# US 10,370,340 B2 · HIV replication inhibiting pyrimidines

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,370,340 B2
- Document ID: US10370340B2
- Status: Granted
- Kind: B2
- Application number: 15/963,352
- Filed: 2018-04-26
- Published: 2018-08-30
- Granted: 2019-08-06
- Earliest claimed: 2001-08-13
- Assignees: Janssen Pharmaceutica NV
- Applicants: Janssen Pharmaceutica NV
- Inventors: Jérôme Emile Georges Guillemont; Patrice Palandjian; Marc René de Jonge; Lucien Maria Henricus Koymans; Hendrik Maarten Vinkers; Frederik Frans Desiré Daeyaert; Jan Heeres; Koen Jeanne Alfons Van Aken; Paulus Joannes Lewi; Paul Adriaan Jan Janssen
- Web page: https://patentgrep.com/patent/US10370340B2

## CPC

- C07D 239/48: Two nitrogen atoms
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/14: for RNA viruses
- A61P 31/18: for HIV
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 255/42: the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
- C07C 257/12: having carbon atoms of amidino groups bound to hydrogen atoms
- C07D 239/47: One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

This invention concerns HIV replication inhibitors of formula the N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and the stereochemically isomeric forms thereof, wherein the ring containing -a1=a2-a3=a4- and -b1=b2-b3=b4- represents phenyl, pyridyl, pyrimidinyl, pirazinyl, pyridazinyl; n is 0 to 5; m is 1 to 4; R1 is hydrogen; aryl; formyl; C1-6alkylcarbonyl; C1-6alkyl; C1-6alkyloxycarbonyl; substituted C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy; substituted C1-6alkyloxyC1-6alkylcarbonyl; R2 is hydroxy, halo, optionally substituted C1-6alkyl, C3-7cycloalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)pR6, —NH—S(═O)pR6, —C(═O)R6, —NHC(═O)H, —C(═O)NHNH2, —NHC(═O)R6, —C(═NH)R6 or a 5-membered heterocycle; X1 is —NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, C1-4alkanediyl, —CHOH—, —S—, —S(═O)p—, —X2—C1-4alkanediyl- or —C1-4alkanediyl-X2—; R3 is NHR13; NR13R14; —C(═O)—NHR13; —C(═O)—NR13R14; —C(═O)—R15; —CH═N—NH—C(═O)—R16; substituted C1-6alkyl; optionally substituted C1-6alkyloxyC1-6alkyl; substituted C2-6alkenyl; substituted C2-6alkynyl; C1-6alkyl substituted with hydroxy and a second substituent; —C(═N—O—R8)—C1-4alkyl; R7; or —X3—R7; R4 is halo, hydroxy, C1-6alkyl, C3-7cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyl, formyl, amino, mono- or di(C1-4alkyl)amino; their use as a medicine, their processes for preparation and pharmaceutical compositions comprising them.

## Claims

### Claim 1

A combination containing (a) a compound of formula (I)
an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein
-a1=a2-a3=a4- represents a bivalent radical of formula:
—CH═CH—CH═CH— (a-1);
-b1=b2-b3=b4- represents a bivalent radical of formula:
—CH═CH—CH═CH— (b-1);
n is 0, 1, 2, 3, 4, or 5;
m is 1, 2, 3, or 4;
R1 is selected from the group consisting of: hydrogen; aryl; formyl; C1-6alkylcarbonyl; C1-6alkyl; C1-6alkyloxycarbonyl; C1-6alkyl, wherein said C1-6alkyl is substituted with a member selected from the group consisting of: formyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, and C1-6alkylcarbonyloxy; and C1-6alkyloxyC1-6alkylcarbonyl, wherein said C1-6alkyloxyC1-6alkylcarbonyl is substituted with C1-6alkyloxycarbonyl;
each R2 independently is selected from the group consisting of: hydroxy, halo, C1-6alkyl optionally substituted with cyano or —C(═O)R6, C3-7cycloalkyl, C2-6alkenyl optionally substituted with one or more halogen atoms or cyano, C2-6alkynyl optionally substituted with one or more halogen atoms or cyano, C1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C1-6alkyl)amino, polyhalomethyl, polyhalomethylthio, —S(═O)pR6, —NH—S(═O)pR6, —C(═O)R6, —NHC(═O)H, —C(═O)NHNH2, —NHC(═O)R6, —C(═NH)R6 and a radical of formula
wherein each A1 independently is N, CH or CR6; and
A2 is NH, O, S or NR6;
X1 is selected from the group consisting of: —NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, C1-4alkanediyl, —CHOH—, —S—, —S(═O)p—, —X2—C1-4alkanediyl- and —C1-4alkanediyl-X2—;
X2 is selected from the group consisting of: —NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, and —S(═O)p—;
R3 is R7;
X3 is selected from the group consisting of: —NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O)p—, —X2—C1-4alkanediyl-, —C1-4alkanediyl-X2a—, —C1-4alkanediyl-X2b—C1-4alkanediyl, and —C(═N—OR8)—C1-4alkanediyl-;
with X2a being selected from the group consisting of: —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, and —S(═O)p—; and
with X2b being selected from the group consisting of: —NH—NH—, —N═N—, —C(═O)—, —S—, and —S(═O)p—;
R4 is selected from the group consisting of: halo, hydroxy, C1-6alkyl, C3-7cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyl, formyl, amino, mono- or di(C1-4alkyl)amino and R7;
R5 is selected from the group consisting of: hydrogen; aryl; formyl; C1-6alkylcarbonyl; C1-6alkyl; C1-6alkyloxycarbonyl; C1-6alkyl, wherein said C1-6alkyl is substituted with a member selected from the group consisting of: formyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl and C1-6alkylcarbonyloxy; and C1-6alkyloxyC1-6alkylcarbonyl, wherein said C1-6alkyloxyC1-6alkylcarbonyl is substituted with C1-6alkyloxycarbonyl;
R6 is C1-4alkyl, amino, mono- or di(C1-4alkyl)amino or polyhaloC1-4alkyl;
R7 is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from the group consisting of: halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, formyl, C1-6alkylcarbonyl,
C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, —CH(═N—O—R8), R7a, —X3—R7a and R7a—C1-4alkyl;
R7a is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from the group consisting of: halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, formyl, C1-6alkylcarbonyl,
C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, and —CH(═N—O—R8);
R8 is selected from the group consisting of: hydrogen, C1-4alkyl, aryl and arylC1-4alkyl;
p is 1 or 2;
aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from the group consisting of: halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, C1-6alkylcarbonyl, C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, R7 and —X3—R7; and
(b) one or more immunomodulating agents.

### Claim 2

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredients (a) a compound of formula (I)
an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein
-a1=a2-a3=a4- represents a bivalent radical of formula:
—CH═CH—CH═CH— (a-1);
-b1=b2-b3=b4- represents a bivalent radical of formula:
—CH═CH—CH═CH— (b-1);
n is 0, 1, 2, 3, 4 or 5;
m is 1, 2, 3, or 4;
R1 is selected from the group consisting of: hydrogen; aryl; formyl; C1-6alkylcarbonyl; C1-6alkyl; C1-6alkyloxycarbonyl; C1-6alkyl, wherein said C1-6alkyl is substituted with a member selected from the group consisting of: formyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, and C1-6alkylcarbonyloxy; and C1-6alkyloxyC1-6alkylcarbonyl wherein said C1-6alkyloxyC1-6alkylcarbonyl is substituted with C1-6alkyloxycarbonyl;
each R2 independently is selected from the group consisting of: hydroxy, halo, C1-6alkyl optionally substituted with cyano or —C(═O)R6, C3-7cycloalkyl, C2-6alkenyl optionally substituted with one or more halogen atoms or cyano, C2-6alkynyl optionally substituted with one or more halogen atoms or cyano, C1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C1-6alkyl)amino, polyhalomethyl, polyhalomethylthio, —S(═O)pR6, —NH—S(═O)pR6, —C(═O)R6, —NHC(═O)H, —C(═O)NHNH2, —NHC(═O)R6, —C(═NH)R6 and a radical of formula
wherein each A1 independently is N, CH or CR6; and
A2 is NH, O, S or NR6;
X1 is selected from the group consisting of: —NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, C1-4alkanediyl, —CHOH—, —S—, —S(═O)p—, —X2—C1-4alkanediyl- and —C1-4alkanediyl-X2—;
X2 is selected from the group consisting of: —NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, and —S(═O)p—;
R3 is R7;
X3 is selected from the group consisting of: —NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O)p—, —X2—C1-4alkanediyl-, —C1-4alkanediyl-X2a—, —C1-4alkanediyl-X2b—C1-4alkanediyl, and —C(═N—OR8)—C1-4alkanediyl-;
with X2a being selected from the group consisting of: —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, and —S(═O)p—; and
with X2b being selected from the group consisting of: —NH—NH—, —N═N—, —C(═O)—, —S—, and —S(═O)p—;
R4 is selected from the group consisting of: halo, hydroxy, C1-6alkyl, C3-7cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyl, formyl, amino, mono- or di(C1-4alkyl)amino and R7;
R5 is selected from the group consisting of: hydrogen; aryl; formyl; C1-6alkylcarbonyl; C1-6alkyl; C1-6 alkyloxycarbonyl; C1-6alkyl, wherein said C1-6alkyl is substituted with a member selected from the group consisting of: formyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl and C1-6alkylcarbonyloxy; and C1-6alkyloxyC1-6alkylcarbonyl substituted with C1-6alkyloxycarbonyl;
R6 is C1-4alkyl, amino, mono- or di(C1-4alkyl)amino or polyhaloC1-4alkyl;
R7 is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from the group consisting of: halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, formyl, C1-6alkylcarbonyl, C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, —CH(═N—O—R8), R7a, —X3—R7a and R7a—C1-4alkyl;
R7a is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from the group consisting of: halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, formyl, C1-6alkylcarbonyl,
C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, and —CH(═N—O—R8);
R8 is selected from the group consisting of: hydrogen, C1-4alkyl, aryl and arylC1-4alkyl;
p is 1 or 2;
aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, C1-6alkylcarbonyl, C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, R7 or —X3—R7; and
(b) one or more immunomodulating agents.

### Claim 3 (depends on 1)

A combination according to claim 1 containing (a) a compound of formula (I′″)
an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein
R1, R2, R3, R4, m and X1 are as defined in claim 1;
n′ is 0, 1, 2, 3 or 4;
R2′ is selected from the group consisting of: halo, C1-6alkyl, trihalomethyl, cyano, aminocarbonyl, and C1-6alkyl substituted with cyano or aminocarbonyl; and
(b) one or more immunomodulating agents.

### Claim 4 (depends on 3)

The combination as claimed in claim 3 wherein R2′ is cyano, aminocarbonyl or C1-6alkyl substituted with cyano or aminocarbonyl.

### Claim 5 (depends on 2)

A pharmaceutical composition according to claim 2 comprising a pharmaceutically acceptable carrier and as active ingredients (a) a compound of formula (I′″)
an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein
R1, R2, R3, R4, m and X1 are as defined in claim 2;
n′ is 0, 1, 2, 3 or 4;
R2′ is a member selected from the group consisting of: halo, C1-6alkyl, trihalomethyl, cyano, aminocarbonyl, and C1-6alkyl substituted with cyano or aminocarbonyl; and
(b) one or more immunomodulating agents.

### Claim 6 (depends on 5)

The composition as claimed in claim 5 wherein R2′ is cyano, aminocarbonyl or C1-6alkyl, wherein said C1-6alkyl is substituted with cyano or aminocarbonyl.

### Claim 7 (depends on 1)

The combination as claimed in claim 1, comprising (a) a compound and an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, selected from the group consisting of:
and (b) one or more immunomodulating agents.

### Claim 8 (depends on 2)

The composition as claimed in claim 2, comprising a pharmaceutically acceptable carrier and as active ingredients (a) a compound and an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, selected from the group consisting of:
and (b) one or more immunomodulating agents.