Certain chemical entities, compositions, and methods

• US 9,688,635 B2
• Filed: 09/24/2013
• Issued: 06/27/2017
• Est. Priority Date: 09/24/2012
• Status: Active Grant

• Current Assignee: NeuPharma, Inc.
• Original Assignee: NeuPharma, Inc.
• Inventors: Qian, Xiangping, Zhu, Yong-liang
• Primary Examiner(s): Bakshi, Pancham
• Application Number:
  US14/430,890
• Publication Number:
  US 20150246885A1
• Time in Patent Office: 1,372 Days
• Field of Search: 51421018, 5142375, 5142348, 5142661
• CPC Class Codes: A61J 1/03 for pills or tablets containers for pills or tablets with special dispensing means therefor B65D83/04
• CPC Class Codes: A61J 1/05 for collecting, storing or administering blood, plasma or medical fluids multiple bags systems for separating or storing blood components A61M1/0209; Infusion or perfusion containers
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 215/14 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 239/74 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring

Abstract

Chemical entities that are kinase inhibitors, pharmaceutical compositions and methods of treatment of cancer are described.

Claims

1. A compound of Formula I:

2. The compound or pharmaceutically acceptable salt of claim 1, wherein R₁, R₂, and R₃ are independently hydrogen, cyano, halo, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, or optionally substituted aminosulfonyl.

3. The compound or pharmaceutically acceptable salt of claim 2, wherein R₁, R₂, and R₃ are independently hydrogen, cyano, or halo.

4. The compound or pharmaceutically acceptable salt of claim 1, wherein R₄ is chosen from hydrogen, optionally substituted lower alkyl, optionally substituted aryl, and optionally substituted heteroaryl.

5. The compound or pharmaceutically acceptable salt of claim 1, wherein R₅ is —

COR₇, —

CO₂R₇, —

CONR₇R₈, —

C(NR₉)NR₇R₈, or —

C(NCN)NR₇R₈, and wherein R₇ is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and

R₈ and R₉ are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl optionally substituted aryl, or optionally substituted heteroaryl.

6. The compound or pharmaceutically acceptable salt of claim 5, wherein R₇ is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl;

and R₈ and R₉ are independently hydrogen or optionally substituted alkyl.

7. The compound or pharmaceutically acceptable salt of claim 1, wherein R₇ and R₈ are joined together with any intervening atoms to form an optionally substituted 4- to 8-membered heterocycloalkyl ring.

8. The compound or pharmaceutically acceptable salt of claim 1, wherein R₄ and R₅ are joined together with any intervening atoms to form an optionally substituted 4- to 8-membered heterocycloalkyl ring.

9. The compound or pharmaceutically acceptable salt of claim 1, wherein Z₁ is 1,5-naphthyridin-2-yl, 1,7-naphthyridin-6-yl, 1H-pyrazolo[3,4-b]pyrazin-3-yl, 1H-pyrazolo[3,4-b]pyridin-3-yl, 5H-pyrrolo[2,3-b]pyrazin-7-yl, 7H-pyrrolo[2,3-c]pyridazin-5-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]thiazol-6-yl, oxazolo[5,4-b]pyridin-5-yl, pyrido[3,4-b]pyrazin-7-yl, quinazolin-6-yl, or quinolin-6-yl.

10. The compound or pharmaceutically acceptable salt of claim 1, wherein, for each occurrence, R₆ is independently hydrogen, cyano, halo, hydroxy, carboxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, or optionally substituted aminosulfonyl.

11. The compound or pharmaceutically acceptable salt of claim 1, wherein, for each occurrence, R₆ is independently hydrogen, cyano, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted amino, optionally substituted alkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

12. The compound or pharmaceutically acceptable salt of claim 1, wherein m is 0, 1, 2 or 3.

13. The compound or pharmaceutically acceptable salt of claim 1 chosen from the group consisting of:

1-(3-fluoro-5-(quinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3-fluoro-5-(3-methylquinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3-(3-cyanoquinoline-6-carbonyl)-5-fluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-fluoro-5-(3-methoxyquinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3-fluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3,4-difluorophenyl)-3-(3-fluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)urea,

1-(3-fluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea,

1-(4-chlorophenyl)-3-(3-fluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)urea,

1-(3-chlorophenyl)-3-(3-fluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)urea,

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)urea,

1-(3-fluoro-5-(3-(pyrrolidin-1-yl)quinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3-fluoro-5-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3,4-difluorophenyl)-3-(3-fluoro-5-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)urea,

1-(3-fluoro-5-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea,

1-(4-chlorophenyl)-3-(3-fluoro-5-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)urea,

1-(3-fluoro-5-(3-(pyridin-3-yl)quinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3-fluoro-5-(3-((2-hydroxyethyl)amino)quinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3-fluoro-5-(3-(2-hydroxyethoxy)quinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3-(3-(1H-pyrazol-4-yl)quinoline-6-carbonyl)-5-fluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(3-(1H-imidazol-1-yl)quinoline-6-carbonyl)-5-fluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-fluoro-5-(quinazoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3-fluoro-5-(quinazoline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea,

1-(3,4-difluorophenyl)-3-(3-fluoro-5-(quinazoline-6-carbonyl)phenyl)urea,

1-(3-fluoro-5-(1,7-naphthyridine-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3,4-difluorophenyl)-3-(3-fluoro-5-(1,7-naphthyridine-6-carbonyl)phenyl)urea,

1-(3-fluoro-5-(3-morpholino-1,7-naphthyridine-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3,4-difluorophenyl)-3-(3-fluoro-5-(3-morpholino-1,7-naphthyridine-6-carbonyl)phenyl)urea,

1-(3-fluoro-5-(pyrido[3,4-b]pyrazine-7-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3-fluoro-5-(pyrido[3,4-b]pyrazine-7-carbonyl)phenyl)-3-(4-fluorophenyl)urea,

1-(3-fluoro-5-(2-morpholinopyrido[3,4-b]pyrazine-7-carbonyl)phenyl)-3-(4-fluorophenyl)urea,

1-(3-fluoro-5-(2-morpholinopyrido[3,4-b]pyrazine-7-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3-fluoro-5-(1,5-naphthyridine-2-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3-fluoro-5-(7-morpholino-1,5-naphthyridine-2-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3-(benzo[d]oxazole-6-carbonyl)-5-fluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(benzo[d]oxazole-5-carbonyl)-5-fluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(benzo[d]thiazole-6-carbonyl)-5-fluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(3a,7a-dihydro-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-5-fluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(7,7a-dihydro-4aH-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-5-fluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(5,7a-dihydro-4aH-pyrrolo[2,3-b]pyrazine-7-carbonyl)-5-fluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(3a,7a-dihydro-1H-pyrazolo[3,4-b]pyrazine-3-carbonyl)-5-fluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(7,7a-dihydro-4aH-pyrrolo[2,3-c]pyridazine-5-carbonyl)-5-fluorophenyl)-3-(3-fluorophenyl)urea,

1-(2,5-difluoro-3-(quinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(2,5-difluoro-3-(3-methylquinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3-(3-cyanoquinoline-6-carbonyl)-2,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(2,5-difluoro-3-(3-methoxyquinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(2,5-difluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(2,5-difluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)-3-(3,4-difluorophenyl)urea,

1-(2,5-difluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea,

1-(4-chlorophenyl)-3-(2,5-difluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)urea,

1-(3-chlorophenyl)-3-(2,5-difluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)urea,

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2,5-difluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)urea,

1-(2,5-difluoro-3-(3-(pyrrolidin-1-yl)quinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(2,5-difluoro-3-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(2,5-difluoro-3-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)-3-(3,4-difluorophenyl)urea,

1-(2,5-difluoro-3-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea,

1-(4-chlorophenyl)-3-(2,5-difluoro-3-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)urea,

1-(2,5-difluoro-3-(3-(pyridin-3-yl)quinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(2,5-difluoro-3-(3-((2-hydroxyethyl)amino)quinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(2,5-difluoro-3-(3-(2-hydroxyethoxy)quinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3-(3-(1H-pyrazol-4-yl)quinoline-6-carbonyl)-2,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(3-(1H-imidazol-1-yl)quinoline-6-carbonyl)-2,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(2,5-difluoro-3-(quinazoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(2,5-difluoro-3-(quinazoline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea,

1-(2,5-difluoro-3-(quinazoline-6-carbonyl)phenyl)-3-(3,4-difluorophenyl)urea,

1-(2,5-difluoro-3-(1,7-naphthyridine-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(2,5-difluoro-3-(1,7-naphthyridine-6-carbonyl)phenyl)-3-(3,4-difluorophenyl)urea,

1-(2,5-difluoro-3-(3-morpholino-1,7-naphthyridine-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(2,5-difluoro-3-(3-morpholino-1,7-naphthyridine-6-carbonyl)phenyl)-3-(3,4-difluorophenyl)urea,

1-(2,5-difluoro-3-(pyrido[3,4-b]pyrazine-7-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(2,5-difluoro-3-(pyrido[3,4-b]pyrazine-7-carbonyl)phenyl)-3-(4-fluorophenyl)urea,

1-(2,5-difluoro-3-(2-morpholinopyrido[3,4-b]pyrazine-7-carbonyl)phenyl)-3-(4-fluorophenyl)urea,

1-(2,5-difluoro-3-(2-morpholinopyrido[3,4-b]pyrazine-7-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(2,5-difluoro-3-(1,5-naphthyridine-2-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(2,5-difluoro-3-(7-morpholino-1,5-naphthyridine-2-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3-(benzo[d]oxazole-6-carbonyl)-2,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(benzo[d]oxazole-5-carbonyl)-2,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(benzo[d]thiazole-6-carbonyl)-2,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(3a,7a-dihydro-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(7,7a-dihydro-4aH-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(5,7a-dihydro-4aH-pyrrolo[2,3-b]pyrazine-7-carbonyl)-2,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(3a,7a-dihydro-1H-pyrazolo[3,4-b]pyrazine-3-carbonyl)-2,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(7,7a-dihydro-4aH-pyrrolo[2,3-c]pyridazine-5-carbonyl)-2,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(3,4-difluoro-5-(quinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3-chlorophenyl)-3-(3,4-difluoro-5-(quinoline-6-carbonyl)phenyl)urea,

1-(4-chloro-3-fluorophenyl)-3-(3,4-difluoro-5-(quinoline-6-carbonyl)phenyl)urea,

1-(3-chloro-4-fluorophenyl)-3-(3,4-difluoro-5-(quinoline-6-carbonyl)phenyl)urea,

1-(4-chlorophenyl)-3-(3,4-difluoro-5-(quinoline-6-carbonyl)phenyl)urea,

1-(3,4-difluoro-5-(quinoline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea,

1-(3,4-difluoro-5-(quinoline-6-carbonyl)phenyl)-3-(3,4-difluorophenyl)urea,

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3,4-difluoro-5-(quinoline-6-carbonyl)phenyl)urea,

1-(3,4-difluoro-5-(3-methylquinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3-(3-cyanoquinoline-6-carbonyl)-4,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(3,4-difluoro-5-(3-methoxyquinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3,4-difluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3,4-difluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)-3-(3,4-difluorophenyl)urea,

1-(3,4-difluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea,

1-(4-chlorophenyl)-3-(3,4-difluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)urea,

1-(3-chlorophenyl)-3-(3,4-difluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)urea,

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3,4-difluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)urea,

1-(3,4-difluoro-5-(3-(pyrrolidin-1-yl)quinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3,4-difluoro-5-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3,4-difluoro-5-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)-3-(3,4-difluorophenyl)urea,

1-(3,4-difluoro-5-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea,

1-(4-chlorophenyl)-3-(3,4-difluoro-5-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)urea,

1-(3,4-difluoro-5-(3-(pyridin-3-yl)quinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3,4-difluoro-5-(3-((2-hydroxyethyl)amino)quinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3,4-difluoro-5-(3-(2-hydroxyethoxy)quinoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3-(3-(1H-pyrazol-4-yl)quinoline-6-carbonyl)-4,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(3-(1H-imidazol-1-yl)quinoline-6-carbonyl)-4,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(3,4-difluoro-5-(quinazoline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3,4-difluoro-5-(quinazoline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea,

1-(4-chlorophenyl)-3-(3,4-difluoro-5-(quinazoline-6-carbonyl)phenyl)urea,

1-(3,4-difluoro-5-(quinazoline-6-carbonyl)phenyl)-3-(3,4-difluorophenyl)urea,

1-(4-chloro-3-fluorophenyl)-3-(3,4-difluoro-5-(quinazoline-6-carbonyl)phenyl)urea,

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3,4-difluoro-5-(quinazoline-6-carbonyl)phenyl)urea,

1-(3-chloro-4-fluorophenyl)-3-(3,4-difluoro-5-(quinazoline-6-carbonyl)phenyl)urea,

1-(3,4-difluoro-5-(1,7-naphthyridine-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3,4-difluoro-5-(1,7-naphthyridine-6-carbonyl)phenyl)-3-(3,4-difluorophenyl)urea,

1-(3,4-difluoro-5-(3-morpholino-1,7-naphthyridine-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3,4-difluoro-5-(3-morpholino-1,7-naphthyridine-6-carbonyl)phenyl)-3-(3,4-difluorophenyl)urea,

1-(3,4-difluoro-5-(pyrido[3,4-b]pyrazine-7-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3,4-difluoro-5-(pyrido[3,4-b]pyrazine-7-carbonyl)phenyl)-3-(4-fluorophenyl)urea,

1-(3,4-difluoro-5-(2-morpholinopyrido[3,4-b]pyrazine-7-carbonyl)phenyl)-3-(4-fluorophenyl)urea,

1-(3,4-difluoro-5-(2-morpholinopyrido[3,4-b]pyrazine-7-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3,4-difluoro-5-(1,5-naphthyridine-2-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3,4-difluoro-5-(7-morpholino-1,5-naphthyridine-2-carbonyl)phenyl)-3-(3-fluorophenyl)urea,

1-(3-(benzo[d]oxazole-6-carbonyl)-4,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(benzo[d]oxazole-5-carbonyl)-4,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(benzo[d]thiazole-6-carbonyl)-4,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(3a,7a-dihydro-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-4,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(7,7a-dihydro-4aH-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-4,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(5,7a-dihydro-4aH-pyrrolo[2,3-b]pyrazine-7-carbonyl)-4,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(3a,7a-dihydro-1H-pyrazolo[3,4-b]pyrazine-3-carbonyl)-4,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(7,7a-dihydro-4aH-pyrrolo[2,3-c]pyridazine-5-carbonyl)-4,5-difluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-(quinoline-6-carbonyl)phenyl)urea,

1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-(3-methylquinoline-6-carbonyl)phenyl)urea,

1-(3-(3-cyanoquinoline-6-carbonyl)-2,4,5-trifluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-(3-methoxyquinoline-6-carbonyl)phenyl)urea,

1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)urea,

1-(3,4-difluorophenyl)-3-(2,4,5-trifluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)urea,

1-(4-fluorophenyl)-3-(2,4,5-trifluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)urea,

1-(4-chlorophenyl)-3-(2,4,5-trifluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)urea,

1-(3-chlorophenyl)-3-(2,4,5-trifluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)urea,

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2,4,5-trifluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)urea,

1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-(3-(pyrrolidin-1-yl)quinoline-6-carbonyl)phenyl)urea,

1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)urea,

1-(3,4-difluorophenyl)-3-(2,4,5-trifluoro-3-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)urea,

1-(4-fluorophenyl)-3-(2,4,5-trifluoro-3-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)urea,

1-(4-chlorophenyl)-3-(2,4,5-trifluoro-3-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)urea,

1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-(3-(pyridin-3-yl)quinoline-6-carbonyl)phenyl)urea,

1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-(3-((2-hydroxyethyl)amino)quinoline-6-carbonyl)phenyl)urea,

1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-(3-(2-hydroxyethoxy)quinoline-6-carbonyl)phenyl)urea,

1-(3-(3-(1H-pyrazol-4-yl)quinoline-6-carbonyl)-2,4,5-trifluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(3-(1H-imidazol-1-yl)quinoline-6-carbonyl)-2,4,5-trifluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-(quinazoline-6-carbonyl)phenyl)urea,

1-(4-fluorophenyl)-3-(2,4,5-trifluoro-3-(quinazoline-6-carbonyl)phenyl)urea,

1-(3,4-difluorophenyl)-3-(2,4,5-trifluoro-3-(quinazoline-6-carbonyl)phenyl)urea,

1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-(1,7-naphthyridine-6-carbonyl)phenyl)urea,

1-(3,4-difluorophenyl)-3-(2,4,5-trifluoro-3-(1,7-naphthyridine-6-carbonyl)phenyl)urea,

1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-(3-morpholino-1,7-naphthyridine-6-carbonyl)phenyl)urea,

1-(3,4-difluorophenyl)-3-(2,4,5-trifluoro-3-(3-morpholino-1,7-naphthyridine-6-carbonyl)phenyl)urea,

1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-(pyrido[3,4-b]pyrazine-7-carbonyl)phenyl)urea,

1-(4-fluorophenyl)-3-(2,4,5-trifluoro-3-(pyrido[3,4-b]pyrazine-7-carbonyl)phenyl)urea,

1-(4-fluorophenyl)-3-(2,4,5-trifluoro-3-(2-morpholinopyrido[3,4-b]pyrazine-7-carbonyl)phenyl)urea,

1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-(2-morpholinopyrido[3,4-b]pyrazine-7-carbonyl)phenyl)urea,

1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-(1,5-naphthyridine-2-carbonyl)phenyl)urea,

1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-(7-morpholino-1,5-naphthyridine-2-carbonyl)phenyl)urea,

1-(3-(benzo[d]oxazole-6-carbonyl)-2,4,5-trifluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(benzo[d]oxazole-5-carbonyl)-2,4,5-trifluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(benzo[d]thiazole-6-carbonyl)-2,4,5-trifluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(3a,7a-dihydro-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4,5-trifluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(7,7a-dihydro-4aH-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2,4,5-trifluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(5,7a-dihydro-4aH-pyrrolo[2,3-b]pyrazine-7-carbonyl)-2,4,5-trifluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(3a,7a-dihydro-1H-pyrazolo[3,4-b]pyrazine-3-carbonyl)-2,4,5-trifluorophenyl)-3-(3-fluorophenyl)urea,

1-(3-(7,7a-dihydro-4aH-pyrrolo[2,3-c]pyridazine-5-carbonyl)-2,4,5-trifluorophenyl)-3-(3-fluorophenyl)urea,

1-(4-fluorophenyl)-3-(2,4,5-trifluoro-3-(quinoline-6-carbonyl)phenyl)urea,

1-(3,4-difluorophenyl)-3-(2,4,5-trifluoro-3-(quinoline-6-carbonyl)phenyl)urea,

1-(3,5-difluorophenyl)-3-(2,4,5-trifluoro-3-(quinoline-6-carbonyl)phenyl)urea,

4-fluoro-N-(2,4,5-trifluoro-3-(quinoline-6-carbonyl)phenyl)benzamide,

3,5-difluoro-N-(2,4,5-trifluoro-3-(quinoline-6-carbonyl)phenyl)benzamide,

3,4-difluoro-N-(2,4,5-trifluoro-3-(quinoline-6-carbonyl)phenyl)benzamide,

3-fluoro-N-(3-fluoro-5-(quinoline-6-carbonyl)phenyl)benzamide,

3,4-difluoro-N-(3-fluoro-5-(quinoline-6-carbonyl)phenyl)benzamide,

4-fluoro-N-(3-fluoro-5-(quinoline-6-carbonyl)phenyl)benzamide,

3-chloro-N-(3-fluoro-5-(quinoline-6-carbonyl)phenyl)benzamide,

4-chloro-3-fluoro-N-(3-fluoro-5-(quinoline-6-carbonyl)phenyl)benzamide,

4-chloro-N-(3-fluoro-5-(quinoline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,

4-chloro-N-(3-fluoro-5-(quinoline-6-carbonyl)phenyl)benzamide,

3-fluoro-N-(3-fluoro-5-(3-methylquinoline-6-carbonyl)phenyl)benzamide,

N-(3-(3-cyanoquinoline-6-carbonyl)-5-fluorophenyl)-3-fluorobenzamide,

3-fluoro-N-(3-fluoro-5-(3-methoxyquinoline-6-carbonyl)phenyl)benzamide,

3-fluoro-N-(3-fluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)benzamide,

3,4-difluoro-N-(3-fluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)benzamide,

4-fluoro-N-(3-fluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)benzamide,

4-chloro-N-(3-fluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)benzamide,

3-chloro-N-(3-fluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)benzamide,

4-chloro-N-(3-fluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,

3-fluoro-N-(3-fluoro-5-(3-(pyrrolidin-1-yl)quinoline-6-carbonyl)phenyl)benzamide,

3-fluoro-N-(3-fluoro-5-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)benzamide,

3,4-difluoro-N-(3-fluoro-5-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)benzamide,

4-fluoro-N-(3-fluoro-5-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)benzamide,

4-chloro-N-(3-fluoro-5-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)benzamide,

3-fluoro-N-(3-fluoro-5-(3-(pyridin-3-yl)quinoline-6-carbonyl)phenyl)benzamide,

3-fluoro-N-(3-fluoro-5-(3-((2-hydroxyethyl)amino)quinoline-6-carbonyl)phenyl)benzamide,

3-fluoro-N-(3-fluoro-5-(3-(2-hydroxyethoxy)quinoline-6-carbonyl)phenyl)benzamide,

N-(3-(3-(1H-pyrazol-4-yl)quinoline-6-carbonyl)-5-fluorophenyl)-3-fluorobenzamide,

N-(3-(3-(1H-imidazol-1-yl)quinoline-6-carbonyl)-5-fluorophenyl)-3-fluorobenzamide,

3-fluoro-N-(3-fluoro-5-(quinazoline-6-carbonyl)phenyl)benzamide,

4-fluoro-N-(3-fluoro-5-(quinazoline-6-carbonyl)phenyl)benzamide,

3,4-difluoro-N-(3-fluoro-5-(quinazoline-6-carbonyl)phenyl)benzamide,

3-fluoro-N-(3-fluoro-5-(1,7-naphthyridine-6-carbonyl)phenyl)benzamide,

3,4-difluoro-N-(3-fluoro-5-(1,7-naphthyridine-6-carbonyl)phenyl)benzamide,

3-fluoro-N-(3-fluoro-5-(3-morpholino-1,7-naphthyridine-6-carbonyl)phenyl)benzamide,

3,4-difluoro-N-(3-fluoro-5-(3-morpholino-1,7-naphthyridine-6-carbonyl)phenyl)benzamide,

3-fluoro-N-(3-fluoro-5-(pyrido[3,4-b]pyrazine-7-carbonyl)phenyl)benzamide,

4-fluoro-N-(3-fluoro-5-(pyrido[3,4-b]pyrazine-7-carbonyl)phenyl)benzamide,

4-fluoro-N-(3-fluoro-5-(2-morpholinopyrido[3,4-b]pyrazine-7-carbonyl)phenyl)benzamide,

3-fluoro-N-(3-fluoro-5-(2-morpholinopyrido[3,4-b]pyrazine-7-carbonyl)phenyl)benzamide,

3-fluoro-N-(3-fluoro-5-(1,5-naphthyridine-2-carbonyl)phenyl)benzamide,

3-fluoro-N-(3-fluoro-5-(7-morpholino-1,5-naphthyridine-2-carbonyl)phenyl)benzamide,

N-(3-(benzo[d]oxazole-6-carbonyl)-5-fluorophenyl)-3-fluorobenzamide,

N-(3-(benzo[d]oxazole-5-carbonyl)-5-fluorophenyl)-3-fluorobenzamide,

N-(3-(benzo[d]thiazole-6-carbonyl)-5-fluorophenyl)-3-fluorobenzamide,

N-(3-(3a,7a-dihydro-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-5-fluorophenyl)-3-fluorobenzamide,

N-(3-(7,7a-dihydro-4aH-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-5-fluorophenyl)-3-fluorobenzamide,

N-(3-(5,7a-dihydro-4aH-pyrrolo[2,3-b]pyrazine-7-carbonyl)-5-fluorophenyl)-3-fluorobenzamide,

N-(3-(3a,7a-dihydro-1H-pyrazolo[3,4-b]pyrazine-3-carbonyl)-5-fluorophenyl)-3-fluorobenzamide,

N-(3-(7,7a-dihydro-4aH-pyrrolo[2,3-c]pyridazine-5-carbonyl)-5-fluorophenyl)-3-fluorobenzamide,

N-(2,5-difluoro-3-(quinoline-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(2,5-difluoro-3-(3-methylquinoline-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(3-(3-cyanoquinoline-6-carbonyl)-2,5-difluorophenyl)-3-fluorobenzamide,

N-(2,5-difluoro-3-(3-methoxyquinoline-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(2,5-difluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(2,5-difluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)-3,4-difluorobenzamide,

N-(2,5-difluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)-4-fluorobenzamide,

4-chloro-N-(2,5-difluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)benzamide,

3-chloro-N-(2,5-difluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)benzamide,

4-chloro-N-(2,5-difluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,

N-(2,5-difluoro-3-(3-(pyrrolidin-1-yl)quinoline-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(2,5-difluoro-3-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(2,5-difluoro-3-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)-3,4-difluorobenzamide,

N-(2,5-difluoro-3-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)-4-fluorobenzamide,

4-chloro-N-(2,5-difluoro-3-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)benzamide,

N-(2,5-difluoro-3-(3-(pyridin-3-yl)quinoline-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(2,5-difluoro-3-(3-((2-hydroxyethyl)amino)quinoline-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(2,5-difluoro-3-(3-(2-hydroxyethoxy)quinoline-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(3-(3-(1H-pyrazol-4-yl)quinoline-6-carbonyl)-2,5-difluorophenyl)-3-fluorobenzamide,

N-(3-(3-(1H-imidazol-1-yl)quinoline-6-carbonyl)-2,5-difluorophenyl)-3-fluorobenzamide,

N-(2,5-difluoro-3-(quinazoline-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(2,5-difluoro-3-(quinazoline-6-carbonyl)phenyl)-4-fluorobenzamide,

N-(2,5-difluoro-3-(quinazoline-6-carbonyl)phenyl)-3,4-difluorobenzamide,

N-(2,5-difluoro-3-(1,7-naphthyridine-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(2,5-difluoro-3-(1,7-naphthyridine-6-carbonyl)phenyl)-3,4-difluorobenzamide,

N-(2,5-difluoro-3-(3-morpholino-1,7-naphthyridine-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(2,5-difluoro-3-(3-morpholino-1,7-naphthyridine-6-carbonyl)phenyl)-3,4-difluorobenzamide,

N-(2,5-difluoro-3-(pyrido[3,4-b]pyrazine-7-carbonyl)phenyl)-3-fluorobenzamide,

N-(2,5-difluoro-3-(pyrido[3,4-b]pyrazine-7-carbonyl)phenyl)-4-fluorobenzamide,

N-(2,5-difluoro-3-(2-morpholinopyrido[3,4-b]pyrazine-7-carbonyl)phenyl)-4-fluorobenzamide,

N-(2,5-difluoro-3-(2-morpholinopyrido[3,4-b]pyrazine-7-carbonyl)phenyl)-3-fluorobenzamide,

N-(2,5-difluoro-3-(1,5-naphthyridine-2-carbonyl)phenyl)-3-fluorobenzamide,

N-(2,5-difluoro-3-(7-morpholino-1,5-naphthyridine-2-carbonyl)phenyl)-3-fluorobenzamide,

N-(3-(benzo[d]oxazole-6-carbonyl)-2,5-difluorophenyl)-3-fluorobenzamide,

N-(3-(benzo[d]oxazole-5-carbonyl)-2,5-difluorophenyl)-3-fluorobenzamide,

N-(3-(benzo[d]thiazole-6-carbonyl)-2,5-difluorophenyl)-3-fluorobenzamide,

N-(3-(3a,7a-dihydro-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,5-difluorophenyl)-3-fluorobenzamide,

N-(3-(7,7a-dihydro-4aH-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2,5-difluorophenyl)-3-fluorobenzamide,

N-(3-(5,7a-dihydro-4aH-pyrrolo[2,3-b]pyrazine-7-carbonyl)-2,5-difluorophenyl)-3-fluorobenzamide,

N-(3-(3a,7a-dihydro-1H-pyrazolo[3,4-b]pyrazine-3-carbonyl)-2,5-difluorophenyl)-3-fluorobenzamide,

N-(3-(7,7a-dihydro-4aH-pyrrolo[2,3-c]pyridazine-5-carbonyl)-2,5-difluorophenyl)-3-fluorobenzamide,

N-(3,4-difluoro-5-(quinoline-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(3,4-difluoro-5-(quinoline-6-carbonyl)phenyl)-3,4-difluorobenzamide,

N-(3,4-difluoro-5-(quinoline-6-carbonyl)phenyl)-4-fluorobenzamide,

3-chloro-N-(3,4-difluoro-5-(quinoline-6-carbonyl)phenyl)benzamide,

4-chloro-N-(3,4-difluoro-5-(quinoline-6-carbonyl)phenyl)-3-fluorobenzamide,

4-chloro-N-(3,4-difluoro-5-(quinoline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,

4-chloro-N-(3,4-difluoro-5-(quinoline-6-carbonyl)phenyl)benzamide,

N-(3,4-difluoro-5-(3-methylquinoline-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(3-(3-cyanoquinoline-6-carbonyl)-4,5-difluorophenyl)-3-fluorobenzamide,

N-(3,4-difluoro-5-(3-methoxyquinoline-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(3,4-difluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(3,4-difluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)-3,4-difluorobenzamide,

N-(3,4-difluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)-4-fluorobenzamide,

4-chloro-N-(3,4-difluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)benzamide,

3-chloro-N-(3,4-difluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)benzamide,

4-chloro-N-(3,4-difluoro-5-(3-morpholinoquinoline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,

N-(3,4-difluoro-5-(3-(pyrrolidin-1-yl)quinoline-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(3,4-difluoro-5-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(3,4-difluoro-5-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)-3,4-difluorobenzamide,

N-(3,4-difluoro-5-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)-4-fluorobenzamide,

4-chloro-N-(3,4-difluoro-5-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)benzamide,

N-(3,4-difluoro-5-(3-(pyridin-3-yl)quinoline-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(3,4-difluoro-5-(3-((2-hydroxyethyl)amino)quinoline-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(3,4-difluoro-5-(3-(2-hydroxyethoxy)quinoline-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(3-(3-(1H-pyrazol-4-yl)quinoline-6-carbonyl)-4,5-difluorophenyl)-3-fluorobenzamide,

N-(3-(3-(1H-imidazol-1-yl)quinoline-6-carbonyl)-4,5-difluorophenyl)-3-fluorobenzamide,

N-(3,4-difluoro-5-(quinazoline-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(3,4-difluoro-5-(quinazoline-6-carbonyl)phenyl)-4-fluorobenzamide,

N-(3,4-difluoro-5-(quinazoline-6-carbonyl)phenyl)-3,4-difluorobenzamide,

N-(3,4-difluoro-5-(1,7-naphthyridine-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(3,4-difluoro-5-(1,7-naphthyridine-6-carbonyl)phenyl)-3,4-difluorobenzamide,

N-(3,4-difluoro-5-(3-morpholino-1,7-naphthyridine-6-carbonyl)phenyl)-3-fluorobenzamide,

N-(3,4-difluoro-5-(3-morpholino-1,7-naphthyridine-6-carbonyl)phenyl)-3,4-difluorobenzamide,

N-(3,4-difluoro-5-(pyrido[3,4-b]pyrazine-7-carbonyl)phenyl)-3-fluorobenzamide,

N-(3,4-difluoro-5-(pyrido[3,4-b]pyrazine-7-carbonyl)phenyl)-4-fluorobenzamide,

N-(3,4-difluoro-5-(2-morpholinopyrido[3,4-b]pyrazine-7-carbonyl)phenyl)-4-fluorobenzamide,

N-(3,4-difluoro-5-(2-morpholinopyrido[3,4-b]pyrazine-7-carbonyl)phenyl)-3-fluorobenzamide,

N-(3,4-difluoro-5-(1,5-naphthyridine-2-carbonyl)phenyl)-3-fluorobenzamide,

N-(3,4-difluoro-5-(7-morpholino-1,5-naphthyridine-2-carbonyl)phenyl)-3-fluorobenzamide,

N-(3-(benzo[d]oxazole-6-carbonyl)-4,5-difluorophenyl)-3-fluorobenzamide,

N-(3-(benzo[d]oxazole-5-carbonyl)-4,5-difluorophenyl)-3-fluorobenzamide,

N-(3-(benzo[d]thiazole-6-carbonyl)-4,5-difluorophenyl)-3-fluorobenzamide,

N-(3-(3a,7a-dihydro-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-4,5-difluorophenyl)-3-fluorobenzamide,

N-(3-(7,7a-dihydro-4aH-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-4,5-difluorophenyl)-3-fluorobenzamide,

N-(3-(5,7a-dihydro-4aH-pyrrolo[2,3-b]pyrazine-7-carbonyl)-4,5-difluorophenyl)-3-fluorobenzamide,

N-(3-(3a,7a-dihydro-1H-pyrazolo[3,4-b]pyrazine-3-carbonyl)-4,5-difluorophenyl)-3-fluorobenzamide,

N-(3-(7,7a-dihydro-4aH-pyrrolo[2,3-c]pyridazine-5-carbonyl)-4,5-difluorophenyl)-3-fluorobenzamide,

3-fluoro-N-(2,4,5-trifluoro-3-(quinoline-6-carbonyl)phenyl)benzamide,

3-fluoro-N-(2,4,5-trifluoro-3-(3-methylquinoline-6-carbonyl)phenyl)benzamide,

N-(3-(3-cyanoquinoline-6-carbonyl)-2,4,5-trifluorophenyl)-3-fluorobenzamide,

3-fluoro-N-(2,4,5-trifluoro-3-(3-methoxyquinoline-6-carbonyl)phenyl)benzamide,

3-fluoro-N-(2,4,5-trifluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)benzamide,

3,4-difluoro-N-(2,4,5-trifluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)benzamide,

4-fluoro-N-(2,4,5-trifluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)benzamide,

4-chloro-N-(2,4,5-trifluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)benzamide,

3-chloro-N-(2,4,5-trifluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)benzamide,

4-chloro-N-(2,4,5-trifluoro-3-(3-morpholinoquinoline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,

3-fluoro-N-(2,4,5-trifluoro-3-(3-(pyrrolidin-1-yl)quinoline-6-carbonyl)phenyl)benzamide,

3-fluoro-N-(2,4,5-trifluoro-3-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)benzamide,

3,4-difluoro-N-(2,4,5-trifluoro-3-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)benzamide,

4-fluoro-N-(2,4,5-trifluoro-3-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)benzamide,

4-chloro-N-(2,4,5-trifluoro-3-(3-(piperazin-1-yl)quinoline-6-carbonyl)phenyl)benzamide,

3-fluoro-N-(2,4,5-trifluoro-3-(3-(pyridin-3-yl)quinoline-6-carbonyl)phenyl)benzamide,

3-fluoro-N-(2,4,5-trifluoro-3-(3-((2-hydroxyethyl)amino)quinoline-6-carbonyl)phenyl)benzamide,

3-fluoro-N-(2,4,5-trifluoro-3-(3-(2-hydroxyethoxy)quinoline-6-carbonyl)phenyl)benzamide,

N-(3-(3-(1H-pyrazol-4-yl)quinoline-6-carbonyl)-2,4,5-trifluorophenyl)-3-fluorobenzamide,

N-(3-(3-(1H-imidazol-1-yl)quinoline-6-carbonyl)-2,4,5-trifluorophenyl)-3-fluorobenzamide,

3-fluoro-N-(2,4,5-trifluoro-3-(quinazoline-6-carbonyl)phenyl)benzamide,

4-fluoro-N-(2,4,5-trifluoro-3-(quinazoline-6-carbonyl)phenyl)benzamide,

3,4-difluoro-N-(2,4,5-trifluoro-3-(quinazoline-6-carbonyl)phenyl)benzamide,

3-fluoro-N-(2,4,5-trifluoro-3-(1,7-naphthyridine-6-carbonyl)phenyl)benzamide,

3,4-difluoro-N-(2,4,5-trifluoro-3-(1,7-naphthyridine-6-carbonyl)phenyl)benzamide,

3-fluoro-N-(2,4,5-trifluoro-3-(3-morpholino-1,7-naphthyridine-6-carbonyl)phenyl)benzamide,

3,4-difluoro-N-(2,4,5-trifluoro-3-(3-morpholino-1,7-naphthyridine-6-carbonyl)phenyl)benzamide,

3-fluoro-N-(2,4,5-trifluoro-3-(pyrido[3,4-b]pyrazine-7-carbonyl)phenyl)benzamide,

4-fluoro-N-(2,4,5-trifluoro-3-(pyrido[3,4-b]pyrazine-7-carbonyl)phenyl)benzamide,

4-fluoro-N-(2,4,5-trifluoro-3-(2-morpholinopyrido[3,4-b]pyrazine-7-carbonyl)phenyl)benzamide,

3-fluoro-N-(2,4,5-trifluoro-3-(2-morpholinopyrido[3,4-b]pyrazine-7-carbonyl)phenyl)benzamide,

3-fluoro-N-(2,4,5-trifluoro-3-(1,5-naphthyridine-2-carbonyl)phenyl)benzamide,

3-fluoro-N-(2,4,5-trifluoro-3-(7-morpholino-1,5-naphthyridine-2-carbonyl)phenyl)benzamide,

N-(3-(benzo[d]oxazole-6-carbonyl)-2,4,5-trifluorophenyl)-3-fluorobenzamide,

N-(3-(benzo[d]oxazole-5-carbonyl)-2,4,5-trifluorophenyl)-3-fluorobenzamide,

N-(3-(benzo[d]thiazole-6-carbonyl)-2,4,5-trifluorophenyl)-3-fluorobenzamide,

N-(3-(3a,7a-dihydro-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-2,4,5-trifluorophenyl)-3-fluorobenzamide,

N-(3-(7,7a-dihydro-4aH-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2,4,5-trifluorophenyl)-3-fluorobenzamide,

N-(3-(5,7a-dihydro-4aH-pyrrolo[2,3-b]pyrazine-7-carbonyl)-2,4,5-trifluorophenyl)-3-fluorobenzamide,

N-(3-(3a,7a-dihydro-1H-pyrazolo[3,4-b]pyrazine-3-carbonyl)-2,4,5-trifluorophenyl)-3-fluorobenzamide, and

N-(3-(7,7a-dihydro-4aH-pyrrolo[2,3-c]pyridazine-5-carbonyl)-2,4,5-trifluorophenyl)-3-fluorobenzamide,

and pharmaceutically acceptable salts thereof.

14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound or pharmaceutically acceptable salt of claim 1.

15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound or pharmaceutically acceptable salt of claim 13.

16. The compound or pharmaceutically acceptable salt of claim 1, wherein Z₁ is an optionally substituted bicyclic heteroaryl.

17. The compound or pharmaceutically acceptable salt of claim 1, wherein Z₁ is an optionally substituted quinolinyl.

18. The compound or pharmaceutically acceptable salt of claim 1, wherein Z₁ is an optionally substituted quinazolinyl.

19. The compound or pharmaceutically acceptable salt of claim 1, wherein R₁ and R₂ are independently a halogen.

20. The compound or pharmaceutically acceptable salt of claim 1, wherein R₁ and R₂ are fluoro.

21. The compound or pharmaceutically acceptable salt of claim 1, wherein R₅ is —

COR₇.

22. The compound or pharmaceutically acceptable salt of claim 21, wherein R₇ is optionally substituted aryl.

23. The compound or pharmaceutically acceptable salt of claim 21, wherein R₄ is hydrogen.