IP Library › Granted Patent US 9,447,051

Granted Patent B2

US 9,447,051 · App. 14/379,155 · Granted Sep 20, 2016

Diaminopyrimidines and uses thereof

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Patent No.: US 9,447,051
App. No.: 14/379,155
Granted: Sep 20, 2016
Kind: B2

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Abstract

This disclosure relates to: (a) compounds and salts thereof that, inter alia, inhibit RSV infection and/or replication; (b) intermediates useful for the preparation of such compounds and salts; (c) compositions comprising such compounds and salts; (d) methods for preparing such intermediates, compounds, salts, and compositions; (e) methods of use of such compounds, salts, and compositions; and (f) kits comprising such compounds, salts, and compositions.

Claims (120)

1. A compound having formula (I), or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is cyclohexyl optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, C 1 -C 10 -haloalkyl, C 2 -C 10 -haloalkenyl, C 2 -C 10 -haloalkynyl, halogen, oxo, cyano, hydroxy, —O—C 1 -C 6 -alkyl, O—C 1 -C 6 -haloalkyl, —C 1 -C 3 -alkylene-O—H, C 1 -C 3 -alkylene-O—C 1 -C 6 -alkyl, —C 1 -C 3 -alkylene-O—C 1 -C 6 -haloalkyl, —C 1 -C 3 -alkylene-NH 2 , —NH 2 , —C(O)O—C 1 -C 6 -alkyl, —N(R b1 )C(O)R b1 , —CON(R a1 )(R b1 ), —C(O)R b1 , —OC(O)R b1 , —OS(O) 2 N(R a1 )(R b1 ), —CO 2 H, —CO 2 R b1 , —N(R b1 )C(O)N(R b1 ) 2 , —S—R b1 , —S(O) 2 R b1 , —S(O)R b1 , —SO 2 N(R a1 )(R b1 ), —N(R a1 )(R a1 ), —N(R b1 )S(O) 2 R b1 , —N(R b1 )C(O)O(R b1 ), —N(R b1 )S(O) 2 O(R b1 ), -L 1a -O—R b1 , -L 1a -CN, -L 1a -N(R b1 )C(O)R b1 , -L 1a -CON(R a1 )(R 1b ), -L 1a -C(O)R b1 , L 1a -OC(O)R b1 , -L 1a -CO 2 H, -L 1a -CO 2 R b1 , -L 1a -N(R b1 )C(O)N(R b1 ) 2 , L 1a -S—R b1 , -L 1a -S(O) 2 R b1 , -L 1a -S(O)R b1 , -L 1a -SO 2 —N(R a1 )R b1 ), -L 1a -(R a1 )(R b1 ), -L 1a -N(R b1 )S(O) 2 R b1 , and -L 1a -N(R b1 )C(O)O(R b1 );

R 2 is methyl or ethyl;

R 3 is methyl or ethyl;

R 4 and R 5 are independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, and C 1 -C 6 -haloalkyl;

R 6 is selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, and C 1 -C 6 -haloalkyl;

G 1 is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—R f , —CN, —N(R f )C(O)R f , —CON(R e )(R f ), —C(O)R f , —OC(O)R f , —CO 2 H, —CO 2 R f , —N(R f )C(O)N(R f ) 2 , —S—R f , —S(O) 2 R f , —S(O)R f , —SO 2 N(R e )(R f ), —N(R e )(R f ), —N(R f )S(O) 2 R f , —N(R f )C(O)O(R f ), -L 3 -O—R f , -L 3 -CN, - L 3 -N(R f )C(O)R f , -L 3 -CON(R e )(R f ), -L 3 -C(O)R f , -L 3 -OC(O)R f , -L 3 -CO 2 H, -L 3 -CO 2 R f , -L 3 -N(R f )C(O)N(R f ) 2 , -L 3 -S—R f , -L 3 -S(O) 2 R f , -L 3 -S(O)R f , -L 3 -SO 2 N(R e )(R f ), -L-N(R e )(R f ), -L 3 -N(R f )S(O) 2 R f , and -L 3 -N(R f )C(O)O(R f );

X is selected from O or NR;

R a , at each occurrence, is each independently hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, or C 3 -C 8 -cycloalkyl, wherein the C 3 -C 8 -cycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, C 1 -C 3 alkyl, and C 1 -C 3 -haloalkyl;

R a1 , at each occurrence, is each independently hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, or C 3 -C 8 -cycloalkyl, wherein the C 3 -C 8 -cycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, C 1 -C 3 alkyl, and C 1 -C 3 -haloalkyl;

R b is each independently hydrogen, C 1 -C 6 -alkyl, or C 1 -C 6 -haloalkyl;

R b1 is each independently hydrogen, C 1 -C 6 -alkyl, or C 1 -C 6 -haloalkyl;

R e , at each occurrence, is each independently hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, or C 3 -C 8 -cycloalkyl, wherein the C 3 -C 8 -cycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, C 1 -C 6 -alkyl, and C 1 -C 3 -haloalkyl;

R f is each independently hydrogen, C 1 -C 6 -alkyl, or C 1 -C 6 -haloalkyl;

R g is hydrogen or C 1 -alkyl;

L 1 , at each occurrence, is each independently C 1 -C 6 -alkylene or C 3 -C 8 -cycloalkyl, wherein L 1 is each optionally substituted with 1, 2, 3, or 4 halogen or 1 or 2 hydroxy;

L 1a , at each occurrence, is each independently C 1 -C 6 -alkylene or C 3 -C 8 cycloalkyl, wherein L 1a is each optionally substituted with 1, 2, 3, or 4 halogen or 1 or 2 hydroxy; and

L 3 , at each occurrence, is each independently C 1 -C 6 -alkylene or C 3 -C 8 -cycloalkyl, wherein L 3 is each optionally substituted with 1, 2, 3, or 4 halogen.

2. The compound of claim 1 , wherein X is O.

3. The compound of claim 1 , wherein X is NR g .

4. The compound of claim 1 , wherein R 2 and R 3 are each methyl; R 4 , R 5 and R 6 are each hydrogen; and X is NR g , wherein R g is hydrogen.

5. A compound selected from the group consisting of:

N 4 -cyclohexyl-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 2 -benzyl-N 4 -cyclohexyl-5,6-dimethylpyrimidine-2,4-diamine;

N 4 -cyclohexyl-5,6-dimethyl-N 2 -(pyridin-3-ylmethyl)pyrimidine-2,4-diamine;

2-({[4-(cyclohexylamino)-5,6-dimethylpyrimidin-2-yl]amino}methyl)-6-methylpyridin-3-ol;

N 4 -cyclohexyl-N 2 -(4-methoxybenzyl)-5,6-dimethylpyrimidine-2,4-diamine;

N 4 -cyclohexyl-N 2 -(4-fluorobenzyl)-5,6-dimethylpyrimidine-2,4-diamine;

N 4 -cyclohexyl-5,6-dimethyl-N 2 -[4-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine;

N 4 -cyclohexyl-N 2 -(4-isopropylbenzyl)-5,6-dimethylpyrimidine-2,4-diamine;

N 4 -cyclohexyl-5,6-dimethyl-N 2 -[4-(trifluoromethyl)benzyl]pyrimidine-2,4-diamine;

N 4 -cyclohexyl-N 2 -(3-fluorobenzyl)-5,6-dimethylpyrimidine-2,4-diamine;

N 4 -cyclohexyl-5,6-dimethyl-N 2 -(1H-pyrazol-5-ylmethyl)pyrimidine-2,4-diamine;

N 4 -cyclohexyl-5,6-dimethyl-N 2 -[(1R)-1-phenylethyl]pyrimidine-2,4-diamine;

N 4 -cyclohexyl-5,6-dimethyl-N 2 -[(1S)-1-phenylethyl]pyrimidine-2,4-diamine;

N 4 -cyclohexyl-5,6-dimethyl-N 2 -[(4-methylpyridin-2-yl)methyl]pyrimidine-2,4-diamine;

N 4 -cyclohexyl-N 2 -[(4-methoxypyridin-2-yl)methyl]-5,6-dimethylpyrimidine-2,4-diamine;

N 4 -cyclohexyl-5,6-dimethyl-N 2 -[(6-methylpyridin-2-yl)methyl]pyrimidine-2,4-diamine;

N 4 -cyclohexyl-5,6-dimethyl-N 2 -{[5-(trifluoromethyl)pyridin-2-yl]methyl}pyrimidine-2,4-diamine;

N 2 -[(4-tert-butylpyridin-2-yl)methyl]-N 4 -cyclohexyl-5,6-dimethylpyrimidine-2,4-diamine;

N 4 -cyclohexyl-5,6-dimethyl-N 2 -(2-thienylmethyl)pyrimidine-2,4-diamine;

N 4 -cyclohexyl-N 2 -[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-5,6-dimethylpyrimidine-2,4-diamine;

N 4 -cyclohexyl-5,6-dimethyl-N 2 -[(1-methyl-1H-imidazol-4-yl)methyl]pyrimidine-2,4-diamine;

N 4 -cyclohexyl-N 2 -(3-methoxybenzyl)-5,6-dimethylpyrimidine-2,4-diamine;

N 4 -cyclohexyl-5,6-dimethyl-N 2 -[(3-methylpyridin-2-yl)methyl]pyrimidine-2,4-diamine;

N 2 -[(4-chloropyridin-2-yl)methyl]-N 4 -cyclohexyl-5,6-dimethylpyrimidine-2,4-diamine;

N 4 -(4,4-difluorocyclohexyl)-5,6-dimethyl-N 2 -[(4-methylpyridin-2-yl)methyl]pyrimidine-2,4-diamine;

N 4 -cyclopentyl-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)-N 4 -(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4-diamine;

5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)-N 4 -[4-(trifluoromethyl)cyclohexyl]pyrimidine-2,4-diamine;

N 4 -(4,4-difluorocyclohexyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(2,3-dihydro-1H-inden-1-yl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

3-({5,6-dimethyl-2-[(pyridin-2-ylmethyl)amino]pyrimidin-4-yl}amino)cyclopentanol;

5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)-N 4 -(1,2,3,4-tetrahydronaphthalen-1-yl)pyrimidine-2,4-diamine;

N 4 -(3,4-dihydro-2H-chromen-4-yl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

cis-4-({5,6-dimethyl-2-[(pyridin-2-ylmethyl)amino]pyrimidin-4-yl}amino)-1-methylcyclohexanol;

trans-4-({5,6-dimethyl-2-[(pyridin-2-ylmethyl)amino]pyrimidin-4-yl}amino)-1-methylcyclohexanol;

N 4 -(bicyclo[2.2.1]hept-2-yl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

5,6-dimethyl-N 4 -(2-methylcyclohexyl)-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(2,3-dimethylcyclohexyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

2-({5,6-dimethyl-2-[(pyridin-2-ylmethyl)amino]pyrimidin-4-yl}amino)cyclohexanol;

[(1R,2S)-2-({5,6-dimethyl-2-[(pyridin-2-ylmethyl)amino]pyrimidin-4-yl}amino)cyclohexyl]methanol;

N 4 -(cyclopentylmethyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -cycloheptyl-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(2,3-dihydro-1H-inden-2-yl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -cyclobutyl-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

5,6-dimethyl-N 4 -(pentan-3-yl)-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(3-fluorophenyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(4-fluorophenyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(2-fluorophenyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

5,6-dimethyl-N 4 -phenyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)-N 4 -[3-(trifluoromethoxy)phenyl]pyrimidine-2,4-diamine;

5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)-N 4 -[3-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine;

N 4 -(2,6-difluorophenyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)-N 4 -[4-(trifluoromethoxy)phenyl]pyrimidine-2,4-diamine;

5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)-N 4 -[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine;

N 4 -(3,4-difluorophenyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)-N 4 -[2-(trifluoromethoxy)phenyl]pyrimidine-2,4-diamine;

N 4 -(2,5-difluorophenyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(1,3-benzodioxol-5-yl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(4-chlorophenyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

5,6-dimethyl-N 4 -(4-methylphenyl)-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(3,5-difluorophenyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(3-chlorophenyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(2-chlorophenyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

5,6-dimethyl-N 4 -(2-methylphenyl)-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(2,6-dimethylphenyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

5,6-dimethyl-N 4 -(3-methylphenyl)-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(1,1-dioxidotetrahydrothiophen-3-yl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(5-fluoro-2-methylphenyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(2-fluoro-6-methylphenyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(4,5-difluoro-2-methylphenyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

5,6-dimethyl-N 4 -(1-methyl-1H-pyrazol-5-yl)-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(4-fluoro-2-methylphenyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(3-fluoro-2-methylphenyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -cyclohexyl-N 4 ,5,6-trimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(3,3-difluorocyclopentyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

trans-4-({5,6-dimethyl-2-[(pyridin-2-ylmethyl)amino]pyrimidin-4-yl}amino)cyclohexanol;

N 4 -(3,3-difluorocyclohexyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

5,6-dimethyl-N 4 -(1-methylpiperidin-4-yl)-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

tert-butyl 4-({5,6-dimethyl-2-[(pyridin-2-ylmethyl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxylate;

5,6-dimethyl-N 4 -(piperidin-4-yl)-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(2,6-diisopropylphenyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

3-({5,6-dimethyl-2-[(pyridin-2-ylmethyl)amino]pyrimidin-4-yl}amino)cyclohexanol;

N 4 -cyclohexyl-5,6-dimethyl-N 2 -[(5-methylpyridin-2-yl)methyl]pyrimidine-2,4-diamine;

N 4 -cyclohexyl-5,6-dimethyl-N 2 -[1-(pyridin-2-yl)ethyl]pyrimidine-2,4-diamine;

N 4 -(2,4-difluorophenyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

5-ethyl-N 4 -(4-fluorophenyl)-6-methyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(4,4-difluorocyclohexyl)-N 2 -[(4-ethylpyridin-2-yl)methyl]-5,6-dimethylpyrimidine-2,4-diamine;

5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)-N 4 -(tetrahydrofuran-2-ylmethyl)pyrimidine-2,4-diamine;

N 4 -(cyclohexylmethyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

5,6-dimethyl-N 4 -(pyridin-3-yl)-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)-N 4 -(1,3,4-thiadiazol-2-yl)pyrimidine-2,4-diamine;

5,6-dimethyl-N 4 -(1,2-oxazol-3-yl)-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine;

5,6-dimethyl-N 4 -(5-methyl-1,2-oxazol-3-yl)-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine; and

N 4 -(4-fluorobenzyl)-5,6-dimethyl-N 2 -(pyridin-2-ylmethyl)pyrimidine-2,4-diamine.

6. A pharmaceutical composition comprising one or more compounds of claim 1 or pharmaceutically acceptable salts thereof; one or more excipients; and optionally one or more additional therapeutic agents.

7. A method for inhibiting replication of an respiratory syncytial virus, comprising exposing the virus to one or more compounds of claim 1 or pharmaceutically acceptable salts thereof, optionally in combination with one or more therapeutic agents.

8. The method of claim 7 , wherein the respiratory syncytial virus is from a mutant of a respiratory syncytial virus.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 10, 2016

From: DEKHTYAR, TATYANA; GOMTSYAN, ARTHUR; MOLLA, M-AKTHHTERUZZAMAN; VASUDEVAN, ANIL; NG, IOK CHAN; CHAFEEV, MIKHAIL

To: ABBVIE INC.

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