IP Library › Granted Patent US 12,454,531

Granted Patent B2

US 12,454,531 · App. 17/785,749 · Granted Oct 28, 2025

Substituted piperazine derivatives useful as T cell activators

Inventors: Upender Velaparthi (Princeton Junction, NJ); Chetan Padmakar Darne (Ewing, NJ); Richard E. Olson (Cambridge, MA); Jayakumar Sankara Warrier (Bangalore, IN)

Assignee: Bristol-Myers Squibb Company

C07D471/04 A61P35/00 C07D519/00

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Quick Facts

Patent No.: US 12,454,531
App. No.: 17/785,749
Granted: Oct 28, 2025
Kind: B2

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Abstract

Disclosed are compounds of Formula (I): or a salt thereof, wherein: R 1 , R 2 , R 4 , R 5 , R 6 , and m are defined herein. Also disclosed are methods of using such compounds to inhibit the activity of one or both of diacylglycerol kinase alpha (DGKα) and diacylglycerol kinase zeta (DGKζ), and pharmaceutical compositions comprising such compounds. These compounds are useful in the treatment of viral infections and proliferatve disorders, such as cancer.

Claims (186)

1. A compound of Formula (I):

or a salt thereof, wherein:

X is N;

Y is CR 3 or N;

R 4 is —CR 4a R 4c -L-R 4b ;

L is L 1 or —(CH 2 ) 1-2 L 1 -;

R is Cl or —CN;

R 2 is —CH 3 ;

R 3 is H;

L 1 is —C(O)—, —C(O)O—, —C(O)NR d —, —C(O)NHO—, —C(O)NHS(O) 2 —, —CH 2 C(O)—, —CH 2 NR d —, —CH 2 NHC(O)—, —CH 2 NHC(O)O—, —CH 2 NHS(O) 2 —, —CH 2 C(O)O—, —CH 2 C(O)NR d —, —CH 2 CH 2 NHC(O)O—, —CH 2 CH 2 NHS(O) 2 —, or —P(O)(CH 3 )—;

R 4a is:

(i) —CH 3 ; or

(ii) phenyl or pyridinyl, each substituted with zero to 2 substituents independently selected from F, —CH 3 , —CF 3 , and —OCH 3 ;

R 4b is:

(i) H, —CN, C 1-4 alkyl, —CH 2 CN, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CH 2 OH, —CH 2 CH 2 CN, —CH 2 CH 2 CF 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH 2 S(O) 2 CH 3 , —CH 2 C(CH 3 ) 2 OH, —CH 2 (cyclopropyl), —CH 2 (hydroxycyclopropyl),

(ii) azetidinyl, cyclopropyl, cyclopentyl, morpholinyl, pyrazolyl, isoxazolyl, piperidinyl, piperazinyl, pyrazolyl, pyrrolidinyl, dioxidothiomorpholinyl, or azaspiro[2.5]octanyl, each substituted with zero to 2 R b ;

each R b is independently F, —OH, —CH 3 , —CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 OCH 3 , —OCH 3 , or —S(O) 2 CH 3 ;

R 4c is H;

R d is H or —CH 3 ;

each R 5 is independently H, —CH 3 , or —CH 2 CH 3 ;

each R 6 is hydrogen; and

m is zero, 1, or 2.

2. The compound according to claim 1 or a salt thereof, wherein: L is L 1 .

3. The compound according to claim 1 or a salt thereof, wherein: L is —(CH 2 ) 1-2 L 1 -.

4. The compound according to claim 1 or a salt thereof, having the structure:

wherein R 5a and R 5c are independently selected from R 5 .

5. The compound according to claim 1 or a salt thereof, having the structure:

6. The compound according to claim 1 or a salt thereof, wherein L 1 is —C(O)— or —C(O)O—.

7. The compound according to claim 1 or a salt thereof, wherein L 1 is —C(O)—, —C(O)O—, —C(O)NR d —, or —C(O)NR d O—.

8. The compound according to claim 1 or a salt thereof, wherein L 1 is —NR d —, —NR d C(O)—, —NR d C(O)O—, or —NR d C(O)NR d —.

9. The compound according to claim 1 or a salt thereof, wherein L 1 is —S(O) 2 —, —S(O) 2 NR d —, —NR d S(O) 2 —, or —P(O)R e —.

10. A compound or a salt thereof, wherein said compound is:

isopropyl 2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(4-fluorophenyl)acetate (1-2);

Methyl 2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(5-fluoropyridin-2-yl)acetate (3-4);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-N-(2,2-difluoroethyl)-2-(4-fluorophenyl)acetamide (5-6);

methyl 2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(4-fluorophenyl)acetate (7-8);

2-((2R,5S)-4-(6-Cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(4-fluorophenyl)acetic acid (9-10);

(8-((2S,5R)-4-(1-(4-fluorophenyl)-2-oxo-2-(piperidin-1-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (11-12);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(4-fluorophenyl)acetamide (13-14);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-N-(1-methyl-1H-pyrazol-3-yl)acetamide (15-16);

8-((2S,5R)-4-(1-(4-fluorophenyl)-2-morpholino-2-oxoethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (17-18);

8-((2S,5R)-4-(1-(4-fluorophenyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (19-20);

8-((2S,5R)-4-(1-(4-fluorophenyl)-2-oxo-2-(pyrrolidin-1-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (21-22);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-N,N-dimethylacetamide (23-24);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-N-methylacetamide (25-26);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-N-(2-hydroxyethyl)acetamide (27-28);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-N-(isoxazol-3-yl)acetamide (29-30);

methyl 3-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-3-(4-fluorophenyl)propanoate (31-32);

N-(tert-butyl)-3-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-3-(4-fluorophenyl)propanamide (33-34);

3-[(2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl]-3-(4-fluorophenyl)-N-(propan-2-yl)propanamide (35);

3-[(2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl]-3-(4-fluorophenyl)-N-(propan-2-yl)propanamide (36);

3-[(2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl]-3-(4-fluorophenyl)propanamide (37);

3-[(2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl]-3-(4-fluorophenyl)propanamide (38);

3-[(2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl]-3-(4-fluorophenyl)-N-methylpropanamide (39);

3-[(2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl]-3-(4-fluorophenyl)-N-methylpropanamide (40);

3-[(2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl]-3-(4-fluorophenyl)-N-methyl-N-(propan-2-yl)propanamide (41);

3-[(2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl]-3-(4-fluorophenyl)-N-methyl-N-(propan-2-yl)propanamide (42);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-N-cyclopentylpropanamide (43-44);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-N-(1-methyl-1H-pyrazol-4-yl)propanamide (45);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-N-(1-methyl-1H-pyrazol-4-yl)propanamide (46);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-N-cyclopropylpropanamide (47);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-N-cyclopropylpropanamide (48);

8-((2S,5R)-4-((dimethylphosphoryl)(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (49-50);

ethyl 2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)acetate (51);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)acetic acid (52);

4-((2S,5R)-2,5-diethyl-4-(2-morpholino-2-oxo-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (53-54);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-N-(2-methoxyethyl)-2-(4-(trifluoromethyl)phenyl)acetamide (55-56);

3-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)propyl 2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(4-fluorophenyl)acetate (57);

methyl 2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(4-methoxyphenyl)acetate (58);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(4-methoxyphenyl)acetic acid (59);

3-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)propyl 2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(4-methoxyphenyl)acetate (60-61);

2-(3-methyl-3H-diazirin-3-yl)ethyl 2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(4-fluorophenyl)acetate (62);

ethyl 2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)acetate (69-70);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)acetic acid (71-72);

2-((2R,5S)-4-(6-Cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-N-((1-hydroxycyclopropyl)methyl)-2-(4-(trifluoromethyl)phenyl) acetamide (73-74);

4-((2S,5R)-2,5-diethyl-4-(2-morpholino-2-oxo-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-6-(12-methyl)-1-methylpyrido[3,2-d]pyrimidin-2 (1H)-one (75-76);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-N-(2-methoxyethyl)-2-(4-(trifluoromethyl)phenyl)acetamide (77-78);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-N-(2-hydroxy-2-methylpropyl)-2-(4-(trifluoromethyl)phenyl)acetamide (79-80);

4-((2S,5R)-2,5-diethyl-4-(2-(3-hydroxy-3-methylazetidin-1-yl)-2-oxo-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (81-82);

4-((2S,5R)-2,5-diethyl-4-(2-oxo-2-(6-azaspiro[2.5]octan-6-yl)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (83-84);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-N-(cyclopropylmethyl)-N-methyl-2-(4-(trifluoromethyl)phenyl) acetamide (85-86);

4-((2S,5R)-2,5-diethyl-4-(2-(3-(hydroxymethyl)azetidin-1-yl)-2-oxo-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (87-88);

4-((2S,5R)-2,5-diethyl-4-(2-(3-(2-hydroxypropan-2-yl)azetidin-1-yl)-2-oxo-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (89-90);

4-((2S,5R)-2,5-diethyl-4-(2-(3-(methylsulfonyl)azetidin-1-yl)-2-oxo-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (91-92);

4-((2S,5R)-2,5-diethyl-4-(2-(4-(methylsulfonyl)piperidin-1-yl)-2-oxo-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (93-94);

4-((2S,5R)-4-(2-(3,3-difluoroazetidin-1-yl)-2-oxo-1-(4-(trifluoromethyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (95-96);

4-((2S,5R)-4-(2-(1,1-dioxidothiomorpholino)-2-oxo-1-(4-(trifluoromethyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (97-98);

4-((2S,5R)-2,5-diethyl-4-(2-(3-methoxy-3-methylazetidin-1-yl)-2-oxo-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (99-100);

4-((2S,5R)-2,5-diethyl-4-(2-((S)-3-hydroxypyrrolidin-1-yl)-2-oxo-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (101-102);

4-((2S,5R)-2,5-diethyl-4-(2-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)-2-oxo-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (103-104);

4-((2S,5R)-2,5-diethyl-4-(2-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)-2-oxo-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (105-106);

4-((2S,5R)-2,5-diethyl-4-(2-((R)-3-hydroxypyrrolidin-1-yl)-2-oxo-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (107-108);

4-((2S,5R)-2,5-diethyl-4-(2-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-2-oxo-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (109-110);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-N-isopropyl-N-methyl-2-(4-(trifluoromethyl)phenyl)acetamide (111-112);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-N-isopropyl-2-(4-(trifluoromethyl)phenyl)acetamide (113-114);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-N-(2-methoxyethyl)-N-methyl-2-(4-(trifluoromethyl)phenyl)acetamide (115-116);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-N-methoxy-2-(4-(trifluoromethyl)phenyl)acetamide (117-118);

N-cyano-2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)acetamide (119-120);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-N-(cyanomethyl)-2-(4-(trifluoromethyl)phenyl)acetamide (121-122);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-N-(2,2,2-trifluoroethyl)-2-(4-(trifluoromethyl)phenyl)acetamide (123-124);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-N-(2-cyanoethyl)-2-(4-(trifluoromethyl)phenyl)acetamide (125-126);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)-N-(3,3,3-trifluoropropyl)acetamide (127-128);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-N-(2-(methylsulfonyl)ethyl)-2-(4-(trifluoromethyl)phenyl)acetamide (129-130);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-N-methoxy-2-(4-(trifluoromethyl)phenyl)acetamide (131-132);

ethyl 2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2-ethyl-5-methylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)acetate (133);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2-ethyl-5-methylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)acetic acid (134);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2-ethyl-5-methylpiperazin-1-yl)-N-methoxy-2-(4-(trifluoromethyl)phenyl)acetamide (135-136);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2-ethyl-5-methylpiperazin-1-yl)-N-(cyanomethyl)-2-(4-(trifluoromethyl)phenyl)acetamide (137-138);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2-ethyl-5-methylpiperazin-1-yl)-N-(2,2,2-trifluoroethyl)-2-(4-(trifluoromethyl)phenyl)acetamide (139-140);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2-ethyl-5-methylpiperazin-1-yl)-N-(2-cyanoethyl)-2-(4-(trifluoromethyl)phenyl)acetamide (141-142);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2-ethyl-5-methylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)-N-(3,3,3-trifluoropropyl)acetamide (143-144);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2-ethyl-5-methylpiperazin-1-yl)-N-(2-(methylsulfonyl)ethyl)-2-(4-(trifluoromethyl)phenyl)acetamide (145-146);

N-cyano-2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2-ethyl-5-methylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)acetamide (147-148);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2-ethyl-5-methylpiperazin-1-yl)-N-(methylsulfonyl)-2-(4-(trifluoromethyl)phenyl)acetamide (149-150);

2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2-ethyl-5-methylpiperazin-1-yl)-N-(cyclopropylsulfonyl)-2-(4-(trifluoromethyl)phenyl)acetamide (151-152);

methyl 3-((2R,5S)-4-(6-chloro-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)propanoate (153);

methyl 3-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)propanoate (154-155);

3-((2R,5S)-4-(6-chloro-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)propanoic acid (156);

3-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)propanoic acid (157-158);

4-((2S,5R)-2,5-diethyl-4-(3-oxo-3-(6-azaspiro[2.5]octan-6-yl)-1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (159-160);

3-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-N-methyl-N-(1-methylpiperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)propanamide (161-162);

3-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-N-(2-methoxyethyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)propanamide (163-164);

4-((2S,5R)-2,5-diethyl-4-(3-((R)-2-(methoxymethyl)pyrrolidin-1-yl)-3-oxo-1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (165-166);

methyl (3-((2R,5S)-4-(6-chloro-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)propyl) carbamate (167);

3-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)propanoic acid (168-169);

N-(3-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)propyl)methanesulfonamide (170-171);

4-((2S,5R)-4-(2-((cyanomethyl)(methyl)amino)-1-(4-(trifluoromethyl)phenyl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (172-173);

4-((2S,5R)-4-(2-((cyanomethyl)amino)-1-(4-(trifluoromethyl)phenyl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (174-175);

4-((2S,5R)-5-ethyl-2-methyl-4-(2-((2,2,2-trifluoroethyl)amino)-1-(4-(trifluoromethyl)phenyl)ethyl) piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (176-177);

4-((2S,5R)-4-(2-((2-cyanoethyl)amino)-1-(4-(trifluoromethyl)phenyl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (178-179);

4-((2S,5R)-5-ethyl-2-methyl-4-(1-(4-(trifluoromethyl)phenyl)-2-((3,3,3-trifluoropropyl)amino)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (180-181);

4-((2S,5R)-4-(2-((cyanomethyl)(methyl)amino)-1-(4-(trifluoromethyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (182-183);

4-((2S,5R)-4-(2-((cyanomethyl)(methyl)amino)-1-(4-(trifluoromethyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (184-185);

4-((2S,5R)-2,5-diethyl-4-(2-((2,2,2-trifluoroethyl)amino)-1-(4-(trifluoromethyl)phenyl)ethyl) piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (186-187);

4-((2S,5R)-4-(2-((2-cyanoethyl)amino)-1-(4-(trifluoromethyl)phenyl)ethyl)-2,5-diethylpiperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (188-189);

4-((2S,5R)-2,5-diethyl-4-(1-(4-(trifluoromethyl)phenyl)-2-((3,3,3-trifluoropropyl)amino) ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (190-191);

N-(2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2-ethyl-5-methylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethyl)acetamide (192-193);

N-(2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2-ethyl-5-methylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethyl)isobutyramide (194-195);

methyl (2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2-ethyl-5-methylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethyl)carbamate (196-197);

isopropyl (2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2-ethyl-5-methylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethyl)carbamate (198-199);

N-(2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2-ethyl-5-methylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethyl)methanesulfonamide (200-201);

N-(2-((2R,5S)-4-(6-Cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethyl)acetamide (202-203);

N-(2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethyl)isobutyramide (204-205);

methyl (2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethyl)carbamate (206-207);

isopropyl (2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethyl)carbamate (208-209); or

N-(2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-4-yl)-2,5-diethylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethyl)methanesulfonamide (210-211).

11. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically-acceptable salt thereof; and a pharmaceutically acceptable carrier.

12. A compound of Formula (I):

or a salt thereof, wherein:

X is CR 6 or N;

Y is CR 3 or N;

R 1 is H, F, Cl, Br, —CN, C 1-3 alkyl substituted with zero to 4 R 1a , C 3-4 cycloalkyl substituted with zero to 4 R 1a , C 1-3 alkoxy substituted with zero to 4 R 1a , —C(O)NR a R a , —NR a R a , —S(O) n R f , or —P(O)R f R f ;

each R 1a is independently F, Cl, —CN, —OH, —OCH 3 , or —NR a R a ;

each R a is independently H or C 1-3 alkyl;

R 2 is H, C 1-3 alkyl substituted with zero to 4 R 2a , C 2-3 alkenyl substituted with zero to 4 R 2a , or C 3-4 cycloalkyl substituted with zero to 4 R 2a ;

each R 2a is 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, —NO 2 , or pyridinyl substituted with zero to 2 R 3a ;

each R 3a is halo, —CN, C 1-3 alkyl, or C 1-3 alkoxy;

R 4 is —CR 4a R 4c -L-R 4b ;

L is L 1 or —(CH 2 ) 1-3 L 1 -;

L 1 is —C(O)—, —C(O)O—, —C(O)NR d —, —C(O)NR d O—, —NR d —, —NR d C(O)—, —NR d C(O)O—, —NR d C(O)NR d —, —C(O)NR d O—, —S(O) 2 —, —S(O) 2 NR d —, —NR d S(O) 2 —, or —P(O)R e —;

R 4a is:

(i) H or C 1-6 alkyl substituted with zero to 4 substituents independently selected from F, Cl, —CN, —OH, —OCH 3 , —SCH 3 , C 1-3 fluoroalkoxy, —NR a R a , —S(O) 2 R f , or —NR a S(O) 2 R f ; or

(ii) C 3-6 cycloalkyl, C 5-14 heterocyclyl, C 6-10 aryl, or C 5-14 heteroaryl, each substituted with zero to 4 R b ;

each R b is independently 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), —C(O)NH 2 , —C(O)NH(C 1-4 alkyl), —C(O)N(C 1-4 alkyl) 2 , —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), C 3-6 cycloalkyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, or —CR c R c (phenyl);

R 4b is:

(i) —CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 NH 2 ;

(ii) —CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 NHC(O)OC(CH 3 ) 3 ; or

R 4c is H or C 1-6 alkyl;

each R c is independently H or C 1-2 alkyl;

each R d is independently H or C 1-6 alkyl;

R e is C 1-6 alkyl;

each R f is independently C 3-4 cycloalkyl or C 1-3 alkyl substituted with zero to 4 R 1a ;

each R 5 is independently F, Cl, —CN, —OH, C 1-6 alkyl substituted with zero to 4 R g , C 1-3 alkoxy substituted with zero to 4 R g , C 2-4 alkenyl substituted with zero to 4 R g , C 2-4 alkynyl substituted with zero to 4 R g , C 3-4 cycloalkyl substituted with zero to 4 R g , phenyl substituted with zero to 4 R g , oxadiazolyl substituted with zero to 3 R g , pyridinyl substituted with zero to 4 R g , —(CH 2 ) 1-2 (heterocyclyl substituted with zero 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), or two R 5 attached to the same carbon atom form ═O;

each R g is independently F, Cl, —CN, —OH, C 1-3 alkoxy, C 1-3 fluoroalkoxy, —O(CH 2 ) 1-2 O(C 1-2 alkyl), C 3-5 cycloalkyl, or —NR c R c ;

each R 6 is H, F, Cl, —CN, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , or —OCH 3 ;

m is zero, 1, 2, or 3; and

n is zero, 1, or 2.

13. The compound according to claim 12 or a salt thereof, wherein said compound is:

tert-butyl (2-(2-(2-(2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(4-fluorophenyl)acetamido)ethoxy)ethoxy)ethyl)carbamate (63);

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(4-fluorophenyl)acetamide, TFA (64);

N-(2-(2-(2-(2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(4-fluorophenyl)acetamido)ethoxy)ethoxy)ethyl)-3′,6′-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9′-xanthene]-5-carboxamide (65);

2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl 2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(4-fluorophenyl)acetate (66);

2-(2-(2-aminoethoxy)ethoxy)ethyl 2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(4-fluorophenyl)acetate, TFA (67); or

2-(2-(2-(3′,6′-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9′-xanthene]-5-carboxamido)ethoxy)ethoxy)ethyl 2-((2R,5S)-4-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperazin-1-yl)-2-(4-fluorophenyl)acetate (68).

Priority Claims (1)

IN 201911053559 · Dec 23, 2019 · national

Continuity (1)

Related Publication 20230118629A1 · Apr 20, 2023

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