1. A monofilament comprising a polyester core and a core coating, said core coating comprising a vinylidene chloride copolymer, wherein the monofilament is drawn at a draw ratio of about 3.0:1 to about 4.5:1 and is heated to a temperature up to about 100\xb0 C., and further wherein the drawn monofilament is heat set at a temperature in the range of 100\xb0 C. to 220\xb0 C.
2. The monofilament of claim 1 wherein said vinylidene chloride copolymer comprises from about 35 to about 96 weight percent vinylidene chloride and from about 4 to about 65 weight percent of at least one other polymerizable olefin monomer based on weight of copolymer.
3. The monofilament of claim 1 wherein said vinylidene chloride copolymer comprises 35 to 96 weight percent vinylidene chloride, from about 3.5 to about 64.5 weight percent of an acrylic ester, and from about 0.5 to about 25 weight percent of itaconic acid based on weight of copolymer.
4. The monofilament of claim 1 wherein said vinylidene chloride copolymer comprises about 75 to about 95 weight percent vinylidene chloride, about 4 to about 20 weight percent of an acrylic ester, and about 1 to about 5 weight percent of itaconic acid based on weight of copolymer.
5. The monofilament of claim 3 wherein said acrylic ester is selected from alkyl esters of acrylic acid or methacrylic acid with 1 to 18 carbon atoms in the alkyl group.
6. The monofilament of claim 1 wherein said vinylidene chloride copolymer is blended with a polyacrylate ester.
7. The monofilament of claim 1 or 6 comprising a second coating wherein the coating comprising a vinylidine chloride is a first coating.
8. The monofilament of claim 7 wherein said second coating is selected from the group consisting of fluorinated surfactants.
9. The monofilament of claim 7 wherein said second coating is selected from the group consisting of polyolefins, cyclic olefin polymers, modified polyolefins, polyolefin copolymers, glycidyl esters of unsaturated acids, ionomers, ethylenevinyl copolymers, ethylenevinyl chloride capolymers, ethylenevinyl acetate copolymers, ethyleneacrylic acid copolymers, ethylenemethacrylic acid copolymers, ethylenevinyl alcohol copolymers, poly(vinyl, poly(vinyl alcohol-cobutyral), polyurethanes, thermoplastic polyurethanes, polyvinyl chloride, polyvinylidene chloride copolymers, liquid crystalline polymers, fluorinated polymers, polyamides, polyimides, polyphenylene sulfide, polyphenylene oxide, polysulfones, polyethersulfones, rubbers, polycarbonate, polyacrylates, terpene resins, polyacetal, styreneacrylonitrile copolymers, styrenemaleic anhydride copolymers, styrenemaleimide copolymers, coumaroneindene copolymers, and combinations thereof.
10. The monofilament of claim 1, having a diameter from about 0.05 mm to about 5 mm.
11. The monofilament of claim 1 wherein said polyester comprises 99 to 100 mole percent of a dicarboxylic acid or lower ester of a dicarboxylic acid, 99 to 100 mole percent of a diol, and 0 to 1 mole percent of a polyfunctional branching agent.
12. The monofilament of claim 1, wherein the monofilament is drawn a second time to a maximum draw ratio of 6.5:1 and is heated at a temperature between the temperature of claim 1 and 250\xb0 C.
13. The monofilament of claim 12, wherein the monofilament is allowed to relax to about 30 percent of its maximum drawn length while heated in a relaxing stage.
14. The monofilament of claim 13, further comprising a second coating.
15. The monofilament of claim 1, wherein the drawn monofilament is heat set at a temperature in the range of 160\xb0 C. to 180\xb0 C.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A compound of Formula (Ia)
including pharmaceutically acceptable salts, hydrates, geometrical isomers, racemates, tautomers, optical isomers, and N-oxides thereof; wherein:
W1 and W3 are N and W2 and W4 are CR12, or W1 and W3 are CR12 and W2 and W4 are N;
A1 is CH2, O, NR10, S, S(O) or S(O)2;
B1 is CH2, O, NR10, S, S(O), S(O)2, C(O) or CONR10, provided that when B\u2032 is O,
NR10, S, S(O), S(O)2, C(O) or CONR10, then A1 is CH2;
D is N, C or CR11, provided that D must be CR11 and said R11 must be hydrogen or methyl when B1 is selected from O, NR10, S, S(O), S(O)2, and CONR10;
is a single bond when D is N or CR11 or a double bond when D is C;
E and G are independently C1-3-alkylene, each optionally independently substituted with a substituent selected from the group consisting of C1-3-alkyl, C1-4-alkoxy, carboxy, fluoro-C1-3-alkyl, hydroxy, hydroxymethyl, and fluoro, provided that the ring formed by D, E, N and G has not more than 7 ring atoms, and further provided that the said ring has 6 or 7 ring atoms when D is N, and yet further provided that the total number of substituents on E and G independently is not more than 2;
R1 is C(O)OR2, C(O)R2, S(O)2R2, C(O)NR2R3, \u2014CH2\u2014C(O)NR2R3, or a 5- or 6-membered heteroaryl group linked via a ring carbon atom, wherein the said heteroaryl group is optionally substituted with C1-4-alkyl;
Ar1 is phenyl which is optionally substituted in one or more positions with a substituent independently selected from:
(a) CF3SO3,
(b) halogen selected from chlorine, bromine and fluorine,
(c) C1-4-alkylsulfinyl,
(d) \u2014S(O)2R4,
(e) \u2014S(O)2NR5R5,
(f) \u2014NR6S(O)2R4,
(g) \u2014CH2\u2014NR6C(O)R4,
(h) \u2014NR6C(O)R4,
(i) \u2014C(O)NR5R5,
(j) \u2014CH2\u2014C(O)NR5R5,
(k) \u2014C(O)R4,
(l) H2N\u2014C(O)O\u2014,
(m) CH3\u2014NH\u2014C(O)O\u2014,
(n) (CH3)2NC(O)O\u2014,
(o) CH3OC(O)NH\u2014,
(p) C-heterocyclyl, optionally substituted with C1-4-alkyl,
(q) \u2014CN,
(r) \u2014OR8,
(s) \u2014SCF3,
(t) \u2014NO2,
(u) phosphonooxy,
(v) C-heterocyclylsulfonyl, optionally substituted with C1-4-alkyl,
(w) \u2014NR5R5,
(x) \u2014C(OH)CH3CF3,
(y) C(OH)CH3CF3\u2014C1-6-alkyl,
(z) cyano-C1-6-alkyl,
(aa) guanidino,
(bb) amidino,
(cc) C1-6-alkyl,
(dd) C1-4-alkoxy-C1-4-alkyl,
(ee) fluoro-C1-4-alkyl,
(ff) C2-6-alkenyl,
(gg) fluoro-C2-4-alkenyl,
(hh) hydroxy-C1-6-alkyl,
(ii) C1-4-alkylsulfonyl-C1-4-alkyl,
(jj) hydroxy-C2-4-alkoxy-C1-4-alkyl,
(kk) C2-3-acyl-C1-3-alkyl,
(ll) C2-6-alkynyl,
(mm) hydroxy-C3-6-cycloalkyl,
(nn) fluoro-C3-6-cycloalkyl,
(oo) methyl-C3-6-cycloalkyl,
(pp) C-heterocyclylcarbonyl, optionally substituted with C1-4-alkyl,
(qq) C3-6-cycloalkyl,
(rr) C3-6-cycloalkyl-C1-4-alkyl,
(ss) R5R5N\u2014C1-2-alkyl,
(tt) \u2014C(O)OR7,
(uu) aryl,
(vv) aryl-C1-4-alkyl,
(ww) aryl-C2-4-alkenyl,
(xx) aryl-C2-4-alkynyl,
(yy) heteroaryl,
(zz) heteroaryl-C1-4-alkyl,
(aaa) heteroaryl-C2-4-alkenyl, and
(bbb) heteroaryl-C2-4-alkynyl,
wherein any aryl or heteroaryl residue, alone or as part of another group, as substituent on Ar1 is optionally substituted in one or more positions with a substituent independently selected from the group Z1 consisting of:
(a) halogen selected from chlorine and fluorine,
(b) C1-4-alkyl,
(c) hydroxy,
(d) C1-4-alkoxy,
(e) \u2014OCF3,
(f) \u2014SCF3,
(g) \u2014CN,
(h) \u2014C(OH)CH3CF3,
(i) hydroxy-C1-4-alkyl,
(i) \u2014CF3,
(k) \u2014S(O)2CH3,
(l) \u2014S(O)2NH2,
(m) \u2014S(O)2NHCH3,
(n) \u2014S(O)2N(CH3)2,
(o) \u2014N(CH3)S(O)2CH3,
(p) \u2014N(CH3)C(O)CH3,
(q) \u2014C(O)NH2,
(r) \u2014C(O)NHCH3,
(s) \u2014C(O)N(CH3)2,
(t) \u2014C(O)CH3,
(u) \u2014NH2,
(v) \u2014NHCH3,
(w) \u2014N(CH3)2,
(x) \u2014NO2, and
(y) methoxycarbonyl;
R2 is selected from:
(a) C1-6-alkyl,
(b) C1-6-alkoxy-C2-6-alkyl,
(c) hydroxy-C2-6-alkyl,
(d) fluoro-C2-6-alkyl,
(e) C3-6-alkynyl,
(f) C3-6-alkenyl,
(g) C3-7-cycloalkyl,
(h) C5-8-cycloalkenyl,
(i) NR9R9, provided that R1 is not selected from C(O)OR2, C(O)NR2R3 and \u2014CH2\u2014C(O)NR2R3,
(j) C-heterocyclyl, optionally substituted with C1-4-alkyl,
(k) C7-8-bicyclyl, optionally substituted with hydroxy,
(l) C7-8-bicyclylmethyl,
(m) azabicyclyl, optionally substituted with hydroxy,
(n) C3-7-cycloalkyl-C1-4-alkyl, wherein cycloalkyl is optionally substituted with methyl,
(o) C1-6-alkylsulfonyl-C2-6-alkyl,
(p) C2-3-acyl-C1-4-alkyl,
(q) arylcarbonyl-C1-4-alkyl,
(r) heteroarylcarbonyl-C1-4-alkyl,
(s) C(OH)CH3CF3\u2014C1-6-alkyl,
(t) N-heterocyclylcarbonyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(u) C-heterocyclylcarbonyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(v) aminocarbonyl-C2-6-alkyl,
(w) C1-3-alkylaminocarbonyl-C2-6-alkyl,
(x) di(C1-3-alkyl)aminocarbonyl-C2-6-alkyl,
(y) hydroxy-C2-4-alkoxy-C2-4-alkyl,
(z) hydroxy-C4-6-cycloalkyl,
(aa) oxo-C4-6-cycloalkyl,
(bb) fluoro-C4-6-cycloalkyl,
(cc) C1-3-alkoxy-C4-6-cycloalkyl,
(dd) methyl-C3-6-cycloalkyl,
(ee) oxo-N-heterocyclyl-C2-4-alkyl,
(ff) fluoro-N-heterocyclyl-C2-4-alkyl,
(gg) amino-N-heterocyclyl-C2-4-alkyl,
(hh) hydroxy-N-heterocyclyl-C2-4-alkyl,
(ii) N-heterocyclyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(jj) C-heterocyclyl-C1-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(kk) aryl,
(ll) aryl-C1-4-alkyl,
(mm) aryl-C3-6-alkenyl,
(nn) aryl-C3-6-alkynyl,
(o) heteroaryl,
(pp) heteroaryl-C1-4-alkyl,
(qq) heteroaryl-C3-6-alkenyl, and
(rr) heteroaryl-C3-6-alkynyl,
wherein any aryl or heteroaryl residue, alone or as part of another group, is optionally independently substituted in one or more position with a substituent selected from the group Z1;
R3 is selected from:
(a) hydrogen,
(b) C1-6-alkyl,
(c) fluoro-C2-6-alkyl,
(d) hydroxy-C2-6-alkyl,
(e) C1-6-alkoxy-C2-6-alkyl,
(f) amino-C2-6-alkyl,
(g) C1-3-alkylamino-C2-6-alkyl,
(h) di(C1-3-alkyl)amino-C2-6-alkyl,
(i) cyano-C1-6-alkyl, and
(j) C1-6-alkylsulfonyl-C2-6-alkyl;
R4 is independently selected from:
(a) C1-6-alkyl,
(b) fluoro-C1-6-alkyl,
(c) hydroxy-C2-6-alkyl,
(d) C1-4-alkoxy-C2-4-alkyl,
(e) C2-4-acyl-C1-4-alkyl,
(f) carboxy-C1-3-alkyl,
(g) C3-6-cycloalkyl,
(h) oxo-C4-6-cycloalkyl,
(i) hydroxy-C4-6-cycloalkyl,
(j) fluoro-C4-6-cycloalkyl,
(k) methyl-C3-6-cycloalkyl,
(l) N-heterocyclylcarbonyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(m) oxo-N-heterocyclyl-C2-4-alkyl,
(n) fluoro-N-heterocyclyl-C2-4-alkyl,
(o) hydroxy-N-heterocyclyl-C2-4-alkyl,
(p) amino-N-heterocyclyl-C2-4-alkyl,
(q) aminocarbonyl-C2-4-alkyl,
(r) C1-3-alkylaminocarbonyl-C2-4-alkyl,
(s) di(C1-3-alkyl)aminocarbonyl-C2-4-alkyl,
(t) C2-3-acylamino-C2-4-alkyl,
(u) hydroxy-C2-4-alkoxy-C2-4-alkyl,
(v) C-heterocyclylcarbonyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(w) C3-6-cycloalkyl-C1-2-alkyl,
(x) aryl,
(y) aryl-C1-2-alkyl,
(z) heteroaryl, and
(aa) heteroaryl-C1-2-alkyl,
wherein any aryl or heteroaryl residue, alone or as part of another group, is optionally substituted in one or more positions with a substituent independently selected from the group Z2 consisting of:
(a) halogen selected from chlorine and fluorine,
(b) C1-4-alkoxy,
(c) hydroxymethyl,
(d) \u2014CN,
(e) \u2014CF3,
(f) C1-4-alkyl,
(g) \u2014OCF3, and
(h) \u2014C(O)CH3;
R5 is each independently selected from:
(a) hydrogen,
(b) C1-6-alkyl,
(c) C3-4-cycloalkyl,
(d) fluoro-C2-4-alkyl,
(e) amino-C2-6-alkyl,
(f) cyano-C1-6-alkyl,
(g) hydroxy-C2-6-alkyl,
(h) dihydroxy-C2-6-alkyl,
(i) C1-4-alkoxy-C2-4-alkyl,
(j) C1-4-alkylamino-C2-4-alkyl,
(k) di(C1-4-alkyl)amino-C2-4-alkyl,
(l) aminocarbonyl-C1-4-alkyl,
(m) C2-3-acylamino-C2-4-alkyl,
(n) C1-4-alkylthio-C2-4-alkyl,
(o) C2-4-acyl-C1-4-alkyl, and
(p) C1-4-alkylsulfonyl-C1-4-alkyl, or
two R5 groups together with the nitrogen to which they are attached form a heterocyclic ring, wherein said heterocyclic ring may be optionally substituted with:
i) a substituent selected from:
(aa) hydroxy,
(bb) amino,
(cc) methylamino,
(dd) dimethylamino,
(ee) hydroxymethyl, and
(ff) aminomethyl;
ii) one or two oxo groups; or
iii) one or two fluorine atoms, provided that when the substituent is selected from fluorine, hydroxy, amino, methylamino and dimethylamino, said substituent is attached to the heterocyclic ring at a position other than alpha to a heteroatom; and when the two R5 groups form a piperazine ring, the nitrogen of the piperazine ring that allows the substitution is optionally substituted with C1-4-alkyl;
R6 is independently selected from:
(a) hydrogen,
(b) C1-4-alkyl, and
(c) hydroxy-C2-4-alkyl;
R7 is independently selected from:
(a) hydrogen, and
(b) C1-4-alkyl;
R8 is independently selected from:
(a) hydrogen,
(b) C1-6-alkyl,
(c) fluoro-C1-6-alkyl,
(d) hydroxy-C2-6-alkyl,
(e) amino-C2-6-alkyl,
(f) C1-3-alkylamino-C2-4-alkyl,
(g) di(C1-3-dialkyl)amino-C2-4-alkyl,
(h) C1-4-alkylsulfonyl-C2-4-alkyl,
(i) N-heterocyclyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(j) C-heterocyclyl, optionally substituted with methyl,
(k) C2-3-acylamino-C2-4-alkyl,
(l) C(OH)CH3CF3\u2014C1-6-alkyl,
(m) C3-6-cycloalkyl,
(n) methyl-C3-6-cycloalkyl,
(o) C3-6-cycloalkyl-C1-2-alkyl,
(p) aryl, and
(q) heteroaryl,
wherein any aryl or heteroaryl residue is optionally independently substituted in one or two positions with a substituent selected from the group Z2;
R9 is each independently selected from:
(a) C1-4-alkoxy-C2-4-alkyl,
(b) amino-C2-4-alkyl,
(c) C1-4-alkylamino-C2-4-alkyl,
(d) di(C1-4-alkyl)amino-C2-4-alkyl,
(e) C2-3-acylamino-C2-4-alkyl,
(f) C1-4-alkylthio-C2-4-alkyl, and
(g) C2-4-acyl-C1-4-alkyl,
or two R9 groups together with the nitrogen to which they are attached form a heterocyclic ring, wherein said heterocyclic ring may be optionally substituted with:
i) a substituent selected from:
(aa) hydroxy,
(bb) amino,
(cc) methylamino,
(dd) dimethylamino,
(ee) hydroxymethyl, and
(ff) aminomethyl;
ii) one or two oxo groups; or
iii) one or two fluorine atoms, provided that when the substituent is selected from fluorine, hydroxy, amino, methylamino and dimethylamino, said substituent is attached to the heterocyclic ring at a position other than alpha to a heteroatom; and when the two R9 groups form a piperazine ring, the nitrogen of the piperazine ring that allows the substitution is optionally substituted with C1-4-alkyl;
R10 is independently selected from:
(a) hydrogen,
(b) C1-6-alkyl,
(c) cyclopropyl,
(d) cyclobutyl,
(e) cyclopropylmethyl,
(f) fluoro-C2-6-alkyl,
(g) hydroxy-C2-6-alkyl,
(h) C1-2-alkoxy-C2-6-alkyl,
(i) amino-C2-6-alkyl,
(j) di(C1-3-alkyl)amino-C2-6-alkyl,
(k) C1-3-alkylamino-C2-6-alkyl,
(l) cyano-C1-4-alkyl,
(m) C2-6-acyl,
(n) C2-6-acyl-C1-6-alkyl,
(o) C1-6-alkylsulfonyl-C1-6-alkyl, and
(p) tetrahydrofuran-2-ylmethyl;
R11 is selected from:
(a) hydrogen,
(b) hydroxy,
(c) fluorine,
(d) C1-4-alkoxy, and
(e) methyl;
R12 is each independently selected from:
(a) hydrogen,
(b) halogen selected from chlorine and fluorine,
(c) \u2014S(O)2CH3,
(d) \u2014S(O)2CF3,
(e) \u2014OS(O)2CF3,
(f) \u2014S(O)NH2,
(g) \u2014S(O)2NHCH3,
(h) \u2014S(O)2N(CH3)2,
(i) \u2014NHS(O)2CH3,
(j) \u2014N(CH3)S(O)2CH3,
(k) \u2014NHC(O)CH3,
(l) \u2014N(CH3)C(O)CH3,
(m) \u2014C(O)NH2,
(n) \u2014C(O)NHCH3,
(o) \u2014C(O)N(CH3)2,
(p) \u2014CN,
(q) \u2014CF3,
(r) guanidino,
(s) amidino,
(t) \u2014OH,
(u) C1-4-alkoxy,
(v) \u2014OCF3,
(w) C3-5-cycloalkyloxy,
(x) \u2014SCF3,
(y) \u2014NO2,
(z) \u2014NR5R5, wherein each R5 is independently selected from the group consisting of hydrogen and C1-4-alkyl; or two R5 groups together with the nitrogen to which they are attached form a pyrrolidine or an azetidine ring,
(aa) \u2014C(OH)CH3CF3,
(bb) C1-3-alkyl,
(cc) C1-3-alkoxy-C1-2-alkyl,
(dd) C2-3-acyl,
(ee) C2-3-alkenyl,
(ff) hydroxy-C1-4-alkyl,
(gg) fluoro-C2-3-alkyl,
(hh) C2-3-alkynyl, and
(ii) C3-5-cycloalkyl.
2. A compound according to claim 1 having Formula (Ib)
wherein
W1 and W3 are N and W2 and W4 are CR12, or W1 and W3 are CR12 and W2 and W4 are N;
A1 is CH2, O, NR10, S, S(O) or S(O)2;
B1 is CH2, O, NR10, S, S(O), S(O)2, C(O) or CONR10, provided that when B1 is O, NR10, S, S(O), S(O)2, C(O) or CONR10, then A1 is CH2;
m is each independently 0 or 1;
D is N or CR11, provided that D must be CR11 and said R11 must be hydrogen or methyl when B1 is selected from O, NR10, S, S(O), S(O)2, and CONR10, and further provided that each m is 1 when D is N;
Ar1, Z1, Z2, R1 to R9 and R12 are as defined in claim 1;
R10 is independently selected from:
(a) hydrogen,
(b) C1-4-alkyl,
(c) cyclopropyl,
(d) cyclobutyl,
(e) cyclopropylmethyl,
(f) fluoro-C2-4-alkyl,
(g) C1-2-alkoxy-C2-3-alkyl,
(h) hydroxy-C2-4-alkyl,
(i) C2-3-acyl,
(j) amino-C2-4-alkyl,
(k) methylamino-C2-4-alkyl,
(l) dimethylamino-C2-4-alkyl,
(m) cyano-C1-4-alkyl, and
(n) tetrahydrofuran-2-ylmethyl;
R11 is selected from:
(a) hydrogen,
(b) hydroxy,
(c) fluorine, and
(d) methyl.
3. A compound according to claim 1 having Formula (Ic)
wherein A1 is CH2, O or NR10;
B1 is CH2, O or NR10, provided that when B1 is O or NR10, then A1 is CH2;
m is each independently 0 or 1;
Z1, Z2, R7 to R1, R9 and R12 are as defined in claim 1, provided that at least one of R12 is hydrogen;
R10 is as defined in claim 2;
Ar1 is phenyl, which is optionally substituted in one, two or three positions with a substituent independently selected from the group Z3 consisting of:
(a) CF3SO3,
(b) halogen selected from bromine, chlorine and fluorine,
(c) C1-4-alkylsulfinyl,
(d) \u2014S(O)2R4,
(e) \u2014S(O)2NR5R5,
(f) \u2014NR6S(O)2R4,
(g) \u2014NR6C(O)R4,
(h) \u2014CH2\u2014NR6C(O)R4,
(i) \u2014C(O)NR5R5,
(j) \u2014CH2\u2014C(O)NR5R5,
(k) \u2014C(O)R4,
(l) H2N\u2014C(O)O\u2014,
(m) CH3\u2014NH\u2014C(O)O\u2014,
(n) (CH3)2NC(O)O,
(o) \u2014NHC(O)OCH3,
(p) C-heterocyclyl, optionally substituted with methyl,
(q) \u2014CN,
(r) \u2014OR8,
(s) \u2014SCF3,
(t) \u2014NO2,
(u) phosphonooxy,
(v) C-heterocyclylsulfonyl, optionally substituted with methyl,
(w) \u2014NR5R5,
(x) \u2014C(OH)CH3CF3,
(y) cyano-C1-6-alkyl,
(z) guanidino,
(aa) amidino,
(bb) C1-6-alkyl,
(cc) C1-4-alkoxy-C1-4-alkyl,
(dd) fluoro-C1-4-alkyl,
(ee) C2-6-alkenyl,
(ff) fluoro-C2-4-alkenyl,
(gg) hydroxy-C1-6-alkyl,
(hh) C1-4-alkylsulfonyl-C1-4-alkyl,
(ii) hydroxy-C2-4-alkoxy-C1-4-alkyl,
(j) C2-3-acyl-C1-3-alkyl,
(kk) C2-6-alkynyl,
(ll) C3-6-cycloalkyl,
(mm) hydroxy-C3-6-cycloalkyl,
(nn) fluoro-C3-6-cycloalkyl,
(o) methyl-C3-6-cycloalkyl,
(pp) C-heterocyclylcarbonyl, optionally substituted with methyl,
(qq) C3-6-cycloalkyl-C1-4-alkyl,
(rr) R5R5N\u2014C1-2-alkyl,
(ss) \u2014C(O)OR7,
(tt) aryl, and
(uu) heteroaryl,
wherein any aryl or heteroaryl residue as substituent on Ar1 is optionally substituted in one or more positions with a substituent independently selected from the group Z1 as defined in claim 1;
R8 is independently selected from:
(g) hydrogen,
(h) C1-4-alkyl,
(i) CF3,
(j) C3-5-cycloalkyl,
(k) methyl-C3-5-cycloalkyl, and
(l) C-heterocyclyl, optionally substituted with methyl.
4. A compound according to claim 3, wherein
A1 is CH2 and B1 is O or NR10, or
A1 is A or NR10 and B1 is CH2; and
m is each 1.
5. A compound according to claim 4, wherein
Ar1 is phenyl, which is optionally substituted in one, two or three positions with a substituent independently selected from the group Z4 consisting of:
(a) halogen selected from chlorine and fluorine,
(b) C1-4-alkylsulfonyl,
(c) C1-4-alkylsulfinyl,
(d) hydroxy-C2-4-alkylsulfonyl,
(e) C3-5-cycloalkylsulfonyl,
(f) methyl-C3-5-cycloalkylsulfonyl,
(g) trifluoromethylsulfonyl,
(h) \u2014S(O)2NR5AR5A,
(i) C1-4-alkylsulfonamido,
(j) C2-4-acylamino,
(k) C2-4-acylaminomethyl,
(l) carboxy-C1-3-alkylcarbonylamino,
(m) \u2014C(O)NR5AR5A,
(n) \u2014CH2\u2014C(O)NR5AR5A
(o) \u2014NHC(O)OCH3,
(p) C2-4-acyl,
(q) C3-5-cycloalkylcarbonyl,
(r) C1-4-alkoxy,
(s) C3-5-cycloalkyloxy,
(t) C-heterocyclyl,
(u) \u2014CN,
(v) \u2014OH,
(w) \u2014OCF3,
(x) \u2014CF3,
(y) \u2014NO2,
(aa) \u2014C(OH)CH3CF3,
(bb) cyano-C1-2-alkyl,
(cc) C1-4-alkyl,
(dd) C3-5-cycloalkyl,
(ee) C1-2-alkoxy-C1-2-alkyl,
(ff) vinyl,
(gg) ethynyl,
(hh) hydroxy-C1-2-alkyl,
(ii) C-heterocyclyloxy, optionally substituted with methyl,
(kk) \u2014C(O)OR7A;
R1 is a group R1A selected from C(O)OR2A, C(O)R2A, S(O)2R2, C(O)NR2AR1A, and \u2014CH2\u2014C(O)NR2AR3A;
R2 is selected from:
(a) C1-6-alkyl,
(b) C1-6-alkoxy-C2-6-alkyl,
(c) hydroxy-C2-6-alkyl,
(d) hydroxy-C2-4-alkoxy-C2-4-alkyl,
(e) fluoro-C2-6-alkyl,
(f) C3-6-alkynyl,
(g) C3-7-cycloalkyl,
(h) C5-8-cycloalkenyl,
(i) NR9AR9A provided that R1A is not selected from C(O)OR2A, C(O)NR2AR3A and \u2014CH2\u2014C(O)NR2AR3A,
(j) C-heterocyclyl, optionally substituted with methyl,
(k) C7-8-bicyclyl,
(l) 2-norbornylmethyl,
(m) azabicyclyl,
(n) C3-6-cycloalkyl-C1-4-alkyl, wherein cycloalkyl is optionally substituted with methyl
(o) C2-3-acyl-C1-4-alkyl,
(p) arylcarbonyl-C1-4-alkyl,
(q) heteroarylcarbonyl-C1-4-alkyl,
(r) C(OH)CH3CF3\u2014C1-6-alkyl,
(s) N-heterocyclylcarbonyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(t) hydroxy-C4-6-cycloalkyl,
(u) oxo-C4-6-cycloalkyl,
(v) fluoro-C4-6-cycloalkyl,
(w) methoxy-C4-6-cycloalkyl,
(x) methyl-C3-6-cycloalkyl,
(y) oxo-N-heterocyclyl-C2-4-alkyl,
(z) hydroxy-N-heterocyclyl-C2-4-alkyl,
(aa) fluoro-N-heterocyclyl-C2-4-alkyl,
(bb) amino-N-heterocyclyl-C2-4-alkyl,
(cc) N-heterocyclyl-C2-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(dd) C-heterocyclyl-C1-4-alkyl, wherein heterocyclyl is optionally substituted with methyl,
(ee) aryl,
(ff) aryl-C1-4-alkyl,
(gg) heteroaryl, and
(hh) heteroaryl-C1-4-alkyl,
wherein any aryl or heteroaryl residue, alone or as apart of another group, is optionally independently substituted in one or more positions with a substituent selected from the group Z5 consisting of:
(a) halogen selected from chlorine and fluorine,
(b) methyl,
(c) ethyl,
(d) methoxy,
(e) ethoxy,
(f) isopropoxy,
(g) hydroxy,
(h) \u2014OCF3,
(i) \u2014CF3,
(j) \u2014CN,
(k) \u2014C(OH)CH3CF3,
(l) dimethylamino,
(m) hydroxymethyl,
(n) \u2014S(O)2CH3,
(o) \u2014(O)CH3, and
(p) \u2014C(O)NH2;
R3A is selected from:
(a) hydrogen,
(b) C1-4-alkyl,
(c) hydroxy-C2-4-alkyl, and
(d) methoxy-C2-4-alkyl;
R5A is each independently selected from:
(a) hydrogen,
(b) C1-3-alkyl,
(c) C1-2-alkoxy-C2-4-alkyl,
(d) C3-4-cycloalkyl,
(e) hydroxy-C2-4-alkyl,
(f) cyano-C1-3-alkyl,
(g) C2-3-acylamino-C2-3-alkyl,
(h) dihydroxy-C2-4-alkyl,
(i) aminocarbonyl-C1-2-alkyl, and
(j) di(C1-2-alkyl)amino-C2-3-alkyl, or
two R5A groups together with the nitrogen to which they are attached form a heterocyclic ring, wherein said heterocyclic ring may be optionally substituted with:
i) a substituent selected from:
(aa) hydroxy,
(bb) amino,
(cc) methylamino,
(dd) dimethylamino,
(ee) hydroxymethyl, and
(ff) aminomethyl;
ii) one or two oxo groups; or
iii) one or two fluorine atoms, provided that when the substituent is selected from fluorine, hydroxy, amino, methylamino and dimethylamino, said substituent is attached to the heterocyclic ring at a position other than alpha to a heteroatom; and when the two R5A groups form a piperazine ring, the nitrogen of the piperazine ring that allows the substitution is optionally substituted with methyl;
R7A is independently from:
(a) hydrogen, and
(b) C1-4-alkyl;
Two groups R9A together with the nitrogen to which they are attached form a heterocyclic ring, wherein said heterocyclic ring may be optionally substituted with: i) one hydroxy or amino group, ii) one or two fluorine atoms, or iii) one or two oxo groups, provided that when the substituent is selected from fluorine, hydroxy and amino, said substituent is attached to the heterocyclic ring at a position other than alpha to a heteroatom; and when the two R9A groups form a piperazine ring, the nitrogen of the piperazine ring that allows the substitution is optionally substituted with methyl;
R10 is independently selected from:
(a) hydrogen, and
(b) C1-3-alkyl;
R12 is each hydrogen.
6. A compound according to claim 5, wherein A1 is O or NR10 and B1 is CH2.
7. A compound according to claim 5, wherein Ar1 is selected from methylsulfonylphenyl, (methoxycarbonyl)aminophenyl, (dimethylamino)carbonyl-phenyl, (acetylamino)phenyl, (diethylamino)carbonylphenyl, (aminocarbonyl)-phenyl, (methylsulfonyl)aminophenyl, (morpholin-4-ylcarbonyl)phenyl, (amino-sulfonyl)phenyl, (2-hydroxyethyl)sulfonylphenyl, (morpholin-4-ylsulfonyl)phenyl, (2,5-dioxoimidazolidin-1-yl)methylphenyl, (dimethylamino)sulfonylphenyl, {2-(dimethylamino)ethylaminocarbonyl}phenyl, {(2-hydroxymethyl)pyrrolidin-1-yl-carbonyl}phenyl, (2,5-dioxopyrrolidin-1-yl)methylphenyl, (4-methylpiperazin-1-yl)carbonylphenyl, (difluoro)hydroxyphenyl, fluoro-(propylamino)carbonyl-phenyl, (aminocarbonyl)fluorophenyl, {3-(dimethylamino)pyrrolidin-1-yl-carbonyl}phenyl(3-hydroxypyrrolidin-1-yl)carbonylphenyl and (hydroxymethyl)-phenyl.
8. A compound according to claim 5, wherein R1A is selected from C(O)OR2A and C(O)R2A.
9. A compound according to claim 5, wherein R1A is C(O)OR2A and wherein R2A is selected from C1-6-alkyl and benzyl.
10. A compound according to claim 5, wherein R1A is C(O)R2A and wherein R2A is selected from C1-6-alkyl and phenyl.
11. A compound according to claim 5, wherein R10 is independently selected from hydrogen and methyl.
12. A compound according to claim 1 having Formula (Id)
wherein A1 is CH2, O or NR10;
B1 is CH2, O or NR10, provided that when B1 is O or NR10, then A1 is CH2;
m is each independently 0 or 1;
Z1, Z2, R1 to R7, R9 and R12 are as defined in claim 1, provided that at least one of R12 is hydrogen;
R8 is as defined in claim 3;
R10 is as defined in claim 2;
Ar1 is phenyl which is optionally substituted in one or two positions with a substituent independently selected from the group Z3 as defined in claim 3.
13. A compound according to claim 12, wherein
A1 is CH2 and B1 is O or NR10, or
A1 is or NR10 and B1 is CH2; and
m is each 1.
14. A compound according to claim 13, wherein
Ar1 is phenyl, which is optionally substituted in one or two positions with a substituent independently selected from the group Z4 as defined in claim 5;
Z5 is as defined in claim 5;
R1 is a group R1A, wherein R1A is as defined in claim 5;
R2A, R3A, R5A, R7A and R9A are as defined in claim 5;
R10 is selected from hydrogen and C1-3-alkyl;
R12 is each hydrogen.
15. A compound according to claim 14 wherein A1 is CH2 and B1 is NR10.
16. A compound according to claim 14, wherein Ar1 is C1-4-alkylsulfonylphenyl.
17. A compound according to claim 14, wherein R1 is C(O)OR2.
18. A compound according to claim 14, wherein R2 is C1-4-alkyl.
19. A compound according to claim 14, wherein R10 is independently selected from hydrogen, methyl and ethyl.
20. A compound according to claim 1, which is selected from:
tert-Butyl 4-({5-4-(hydroxymethyl)phenylpyrimidin-2-yl}oxy)methyl-piperidine-1-carboxylate;
tert-Butyl 4-({5-4-(methylsulfonyl)phenylpyrimidin-2-yl}oxy)methyl-piperidine-1-carboxylate;
Benzyl 4-({5-4-(methylsulfonyl)phenylpyrimidin-2-yl}oxy)methyl-piperidine-1-carboxylate;
2-(1-Benzoylpiperidin-4-yl)methoxy-5-4-(methylsulfonyl)phenyl-pyrimidine;
tert-Butyl 4-{(5-{4-(methoxycarbonyl)aminophenyl}pyrimidin-2-yl)oxy-methyl}piperidine-1-carboxylate;
tert-Butyl 4-{(5-{4-(dimethylamino)carbonylphenyl}pyrimidin-2-yl)oxy-methyl}piperidine-1-carboxylate;
tert-Butyl 4-({5-4-(acetylamino)phenylpyrimidin-2-yl}oxy)methyl-piperidine-1-carboxylate;
tert-Butyl 4-{(5-{4-(diethylamino)carbonylphenyl}pyrimidin-2-yl)oxy-methyl}piperidine-1-carboxylate;
tert-Butyl 4-({5-4-(aminocarbonyl)phenylpyrimidin-2-yl}oxy)methyl-piperidine-1-carboxylate;
tert-Butyl 4-{(5-{4-(methylsulfonyl)aminophenyl}pyrimidin-2-yl)oxy-methyl}piperidine-1-carboxylate;
tert-Butyl 4-({5-4-(morpholin-4-ylcarbonyl)phenylpyrimidin-2-yl}oxy)-methylpiperidine-1-carboxylate;
tert-Butyl 4-(f{5-4-(aminosulfonyl)phenylpyrimidin-2-yl}oxy)methyl-piperidine-1-carboxylate;
tert-Butyl 4-{(5-{4-(2-hydroxyethyl)sulfonylphenyl}pyrimidin-2-yl)oxy-methyl}piperidine-1-carboxylate;
tert-Butyl 4-({5-4-(morpholin-4-ylsulfonyl)phenylpyrimidin-2-yl}oxy)-methylpiperidine-1-carboxylate;
tert-Butyl 4-{(5-{4-(2,5-dioxoimidazolidin-1-yl)methylphenyl}pyrimidin-2-yl)oxymethyl}piperidine-1-carboxylate;
tert-Butyl 4-{(5-{4-(dimethylamino)sulfonylphenyl}pyrimidin-2-yl)oxy-methyl}piperidine-1-carboxylate;
tert-Butyl 4-({5-4-({2-(dimethylamino)ethylamino}carbonyl)phenyl-pyrimidin-2-yl}oxy)methylpiperidine-1-carboxylate;
tert-Butyl 4-({5-4-(aminocarbonyl)-3-fluorophenylpyrimidin-2-yl}oxy)-methylpiperidine-1-carboxylate;
Isopropyl 4-({5-4-(methylsulfonyl)phenylpyrimidin-2-yl}amino)methyl-piperidine-1-carboxylate;
Ethyl 4-({5-4-(methylsulfonyl)phenylpyrimidin-2-yl}amino)methyl-piperidine-1-carboxylate;
N-{1-(3,3-dimethylbutanoyl)piperidin-4-ylmethyl}-5-4-(methylsulfonyl)-phenylpyrimidin-2-amine;
tert-Butyl 4-({5-4-(methylsulfonyl)phenylpyrimidin-2-yl}amino)methyl-piperidine-1-carboxylate;
Benzyl 4-({5-4-(methylsulfonyl)phenylpyrimidin-2-yl}amino)methyl-piperidine-1-carboxylate;
tert-Butyl 4-({5-(4-{(2R)-2-(hydroxymethyl)pyrrolidin-1-ylcarbonyl}-phenyl)pyrimidin-2-yloxy}methyl)piperidine-1-carboxylate;
tert-Butyl 4-{(5-{4-(2,5-dioxopyrrolidin-1-yl)methylphenyl}pyrimidin-2-yl)oxymethyl}piperidine-1-carboxylate;
tert-Butyl 4-{(5-{4-(4-methylpiperazin-1-yl)carbonylphenyl}pyrimidin-2-yl)oxymethyl}piperidine-1-carboxylate;
tert-Butyl 4-({5-(3,5-difluoro-4-hydroxyphenyl)pyrimidin-2-yloxy}methyl) -piperidine-1-carboxylate;
tert-Butyl 4-({5-(4-{3-(dimethylamino)pyrrolidin-1-ylcarbonyl}phenyl) -pyrimidin-2-yloxy}methyl)piperidine-1-carboxylate;
tert-Butyl 4-{(5-{3-fluoro-4-(propylamino)carbonylphenyl}pyrimidin-2-yl)-oxymethyl}piperidine-1-carboxylate;
tert-Butyl 4-{(5-{4-(3-hydroxypyrrolidin-1-yl)carbonylphenyl}pyrimidin-2-yl)oxymethyl}piperidine-1-carboxylate;
tert-Butyl 4-({2-4-(methylsulfonyl)phenylpyrimidin-5-yl}methyl)amino-piperidine-1-carboxylate; and
tert-Butyl 4-methyl({2-4-(methylsulfonyl)phenylpyrimidin-5-yl}methyl)-aminopiperidine-1-carboxylate.
21. A method for the treatment or prophylaxis of a disorder relating to GPR119 activity which comprises administering to a mammal, including man, in need of such treatment an effective amount of a compound according to claim 1.
22. The method according to claim 21, wherein said disorder relating to GPR119 activity is selected from the group consisting of Type 1 diabetes, Type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, syndrome X, metabolic syndrome, obesity, hypertension, chronic systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, reduced fibrinolysis, and endothelial dysfunction.
23. A pharmaceutical formulation containing a compound according to claim 1 as active ingredient in combination with a pharmaceutically acceptable diluent or carrier.
24. A method for the treatment or prophylaxis of a disorder relating to GPR119 activity which comprises administering to a mammal, including man, in need of such treatment an effective amount of a compound according to claim 1 in combination with a DPP-IV inhibitor.
25. The method according to claim 24, wherein said disorder relating to GPR119 activity is selected from the group consisting of Type 1 diabetes, Type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, syndrome X, metabolic syndrome, obesity, hypertension, chronic systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, reduced fibrinolysis, and endothelial dysfunction.
26. The pharmaceutical formulation according to claim 23 which in addition comprises a DPP-IV inhibitor.