IP Library › Granted Patent US 8,067,434

Granted Patent B2

US 8,067,434 · App. 12/082,665 · Granted Nov 29, 2011

Compounds and methods for development of Ret modulators

Assignee: Plexxikon Inc.

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Quick Facts

Patent No.: US 8,067,434
App. No.: 12/082,665
Granted: Nov 29, 2011
Kind: B2

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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 (234)

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,

or a prodrug or pharmaceutically acceptable salt thereof,

wherein:

R 1 and R 5 are hydrogen;

R 2 is optionally substituted aralkyl, optionally substituted heteroaralkyl, —C(X)R 20 , —NR 22 R 23 , or —S(O) n R 21 ;

R 3 and R 4 are independently hydrogen, halo, hydroxy, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl, —C(X)R 20 , —C(X)NR 16 R 17 , —S(O) 2 NR 16 R 17 , —NR 22 R 23 , or —S(O) n R 21 ;

R 16 and R 17 are independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl, or R 16 and R 17 together form a 5-7 membered carbocyclic or heterocyclic ring;

R 20 is hydroxyl, optionally substituted lower alkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;

R 21 is optionally substituted lower alkyl, optionally substituted amine, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl;

R 22 and R 23 are independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(X)R 20 , C(X)NR 16 R 17 , or —S(O) 2 R 21 ;

X=O or S; and

n=0, 1, or 2.

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

wherein:

R 24 is optionally substituted aryl or optionally substituted heteroaryl.

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 R 2 is selected from the group consisting of —CH 2 -(optionally substituted aryl), —CH 2 -(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 R 2 is selected from the group consisting of —CH 2 -(optionally substituted aryl), —CH 2 -(optionally substituted heteroaryl), —C(O)-(optionally substituted aryl), and —C(O)-(optionally substituted heteroaryl).

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

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 12, 2014

From: IBRAHIM, PRABHA; ARTIS, DEAN RICHARD; BREMER, RYAN; HABETS, GASTON; HURT, CLARENCE R.; MAMO, SHUMEYE; NESPI, MARIKA; ZHANG, CHAO; ZHANG, JIAZHONG; ZHU, YONG; ZUCKERMAN, REBECCA; KRUPKA, HEIKE; KUMAR, ABHINAV; WEST, BRIAN

To: PLEXXIKON INC.

Reel/Frame 032420/0893 →

Continuity (4)

Continuation 11016350 · Dec 17, 2004

Provisional Application 60531281 · Dec 19, 2003

Provisional Application 60558581 · Mar 31, 2004

Related Publication 20100324065A1 · Dec 23, 2010