US 5,872,136 AGranted

Arylheteroaryl inhibitors of farnesyl-protein transferase

AssigneeMerck & Co., Inc.

InventorsNeville J. Anthony, Robert P. Gomez, Samuel L. Graham

Life of this patent

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Abstract

The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.

Claims30

Dependent claims

A compound which inhibits farnesyl-protein transferase of the formula A:

##STR28## wherein:
from 1-2 of f(s) are independently N or N.fwdarw.O, and the remaining f's are independently CH;
R.sup.1 and R.sup.2 are independently selected from:
a) hydrogen,
b) aryl, heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, R.sup.11 C(O)O--, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --,
c) unsubstituted or substituted C.sub.1 -C.sub.6 alkyl wherein the substituent on the substituted C.sub.1 -C.sub.6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, and R.sup.11 OC(O)--NR.sup.10 --;
R.sup.3, R.sup.4 and R.sup.5 are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, halogen, C.sub.1 -C.sub.6 perfluoroalkyl, R.sup.12 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.11 C(O)O--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --,
c) unsubstituted C.sub.1 -C.sub.6 alkyl,
d) substituted C.sub.1 -C.sub.6 alkyl wherein the substituent on the substituted C.sub.1 -C.sub.6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.12 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, and R.sup.11 OC(O)--NR.sup.10 --;
R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d and R.sup.6e are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, halogen, C.sub.1 -C.sub.6 perfluoroalkyl, R.sup.12 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.11 C(O)O--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --,
c) unsubstituted C.sub.1 -C.sub.6 alkyl,
d) substituted C.sub.1 -C.sub.6 alkyl wherein the substituent on the substituted C.sub.1 -C.sub.6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.12 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, and R.sup.11 OC(O)--NR.sup.10 --;
or
any two of R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d and R.sup.6e on adjacent carbon atoms are combined to form a diradical selected from --CH.dbd.CH--CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 --, --(CH.sub.2).sub.4 -- and --(CH.sub.2).sub.3 --;
provided that when R.sup.3, R.sup.4, R.sup.5, R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d or R.sup.6e is unsubstituted or substituted heterocycle, attachment of R.sup.3, R.sup.4, R.sup.5, R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d or R.sup.6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a heterocycle ring carbon;
R.sup.7 is selected from:
H;
C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, aryilsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C.sub.1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO, ##STR29## f) --SO.sub.2 R.sup.11, g) N(R.sup.10).sub.2 or
h) C.sub.1-4 perfluoroalkyl;
R.sup.8 is independently selected from:
a) hydrogen,
b) aryl, substituted aryl, heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NH--, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.10 OC(O)NH--;
provided that when R.sup.8 is heterocycle, attachment of R.sup.8 to V is through a ring carbon;
R.sup.9 is independently selected from:
a) hydrogen,
b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.11 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --;
R.sup.10 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R.sup.11 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
R.sup.12 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 aralkyl, C.sub.1 -C.sub.6 substituted aralkyl, C.sub.1 -C.sub.6 heteroaralkyl, C.sub.1 -C.sub.6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C.sub.1 -C.sub.6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A.sup.1 and A.sup.2 are independently selected from:
a bond, --CH.dbd.CH--, --C.tbd.C--, --C(O)--, --C(O)NR.sup.10 --, --NR.sup.10 C(O)--, O, --N(R.sup.10)--, --S(O).sub.2 N(R.sup.10)--, --N(R.sup.10)S(O).sub.2 --, or S(O).sub.m ;
V is selected from:
a) hydrogen,
b) heterocycle,
c) aryl,
d) C.sub.1 -C.sub.20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and
e) C.sub.2 -C.sub.20 alkenyl, provided that V is not hydrogen if A.sup.1 is S(O).sub.m and V is not hydrogen if A.sup.1 is a bond, n is 0 and A.sup.2 is S(O).sub.m ;
provided that when V is heterocycle, attachment of V to R.sup.8 and to A.sup.1 is through a ring carbon;
W is a heterocycle;
X is a bond, --CH.dbd.CH--, O, --C(.dbd.O)--, --C(O)NR.sup.7 --, --NR.sup.7 C(O)--, --C(O)O--, --OC(O)--, --C(O)NR.sup.7 C(O)--, --NR.sup.7 --, --S(O).sub.2 N(R.sup.10)--, --N(R.sup.10)S(O).sub.2 -- or --S(.dbd.O).sub.m --;
m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
q is 0, 1, 2or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen;
and
t is 0 or 1;
or a pharmaceutically acceptable salt thereof.

55 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/827,483Filed 27 Mar 1997
Granted: 16 Feb 1999
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 233/56
Having two double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms or radicals containing only…
C07D 233/64
Having two double bonds between ring members or between ring members and non-ring members: with substituted hydrocarbon radicals attached to ring…
C07D 233/70
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms

Family

No related US applications are recorded in the indexed filing history.

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Abstract

A compound which inhibits farnesyl-protein transferase of the formula A:

##STR28## wherein:
from 1-2 of f(s) are independently N or N.fwdarw.O, and the remaining f's are independently CH;
R.sup.1 and R.sup.2 are independently selected from:
a) hydrogen,
b) aryl, heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, R.sup.11 C(O)O--, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --,
c) unsubstituted or substituted C.sub.1 -C.sub.6 alkyl wherein the substituent on the substituted C.sub.1 -C.sub.6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, and R.sup.11 OC(O)--NR.sup.10 --;
R.sup.3, R.sup.4 and R.sup.5 are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, halogen, C.sub.1 -C.sub.6 perfluoroalkyl, R.sup.12 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.11 C(O)O--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --,
c) unsubstituted C.sub.1 -C.sub.6 alkyl,
d) substituted C.sub.1 -C.sub.6 alkyl wherein the substituent on the substituted C.sub.1 -C.sub.6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.12 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, and R.sup.11 OC(O)--NR.sup.10 --;
R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d and R.sup.6e are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, halogen, C.sub.1 -C.sub.6 perfluoroalkyl, R.sup.12 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.11 C(O)O--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --,
c) unsubstituted C.sub.1 -C.sub.6 alkyl,
d) substituted C.sub.1 -C.sub.6 alkyl wherein the substituent on the substituted C.sub.1 -C.sub.6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.12 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, and R.sup.11 OC(O)--NR.sup.10 --;
or
any two of R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d and R.sup.6e on adjacent carbon atoms are combined to form a diradical selected from --CH.dbd.CH--CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 --, --(CH.sub.2).sub.4 -- and --(CH.sub.2).sub.3 --;
provided that when R.sup.3, R.sup.4, R.sup.5, R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d or R.sup.6e is unsubstituted or substituted heterocycle, attachment of R.sup.3, R.sup.4, R.sup.5, R.sup.6a, R.sup.6b, R.sup.6c, R.sup.6d or R.sup.6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a heterocycle ring carbon;
R.sup.7 is selected from:
H;
C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, aryilsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C.sub.1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO, ##STR29## f) --SO.sub.2 R.sup.11, g) N(R.sup.10).sub.2 or
h) C.sub.1-4 perfluoroalkyl;
R.sup.8 is independently selected from:
a) hydrogen,
b) aryl, substituted aryl, heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NH--, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.10 OC(O)NH--;
provided that when R.sup.8 is heterocycle, attachment of R.sup.8 to V is through a ring carbon;
R.sup.9 is independently selected from:
a) hydrogen,
b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.11 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --;
R.sup.10 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R.sup.11 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
R.sup.12 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 aralkyl, C.sub.1 -C.sub.6 substituted aralkyl, C.sub.1 -C.sub.6 heteroaralkyl, C.sub.1 -C.sub.6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C.sub.1 -C.sub.6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A.sup.1 and A.sup.2 are independently selected from:
a bond, --CH.dbd.CH--, --C.tbd.C--, --C(O)--, --C(O)NR.sup.10 --, --NR.sup.10 C(O)--, O, --N(R.sup.10)--, --S(O).sub.2 N(R.sup.10)--, --N(R.sup.10)S(O).sub.2 --, or S(O).sub.m ;
V is selected from:
a) hydrogen,
b) heterocycle,
c) aryl,
d) C.sub.1 -C.sub.20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and
e) C.sub.2 -C.sub.20 alkenyl, provided that V is not hydrogen if A.sup.1 is S(O).sub.m and V is not hydrogen if A.sup.1 is a bond, n is 0 and A.sup.2 is S(O).sub.m ;
provided that when V is heterocycle, attachment of V to R.sup.8 and to A.sup.1 is through a ring carbon;
W is a heterocycle;
X is a bond, --CH.dbd.CH--, O, --C(.dbd.O)--, --C(O)NR.sup.7 --, --NR.sup.7 C(O)--, --C(O)O--, --OC(O)--, --C(O)NR.sup.7 C(O)--, --NR.sup.7 --, --S(O).sub.2 N(R.sup.10)--, --N(R.sup.10)S(O).sub.2 -- or --S(.dbd.O).sub.m --;
m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
q is 0, 1, 2or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen;
and
t is 0 or 1;
or a pharmaceutically acceptable salt thereof.

55 more elements

Facts

Application

08/827,483Filed 27 Mar 1997

Granted

16 Feb 1999

Term ends

Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 233/56
Having two double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms or radicals containing only…
C07D 233/64
Having two double bonds between ring members or between ring members and non-ring members: with substituted hydrocarbon radicals attached to ring…
C07D 233/70
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms