the provided embodiments, at the end of the period, if the subject shows a complete response (CR) after treatment or the cancer progresses or recurs following remission after treatment, the inhibitor of DGKα and / or DGKζ and optionally the checkpoint antagonist are discontinued. In some of any of the provided embodiments, at the end of the period, if the subject shows a complete response (CR) after treatment or the cancer progresses or recurs following remission after treatment, the inhibitor of DGKα and / or DGKζ and the checkpoint antagonist are discontinued. [Brief description of the drawings]

[0074] [Figure 1A] Figure 1A and Figure 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 (with vs. without 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 (with vs. without compound 17) following stimulation with a CAR-specific anti-idiotypic antibody at 3 μg / mL (left panel) or 30 μg / mL (right panel). In Figure 1A and Figure 1B, positive values ​​are indicated by circles. [Figure 1B]Figure 1A and Figure 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 (with vs. without 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 (with vs. without compound 17) following stimulation with a CAR-specific anti-idiotypic antibody at 3 μg / mL (left panel) or 30 μg / mL (right panel). In Figure 1A and Figure 1B, positive values ​​are indicated by circles. [Diagram 2] FIG. 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. [Diagram 3] Figure 3 shows the percent of 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 (middle 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) during 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 h of 2D co-culture 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-B and 8A-B show 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) during 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 normalized tumor volumes of A549.CD19 (left panel) and Granta-519 tumor spheroids (right panel) on 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] Figure 9B and Figure 10 show the cytolytic activity and proliferation of chronically stimulated T cells expressing engineered T cell receptors (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, shown 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. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0075] Provided herein is a combination therapy for use in treating a disease or condition, involving administration of a DGK inhibitor with T cell therapy 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, where the cells are engineered with a recombinant receptor (e.g., CAR or eTCR) that targets the antigen. In some embodiments, the disease or condition can 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 selected from compounds 1-34, a compound of formula (I) or (II), or a pharma- ceutically acceptable salt thereof. 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.

[0076] T cell-based therapies, such as adoptive T cell therapy (including those 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 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).

[0077] In certain circumstances, the available approaches for 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 (CR) have been observed in subjects with NHL compared to subjects with ALL. More specifically, higher overall response rates of up to 80% (CR rate 47%-60%) have been reported after CAR T cell infusion, but responses in some cases were shown to be transient and subjects relapsed 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).

[0078] In some embodiments, the explanation for this is the immunological exhaustion of circulating T cells, e.g., CAR-expressing T cells, and / or the change in T lymphocyte populations of T cell therapy. In some circumstances, optimal efficacy may depend on the ability of administered cells to recognize, bind to, and successfully transport to, localize and enter into the appropriate site within the subject, tumor and its environment. In some circumstances, optimal efficacy may depend on the ability of administered cells to become activated, to increase, to exert various effector functions, including cytotoxic killing and secretion of various factors such as cytokines, to persist, including long-term, to differentiate into, transition to or engage in reprogramming of a certain phenotypic state (such as long-lived memory, low differentiation and effector state), to avoid or reduce the immunosuppressive state in the local microenvironment of the disease, to produce an effective and robust recall response after clearance and reexposure to target ligand or antigen, and to avoid or reduce exhaustion, anergy, peripheral tolerance, terminal differentiation and / or differentiation into suppressive state.

[0079] In some embodiments, the exposure and persistence of engineered cells of T cell therapy is reduced or diminished after administration to a subject. Nevertheless, observations indicate that in some cases, increasing the exposure of a subject to administered cells expressing recombinant receptors (e.g., increasing the number or duration of cells over time) can improve efficacy and therapeutic outcomes in adoptive cell therapy. Preliminary analysis conducted after administration of different CD19-targeting CAR-expressing T cells to subjects with various CD19-expressing cancers in multiple clinical trials revealed a correlation between a greater and / or longer degree of exposure to CAR-expressing cells and therapeutic outcomes. Such outcomes include patient survival and remission, even in individuals with severe or significant tumor burden.

[0080] In some embodiments, after long-term stimulation or exposure to antigen and / or exposure under conditions in tumor microenvironment, T cells can become hypofunctional and / or show characteristics associated with exhausted state over time.In some aspects, this reduces the persistence and effectiveness of T cells against antigen and limits their ability to be effective.In particular, there is a need for methods to improve the effectiveness and function of T cells, such as CAR-expressing T cells or eTCR-expressing T cells, in T cell therapy, to minimize, reduce, prevent or reverse hypofunctional or exhausted state.

[0081] Diacylglycerol kinase (DGK) is a lipid kinase that mediates the conversion of diacylglycerol to phosphatidic acid, thereby terminating T cell function propagated through the TCR signaling pathway. Thus, DGK functions as an intracellular checkpoint, and inhibition of DGK is expected to enhance T cell signaling pathway and T cell activation. Supporting evidence includes knockout mouse models of either DGKα or DGKζ, which show 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 were observed to overexpress DGKα, which resulted in inhibited T cell function (Prinz, PU et al., J Immunology (2012) 12:5990-6000). Thus, 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).

[0082] The provided methods are based on the observation that DGKi, such as the exemplary compound 17 described herein, 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. It is found that such methods and uses provide or achieve improved or better T cell functionality and, thus, improved anti-tumor efficacy.

[0083] In addition to enhancing T cell function, it is also found herein that such DGKi, e.g., compound 17, exhibits the effect of reversing, delaying or preventing T cell exhaustion, including by increasing T cell signaling and / or modifying one or more genes that are differentially regulated after chronic (long-term) stimulation.Thus, it is found herein that the activity of such DGKi, e.g., compound 17, exerting an enhancing effect on T cell activity is uncoupled from T cell exhaustion, although in some cases, agents that increase or enhance T cell activity can drive cells into an exhausted state.In some embodiments, the provided methods involving compound administration of such DGKi, e.g., compound 17, can enhance the activity of T cells and delay, limit, reduce, inhibit or prevent exhaustion.

[0084] Furthermore, the observations herein show that DGKi, e.g., compound 17, exhibit activity to rescue 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 show that exposure of chronically stimulated T cells exhibiting characteristics of exhausted T cells to DGKi described herein, such as compound 17, can revive activity or restore or partially restore the activity. The observations herein support that the methods provided can also achieve improved or more durable responses, such as in certain groups of treated subjects, compared to certain alternative methods.

[0085] 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 evaluate the impact of DGKi such as compound 17 on the function of 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 show that subsequent exposure to a DGKi, e.g., compound 17, can rescue or restore T cell function, including cytokine production and cytolytic activity, of exhausted T cells. Furthermore, results were observed with different recombinant antigen receptors, including CAR and eTCR.

[0086] 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 pharma- ceutically acceptable salt thereof, such as a compound selected from compounds 1-34, in methods involving T cell therapy, such as involving administration of a composition of engineered T cells, achieves improved function of the T cell therapy, such as by 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 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 a T cell therapy (e.g., CAR T cells or eTCR T cells) and a DGKi of a compound that is 4-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile or a stereoisomer thereof. In some embodiments, the combination therapy involves administration or use of a T cell therapy (e.g., CAR T cells or eTCR T cells) and a DGKi that is 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.

[0087] 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 was incorporated herein by individual reference. To the extent that the definitions set forth herein are contrary to or otherwise inconsistent with the definitions set forth in the patents, applications, published applications and other publications incorporated herein by reference, the definitions set forth herein take precedence over the definitions incorporated herein by reference.

[0088] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0089] I. Combination Therapy In some embodiments, provided herein is a method of treatment 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).

[0090] In some embodiments, the DGK inhibitor, for example, an inhibitor of DGKα and / or DGKζ, is administered before T cell therapy, for example, the initiation of administration of the inhibitor is performed, accomplished, or occurs before the initiation of administration of the T cell therapy. In some embodiments, the DGK inhibitor, for example, an inhibitor of DGKα and / or DGKζ, is administered simultaneously with T cell therapy, for example, the initiation of administration of the inhibitor is performed, accomplished, or occurs simultaneously with administration of the T cell therapy. In some embodiments, the DGK inhibitor, for example, an inhibitor of DGKα and / or DGKζ, is administered after T cell therapy, for example, the initiation of administration of the inhibitor is performed, accomplished, or occurs after the initiation of administration of the T cell therapy.

[0091] In some embodiments, also provided herein is a method of treatment comprising administering an inhibitor of DGK to a subject having a disease or condition. In some embodiments, also provided herein is a method of 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 is a method of 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 been administered cell therapy, e.g., T cell therapy, for the treatment of a disease or condition.

[0092] Combination therapies, including engineered cells expressing recombinant receptors such as chimeric antigen receptors (CARs) and DGK inhibitors, or compositions comprising engineered cells and / or DGK inhibitors as described herein, are useful in a variety of therapeutic, diagnostic and prophylactic indications. For example, the combinations are useful in treating a variety of diseases and disorders in subjects. Such methods and uses include therapeutic methods and uses involving administration of a composition comprising engineered cells, DGK inhibitors, and / or one or both to a subject having a disease, condition or disorder, such as a tumor or cancer. In some embodiments, the composition comprising engineered cells, DGK inhibitors, and / or one or both is administered in an effective amount to effect treatment of the disease or disorder. Uses include the use of compositions comprising engineered cells, DGK inhibitors, and / or 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 a composition comprising engineered cells, DGK inhibitors, and / or 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.

[0093] The disease or condition to be treated may be one in which the expression of an antigen is associated with and / or involved in the etiology of the disease or condition, e.g., the antigen expression causes, exacerbates or is otherwise involved in such disease or condition. Exemplary diseases and conditions include diseases or conditions associated with malignant lesions or transformation of cells (e.g., cancer), autoimmune or inflammatory diseases, or infectious diseases caused, e.g., by 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.

[0094] In some embodiments, the disease or condition includes tumors, including solid tumors, hematological malignancies and melanomas, and including localized and metastatic tumors, infectious diseases, such as infections with 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's lymphoma, Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), anaplastic large cell lymphoma (ALCL), follicular lymphoma, refractory follicular lymphoma, diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM).

[0095] 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 transformed from low grade), 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).

[0096] 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.

[0097] In some embodiments, the disease or condition is an infectious disease or condition, including, but not limited to, viral, retroviral, bacterial and protozoan infections, immunodeficiencies, 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 I diabetes, systemic lupus erythematosus (SLE), inflammatory bowel disease, psoriasis, scleroderma, autoimmune thyroid disease, Graves' disease, Crohn's disease, multiple sclerosis, asthma, and / or transplant-related diseases or conditions.

[0098] 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 or a solid tumor. In some embodiments, the disease or disorder is a pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular 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 a bladder, lung, brain, melanoma (e.g., small cell lung, melanoma), breast, cervical, ovarian, colorectal, pancreatic, endometrial, esophageal, kidney, liver, prostate, skin, thyroid or uterine 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 cancer, bone cancer, or soft tissue sarcoma.

[0099] 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 B2, cyclin D2, cyclin D3, cyclin D4, cyclin D5, cyclin D6, cyclin D7, cyclin D8, cyclin D9, cyclin D10, cyclin D11, cyclin D22, cyclin D12, cyclin D13, cyclin D24, cyclin D15, cyclin D25, cyclin D16, cyclin D26, cyclin D17, cyclin D28, cyclin D3, cyclin D40, cyclin D18, cyclin D29, cyclin D21, cyclin D22, cyclin D19, cyclin D22, cyclin D15, cyclin D25, cyclin D15, cyclin D27, cyclin D19, cyclin D28, cyclin D15, cyclin D29, cyclin D14, cyclin D25, cyclin D15, cyclin D26, cyclin D15, cyclin D27, cyclin D15, cyclin D29, cyclin D16, cyclin D17, cyclin D27, cyclin D18, cyclin D19, cyclin D29, cyclin D14, cyclin D15, cyclin D27, cyclin D1 , 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 protein (EGFR), epidermal growth factor receptor type III mutation (EGFR 1). 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 (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.

[0100] In some embodiments, the disease or condition is a B-cell malignancy. In some embodiments, the disease or condition is a 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 transformed from low grade), 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 any of such embodiments, the disease or condition has relapsed or is refractory to one or more previous treatments (relapsed or refractory disease; R / R). In some aspects, the recombinant receptor, e.g., CAR or TCR, specifically binds to an antigen associated with the disease or condition or an antigen expressed in cells in the environment of the lesion associated with the B cell malignancy. The antigen targeted by the receptor, in some embodiments, includes an antigen associated with the 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, the antigen, in some embodiments, is BAFF-R and the CAR is as described in Qin et al., Science Translational Medicine 11 (511): eaaw9414 (2019). In some embodiments, the antigen targeted by the receptor is CD19.For example, the recombinant receptor can be a CAR that is axicabtagene siloleucel (Yescarta), tisagenlecleucel (Kymriah), or lysocabtagene maraleucel (Breyanzi) CAR. In some embodiments, the recombinant receptor can be a CAR that is a TECARTUS™ (brexcabtagene autreucel) CAR. In some embodiments, the T cell therapy, e.g., anti-CD19 CAR T cell therapy, is axicabtagene siloleucel (Yescarta), tisagenlecleucel (Kymriah), lysocabtagene maraleucel (Breyanzi), or TECARTUS™ (brexcabtagene autreucel).

[0101] 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 not otherwise specified (DLBCL) (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 lysocabtagene 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 lysocabtagene maraleucel (Breyanzi, see Sehgal et al., 2020, Journal of Clinical Oncology 38:15_suppl, 8040; Teoh et al., 2019, Blood 134(Supplement_1):593; and Abramson et al., 2020, The Lancet 396(10254): 839-852).

[0102] 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 a 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 autorucel, see Mian and Hill, 2021, Expert Opin Biol Ther; 21(4):435-441; and Wang et al., 2021, Blood 138(Supplement 1):744).

[0103] 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 CAR of tisagenlecleucel (Kymriah). In some embodiments, the T cell therapy is an anti-CD19 CAR T cell therapy. In some embodiments, the anti-CD19 CAR T cell therapy is tisagenlecleucel (Kymriah, see Bishop et al., 2022, N Engl J Med 386:629:639; Schuster et al., 2019, N Engl J Med 380:45-56; Halford et al., 2021, Ann Pharmacother 55(4):466-479; Mueller et al., 2021, Blood Adv. 5(23):4980-4991; and Fowler et al., 2022, Nature Medicine 28:325-332).

[0104] In some embodiments, the disease or condition is a B cell lymphoma. In some embodiments, the B cell lymphoma is a relapsed or refractory B cell lymphoma. In some embodiments, the B cell lymphoma is a diffuse large B cell lymphoma (DLBCL), a primary mediastinal B cell lymphoma, a high-grade B cell lymphoma, a DLBCL resulting from follicular lymphoma, or a 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 an axicabtagene silol-eucel (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).

[0105] 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 comprises 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 No. 8,153,765; U.S. Patent No. 8,603477, U.S. Patent No. 8,008,450; U.S. Publication No. US20120189622 or U.S. Patent No. US20100260748; and / or International PCT Publication No. WO2006099875, WO2009080829 or WO2012092612 or WO2014210064. In some embodiments, such antibodies or antigen-binding fragments thereof (e.g., scFv) are contained in a multispecific antibody, a multispecific chimeric receptor, such as a multispecific CAR and / or a multispecific cell.

[0106] 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® (idecabutagen-bikurueucel) or CARVYKTI™ (siltacabtagene-autorueucel) CAR, e.g., an anti-BCMA CAR. In some embodiments, the T cell therapy, e.g., anti-BCMA CAR T cell therapy, is ABECMA® (idecabutagen-carbeucel) or CARVYKTI™ (siltacbutagen-autolucel).

[0107] 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™ (siltacavtagene autrucel) 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™ (siltacavtagene autrucel, see Berdeja et al., Lancet. 2021 Jul 24;398(10297):314-324; and Martin, Abstract #549 [Oral], presented at 2021 American Society of Hematology (ASH) Annual Meeting & Exposition).

[0108] 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).

[0109] 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., CAR or TCR, specifically binds to an antigen associated with CLL, e.g., specifically binds to ROR1.

[0110] 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., 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.

[0111] 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., 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.

[0112] 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., 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).

[0113] 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., 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).

[0114] 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., 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).

[0115] 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. Administration of AT cell therapy

[0116] In some aspects, the methods provided herein include combination therapy by administering a cell therapy, e.g., T cell therapy, to a subject having a disease or condition, such as any disease or condition described above, in combination with a DGK inhibitor. In some aspects, the methods provided herein include administering a DGK inhibitor to a subject in combination with (e.g., before, simultaneously with, or after) administration of a cell therapy, e.g., T cell therapy. In some embodiments, the methods provided include administering a DGK inhibitor to a subject who has previously been administered a cell therapy, e.g., T cell therapy, for treatment of a disease or condition. In some embodiments, the cell therapy, e.g., T cell therapy, is administered to the subject prior to administration of a DGKi to the subject. In some embodiments, the cell therapy, e.g., T cell therapy and the DGKi are administered simultaneously.

[0117] In some embodiments, the cell therapy is a T cell therapy. The 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, the 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, the 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. The T cell therapy for use in the provided methods includes any of a variety of CAR-expressing or eTCR-expressing T cells. It is within the level of skill of one of ordinary skill in the art to select an appropriate recombinant receptor (e.g., CAR or eTCR)-expressing T cell therapy to treat a disease or condition. Examples of T cell therapies including CAR-expressing T cells and eTCR-expressing T cells are described in Section II. In some embodiments, the T cells of the T cell therapy are allogeneic to the subject being treated. In some embodiments, the T cells of the T cell therapy are autologous to the subject being treated.

[0118] Methods for administering cells for adoptive cell therapy are known and can be used in connection with the provided methods, compositions and articles of manufacture and kits.For example, methods for adoptive T cell therapy are 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).See, for example, 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.

[0119] 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 who is to receive cell therapy or from a sample derived from such a subject. Thus, in some aspects, cells are derived from a subject, e.g., a patient, in need of treatment, and the cells are administered to the same subject after isolation and processing.

[0120] In some embodiments, cell therapy, for example, adoptive T cell therapy, is carried out by allogeneic transfer, whereby cells are isolated and / or otherwise prepared from a subject other than the subject that is to receive or will eventually receive cell therapy, for example, a first subject. In such an embodiment, the cells are then administered to a different subject of the same species, for example, 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.

[0121] 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 number or relative number of cells or engineered cells, and / or two or more subtypes of a defined ratio or composition within a composition, such as CD4 vs. CD8 T cells.

[0122] The cells can be administered by any suitable means, for example, by bolus injection, injection, for example, intravenous or subcutaneous injection, intraocular injection, periocular injection, subretinal injection, intravitreal injection, transseptal injection, subscleral injection, intrachoroidal injection, intracameral injection, subconjectval injection, subconjuntival injection, sub-Tenon injection, retrobulbar injection, peribulbar injection, or posterior juxtascleral delivery. In some embodiments, the cells are administered parenterally, intrapulmonary and intranasally, and, if desired for localized treatment, intralesional administration. Parenteral injection includes 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, 3 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.

[0123] For treatment of disease, the appropriate dosage may 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 attending physician. The compositions and cells, in some embodiments, are suitably administered to the subject at one time or over a series of treatments.

[0124] After administration of the cells, the biological activity of the engineered cell population is measured in some embodiments, for example, 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, for example, by imaging, or ex vivo, for example, 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, for example, cytotoxicity assays as 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, the biological activity is measured by evaluating clinical outcomes, such as reduction in tumor burden or burden.

[0125] 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 methods provided, such as in the prevention or treatment of diseases, conditions, and disorders.

[0126] In some embodiments, T cell therapy, such as engineered T cells (e.g., CAR or TCR T cells), is formulated with a pharma- ceutically 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. Thus, there are a variety of suitable formulations. 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, by Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed and may include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; 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).

[0127] A buffering agent is included in the composition in some embodiments. 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 mixtures thereof are typically present in an amount of about 0.001% to about 4% by weight of the total composition. Methods for preparing administrable pharmaceutical compositions are known. Exemplary methods are described in more detail, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins; 21st ed. (May 1, 2005).

[0128] The formulation may include 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 cell 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 other pharmacologic active agents or drugs, such as chemotherapeutic agents, for example, asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine, vincristine, etc.

[0129] The pharmaceutical composition, in some embodiments, contains cells in an amount effective for treating or preventing a disease or condition, such as a therapeutically effective or prophylactically effective amount. The therapeutic or prophylactic effectiveness is, in some embodiments, 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 regimes may be useful and can be determined. The desired dosage can be delivered by a single bolus administration of the composition, by multiple boluses of the composition, or by continuous infusion administration of the composition.

[0130] The cells can be administered using standard administration techniques, formulations and / or devices. Formulations and devices such as syringes and vials are provided for the storage and administration of the compositions. With respect to cells, administration can be autologous or xenogeneic. For example, immunoresponsive cells or precursors can be obtained from one subject and administered to the same subject or to a different compatible subject. Peripheral blood-derived immunoresponsive cells or their progeny (e.g., from 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).

[0131] Formulations include formulations 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 the subject using peripheral systemic delivery by intravenous, intraperitoneal, or subcutaneous injection.

[0132] The composition is provided in some embodiments as a sterile liquid preparation, for example, an isotonic aqueous solution, suspension, emulsion, dispersion or viscous composition, which in some aspects may be buffered to a selected pH. Liquid preparations are usually easier to prepare than gels, other viscous compositions and solid compositions. Moreover, liquid compositions are somewhat more convenient to administer, especially by injection. Viscous compositions, on the other hand, can be formulated within an appropriate viscosity range to provide longer contact periods with specific tissues. Liquid or viscous compositions can include carriers that can be solvents or dispersion media, including, for example, water, saline, phosphate buffered saline, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol) and suitable mixtures thereof.

[0133] 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, etc. The composition may 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, etc., depending on the desired route of administration and preparation. Standard texts can be consulted in some aspects to prepare suitable preparations.

[0134] Various additives that enhance the stability and sterility of the composition can be added, including antimicrobial preservatives, antioxidants, chelating agents and buffers. Prevention of microbial action can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents that delay absorption, such as aluminum monostearate and gelatin.

[0135] The formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, for example, by filtration through sterile filtration membranes.

[0136] For prevention or treatment of disease, the appropriate dosage may depend on the type of disease to be 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.

[0137] In some cases, the cell therapy is administered as a single pharmaceutical composition comprising cells. In some embodiments, a given dose is administered by a single bolus of cells or agent. In some embodiments, it is administered by multiple boluses of cells or agent over a period of, for example, 3 days or less, or by continuous infusion of cells or agent.

[0138] In some embodiments, the dose of cells is administered to the subject in accordance with the method of combination therapy provided.In some embodiments, the size or timing of the dose is determined as a function of the specific disease or condition in the subject.Given the explanation provided, the size or timing of the dose for a specific disease can be empirically determined.

[0139] 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 the subject's 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). or a range defined by any two of the above 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 above 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, or a range defined by any two of the above values). 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 preceding 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 about 450 million cells, about 650 million cells, about 800 million cells, about 900 million cells, about 3 billion cells, about 30 billion cells, about 45 billion cells), about 10 million to about 600 million cells, about 100 million to about 600 million cells, about 100 million to about 450 million cells, about 150 million cells to about 300 million or 450 million cells, or any value between these ranges, and / or per kilogram of the subject's body weight. Dosages may vary depending on the disease or disorder and / or the specific characteristics of the 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.

[0140] In some embodiments, the cell therapy comprises 1×105 ~1×10 8 pcs or approx. 1×10 5 ~Approx. 1×10 8 Total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs), 5 x 10 5 ~1×10 7 Pieces or about 5 x 10 5 ~Approx. 1×10 7 total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs), or 1 x 10 6 ~1×10 7 pcs or approx. 1×10 6 ~Approx. 1×10 7 In some embodiments, the cell therapy comprises administration of a dose comprising at least 1×10 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs) cell numbers, each including upper and lower limits. In some embodiments, the cell therapy comprises administration of at least 1×10 5 or at least about 1 x 10 5 10 total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs), e.g., at least 1×10 6 or at least about 1 × 10 6 , at least 1 × 10 7 or at least about 1 × 10 7 , at least 1 × 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.

[0141] In some embodiments, for example, when the subject is a human, the dose is about 5×10 8 Fewer than about 1 x 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 Such cells in the range of, for example, 2 x 10 6 , 5×10 6 , 1×10 7 , 5×10 7 , 1×10 8 Or 5 x 10 8 1 such cells, or a range between any two of the preceding values.

[0142] In some embodiments, the numbers refer to the total number of CD3+ or CD8+, and in some cases, recombinant receptor-expressing (e.g., TCR+ or CAR+) cells. In some embodiments, the cell therapy is administered at a concentration of 1×10 5 ~1×10 8 pcs or approx. 1×10 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 about 5 x 10 5 ~Approx. 1×10 7 10 CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells, or 1 x 10 6 ~1×10 7 pcs or approx. 1×10 6 ~Approx. 1×10 7 In some embodiments, the cell therapy comprises administering a dose comprising a cell count of 1×10 CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells, each inclusive. 5 ~1×10 8 pcs or approx. 1×10 5 ~Approx. 1×10 8 Total CD3+ / CAR+ or CD8+ / CAR+ cells, 5×10 5 ~1×10 7 Pieces or about 5 x 10 5 ~Approx. 1×10 7 total CD3+ / CAR+ or CD8+ / CAR+ cells, or 1 × 10 6 ~1×10 7 pcs or approx. 1×10 6 ~Approx. 1×10 7 The method includes administering a dose containing a total CD3+ / CAR+ or CD8+ / CAR+ cell count (upper and lower limits included, respectively).

[0143] In some embodiments, the dose of engineered cells is 1×10 5 ~5×10 8 Total recombinant receptor-expressing T cells, 1 x 105 ~2.5×10 8 Total recombinant receptor-expressing T cells, 1 x 10 5 ~1×10 8 Total recombinant receptor-expressing T cells, 1 x 10 5 ~5×10 7 Total recombinant receptor-expressing T cells, 1 x 10 5 ~2.5×10 7 Total recombinant receptor-expressing T cells, 1 x 10 5 ~1×10 7 Total recombinant receptor-expressing T cells, 1 x 10 5 ~5×10 6 Total recombinant receptor-expressing T cells, 1 x 10 5 ~2.5×10 6 Total recombinant receptor-expressing T cells, 1 x 10 5 ~1×10 6 Total recombinant receptor-expressing T cells, 1 x 10 6 ~5×10 8 Total recombinant receptor-expressing T cells, 1 x 10 6 ~2.5×10 8 Total recombinant receptor-expressing T cells, 1 x 10 6 ~1×10 8 Total recombinant receptor-expressing T cells, 1 x 10 6 ~5×10 7 Total recombinant receptor-expressing T cells, 1 x 10 6 ~2.5×10 7 Total recombinant receptor-expressing T cells, 1 x 10 6 ~1×10 7 Total recombinant receptor-expressing T cells, 1 x 10 6 ~5×10 6 Total recombinant receptor-expressing T cells, 1 x 10 6 ~2.5×10 6 Total recombinant receptor-expressing T cells, 2.5 x 10 6 ~5×10 8 Total recombinant receptor-expressing T cells, 2.5 x 10 6 ~2.5×10 8 Total recombinant receptor-expressing T cells, 2.5 x 10 6 ~1×10 8 Total recombinant receptor-expressing T cells, 2.5 x 10 6 ~5×10 7Total recombinant receptor-expressing T cells, 2.5 x 10 6 ~2.5×10 7 Total recombinant receptor-expressing T cells, 2.5 x 10 6 ~1×10 7 Total recombinant receptor-expressing T cells, 2.5 x 10 6 ~5×10 6 Total recombinant receptor-expressing T cells, 5 x 10 6 ~5×10 8 Total recombinant receptor-expressing T cells, 5 x 10 6 ~2.5×10 8 Total recombinant receptor-expressing T cells, 5 x 10 6 ~1×10 8 Total recombinant receptor-expressing T cells, 5 x 10 6 ~5×10 7 Total recombinant receptor-expressing T cells, 5 x 10 6 ~2.5×10 7 Total recombinant receptor-expressing T cells, 5 x 10 6 ~1×10 7 Total recombinant receptor-expressing T cells, 1 x 10 7 ~5×10 8 Total recombinant receptor-expressing T cells, 1 x 10 7 ~2.5×10 8 Total recombinant receptor-expressing T cells, 1 x 10 7 ~1×10 8 Total recombinant receptor-expressing T cells, 1 x 10 7 ~5×10 7 Total recombinant receptor-expressing T cells, 1 x 10 7 ~2.5×10 7 Total recombinant receptor-expressing T cells, 2.5 x 10 7 ~5×10 8 Total recombinant receptor-expressing T cells, 2.5 x 10 7 ~2.5×10 8 Total recombinant receptor-expressing T cells, 2.5 x 10 7 ~1×10 8 Total recombinant receptor-expressing T cells, 2.5 x 10 7 ~5×10 7 Total recombinant receptor-expressing T cells, 5 x 10 7 ~5×10 8 Total recombinant receptor-expressing T cells, 5 x 107 ~2.5×10 8 Total recombinant receptor-expressing T cells, 5 x 10 7 ~1×10 8 Total recombinant receptor-expressing T cells, 1 x 10 8 ~5×10 8 Total recombinant receptor-expressing T cells, 1 x 10 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 an approximation thereof.

[0144] In some embodiments, the dose of engineered cells is at least 1×10 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 × 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 × 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 × 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 The antibody comprises a TCR- or CAR-expressing cell.

[0145] 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.

[0146] In some embodiments, the dose of engineered cells is at least 1×10 5 or at least about 1×10 5 Recombinant receptor-expressing cells, at least 2.5 x 10 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 Recombinant receptor-expressing cells, at least 2.5 x 10 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 7Recombinant receptor-expressing cells, at least 2.5 x 10 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 Recombinant receptor-expressing cells, at least 2.5 x 10 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.

[0147] In some embodiments, the cell therapy comprises 1×10 5 ~1×10 8 5 x 10 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs) or approximately 5 ~1×10 7 or approximately 1 x 10 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs) 6 ~1×10 7 In some embodiments, the cell therapy comprises administration of a dose comprising at or about 1×10 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMC) cells, each inclusive. In some embodiments, the cell therapy comprises administration of at least or about at least 1×10 5 10 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 × 10 7 , at least or about at least 1 × 10 8 The method includes administering a dose of cells comprising a cell number of such cells.

[0148] In some embodiments, for example, when the subject is a human, the dose is about 5×10 8Fewer than about 1 x 10 total recombinant receptor (e.g., CAR or TCR) expressing cells, T cells or peripheral blood mononuclear cells (PBMCs), for example, about 1 x 10 6 ~5×10 8 Such cells in the range of, for example, 2 x 10 6 , 5×10 6 , 1×10 7 , 5×10 7 , 1×10 8 Or 5 x 10 8 1 such cells, or a range between any two of the preceding values.

[0149] In some embodiments, the numbers refer to total numbers 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 of 1×10 5 ~1×10 8 pcs or approx. 1×10 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 about 5 x 10 5 ~Approx. 1×10 7 10 CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells, or 1 x 10 6 ~1×10 7 pcs or approx. 1×10 6 ~Approx. 1×10 7 In some embodiments, the cell therapy comprises administering a dose comprising a cell count of 1×10 CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells, each inclusive. 5 ~1×10 8 pcs or approx. 1×10 5 ~Approx. 1×10 8 Total CD3+ / recombinant receptor+ or CD8+ / recombinant receptor+ cells, 5 × 10 5 ~1×10 7 Pieces or about 5 x 10 5 ~Approx. 1×10 7total CD3+ / recombinant receptor+ or CD8+ / recombinant receptor+ cells, or 1 x 10 6 ~1×10 7 pcs or approx. 1×10 6 ~Approx. 1×10 7 This includes administration of a dose containing a cell count of 10 total CD3+ / recombinant receptor+ or CD8+ / recombinant receptor+ cells (upper and lower limits of each).

[0150] In some embodiments, the cell therapy comprises 1×10 5 ~5×10 8 pcs or approx. 1×10 5 ~Approx. 5×10 8 Total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs), 5 x 10 5 ~1×10 7 Pieces or about 5 x 10 5 ~Approx. 1×10 7 total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs), or 1 x 10 6 ~1×10 7 pcs or approx. 1×10 6 ~Approx. 1×10 7 In some embodiments, the cell therapy comprises administration of a dose comprising at least about 1×10 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs) cell numbers, each including upper and lower limits. In some embodiments, the cell therapy comprises administration of at least about 1×10 5 10 total recombinant receptor-expressing cells, total T cells or total peripheral blood mononuclear cells (PBMCs), e.g., at least 1×10 6 or at least about 1 x 10 6 Pieces, at least 1 × 10 7 or at least about 1 x 10 7 Pieces, at least 1 × 10 8 or at least about 1 x 10 8 The present invention includes administering a dose of cells comprising a cell number 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 cell therapy comprises administering a dose of cells comprising a cell number of 1×10 5 ~5×10 8pcs or approx. 1×10 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 about 5 x 10 5 ~Approx. 1×10 7 10 CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells, or 1 x 10 6 ~1×10 7 pcs or approx. 1×10 6 ~Approx. 1×10 7 In some embodiments, the cell therapy comprises administering a dose comprising a cell count of 1×10 CD3+ or CD8+ total T cells or CD3+ or CD8+ recombinant receptor-expressing cells, each inclusive. 5 ~5×10 8 pcs or approx. 1×10 5 ~Approx. 5×10 8 Total CD3+ / recombinant receptor+ or CD8+ / recombinant receptor+ cells, 5 × 10 5 ~1×10 7 Pieces or about 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 pcs or approx. 1×10 6 ~Approx. 1×10 7 This includes administration of a dose containing a cell count of 10 total CD3+ / recombinant receptor+ or CD8+ / recombinant receptor+ cells (upper and lower limits of each).

[0151] In some embodiments, the dose of T cells comprises CD4+ T cells, CD8+ T cells, or CD4+ and CD8+ T cells.

[0152] In some embodiments, for example, when the subject is a human, the dose of CD8+ T cells, including in a dose including CD4+ and CD8+ T cells, is about 1×10 6 ~5×10 8Between about 5×10 total recombinant receptor (e.g., CAR or TCR)-expressing CD8+ cells, for example, 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, each of the doses or the total dose can fall within any of the aforementioned values. In some embodiments, the dose of cells is 1×10 to 1×10 7 ~0.75×10 8 pcs or approx. 1×10 7 ~Approx. 0.75×10 8 Total recombinant receptor-expressing CD8+ T cells, 1 x 10 7 ~2.5×10 7 Total recombinant receptor-expressing CD8+ T cells, 1 x 10 7 ~0.75×10 8 pcs or approx. 1×10 7 ~Approx. 0.75×10 8 In some embodiments, the dose of cells comprises administration of 1×10 total recombinant receptor-expressing CD8+ T cells, 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.

[0153] In some embodiments, the dose of cells, e.g., recombinant receptor-expressing T cells, is administered to the subject as a single dose, or is administered only once within a period of two weeks, one month, three months, six months, one year or more.

[0154] In some embodiments, the cell therapy comprises at least or at least about 0.1 x 10 6 Cells / kg (subject weight), 0.2 x 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 5×10 6 It includes administration of a dose that includes a number of cells that is or is an approximation of cells / kg.

[0155] In some embodiments, the cell therapy comprises 0.1×10 6 Cells / kg (subject weight) ~ 1.0 x 10 7 Between 0.1 x 10 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 cells / kg, 0.5 x 10 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 cells / kg, 0.5 x 10 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 cells / kg, 1.0 x 10 6 Cells / kg (subject weight) ~ 5 x 10 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 cells / kg, 1.0 x 10 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 cells / kg, 1.0 x 10 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 Cells / kg (subject weight) ~ 5 x 10 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 Cells / kg (subject weight) ~ 5 x 10 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 administration of doses containing cell numbers between (and including) the upper and lower limits.

[0156] In some embodiments, the dose of cells is 2×10 5 pcs or approx. 2 x 10 5 Cells / kg ~ 2×10 6 pcs or approx. 2 x 10 6 between 4 x 10 cells / kg, for example 5 pcs or approx. 4 x 10 5 Cells / kg ~ 1×10 6 pcs or approx. 1×10 6 Between 6 x 10 cells / kg 5 pcs or approx. 6 x 10 5 Cells / kg ~ 8×10 5 Pieces or about 8 x 10 5 In some embodiments, the dose of cells is between 2×10 cells / kg per kilogram 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 is at least or at least about 2×10 cells / kg or less per kilogram of subject body weight. 5 pcs or 2×10 5 pcs or approx. 2×10 5 cells (e.g., antigen-expressing, e.g., CAR-expressing or TCR-expressing cells) (cells / kg), e.g., at least 3×10 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 x 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 x 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.

[0157] In the context of adoptive cell therapy, administration of a given "dose" of cells includes administration of a given amount or number of cells as a single composition and / or a single uninterrupted administration, for example, as a single injection or continuous infusion, and also includes administration of a given amount or number of cells as divided doses provided in multiple individual compositions or infusions over a specified period of time that is 3 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 3 days or less, such as once a day for 3 or 2 days, or by multiple infusions over a period of 1 day.

[0158] 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 together contain the dose of cells.

[0159] The term "split dose" refers to a dose that is divided so as to be administered for more than one day. This type of administration is encompassed by the present method and considered to be a single dose. In some embodiments, the split dose of cells is administered in multiple compositions that together comprise the dose of cells over a period of 3 days or less.

[0160] 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 beyond three days.

[0161] In some embodiments, the dose of cells is generally high enough to be effective in reducing the disease burden.

[0162] 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 based in some embodiments on the total number of cells (or number per kg body weight) and the desired ratio of individual populations or subtypes, for example, CD4+ to CD8+ ratio. In some embodiments, the dosage of cells is based on the desired total number of cells (or number per kg body weight) in each population or 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.

[0163] 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 (CD4 + vs. CD8 + ) within a certain acceptable difference or error of such ratio.

[0164] In some embodiments, the 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 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.

[0165] Thus, in some embodiments, the 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, the dosage is based on a desired fixed or minimum dose of T cells and CD4 + vs. CD8 + Based on the desired ratio of cells and / or CD4 + and / or CD8 + Based on desired fixation or minimum dose of cells.

[0166] In some embodiments, the 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 can be a range of ratios. For example, in some embodiments, the desired ratio (e.g., CD4 + vs. CD8 + The ratio of cells is between 5:1 or about 5:1 and 5:1 or about 5:1 (or between 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 between 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 between 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.

[0167] 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 total cells, T cells or peripheral blood mononuclear cells (PBMCs) administered.

[0168] 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, stage of metastasis, 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 a host immune response, to the cells and / or recombinant receptor being administered.

[0169] In some embodiments, administration of a DGK inhibitor in combination with cells can significantly increase the expansion or proliferation of cells, and thus allow a lower dose of cells to be administered to the 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 the method 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 the method in which the cell therapy is administered without the administration of a DGK inhibitor.

[0170] In some embodiments, for example, the dose is 5.0×10 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 5×10 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.

[0171] In some embodiments, for example, the lower dose is about 5×10 per kilogram of subject body weight. 6 Less than about 4.5 x 10 cells, recombinant receptor (e.g., TCR or CAR) expressing cells, T cells and / or PBMCs, e.g., less than 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 6contains less than 10 such cells, or a value within a range between any two of the preceding values. In some embodiments, such a value refers to the number of recombinant receptor-expressing cells; in other embodiments, it refers to the number of T cells or PBMCs or total cells administered.

[0172] In some embodiments, the subject receives multiple doses of cells, e.g., two or more consecutive doses. In some embodiments, two doses are administered to the subject. In some embodiments, the subject receives consecutive doses, e.g., the 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, the first dose is followed by multiple consecutive doses, such that the additional dose is administered following administration of the consecutive doses. In some aspects, the number of cells administered to the 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 the 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, administration of T cell therapy may be repeated, such as administering a first and / or second dose of cells.

[0173] In some embodiments, the start of administration of the cell therapy, e.g., a dose of cells or a first dose of a divided dose of cells, is administered prior to (before), simultaneously with, or after (following or subsequent to) 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.

[0174] In some embodiments, the method involves evaluating a sample from the subject for one or more functions of T cells, such as expansion or persistence of cells as determined by levels or amounts in blood, or other phenotypes or desired outcomes described herein, such as those described in Section III, following administration of a dose of cells of T cell therapy, e.g., adoptive T cell therapy, but prior to administration of a DGK inhibitor. In some embodiments, the method involves evaluating a sample from the subject for expression of one or more exhaustion markers following administration of a dose of cells of T cell therapy, e.g., adoptive T cell therapy, but prior to administration of a DGK inhibitor. Various parameters for determining or evaluating combination therapy regimens are described in Section III.

[0175] 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 disease or condition described above. The DGKi can be administered before, simultaneously with, or after administration of 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 cell therapy, e.g., T cell therapy, are administered to the subject simultaneously.

[0176] 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.

[0177] 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; (iii) they enhance tumor cell killing. When inhibitors of DGKα and / or DGKζ enhance tumor cell killing, this activity can be dependent 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 can be dependent on NK cells, as shown, for example, in the CT26 animal model. When an inhibitor of DGKα and / or DGKζ enhances tumor cell killing, this activity may depend on CD8+ T cells and NK cells, for example, as shown in the CT26 animal model.When an inhibitor of DGKα and / or DGKζ enhances tumor cell killing, this activity may be enhanced by CD4 cell depletion, for example, in the CT-26 animal model.In certain embodiments, an inhibitor of DGKα and / or DGKζ enhances AH1+ tetramer antigen presentation in the CT-26 animal model.An inhibitor of DGKα and / or DGKζ preferably includes one or more of the above-cited characteristics, and may include all of them.

[0178] 1. Exemplary Inhibitors of DGKα and / or DGKζ Enzyme Activity Exemplary compounds, such as compounds of formula I described herein and pharma- ceutically 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 compounds of formula II described herein and pharma- ceutically acceptable salts thereof, are described in PCT / US2020 / 048070, the contents of which are specifically incorporated herein by reference.

[0179] In some embodiments, the provided combination therapy of T cell therapy and DGK inhibitor has formula (I):

[0180] [ka] (I) (In the formula, R 1 is H, F, Cl, Br, -CN, 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, -OCH 3 or -NR a R a and; Each R a are independently H or C 1~3 is alkyl; Each R e is independently 3~4 Cycloalkyl or 0 to 4 R 1a C replaced with 1~3 is alkyl; R 2 is H, 0 to 4 R2a 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; R 3 are 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 -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 1~4Hydroxyalkyl, -(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 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 1~4Alkyl, 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, -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 R 4a and R 4b Together with the carbon atom to which they are attached, they form 0 to 3 R f C, each replaced by 3~6 forms 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 cR 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 -OCH 3 and; Each R c are independently H or C 1~2 is alkyl; R d are 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 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 0-3 R g oxadiazolyl substituted with 0 to 4 R g Pyridinyl substituted with -(CH 2 ) 1~2 (0 to 4 R g -(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 pharma- ceutically acceptable salt thereof.

[0181] In some embodiments, the provided combination therapy of T cell therapy and DGK inhibitor is a compound of formula (I), wherein: R 1 is H, F, Cl, Br, -CN, 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 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; 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; R 3 are H, F, Cl, Br, -CN, C 1~2 Alkyl, -CF 3 , cyclopropyl or -NO 2 and; R 4a and R 4b is, 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 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 Together with the carbon atom to which they are attached, they form 0 to 3 R f C, each replaced by 3~6 forms 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 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 R 5 are 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 with3~4 Cycloalkyl, 0 to 3 R g Phenyl substituted with 0-3 R g oxadiazolyl substituted with 0-3 R g Pyridinyl substituted with -(CH 2 ) 1~2 (0 to 4 R g -(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), The present invention relates to the administration or use of an inhibitor of DGKα and / or DGKζ, which is a compound or a pharma- ceutically acceptable salt thereof.

[0182] In some embodiments, the provided combination therapy of T cell therapy and DGK inhibitor has the structure: [ka] (In the formula, R 1 is -CN; R 2 is -CH 3 and; R 3 is H, F or -CN; R 4 teeth, [ka] is) or a pharma- ceutically acceptable salt thereof.

[0183] 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 pharma- ceutically acceptable salt thereof.

[0184] In some embodiments, the provided combination therapy of T cell therapy and DGK inhibitor has formula (II): [ka] (II) (In the formula, R 1 is H, F, Cl, Br, -CN, -OH, 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, -OCH 3 or -NR a R a and; Each R a are independently H or C 1~3 is alkyl; Each R e is independently 3~4 Cycloalkyl or 0 to 4 R 1a C replaced with 1~3 is alkyl; R 2 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; R 4 -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 1~3Alkyl), 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 Rx ) 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 each substituted with 0 to 4 substituents independently selected from 3~8 carbocyclyl, 4-10 membered heterocyclyl, phenyl or 5-10 membered heteroaryl; or (iii) C3~6 C substituted with one cyclic group selected from cycloalkyl, 4-10 membered heterocyclyl, monocyclic or bicyclic aryl, or 5-10 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 it alkyl; Or R 4a and R 4b Together with the carbon atom to which they are attached, they form 0 to 3 R f C, each replaced by 3~6 forms 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 1~6Alkyl, 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 -OCH 3 and; Each R c are independently H or C 1~2 is alkyl; R d are 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 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 0-3 R g oxadiazolyl substituted with 0 to 4 R g Pyridinyl substituted with -(CH 2 ) 1~2 (0 to 4 R g 4-10 membered heterocyclyl substituted with -(CH 2 ) 1~2 NR c C(O)(C 1~4 alkyl), -(CH 2 ) 1~2 NRc 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.

[0185] In some embodiments, the provided combination therapy of T cell therapy and DGK inhibitor has formula (II): [ka] (II) (In the formula, R 1 is H, F, Cl, Br, -CN, 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 eOr -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 is independently 3~4 Cycloalkyl or 0 to 4 R 1a C replaced with 1~3 is alkyl; R 2 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; R 4 -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 Re 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 2 ) 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 , -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 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 R 4a and R 4b Together with the carbon atom to which they are attached, they form 0 to 3 R f C, each replaced by 3~6 forms 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, C1~3 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 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 -OCH 3 and; Each R c are independently H or C 1~2 is alkyl; R d are 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 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 0-3 Rg oxadiazolyl substituted with 0 to 4 R g Pyridinyl substituted with -(CH 2 ) 1~2 (0 to 4 R g 4-10 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.

[0186] In one embodiment, there is provided a compound of formula (II), wherein R 1 is H, F, Cl, Br, -CN, -OH, 0 to 4 R 1a C replaced with 1~3 Alkyl, 0 to 3 R 1aCyclopropyl substituted with 0-3 R 1a C replaced with 1~3 Alkoxy, -NR a R a , -S(O) n CH 3 or -P(O)(CH 3 ) 2 ;R 2 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, -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 1~3Cyanoalkoxy, -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 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, 4-10 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, -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 1~4Alkyl) and C 3~4 substituted with 0 to 3 substituents independently selected from cycloalkyl; 1~3 alkyl; or R 4a and R 4b Together with the carbon atom to which they are attached, they form 0 to 3 R f C, each replaced by 3~6 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, -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 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 is cycloalkyl; each R 5 are 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 gC replaced with 3~4 Cycloalkyl, 0 to 3 R g Phenyl substituted with 0-3 R g oxadiazolyl substituted with 0-3 R g Pyridinyl substituted with -(CH 2 ) 1~2 (0 to 4 R g 4-10 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 m is 1, 2 or 3; or a salt thereof is administered.

[0187] In one embodiment, there is provided a compound of formula (II), wherein R 1 is H, F, Cl, Br, -CN, 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 CH 3 or -P(O)(CH3 ) 2 and each R 1a is independently F, Cl, or -CN; each R a are independently H or C 1~3 R is alkyl; 2 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, -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 2 ) 1~2 O(C 1~2 Alkyl), C 1~3 Fluoroalkoxy, -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 1~3alkyl), -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 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, -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; or R 4a and R4b Together with the carbon atom to which they are attached, they form 0 to 3 R f C, each replaced by 3~6 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, -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 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 is cycloalkyl; each R 5 are 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 0-3 R g oxadiazolyl substituted with 0-3 Rg Pyridinyl substituted with -(CH 2 ) 1~2 (0 to 4 R g -(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), -C(O)(C 1~4 alkyl), -(CH 2 ) 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.

[0188] In one embodiment, there is provided a compound of formula (II), wherein R 1 is Cl or -CN; R 2 is -CH 3 ;R 4 is -CH 2 R 4a or -CHR 4a R 4b ;R 4a are F, Cl, -CN, -CH 3 , -CH(CH 3 ) 2 , -CF 3 , -OCH 3 , -OCH(CH 3 ) 2 , -OCHF 2 , -OCF 3 , -OCH 2R is cyclopropyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, phenyl, pyridinyl, pyrimidinyl, oxadiazolyl, benzo[d][1,3]dioxolyl, or oxodihydrobenzo[d]oxazolyl, each of which is substituted with 0 to 3 substituents independently selected from (cyclopropyl) and cyclopropyl; 4b is (i)-CH 3 and -CH 2 CH 3 or (ii) F, Cl, -CH 3 , -C(CH 3 ) 3 , -CF 3 , -OCF 3 and cyclopropyl; each R is phenyl, isoxazolyl, oxadiazolyl, or thiazolyl, each of which is substituted with 0 to 3 substituents independently selected from 5 are independently -CH 3 , -CH 2 CH 3 , -CH 2 OH or -CH 2 OCH 3 and m is 2, or a salt thereof is administered.

[0189] In one embodiment, there is provided a compound of formula (II), wherein R 1 -Cl, -CN, -OH, -CHF 2 , -CH 2 OH, -CH 2 OCH 3 , -OCH 3 , -OCH 2 CH 3 , -OCHF 2 , -OCH 2 CH 2 OCH 3 or -OCH 2 CH 2 N(CH 3 ) 2 ;R 2 -H, -CH 3 OR -CD 3 ;R 4 is -CH 2 R4a or -CHR 4a R 4b ;R 4a are F, Cl, Br, -CN, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 OH, -CHF 2 , -CF 3 , -CH 2 Br, -CH 2 NH 2 , -CH 2 NHC(O)OCH 3 , -C(CH 3 ) 2 CN, -OCH 3 , -OCD 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCHF 2 , -OCF 3 , -OCH 2 CH 2 CF 3 , -OC(CH 3 ) 2 CN, -OC(CH 3 ) 2 CH 2 OH, -OC(CH 3 ) 2 CH 2 OCH 3 , -N(CH 3 ) 2 , -C(O)OCH 3 , cyclopropyl, cyanocyclopropyl, methylcyclopropyl, -O(cyclopropyl), -O((ethoxycarbonyl)cyclopropyl), morpholinyl, pyrrolidinonyl, tetrahydropyranyl, dioxolanyl, -CH 2 (morpholinyl), -CH 2 (difluoromorpholinyl), -CH 2 (dimethylmorpholinyl), -CH 2 (oxazabicyclo[2.2.1]heptanyl), -CH 2(oxazaspiro[3.3]heptanyl), -CH 2 (Methylpiperazinonyl), -CH 2 (acetylpiperazinyl), -CH 2 (Piperidinyl), -CH 2 (difluoropiperidinyl), -CH 2 (Methoxypiperidinyl), -CH 2 (hydroxypiperidinyl), -C(CH 3 ) 2 (morpholinyl), -OCH 2 (cyclopropyl), -OCH 2 (Methylcyclopropyl), -OCH 2 (Methylazetidinyl), -OCH 2 (Oxetanyl), -OCH 2 (Tetrahydropyranyl), -OCH 2 (Thiazolyl) or -OCH 2 CH 2 (cyclopropyl), cyclohexyl, phenyl, pyridinyl, pyrimidinyl, oxadiazolyl, benzo[d][1,3]dioxolyl, or oxodihydrobenzo[d]oxazolyl, each of which is substituted with 0 to 3 substituents independently selected from 4b (i) -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 or (ii) F, Cl, Br, -CH 3 , -C(CH 3 ) 3 , -CF 3 , -OCF 3 and cyclopropyl; each R is phenyl, isoxazolyl, oxadiazolyl, thiazolyl, or triazolyl, each of which is substituted with 0 to 3 substituents independently selected from 5 are independently -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH3 , -CH 2 OH, -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 NH 2 , -CH 2 N 3 or -CH 2 NHC(O)OCH 3 and m is 2, or a salt thereof is administered.

[0190] In one embodiment, there is provided a compound of formula (II), wherein R 1 is H, F, Cl, Br, -CN, -OH, 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 CH 3 or -P(O)(CH 3 ) 2 In some embodiments, a compound of formula (II) is administered, wherein R 1 -Cl, -CN, -OH, -CHF 2 , -CH 2 OH, -CH 2 OCH 3 , -OCH 3 , -OCH 2 CH 3 , -OCHF 2 , -OCH 2 CH 2 OCH 3 or -OCH 2 CH 2 N(CH 3 ) 2 or a salt thereof is administered.

[0191] In one embodiment, there is provided a compound of formula (II), wherein R 1is H, F, Cl, Br, -CN, 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 CH 3 or -P(O)(CH 3 ) 2 In some embodiments, a compound of formula (II) is administered, wherein R 1 are H, F, Cl, Br, -CN, -CH 3 , cyclopropyl, -OCH 3 or -NH 2 In some embodiments, a compound of formula (II) is administered, wherein R 1 In some embodiments, a compound of formula (II) is administered, wherein R is Cl or -CN, or a salt thereof. 1 is -CN, or a salt thereof is administered.

[0192] In one embodiment, there is provided a compound of formula (II), wherein R 2 is H, 0 to 4 R 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 cycloalkyl, or a salt thereof. 2 is H or 0 to 2 R 2a C replaced with 1~2 In some embodiments, a compound of formula (II) is administered, wherein R is an alkyl group, or a salt thereof. 2 is H or -CH 3 In some embodiments, a compound of formula (II) is administered, wherein R 1 -CH 3In some embodiments, a compound is administered, which is represented by formula (II), wherein R 2 -H, -CH 3 OR -CD 3 or a salt thereof is administered.

[0193] In one embodiment, there is provided a compound of formula (II), wherein R 2 is H, a compound or a salt thereof is administered.

[0194] In one embodiment, there is provided a compound of formula (II), wherein R 2 is -CH 3 or a salt thereof is administered.

[0195] In one embodiment, there is provided a compound of formula (II), wherein R 2 -CD 3 or a salt thereof is administered.

[0196] In one embodiment, there is provided a compound of formula (II), wherein R 4 is -CH 2 R 4a or -CH 2 CH 2 R 4a In some embodiments, a compound is administered, which is represented by formula (II), wherein R 4 is -CH 2 R 4a OR -CD 2 R 4a In some embodiments, a compound is administered, which is represented by formula (II), wherein R 4a are F, Cl, Br, -CN, -OH, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CHF 2 , -CF 3 , -OCH 3 , -OCH 2CH 3 , -OCH(CH 3 ) 2 , -OCHF 2 , -OCF 3 , -C(O)CH 3 , -C(O)OC(CH 3 ) 3 , -N(CH 3 ) 2 In some embodiments, a compound or salt thereof is administered, which is phenyl, pyridinyl, tetrahydropyranyl, benzoxazinyl, benzo[d][1,3]dioxolyl, benzoxazinonyl, indazolyl, indolyl, or quinolinyl, each of which is substituted with 0-3 substituents independently selected from R, cyanocyclopropyl, and phenyl. 4a are F, Cl, -CN, -CH 3 , -CH(CH 3 ) 2 , -CF 3 , -OCH 3 , -OCH(CH 3 ) 2 , -OCHF 2 , -OCF 3 , -OCH 2 The compound or a salt thereof is administered, which is phenyl, pyridinyl, or benzo[d][1,3]dioxolyl, each of which is substituted with 0-3 substituents independently selected from (cyclopropyl) and cyclopropyl.

[0197] In one embodiment, there is provided a compound of formula (II), wherein R 4 is -CH 2 R 4a In some embodiments, a compound is administered, which is represented by formula (II), wherein R 4a are F, Cl, Br, -CN, -OH, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CHF 2 , -CF 3 , -OCH3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCHF 2 , -OCF 3 , -C(O)CH 3 , -C(O)OC(CH 3 ) 3 , -N(CH 3 ) 2 In some embodiments, a compound or salt thereof is administered, which is phenyl, pyridinyl, tetrahydropyranyl, benzoxazinyl, benzo[d][1,3]dioxolyl, benzoxazinonyl, indazolyl, indolyl, or quinolinyl, each of which is substituted with 0-3 substituents independently selected from R, cyanocyclopropyl, and phenyl. 4a are F, Cl, -CN, -CH 3 , -CH(CH 3 ) 2 , -CF 3 , -OCH 3 , -OCH(CH 3 ) 2 , -OCHF 2 , -OCF 3 , -OCH 2 The compound or a salt thereof is administered, which is phenyl, pyridinyl, or benzo[d][1,3]dioxolyl, each of which is substituted with 0-3 substituents independently selected from (cyclopropyl) and cyclopropyl.

[0198] In one embodiment, there is provided a compound of formula (II), wherein R 4 is -CH 2 R 4a ;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, -(CH 2 ) 1~2 O(C 1~3 Alkyl), C1~4 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 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.

[0199] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CH 2 R 4a ;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 1~2 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 1~4alkyl), -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(CH2 ) 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 each substituted with 0 to 4 substituents independently selected from 3~6 In some embodiments, a compound of formula (II) is administered, wherein R is cycloalkyl, 4-10 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl, or a salt thereof. 4a are F, Cl, -CH(CH 3 ) 2 , -CF 3 , -OCH 2 CH 3 , -OCF 3 , cyclopropyl and -OCH 2 (cyclopropyl), cyclohexyl, phenyl, or benzo[d][1,3]dioxolyl, each of which is substituted with 1 to 3 substituents independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 29, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,

[0200] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R 4b ;R 4a are (i) 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 1~4Alkoxy, -O(C 1~4 Hydroxyalkyl), -O(CH 2 ) 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 , -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 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 1~4 Alkyl, wherein the cyclic group is F, Cl, Br, -OH, -CN, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C1~3 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 R is alkyl; 4b are 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 2 ) 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 , -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 In some embodiments, a compound or salt thereof is administered, wherein R is phenyl or heteroaryl, each of which is substituted with 0-4 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, -CH 2 OH, -(CH 2 ) 1~2 O(C 1~2 Alkyl), C 1~4 Alkoxy, -O(C 1~4 Hydroxyalkyl), -O(CH 2 ) 1~2 O(C 1~2 Alkyl), C 1~3 Fluoroalkoxy, -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), -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 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, -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 R is alkyl; 4b is F, Cl, -CH 3 , -C(CH 3 ) 3 , -CF 3 , -OCF 3In some embodiments, a compound or salt thereof is administered, wherein R is phenyl, isoxazolyl, oxadiazolyl, or thiazolyl, each of which is substituted with 0-3 substituents independently selected from: 4a are F, Cl, -CN, -CH 3 , -CH(CH 3 ) 2 , -CF 3 , -OCH 3 , -OCH(CH 3 ) 2 , -OCHF 2 , -OCF 3 , -OCH 2 R is phenyl, pyridinyl, or benzo[d][1,3]dioxolyl, each of which is substituted with 0 to 3 substituents independently selected from (cyclopropyl) and cyclopropyl; 4b is F, Cl, -CH 3 , -C(CH 3 ) 3 , -CF 3 , -OCF 3 and cyclopropyl, isoxazolyl, oxadiazolyl, or thiazolyl, each of which is substituted with 0-3 substituents independently selected from phenyl, isoxazolyl, oxadiazolyl, or thiazolyl.

[0201] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R 4b ;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, -(CH 2 ) 1~2 O(C 1~3 Alkyl), C 1~4 Alkoxy, C 1~3 Fluoroalkoxy, C 1~3 Cyanoalkoxy, -O(C 1~4Hydroxyalkyl), -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), -(CRx 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 each substituted with 0 to 4 substituents independently selected from 3~6carbocyclyl, 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, -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 R is alkyl; 4b are F, Cl, Br, -CH 3 , -C(CH 3 ) 3 , -CF 3 , -OCF 3 and cyclopropyl, isoxazolyl, oxadiazolyl, thiazolyl, or triazolyl, each of which is substituted with 0-3 substituents independently selected from phenyl, isoxazolyl, oxadiazolyl, thiazolyl, or triazolyl, or a salt thereof is administered.

[0202] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R 4b ;R 4a are (i) 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 2 ) 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 , -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 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 1~4Alkyl, 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, -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 R is alkyl; 4b are 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 In some embodiments, a compound of formula (II) is administered, wherein R is an alkyl group, or a salt thereof. 4a are 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 2 ) 1~2 O(C 1~2 Alkyl), C 1~3 Fluoroalkoxy, -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), -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 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, -OCH 2 CH=CH 2 , -OCH 2 C≡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; 1~3 R is alkyl; 4b are 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 In some embodiments, a compound of formula (II) is administered, wherein R is an alkyl group, or a salt thereof. 4a are F, Cl, -CN, -CH 3 , -CH(CH 3 ) 2 , -CF 3 , -OCH 3 , -OCH(CH 3 ) 2 , -OCHF 2 , -OCF 3 , -OCH 2 R is phenyl, pyridinyl, or benzo[d][1,3]dioxolyl, each of which is substituted with 0 to 3 substituents independently selected from (cyclopropyl) and cyclopropyl; 4b -CH 3 and -CH 2 CH 3 or a salt thereof is administered.

[0203] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R 4b ;R 4a are (i) F, Cl, Br, -CN, -OH, C 1~6 Alkyl, C 1~3 Fluoroalkyl, C 1~2 Bromoalkyl, C1~2 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 xR 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 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) C 3~6 C substituted with one cyclic group selected from cycloalkyl, 4-10 membered heterocyclyl, monocyclic or bicyclic aryl, or 5-10 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 R is alkyl; 4b is -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 from1~6 In some embodiments, a compound of formula (II) is administered, wherein R is an alkyl group, or a salt thereof. 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, -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 (C3~4 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 Rd 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, 4-10 membered heterocyclyl, monocyclic or bicyclic aryl, or 5-10 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, -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 R is alkyl; 4b is -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 A compound or a salt thereof is administered.

[0204] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R 4b ;R 4b -CN, -CH 3 , -CH 2 CH3 , -CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 or a salt thereof is administered.

[0205] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R 4b ;R 4b -CN, -CH 3 or -CH 2 CH 3 or a salt thereof is administered.

[0206] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R 4b ;R 4b is -CN, or a salt thereof is administered.

[0207] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R 4b ;R 4b -CH 3 or -CH 2 CH 3 or a salt thereof is administered.

[0208] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R 4b ;R 4b -CH 3 or a salt thereof is administered.

[0209] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R 4b ;R 4b -CH 2 CH 3or a salt thereof is administered.

[0210] In one embodiment, there is provided a compound of Formula (II), wherein m is 1, 2 or 3; 5 are 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 0-3 R g oxadiazolyl substituted with 0-3 R g Pyridinyl substituted with -(CH 2 ) 1~2 (0 to 4 R g 4-10 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 In some embodiments, a compound of formula (II) is administered, wherein each R is cycloalkyl, or a salt thereof. 5 are independently -CH 3 , -CH 2 CH 3 , -CH2 OH or -CH 2 OCH 3 or a salt thereof is administered.

[0211] In one embodiment, a compound of formula (II), wherein m is 0, or a salt thereof, is administered.

[0212] 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.

[0213] 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.

[0214] In one embodiment, a compound of formula (II) wherein m is 3, or a salt thereof, is administered.

[0215] In one embodiment, the compound of formula (III): [ka] (III) (In the formula, R 5a , R 5b , R 5c and R 5d 1, 2 or 3 of the 5 and R 5a , R 5b , R 5c and R 5d The remainder are hydrogen. In some embodiments, a compound of formula (II) having the structure: 5 are independently -CN, -CH3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CHC(CH 3 ) 2 , -CH 2 F, -C(CH 3 ) 2 F, -CF(CH 3 )CH(CH 3 ) 2 , -CH 2 OH, -C(CH 3 ) 2 OH, -C(CH 3 )(OH)CH(CH 3 ) 2 , -CH 2 OCH 3 , -C(O)C(CH 3 ) 2 , -C(O)OH, -C(O)OCH 3 , -C(O)OC(CH 3 ) 2 , -C(O)NH 2 In some embodiments, a compound of formula (III) is administered, wherein each R is -C(O)NH(cyclopropyl), -C(O)O(cyclopropyl), cyclopropyl, phenyl, methyloxadiazolyl, or methylpyridinyl, or a salt thereof. 5 are independently -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 OH, -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 NH 2 , -CH 2 N 3 or -CH 2 NHC(O)OCH 3 or a salt thereof is administered.

[0216] In one embodiment, the compound of formula (IV): [ka] (IV) (In the formula, R 5a and R 5c are R 5 and R 5b and R 5d are hydrogen.) In some embodiments, a compound of formula (II) having the structure: 5a is -CH 3 or -CH 2 CH 3 and R 5c is -CH 3 or -CH 2 CH 3 or (ii) R 5a is -CH 3 and R 5c is -CH 2 OH or -CH 2 OCH 3 or a salt thereof is administered.

[0217] In one embodiment, there is provided a compound of formula (IV), wherein R 5a Ha-CH 3 and R 5c Ha-CH 3 or a salt thereof is administered.

[0218] In one embodiment, there is provided a compound of formula (IV), wherein R 5a Ha-CH 3 and R 5c Ha-CH 2 CH 3 or a salt thereof is administered.

[0219] In one embodiment, there is provided a compound of formula (IV), wherein R 5a Ha-CH 2 CH 3 and R 5c Ha-CH 3or a salt thereof is administered.

[0220] In one embodiment, there is provided a compound of formula (IV), wherein R 5a Ha-CH 2 CH 3 and R 5c Ha-CH 2 CH 3 or a salt thereof is administered.

[0221] In one embodiment, there is provided a compound of formula (IV), wherein R 5a Ha-CH 3 and R 5c Ha-CH 2 OH, or a salt thereof, is administered.

[0222] In one embodiment, there is provided a compound of formula (IV), wherein R 5a Ha-CH 3 and R 5c Ha-CH 2 OCH 3 or a salt thereof is administered.

[0223] In one embodiment, there is provided a compound of formula (IV), wherein R 5a Ha-CH 3 and R 5c Ha-CH 2 OCH 2 CH 3 or a salt thereof is administered.

[0224] In one embodiment, there is provided a compound of formula (IV), wherein R 5a Ha-CH 3 and R 5c Ha-CH 2 CH 2 CH 3 or a salt thereof is administered.

[0225] In one embodiment, there is provided a compound of formula (IV), wherein R 5a Ha-CH 3 and R 5c Ha-CH2 N 3 or a salt thereof is administered.

[0226] In one embodiment, there is provided a compound of formula (IV), wherein R 5a Ha-CH 3 and R 5c Ha-CH 2 NH 2 or a salt thereof is administered.

[0227] In one embodiment, there is provided a compound of formula (IV), wherein R 5a Ha-CH 3 and R 5c Ha-CH 2 NHC(O)OCH 3 or a salt thereof is administered.

[0228] In one embodiment, there is provided a compound of formula (IV), wherein R 5a Ha-CH 2 OH and R 5c Ha-CH 3 or a salt thereof is administered.

[0229] In one embodiment, there is provided a compound of formula (IV), wherein R 5a Ha-CH 2 OCH 3 and R 5c Ha-CH 3 or a salt thereof is administered.

[0230] In one embodiment, the structure: [ka] or a salt thereof.

[0231] In one embodiment, the structure: [ka] or a salt thereof.

[0232] In one embodiment, the structure: [ka] or a salt thereof.

[0233] In one embodiment, the structure: [ka] or a salt thereof.

[0234] In one embodiment, there is provided a compound of formula (II), wherein R 4 teeth, (i); [ka] [ka] (ii); [ka] [ka] or (iii) [ka] In some embodiments, a compound is administered, which is represented by formula (II), wherein R 1 is H, Br, -CN or -OCH 3 ;R 2 Ha-CH 3 or a salt thereof is administered.

[0235] In one embodiment, there is provided a compound of formula (II), wherein R 4 teeth, [ka] In some embodiments, a compound is administered, which is represented by formula (II), wherein R 1 is H, Br, -CN or -OCH 3 ;R 2 Ha-CH 3 In some embodiments, a compound is administered, which is represented by formula (II), wherein R 1 is -CN; R 2 Ha-CH 3 or a salt thereof is administered.

[0236] In one embodiment, there is provided a compound of formula (II), wherein R 1 is -CN; R 2 Ha-CH 3 or a salt thereof is administered.

[0237] In one embodiment, there is provided a compound of formula (IV), wherein R 1 is -CN; R 2 Ha-CH 3 or a salt thereof is administered.

[0238] In one embodiment, there is provided a compound of formula (IV), wherein R 1 is -CN; R 2 Ha-CH 3 ;R 5a Ha-CH 3 ;R 5c Ha-CH 3 or a salt thereof is administered.

[0239] In one embodiment, there is provided a compound of formula (IV), wherein R 1 is -CN; R 2 Ha-CH 3 ;R 5a Ha-CH 3 ;R 5c Ha-CH 2 CH 3 or a salt thereof is administered.

[0240] In one embodiment, there is provided a compound of formula (IV), wherein R 1 is -CN; R 2 Ha-CH 3 ;R 5a Ha-CH 3 ;R 5c Ha-CH 2 CH 2 CH 3 or a salt thereof is administered.

[0241] In one embodiment, there is provided a compound of formula (IV), wherein R 1 is -CN; R 2 Ha-CH 3 ;R 5a Ha-CH 2 CH 3 ;R 5c Ha-CH 2 CH 3 or a salt thereof is administered.

[0242] In one embodiment, there is provided a compound of formula (IV), wherein R 1 is -CN; R 2 Ha-CH 3 ;R 5a Ha-CH 3 ;R 5c is -CH 3 , -CH 2 CH 3 or -CH 2 CH 2 CH 3 or a salt thereof is administered.

[0243] In one embodiment, there is provided a compound of formula (II), wherein R 1 is -CN; R 2 Ha-CH 3 ;R 4 -CHR 4a R 4b ;R 4b Ha-CH 3 or a salt thereof is administered.

[0244] In one embodiment, there is provided a compound of formula (II), wherein R 1 is -CN; R 2 Ha-CH 3 ;R 4 -CHR 4a R 4b ;R 4b Ha-CH 2 CH 3 or a salt thereof is administered.

[0245] In one embodiment, there is provided a compound of formula (II), wherein R 1 is -CN; R 2 Ha-CH 3 ;R 4 -CHR 4a R 4b ;R 4b Ha-CH 2 CH 2 CH 3 or a salt thereof is administered.

[0246] In one embodiment, there is provided a compound of formula (II), wherein R 1 is -CN; R 2 Ha-CH 3 ;R 4 -CHR 4a R 4b ;R 4b -CH 3 , -CH 2 CH 3 or -CH 2 CH 2 CH 3 or a salt thereof is administered.

[0247] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R 4b ;R 4a -F, Cl, -CF 3 , -OCF 3 or -OCH 2In some embodiments, a compound of formula (II), or a salt thereof, is administered, wherein R is phenyl substituted with 1 to 2 substituents independently selected from R(cyclopropyl), ... 1 is -CN; R 2 Ha-CH 3 or a salt thereof is administered.

[0248] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R 4b ;R 4a -CF 3 Or -OCF 3 phenyl substituted with R 4b is -CH 3 , -CH 2 CH 3 or -CH 2 CH 2 CH 3 In some embodiments, a compound is administered, which is represented by formula (II), wherein R 1 is -CN; R 2 Ha-CH 3 or a salt thereof is administered.

[0249] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R 4b ;R 4a -CF 3 Or -OCF 3 phenyl substituted with R 4b Ha-CH 3 In some embodiments, a compound is administered, which is represented by formula (II), wherein R 1 is -CN; R 2 Ha-CH 3 or a salt thereof is administered.

[0250] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R4b ;R 4a -CF 3 Or -OCF 3 phenyl substituted with R 4b Ha-CH 2 CH 3 In some embodiments, a compound of formula (II) is administered, wherein R 1 is -CN; R 2 Ha-CH 3 or a salt thereof is administered.

[0251] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R 4b ;R 4a -CF 3 Or -OCF 3 is phenyl substituted with R 4b Ha-CH 2 CH 2 CH 3 In some embodiments, a compound of formula (II) is administered, wherein R 1 is -CN; R 2 Ha-CH 3 or a salt thereof is administered.

[0252] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R 4b ;R 4a -F, Cl, -CF 3 , -OCF 3 or -OCH 2 (cyclopropyl), R 4b -CH 3 , -CH 2 CH 3 or -CH 2 CH 2 CH 3 In some embodiments, a compound of formula (II) is administered, wherein R1 is -CN; R 2 Ha-CH 3 or a salt thereof is administered.

[0253] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R 4b ;R 4a In some embodiments, a compound of formula (II) is administered, wherein R is pyridinyl, or a salt thereof. 1 is -CN; R 2 Ha-CH 3 or a salt thereof is administered.

[0254] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R 4b ;R 4a -CF 3 In some embodiments, a compound of formula (II) is administered, wherein R is pyridinyl substituted with R, or a salt thereof. 1 is -CN; R 2 Ha-CH 3 or a salt thereof is administered.

[0255] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R 4b ;R 4a is pyridinyl; R 4a In some embodiments, a compound of formula (II), wherein R is phenyl substituted with Cl, or a salt thereof, is administered. 1 is -CN; R 2 Ha-CH 3 or a salt thereof is administered.

[0256] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R 4b;R 4a -CF 3 pyridinyl substituted with R 4b is phenyl substituted with F. In some embodiments, a compound of formula (II) or a salt thereof is administered, wherein R 1 is -CN; R 2 Ha-CH 3 or a salt thereof is administered.

[0257] In one embodiment, there is provided a compound of formula (II), wherein R 4 -CHR 4a R 4b ;R 4a and R 4b is phenyl substituted with F; R 4a and R 4b and the other is oxadiazolyl substituted with cyclopropyl. In some embodiments, a compound of formula (II) is administered, wherein R 1 is -CN; R 2 Ha-CH 3 or a salt thereof is administered.

[0258] 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;4-((2S,5R)-2,5-dimethyl-4-(3,4,5-trifluorobenzyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydro 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.

[0259] 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 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 (25-26);4-((2S,5R)-2-ethyl-4-((4-fluorophenyl)(5-(trifluoromethyl)pyridin-2-yl)methyl)-5-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-2-ethyl-4-((4-fluorophenyl)(5-(trifluoromethyl)pyridin-2-yl)methyl)-5-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile lopyrido[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 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-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.

[0260] 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 4-((2S,5R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-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-((2S,5R)-4-(1-(4-cyclopropylphenyl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-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;4-((2S,5R)-4-(1-(4-(cyclopropylmethoxy)-2-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido [3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethoxy)phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-2,5-diethyl-4-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-4-(1-(4-cyclopropyl-2-fluorophenyl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-2,5-diethyl-4-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-5-ethyl-2-methyl -4-(1-(4-(trifluoromethoxy)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-5-ethyl-4-(1-(4-isopropoxyphenyl)ethyl)-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-5-ethyl-4-(1-(4-methoxyphenyl)ethyl)-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-5-ethyl-4-(1-(4-methoxyphenyl)ethyl)-2-methylpiperazin- 1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-5-ethyl-4-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-4-(1-(4-cyanophenyl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile 4-((2S,5R)-4-(1-(4-cyclopropylphenyl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-4-(1-(4-(cyclopropylmethoxy)phenyl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-4-(1-(4-(cyclopropylmethoxy)-2-fluorophenyl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6 -carbonitrile;4-((2S,5R)-4-(1-(4-(difluoromethoxy)phenyl)propyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine- 6-Carbonitrile;4-((2S,5R)-5-ethyl-4-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-5-ethyl-2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile 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- 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-dimethyl4-(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-dimethyl4-(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-dimethyl4-(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;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 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 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,5 R)-2,5-diethyl-4-(1-(4-((1-hydroxy-2-methylpropan-2-yl)oxy)phenyl)ethyl)piperazin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one;6-chloro-4-((2S,5R)-2,5-diethyl-4-(1-(4-((1-methoxy-2-methylpropan-2-yl)oxy)phenyl)ethyl)piperazin-1-yl )-1-Methylpyrido[3,2-d]pyrimidin-2(1H)-one;6-chloro-4-((2S,5R)-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;4-((2S,5R)-2,5-diethyl-4-(1-(4-(methoxy-d; 3)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)furan 4-((2S,5R)-4-(1-(4-(2-cyanopropan-2-yl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-4-(1-(4-(cyclopropylmethoxy)-2-fluorophenyl)propionyl) 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-di 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-d 34-((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)-2,5-diethyl-4-(1-(6-methoxypyridin-2-yl)ethyl)piperazin-1-yl)-1-methyl 4-((2S,5R)-2,5-diethyl-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-(4-(1-methylcyclopropyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile -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)-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-(difluorometh 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-(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 4-((2S,5R)-4-(1-(4-chloro-2-fluorophenyl)propyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-4-(1-(6-(difluoromethoxy)pyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-4-(1-(6-(difluoromethoxy)pyridin-2-yl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile;4-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)butyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (31-32);4-((2S,5R)-2,5-diethyl-4-(1-(6-(trifluoromethoxy)pyridin-2-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-2,5-diethyl-4-(1-(4-(2-morpholinopropan-2-yl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile; 4-((2S,5R)-2,5-diethyl-4-(1-(4-methoxyphenyl)-2-methylpropyl)piperazin 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-(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; 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;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 4-((2S,5R)-4-(1-(4-cyclopropylmethoxy)phenyl)propyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-4-(1-(4-cyclopropoxyphenyl)propyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-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 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 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;Methyl(4-(1-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2-ethyl-5-methylpiperazin-1-yl 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-((1S,4S)-2-oxa-5-azabicyclo[ ... 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[3,2-d]pyrimidine-6-carbonitrile ... 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-(hydroxy 6-Chloro-4-((2R,5R)-2-(methoxymethyl)-5-methyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one;4-((2R,5R)-2-(methoxymethyl)-5-methyl-4-(1-(4 -(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2R,5R)-5-ethyl-2-(hydroxymethyl)-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile;4-((2S,5R)-5-ethyl-2-methyl ... 4-((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-d; 3) 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-d 3)-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(1 H)-one;4-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-6-(methoxymethyl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one;6-chloro-4-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one; ... 4-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-6-methoxy-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one;4-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-6-ethoxy-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one;4-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-6-(2-(dimethylamino)ethoxy) 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)pyrido[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;6-chloro-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 -((2S,5R)-2,5-dimethyl 4-(1-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)propyl)piperazin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (diastereomeric mixture); 4-((2S,5R)-2,5-dimethyl 4-(1-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)propyl)piperazin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (diastereomeric mixture); 4-((2S,5R)-4-(1-(3,3-difluorocyclobutyl)-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)-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.

[0261] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being [ka] It is.

[0262] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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).

[0263] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

[0264] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

[0265] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being [ka] It is.

[0266] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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).

[0267] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

[0268] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

[0269] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being [ka] It is.

[0270] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

[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-((S)-1-(4-(trifluoromethoxy)phenyl)propyl)piperazin-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)-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.

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

[0274] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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).

[0275] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

[0276] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

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

[0278] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

[0279] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

[0280] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

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

[0282] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

[0283] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

[0284] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

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

[0286] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

[0287] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

[0288] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

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

[0290] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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).

[0291] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

[0292] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

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

[0294] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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).

[0295] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

[0296] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

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

[0298] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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).

[0299] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

[0300] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

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

[0302] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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).

[0303] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

[0304] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

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

[0306] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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).

[0307] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

[0308] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

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

[0310] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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).

[0311] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

[0312] In one embodiment, a compound of formula (II) or a salt thereof is administered, said compound being 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.

[0313] 2. Composition and Dosing For example, a compound described herein according to Formula (I) or (II), e.g., a compound selected from Compounds 1-34, and / or a pharma- ceutically 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.

[0314] 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 pharma- ceutically acceptable salt thereof; and one or more non-toxic pharma- ceutically acceptable carriers and / or diluents and / or adjuvants (collectively referred to herein as "carrier" materials), and, if desired, 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 to such route, and in a dose effective for the intended treatment. The compounds and compositions described herein can be administered orally, mucosally, or parentally, including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally, e.g., in a dosage unit formulation containing conventional pharma- cetically 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 lubricants, e.g., magnesium stearate, and disintegrants, e.g., crospovidone. The carrier mixture may be filled into gelatin capsules or compressed into tablets. The pharmaceutical composition may be administered, for example, as an oral dosage form or injection.

[0315] 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 renal and hepatic function of the patient.

[0316] As a general guidance, the daily oral dosage of each active ingredient, when used for the indicated effect, will range between about 0.001 to about 5000 mg per day, preferably between about 0.01 to about 1000 mg per day, and most preferably between about 0.1 to about 250 mg per day. Intravenously, the most preferred doses will range from about 0.01 to about 10 mg / kg / min 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.

[0317] 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.

[0318] Dosage forms (pharmaceutical compositions) suitable for administration can contain 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 about 0.1 to 95% by weight based on the total weight of the composition.

[0319] 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.

[0320] 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.

[0321] For oral administration, the pharmaceutical compositions described herein may be in the form of, for example, tablets, capsules, liquid capsules, suspensions or liquids. The pharmaceutical compositions are preferably made in the form of dosage units containing a specific amount of the active ingredient. For example, the pharmaceutical compositions may be provided as tablets or capsules containing an amount of active ingredient within the range of about 0.1-1000 mg, preferably about 0.25-250 mg, more preferably about 0.5-100 mg. A daily dose suitable for a human or other mammal may vary widely depending on the patient's condition and other factors, but can be determined using routine methods.

[0322] 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 pharma- ceutical acceptable dosage forms by conventional methods known to those skilled in the art.

[0323] The actual dosage level of the active ingredient in the pharmaceutical composition containing DGK inhibitor can be varied to obtain the amount of active ingredient that is effective for achieving 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 or its ester, salt or amide used, 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 arts.

[0324] A physician having ordinary skill in the art can easily determine and prescribe the effective amount of the pharmaceutical composition required.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 therapeutic effect, and gradually increase the dosage until effect is achieved.

[0325] In general, a suitable daily dose of a DGK inhibitor will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above. In general, 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 an active compound can be administered as 2, 3, 4, 5, 6 or more sub-doses administered separately at appropriate intervals throughout the day, conveniently in a unit dosage form. In certain embodiments, the dosage is a single administration per day.

[0326] Any pharmaceutical composition contemplated herein can be delivered orally, for example, via any acceptable and suitable oral preparation.Exemplary oral preparations include, but are not limited to, for example, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs.The pharmaceutical composition intended for oral administration can be prepared according to any method known in the art for manufacturing 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.

[0327] Tablets can be prepared, for example, by mixing at least one compound, for example, a compound of formula (I) or (II), for example, a compound selected from compounds 1-34, and / or at least one pharma- ceutically acceptable salt thereof, with at least one non-toxic pharma- ceutically acceptable excipient suitable for the manufacture of tablets. Exemplary excipients include, for example, 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, sodium crosscarmellose, corn starch, and alginic acid; binding agents, such as starch, gelatin, polyvinylpyrrolidone, and acacia; and lubricants, such as magnesium stearate, stearic acid, and talc. Moreover, the tablet may be uncoated or may be coated by any known technique to mask the unpleasant taste of unpleasant tasting drugs or to delay the disintegration and absorption of active ingredients in the gastrointestinal tract, thereby sustaining the effect of 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.

[0328] 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 pharma- ceutically acceptable salt thereof, with at least one inert solid diluent, such as, for example, calcium carbonate; calcium phosphate; and kaolin.

[0329] 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 pharma- ceutically acceptable salt thereof, with at least one water-soluble carrier, such as, for example, polyethylene glycol; and at least one oil medium, such as, for example, peanut oil, liquid paraffin, and olive oil.

[0330] Aqueous suspensions can be prepared, for example, by mixing at least one compound, such as a compound of formula (I) or (II), such as a compound selected from compounds 1-34, and / or at least one pharma- ceutically 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, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents such as, for example, naturally occurring phosphatides, for example, lecithin; condensation products of alkylene oxides with fatty acids, for example, polyoxyethylene stearates; condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethylene-oxycetanol; condensation products of ethylene oxide with fatty acids and partial esters derived from hexitols, for example, polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides, 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.

[0331] The oil suspension can be prepared, for example, by suspending at least one compound, for example a compound of formula (I) or (II), for example a compound selected from compounds 1-34, and / or at least one pharma- ceutically acceptable salt thereof, either in a vegetable oil, for example peanut oil; olive oil; sesame oil; and coconut oil; or in a mineral oil, for example liquid paraffin. The oil suspension can also contain at least one thickening agent, for example beeswax; hard paraffin; and cetyl alcohol. To provide an acceptable oil suspension, at least one of the sweeteners and / or at least one flavoring agent already described above can be added to the oil suspension. The oil suspension can further contain at least one preservative, including, for example, but not limited to, an antioxidant, for example butylated hydroxyanisole and alpha-tocopherol.

[0332] Dispersible powders and granules can be prepared, for example, by mixing at least one compound, for example, a compound of formula (I) or (II), for example, a compound selected from compounds 1-34, and / or at least one pharma- ceutically 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, for example, but are not limited to, antioxidants, such as ascorbic acid. In addition, dispersible powders and granules can also contain at least one excipient, for example, but are not limited to, sweeteners; flavoring agents; and coloring agents.

[0333] An emulsion of at least one compound, for example a compound of formula (I) or (II), for example a compound selected from compounds 1-34, and / or at least one pharma- ceutically acceptable salt thereof, can be prepared, for example, as an oil-in-water emulsion. The oily phase of an emulsion comprising a compound of formula (I) or (II), for example 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, but not limited to, by vegetable oils, for example olive oil and peanut oil; mineral oils, for example liquid paraffin; and mixtures thereof. The phase can simply comprise an emulsifier, but can also 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 and 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 oils and fats.Taken together, the emulsifier with or without stabilizer creates the so-called emulsifying wax, and the wax together with oils and fats creates the 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 together with waxes or other materials well known in the art.

[0334] The compound, e.g., a compound of formula (I) or (II), e.g., a compound selected from compounds 1-34, and / or at least one pharma- ceutically acceptable salt thereof, can also be delivered, e.g., intravenously, subcutaneously, and / or intramuscularly, via any pharma- ceutically acceptable and suitable injectable form. Exemplary injectable forms include, for example, but are not limited to, sterile aqueous solutions, including acceptable vehicles and solvents, such as, for example, water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and aqueous or oleaginous suspensions.

[0335] 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 cyclodextrin (i.e., Captisol), cosolvent solubilization (i.e., propylene glycol) or micelle solubilization (i.e., Tween 80).

[0336] Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used, water, Ringer's solution and isotonic sodium chloride solution are specifically mentioned. In addition, sterile fixed oils have been conventionally used as solvents or suspending media. For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectable solutions.

[0337] 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 pharma-ceutically acceptable salt thereof, in an oily phase, e.g., a mixture of soybean oil and lecithin; 2) combining the oily phase-containing compound, e.g., a compound of Formula (I) and / or a pharma-ceutically acceptable salt thereof, with a water and glycerol mixture; and 3) processing the combination to form a microemulsion.

[0338] 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 suspension media, such as sterile fixed oils, synthetic mono- or diglycerides; and fatty acids, such as oleic acid.

[0339] Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the 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), partial glyceride mixtures 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.

[0340] The pharma- ceutically 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. The 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, and the like. Tablets and pills can be prepared with enteric coatings as well. Such compositions can also contain adjuvants, such as wetting agents, sweeteners, flavorings, and aromatic agents.

[0341] The amount of compound administered and the dosage regimen for treating a disease state with the compounds and / or compositions described herein will depend on a variety of factors, including the age, weight, sex, medical condition of the subject, type of disease, severity of disease, route and frequency of administration, and the particular compound used. Thus, the dosage regimen may vary widely, but can be routinely determined using standard methods. A daily dose of about 0.001 to 100 mg / kg body weight, preferably between about 0.0025 to about 50 mg / kg body weight, and most preferably between about 0.005 to 10 mg / kg body weight, may be appropriate. The daily dose may be administered in 1 to 4 doses per day. Other dosing schedules include one dose per week and one dose per two-day cycle.

[0342] For therapeutic purposes, the active compound described herein is usually combined with one or more adjuvants suitable for the 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 phosphoric acid and sulfate, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.Such capsules or tablets can contain controlled release formulations, such as can be provided in the dispersion of active compound in hydroxypropylmethylcellulose.

[0343] The pharmaceutical compositions described herein include at least one compound, e.g., a compound of formula (I), and / or at least one pharma- ceutically acceptable salt thereof, and, optionally, an additional agent selected from any pharma- ceutically acceptable carrier, adjuvant, and vehicle. Other compositions described herein include 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 pharma- ceutically acceptable carrier, adjuvant, or vehicle.

[0344] In some embodiments, administration of the DGKα and / or DGKζ inhibitor is initiated prior to, following, during, during the course of, simultaneously with, nearly 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 dosage schedule includes initiating administration of the DGKα and / or DGKζ inhibitor contemporaneously or simultaneously with administration of T cell therapy.

[0345] In some embodiments, the inhibitor of DGKα and / or DGKζ is administered in a cycle. 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, for example, counted from the beginning of administration of the inhibitor of DGKα and / or DGKζ, is more than or about 21 days, 28 days, 30 days, 40 days, 50 days, 60 days or more.

[0346] In some embodiments, the initiation of administration of the inhibitor of DGKα and / or DGKζ and the initiation of administration of T cell therapy are performed on the same day, or optionally simultaneously, in at least one cycle. In some embodiments, the initiation of administration of the inhibitor of DGKα and / or DGKζ in at least one cycle is prior to the initiation of administration of T cell therapy. In some embodiments, the initiation of administration of the inhibitor of DGKα and / or DGKζ in at least one cycle is performed 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 administered 0-30 days or about 0-30 days prior to the initiation of T cell therapy, e.g., 0-15 days, 0-6 days, 0-96 hours, 0-24 hours, 0-12 hours, 0-6 hours or 0-2 hours, 2 hours to 15 days, 2 hours to 6 days, 2 hours to 96 hours, 2 hours to 24 hours, 2 hours to 12 hours, 2 hours to 6 hours, 6 hours to 30 days, 6 hours to 15 days, 6 hours to 6 hours, hours to 6 days, 6 hours to 96 hours, 6 hours to 24 hours, 6 hours to 12 hours, 12 hours to 30 days, 12 hours to 15 days, 12 hours to 6 days, 12 hours to 96 hours, 12 hours to 24 hours, 24 hours to 30 days, 24 hours to 15 days, 24 hours to 6 days, 24 hours to 96 hours, 96 hours to 30 days, 96 hours to 15 days, 96 hours to 6 days, 6 days to 30 days, 6 days to 15 days, or 15 days to 30 days prior to initiation of T cell therapy. In some embodiments, the inhibitor of DGKα and / or DGKζ is administered within about 96 hours, 72 hours, 48 ​​hours, 24 hours, 12 hours, 6 hours, 2 hours, or 1 hour prior to initiation of T cell therapy.

[0347] In some of such embodiments in which an inhibitor of DGKα and / or DGKζ is given prior to cell therapy (e.g., T cell therapy), administration of the inhibitor of DGKα and / or DGKζ continues at regular intervals until the initiation of cell therapy (e.g., T cell therapy) and / or for a period of time after the initiation of cell therapy (e.g., T cell therapy).

[0348] In some embodiments, the inhibitor of DGKα and / or DGKζ is administered after or in addition to administration of cell therapy (e.g., T cell therapy). In some embodiments, the inhibitor of DGKα and / or DGKζ is administered within or about 1 hour, 2 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 96 hours, 4 days, 5 days, 6 days or 7 days, 14 days, 15 days, 21 days, 24 days, 28 days, 30 days, 36 days, 42 days, 60 days, 72 days or 90 days after the start of administration of cell therapy (e.g., T cell therapy). In some embodiments, the methods provided involve continued administration, such as at regular intervals, of the inhibitor of DGKα and / or DGKζ after the start of administration of cell therapy.

[0349] In some embodiments, the inhibitor of DGKα and / or DGKζ is administered up to or up to about 1 day, up to or up to about 2 days, up to or up to about 3 days, up to or up to about 4 days, up to or up to about 5 days, up to or up to about 6 days, up to or up to about 7 days, up to or up to about 12 days, up to or up to about 14 days, up to or up to about 21 days, up to or up to about 24 days, up to or up to about 28 days, up to or up to about 30 days, up to or up to about 35 days, up to or up to about 42 days, up to or up to about 60 days, or up to or up to about 90 days, up to or up to about 120 days, up to or up to about 180 days, up to or up to about 240 days, up to or up to about 360 days, or up to or up to about 720 days or more after the start of administration of the cell therapy (e.g., T cell therapy).

[0350] In some of any such aforementioned embodiments, an inhibitor of DGKα and / or DGKζ is administered prior to and after the initiation of administration of cell therapy (eg, T cell therapy).

[0351] In some embodiments, initiation of administration of the inhibitor of DGKα and / or DGKζ occurs when or after the peak or maximum level of cells of the T cell therapy become detectable in the blood of the subject, optionally immediately thereafter or within 1-3 days thereafter. In some embodiments, initiation of administration of the inhibitor of DGKα and / or DGKζ occurs when or after the number of cells of the T cell therapy detectable in the blood becomes undetectable or reduced, optionally reduced compared to a previous time point after administration of the T cell therapy, after being detectable in the blood, optionally immediately thereafter or within 1-3 days thereafter. In some embodiments, initiation of administration of the inhibitor of DGKα and / or DGKζ occurs when or after the number of cells of the T cell therapy detectable in the blood becomes undetectable or reduced, optionally reduced compared to a previous time point after administration of the T cell therapy, optionally immediately thereafter or within 1-3 days thereafter. In some embodiments, initiation of administration of the inhibitor of DGKα and / or DGKζ occurs when or after the number of cells of the T cell therapy detectable in the blood becomes less than 1.5-fold, 2.0-fold, 3.0-fold, 4.0-fold, 5.0-fold, 10-fold or less of the peak or maximum number of cells of the T cell therapy detectable in the blood of the subject after initiation of administration of the T cell therapy, optionally immediately thereafter or within 1-3 days thereafter. In some embodiments, initiation of administration of the inhibitor of DGKα and / or DGKζ occurs when or after, as appropriate, shortly thereafter or within 1-3 days after the number of T cells detectable in the blood from the subject is less than 10%, less than 5%, less than 1%, or less than 0.1% of the total peripheral blood mononuclear cells (PBMCs) in the blood of the subject at a time point after the peak or maximum level of T cell therapy cells is detectable in the blood of the subject. In some embodiments, initiation of administration of the inhibitor of DGKα and / or DGKζ occurs when or after, as appropriate, shortly thereafter or within 1-3 days after the number of exhausted, blood detectable T cell therapy cells is increased to more than 1.5-fold, 2.0-fold, 3.0-fold, 4.0-fold, 5.0-fold, 10-fold or more of the peak or maximum number of non-exhausted, blood detectable T cell therapy cells after initiation of administration of the T cell therapy. In some embodiments, administration of the DGKα and / or DGKζ inhibitor is initiated when or after a subject exhibits disease progression and / or relapse following remission after treatment with T cell therapy, as appropriate, immediately thereafter or within 1-3 days thereafter.In some embodiments, initiation of administration of the DGKα and / or DGKζ inhibitor occurs when or after the subject exhibits an increased tumor burden compared to the tumor burden at a time point prior to or after administration of the T cells and prior to initiation of administration of the DGKα and / or DGKζ inhibitor, optionally immediately thereafter or within 1-3 days thereafter.

[0352] In some embodiments, the initiation of administration of the inhibitor of DGKα and / or DGKζ in at least one cycle follows the initiation of administration of T cell therapy. In some embodiments, the initiation of administration of the inhibitor of DGKα and / or DGKζ follows at least or about at least 1 day, at least or about at least 2 days, at least or about at least 3 days, at least or about at least 4 days, at least or about at least 5 days, at least or about at least 6 days, at least or about at least 7 days, at least or about at least 8 days, at least or about at least 9 days, at least or about at least 10 days, at least or about at least 12 days, at least or about at least 14 days, at least or about at least 15 days, at least or about at least 21 days, at least or about at least 24 days, at least or about at least 28 days, at least or about at least 30 days, at least or about at least 35 days, or at least or about at least 42 days, at least or about at least 60 days, or at least or about at least 90 days after the initiation of administration of T cell therapy. In some embodiments, the initiation of administration of the DGKα and / or DGKζ inhibitor occurs at least 2 days, at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks after the initiation of administration of the T cell therapy. The initiation of administration of the DGKα and / or DGKζ inhibitor occurs 2-35 days after the initiation of administration of the T cell therapy. In some embodiments, the initiation of administration of the DGKα and / or DGKζ inhibitor occurs 2-28 days after the initiation of administration of the T cell therapy. In some embodiments, the initiation of administration of the DGKα and / or DGKζ inhibitor occurs 2-21 days after the initiation of administration of the T cell therapy. In some embodiments, the initiation of administration of the DGKα and / or DGKζ inhibitor occurs 2-14 days after the initiation of administration of the T cell therapy. In some embodiments, the initiation of administration of the DGKα and / or DGKζ inhibitor occurs 7-21 days after the initiation of administration of the T cell therapy. In some embodiments, initiation of administration of the inhibitor of DGKα and / or DGKζ occurs 7-14 days after initiation of administration of the T cell therapy.In some embodiments, initiation of administration of the inhibitor of DGKα and / or DGKζ occurs more than or about 14, 15, 16, 17, 18, 19, 20, 21, 24, or 28 days after initiation of administration of the T cell therapy.

[0353] In some embodiments, the inhibitor of DGKα and / or DGKζ is administered several times a day, twice a day, daily, every other day, three times a week, twice a week, or once a week after the initiation of cell therapy. In some embodiments, the inhibitor of DGKα and / or DGKζ is administered daily. In some embodiments, the inhibitor of DGKα and / or DGKζ is administered twice a day. In some embodiments, the inhibitor of DGKα and / or DGKζ is administered three times a day. In other embodiments, the inhibitor of DGKα and / or DGKζ is administered every other day. In some embodiments, the inhibitor of DGKα and / or DGKζ is administered daily. In some embodiments, the inhibitor of DGKα and / or DGKζ is administered during an administration period that spans several consecutive days, such as up to about 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more consecutive days. In some embodiments, the inhibitor of DGKα and / or DGKζ is administered for more than or about 7 consecutive days, more than or about 14 consecutive days, more than or about 21 consecutive days, more than or about 21 consecutive days, or more than or about 28 consecutive days. In some embodiments, the inhibitor of DGKα and / or DGKζ is administered during an administration period that spans up to 21 consecutive days. In some embodiments, the inhibitor of DGKα and / or DGKζ is administered during an administration period lasting up to 21 cons...

Claims

1. 1. A medicament for treating a disease or condition, comprising T cell therapy, comprising: (a) administering a T cell therapy to a subject having said disease or condition, said T cell therapy comprising engineered T cells expressing a recombinant receptor; and (b) administering to the subject an inhibitor of DGKα and / or DGKζ. A medicine for use in

2. The pharmaceutical composition of claim 1 , wherein administration of the DGKα and / or DGKζ inhibitor is initiated after administration of T cell therapy is initiated.

3. A pharmaceutical for treating a disease or condition, comprising an inhibitor of DGKα and / or DGKζ, characterized in that it is used in a step of administering the inhibitor of DGKα and / or DGKζ to a subject having the disease or condition, wherein at the start of administration of the inhibitor of DGKα and / or DGKζ, the subject has previously been administered T cell therapy comprising engineered T cells expressing a recombinant receptor for the treatment of the disease or condition.

4. A pharmaceutical for rescuing engineered T cells of a T cell therapy from exhaustion, comprising an inhibitor of DGKα and / or DGKζ, characterized in that it is used in a step of administering the inhibitor of DGKα and / or DGKζ to a subject, wherein at the start of administration of the inhibitor of DGKα and / or DGKζ, the subject has previously been administered a T cell therapy comprising engineered T cells expressing a recombinant receptor for the treatment of a disease or condition.

5. A pharmaceutical for reducing or delaying the onset of T cell exhaustion in T cells of a T cell therapy comprising an inhibitor of DGKα and / or DGKζ, characterized in that it is used in a step of administering the inhibitor of DGKα and / or DGKζ to a subject, wherein at the start of administration of the inhibitor of DGKα and / or DGKζ, the subject has previously been administered a T cell therapy comprising engineered T cells expressing a recombinant receptor for the treatment of a disease or condition.

6. The pharmaceutical agent according to any one of claims 1 to 5, wherein administration of the DGKα and / or DGKζ inhibitor is initiated 1 to 28 days after the initiation of administration of T cell therapy.

7. The pharmaceutical agent according to any one of claims 1 to 6, wherein upon administration of the inhibitor of DGKα and / or DGKζ, at least or about 10%, at least or about 20%, at least or about 30%, at least or about 40%, or at least or about 50% of the total recombinant receptor-expressing T cells in a biological sample from the subject have an exhausted phenotype.

8. The pharmaceutical agent of any one of claims 1 to 7, wherein administration of the inhibitor of DGKα and / or DGKζ is initiated at, or approximately at, or within about one week of the time when peak or maximum levels of T cell therapy cells are detected or become detectable in the subject's blood.

9. The pharmaceutical composition of claim 1 , wherein administration of the DGKα and / or DGKζ inhibitor is initiated simultaneously with administration of T cell therapy.

10. The pharmaceutical composition of claim 1 , wherein administration of the DGKα and / or DGKζ inhibitor is initiated prior to the initiation of administration of T cell therapy.

11. A pharmaceutical for treating a disease or condition, comprising T cell therapy, characterized in that the pharmaceutical is used in the step of administering the T cell therapy, comprising engineered T cells expressing a recombinant receptor, to a subject having the disease or condition, wherein at the start of administration of the T cell therapy, the subject has previously been administered an inhibitor of DGKα and / or DGKζ.

12. The pharmaceutical according to any one of claims 1 to 11, wherein the inhibitor of DGKα and / or DGKζ is an inhibitor of DGKα and is not a significant inhibitor of DGKζ.

13. The pharmaceutical agent according to any one of claims 1 to 12, wherein the inhibitor of DGKα and / or DGKζ is an inhibitor of DGKζ and is not a significant inhibitor of DGKα.

14. The pharmaceutical according to any one of claims 1 to 13, wherein the inhibitor of DGKα and / or DGKζ is an inhibitor of DGKα and DGKζ.

15. The pharmaceutical according to any one of claims 1 to 14, wherein the inhibitor of DGKα and / or DGKζ is not a significant inhibitor of other DGKs.

16. The inhibitor of DGKα and / or DGKζ has the formula (I): 【Chemistry 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 is 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 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 N.R. 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 R ４ａ and R ４ｂ Together with the carbon atom to which they are attached, they represent 0 to 3 R ｆ C each substituted with ３～６ forms 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 N.R. ｃ C(O)(C １～４ alkyl), -(CH ２ ) １～２ N.R. ｃ C(O)O(C １～４ alkyl), -(CH ２ ) １～２ N.R. 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. The pharmaceutical agent according to any one of claims 1 to 14, which is a compound of the formula (I) or a pharma- ceutically acceptable salt thereof.

17. The inhibitor of DGKα and / or DGKζ has the formula (II): 【Chemistry 2】 (II) (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 is 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 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 N.R. 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 N.R. 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 N.R. 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 it alkyl; Or R ４ａ and R ４ｂ Together with the carbon atom to which they are attached, they represent 0 to 3 R ｆ C each substituted with ３～６ forms 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 4-10 membered heterocyclyl substituted with -(CH ２ ) １～２ N.R. ｃ C(O)(C １～４ alkyl), -(CH ２ ) １～２ N.R. ｃ C(O)O(C １～４ alkyl), -(CH ２ ) １～２ N.R. 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. The pharmaceutical agent according to any one of claims 1 to 16, which is a compound represented by the formula:

18. The inhibitor of DGKα and / or DGKζ has the structure: 【Chemistry 3】 18. The medicament according to claim 17, which is a compound of formula (II) having the formula:

19. The pharmaceutical of any one of claims 1 to 18, wherein the inhibitor of DGKα and / or DGKζ is administered in an amount, at a time, for a duration and / or with a frequency effective to result in an increase in antigen-specific or antigen receptor-driven activity of engineered T cells.

20. The pharmaceutical of any one of claims 1 to 19, wherein the inhibitor of DGKα and / or DGKζ is administered in an amount, at a time, for a duration and / or with a frequency effective to prevent, inhibit or delay the development of an exhausted phenotype in engineered T cells.

21. The pharmaceutical of any one of claims 1 to 20, wherein the inhibitor of DGKα and / or DGKζ is administered in an amount, at a time, for a duration and / or at a frequency effective to at least partially reverse the exhaustion phenotype in the engineered T cells.

22. The pharmaceutical of any one of claims 1 to 21, wherein the level of exhaustion of the engineered T cells expressing the recombinant receptor is determined by measuring the level of one or more exhaustion markers on the cell surface of the engineered T cells expressing the recombinant receptor.

23. The method of any one of claims 1 to 22, wherein the inhibitor of DGKα and / or DGKζ is administered in an amount of 0.25 mg to 250 mg or about 0.25 mg to about 250 mg.

24. The method of any one of claims 1 to 23, wherein the inhibitor of DGKα and / or DGKζ is administered in an amount of 0.5 mg to 100 mg or about 0.5 mg to about 100 mg.

25. The method of any one of claims 1 to 24, wherein the recombinant receptor is an engineered T cell receptor (eTCR).

26. The pharmaceutical according to any one of claims 1 to 25, wherein the recombinant receptor is a chimeric antigen receptor (CAR).

27. The pharmaceutical agent of claim 26, wherein the CAR is a BREYANZI® (lysocabtagene marallucel), TECARTUS™ (brexcabtagene autolucel), KYMRIAH™ (tisagenlecleucel), YESCARTA™ (axicabtagene siloleucel), ABECMA® (idecabtagene bileucel), or CARVYKTI™ (siltacabtagene autolucel) CAR.

28. The pharmaceutical of any one of claims 1 to 27, wherein the recombinant receptor binds to a target antigen that is associated with, specific for, and / or expressed in cells or tissues of the disease or condition.

29. The pharmaceutical composition according to any one of claims 1 to 28, wherein the disease or condition is cancer, an autoimmune or inflammatory disease, or an infectious disease.

30. The pharmaceutical composition according to any one of claims 1 to 29, wherein the disease or condition is cancer.

31. The pharmaceutical agent according to any one of claims 1 to 30, wherein the disease or condition is a B-cell malignant cancer.

32. The dose of cells of the T cell therapy is 1×10 ５ ~1×10 ９ pcs or about 1 x 10 ５ ~Approx. 1×10 ９ The medicament according to any one of claims 1 to 31, comprising total recombinant receptor-expressing T cells (upper and lower limits inclusive).

33. The dose of cells for T cell therapy is 1×10 ５ ~5×10 ８ 1 piece or about 1 x 10 ５ ~Approx. 5×10 ８ Total recombinant receptor-expressing T cells, 1 x 10 ６ ~2.5 x 10 ８ 1 piece or about 1 x 10 ６ ~Approx. 2.5×10 ８ Total recombinant receptor-expressing T cells, 5 x 10 ６ ~1×10 ８ Pieces or about 5 x 10 ６ ~Approx. 1×10 ８ Total recombinant receptor-expressing T cells, 1 x 10 ７ ~2.5 x 10 ８ Pieces or about 1 x about 10 ７ ~2.5 x 10 ８ total recombinant receptor-expressing T cells or 5 x 10 ７ ~1×10 ８ Pieces or about 5 x 10 ７ ~Approx. 1×10 ８ The medicament according to any one of claims 1 to 32, comprising total recombinant receptor-expressing T cells (upper and lower limits included).

34. The method of any one of claims 1 to 33, wherein the dose of cells for the T cell therapy is administered parenterally, optionally intravenously.

35. The method of any one of claims 1 to 34, wherein the T cell therapy comprises primary T cells obtained from the subject.

36. The medicament of any one of claims 1 to 35, wherein the T cells of the T cell therapy are autologous to the subject.

37. The method of any one of claims 1 to 36, wherein the T cells of the T cell therapy are allogeneic to the subject.

38. The pharmaceutical composition of any one of claims 1 to 37, further comprising administering to the subject a checkpoint antagonist.

39. The pharmaceutical composition of any one of claims 1 to 38, further comprising the step of administering to the subject a PD1 / PD-L1 axis antagonist and a CTLA4 antagonist.

40. The pharmaceutical of any one of claims 1 to 39, wherein the inhibitor of DGKα and / or DGKζ, and optionally a checkpoint antagonist, are administered for a period of up to 3 months after the start of administration of T cell therapy.

41. The pharmaceutical of any one of claims 1 to 40, wherein the inhibitor of DGKα and / or DGKζ, and optionally a checkpoint antagonist, are administered for a period of up to 6 months after the start of administration of T cell therapy.

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