1. A method for determining tensile stress within a liquid, comprising the steps of:
(a) measuring the liquid’s gravity-driven drainage time;
(b) measuring the liquid’s stretched drainage time; and
(c) calculating the tensile stress of the liquid as a function of the difference between the liquid’s gravity-driven drainage time and the liquid’s stretched drainage time.
2. The method according to claim 1, wherein said step (a) comprises the steps of:
(a1) filling a reservoir with a known amount of the liquid; and
(a2) draining said reservoir by allowing the liquid to pass through a capillary attached to said reservoir; and
(a3) measuring how long it takes to drain said reservoir.
3. The method according to claim 1, wherein said step (b) comprises the steps of:
(b1) filling a reservoir with a known amount of the liquid;
(b2) draining said reservoir by allowing the liquid to pass through a first capillary attached to said reservoir;
(b3) drawing the liquid as it emerges from said first capillary into a second capillary, wherein said second capillary is positioned below said first capillary such that a gap exists between said first capillary and said second capillary; and
(b4) measuring how long it takes to drain said reservoir.
4. The method according to claim 3, wherein each of said first and second capillaries has a diameter such that the diameter of said second capillary is equal to or less than the diameter of said first capillary.
5. The method according to claim 1, wherein the difference between the liquid’s stretched drainage time and the liquid’s gravity-driven drainage time is at least one second.
6. A method for determining extensional viscosity of a solution, comprising the steps of:
(a) calculating tensile stress within the solution;
(b) calculating the solution’s stretch rate; and
(c) calculating extensional viscosity of the solution as a ratio of tensile stress to stretch rate.
7. The method according to claim 6, wherein said step (a) comprises the steps of:
(a) measuring the liquid’s gravity-driven drainage time;
(b) measuring the liquid’s stretched drainage time; and
(c) calculating the tensile stress of the liquid as a function of the difference between the liquid’s gravity-driven drainage time and the liquid’s stretched drainage time.
8. The method according to claim 7, wherein said step (a) comprises the steps of:
(a1) filling a reservoir with a known amount of the solution; and
(a2) draining said reservoir by allowing the solution to pass through a capillary attached to said reservoir; and
(a3) measuring how long it takes to drain said reservoir.
9. The method according to claim 7, wherein said step (b) comprises the steps of:
(b1) filling a reservoir with a known amount of the solution;
(b2) draining said reservoir by allowing the solution to pass through a first capillary attached to said reservoir;
(b3) suctioning the solution as it emerges from said first capillary into a second capillary positioned below said first capillary such that a gap exists between said first capillary and said bottom capillary; and
(b4) measuring how long it takes to drain the reservoir.
10. The method according to claim 8, wherein each of said first and second capillaries has a diameter and the diameter of said second capillary is equal to or less than the diameter of said first capillary.
11. The method according to claim 7, wherein the difference between the solution’s stretched drainage time and the solution’s gravity-driven drainage time is at least one second.
12. An extensional viscometer for measuring tensile stress within a liquid, comprising:
a liquid reservoir without a pressure measuring device;
a first capillary through which liquid drains, connected to said liquid reservoir; and
a second capillary positioned beneath said first capillary thereby creating a gap between said first and second capillaries, such that the liquid is stretched as it passes from said first capillary to said second capillary.
13. The extensional viscometer according to claim 12, further comprising a water bath in which said liquid reservoir is immersed.
14. The extensional viscometer according to claim 13, further comprising a circulator for maintaining said water bath at a constant temperature.
15. The extensional viscometer according to claim 12, wherein each of said first and second capillaries has a diameter and the diameter of said second capillary is equal to or less than the diameter of said first capillary.
16. The extensional viscometer according to claim 12, wherein said liquid reservoir has a first mark and a second mark.
17. The extensional viscometer according to claim 16, wherein a collection area is positioned between said first mark and said second mark.
18. A method for determining extensional viscosity of a liquid, comprising the step of:
(a) inferring fluid stress by measuring change in flow rate of the liquid during passage through a vertical capillary, wherein the change in flow rate is calculated by:
determining the liquid’s gravity-driven flow rate;
determining the liquid’s stretched flow rate; and
subtracting the stretched flow rate from the gravity-driven flow rate.
19. The method according to claim 18, wherein the stretched flow rate of the liquid is determined by positioning a second capillary beneath a first capillary, such that said second capillary creates a force that pulls the liquid from said first capillary into said second capillary.
20. The method according to claim 19, wherein each of said first and second capillaries has a diameter and the diameter of said second capillary is equal to or less than the diameter of said first capillary.
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 (I),
pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or pro-drugs thereof, wherein
X is N or CH;
A is optionally substituted phenyl,
or A is
r is 1 and D1, G1, J1, L1 and M1 are each independently selected from the group consisting of CRa and N, provided that at least two of D1, G1, J1, L1 and M1 are CRa; or
r is 0, and one of D1, G1, L1 and M1 is NRa, one of D1, G1, L1 and M1 is CRa and the remainder are independently selected from the group consisting of CRa and N, wherein Ra is as defined below;
L is NH, optionally substituted alkyl, carbonyl, \u2014O-optionally substituted alkyl, NH(optionally substituted aliphatic) or S;
R1 is \u2014C(\u2550O)\u2014N(R100)2 wherein R100 for each occurrence is independently hydrogen or alkyl;
or R1 is
or an optionally substituted group selected from the group consisting of an aliphatic group, benzimidazolyl, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, cycloalkyl, 2,3-dihydrobenzofuranyl, 1,1-dioxybenzoisothiazolyl, furanyl, 1H-imidazo1,2-aimidazolyl, imidazo1,2-apyridinyl, imidazo1,2-apyrimidinyl, imidazo2,1-b1,3thiazolyl, indazolyl, indolinyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyl, oxadiazolyl, oxazolyl, phenylsulfonyl, phthalazinyl, piperidinyl, pyrazolyl, H-pyridinone, pyridinyl, pyrido-oxazolyl, pyrido-thiazolyl, pyrimido-oxazolyl, pyrimido-thiazolyl, pyrrolidinyl, pyrrolopyridinyl, pyrrolyl, quinolinyl, quinoxalinyl, quinazolinyl, tetrahydrofuranyl, tetrahydronaphthyl, tetrahydropyranyl,
thiadiazolyl, thiazolyl thienyl,
wherein the foregoing optionally substituted groups are optionally substituted by one or more Rb;
u is 1 and D2, G2, J2, L2 and M2 are each independently selected from the group consisting of CRa and N, provided that at least two of D2, G2, J2, L2 and M2 are CRa; or
u is 0, and one of D2, G2, L2 and M2 is NRa, one of D2, G2, L2 and M2 is CRa and the remainder are independently selected from the group consisting of CRa and N;
Ra and Rb each represent one or more substituents and for each occurrence is independently selected from the optionally substituted group consisting of an aliphatic group, alkoxy, alkylamino, aliphatic-carbonyl, aliphatic-cycloalkyl, aliphatic-heterocyclyl, alkyl-S\u2014, alkyl-S(O)p\u2014, amido groups, amino, aminoalkyl, carboxamido, \u2014CF3, \u2014CN, \u2014C(O)-aliphatic, \u2014C(O)-cycloalkyl, \u2014C(O)-heterocyclyl, \u2014C(O)H, C(O)OH, \u2014C(O)O-aliphatic, C(O)O\u2014C(O)O-heterocyclyl, cycloalkyl, cycloalkyl-aliphatic, cycloalkyl-S, cycloalkyl-S(O)p, cycloalkylthio, dialkylaminoalkoxy, a halo, heterocyclyl, heterocycloalkoxy, heterocycloalkyl, heterocyclyloxy, heterocyclo-S, heterocyclo-S(O)p, heterocyclothio, heterocycloalkyl-S, hydrogen, \u2014NO2, \u2014OCF3, \u2014OH, tetrazolyl, trifluoromethylcarbonylamino, trifluoromethylsulfonamido, -Z105-C(O)N(R)2, -Z105-N(R)\u2014C(O)-Z200, -Z105-N(R)\u2014S(O)2-Z200, -Z105-N(R)\u2014C(O)\u2014N(R)-Z200, \u2014N(R)-C(O)R, \u2014N(R)\u2014C(O)OR, O\u2014R\u2014C(O)-heterocyclyl-OR, Rc and \u2014CH2ORc;
where Rc for each occurrence is independently hydrogen, optionally substituted aliphatic , optionally substituted heterocyclyl-(C1-C6)\u2014NRdRe, \u2014W\u2014(CH2)t\u2014NRdRe, \u2014W\u2014(CH2)t\u2014O-alkyl, \u2014W\u2014(CH2)t\u2014S-alkyl, or \u2014W\u2014(CH2)t\u2014OH;
Z105 for each occurrence is independently a covalent bond or an aliphatic group;
Z200 for each occurrence is independently selected from an optionally substituted group selected from the group consisting of an aliphatic group, aliphatic-phenyland phenyl;
Rd and Re for each occurrence are independently H, an aliphatic group, alkanoyl or SO2-alkyl; or Rd, Re and the nitrogen atom to which they are attached together form a five- or six-membered heterocyclic ring;
t for each occurrence is independently an integer from 2 to 6;
W for each occurrence is independently a bond or O, S, S(O), S(O)2, or NRf, wherein Rf for each occurrence is independently H or an aliphatic group; or
Ra is an optionally substituted cycloalkyl or heterocyclyl ring fused with the ring to which it is attached;
B is a bond or a) hydrogen; b) optionally substituted trityl; c) optionally substituted cycloalkyl; d) azaheterocyclyl substituted with an optionally substituted aliphatic group; e) azacycloalkyl which is substituted with one or more substituents selected from the optionally substituted group consisting of \u2014(C1-C6)-alkyl, \u2014(C1-C6)-alkyl-OR, \u2014C(O)\u2014(C1-C6)-alkyl-N(R)2, \u2014(C1-C6)-alkyl-N(R)2, \u2014(C1-C6)-alkyl-cycloalkyl, tetrahydrothienyl, and tetrahydrothiopyranyl; f) a group of the formula
wherein E1 is selected from an optionally substituted group consisting of amido, amino, imidazolyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, or tetrahydrothiazolyl, and wherein E1 is optionally substituted with one or more substituents selected from \u2014(C0-C6)-alkyl-OR, \u2014(C1-C6)-alkyl-C(O)OR, (C1-C6)alkyl-heterocylyl-(C1-C6)-alkyl-heterocycloalkyl, \u2014(C1-C6)-alkyl-N(R)2, cyclohexanone, alkoxyalkyl, and pyranyl, g) optionally substituted (C1-C6)-alkyl, h) optionally substituted cycloalkyl, i) optionally substituted alkoxyalkoxy, j) optionally substituted alkylamino, k) optionally substituted dialkylamino, l) alkylester, m) alkenyl, n) optionally substituted alkoxy, o) optionally substituted heterocyclyl, p) optionally substituted phenyl, q) optionally substituted 1,4-dioxa-spiro4.5decane, r) optionally substituted 1-oxa-2-aza-spiro4.5dec-2-ene, s) optionally substituted 1,3dioxolane, t) \u2014R200\u2014O\u2014(R200)2\u2014Si(R200)3, u) a bond, provided that B, Z and E are not each a bond, v) alkoxyalkyl or w) phenylalkyl;
Z is a bond, carbonyl, R200\u2014O\u2014, amino, \u2014O\u2014, \u2014S\u2014 or SO2;
E is a bond or H, or is an optionally substituted group selected from the group consisting of alkoxy, alkoxy-aliphatic, alkoxyamino, alkoxyalkoxy, alkoxycarbonyl-aliphatic, aliphatic group, aliphatic-aminoaliphatic, aliphaticcarbonyl, alkylsulfonyl, amino, amino-aliphatic, amino-aliphatic-carbonyl, aminocarbonyl, aminocarbonyl-aliphatic, aminosulfonyl-aliphatic, CH2\u2014C(CH3)2(OH), \u2014C(CH3)2N(CH3)(H), cycloalkyl, di-aliphatic-amino, di-aliphatic-amino-aliphatic, di-aliphatic-amino-aliphatic-amino, di-aliphatic-aminocarbonyl, di-aliphatic-aminocarbonyl-aliphatic, heterocyclyl, heterocyclo-aliphatic, morpholinocarbonyl-aliphatic, phenyl, piperidinylalkoxy, tetrahydropyranyl-aliphatic, thiopyranyl, tetrahydrothiopyran-1,1-dioxide, triazolyl-aliphatic and urea; or
E is
\u2014CH(R200)\u2014C(O)\u2014N(C1-C6)\u2014N(R200)2,
\u2014N(R200)\u2014(C1-C6)\u2014C(O)\u2014N(R200)2,
\u2014N(R200)\u2014(C1-C6)\u2014C(O)\u2014OH,
\u2014N(R200)\u2014(C1-C6)\u2014C(O)-morpholinyl,
\u2014(C1-C6)\u2014S\u2014CH3,
\u2014C(R200)(CH2OH)\u2014(C1-C6)\u2014OH,
\u2014C(R200)2\u2014N(R200)2,
\u2014C(O)\u2014OH,
\u2014C(R200)2(OH),
\u2014C(R200)2\u2014O\u2014(C1-C6)\u2014C(R200)2(OH),
\u2014C(R200)2C(R200)2(OH),
wherein R200 is independently hydrogen or alkyl;
R2 is H, \u2014NH2, \u2014S(C1-C6)alkyl, \u2014SO2(C1-C6)alkyl, optionally substituted alkyl, \u2014OR7, \u2014N(H)SO2R7, \u2014N(R7)SO2R7, \u2014N(R7)C(O)N(H)R7, \u2014N(R7)C(O)NR7, \u2014N(H)C(O)R7, \u2014N(R7)2, \u2014N(R7)C(O)R7, \u2014NHC(O)NHR7, or \u2014NHR7;
R7 is (C1-C6)-aliphatic optionally substituted by one or more substituents each independently selected from the group consisting of (C1-C6)alkoxy, heterocyclyl, hydroxyl, \u2014NR5R6 optionally substituted phenyl, \u2014C(O)R4 and heterocyclyl;
wherein any of said alkoxy, aliphatic and heterocyclyl may be optionally substituted;
wherein R5 and R6 are independently H or (C1-C6)alkyl, \u2014NHS(O)2R4, \u2014NHC(O)R4 or \u2014NHC(\u2550NH)R4;
wherein R4 is selected from (C1-C6)alkyl and H;
Y is H, OR3 or N(R3)2 wherein R3 is independently selected from H or an optionally substituted group consisting of aliphatic, \u2014(CH2)2\u2014C(O)\u2014NH2, \u2014C(O)-aliphatic, \u2014C(O)-cycloalkyl, and \u2014C(O)-heterocyclyl;
where R for each occurrence is independently H or selected from an optionally substituted group consisting of aliphatic, heterocyclyl and heterocyclo-aliphatic;
n is an integer from 1 to 6; and
p is 1 or 2;
provided that
when A-L-R1 is
then B-Z-E is not a pyrrolidinyl which is substituted with 2-methoxyethyl, N,N-dimethylaminomethyl, N,N-dimethylamino-1-oxoethyl, or 2-(N-methylamino)-1-oxopropyl;
when X is N; Y is NH2; R2 is H; L is NH; A is phenyl optionally substituted with fluoro or methoxy; B is cyclohexyl; Z is a bond and E is piperazinyl substituted with methyl, then R1 is not:
phenyl optionally substituted with C2H4OH or chloro,
benzofuranyl optionally substituted with chloro,
imidazolyl optionally substituted with methyl,
benzoxazolyl optionally substituted with one or two methyls,
benzoxazolyl optionally substituted with one or two chloros,
benzoxazolyl optionally substituted with methoxy,
benzoxazolyl optionally substituted with ethyl,
benzoxazolyl optionally substituted with carbonitrile,
benzoxazolyl optionally substituted with isopropyl,
benzothiazolyl optionally substituted with one or two methyls,
benzothiazolyl optionally substituted with propyl,
benzothiazolyl optionally substituted with isopropyl,
benzothiazolyl optionally substituted with ethyl and phenyl,
thiazolyl substituted with ethyl,
thiazolyl optionally substituted phenyl,
thiazolyl optionally substituted with phenylmethyl,
thiazolyl optionally substituted with nitrophenyl,
thiazolyl optionally substituted with two methyls,
thiazolyl substituted with phenyl and methyl,
thiazolyl substituted with phenyl and propyl,
thiazolyl substituted with phenyl and isopropyl,
thiazolyl substituted with ethyl and methylphenyl,
benzoisothiazolyl optionally substituted with CF3,
benzoisothiazolyl optionally substituted with one or two oxo,
benzoisoxazolyl substituted with CF3,
indazolyl, or pyrimidinyl; or
when X is N; Y is NH2; R is H; L is NH; A is phenyl optionally substituted with fluoro; R1 is benzoxazolyl substituted with one or two methyls, benzothiazolyl or ethyl; Z is a bond; and E is COOH, piperazinyl substituted with methyl, piperazinyl substituted with oxo, or ethyl substituted with oxo;
then B is not ethyl, cyclohexyl, piperidinyl substituted with dimethylamino, or phenyl substituted with CN; or
when X is N; Y is NH2; R2is H; L is NH; A is phenyl; B is a bond; Z is a bond; and R1 is benzofuranyl, benzoisoxazolyl, piperidinyl, pyrrolyl, isooxazolyl substituted with phenyl, isoxazolyl substituted with trifluoromethyl, benzoxazolyl optionally substituted with one or two methyls, benzoxazolyl optionally substituted with ethyl, benzoxazolyl optionally substituted with chloro, or benzoxazolyl optionally substituted with isopropyl then
E is not:
piperidinyl optionally substituted with substituted alkyl,
piperazinyl,
pyrrolidinyl optionally substituted with methoxyethyl,
piperidinyl optionally substituted with dihydroxypropyl,
piperidinyl optionally substituted with hydroxyethyl,
piperidinyl optionally substituted with methoxyethyl,
piperidinyl optionally substituted with methylsulfanylethyl,
piperidinyl optionally substituted with optionally substituted ethyl,
piperidinyl optionally substituted with optionally substituted propyl,
imidazolyl optionally substituted with methyl,
imidazolyl optionally substituted with amino,
aminoalkylcarbonyl,
cyclohexanecarboxylate, or
pyrimidinyl substituted with CN; or
when X is N; Y is NH2; R2 is H; A is phenyl; R1 is phenyl; B is cyclohexyl; Z is a bond; and E is piperazinyl substituted with methyl; then L is not methyl substituted by \u2550N\u2014OCH3, \u2550N\u2014OH, NH2 or CN; or
when X is N; Y is NH2; R2 is H; L is NH; A is phenyl; R1 is benzoxazolyl substituted with two methyls; B is pyrrolidinyl optionally substituted with methylaminomethyl and ethyl, or pyrrolidinyl optionally substituted by dimethylamino and ethyl; and Z is carbonyl; then E is not dialkylamino, a bond or alkyl substituted with methylamino; or
when X is N; L is NH; A is phenyl; R1 is benzoxazolyl optionally substituted with two methyls; B is cyclohexyl; and Z is a bond; then E is not dimethylamino or morpholino; or
when X is N; L is NH; A is phenyl; R1 is benzoxazolyl optionally substituted with two methyls; B is cyclohexyl; and Z is NH; then E is not methoxyethyl or methyl; or
when X is N; Y is NH2; R2 is H; L is NH; A is phenyl; R1 is benzoxazolyl substituted with two methyls; B is piperidinyl; and Z is a bond; then E is not a bond; or
when X is N; L is O-alkyl; A is phenyl; B is cyclohexyl or a bond; Z is a bond; and E is cyclopentyl or piperazinyl substituted with methyl; then R1 is not phenyl optionally substituted with benzenesulfonamide or phenyl optionally substituted with benzylurea; or
when X is N, Y is NH2, R2 is H, L is NH, A is phenyl optionally substituted with fluoro, R1 is benzoxazolyl substituted with ethyl, benzoxazolyl substituted with chloro, or benzoxazolyl substituted with one or two methyls; B is piperidinyl, azetidinyl, pyrrolyl, or cyclohexyl; and Z is a bond; then E is not:
methoxyethyl,
methoxypropyl,
methyl,
ethyl optionally substituted with hydroxyl,
piperazinyl substituted with oxo, or
imidazolyl optionally substituted with amino;
or
when X is N; Y is NH2; R2 is H; L is NH; A is phenyl; B is piperidinyl; Z is carbonyl; and R1 is benzoxazolyl optionally substituted with two methyls or benzoxazolyl optionally substituted with chloro; then
E is not:
morpholinoalkyl,
dimethylaminomethyl,
piperidinyl optionally substituted with methyl,
isopropyl substituted with methylamine,
pyrrolidinyl,
ethyl optionally substituted with methyl and methylamino, or
ethyl optionally substituted with substituted alkyl; or
when X is N; Y is NH2; R2 is H; L is carbonyl; A is phenyl; Z is a bond; E is piperidinyl or pyridinyl; and B is a bond; then
R1 is not:
oxazolyl,
isoxazolyl optionally substititued with methyl,
isoxazolyl optionally substituted with phenyl,
pyrazolyl optionally substituted with benzyl,
pyrazolyl optionally substituted with benzoyl,
pyrazolyl optionally substituted with methyl, or
pyrazolyl optionally substituted with ethanone; or
when X is N; Y is NH2; R2 is H; L is carbonyl; A is phenyl; Z is a bond; R1 is phenyl; and B is cyclohexyl; then E is not piperazinyl substituted with methyl; or
when X is N; L is alkyl optionally substituted with OH; A is phenyl optionally substituted with methoxy; R1 is benzoxazolyl or benzimidazolyl; B is cyclohexyl; and Z is a bond; then E is not piperazinyl substituted with methyl.
2. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or pro-drugs thereof, of claim 1 wherein Y is \u2014N(R3)2.
3. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or pro-drugs thereof, of claim 2 wherein:
X is N;
A is optionally substituted phenyl;
R1 is optionally substituted benzoxazolyl or optionally substituted benzothiazolyl;
B is a bond or is selected from an optionally substituted group consisting of alkenyl, alkyl, alkoxyalkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, heterocyclyl, phenyl, 1,4-dioxa-spiro4.5dec-2-ene, 2,2-dipropyl1,3dixolane, 1-oxa-2-aza-spiro4.5dec-2-ene, 1,4-dioxa-spiro4.5decane and 2,2-dipropyl1,3dioxolane;
E is H or selected from an optionally substituted group consisting of alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxyamino, alkyl, alkylaminoalkyl, aminoalkyl, aminoalkylcarbonyl, aminocarbonyl, azetidinyl, benzimidazolyl, \u2014C(CH3)(CH2OH)\u2014CH2\u2014OH, \u2014C(CH3)2, \u2014NH(CH3), \u2014C(CH3)2\u2014O\u2014CH2\u2014C(CH3)2(OH), \u2014CH2\u2014C(CH3)2(OH), \u2014(CH2)2\u2014S\u2014CH3, COOH, cycloalkyl, diazepanyl, dimethylamino, dimethylaminoalkyl, dimethylaminoalkylamino, dimethylaminocarbonyl, dimethylaminocarbonylalkyl, furanyl, imidazolinyl, imidazolyl, imidazolylalkyl, isoxazolyl, morpholinyl, morpholinylalkyl, \u2014N(CH3)\u2014CH2\u2014C(\u2550O)-morpholinyl, \u2014N(CH3)\u2014CH2\u2014C(\u2550O)\u2014N(CH3)2, \u2014N(CH3)\u2014CH2\u2014C(\u2550O)\u2014OH, oxodiazolyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrrolyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiopyranyl, thienyl, triazolyl and triazolylalkyl;
R2 is H, SCH3, NH2, or S(O)2\u2014CH3; and
R3 for each occurrence is independently H or \u2014(CH2)2\u2014C(\u2550O)NH2.
4. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or pro-drugs thereof, of claim 3 wherein:
A is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, chloro and fluoro;
R1 is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, alkoxyalkoxy, alkoxycarbonylpiperidinylalkoxy, alkylcarbonyl, aminocarbonyl, bromo, CF3, chloro, C(\u2550O)\u2014O(CH3)3, dialkylaminoalkoxy, dialkylaminocarbonyl, dialkylaminocarbonylalkoxy, fluoro, \u2014OH, morpholinoalkoxy, NO2, OCF3, phenyl-S-alkoxy, optionally substituted piperidinylalkoxy, optionally substituted pyridinylalkoxy, optionally substituted pyrrollidinylalkoxy and optionally substituted thienylalkoxy;
B is a bond or an optionally substituted group selected from the group consisting of alkoxyalkyl, alkyl, azetidinyl, cycloalkenyl, cycloalkyl, isoxazolyl, phenyl, piperidinyl, pyranyl, pyridinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, 1,4-dioxa-spiro4.5dec-2-ene, 1,3dioxolane, 1-oxa-2-aza-spiro4.5dec-2-ene, and 1,4-dioxa-spiro4.5decane;
E is H, dimethylaminoalkyl, dimethylaminocarbonyl or an optionally substituted group selected from the group consisting of alkyl, alkoxyalkyl, azetidinyl, benzimidizolyl, diazepanyl, furanyl, imidazolyidinyl, imidazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, phenyl, piperidinyl, piperazinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyran 1,1-dioxide, tetrazolyl, thiadiazolyl, thienyl, thiopyranyl, and triazolyl; and
wherein the group is optionally substituted by one or more substituents selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, alkylcarbonyl, alkylsulfonyl, dialkylaminosulfonyl, fluoro, hydroxy, hydroxyalkyl, nitrile, oxo, S(O)2CH3, and S(O)2CF3.
5. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or pro-drugs thereof, of claim 4 wherein L is NH, C(OH)H or carbonyl;
B is a bond or is selected from the optionally substituted group consisting of alkyl, azetidinyl, cycloalkyl, isoxazolyl, phenyl, piperidinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-dioxa-spiro4.5dec-2-ene, 1,3dioxolane, 1-oxa-2-aza-spiro4.5dec-2-ene, and 1,4-dioxa-spiro4.5decane;
wherein the group is substituted by one or more substituents selected from the group consisting of alkoxy, alkyl, CF3, C\u2261N, cycloalkyl, fluoro, and hydroxyl.
6. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or pro-drugs thereof, of claim 5 wherein R2 is H.
7. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or pro-drugs thereof, of claim 6 wherein R3 for each occurrence is H.
8. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or pro-drugs thereof, of claim 7 wherein R1 is benzoxazolyl or benzothiazolyl, each optionally substituted by one or more substituents selected from the group consisting of alkenyl, alkoxy, alkyl, bromo, CF3, chloro, dimethylaminocarbonyl, fluoro, hydroxyl, OCF3 and nitrile.
9. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or prodrugs thereof, of claim 8 wherein A is phenyl optionally substituted by fluoro or alkoxy;
L is NH;
R1 is benzoxazolyl optionally substituted by one or more substituents selected from the group consisting of CF3, CH3 and chloro;
Z is a bond, carbonyl, R200\u2014O\u2014, \u2014O\u2014 or \u2014S\u2014; and
E is H or selected from the optionally substituted group consisting of alkoxyalkyl alkoxyamino, alkyl, COOH, cycloalkyl, diazepanyl, dimethylaminocarbonyl, furanyl, imidazolylalkyl, imidazolidinyl, imidazolyl, isoxazolyl, morpholinyl, \u2014N(R200)\u2014R200\u2014C(\u2550O)\u2014N(R200)2, \u2014N(R200)\u2014R200\u2014C(\u2550O)\u2014OH, \u2014N(R200)\u2014R200\u2014C(\u2550O)-morpholinyl, OH, oxazolyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thienyl, and triazolyl;
wherein R200 is alkyl.
10. The compound of claim 9 wherein the compound is
3-3-(fluoro-4-(5-trifluoromethyl-benzoxazol-2-ylamino)-phenyl-1-4-(2-methoxy-ethoxy)-cyclohexyl-1H-pyrazolo3,4-dpyrimidin-4-ylamine,
3-4-(7-chloro-5-methyl-benzoxazol-2-ylamino-phenyl-1-4-(2-methoxy-ethoxy)-cyclohexyl)-1H-pyrazolo3,4-dpyrimidin-4-ylamine, or
1-(4-{4-amino-3-4-(5-chloro-benzoxazol-2-ylamino)-3-fluoro-phenyl-pyrazolo3,4-dpyrimidin-1-yl )-cyclohexyloxy)-2-methyl-propan-2-ol.
11. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or pro-drugs thereof, of claim 1 wherein:
X is CH;
A is optionally substituted phenyl;
R1 is optionally substituted benzoxazolyl;
B is H or selected from the optionally substituted group consisting of alkoxyalkyl, alkyl, cycloalkyl and heterocyclyl;
E is H, or is selected from an optionally substituted group consisting of alkoxy, alkyl, alkylsulfonyl, aminocarbonylalkyl, diazepanyl, dimethylamino, morpholinyl, phenyl, piperazinyl, tetrazolyl and urea;
R2 is H, NH2, SCH3, or SO2CH3; and
R3 for each occurrence is H.
12. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or pro-drugs thereof, of claim 11 wherein:
A is optionally substituted by fluoro;
R1 is an optionally substituted benzoxazolyl substituted by one or more substituents selected from the group consisting of alkoxy, alkyl, bromo, chloro, CF3, dialkylaminoethoxy, fluoro, morpholinylalkoxy, morpholinylalkyl and nitrile;
B is H or is selected from the optionally substituted group consisting of cycloalkyl, alkyl, piperidinyl and pyrrolidinyl;
wherein the substituents are selected from the group consisting of alkyl, hydroxyl, oxo, nitrile and nitro;
E is H or selected from the optionally substituted group consisting of alkyl, alkoxy, alkoxyalkyl, alkylsulfonyl, aminocarbonylalkyl, diazepanyl, dimethylamino, morpholinyl, piperazinyl, phenyl, tetrazolyl and urea;
wherein the group is optionally substituted by one or more substituents selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, cycloalkyl, hydroxyl, nitrile, nitro, NH2 and oxo; and
Z is a bond, R200\u2014O\u2014, NH or \u2014O\u2014.
13. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or pro-drugs thereof, of claim 12 wherein L is NH or N(alkenyl).
14. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or pro-drugs thereof, of claim 13 wherein R is H.
15. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or pro-drugs thereof, of claim 14 wherein R1 is optionally substituted benzoxazolyl substituted by one or more substituents selected from the group consisting of alkyl, bromo, CF3, chloro, fluoro and nitrile.
16. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or pro-drugs thereof, of claim 15 wherein
A is phenyl or phenyl substituted by fluoro;
L is NH;
R1 is benzoxazolyl substituted by one or more substituents selected from the group consisting of alkyl, bromo, CF3 and chloro;
Z is a bond or \u2014O\u2014; and
E is optionally substituted alkyl, alkoxyalkyl, diazepanyl, piperazinyl or tetrazolyl.
17. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or pro-drugs thereof, of claim 2 wherein:
X is CH;
A is optionally substituted phenyl;
R1 is optionally substituted benzoxazolyl;
B is H or a bond or selected from the optionally substituted group consisting of alkyl and cycloalkyl;
Z is a bond, \u2014R200\u2014O\u2014, amino or \u2014O\u2014;
E is H, a bond or an optionally substituted group selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, aminocarbonylalkyl, dialkylamino, heterocyclyl, phenyl and urea;
R2 is H, NH2, \u2014S(C1-C6)alkyl, or \u2014SO2(C1-C6)alkyl; and
R3 for each occurrence is H.
18. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or pro-drugs thereof, of claim 17 wherein
A is optionally substituted by one or more fluoro;
R1 is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, aminoalkoxy, bromo, CF3, chloro, fluoro, morpholinoalkoxy, morpholinoalkyl and nitrile;
E is H or an optionally substituted group selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, aminocarbonylalkyl, diazapenyl, dimethylamino, morpholinyl, phenyl, piperazinyl, pyridinyl, pyrrolidinyl, tetrazolyl and urea;
wherein the optionally substituted group is optionally substituted by one or more alkoxy, alkyl, amino, bromo, cycloalkyl, dimethylamino, hydroxyl, oxo, nitrile, NO2 or sulfonyl; and
R2 is H.
19. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or pro-drugs thereof, of claim 18 wherein
L is NH or N-alkenyl;
R1 is substituted by one or more alkyl, bromo, CF3, chloro, fluoro, or nitrile;
A is phenyl optionally substituted by fluoro;
B is a bond or is selected from the optionally substituted group consisting of alkyl, cycloalkenyl, cyclopentyl or cyclohexyl;
Z is a bond, \u2014O\u2014 or \u2014R200\u2014O\u2014; and
E is H, or selected from an optionally substituted group consisting of alkoxy, alkenyl, alkyl, cycloalkyl, diazapenyl, piperazinyl and tetrazolyl.
20. The compound, pharmaceutically acceptable salts thereof, metabolites thereof, isomers thereof, or pro-drugs thereof, of claim 19 wherein:
R1 is substituted by alkyl, bromo or chloro; L is NH; B is cyclohexyl; Z is a bond or \u2014R200\u2014O\u2014;
wherein R200 is alkyl;
E is alkoxy or optionally substituted piperazinyl; and Y is NH.
21. The compound of claim 20 wherein the compound is
4-(4-{4-Amino-5-4-(5-chloro-benzoxazol-2-ylamino)-3-fluoro-phenyl-pyrrolyl2,3-dpyrimidin-7-yl}-cyclohexyl-1-methyl-piperazin-2-one
5-4-(5-Chloro-benzooxazol-2-ylamino)-phenyl-7-4-(2-methoxy-ethoxy)-cyclohexyll-7H-pyrrolo2,3-dpyrimidin-4-ylamine; or
5-4-(5-Bromo-7-methyl-benzooxazol-2-ylamino)-phenyl-7-4-(2-methoxyethoxy)-cyclohexyl-7H-pyrrolo2,3-dpyrimidin-4-ylamine.
22. A method of treating a disease or condition in a patient in need thereof, comprising administering a compound according to claim 1 to said patient, wherein the disease or condition is selected from the group consisting of rheumatoid arthritis, thyroiditis, type 1 diabetes, multiple sclerosis, sarcoidosis, inflammatory bowel disease, Crohn’s disease, myasthenia gravis, systemic lupus erythematosus, psoriasis, organ transplant rejection, benign and neoplastic proliferative diseases, lung cancer, breast cancer, stomach cancer, bladder cancer, colon cancer, pancreas cancer, ovarian cancer, prostate cancer, rectal cancer, hematopoietic malignancies, diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, infantile hemangiomas, edema, ascites, effusions, exudates, cerebral edema, acute lung injury, adult respiratory distress syndrome, blood vessel proliferative disorders, fibrotic disorders, mesangial cell proliferative disorders, metabolic diseases, atherosclerosis, restenosis, psoriasis, hemangiomas, myocardial angiogenesis, coronary collaterals, cerebral collaterals, ischemic limb angiogenesis, ischemiareperfusion injury, wound healing, peptic ulcer Helicobacter related diseases, virally-induced angiogenic disorders, fractures, Crow-Fukase syndrome (POEMS), preeclampsia, menometrorrhagia, cat scratch fever, rubeosis, neovascular glaucoma, retinopathies, malignant ascites, von Hippel Lindau disease, hematopoietic cancers, hyperproliferative disorders, burns, chronic lung disease, stroke, polyps, anaphylaxis, chronic inflammation, allergic inflammation, delayed-type hypersensitivity, ovarian hyperstimulation syndrome, angina, ankylosing spondylitis, asthma, congestive obstructive pulmonary disease (COPD), hepatitis C virus (HCV), idiopathic pulmonary fibrosis, myocardial infarct, psoriatic arthritis, restinosis and sciatica.
23. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.
24. A method of making an optionally substituted 2-aminobenzoxazole comprising the step of:
reacting an optionally substituted N-(2-hydroxyphenyl)thiourea with an oxidant and a base but not including a toxic metal until the reaction is substantially complete;
wherein the oxidant is selected from the group consisting of hydrogen peroxide, oxygen, peracids, chlorine, sodium periodate, potassium periodate, tert-butyl peroxide, tert-butyl hypochlorite, sodium perborate, sodium percarbonate, urea hydrogen peroxide adduct, sodium hypochlorite, potassium hypochlorite, sodium hypobromite, potassium hypobromite, sodium bromate, potassium bromate, potassium permanganate and barium manganate; and the base is selected from the group consisting of metal and tetraalkylammonium hydroxides, metal and tetraalkylammonium carbonates, metal and tetraalkylammonium bicarbonates, metal and tetraalkylammonium alkoxides, metal and tetraalkylammonium phosphates, metal and tetraalkylammonium dibasic phophates.