US 2022/0033393 A1 · Compounds for Treating Cannabinoid Toxicity and Acute Cannabinoid Overdose

Abstract

The present invention relates to novel compounds that can act as antidotes for treating “Acute Cannabinoid Overdose” produced by classical cannabinoids such as Δ9-tetrahydrocannabinol (THC) and several synthetic psychoactive cannabinoids (SPCs). The cannabis constituent THC exerts its psychotropic effects via CB1 receptor activation and SPCs mimic the effects of THC with higher potency and severe neurotoxicity. Compounds disclosed in this invention, their enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers, metabolites, N-oxides, salts, solvates, hydrates, isotopic variations and their polymorphic forms can be therapeutically useful in an emergency setting for counteracting the intoxicating effects of acute THC ingestion and SPC overdose. Also, aspects of the invention are concerned with pyrazoles, imidazoles, triazoles, thiazoles, oxazoles, dihydropyrazoles, pyrrolidinones, azetidines, oxyazetidines and azaspiro[3.3]heptanes with unique pharmacokinetic and pharmacodynamic properties for treating “Acute Cannabinoid Overdose”.

A compound represented by the following structural formula

its enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers, isotopic variations, salts, N-oxides, hydrates and polymorphic forms (crystalline or amorphous):
wherein:
R is a heteroaromatic, heterocyclic or heterobicyclic ring;
A, Z5 and B, if present, are independently selected from the group consisting of >C(═O), >N(R6), —C(═Nalkyl), and a direct bond, wherein
R6 is hydrogen, —OH, —S(O2)alkyl, alkyl or substituted alkyl;
R1 and R2 are each independently —(CH2)n—Z;
n is an integer from 0 to about 7;
Z is selected from the group consisting of H, halogen, ester, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, —C(═O)N—O—X1, —C(═N—O—X1)X2, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, O-aroyl, O(CH2)jOX3, O(CH2)jNX1X2, alkyl-CN, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, —CH═CHX8, —C≡CX8;
X1, X2, and X3 are each independently selected from H or alkyl, or NX1X2, alkylamino, di-alkylamino, ammonium salt, quaternary ammonium salt, or a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
X1 and X2 together form part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
X1 and X2 together form part of an imide ring having about 5 to about 6 members,
X3 is selected from the group consisting of H, alkyl, aryl, NO2, NO, (CH2)mCN, hydroxyloweralkyl, and alkyl-NX1X2,
X4, X5, and X6 are each independently selected from H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7, wherein
X7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONX8, SO3H, and COX8, wherein
X8 is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or —CX9═CHX10 wherein
X9 and X10 are each independently H or alkyl;
wherein m is an integer from 0 to 7;
j is an integer from 0 to about 6;
k is an integer from 0 to about 2;
R1 and R2 are each independently —(CH2)n—Z;
n is an integer from 0 to about 7;
Z is selected from the group consisting of carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycyclic ring;
or any above group substituted on at least one available ring atom by an alkyl group;
or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group and a substituted benzhydryl group;
and wherein the connecting point between the —(CH2)n— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom;
or
R1 and R2 are each independently —(CH2)n—Z, wherein
n is an integer from 0 to about 7;
Z is selected from the group consisting of a 5 member unsaturated ring having 0 to 4 independently selected heteroatoms as ring members, a substituted 5 member unsaturated ring having 0 to 4 independently selected heteroatoms as ring members, a 6 member aromatic ring having 0 to 5 independently selected heteroatoms as ring members or a substituted 6 member aromatic ring having 0 to 5 independently selected heteroatoms;
and wherein the connecting point between the —(CH2)n— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom;
or
R1 and R2 are each independently —(CH2)n—Z;
n is an integer from 0 to about 7;
Z is selected from the group consisting of 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofuranyl;
or any above group substituted on at least one available ring atom by an alkyl group;
or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group and a substituted benzhydryl group;
and wherein the connecting point between the —(CH2)n— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom;
or
R1 and R2 are each independently —(CH2)n—Z;
n is an integer from 0 to about 7;
Z is selected from the group consisting of
wherein X and Y are each independently selected from H, halogen, ester, CF3, CF2H, NS, NCS, CN, NO2, NX1X2, —C(═O)N—O—X1, —C(═N—O—X1)X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O— alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, —CH═CHX8, —C≡CX8;
X1, X2, and X3 are each independently H or alkyl, or NX1X2, alkylamino, di-alkylamino, ammonium salt, quaternary ammonium salt, or a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S;
X1 and X2 together form part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
X1 and X2 together form part of an imide ring having about 5 to about 6 members,
X3 is selected from the group consisting of H, alkyl, aryl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X5, and X6 are each independently selected from H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7;
wherein
X7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONX8, SO3H, COX8, wherein
X8 is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or —CX9═CHX10 wherein
X9 and X10 are each independently H or alkyl;
wherein m is an integer from 0 to 7;
j is an integer from 0 to about 6, or
W comprises H or alkyl;
k is an integer from 0 to about 2;
or
R1 and R2 are each independently —(CH2)n—Z;
n is an integer from 0 to about 7;
Z is selected from the group consisting of a carbocyclic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, a carbocyclic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, a heterocyclic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, an heterocyclic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, an aromatic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, an aromatic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, a heteroaromatic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms or a heteroaromatic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms;
or
R1 and R2 are each independently —(CH2)n—Z;
n comprises an integer from 0 to about 7;
Z is selected from the group consisting of an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 3 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 4 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members;
or
R1 and R2 are each independently —(CH2)m-Q1-(CH2)n—Z;
Q1 is selected from the group consisting of NH, O, S, —CH═CH—, —C≡C—, —CO, SO2 or OSO2;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7;
Z is selected from the group consisting of H, halogen, ester, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, —C(═O)N—O—X1, —C(═N—O—X1)X2, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, O-aroyl, O(CH2)jOX3, O(CH2)jNX1X2, alkyl-CN, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O— alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, —CH═CHX8, —C≡CX8;
X1, X2, and X3 are each independently selected from H or alkyl, or NX1X2, alkylamino, di-alkylamino, ammonium salt, quaternary ammonium salt, and a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S;
X1 and X2 together form part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
X1 and X2 together form part of an imide ring having about 5 to about 6 members;
X3 is selected from the group consisting of H, alkyl, NO2, NO, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2;
X4, X5, and X6 are each independently selected from H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7, wherein
X7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONX8, SO3H, and COX8, wherein
X8 is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or —CX9═CHX10, wherein
X9 and X10 are each independently H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6;
and
k is an integer from 0 to about 2;
or
R1 and R2 are each independently -Q2-(CH2)n—Z;
Q2 is optionally present and if present is selected from the group consisting of —CH2—NH, —CH2—O, —CH2—S, —CH2—SO2 and —CH2—OSO2;
n is an integer from 0 to about 7;
Z is selected from the group consisting of H, halogen, ester, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, —C(═O)N—O—X1, —C(═N—O—X1)X2, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, O-aroyl, O(CH2)jOX3, O(CH2)jNX1X2, alkyl-CN, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, —CH═CHX8, and —C≡CX8;
X1, X2, and X3 are each independently selected from H or alkyl, or NX1X2, alkylamino, di-alkylamino, ammonium salt, quaternary ammonium salt, and a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S
X1 and X2 together form part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
X1 and X2 together form part of an imide ring having about 5 to about 6 members,
X3 is selected from the group consisting of H, alkyl, NO2, NO, (CH2)mCN, hydroxyloweralkyl, and alkyl-NX1X2,
X4, X5, and X6 are each independently selected from the group consisting of H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX8, CONX3, OX7, and O-alkyl-X7, wherein
X7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONX8, SO3H and COX8, wherein
X8 is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and —CX9═CHX10 wherein
X9 and X10 are each independently H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6;
and
k is an integer from 0 to about 2;
or
R1 and R2 are each independently —(CH2)m-Q1-(CH2)n—Z;
Q1 is selected from the group consisting of NH, O, S, CH═CH, C≡C, CO, SO2 or OSO2;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7;
and
Z is selected from the group consisting of a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring;
R1 and R2 are each independently —(CH2)m-Q1-(CH2)n—Z;
Q1 is selected from the group consisting of NH, O, S, CH═CH, C≡C, CO, SO2 and OSO2;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7;
Z is selected from the group consisting of a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members;
a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycyclic ring or any above group substituted on at least one available ring atom by an alkyl group or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group;
and wherein the connecting point between the —(CH2)n— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom;
or
R1 and R2 are each independently —(CH2)m-Q1-(CH2)n—Z;
Q1 is selected from the group consisting of N, O, S, CH═CH, C≡C, CO, SO2 and OSO2;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7;
and
Z is selected from the group consisting of a 5 member unsaturated ring having 0 to 4 independently selected heteroatoms as ring members, a substituted 5 member unsaturated ring having 0 to 4 independently selected heteroatoms as ring members, a 6 member aromatic ring having 0 to 5 independently selected heteroatoms as ring members or a substituted 6 member aromatic ring having 0 to 5 independently selected heteroatoms;
and wherein the connecting point between the —(CH2)n— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom;
or
R1 and R2 are each independently —(CH2)m-Q1-(CH2)n—Z;
Q1 is selected from the group consisting of NH, O, S, CH═CH, C≡C, CO, SO2 or OSO2;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7;
and
Z is selected from the group consisting of 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofuranyl;
or any above group substituted on at least one available ring atom by an alkyl group;
or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group and a substituted benzhydryl group;
and wherein the connecting point between the —(CH2)n— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom;
or
R1 and R2 are each independently —(CH2)m-Q1-(CH2)n—Z;
Q1 comprises N, O, S, CH═CH, C≡C, CO, SO2 or OSO2;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7;
Z is selected from the group consisting of
wherein X and Y are each independently selected from H, halogen, ester, CF3, CF2H, N3, NCS, CN, NO2, —C(═O)N—O—X1, —C(═N—O—X1)X2, NX1X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O— alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, —CH═CHX8, and —C≡CX8;
X1, X2, and X3 are each independently selected from H or alkyl, or NX1X2, alkylamino, di-alkylamino, ammonium salt, quaternary ammonium salt, or a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S;
X1 and X2 together form part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
X1 and X2 together form part of an imide ring having about 5 to about 6 members,
X3 is selected from the group consisting of H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X5, and X6 are each independently selected from H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7, wherein
X7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONX8, SO3H and COX8, wherein
X8 is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and —CX9═CHX10 wherein
X9 and X10 are each independently H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6;
k is an integer from 0 to about 2;
and
W is H or alkyl;
R1 and R2 are each independently —(CH2)m-Q1-(CH2)n—Z;
Q1 comprises NH, O, S, CH═CH, C≡C, CO, SO2 or OSO2;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7;
and
Z is selected from the group consisting of an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 4 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members;
R1 and R2 are each independently —(CH2)m-Q1-(CH2)n—Z;
Q1 is selected from the group consisting of NH, O, S, CH═CH, C≡C, CO, SO2 or OSO2;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7;
and
Z is selected from the group consisting of
or
R1 and R2 are each independently -T-(CH2)n—Z;
n is an integer from 0 to about 7;
T is selected from the group consisting of a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring;
Z is selected from the group consisting of H, halogen, ester, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, —C(═O)N—O—X1, —C(═N—O—X1)X2, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, O-aroyl, O(CH2)jOX3, O(CH2)jNX1X2, alkyl-CN, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, —CH═CHX8, —C≡CX8;
X1, X2, and X3 are each independently H or alkyl, or NX1X2, alkylamino, di-alkylamino, ammonium salt, quaternary ammonium salt, and a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S
X1 and X2 together form part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
X1 and X2 together form part of an imide ring having about 5 to about 6 members,
X3 is selected from the group consisting of H, alkyl, NO2, NO, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X5, and X6 are each independently selected from H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7, wherein
X7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONX8, SO3H, and COX8, wherein
X8 is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or —CX9═CHX10, wherein
X9 and X10 are each independently H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6;
and
k is an integer from 0 to about 2;
or
R1 and R2 are each independently -T-(CH2)n—Z;
n is an integer from 0 to about 7;
T is selected from the group consisting of a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring;
and
Z is selected from the group consisting of a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycyclic ring;
or any above group substituted on at least one available ring atom by an alkyl group;
or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group;
and wherein the connecting point between the —(CH2)n— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom;
R1 and R2 are each independently -T-(CH2)n—Z;
n is an integer from 0 to about 7;
T is selected from the group consisting of a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring;
and
Z is selected from the group consisting of 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofuranyl;
or any above group substituted on at least one available ring atom by an alkyl group;
or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group;
and wherein the connecting point between the —(CH2)n— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom;
or
R1 and R2 are each independently -T-(CH2)n—Z;
n is an integer from 0 to about 7;
T is selected from the group consisting of a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring;
Z is selected from the group consisting of
wherein X and Y are each independently selected from H, halogen, ester, CF3, CF2H, NS, NCS, CN, NO2, NX1X2, —C(═O)N—O—X1, —C(═N—O—X1)X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, —CH═CHX8 and —C≡CX8;
X1, X2, and X3 are each independently selected from H or alkyl, or NX1X2, alkylamino, di-alkylamino, ammonium salt, quaternary ammonium salt, and a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S
X1 and X2 together form part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
X1 and X2 together form part of an imide ring having about 5 to about 6 members,
X3 is selected from the group consisting of H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X5, and X6 are each independently selected from H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7 wherein
X7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONX8, SO3H and COX8, wherein
X8 is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or —CX9═CHX10 wherein
X9 and X10 are each independently H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6;
k is an integer from 0 to about 2;
and
W is H or alkyl;
or
R1 and R2 are each independently -T-(CH2)n—Z;
n is an integer from 0 to about 7;
T is selected from the group consisting of a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring;
Z is selected from the group consisting of an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 3 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members;
or
R1 and R2 are each independently -T-(CH2)m-Q1-(CH2)n—Z;
m and n are independently an integer from 0 to about 7;
T is selected from the group consisting of a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring;
Q1 is selected from the group consisting of NH, O, S, CH═CH, C≡C, CO, SO2 or OSO2;
Z is selected from the group consisting of H, halogen, ester, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, —C(═O)N—O—X1, —C(═N—O—X1)X2, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, O-aroyl, O(CH2)jOX3, O(CH2)jNX1X2, alkyl-CN, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, —CH═CHX8 and —C≡CX8;
X1, X2, and X3 are each independently selected from H or alkyl, or NX1X2, alkylamino, di-alkylamino, ammonium salt, quaternary ammonium salt, or a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S
X1 and X2 together form part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
X1 and X2 together form part of an imide ring having about 5 to about 6 members,
X3 is selected from the group consisting of H, alkyl, NO2, NO, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X5, and X6 are each independently selected from H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7, wherein
X7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONX8, SO3H and COX8, wherein
X8 is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and —CX9═CHX10 wherein
X9 and X10 are each independently H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6;
and
k is an integer from 0 to about 2;
or
R1 and R2 are each independently -T-(CH2)m-Q1-(CH2)n—Z;
m and n are independently an integer from 0 to about 7;
T is selected from the group consisting of a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring;
Q1 is selected from the group consisting of NH, O, S, CH═CH, C≡C, CO, SO2 and OSO2;
Z is selected from the group consisting of a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a polycyclic ring, a heteropolycyclic ring;
or any above group substituted on at least one available ring atom by an alkyl group;
or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group;
and wherein the connecting point between the —(CH2)n— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom;
or
R1 and R2 are each independently -T-(CH2)m-Q1-(CH2)n—Z;
m and n are independently an integer from 0 to about 7;
T is selected from the group consisting of a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring;
Q1 is selected from the group consisting of NH, O, S, CH═CH, C≡C, CO, SO2 or OSO2;
Z is selected from the group consisting of 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofuranyl;
or any above group substituted on at least one available ring atom by an alkyl group;
or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group;
and wherein the connecting point between the —(CH2)n— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom;
or
R1 and R2 are each independently -T-(CH2)m-Q1-(CH2)n—Z;
m and n are independently an integer from 0 to about 7;
T is selected from the group consisting of a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring;
Q1 is selected from the group consisting of NH, O, S, CH═CH, C≡C, CO, SO2 and OSO2;
Z is selected from the group consisting of
wherein X and Y are each independently selected from H, halogen, ester, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, —C(═O)N—O—X1, —C(═N—O—X1)X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, —CH═CHX8 and —C≡CX8;
X1, X2, and X3 are each independently selected from H or alkyl, or NX1X2, alkylamino, di-alkylamino, ammonium salt, quaternary ammonium salt, or a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S
X1 and X2 together form part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
X1 and X2 together form part of an imide ring having about 5 to about 6 members,
X3 is selected from the group consisting of H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, and alkyl-NX1X2,
X4, X5, and X6 are each independently selected from H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7, wherein
X7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONX8, SO3H, COX8, wherein
X8 is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or —CX9═CHX10, wherein
X9 and X10 are each independently H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6;
k is an integer from 0 to about 2;
and
W comprises H or alkyl;
or
R1 and R2 are each independently -T-(CH2)m-Q1-(CH2)n—Z;
m and n are independently an integer from 0 to about 7;
T is selected from the group consisting of a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring;
Q1 is selected from the group consisting of NH, O, S, CH═CH, C≡C, CO, SO2 and OSO2;
and
Z is selected from the group consisting of an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 3 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members;
or
R1 and R2 are each independently -T-(CH2)m-Q1-(CH2)n—Z;
T is selected from the group consisting of a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring;
m and n are independently an integer from 0 to about 7;
Q1 is selected from the group consisting of NH, O, S, CH═CH, C≡C, CO, SO2 and OSO2;
Z is
wherein E is selected from the group consisting of a C1 to about C4, linear or branched alkyl group, a phenyl group, a substituted phenyl group, a benzyl group or a substituted benzyl group;
or
R1 and R2 are each independently -T-(CH2)m-Q1-(CH2)n—Z;
T is selected from the group consisting of a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring;
m and n are independently an integer from 0 to about 7;
Q1 is selected from the group consisting of NH, O, S, CH═CH, C≡C, CO, SO2 and OSO2;
Z is selected from the group consisting of
wherein k is an integer from 1 to about 5;
A1 and A2 are each independently selected from a C1 to about C4 alkyl group, a phenyl group or a substituted phenyl group;
or
R1 and R2 are each independently -T-(CH2)m-Q-(CH2)n—(C(X1)(X2))p—Z;
m, n and p are each independently an integer from 0 to about 7;
T is selected from the group consisting of an aromatic ring having 5 to about 8 carbon atoms as ring members or a heteroaromatic ring having 5 to about 8 ring members;
Q is C≡C;
and
Z is selected from the group consisting of CN, alkyl-CN, OH, CONX1X2 or ONO2;
or
R1 is represented by the formula XII
wherein;
R5 and R6 are each independently —(CH2)—Z or -T-(CH2)-Q-(CH2)—Z or -T-(CH2)n—Z;
T an aromatic or a heteroaromatic ring having 5 to about 8 carbon atoms as ring members;
Q is selected from the group consisting of NH, O, S, CH═CH, C≡C, CO, SO2 or OSO2;
m and n are independently an integer from 0 to about 7;
Z is selected from the group consisting of H, halogen, ester, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, —C(═O)N—O—X1, —C(═N—O—X1)X2, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, O-aroyl, O(CH2)jOX3, O(CH2)jNX1X2, alkyl-CN, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, —CH═CHX8 and —C≡CX8;
X1, X2, and X3 are each independently selected from H or alkyl, or NX1X2, alkylamino, di-alkylamino, ammonium salt, quaternary ammonium salt, or a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S
X1 and X2 together form part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
X1 and X2 together form part of an imide ring having about 5 to about 6 members,
X3 is selected from the group consisting of H, alkyl, aryl, NO2, NO, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X5, and X6 are each independently selected from H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7, wherein
X7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONX8, SO3H and COX8, wherein
X8 is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and —CX9═CHX10 herein
X9 and X10 are each independently H or alkyl;
wherein m is an integer from 0 to 7;
j is an integer from 0 to about 6, or
k is an integer from 0 to about 2
R3 is selected from the group consisting of a carbocyclic ring having about 4 to about 7 members, a heterocyclic ring having about 4 to about 7 members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring;
R3 is
wherein G is selected from the group consisting of CH, C(CH3), C(CN) and N;
L, K and J are each independently selected from (CH2)n, (CH3)2, C═O, O, —CHOH, C(CH3)OM1, C(CH2)n(X)Y, NM1, SO2SO and S;
n is an integer from 0 to about 7;
M1 is H, alkyl or C(O)M2, wherein
M2 is selected from the group consisting of H, alkyl, NM3M4, OM5, and
M3, M4 and M5 are independently selected from H, OH or alkyl, and
X and Y are each independently selected from H, halogen, ester, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, —C(═O)N—O—X1, —C(═N—O—X1)X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX8, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, —CH═CHX8 and —C≡CX8;
X1, X2, and X3 are each independently selected from H or alkyl, or NX1X2, alkylamino, di-alkylamino, ammonium salt, quaternary ammonium salt, or a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S;
X1 and X2 together form part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
X1 and X2 together form part of an imide ring having about 5 to about 6 members,
X3 is selected from the group consisting of H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X5, and X6 are each independently selected from H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, or O-alkyl-X7, wherein
X7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONX8, SO3H, COX8, wherein
X8 is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or —CX9═CHX10 wherein
X9 and X10 are each independently H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6;
and
k is an integer from 0 to about 2;
or
R3 is
wherein G, L and J are each independently CH or N;
or
R3 is selected from the group consisting of
wherein X and Y are each independently selected from H, halogen, ester, CF3, CF2H, NS, NCS, CN, NO2, NX1X2, —C(═O)N—O—X1, —C(═N—O—X1)X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, —CH═CHX8 and —C≡CX8;
X1, X2, and X3 are each independently selected from H or alkyl, or NX1X2, alkylamino, di-alkylamino, ammonium salt, quaternary ammonium salt, or a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S;
X1 and X2 together form part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
X1 and X2 together form part of an imide ring having about 5 to about 6 members,
X3 is selected from the group consisting of H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X5, and X6 are each independently selected from H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, or O-alkyl-X7, wherein
X7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONX8, SO3H, COX8, wherein
X8 is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or —CX9═CHX10, wherein
X9 and X10 each independently comprise H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6;
k is an integer from 0 to about 2;
and
W comprises H or alkyl;
or
R3 is selected from the group consisting of a carbocyclic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, a carbocyclic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, a heterocyclic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, a heterocyclic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, an aromatic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, an aromatic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, a heteroaromatic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms or a heteroaromatic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms;
R4 is selected from the group consisting of H, halogen, ester, CF3, CF2H, N3, NCS, CN, NO2, phenyl, NX1X2, —C(═O)N—O—X1, —C(═N—O—X1)X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, —CH═CHX8, —C≡CX8;
X1, X2, and X3 are each independently selected from H or alkyl, or NX1X2, alkylamino, di-alkylamino, ammonium salt, quaternary ammonium salt, or a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S;
X1 and X2 together form part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
X1 and X2 together form part of an imide ring having about 5 to about 6 members,
X3 is selected from the group consisting of H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X5, and X6 are each independently selected from H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, or O-alkyl-X7, wherein
X7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONX8, SO3H, COX8, wherein
X8 is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or —CX9═CHX10, wherein
X9 and X10 are each independently H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6;
and
k is an integer from 0 to about 2;
or
R4 is selected from the group consisting of a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring;
or
R4 is selected from the group consisting of
R4 is —(CH2)d—Z;
d is an integer from 1 to about 6;
Z is selected from the group consisting of H, esterm halogen, CF3, CF2H, N3, NCS, CN, NO2, phenyl, NX1X2, —C(═O)N—O—X1, —C(═N—O—X1)X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, —CH═CHX8, —C≡CX8;
X1, X2, and X3 are each independently selected from H or alkyl, or NX1X2, alkylamino, di-alkylamino, ammonium salt, quaternary ammonium salt, or a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S;
or
X1 and X2 together form part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
X1 and X2 together form part of an imide ring having about 5 to about 6 members,
X3 is selected from the group consisting of H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NX1X2,
X4, X5, and X6 are each independently selected from H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, or O-alkyl-X7, wherein
X7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONX8, SO3H, COX8, wherein
X8 is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or —CX9═CHX10, wherein
X9 and X10 are each independently H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6;
and
k is an integer from 0 to about 2;
or
R4 is —CH2OH or —CH2Oalkyl;
or
R4 is —(CH2)d—Z;
d is an integer from 1 to about 6;
and
Z is selected from the group consisting of a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycyclic ring;
or any above group substituted on at least one available ring atom by an alkyl group;
or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group;
and wherein the connecting point between the —(CH2)d— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom;
or
R4 is —(CH2)d—Z;
d is an integer from 1 to about 6;
and
Z is selected from the group consisting of 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofuranyl;
or any above group substituted on at least one ring atom by an alkyl group;
or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group;
and wherein the connecting point between the —(CH2)d— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom;
or
R4 is —(CH2)m-Q1-(CH2)n—Z;
Q1 is selected from the group consisting of NH, O, S, CH═CH, C≡C, CO, SO2 or OSO2;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7;
Z is selected from the group consisting of H, halogen, ester, CF3, CF2H, N3, NCS, CN, NO2, phenyl, NX1X2, —C(═N—O—X1) X1, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, —CH═CHX8, —C≡CX8;
X1, X2, and X3 are each independently selected from H or alkyl, or NX1X2, alkylamino, di-alkylamino, ammonium salt, quaternary ammonium salt, or a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S;
or
X1 and X2 together form part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
X1 and X2 together form part of an imide ring having about 5 to about 6 members,
X3 is selected from the group consisting of H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, and alkyl-NX1X2,
X4, X5, and X6 are each independently selected from H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, or O-alkyl-X7, wherein
X7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONX8, SO3H, COX8, wherein
X8 is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or —CX9═CHX10, wherein
X9 and X10 are each independently H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6;
and
k is an integer from 0 to about 2;
or
R4 is —(CH2)m-Q1-(CH2)n—Z;
Q1 is selected from the group consisting of NH, O, S, CH═CH, C≡C, CO, SO2 or OSO2;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7;
and
Z is selected from the group consisting of a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members;
a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycyclic ring;
or any above group substituted on at least one available ring atom by an alkyl group;
or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group;
and wherein the connecting point between the —(CH2)n— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom;
or
R4 is —(CH2)m-Q1-(CH2)n—Z;
Q1 is selected from the group consisting of NH, O, S, CH═CH, C≡C, CO, SO2 or OSO2;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7;
Z is selected from the group consisting of 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofuranyl;
or any above group substituted on at least one available ring atom by an alkyl;
or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group;
and wherein the connecting point between the —(CH2)n— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom;
or
R4 is —(CH2)m-Q1-(CH2)n—Z;
Q1 is selected from the group consisting of NH, O, S, CH═CH, C≡C, CO, SO2 or OSO2;
m is an integer from 1 to about 7;
n is an integer from 0 to about 7;
Z is selected from the group consisting of
wherein X and Y are each independently selected from H, halogen, ester, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, —C(═O)N—O—X1, —C(═N—O—X1) X1, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNX1X2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, —CH═CHX8, —C≡CX8;
X1, X2, and X3 are each independently selected from H or alkyl, or NX1X2, alkylamino, di-alkylamino, ammonium salt, quaternary ammonium salt, or a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S;
X1 and X2 together form part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
X1 and X2 together form part of an imide ring having about 5 to about 6 members,
X3 is selected from the group consisting of H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, and alkyl-NX1X2,
X4, X5, and X6 are each independently selected from H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7, wherein
X7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONX8, SO3H, COX8, wherein
X8 is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or —CX9═CHX10, wherein
X9 and X10 are each independently H or alkyl;
m is an integer from 0 to 7;
j is an integer from 0 to about 6;
k is an integer from 0 to about 2;
W is H or alkyl;
A is a direct bond;
B is N(R5);
and
either of R1 and R2 is phenyl [optionally substituted with one more halogen atoms, (C1-C6) alkyl, (C1-C6) alkoxy, trifluoromethyl, cyano, nitro, (C1-C6) alkyl sulfonyl, (C1-C6) alkyl sulfonyl amino, (C1-C6) alkyl carbonyl-amino, (C1-C6) alkyl amino-carbonyl-amino or phenyl], (C2-C6) alkyl, cyclohexyl [optionally substituted with (C1-C6) alkyl, (C1-C6) alkoxy, trifluoromethyl, cyano or one or more fluorine atoms], 1-napthyl or 2-napthyl [optionally substituted with one or more halogen atoms, (C1-C6) alkyl, (C1-C6) alkoxy, trifluoromethyl or cyano], benzyl [optionally substituted on the phenyl ring with one or more halogen atoms, (C1-C6) alkyl, (C1-C6) alkoxy, trifluoromethyl or cyano], a 5- to 10-membered saturated or unsaturated heterocyclic radical [optionally substituted with one or more fluorine atoms, (C1-C6) alkyl, (C1-C6) alkoxy, trifluoromethyl or cyano] and a 5- to 10-membered aromatic monocyclic or bicyclic heterocyclic radical [optionally substituted with one more halogen atoms, (C1-C6) alkyl, (C1-C6) alkoxy, trifluromethyl, cyano, nitro or phenyl] and R3 is any above described variation;
then R4 can not be H, (C1-C6) alkyl, benzyl, chloro, or bromo;
or
A is a direct bond;
B is N(R5);
and
either R1 or R2 is phenyl, thienyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl or any above group substituted with 1, 2, 3 or 4 substituents which can be the same or different, selected from C1-3 alkyl, C1-3 alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C1-2)-amino, mono- or dialkyl (C1-2)-amido, (C1-3)-alkoxycarbonyl, carboxyl, cyano, carbomyl, acetyl and naphthyl;
and R3 is any above described variation;
then R4 cannot be H, halogen, CN, carbomyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl, methylsulfanyl, branched or unbranched C1-4 alkyl group, which C1-4 alkyl group may be substituted with 1 to 3 fluoro atoms or with a single bromo, chloro, iodo, cyano or hydroxy group.

484 more elements

Compounds for Treating Cannabinoid Toxicity and Acute Cannabinoid Overdose

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Compounds for Treating Cannabinoid Toxicity and Acute Cannabinoid Overdose

Life of this patent

Abstract

Claims20