# US 7,071,192 B1 · Respiratory syncytial virus replication inhibitors

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- Number: US 7,071,192 B1
- Document ID: US7071192B1
- Status: Granted
- Kind: B1
- Application number: 10/019,376
- Filed: 2000-06-20
- Granted: 2006-07-04
- Earliest claimed: 1999-06-28
- Assignees: Janssen Pharmaceutica NV
- Inventors: Frans Eduard Janssens; Jean Fernand Armand Lacrampe; Jérôme Emile Georges Guillemont; Marc Gaston Venet; Koenraad Jozef Lodewijk Marcel Andries
- Web page: https://patentgrep.com/patent/US7071192B1

## CPC

- C07D 401/14: containing three or more hetero rings
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 409/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

The present invention concerns compounds of formula (I), prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms thereof wherein -a1=a2-a3=a4-represents a radical of formula —CH═CH—CH═CH—; —N—CH—CH═CH—; —CH═N—CH═CH—; —CH═CH—N═CH—; —CH═CH—CH═N—; wherein each hydrogen atom may optionally be substituted; Q is a radical of formulae (b-1), (b-2), (b-3), (b-4), (b-5), (b-6), (b-7) and (b-8), wherein Alk is C1-6alkanediyl; Y1 is a bivalent radical of formula —NR2— or —CH(NR2R4)—; X1 is NR4, S, S(═O), S(═O)2, O, CH2, C(═O), CH(═CH2), CH(OH), CH(CH3), CH(OCH3), CH(SCH3), CH(NR5aR5b), CH2—NR4 or NR4—CH2; X2 is a direct bond, CH2, C(═O), NR4, C1-4alkyl-NR4, NR4—C1-4alkyl, t is 2 to 5; u is 1 to 5; v is 2 or 3; and whereby each hydrogen in Alk and in (b-3), (b-4), (b-5), (b-6), (b-7) and (b-8), may optionally be replaced by R3: provided that when R3 is hydroxy or C1-6alkyloxy, then R3 cannot replace a hydrogen atom in the a position relative to a nitrogen atom; G is a direct bond or optionally substituted C1-10alkanediyl; R1 is an optionally substituted bicyclic heterocycle; R2 is hydrogen, formyl, C1-6alkylcarbonyl, Hetcarbonyl, pyrrolidinyl, piperidinyl, homopiperidinyl, C3-7cycloalkyl or C1-10alkyl substituted with N(R6)2 and optionally with another substituent; R3 is hydrogen, hydroxy, C1-6alkyl, C1-6alkyloxy, aryl C1-6alkyl or aryl C1-6alkyloxy, R4 is hydrogen, C1-6alkyl or aryl C1-6alkyl; R5a, R5b, R5c and R5d are hydrogen or C1-6alkyl; or R5a and R5b, or R5c and R5d taken together from a bivalent radical of formula —(CH2)5- wherein S is 4 or 5; R6 is hydrogen, C1-4alkyl, formyl, hydroxy C1-6alkyl, C1-6alkylcarbonyl or C1-6alkyloxycarbonyl; aryl is optionally substituted phenyl; Het is pyridyl, pyrimidinyl, pyridazinyl, pyridazinyl; as respiratory syncytial virus replication inhibitors; their preparation, compositions containing them and their use as a medicine.

## Claims

### Claim 1

A compound of formula
an N-oxide, addition salt, quaternary amine, metal complex or stereochemically isomeric form thereof
wherein -a1=a2-a3=a4- represents a bivalent radical of formula —CH═CH—CH═CH— (a-1);
wherein each hydrogen atom in the radical (a-1) may optionally be replaced by halo, CH6alkyl, nitro, amino, hydroxy, CH6alkyloxy, polyhaloC1-6alkyl, carboxyl, aminoC1-6alkyl, mono- or di(C1-4alkyl)aminoC1-6alkyl, C1-6alkyloxycarbonyl, hydroxyC1-6alkyl, or a radical of formula
wherein ═Z is ═O, ═CH—C(═O)_NR5a R5b, ═CH2, ═CH—C1-6alkyl, ═N—OH or ═N—O—C1-6 alkyl;
Q is a radical of formula
wherein
Alk is C1-6alkanediyl;
Y1 is a bivalent radical of formula —NR2_or —CH(NR2R4)—;
X1 is NR4, S, S(═O), S(═O)2, O, CH2, C(═O), C(═CH2), CH(OH), CH(CH3), CH(OCH3), CH(SCH3), CH(NR5aR5b), CH2—NR4 or NR4—CH2;
X2 is a direct bond, CH2, C(═O), NR4, C1-4alkylene-NR4, or NR4—C1-4alkylene;
t is 2, 3, 4 or 5;
u is 1,2,3, 4 or 5;
v is 2 or 3; and
whereby each hydrogen atom in Alk and the carbocycles and the heterocycles defined in radicals (b-3), (b-4), (b-5), (b-6), (b-7) and (b-8) may optionally be replaced by R3; with the proviso that when R3 is hydroxy or C1-6alkyloxy, then R3 can not replace a hydrogen atom in the α position relative to a nitrogen atom;
G is a direct bond or C1-10alkanediyl optionally substituted with one, two or three substituents selected from hydroxy, C1-6alkyloxy, arylC1-6alkyloxy, C1-6alkylthio, arylC1-6alkylthio, arylcarbonyl, HO(—CH2—CH2—O)n—, C1-6alkyloxy(—CH2CH2—O)n—, arylC1-6alkyloxy(—CH2—CH2—O)n—, amino, mono-or di(C1-6alkyl)amino, C1-6alkyloxycarbonylamino and aryl;
R1 is a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, pyridopyridyl, naphthyridinyl, 1H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5b]pyridinyl, imidazo[1,2-a]pyridinyl, 2,3-dihydro-1,4-dioxino[2,3-b]pyridyl or a radical of formula
and said bicyclic heterocycles may optionally be substituted in either of the two cycles with 1 or where possible more substituents selected from halo, hydroxy, amino, cyano, carboxy, C1-6alkyl, C1-6alkyloxy, C1-6alkylthio, C1-6alkyloxyC1-6alkyl, aryl, arylC1-6alkyl, arylC1-6alkyloxy, hydroxyC1-6alkyl, mono-or di(C1-6alkyl)amino, mono-or di(C1-6alkyl)aminoC1-6alkyl, polyhaloC1-6alkyl, C1-6alkylcarbonylamino, C1-6alkyl-SO2—NR5c—, aryl-SO2—NR5c—, C1-6alkyloxycarbonyl, —C(═O)—NR5cR5d, HO(—CH2-CH2—O)n—, halo(—CH2—CH2—O)n—, C1-6alkyloxy(—CH2—CH2—O)n—, arylC1-6alkyloxy(—CH2CH2—O)n— and mono-or di(C1-6alkyl)amino(—CH2—CH2—O)n—;
each n independently is 1, 2, 3 or 4;
each m independently is 1 or 2;
each p independently is 1 or 2;
each R2 independently is hydrogen, formyl, C1-6alkylcarbonyl, Hetcarbonyl, pyrrolidinyl, piperidinyl, homopiperidinyl, C3-7cycloalkyl substituted with N(R6)2, or C1-10alkyl substituted with N(R6)2 and optionally with a second, third or fourth substituent selected from amino, hydroxy, C3-7cycloalkyl, C2-5alkanediyl (wherein said C2-5alkanediyl is substituted on one carbon atom of said C1-10 alkyl substituted with N(R 6)2 to form a spiro moiety), piperidinyl, mono-or di(C1-6alkyl)amino, C1-6alkyloxycarbonylamino, aryl and aryloxy;
R3 is hydrogen, hydroxy, C1-6alkyl, C1-6alkyloxy, arylC1-6alkyl or arylC1-6alkyloxy;
R4 is hydrogen, C1-6alkyl or arylC1-6alkyl;
R5a, R5b, R5c and R5d each independently are hydrogen or CH6alkyl; or
R5a and R5b, or R5c and R5d taken together form a bivalent radical of formula —(CH2)n— wherein s is 4 or 5;
R6 is hydrogen, CH4alkyl, formyl, hydroxyC1-6alkyl, CH6alkylcarbonyl or C1-6alkyloxycarbonyl;
aryl is phenyl or phenyl substituted with 1 or more substituents selected from halo, hydroxy, CH6alkyl, hydroxyC1-6alkyl, polyhaloC1-6alkyl, and CH6alkyloxy; and
Het is pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein Q is a radical of formula (b-5) wherein v is 2 and Y1 is —NR2—.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein R2 is C1-10alkyl substituted with NHR6.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein G is a direct bond or C1-10alkanediyl optionally substituted with one, two or three substituents selected from the group consisting of hydroxy, C1-6alkyloxy, arylC1-6alkyloxy, HO(—CH2—CH2—O)n—, C1-6alkyloxy(—CH2—CH2—O)n—, and arylC1-6alkyloxy(—CH2—CH2—O)n—.

### Claim 5

A compound wherein the compound is
(±)-N-[1-(2-aminoethyl)-4-piperidinyl]-4-methyl-1-[1-(8-quinolinyl)ethyl]-1H-benzimidazol-2-amine monohydrate;
(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-(2-bromo-5,6,7,8-tetrahydro-8-quinolinyl)-1H-benzimidazol-2-amine trihydrochloride trihydrate;
(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(2-ethoxyethoxy)-8-quinolinylmethyl]-4-methyl-1H-benzimidazol-2-amine;
(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-(2-chloro-5,6,7,8-tetrahydro-5-quinoxalinyl)-1H-benzimidazol-2-amine trihydrochloride trihydrate; (±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(1-methyl-1H-benzimidazol-4-yl)methyl]-1H-benzimidazol-2-amine;
(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-(ethoxy-8-quinolinylmethyl)-1H-benzimidazol-2-amine;
(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-4-methyl-1-(5,6,7,8-tetrahydro-5-quinoxalinyl)-1H-benzimidazol-2-amine;
N-[1-(2-aminoethyl)-4-piperidinyl]-4-methyl-1-(8-quinolinylmethyl)-1H-benzimidazol-2-amine;
N-[1-(8-quinolinylmethyl)-1H-benzimidazol-2-yl]-1,3-propanediamine trihydrochloride monohydrate;
(±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(2-ethoxyethoxy)-8-quinolinylmethyl]-1H-benzimidazol-2-amine trihydrochloride dihydrate;
(±)-N-[1-[1-(aminomethyl)-2-methylpropyl]-4-piperidinyl]-1-[(2-ethoxyethoxy)-8-quinolinylmethyl]-1H-benzimidazol-2-amine;
(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-(1-isoquinolinylmethyl)1H-benzimidazol-2-amine trihydrochloride trihydrate;
N-[1-(2-aminoethyl)-4-piperidinyl]-1-(5,6,7,8-tetrahydro-5-quinoxalinyl)-1H-benzimidazol-2-amine trihydrochloride trihydrate;
(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-4-methyl-1-(8-quinolinylmethyl)-1H-benzimidazol-2-amine;
(±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-(2-chloro-5,6,7,8-tetrahydro-5-quinoxalinyl)-4-methyl-1H-benzimidazol-2-amine trihydrochloride trihydrate;
(±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-(5,6,7,8-tetrahydro-2,3-dimethyl-5-quinoxalinyl)-1H-benzimidazol-2-amine trihydrochloride trihydrate;
(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-[(2-ethoxyethoxy)-8-quinolinylmethyl]-1H-benzimidazol-2-amine;
(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-(3-chloro-5,6,7, 8-tetrahydro-5-quinoxalinyl)-1H-benzimidazol-2-amine trihydrochloride monohydrate;
(±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-(3-chloro-5,6,7,8-tetrahydro-5-quinoxalinyl)-4-methyl-1H-benzimidazol-2-amine trihydrochloride dihydrate;
(±)-N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(2-ethoxyethoxy)-8-quinolinylmethyl]-4-methyl-1H-benzimidazol-2-amine monohydrate;
(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-4-methyl-1-[(1-methyl-1H-benzimidazol-4-yl)methyl]-1H-benzimidazol-2-amine;
(±)-N-[1-(2-amino-3-methylbutyl)-4-piperidinyl]-1-(2-chloro-5,6,7,8-tetrahydro-5-quinoxalinyl)-4-methyl-1H-benzimidazol-2-amine;
((1-isoquinolin-1-ylmethyl)-1H-benzoimidazol-2-yl)-piperidin-4-yl-amine;
(1-(4-(1-isoquinolin-1-ylmethyl-1H-benzoimidazol-2-ylamino)-piperidin-1-ylmethyl)-2-methyl-propyl)-carbamic acid tert-butyl ester; or
an N-oxide, addition salt, quaternary amine, metal complex or stereochemically isomeric form thereof.

### Claim 6 (depends on 1, 3, 4, 5, 6)

A method of treating a respiratory syncytial viral infection, comprising the step of administering a therapeutically effective amount of a compound as claimed in any one of claims 1 and 3 to 6.

### Claim 7 (depends on 1, 2, 3, 4, 5)

A pharmaceutical composition, comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound as claimed in any one of claims 1 and 2 to 5.

### Claim 8 (depends on 7)

A process of preparing a composition as claimed in claim 7, comprising the step of intimately mixing said carrier with said compound.

### Claim 9 (depends on 1)

An intermediate of formula
with R1, G and -a1=a2-a3=a4- defined as in claim 1, P being a protective group, and Q1 being defined as Q according to claim 1 but being devoided of the R2 or R6 substituent.

### Claim 10 (depends on 1)

An intermediate of formula
with R1, G and -a1=a2-a3=a4- defined as in claim 1, and (O═)Q3 being a carbonyl derivative of Q, said Q being defined according to claim 1, provided that it is devoided of the NR2R4 or NR2 substituent.

### Claim 11 (depends on 1)

An intermediate of formula
with R1, Q and -a1=a2-a3=a4- defined as in claim 1, and (O═)G2 being a carbonyl derivative of G, said G being defined according to claim 1.

### Claim 12 (depends on 1)

A process of preparing a compound as claimed in claim 1, comprising at least one step selected from the group consisting of:
a) reacting an intermediate of formula (II-a) or (II-b) with an intermediate of formula (III)
with R1, G, Q and -a1=a2-a3=a4- defined as in claim 1, and W1 being a suitable leaving group, in the presence of a suitable base and in a suitable reaction-inert solvent;
b) deprotecting an intermediate of formula (IV)
with R1, G, and -a1=a 2-a3=a4- defined as in claim 1, H-Q, being defined as Q according to claim 1 provided that R2 or at least one R6 substituent is hydrogen, and P being a protective group;
c) deprotecting and reducing an intermediate of formula (IV-a)
with R1, G, and -a1=a2-a3=a4- defined as in claim 1, H-Q1 being defined as Q according to claim 1 provided that R2 or at least one R6 substituent is hydrogen, Q1a(CH═CH) being defined as Q1 provided that Q1 comprises an unsaturated bond, and P being a protective group;
d) deprotecting an intermediate of formula (V)
with R1, G, and -a1=a2-a3=a4- defined as in claim 1, and H2N-Q2 being defined as Q according to claim 1 provided that both R6 substituents are hydrogen or R2 and R4 are both hydrogen;
e) deprotecting an intermediate of formula (VI)
with R1, G, and -a1=a2-a3=a4- defined as in claim 1, and H2N-Q2 being defined as Q according to claim 1 provided that both R6 substituents are hydrogen or R2 and R4 are both hydrogen, and P being a protective group;
f) deprotecting an intermediate of formula (VII) or (VIII)
with R1, G, and -a1=a2-a3=a4- defined as in claim 1, H-Q1′(OH) being defined as Q according to claim 1 provided that R2 or at least one R6 substituent is hydrogen and provided that Q comprises a hydroxy moiety, H2N-Q2′(OH) being defined as Q according to claim 1 provided that both R6 substituents are hydrogen or R2 and R4 are both hydrogen and provided that Q comprises a hydroxy moiety, and P being a protective group;
g) amination of an intermediate of formula (IX)
with R1, G, and -a1=a2-a3=a4- defined as in claim 1, and H2N-Q3H being defined as Q according to claim 1 provided that both R6 substituents are hydrogen or R2 and R4 are both hydrogen, and the carbon adjacent to the nitrogen carrying the R6, or R2 and R4 substituents contains at least one hydrogen, in the presence of a suitable amination reagent;
h) reducing an intermediate of formula (X)
with R1, G, and -a1=a2-a3=a4- defined as in claim 1, and H2N—CH2—Q4 being defined as Q according to claim 1 provided that Q comprises a —CH2—NH2 moiety, in the presence of a suitable reducing agent;
i) reducing an intermediate of formula (X-a)
with G, and -a1=a2-a3=a4- defined as in claim 1, H2N—CH2—Q4 being defined as Q according to claim 1 provided that Q comprises a —CH2—NH2 moiety, and R1′ being defined as R1 according to claim 1 provided that it comprises at least one substituent, in the presence of a suitable reducing agent and suitable solvent;
j) amination of an intermediate of formula (XI)
with R1, G, and -a1=a2-a3=a4- defined as in claim 1, and H2N—CH2—CHOH—CH2—Q4 being defined as Q according to claim 1 provided that Q comprises a CH2—CHOH—CH2—NH2 moiety, in the presence of a suitable amination reagent;
k) reacting an intermediate of formula (XII) with formic acid, formamide and ammonia
with R1, G, and -a1=a2-a3=a4- defined as in claim 1, and H—C(═O)-Q1 being defined as Q according to claim 1 provided that R2 or at least one R6 substituent is formyl;
l) amination of an intermediate of formula (XIII) by reaction with an intermediate of formula (XIV)
with R1, G, and -a1=a2-a3=a4- defined as in claim 1, and R2a—NH-HQ5 being defined as Q according to claim 1 provided that R2 is other than hydrogen and is represented by R2a, R4 is hydrogen, and the carbon atom adjacent to the nitrogen atom carrying the R2 and R4 substituents, carries also at least one hydrogen atom, in the presence of a suitable reducing agent;
m) reducing an intermediate of formula (XV)
with R1, G, and -a1=a2-a3=a4- defined as in claim 1, and (R6)2N-[(C1-9alkyl)CH2OH]—NH-HQ5 being defined as Q according to claim 1 provided that R2 is other than hydrogen and is represented by C1-10alkyl substituted with N(R6)2 and with hydroxy, and the carbon atom carrying the hydroxy, carries also two hydrogen atoms, and provided that R4 is hydrogen, and the carbon atom adjacent to the nitrogen atom carrying the R2 and R4 substituents, carries also at least one hydrogen atom, with a suitable reducing agent;
n) deprotecting an intermediate of formula (XVI), (XVI-a) or (XVI-b)
with G, and -a1=a2-a3=a4- defined as in claim 1, and H-Q, being defined as Q according to claim 1 provided that R2 or at least one R6 substituent is hydrogen, and R1a(A—O—H)w, R1a′-(A—O—H)2 and R1a′-(A—O—H)3 being defined as R1 according to claim 1 provided that R1 is substituted with hydroxy, hydroxyC1-6alkyl, or HO(—CH2—CH2—O)n—, with w being an integer from 1 to 4 and P or P1 being a suitable protecting group, with a suitable acid;
o) amination of an intermediate of formula (XVII)
with R1, G, -a1=a2-a 3=a4-, Alk, X1 R2 and R4 defined as in claim 1, in the presence of a suitable amination agent;
p) amination of an intermediate of formula (XIX)
with R1, G, and -a1=a2-a3=a4- defined as in claim 1, and Q6N—CH2—C1-3alkyl-NR4 being defined as Q according to claim 1 provided that in the definition of Q, X2 is C2-4alkyl-NR4, in the presence of a suitable amination agent;
q) deprotecting an intermediate of formula (XXI)
with R1, Q, and -a1=a2-a3=a4- defined as in claim 1, and HO-G1 being defined as G according to claim 1 provided that G is substituted with hydroxy or HO(CH2CH2O—)n; and
r) reducing an intermediate of formula (XXII)
with R1, Q, and -a1=a 2-a3=a4- defined as in claim 1, and H-G2-OH being defined as G according to claim 1 provided that G is substituted with hydroxy and the carbon atom carrying the hydroxy substituent carries also at least one hydrogen, in the presence of a suitable reducing agent.

### Claim 13 (depends on 12)

The process of claim 12, further comprising the step of converting compound of formula (I′), stereochemically isomeric forms, metal complexes, quaternary amines or N-oxide forms thereof, into a therapeutically active non-toxic acid addition salt by treatment with an acid.

### Claim 14 (depends on 12)

The process of claim 12, further comprising the step of converting compound of formula (I′), stereochemically isomeric forms, metal complexes, quaternary amines or N-oxide forms thereof, into a therapeutically active non-toxic base addition salt by treatment with alkali.

### Claim 15 (depends on 12)

The process of claim 12, further comprising the step of converting the acid addition salt form of compound of formula (I′), stereochemically isomeric forms, metal complexes, quaternary amines or N-oxide forms thereof, into the free base by treatment with alkali.

### Claim 16 (depends on 12)

The process of claim 12, further comprising the step of converting the base addition salt form of compound of formula (I), stereochemically isomeric forms, metal complexes, quaternary amines or N-oxide forms thereof, into the free acid by treatment with acid.