Inhibitors of protein arginine deiminases

1. A method of providing therapeutic benefit to a patient with rheumatoid arthritis comprising administering to the patient a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein the compound of Formula (I) is described by the following structure:

wherein,

R 5 is selected from halogen;

R 6 is selected from fluoro;

R 7 is selected from fluoro;

X is selected from:

(a)

 wherein n is 2, 3, or 4; each R 1 is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl; and each R 2 is independently hydrogen or optionally substituted alkyl;

(b)

 wherein p is 1, 2, 3, or 4; q is 1, 2, 3, or 4; each R 1 is independently selected from hydrogen, halogen, —OH, —NH 2 , optionally substituted alkyl, or optionally substituted alkoxy; each R 2 is hydrogen or optionally substituted alkyl; and

R 3 is hydrogen or optionally substituted alkyl; or

(c)

 wherein p is 1, 2, 3, or 4; q is 1, 2, 3, or 4; each R 1 is independently selected from hydrogen, halogen, —OH, —NH 2 , optionally substituted alkyl, or optionally substituted alkoxy; each R 2 is hydrogen or optionally substituted alkyl; and

R 3 is hydrogen or optionally substituted alkyl.

2. The method of claim 1 , wherein X is:

wherein n is 2, 3, or 4; each R 1 is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl; and each R 2 is independently hydrogen or optionally substituted alkyl.

3. The method of claim 2 , wherein each R 1 is independently selected from hydrogen, optionally substituted alkyl; each R 2 is hydrogen; and n is 2 or 3.

4. The method of claim 1 , wherein X is:

wherein p is 1, 2, 3, or 4; q is 1, 2, 3, or 4; each R 1 is independently selected from hydrogen, halogen, —OH, —NH 2 , optionally substituted alkyl, or optionally substituted alkoxy; each R 2 is hydrogen or optionally substituted alkyl; and R 3 is hydrogen or optionally substituted alkyl.

5. The method of claim 4 , wherein R 2 is hydrogen, and R 3 is hydrogen.

6. The method of claim 4 , wherein each R 1 is independently selected from hydrogen or optionally substituted alkyl.

7. The method of claim 4 , wherein p is 2, and q is 1.

8. The method of claim 4 , wherein X is 3-amino-4-hydroxypyrrolidin-1-yl.

9. The method of claim 1 , wherein X is:

wherein p is 1, 2, 3, or 4; q is 1, 2, 3, or 4; each R 1 is independently selected from hydrogen, halogen, —OH, —NH 2 , optionally substituted alkyl, or optionally substituted alkoxy; each R 2 is hydrogen or optionally substituted alkyl; and R 3 is hydrogen or optionally substituted alkyl.

10. The method of claim 9 , wherein R 2 is hydrogen, R 3 is hydrogen, p is 2, q is 1, and each R 1 is independently selected from hydrogen or optionally substituted alkyl.

11. The method of claim 1 , wherein R 5 is chloro, R 6 is fluoro, and R 7 is fluoro.

12. A method of providing therapeutic benefit to a patient with rheumatoid arthritis comprising administering to the patient a compound, or pharmaceutically acceptable salt or solvate thereof, selected from:

(R)-(3-Aminopyrrolidin-1-yl)(5-chloro-6,7-difluoro-1H-indol-2-yl)methanone,

(R)-(3-Aminopyrrolidin-1-yl)(5,6,7-trifluoro-1H-indol-2-yl)methanone,

(R)-(3-Aminopyrrolidin-1-yl)(5-bromo-6,7-difluoro-1H-indol-2-yl)methanone,

((3S,4R)-3-Amino-4-fluoro-pyrrolidin-1-yl)-(5-chloro-6,7-difluoro-1H-indol-2-yl)-methanone,

(S)—N-(1-Aminopropan-2-yl)-5-chloro-6,7-difluoro-1H-indole-2-carboxamide,

(S)—N-(1-Aminobutan-2-yl)-5-chloro-6,7-difluoro-1H-indole-2-carboxamide,

N-(2-Amino-1-cyclopropylethyl)-5-chloro-6,7-difluoro-1H-indole-2-carboxamide,

N-(3-(Aminomethyl)oxetan-3-yl)-5-chloro-6,7-difluoro-1H-indole-2-carboxamide,

5-Chloro-6,7-difluoro-N-((3S,4R)-4-methylpyrrolidin-3-yl)-1H-indole-2-carboxamide,

5-Chloro-6,7-difluoro-N-((3S,4S)-4-methylpyrrolidin-3-yl)-1H-indole-2-carboxamide,

5-Chloro-6,7-difluoro-N-((3R,4R)-4-hydroxypyrrolidin-3-yl)-1H-indole-2-carboxamide,

5-Chloro-6,7-difluoro-N-((3R,4S)-4-hydroxypyrrolidin-3-yl)-1H-indole-2-carboxamide,

5-Chloro-6,7-difluoro-N-((3S,4R)-4-hydroxypyrrolidin-3-yl)-1H-indole-2-carboxamide,

5-Chloro-6,7-difluoro-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-1H-indole-2-carboxamide,

(S)—N-(1-Amino-4-methylpentan-2-yl)-5-chloro-6,7-difluoro-1H-indole-2-carboxamide,

5-Chloro-6,7-difluoro-N-((3R,4R)-4-methylpyrrolidin-3-yl)-1H-indole-2-carboxamide,

(R)—N-(1-Aminopropan-2-yl)-5-chloro-6,7-difluoro-1H-indole-2-carboxamide,

((3S,4S)-3-Amino-4-hydroxypyrrolidin-1-yl)(5-chloro-6,7-difluoro-1H-indol-2-yl)methanone,

N-(Azetidin-3-yl)-5-chloro-6,7-difluoro-1H-indole-2-carboxamide,

(3-Aminoazetidin-1-yl)(5-chloro-6,7-difluoro-1H-indol-2-yl)methanone,

(R)-5-Chloro-6,7-difluoro-N-(pyrrolidin-3-yl)-1H-indole-2-carboxamide,

(S)-5-Chloro-6,7-difluoro-N-(pyrrolidin-3-yl)-1H-indole-2-carboxamide,

(S)-(3-Aminopyrrolidin-1-yl)(5-chloro-6,7-difluoro-1H-indol-2-yl)methanone,

(S)—N-(1-Amino-3,3-dimethylbutan-2-yl)-5-chloro-6,7-difluoro-1H-indole-2-carboxamide,

(5-Chloro-6,7-difluoro-1H-indol-2-yl)((3 S,4S)-3,4-diaminopyrrolidin-1-yl)methanone,

N-((3S,4S)-4-Aminopyrrolidin-3-yl)-5-chloro-6,7-difluoro-1H-indole-2-carboxamide,

N-((3R,4S)-4-Aminopyrrolidin-3-yl)-5-chloro-6,7-difluoro-1H-indole-2-carboxamide,

((3S,4R)-3-Amino-4-hydroxypyrrolidin-1-yl)(5-chloro-6,7-difluoro-1H-indol-2-yl)methanone,

5-Chloro-6,7-difluoro-N-((3S,4S)-4-methoxypyrrolidin-3-yl)-1H-indole-2-carboxamide,

5-Chloro-6,7-difluoro-N-((3R,4R)-4-methoxypyrrolidin-3-yl)-1H-indole-2-carboxamide,

((3S,4S)-3-Amino-4-methoxypyrrolidin-1-yl)(5-chloro-6,7-difluoro-1H-indol-2-yl)methanone,

5-Chloro-6,7-difluoro-N-((3R,4S)-4-methylpyrrolidin-3-yl)-1H-indole-2-carboxamide,

((3S,4S)-3-Amino-4-fluoropyrrolidin-1-yl)(5-chloro-6,7-difluoro-1H-indol-2-yl)methanone,

(R)-(3-Aminopiperidin-1-yl)(5-chloro-6,7-difluoro-1H-indol-2-yl)methanone,

(S)-5-Chloro-6,7-difluoro-N-(piperidin-3-yl)-1H-indole-2-carboxamide,

(R)-5-Chloro-6,7-difluoro-N-(piperidin-3-yl)-1H-indole-2-carboxamide,

5-Chloro-6,7-difluoro-N-((3R,4S)-4-methylpiperidin-3-yl)-1H-indole-2-carboxamide,

((3S,4S)-3-Amino-4-fluoropiperidin-1-yl)(5-chloro-6,7-difluoro-1H-indol-2-yl)methanone,

and

((3S,4R)-3-Amino-4-fluoropiperidin-1-yl)(5-chloro-6,7-difluoro-1H-indol-2-yl)methanone.

13. A method of providing therapeutic benefit to a patient with rheumatoid arthritis comprising administering to the patient a compound, or pharmaceutically acceptable salt or solvate thereof, selected from:

(S)-5-chloro-6,7-difluoro-N-methyl-N-(pyrrolidin-3-yl)-1H-indole-2-carboxamide,

N-(azetidin-3-yl)-5-chloro-6,7-difluoro-N-methyl-1H-indole-2-carboxamide,

5-chloro-6,7-difluoro-N-(3-methylazetidin-3-yl)-1H-indole-2-carboxamide,

5-chloro-6,7-difluoro-N-((2S,3S)-2-methylazetidin-3-yl)-1H-indole-2-carboxamide,

5-chloro-6,7-difluoro-N-((2R,3R)-2-methylazetidin-3-yl)-1H-indole-2-carboxamide,

(1R,5S)-3,6-diazabicyclo[3.2.0]heptan-6-yl(5-chloro-6,7-difluoro-1H-indol-2-yl)methanone,

(5-chloro-6,7-difluoro-1H-indol-2-yl)((3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)methanone,

(5-chloro-6,7-difluoro-1H-indol-2-yl)((3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)methanone,

(5-chloro-6,7-difluoro-1H-indol-2-yl)((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone,

(5-chloro-6,7-difluoro-1H-indol-2-yl)(2,6-diazaspiro[3.3]heptan-2-yl)methanone,

(5-chloro-6,7-difluoro-1H-indol-2-yl)(2,6-diazaspiro[3.4]octan-2-yl)methanone,

(S)-5-chloro-6,7-difluoro-N-(pyrrolidin-3-ylmethyl)-1H-indole-2-carboxamide,

(R)-5-chloro-6,7-difluoro-N-(pyrrolidin-3-ylmethyl)-1H-indole-2-carboxamide,

(S)—N-(1-aminopropan-2-yl)-5-chloro-6,7-difluoro-N-methyl-1H-indole-2-carboxamide,

((3S,4S)-3-amino-4-hydroxypyrrolidin-1-yl)(5-bromo-6,7-difluoro-1H-indol-2-yl)methanone,

((3S,4S)-3-amino-4-hydroxypyrrolidin-1-yl)(6,7-difluoro-5-iodo-1H-indol-2-yl)methanone, and

((3S,4R)-3-amino-4-hydroxypyrrolidin-1-yl)(5-bromo-6,7-difluoro-1H-indol-2-yl)methanone.

14. The method of claim 13 , wherein the compound, or pharmaceutically acceptable salt or solvate thereof, is selected from:

(S)—N-(1-Aminopropan-2-yl)-5-chloro-6,7-difluoro-1H-indole-2-carboxamide; or

5-Chloro-6,7-difluoro-N-((3S,4S)-4-methylpyrrolidin-3-yl)-1H-indole-2-carboxamide.

15. The method of claim 13 , wherein the compound, or pharmaceutically acceptable salt or solvate thereof, is selected from:

((3S,4S)-3-Amino-4-hydroxypyrrolidin-1-yl)(5-chloro-6,7-difluoro-1H-indol-2-yl)methanone; or

((3S,4R)-3-Amino-4-hydroxypyrrolidin-1-yl)(5-chloro-6,7-difluoro-1H-indol-2-yl)methanone.

16. The method of claim 13 , wherein the compound, or pharmaceutically acceptable salt or solvate thereof, is selected from:

((3S,4S)-3-amino-4-hydroxypyrrolidin-1-yl)(5-bromo-6,7-difluoro-1H-indol-2-yl)methanone; or

((3S,4R)-3-amino-4-hydroxypyrrolidin-1-yl)(5-bromo-6,7-difluoro-1H-indol-2-yl)methanone.