# US 8,541,584 B2 · 3-(1,2,3-triazol-4-yl) pyrrolo [2,3-b] pyridine derivatives

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- Number: US 8,541,584 B2
- Document ID: US8541584B2
- Status: Granted
- Kind: B2
- Application number: 13/318,518
- Filed: 2010-04-08
- Published: 2012-03-01
- Granted: 2013-09-24
- Earliest claimed: 2009-05-05
- Assignees: Merck Patent GmbH
- Applicants: Dieter Dorsch; Margarita Wucherer-Plietker; Thomas J. J. Mueller; Eugen Merkul
- Inventors: Dieter Dorsch; Margarita Wucherer-Plietker; Thomas J. J. Mueller; Eugen Merkul
- Web page: https://patentgrep.com/patent/US8541584B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds of the formula (I), in which R1, R2 and R3 have the meanings indicated in claim (1), are inhibitors of PDK1 and cell proliferation/cell vitality and can be employed for the treatment of tumors.

## Claims

### Claim 1

A compound of formula I
in which
R1 denotes A, —[C(R3)(R4)]nAr, —[C(R3)(R4)]nHet or —[C(R3)(R4)]nCyc,
R2 denotes H, A, Hal, CN, —[C(R3)2]n—Ar′, —[C(R3)2]n—Het′, —[C(R3)2]n—Cyc, OR3 or N(R3)2,
R3 denotes H or A,
R4 denotes H, A, —[C(R3)2]nOR3, —[C(R3)2]nCOOR3, —[C(R3)2]nN(R3)2 or —[C(R3)2]nHet,
A denotes unbranched or branched alkyl having 1-6 C atoms, in which one or two CH2 groups are each optionally replaced by O, N or S atoms or —CH═CH— groups and/or 1-7 H atoms are each optionally replaced by F,
Cyc denotes cycloalkyl having 3, 4, 5, 6 or 7 C atoms,
Ar denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, —[C(R3)2]nOR3, N(R3)2, NO2, CN, COOR3, CON(R3)2, NR3COA, NR3SO2A, COR3, SO2N(R3)2 and/or S(O)nA,
Ar′ denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OR3, N(R3)2, SR3, NO2, CN, COOR3, CON(R3)2, NR3COA, NR3SO2A, SO2N(R3)2, S(O)nA, CO—Het1, Het1, [C(R3)2]nN(R3)2, [C(R3)2]nHet1, O[C(R3)2]nN(R3)2, O[C(R3)2]nHet1, NHCOOA, NHCON(R3)2, NHCOO[C(R3)2]nN(R3)2, NHCOO[C(R3)2]nHet1, NHCONH[C(R3)2]nN(R3)2, NHCONH[C(R3)2]nHet1, OCONH[C(R3)2]n—N(R3)2, OCONH[C(R3)2]nHet1, CO—Het1, CHO and/or COA,
Het denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, and/or O and/or S atoms which is unsubstituted or mono- or disubstituted by Hal, A, OR3, N(R3)2, NO2, CN, COOR3, CON(R3)2, NR3COA, NR3SO2A, COR3, SO2NR3 and/or S(O)nA,
Het′ denotes a mono-, bi- or tricyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms which is unsubstituted or may be mono- or disubstituted by Hal, A, OR3, N(R3)2, SR3, NO2, CN, COOR3, CON(R3)2, NR3COA, NR3SO2A, SO2N(R3)2, S(O)nA, CO—Het1, Het1, [C(R3)2]nN(R3)2, [C(R3)2]nHet1, O[C(R3)2]nN(R3)2, O[C(R3)2]nHet1, NHCOOA, NHCON(R3)2, NHCOO[C(R3)2]nN(R3)2, NHCOO[C(R3)2]n—Het1, NHCONH[C(R3)2]nN(R3)2, NHCONH[C(R3)2]nHet1, OCONH[C(R3)2]nN(R3)2, OCONH[C(R3)2]nHet1, CO—Het1, CHO, COA, ═S, ═NH, ═NA and/or ═O,
Het1 denotes a monocyclic saturated heterocycle having 1 to 2 N and/or O atoms, which is unsubstituted or mono- or disubstituted by A, OA, OH, Hal and/or ═O,
Hal denotes F, Cl, Br or I
N denotes 0, 1 or 2,
or a pharmaceutically usable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

### Claim 2 (depends on 1)

A compound according to claim 1, in which Ar denotes phenyl which is unsubstituted or mono- or disubstituted by Hal, —[C(R3)2]nOR3, COOR3, CN and/or A.

### Claim 3 (depends on 1)

A compound according to claim 1, in which Het denotes a mono- or bicyclic saturated aromatic heterocycle having 1 to 4 N, and/or O and/or S atoms which is unsubstituted or mono- or disubstituted by A and/or Hal.

### Claim 4 (depends on 1)

A compound according to claim 1, in which Het′ denotes a mono- or bicyclic aromatic heterocycle having 1 to 4 N, O and/or S atoms which is unsubstituted or mono- or disubstituted by A and/or [C(R3)2]nHet1.

### Claim 5 (depends on 1)

A compound according to claim 1, in which Het1 denotes a monocyclic saturated heterocycle having 1 to 2 N and/or O atoms, which may be mono- or disubstituted by A.

### Claim 6 (depends on 1)

A compound according to claim 1, in which Het denotes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, thiadiazole, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl, 1,3-benzodioxolyl, pyrrolidinyl, tetrahydroimidazolyl, tetrahydropyrazolyl, piperidinyl, morpholinyl, piperazinyl, oxazolidinyl or isoxazolidinyl, each of which is unsubstituted or mono- or disubstituted by A and/or Hal.

### Claim 7 (depends on 1)

A compound according to claim 1, in which Het′ denotes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, thiadiazole, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl or 1,3-benzodioxolyl, each of which is unsubstituted or mono- or disubstituted by A and/or [C(R3)2]nHet1.

### Claim 8 (depends on 1)

A compound according to claim 1, in which Het1 denotes pyrrolidinyl, tetrahydroimidazolyl, tetrahydropyrazolyl, piperidinyl, morpholinyl, piperazinyl, oxazolidinyl or isoxazolidinyl, each of which is unsubstituted or mono- or disubstituted by A.

### Claim 9 (depends on 1)

A compound according to claim 1, in which
R1 denotes —C(R3)(R4)—Ar or C(R3)(R4)—Het,
R2 denotes H, A or —[C(R3)2]n—Het′,
R3 denotes H or A,
R4 denotes H, —[C(R3)2]nOR3 or -[C(R3)2]nCOOR3,
A denotes unbranched or branched alkyl having 1-6 C atoms, in which one CH2 group is optionally replaced by an O, N or S atom and optionally 1-7 H atoms are each replaced by F,
Ar denotes phenyl which is unsubstituted or mono- or disubstituted by Hal, —[C(R3)2]nOR3, COOR3, CN and/or A,
Het denotes a mono- or bicyclic saturated aromatic heterocycle having 1 to 4 N, and/or O and/or S atoms which is unsubstituted or mono- or disubstituted by A and/or Hal,
Het′ denotes a mono- or bicyclic aromatic heterocycle having 1 to 4 N, O and/or S atoms which is unsubstituted or may be mono- or disubstituted by A and/or [C(R3)2]nHet1,
Het1 denotes a monocyclic saturated heterocycle having 1 to 2 N and/or O atoms, which is unsubstituted or mono- or di-substituted by A,
Hal denotes F, Cl, Br or I, and
n denotes 0, 1 or 2.

### Claim 10 (depends on 1)

A compound according to claim 1, selected from the group:
Compound
No.
Name and/or structure
“A1”
3-(1-Benzyl-1H-1,2,3-triazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
“A2”
3-[1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-
pyrrolo[2,3-b]pyridine
“A3”
3-(1-Benzyl-1H-1,2,3-triazol-4-yl)-2-methyl-1H-
pyrrolo[2,3-b]pyridine
“A4”
3-(1-Benzyl-1H-1,2,3-triazol-4-yl)-5-(1-methyl-1H-
pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
“A5”
3-[1-(3-Fluorobenzyl)-1H-1,2,3-triazol-4-yl]-5-(1-
methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
“A6”
3-[1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl]-5-(1-
methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
“A7”
3-[1-(3-Methylbenzyl)-1H-1,2,3-triazol-4-yl]-5-(1-
methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
“A8”
5-(1-Methyl-1H-pyrazol-4-yl)-3-[1-(1-phenylethyl)-1H-
1,2,3-triazol-4-yl]-1H-pyrrolo[2,3-b]pyridine
“A9”
5-(1-Methyl-1H-pyrazol-4-yl)-3-(1-pyridin-4-ylmethyl-
1H-1,2,3-triazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
“A10”
“A11”
“A12”
“A13”
“A14”
2-{4-[3-(1-Benzyl-1H-1,2,3-triazol-4-yl)-1H-pyrrolo-
[2,3-b]pyridin-5-yl]pyrazol-1-yl}ethanol
“A15”
3-(1-Benzyl-1H-1,2,3-triazol-4-yl)-4-methoxy-1H-
pyrrolo[2,3-b]pyridine
“A16”
5-(1-Methyl-1H-pyrazol-4-yl)-3-(1-phenethyl-1H-1,2,3-
triazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
“A17”
3-[1-(2-Fluorobenzyl)-1H-1,2,3-triazol-4-yl]-5-(1-
methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
“A18”
5-(1-Methyl-1H-pyrazol-4-yl)-3-[1-(2-morpholin-4-yl-
ethyl)-1H-1,2,3-triazol-4-yl]-1H-pyrrolo[2,3-b]pyridine
“A19”
5-(1-Methyl-1H-pyrazol-4-yl)-3-{1-[1-(3-trifluoro-
methylphenyl)ethyl]-1H-1,2,3-triazol-4-yl}-1H-pyrrolo[2,3-b]pyridine
“A20”
5-(1-Methyl-1H-pyrazol-4-yl)-3-{1-[1-(2-trifluoro-
methylphenyl)ethyl]-1H-1,2,3-triazol-4-yl}-1H-pyrrolo[2,3-b]pyridine
“A21”
3-[1-(2,4-Difluorobenzyl)-1H-1,2,3-triazol-4-yl]-5-(1-
methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
“A22”
3-[1-(2-Fluoro-3-trifluoromethylbenzyl)-1H-1,2,3-
triazol-4-yl]-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
“A23”
3-[1-(3-Chloro-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl]-
5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
“A24”
3-[1-(2-Fluoro-6-trifluoromethylbenzyl)-1H-1,2,3-
triazol-4-yl]-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
“A25”
3-[1-(2,3-Difluorobenzyl)-1H-1,2,3-triazol-4-yl]-5-(1-
methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
“A26”
3-[1-(2-Fluoro-4-trifluoromethylbenzyl)-1H-1,2,3-
triazol-4-yl]-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
“A27”
4-(1-{4-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo-
[2,3-b]pyridin-3-yl]-1,2,3-triazol-1-yl}ethyl)benzoic acid
“A28”
3-{4-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]-
pyridin-3-yl]-1,2,3-triazol-1-yl}-3-phenylpropionic acid
“A29”
6-{4-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]-
pyridin-3-yl]-1,2,3-triazol-1-ylmethyl}quinoline
“A30”
[4-(1-{4-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo-
[2,3-b]pyridin-3-yl]-1,2,3-triazol-1-yl}ethyl)phenyl]methanol
“A31”
2-{4-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]-
pyridin-3-yl]-1,2,3-triazol-1-yl}-1-phenylethanol
“A32”
3-[1-(3-Fluoropyridin-4-ylmethyl)-1H-1,2,3-triazol-4-
yl]-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
“A33”
3-[1-(2-Chlorobenzyl)-1H-1,2,3-triazol-4-yl]-5-(1-
methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
“A34”
3-[1-(3-Methoxybenzyl)-1H-1,2,3-triazol-4-yl]-5-(1-
methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
“A35”
(2-{4-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo-
[2,3-b]pyridin-3-yl]-1,2,3-triazol-1-ylmethyl}phenyl)methanol
“A36”
3-[1-(4-Difluoromethoxybenzyl)-1H-1,2,3-triazol-4-yl]-
5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
“A37”
Methyl 3-{4-[5-(1-methyl-1H-pyrazol-4-yl)-1H-
pyrrolo[2,3-b]pyridin-3-yl]-1,2,3-triazol-1-ylmethyl}benzoate
“A38”
2-{4-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]-
pyridin-3-yl]-1,2,3-triazol-1-ylmethyl}benzonitrile
“A39”
3-[1-(3-Difluoromethoxybenzyl)-1H-1,2,3-triazol-4-yl]-
5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
“A40”
3-{4-[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]-
pyridin-3-yl]-[1,2,3-triazol-1-yl}-3-phenylpropan-1-ol
and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

### Claim 11 (depends on 1)

A process for the preparation of compounds of formula I according to claim 1, and pharmaceutically usable salts, tautomers and stereoisomers thereof, said process comprising:
cleaving off the indole-protecting group R is from a compound of the formula II
and/or converting a base or acid compound of formula I into one of its salts.

### Claim 12 (depends on 1)

A pharmaceutical formulation comprising at least one compound according to claim 1.

### Claim 13 (depends on 1)

A compound according to claim 1, in which R1 is —C(R3)(R4)—Ar or C(R3)(R4)—Het.

### Claim 14 (depends on 1)

A compound according to claim 1, in which R2 is H, A or —[C(R3)2]n—Het′.

### Claim 15 (depends on 1)

A compound according to claim 1, in which R3 is H, methyl, ethyl, propyl or butyl.

### Claim 16 (depends on 1)

A compound according to claim 1, in which R4 is H, —[C(R3)2]nOR3 or —[C(R3)2]nCOOR3.