Compounds and methods for development of Ret modulators

• US 8,067,434 B2
• Filed: 04/11/2008
• Issued: 11/29/2011
• Est. Priority Date: 12/19/2003
• Status: Active Grant

• Current Assignee: Plexxikon Inc (Daiichi Sankyo Company Limited)
• Original Assignee: Plexxikon Inc (Daiichi Sankyo Company Limited)
• Inventors: Kumar, Abhinav, Krupka, Heike, Artis, Dean Richard, Habets, Gaston, Zhang, Jiazhong, West, Brian, Zhang, Chao, Mamo, Shumeye, Bremer, Ryan, Nespi, Marika, Hurt, Clarence R., Ibrahim, Prabha, Zhu, Yong-Liang, Zuckerman, Rebecca
• Primary Examiner(s): Seaman; D M
• Assistant Examiner(s): Rahmani; Niloofar
• Application Number:
  US12/082,665
• Publication Number:
  US 20100324065A1
• Time in Patent Office: 1,327 Days
• Field of Search: 514/300
• US Class Current: 514/300
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Compounds active on Ret are described, as well as methods of using such compounds. Also described are crystal structures of Ret surrogates that were determined using X-ray crystallography. The use of such Ret surrogate crystals and structural information can, for example, be used for identifying molecular scaffolds and for developing ligands that bind to and modulate Ret and for identifying improved ligands based on known ligands.

Claims

1. A method for treating a patient suffering from or at risk of a RET-mediated condition selected from the group consisting of multiple endocrine neoplasia, type IIA (MEN2A), multiple endocrine neoplasia, type JIB (MEN2B), medullary thyroid carcinoma (MTC), familial medullary thyroid carcinomas (FMTC), and papillary thyroid carcinomas (PTC) for which Ret modulation provides a therapeutic benefit, said method comprising administering to said patient a Ret modulator having a chemical structure of Formula I,

2. The method of claim 1, wherein said Ret modulator is selected from the group consisting of

3. The method of claim 1, wherein said compound is selected from the group consisting of:

3-(6-Chloro-pyridin-3-ylmethyl)-4-phenyl-1H-pyrrolo[2,3-b]pyridine,

3-(3-Methoxy-benzyl)-5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridine,

{3-[3-(Thiophen-2-ylsulfanyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-methanol,

[3-(3-p-Tolylsulfanyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-phenyl]-methanol,

4-(3-Fluoro-phenyl)-3-(thiophen-2-ylsulfanyl)-1H-pyrrolo[2,3-b]pyridine,

5-Bromo-3-(3-methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine,

(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methanone,

3-{3-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-benzyl}-5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridine,

3-(3-Methoxy-benzyl)-5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridine,

Phenyl-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

4-[3-(3-Methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenylamine,

4-[3-(3-Methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide,

3-(6-Chloro-pyridin-3-ylmethyl)-5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridine,

(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-methoxy-phenyl)-methanone,

4-Bromo-3-(3-methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine,

3-(5-Thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenol,

(4-Amino-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methanone,

(3-Methoxy-phenyl)-[5-(1H-pyrrol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone,

(3-Methoxy-phenyl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

4-(5-Thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-benzene-1,2-diol,

3-Methoxy-5-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenol,

5-(5-Thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-benzene-1,3-diol,

[4-(3,5-Difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-phenyl-methanone,

[4-(3,5-Difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(3-methoxy-phenyl)-methanone,

(2,5-Difluoro-phenyl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(2,5-Difluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-phenyl)-methanone,

(2-Fluoro-phenyl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(2-Fluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(4-chloro-phenyl)-methanone,

(4-Chloro-phenyl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(4-Chloro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-o-tolyl-methanone,

[4-(3,5-Difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(3-fluoro-phenyl)-methanone,

3-(6-Methoxy-pyridin-2-ylmethyl)-4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridine,

3-(6-Methoxy-pyridin-3-ylmethyl)-4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridine,

4-Bromo-3-(6-methoxy-pyridin-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridine,

(3-Hydroxy-phenyl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-fluoro-phenyl)-methanone,

(2,5-Difluoro-phenyl)-[4-(3,5-difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone,

(2,3-Difluoro-phenyl)-[4-(3,5-difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone,

(2,4-Difluoro-phenyl)-[4-(3,5-difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone,

(2,6-Difluoro-phenyl)-[4-(3,5-difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone,

[4-(3,5-Difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2-fluoro-phenyl)-methanone,

3-(6-Chloro-pyridin-3-ylmethyl)-4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridine,

(3-Methoxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(3-Hydroxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

[4-(3,5-Difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(3-hydroxy-phenyl)-methanone,

(5-Methyl-isoxazol-3-yl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(5-Methyl-isoxazol-3-yl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

4-[3-(1,5-Dimethyl-1H-pyrazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide,

(1,5-Dimethyl-1H-pyrazol-3-yl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

N-{3-[3-(5-Methyl-isoxazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acetamide,

4-[3-(5-Fluoro-2-methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide,

(5-Fluoro-2-methyl-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

[5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(5-fluoro-2-methyl-phenyl)-methanone,

(5-Fluoro-2-methyl-phenyl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

[5-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(5-fluoro-2-methyl-phenyl)-methanone,

[5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2,3-dichloro-phenyl)-methanone,

(2,3-Diehloro-phenyl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(2,3-Dichloro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

3-[3-(1,5-Dimethyl-1H-pyrazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide,

(5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-o-tolyl-methanone,

3-[3-(2,5-Dimethyl-2H-pyrazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide,

N-{3-[3-(2-Fluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acetamide,

(5-Thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-o-tolyl-methanone,

(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-hydroxy-phenyl)-methanone,

(3-Methoxy-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

[5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(3-methoxy-phenyl)-methanone,

(E)-3-{3-[3-(3-Methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acrylic acid,

[5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2-fluoro-phenyl)-methanone,

(E)-3-{3-[3-(2-Fluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acrylic acid,

[5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(4-chloro-phenyl)-methanone,

[5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-o-tolyl-methanone,

[5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(5-methyl-isoxazol-3-yl)-methanone,

[5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(1,5-dimethyl-1H-pyrazol-3-yl)-methanone,

N-{3-[3-(5-Fluoro-2-methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide,

N-{3-[3-(2,5-Dimethyl-2H-pyrazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide,

[5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2,5-dimethyl-2H-pyrazol-3-yl)-methanone,

[5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-benzo[1,2,5]thiadiazol-5-yl-methanone,

N-{3-[3-(4-Chloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide,

(3-Fluoro-phenyl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-3-methoxy-phenyl)-methanone,

(2-Hydroxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(2-Fluoro-3-methoxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(2-Fluoro-5-methoxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(2-Fluoro-3-hydroxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-ye-methanone,

(2-Fluoro-5-hydroxy-phenyl)-(5-thiophen-2-yl -1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

4-[3-(2,5-Dimethyl-2H-pyrazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide,

(2,5-Dimethyl-2H-pyrazol-3-yl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

4-[3-(2-Methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide,

4-[3-(2,3-Dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide,

4-[3-(Benzo[1,2,5]thiadiazole-5-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide,

(E)-3-{3-[3-(Benzo[1,2,5]thiadiazole-5-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acrylic acid,

N-{3-[3-(Benzo[1,2,5]thiadiazole-5-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide,

4-[3-(3-Methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide,

4-[3-(2-Fluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide,

(E)-3-{3-[3-(2,3-Dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acrylic acid,

(E)-3-{3-[3-(5-Methyl-isoxazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acrylic acid,

(E)-3-{3-[3-(1,5-Dimethyl-1H-pyrazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acrylic acid,

4-[3-(4-Chloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide,

(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-hydroxy-phenyl)-methanone,

(5-Chloro-2-fluoro-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(4-Methoxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(4-Hydroxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(3-Methoxy-phenyl)-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

4-[3-(3-Hydroxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide,

[5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(3-hydroxy-phenyl)-methanone,

(5-Ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-hydroxy-phenyl)-methanone,

(2-Fluoro-phenyl)-[4-(2-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone,

N-{3-[3-(2-Fluoro-5-methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acetamide,

N-{3-[3-(2-Fluoro-5-hydroxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acetamide,

(2-Fluoro-5-methoxy-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2,3-dichloro-phenyl)-methanone,

(3-Methoxy-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(2-Fluoro-5-hydroxy-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

3-[3-(3-Methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide,

3-Benzenesulfinyl-5-bromo-1H-pyrrolo[2,3-b]pyridine,

(2-Fluoro-5-hydroxy-phenyl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

[4-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(3-methoxy-phenyl)-methanone,

(3-Hydroxy-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-5-hydroxy-phenyl)-methanone,

(2-Fluoro-5-hydroxy-phenyl)-(4-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

[5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2-fluoro-5-hydroxy-phenyl)-methanone,

(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-5-methoxy-phenyl)-methanone,

[4-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2,5-difluoro-phenyl)-methanone,

[4-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2,3-dichloro-phenyl)-methanone,

(2,5-Difluoro-phenyl)-(4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(4-Chloro-phenyl)-(4-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

[4-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(4-chloro-phenyl)-methanone,

[4-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2-fluoro-phenyl)-methanone,

4-[3-(2-Methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide,

4-[3-(2,5-Difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide,

4-[3-(2-Fluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide,

(E)-3-{3-[3-(4-Chloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acrylic acid,

N-{3-[3-(4-Chloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acetamide,

N-{3-[3-(2,3-Dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acetamide,

3-[3-(2,5-Difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide,

3-[3-(2,3-Dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide,

N-{3-[3-(4-Chloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-methanesulfonamide,

N-{3-[3-(2-Methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-methanesulfonamide,

N-{3-[3-(2,5-Difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-methanesulfonamide,

(2-Fluoro-phenyl)-[4-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone,

(2-Fluoro-phenyl)-[4-(6-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone,

(4-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-o-tolyl-methanone,

[4-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2,3-dichloro-phenyl)-methanone,

(E)-3-{3-[3-(2,5-Difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acrylic acid,

N-{3-[3-(2-Methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acetamide,

N-{3-[3-(2,5-Difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acetamide,

N-{3-[3-(2-Fluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acetamide,

3-[3-(4-Chloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide,

N-{3-[3-(2-Fluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-methanesulfonamide,

(2,5-Difluoro-phenyl)-[4-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone,

(2,3-Dichloro-phenyl)-[4-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone,

[4-(6-Methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-o-tolyl-methanone,

(2,3-Dichloro-phenyl)-[4-(6-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone,

(2,5-Difluoro-phenyl)-(4-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

3-[3-(2-Fluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide,

[4-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-o-tolyl-methanone,

[4-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2-fluoro-phenyl)-methanone,

(2-Fluoro-phenyl)-(4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(2,3-Dichloro-phenyl)-(4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(2-Fluoro-phenyl)-(4-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(2,3-Dichloro-phenyl)-(4-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

[4-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-o-tolyl-methanone,

[4-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2,5-difluoro-phenyl)-methanone,

4-[3-(4-Chloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide,

4-[3-(2,3-Dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide,

(E)-3-{3-[3-(2-Methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acrylic acid,

(E)-3-{3-[3-(2-Fluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acrylic acid,

(E)-3-{3-[3-(2,3-Dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acrylic acid,

3-[3-(2-Methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide,

N-{3-[3-(2,3-Dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-methanesulfonamide,

(4-Chloro-phenyl)-[4-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone,

[4-(3-Methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-o-tolyl-methanone,

(E)-3-{3-[3-(5-tert-Butyl-2-methyl-2H-pyrazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acrylic acid,

N-{3-[3-(3-Methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-methanesulfonamide,

[4-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(5-fluoro-2-methyl-phenyl)-methanone,

[4-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(5-methyl-isoxazol-3-yl)-methanone,

[4-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2,5-dimethyl-2H-pyrazol-3-yl)-methanone,

(5-Methyl-isoxazol-3-yl)-(4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

N-{3-[3-(5-Fluoro-2-methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acetamide,

N-{3-[3-(5-Methyl-isoxazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-methanesulfonamide,

(5-Fluoro-2-methyl-phenyl)-[4-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone,

[4-(3-Methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(5-methyl-isoxazol-3-yl)-methanone,

(3-Methoxy-phenyl)-[4-(6-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone,

[4-(6-Methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(5-methyl-isoxazol-3-yl)-methanone,

(5-Fluoro-2-methyl-phenyl)-[4-(6-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone,

[4-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(3-methoxy-phenyl)-methanone,

(3-Methoxy-phenyl)-(4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(5-Fluoro-2-methyl-phenyl)-(4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(3-Methoxy-phenyl)-(4-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(5-Fluoro-2-methyl-phenyl)-(4-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

(5-Methyl-isoxazol-3-yl)-(4-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,

[4-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(5-fluoro-2-methyl-phenyl)-methanone,

4-[3-(3-Methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide,

4-[3-(5-Fluoro-2-methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide,

4-[3-(5-Methyl-isoxazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide,

(E)-3-{3-[3-(3-Methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acrylic acid,

(E)-3-{3-[3-(5-Fluoro-2-methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acrylic acid,

(E)-3-{3-[3-(5-Methyl-isoxazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acrylic acid,

(E)-3-{3-[3-(2,5-Dimethyl-2H-pyrazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acrylic acid,

N-{3-[3-(3-Methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acetamide,

N-{3-[(5-Methyl-isoxazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acetamide,

3-[3-(3-Methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide,

3-[3-(5-Fluoro-2-methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide,

3-[3-(5-Methyl-isoxazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide,

N-{3-[3-(5-Fluoro-2-methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-methanesulfonamide,

[4-(3-Methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(3-methoxy-phenyl)-methanone,

(3-Hydroxy-phenyl)-(5-phenylamino-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, and

pharmaceutically acceptable salts thereof.

4. The method of claim 1, wherein said Ret modulator is approved for administration to a human.

5. The method of claim 1, wherein R² is selected from the group consisting of —

CH₂-(optionally substituted aryl), —

CH₂-(optionally substituted heteroaryl), —

C(O)-(optionally substituted aryl), —

C(O)-(optionally substituted heteroaryl), —

S-(optionally substituted aryl), —

S-(optionally substituted heteroaryl), —

S(O)-(optionally substituted aryl), —

S(O)-(optionally substituted heteroaryl), —

S(O)₂-(optionally substituted aryl), and —

S(O)₂-(optionally substituted heteroaryl).

6. The method of claim 5, wherein R² is selected from the group consisting of —

CH₂-(optionally substituted aryl), —

CH₂-(optionally substituted heteroaryl), —

C(O)-(optionally substituted aryl), and —

C(O)-(optionally substituted heteroaryl).

7. The method of claim 5, wherein R³ is hydrogen and R⁴ is selected from the group consisting of optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, —

O-(optionally substituted lower alkyl), —

O-(optionally substituted aryl), —

O-(optionally substituted heteroaryl), —

NH-(optionally substituted lower alkyl), —

NH-(optionally substituted aryl), and —

NH-(optionally substituted heteroaryl).

8. The method of claim 6, wherein R³ is hydrogen and R⁴ is selected from the group consisting of optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, —

O-(optionally substituted lower alkyl), —

O-(optionally substituted aryl), —

O-(optionally substituted heteroaryl), —

NH-(optionally substituted lower alkyl), —

NH-(optionally substituted aryl), and —

NH-(optionally substituted heteroaryl).

9. The method of claim 5, wherein R⁴ is hydrogen and R³ is selected from the group consisting of optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, —

NH-(optionally substituted lower alkyl), —

NH-(optionally substituted aryl), and —

NH-(optionally substituted heteroaryl).

10. The method of claim 6, wherein R⁴ is hydrogen and R³ is selected from the group consisting of optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, —

NH-(optionally substituted lower alkyl), —

NH-(optionally substituted aryl), and —

NH-(optionally substituted heteroaryl).