IP Library › Granted Patent US 9,597,340

Granted Patent B2

US 9,597,340 · App. 14/001,132 · Granted Mar 21, 2017

Cannabinoid receptor modulators

Inventors: Jayant Thatte (San Diego, CA); Anthony C. Blackburn (San Diego, CA); Sangdon Han (San Diego, CA); Robert M. Jones (San Diego, CA); Jae-Kyu Jung (San Diego, CA); Antonio Garrido Montalban (San Diego, CA); Biman B. Pal (San Diego, CA); Jaimie Karyn Rueter (San Diego, CA); Sonja Strah-Pleynet (Newton, MA); Lars Thoresen (San Diego, CA); Yifeng Xiong (San Diego, CA); Dawei Yue (San Diego, CA); Xiuwen Zhu (San Diego, CA)

Assignee: Arena Pharmaceuticals, Inc.

A61K31/675 A61K31/416 A61K31/4439 A61K31/497 A61K45/06

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Quick Facts

Patent No.: US 9,597,340
App. No.: 14/001,132
Granted: Mar 21, 2017
Kind: B2

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Abstract

Provided are certain methods useful in the treatment of cancer comprising administering a compound of Formula Ia and pharmaceutical compositions thereof that modulate the activity of the cannabinoid CB 2 receptor;

Claims (150)

1. A composition comprising a compound selected from compounds of Formula Ia and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:

wherein:

R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from: H and C 1 -C 6 alkyl;

X is NR 7 and Y is CC(O)N(R 8 )R 9 ; or

X is CC(O)N(R 8 )R 9 and Y is NR 7 ;

R 7 is —R 10 —R 11 —R 12 —R 13 ; wherein:

R 10 is selected from: C 1 -C 6 alkylene, heteroarylene, and heterocyclylene; or R 10 is absent;

R 11 is selected from: —C(O)NH— and C 1 -C 6 alkylene; or R 11 is absent;

R 12 is C 1 -C 6 alkylene; or R 12 is absent; and

R 13 is selected from: C 1 -C 6 alkyl, aryl, C 3 -C 7 cycloalkyl, heteroaryl, heterocyclyl, and hydroxyl; wherein said C 1 -C 6 alkyl, aryl, and heteroaryl are each optionally substituted with one or two substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylsulfonyl, amino, C 3 -C 7 cycloalkyl, cyano, C 2 -C 8 dialkylamino, C 1 -C 6 haloalkyl, halogen, and hydroxyl;

R 8 is —R 14 —R 15 —R 16 —R 17 ; wherein:

R 14 is selected from: C 1 -C 6 alkylene, C 3 -C 7 cycloalkenylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said C 1 -C 6 alkylene and heterocyclylene are each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl, carboxy, heteroaryl, heterocyclyl, and hydroxyl; wherein said C 1 -C 6 alkyl and aryl are optionally substituted with one substituent selected from: C 1 -C 6 alkoxy, aryl, halogen, heteroaryl, and hydroxyl; or R 14 is absent;

R 15 is selected from: —C(O)NH—, —C(O)—, —C(O)O—, C 1 -C 6 alkylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said heterocyclylene is optionally substituted with C 1 -C 6 alkyl; or R 15 is absent;

R 16 is C 1 -C 6 alkylene; or R 16 is absent; and

R 17 is selected from: H, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylcarboxamide, C 2 -C 6 alkynyl, ureyl, amino, aryl, arylamino, arylcarbonyl, aryloxy, carbo-C 1 -C 6 -alkoxy, carboxamide, carboxy, cyano, C 3 -C 7 cycloalkyl, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkylamino, C 2 -C 8 dialkylamino, C 2 -C 8 dialkylsulfonamide, C 1 -C 6 haloalkyl, heteroaryl, heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy; wherein said C 1 -C 6 alkylamino, amino, aryl, arylamino, aryloxy, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylamino, heteroaryl, heterobicyclyl, heterocyclyl, and ureyl are each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkylsulfonyl, amino, aryl, carboxy, cyano, C 3 -C 7 cycloalkyl, C 2 -C 8 dialkylamino, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl, heterocyclyl, and hydroxyl; and

R 9 is selected from: H, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl; or

R 8 and R 9 together with the nitrogen atom to which they are both bonded form a group selected from: heterocyclyl and heterobicyclyl, each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkyl, aryl, carbo-C 1 -C 6 -alkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl, heteroaryloxy, heterocyclyl, and hydroxyl; wherein said aryl, C 1 -C 6 alkyl, and heteroaryl are optionally substituted with one substituent selected from: C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, halogen, and hydroxyl,

and one or more known pharmaceutical agents selected from: inhibitors of inherent multidrug resistance, anti-emetic agents, agents useful in the treatment of anemia, agents useful in the treatment of neutropenia, immunologic-enhancing agents, and anticancer agents.

2. A composition comprising a compound selected from compounds of Formula Ia and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:

wherein:

R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from: H and C 1 -C 6 alkyl;

X is NR 7 and Y is CC(O)N(R 8 )R 9 ; or

X is CC(O)N(R 8 )R 9 and Y is NR 7 ;

R 7 is —R 10 —R 11 —R 12 —R 13 ; wherein:

R 10 is selected from: C 1 -C 6 alkylene, heteroarylene, and heterocyclylene; or R 10 is absent;

R 11 is selected from: —C(O)NH— and C 1 -C 6 alkylene; or R 11 is absent;

R 12 is C 1 -C 6 alkylene; or R 12 is absent; and

R 8 is —R 14 —R 15 —R 16 —R 17 ; wherein:

R 16 is C 1 -C 6 alkylene; or R 16 is absent; and

R 9 is selected from: H, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl; or

one or more known pharmaceutical agents selected from: inhibitors of inherent multidrug resistance, anti-emetic agents, agents useful in the treatment of anemia, agents useful in the treatment of neutropenia, immunologic-enhancing agents, and anticancer agents, and

a pharmaceutically acceptable carrier.

3. A pharmaceutical product selected from: a pharmaceutical composition, a formulation, a dosage form, a combined preparation, a twin pack, and a kit; comprising a compound selected from compounds of Formula Ia and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:

wherein:

R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from: H and C 1 -C 6 alkyl;

X is NR 7 and Y is CC(O)N(R 8 )R 9 ; or

X is CC(O)N(R 8 )R 9 and Y is NR 7 ;

R 7 is —R 10 —R 11 —R 12 —R 13 ; wherein:

R 10 is selected from: C 1 -C 6 alkylene, heteroarylene, and heterocyclylene; or R 10 is absent;

R 11 is selected from: —C(O)NH— and C 1 -C 6 alkylene; or R 11 is absent;

R 12 is C 1 -C 6 alkylene; or R 12 is absent; and

R 8 is —R 14 —R 15 —R 16 —R 17 ; wherein:

R 16 is C 1 -C 6 alkylene; or R 16 is absent; and

R 9 is selected from: H, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl; or

4. The pharmaceutical product according to claim 3 , wherein said pharmaceutical product comprises a pharmaceutical composition.

5. The pharmaceutical product according to claim 3 , wherein said pharmaceutical product comprises a formulation.

6. The pharmaceutical product according to claim 3 , wherein said pharmaceutical product comprises a dosage form.

7. The pharmaceutical product according to claim 3 , wherein said pharmaceutical product comprises a combined preparation.

8. The pharmaceutical product according to claim 3 , wherein said pharmaceutical product comprises a twin pack.

9. The pharmaceutical product according to claim 3 , wherein said pharmaceutical product comprises a kit.

10. The pharmaceutical product according to claim 9 , wherein said kit comprises a first package comprising a compound selected from compounds of Formula Ia and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:

wherein:

R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from: H and C 1 -C 6 alkyl;

X is NR 7 and Y is CC(O)N(R 8 )R 9 ; or

X is CC(O)N(R 8 )R 9 and Y is NR 7 ;

R 7 is —R 10 —R 11 —R 12 —R 13 ; wherein:

R 10 is selected from: C 1 -C 6 alkylene, heteroarylene, and heterocyclylene; or R 10 is absent;

R 11 is selected from: —C(O)NH— and C 1 -C 6 alkylene; or R 11 is absent;

R 12 is C 1 -C 6 alkylene; or R 12 is absent; and

R 8 is —R 14 —R 15 —R 16 —R 17 ; wherein:

R 16 is C 1 -C 6 alkylene; or R 16 is absent; and

R 9 is selected from: H, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl; or

or a pharmaceutical composition thereof, and a second package comprising one or more known pharmaceutical agents selected from inhibitors of inherent multidrug resistance, anti-emetic agents, agents useful in the treatment of anemia, agents useful in the treatment of neutropenia, immunologic-enhancing agents, and anticancer agents or a pharmaceutical composition thereof.

11. The composition according to claim 1 , wherein the amount of the compound selected from compounds of Formula Ia and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof alone and the amount of the one or more known pharmaceutical agents alone are therapeutically ineffective.

12. The composition according to claim 1 , wherein the compound selected from compounds of Formula Ia and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof and the one or more known pharmaceutical agents are admixed with a pharmaceutically acceptable carrier.

13. The composition according to claim 1 , wherein the compound selected from compounds of Formula Ia and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof and the one or more known pharmaceutical agents are each admixed with a different pharmaceutically acceptable carrier.

14. The composition according to claim 1 , wherein the compound selected from compounds of Formula Ia and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof is selected from compounds of Formula Ie and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof:

wherein:

R 7 is —R 10 —R 11 —R 12 —R 13 ; wherein:

R 10 is selected from: C 1 -C 6 alkylene, heteroarylene, and heterocyclylene; or R 10 is absent;

R 11 is selected from: —C(O)NH— and C 1 -C 6 alkylene; or R 11 is absent;

R 12 is C 1 -C 6 alkylene; or R 12 is absent; and

R 8 is —R 14 —R 15 —R 16 —R 17 ; wherein:

R 16 is C 1 -C 6 alkylene; or R 16 is absent; and

R 17 is selected from: H, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylcarboxamide, C 2 -C 6 alkynyl, ureyl, amino, aryl, arylamino, arylcarbonyl, aryloxy, carbo-C 1 -C 6 -alkoxy, carboxamide, carboxy, cyano, C 3 -C 7 cycloalkyl, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkylamino, C 2 -C 8 dialkylamino, C 2 -C 8 dialkylsulfonamide, C 1 -C 6 haloalkyl, heteroaryl, heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy; wherein said C 1 -C 6 alkylamino, aryl, arylamino, aryloxy, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkyl, heteroaryl, heterobicyclyl, heterocyclyl, and ureyl are each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkylsulfonyl, amino, aryl, carboxy, cyano, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylamino, C 2 -C 8 dialkylamino, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl, heterocyclyl, and hydroxyl; and

R 9 is selected from: H, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl; or

15. The composition according to claim 1 , wherein the compound selected from compounds of Formula Ia and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof is selected from the following compounds and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Compound 151: (1aR,5aR)-2-(5-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;

Compound 174: (1aR,5aR)-2-(2,4-Dichloro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1-hydroxymethyl-cyclopropyl)-amide;

Compound 264: (1aR,5aR)-2-(5-Cyano-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;

Compound 309: (1aR,5aR)-2-(5-Fluoro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;

Compound 493: (1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;

Compound 515: 1-(2,4-Difluoro-phenyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;

Compound 593: (1aR,5aR)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid tert-butylamide;

Compound 625: (1aR,5aR)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (cyano-dimethyl-methyl)-amide;

Compound 642: (1aR,5aR)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide;

Compound 644: (1aR,5aR)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;

Compound 646: Phosphoric acid mono-(2-{[(1aR,5aR)-2-(4-cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-2-methyl-propyl) ester;

Compound 667: (1aR,5aR)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid [2,2-dimethyl-14(S)-methylcarbamoyl)-propyl]-amide;

Compound 683: Phosphoric acid mono-{(S)-3,3-dimethyl-2-[((1aR,5aR)-2-pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl)-amino]-butyl}ester;

Compound 684: (1aR,5aR)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-2-hydroxy-1-tetrahydro-pyran-4-yl-ethyl)-amide;

Compound 690: (1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2-methyl-propyl)-amide;

Compound 696: (1 aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide;

Compound 698: (1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1-hydroxymethyl-cyclobutyl)-amide;

Compound 699: (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide;

Compound 700: (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1-pyridin-2-yl-cyclobutyl)-amide;

Compound 703: Phosphoric acid mono-((S)-3,3-dimethyl-2-{[(1aR,5aR)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butyl) ester;

Compound 704: (1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide;

Compound 722: (1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-methylcarbamoyl-phenyl-methyl)-amide;

Compound 746: (S)-3,3-Dimethyl-2-{[(1aR,5aR)-2-(4-oxy-pyrazin-2-yl)-1a,2,5, 5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butyric acid methyl ester;

Compound 764: (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1-trifluoromethyl-cyclopropyl)-amide;

Compound 765: (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1-trifluoromethyl-cyclobutyl)-amide;

Compound 766: (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((R)-2,2-dimethyl-1-pyridin-2-yl-propyl)-amide;

Compound 767: (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-2,2-dimethyl-1-pyridin-2-yl-propyl)-amide;

Compound 820: (1aR,5aR)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide;

Compound 821: (1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1-methyl-cyclobutyl)-amide;

Compound 828: (1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((R)-1,2-dimethyl-propyl)-amide;

Compound 841: (1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid [(S)-2-hydroxy-1-(tetrahydro-pyran-4-yl)-ethyl]-amide;

Compound 844: (1aR,5aR)-Pentanedioic acid mono-((S)-3-methyl-2-{[(1aR,5aR)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butyl) ester;

Compound 848: (1aS,5aS)—(S)-2-Amino-3-methyl-butyric acid (S)-3,3-dimethyl-2-{[2-(4-oxy-pyrazin-2-yl)-1a,2, 5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butyl ester;

Compound 889: (1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-fluoro-1-fluoromethyl-1-hydroxymethyl-ethyl)-amide;

Compound 891: (1 aS,5aS)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-3,3,3-trifluoro-1-hydroxymethyl-propyl)-amide;

Compound 896: (1 aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2-methyl-propyl)-amide;

Compound 897: (1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-fluoro-1,1-dimethyl-ethyl)-amide;

Compound 902: (1 aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid N′-tert-butyl-hydrazide;

Compound 904: (1 aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-fluoro-1,1-dimethyl-ethyl)-amide;

Compound 912: (1 aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((R)-1,2-dimethyl-propyl)-amide;

Compound 913: (1 aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-2-hydroxy-1-phenyl-ethyl)-amide;

Compound 918: (1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-fluoromethyl-2,2-dimethyl-propyl)-amide;

Compound 919: (1 aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide;

Compound 920: (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((1S,2S)-2-hydroxy-indan-1-yl)-amide;

Compound 921: (1 aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((1S,2R)-2-hydroxy-indan-1-yl)-amide;

Compound 924: (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1-fluoromethyl-cyclobutyl)-amide;

Compound 926: (1 aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1-trifluoromethyl-cyclobutyl)-amide;

Compound 927: (1 aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide;

Compound 930: (1 aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1-trifluoromethyl-cyclopropyl)-amide; and

Compound 931: (1aR,5aR)-2-(4-Fluoro-pyridin-2-yl)-1a,2, 5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide.

16. The composition according to claim 1 , wherein the compound selected from compounds of Formula Ia and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof is selected from the following compound and pharmaceutically acceptable salts, solvates, and hydrates thereof:

Compound 699: (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide.

17. The composition according to claim 1 , wherein the one or more known pharmaceutical agents is chosen from anticancer agents.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 10, 2014

From: THATTE, JAYANT; BLACKBURN, ANTHONY C.; HAN, SANGDON; JONES, ROBERT M.; JUNG, JAE-KYU; MONTALBAN, ANTONIO GARRIDO; PAL, BIMAN B.; RUETER, JAMIE KARYN; STRAH-PLEYNET, SONJA; THORESEN, LARS; XIONG, YIFENG; YUE, DAWEI; ZHU, XIUWEN

To: ARENA PHARMACEUTICALS, INC.

Reel/Frame 034453/0629 →

Continuity (2)

Provisional Application 61446727 · Feb 25, 2011

Related Publication 20150126477A1 · May 7, 2015