IP Library › Granted Patent US 10,590,108

Granted Patent B2

US 10,590,108 · App. 15/761,995 · Granted Mar 17, 2020

Benzimidazoles for use in the treatment of cancer and inflammatory diseases

Inventor: Yun Long (San Diego, CA)

Assignee: CAPELLA THERAPEUTICS, INC.

C07D401/14 A61P35/00 C07D405/14

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Quick Facts

Patent No.: US 10,590,108
App. No.: 15/761,995
Granted: Mar 17, 2020
Kind: B2

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Abstract

Provided herein are methods for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease mediated by a lipid kinase or a protein kinase with benzimidazoles, for example, of Formula I or II, and pharmaceutical compositions thereof. Also provided herein are benzimidazoles, and pharmaceutical compositions thereof; and methods of their use for treating, preventing, or ameliorating one or more symptoms of a proliferative disease.

Claims (67)

1. A compound selected from:

(R)—N-(1-(1-acryloylazepan-3-yl)-7-chloro-5-(oxetan-3-yloxy)-1H-benzo[d]imidazol-2-yl)-2-(trifluoromethyl)isonicotinamide A14;

(R)—N-(1-(1-acryloylazepan-3-yl)-7-chloro-5-(oxetan-3-yloxy)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide A15;

(R)—N-(1-(1-acryloylazepan-3-yl)-7-chloro-5-(oxetan-3-yloxy)-1H-benzo[d]imidazol-2-yl)-2-(difluoromethyl)isonicotinamide A16;

(R)—N-(1-(1-acryloylazepan-3-yl)-7-chloro-5-((tetrahydro-2H-pyran-4-yl)oxy)-1H-benzo[d]imidazol-2-yl)-2-(trifluoromethyl)isonicotinamide A17;

(R)—N-(1-(1-acryloylazepan-3-yl)-7-chloro-5-((tetrahydro-2H-pyran-4-yl)oxy)-1H-benzo[d]imidazol-2-yl)-2-(difluoromethyl)isonicotinamide A18;

(S)—N-(1-(1-acryloylazepan-3-yl)-7-chloro-5-((tetrahydro-2H-pyran-4-yl)oxy)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide A19;

(R)—N-(5-((1-acetylpiperidin-4-yl)oxy)-1-(1-acryloylazepan-3-yl)-7-chloro-1H-benzo[d]imidazol-2-yl)-2-(trifluoromethyl)isonicotinamide A20;

(R)—N-(5-((1-acetylpiperidin-4-yl)oxy)-1-(1-acryloylazepan-3-yl)-7-chloro-1H-benzo[d]imidazol-2-yl)-2-(difluoromethyl)isonicotinamide A21;

(R)—N-(5-((1-acetylpiperidin-4-yl)oxy)-1-(1-acryloylazepan-3-yl)-7-chloro-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide A22;

(R)-1-(1-acryloylazepan-3-yl)-7-chloro-2-(2-methylisonicotinamido)-1H-benzo[d]imidazol-5-yl morpholine-4-carboxylate A23;

(R)-1-(1-acryloylazepan-3-yl)-7-chloro-2-(2-methylisonicotinamido)-1H-benzo[d]imidazol-5-yl azetidine-1-carboxylate A24;

(R)—N-(1-(1-acryloylazepan-3-yl)-7-chloro-6-(oxetan-3-yloxy)-1H-benzo[d]imidazol-2-yl)-2-(trifluoromethyl)isonicotinamide C19;

(R)—N-(1-(1-acryloylazepan-3-yl)-7-chloro-6-(oxetan-3-yloxy)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide C20;

(R)—N-(1-(1-acryloylazepan-3-yl)-7-chloro-6-(oxetan-3-yloxy)-1H-benzo[d]imidazol-2-yl)-2-(difluoromethyl)isonicotinamide C21;

(R)—N-(1-(1-acryloylazepan-3-yl)-7-chloro-6-(oxetan-3-yloxy)-1H-benzo[d]imidazol-2-yl)imidazo[1,5-a]pyridine-7-carboxamide C22;

(R)—N-(1-(1-acryloylazepan-3-yl)-7-chloro-6-(oxetan-3-yloxy)-1H-benzo[d]imidazol-2-yl)imidazo[1,2-a]pyridine-7-carboxamide C23;

(R)—N-(1-(1-acryloylazepan-3-yl)-7-chloro-6-(oxetan-3-yloxy)-1H-benzo[d]imidazol-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-7-carboxamide C24;

(R)-1-(1-acryloylazepan-3-yl)-7-chloro-2-(2-methylisonicotinamido)-1H-benzo[d]imidazol-6-yl morpholine-4-carboxylate C25;

(R)—N-(1-(1-acryloylazepan-3-yl)-7-((tetrahydro-2H-pyran-4-yl)oxy)-1H-benzo[d]imidazol-2-yl)-2-(trifluoromethyl)isonicotinamide D12;

(R)—N-(1-(1-acryloylazepan-3-yl)-7-(piperidin-4-yloxy)-1H-benzo[d]imidazol-2-yl)-2-(trifluoromethyl)isonicotinamide D13; and

(R)—N-(7-((1-acetylpiperidin-4-yl)oxy)-1-(1-acryloylazepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-(difluoromethyl)isonicotinamide D14;

and single enantiomers, racemic mixtures, mixtures of diastereomers, and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

2. A compound of Formula XIXa:

or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein:

R 1 is selected from:

R 2 is C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl;

R 4 and R 5 are each independently (a) hydrogen, cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;

R 6a is —C(O)OR 1a or —C(O)NR 1b R 1c ; and

each R 1a , R 1b , R 1c , and R 1d is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or R 1a and R 1c together with the C and N atoms to which they are attached form heterocyclyl; or R 1b and R 1c together with the N atom to which they are attached form heterocyclyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more substituents Q, where each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more substituents Q a ; and (c) —C(O)R a , —C(O)OR a , —C(O)NR b R c , —C(NR a )NR b R c , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR b R c , —OC(═NR a )NR b R c , —OP(O)(OR a ) 2 , —OS(O)R a , —OS(O) 2 R a , —OS(O)NR b R c , —OS(O) 2 NR b R c , —NR b R c , —NR a C(O)R d , —NR a C(O)OR d , —NR a C(O)NR b R c , —NR a C(═NR d )NR b R c , —NR a S(O)R d , —NR a S(O) 2 R d , —NR a S(O)NR b R c , —NR a S(O) 2 NR b R c , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR b R c , and —S(O) 2 NR b R c , wherein each R a , R b , R c , and R d is independently (i) hydrogen; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q a ;

wherein each Q a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R f , —C(O)OR f , —C(O)NR g R h , —C(NR f )NR g R h , —OR f , —OC(O)R f , —OC(O)OR f , —OC(O)NR g R h , —OC(═NR f )NR g R h , —OP(O)(OR f ) 2 , —OS(O)R f , —OS(O) 2 R f , —OS(O)NR g R h , —OS(O) 2 NR g R h , —NR g R h , —NR f C(O)R k , —NR f C(O)OR k , —NR f C(O)NR g R h , —NR f C(═NR k )NR g R h , —NR f S(O)R k , —NR f S(O) 2 R k , —NR f S(O)NR g R h , —NR f S(O) 2 NR g R h , —SR f , —S(O)R f , —S(O) 2 R f , —S(O)NR g R h , and —S(O) 2 NR g R h ; wherein each R f , R g , R h , and R k is independently (i) hydrogen; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R g and R h together with the N atom to which they are attached form heterocyclyl.

3. The compound of claim 2 , wherein R 6a is —C(O)OR 1a .

4. The compound of claim 3 , wherein R 1a is C 1-6 alkyl, C 3-10 cycloalkyl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q.

5. The compound of claim 4 , wherein R 1a is methyl, isopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuryl, or tetrahydro-2H-pyranyl, each of which is optionally substituted with one or more substituents Q.

6. The compound of claim 2 , wherein R 6a is —C(O)NR 1b R 1c .

7. The compound of claim 6 , wherein R 1b and R 1c are each independently C 1-6 alkyl, optionally substituted with one or more substituents Q; or R 1b and R 1c together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q.

8. The compound of claim 2 , wherein R 6a is methoxycarbonyl, isopropoxycarbonyl, cyclobutoxycarbonyl, cyclopentoxycarbonyl, cyclohexoxycarbonyl, oxetan-3-oxycarbonyl, tetrahydrofuran-3-oxycarbonyl, tetrahydro-2H-pyran-4-oxycarbonyl, N,N-dimethylaminecarbonyl, N-methyl-N-isopropylaminecarbonyl, aziridin-1-ylcarbonyl, azetidin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, 3-fluoro-pyrrolidin-1-ylcarbonyl, 3-methoxy-pyrrolidin-1-ylcarbonyl, 3,3-difluoro-pyrrolidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, 4-isopropyl-piperazin-1-ylcarbonyl, 4-cyclopropyl-piperazin-1-ylcarbonyl, 4-acetyl-piperazin-1-ylcarbonyl, or 1,1-dioxo-thiomorpholin-4-ylcarbonyl.

9. The compound of claim 2 , wherein R 4 is hydrogen.

10. The compound of claim 2 , wherein R 5 is hydrogen.

11. The compound of claim 2 , having the structure of Formula XXI:

or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein R 6a is methoxycarbonyl, isopropoxycarbonyl, cyclobutoxycarbonyl, cyclopentoxycarbonyl, cyclohexoxycarbonyl, oxetan-3-oxycarbonyl, tetrahydrofuran-3-oxycarbonyl, tetrahydro-2H-pyran-4-oxycarbonyl, N,N-dimethylaminecarbonyl, N-methyl-N-isopropylaminecarbonyl, aziridin-1-ylcarbonyl, azetidin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, 3-fluoro-pyrrolidin-1-ylcarbonyl, 3-methoxy-pyrrolidin-1-ylcarbonyl, 3,3-difluoro-pyrrolidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, 4-isopropyl-piperazin-1-ylcarbonyl, 4-cyclopropyl-piperazin-1-ylcarbonyl, 4-acetyl-piperazin-1-ylcarbonyl, or 1,1-dioxo-thiomorpholin-4-ylcarbonyl.

12. A compound of Formula XXV:

or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof;

wherein:

R 1 is selected from:

R 2 is C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl;

R 4 , R 5 , and R 7 are each independently (a) hydrogen, cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; and

13. The compound of claim 12 , wherein R 7 is halo.

14. The compound of claim 12 , wherein R 7 is chloro.

15. The compound of claim 12 , wherein R 4 is hydrogen.

16. The compound of claim 12 , wherein R 5 is hydrogen.

17. The compound of claim 12 , wherein the compound is