Substituted 4-(indazol-3-yl)phenols

A pharmaceutical composition, which comprises a compound of formulae I or II having the structure

• 15
• wherein
• R1 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S;
• R2, R3, R4, and R5, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CN, —NO2, —CHO, or —CO2R11;
• R6, R7, R8, and R9, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CO2R11, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S wherein the nitrogen or sulfur atoms are optionally oxidized and nitrogen is optionally quaternized;
• R10 is hydrogen, —COR11, —CONHR11, —P(═O)(OH)OR11, or —CO(CH2)nCH(NHR12)CO2R11;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-20 carbon atoms, or arylalkyl of 7-26 carbon atoms;
• R12 is hydrogen or —CO2R11;
• n=0-3,
• or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

A method of treating or inhibiting chronic inflammatory disease in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formulae I or II having the structure

• 16
• wherein
• R1 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S;
• R2, R3, R4, and R5, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CN, —NO2, —CHO, or —CO2R11;
• R6, R7, R8, and R9, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CO2R11, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S wherein the nitrogen or sulfur atoms are optionally oxidized and nitrogen is optionally quaternized;
• R10 is hydrogen, —COR11, —CONHR11, —P(═O)(OH)OR11, or —CO(CH2)nCH(NHR12)CO2R11;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-20 carbon atoms, or arylalkyl of 7-26 carbon atoms;
• R12 is hydrogen or —CO2R11;
• n=0-3,
• or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting rheumatoid arthritis, spondyloarthropathies, osteoarthritis, psoriatic arthritis, or juvenile arthritis in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formulae I or II having the structure

• 17
• wherein
• R1 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S;
• R2, R3, R4, and R5, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CN, —NO2, —CHO, or —CO2R11;
• R6, R7, R8, and R9, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CO2R11, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S wherein the nitrogen or sulfur atoms are optionally oxidized and nitrogen is optionally quaternized;
• R10 is hydrogen, —COR11, —CONHR11, —P(═O)(OH)OR11, or —CO(CH2)nCH(NHR12)CO2R11;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-20 carbon atoms, or arylalkyl of 7-26 carbon atoms;
• R12 is hydrogen or —CO2R11;
• n=0-3,
• or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting inflammatory bowel disease, Crohn's disease, ulcerative colitis, or indeterminate colitis in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formulae I or II having the structure

• 18
• wherein
• R1 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S;
• R2, R3, R4, and R5, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CN, —NO2, —CHO, or —CO2R11;
• R6, R7, R8, and R9, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CO2R11, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S wherein the nitrogen or sulfur atoms are optionally oxidized and nitrogen is optionally quaternized;
• R10 is hydrogen, —COR11, —CONHR11, —P(═O)(OH)OR11, or —CO(CH2)nCH(NHR12)CO2R11;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-20 carbon atoms, or arylalkyl of 7-26 carbon atoms;
• R12 is hydrogen or —CO2R11;
• n=0-3,
• or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting psoriasis in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formulae I or II having the structure

• 19
• wherein
• R1 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S;
• R2, R3, R4, and R5, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CN, —NO2, —CHO, or —CO2R11;
• R6, R7, R8, and R9, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CO2R11, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S wherein the nitrogen or sulfur atoms are optionally oxidized and nitrogen is optionally quaternized;
• R10 is hydrogen, —COR11, —CONHR11, —P(═O)(OH)OR11, or —CO(CH2)nCH(NHR12)CO2R11;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-20 carbon atoms, or arylalkyl of 7-26 carbon atoms;
• R12 is hydrogen or —CO2R11;
• n=0-3,
• or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting asthma or chronic obstructive pulmonary disease in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formulae I or II having the structure

• 20
• wherein
• R1 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S;
• R2, R3, R4, and R5, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CN, —NO2, —CHO, or —CO2R11;
• R6, R7, R8, and R9, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CO2R11, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S wherein the nitrogen or sulfur atoms are optionally oxidized and nitrogen is optionally quaternized;
• R10 is hydrogen, —COR11, —CONHR11, —P(═O)(OH)OR11, or —CO(CH2)nCH(NHR12)CO2R11;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-20 carbon atoms, or arylalkyl of 7-26 carbon atoms;
• R12 is hydrogen or —CO2R11;
• n=0-3,
• or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting stroke, ischemia, or reperfusion injury in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formulae I or II having the structure

• 21
• wherein
• R1 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S;
• R2, R3, R4, and R5, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CN, —NO2, —CHO, or —CO2R11;
• R6, R7, R8, and R9, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CO2R11, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S wherein the nitrogen or sulfur atoms are optionally oxidized and nitrogen is optionally quaternized;
• R10 is hydrogen, —COR11, —CONHR11, —P(═O)(OH)OR11, or —CO(CH2)nCH(NHR12)CO2R11;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-20 carbon atoms, or arylalkyl of 7-26 carbon atoms;
• R12 is hydrogen or —CO2R11;
• n=0-3,
• or a pharmaceutically acceptable salt thereof.

A method of lowering cholesterol, triglycerides, Lp(a), and LDL levels;

• inhibiting or treating hypercholesteremia, hyperlipidemia, cardiovascular disease, atherosclerosis, acute coronary syndrome, peripheral vascular disease, restenosis, or vasospasm in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formulae I or II having the structure
• 22
• wherein
• R1 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S;
• R2, R3, R4, and R5, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CN, —NO2, —CHO, or —CO2R11;
• R6, R7, R8, and R9, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CO2R11, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S wherein the nitrogen or sulfur atoms are optionally oxidized and nitrogen is optionally quaternized;
• R10 is hydrogen, —COR11, —CONHR11, —P(═O)(OH)OR11, or —CO(CH2)nCH(NHR12)CO2R11;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-20 carbon atoms, or arylalkyl of 7-26 carbon atoms;
• R12 is hydrogen or —CO2R11;
• n=0-3,
• or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting Alzheimer's disease, cognitive decline, or senile dementia in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formulae I or II having the structure

• 23
• wherein
• R1 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S;
• R2, R3, R4, and R5, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CN, —NO2, —CHO, or —CO2R11;
• R6, R7, R8, and R9, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CO2R11, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S wherein the nitrogen or sulfur atoms are optionally oxidized and nitrogen is optionally quaternized;
• R10 is hydrogen, —COR11, —CONHR11, —P(═O)(OH)OR11, or —CO(CH2)nCH(NHR12)CO2R11;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-20 carbon atoms, or arylalkyl of 7-26 carbon atoms;
• R12 is hydrogen or —CO2R11;
• n=0-3,
• or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting type ll diabetes in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formulae I or II having the structure

• 24
• wherein
• R1 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S;
• R2, R3, R4, and R5, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CN, —NO2, —CHO, or —CO2R11;
• R6, R7, R8, and R9, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CO2R11, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S wherein the nitrogen or sulfur atoms are optionally oxidized and nitrogen is optionally quaternized;
• R10 is hydrogen, —COR11, —CONHR11, —P(═O)(OH)OR11, or —CO(CH2)nCH(NHR12)CO2R11;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-20 carbon atoms, or arylalkyl of 7-26 carbon atoms;
• R12 is hydrogen or —CO2R11;
• n=0-3,
• or a pharmaceutically acceptable salt thereof.

A method of treating or inhibiting sepsis in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formulae I or II having the structure

• 25
• wherein
• R1 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S;
• R2, R3, R4, and R5, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CN, —NO2, —CHO, or —CO2R11;
• R6, R7, R8, and R9, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6-20 carbon atoms, halogen, trifluoromethyl, —CO2R11, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S wherein the nitrogen or sulfur atoms are optionally oxidized and nitrogen is optionally quaternized;
• R10 is hydrogen, —COR11, —CONHR11, —P(═O)(OH)OR11, or —CO(CH2)nCH(NHR12)CO2R11;
• R11 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-20 carbon atoms, or arylalkyl of 7-26 carbon atoms;
• R12 is hydrogen or —CO2R11;
• n=0-3,
• or a pharmaceutically acceptable salt thereof.