MXPA05009576A - Fused tri and tetra-cyclic pyrazole kinase inhibitors. - Google Patents

Fused tri and tetra-cyclic pyrazole kinase inhibitors.

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Publication number
MXPA05009576A
MXPA05009576A MXPA05009576A MXPA05009576A MXPA05009576A MX PA05009576 A MXPA05009576 A MX PA05009576A MX PA05009576 A MXPA05009576 A MX PA05009576A MX PA05009576 A MXPA05009576 A MX PA05009576A MX PA05009576 A MXPA05009576 A MX PA05009576A
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Mexico
Prior art keywords
dihydroindeno
pyrazol
methoxy
hydroxy
biphenyl
Prior art date
Application number
MXPA05009576A
Other languages
Spanish (es)
Inventor
Tao Zhi-Fu
Original Assignee
Abbott Lab
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Publication date
Priority claimed from US10/792,564 external-priority patent/US7320986B2/en
Application filed by Abbott Lab filed Critical Abbott Lab
Publication of MXPA05009576A publication Critical patent/MXPA05009576A/en

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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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Abstract

Compounds having the formula (I) (I), are useful for inhibiting protein kinases. Also disclosed are methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.

Description

INHIBITORS OF PIRAZOL-CIN ASA TRICICLICOS AND TETRACICUCOS, FUSIONADOS TECHNICAL FIELD The present invention relates to fused pyrazoles, to methods for preparing the compounds, to compositions containing the compounds, and to methods of treatment using the compounds.
BACKGROUND OF THE INVENTION Protein kinases are important in the progression of many disease states that are induced by the inappropriate proliferation of cells. These kinases are usually found to be over-regulated in many hyperproliferative states, such as cancer. These kinases may also be important in cell signaling, where their inappropriate activation induces cells to proliferate (eg, EGFR, ERBB2, VEGFR, FGFR, PDGFR, c-Met, IGF-1R, RET, TIE2). Alternatively, the kinases may be involved in the signal transduction within the cells (eg, c-Src, PKC, Akt, PKA, c-Abl, PDK-1), where these signal transduction genes are proto- recognized oncogenes. Many of these kinases control the progression of the cell cycle near the transition G1-S (for example, Cdk2, Cdk-4), at the G2-M transition (for example, Wee1, Myt1, Chk1, Cdc2), or at the spindle check point (Plk, Auroral or 2, Bubl or 3). In addition, the kinases are intimately linked to the DNA damage response (eg, ATM, ATR, Chk1, Chk2). The de-regulation of these cellular functions: cell signaling, signal transduction, cell cycle control, and DNA repair are all important aspects of hyperproliferative diseases, particularly cancer. Therefore, the pharmacological modulation of one or more kinases could be useful in reducing or stopping diseases that are induced by the inappropriate proliferation of cells, such as cancer.
COMPENDIUM OF THE INVENTION In the main embodiment, the present invention relates to positions of the formula (I): or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, wherein: Ri and R2 are independently selected from the group consisting of hydrogen, alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alcoxialcoxialquinilo, UUO alcoxialq, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, arylsulfinyl, arylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cicloalquenilalcoxi, cycloalkylalkoxy, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkyloxy, formyl, haloalkoxy, haloalcoxialquinilo, haloalkyl halogen, heteroarylalkoxy, heteroarylalkoxyalkoxy, heteroarylalkyl, heteroarylalkynyl, heteroaryloxyalkyl, heterocycle, heterocycloalkoxy, heterocycloalkyl, heterocyclecarbonyl, heterocycle, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, hydroxysulfonyl, hydroxysulfonylalkyl, mercapto, mercaptoalkyl, nitro, -NRARB, (NRARB) alkoxy, NRARB) alkyl, (NRARB) alkynyl, (NRARB) carbonyl, (N RARB) carbonylalcoxy, (NRARB) carbonylalkyl, and (NRGRH) alkoxy; or Ri and R2 together with the carbon atoms to which they are attached form a non-aromatic ring of 5, 6, 7 or 8 members, wherein the ring contains 0, 1 or 2 heterogeneous atoms selected from the group consisting of O, N (RC), and N (RD) wherein the non-aromatic ring is substituted with 0, 1 or 2 substituents selected from the group consisting of alkyl and hydroxy; R3 is selected from the group consisting of hydrogen, alkenyl, alkenyloxy, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NRERF, (NRERF) alkoxy (NRERF) alkyl, (NRERF) carbonyl, and (NRE F) carbonylalkyl; R 4 is selected from the group consisting of hydrogen, alkoxycarbonyl, alkylcarbonylalkoxy, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, halogen, heteroaryl, heteroarylalkoxy, heteroarylalkyl, heteroaryloxy, heterocycle, heterocycloalkoxy, heterocycloalkyl, heterocycle, hydroxy, -NRERF, and (NRERF) carbonyl; R5 is absent or selected from the group hydrogen, alkoxycarbonyl, carboxy, halogen, heteroaryl, hydroxy, nitro, -NRERF, and (NRERF) carbonyl; or R4 and R5, together with the atoms to which they are attached, form a phenyl ring optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl , alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NRGRH, (NRGRH) alkoxy, (NRGRH) aikil, (NRGRH) carbonyl, and (NRGRH) sulfonyl; or R4 and 5, together with the carbon atoms to which they are attached, form a heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, -NRGRH, (NRcR ^ alkoxy, (N RGRH) alkyl, and (NRGRH) carbonyl; provided that when R5 is hydrogen, R4 is other than hydrogen, Re is selected from the group consisting of hydrogen, lower alkoxy, lower alkyl, halogen, hydroxy, and -NRERF, Ra and RB are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkyl alkoxycarbonyl, alkoxysulfonyl, alcoxisulfonilalquilo, alcoxisulfonilalquilcarbonilo, alkyl, alkylcarbonyl, alkynyl, aryl, carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkylcarbonyl, cycloalkylcarbonyl, cicloalquilcarbonilal Uilo, ci carbonyl oalquilcarboniialquil, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, heterocyclic o-alkylcarbonyl, heterocyclecarbonyl, heterocyclecarbonylalkyl, heterocyclecarbonylalkylcarbonyl, hydroxyalkyl, hydroxyalkylcarbonyl, hydroxysulfonyl, hydroxysulfonylalkyl, hydroxysulfonylalkylcarbonyl, (NRERF) alkyl, (RERF) alkylcarbonyl, (RERF) carbonyl, (RERF) carbonylalkyl, (NRERF) carbonylalkylcarbonyl, (NRERF) sulfonyl, (NRERF) ) sulfonylalkyl, and (NRERF) sulfonylalkylcarbonyl; RC and D are independently selected from the group that consists of hydrogen, alkoxycarbonyl, alkyl, and alkylcarbonyl; RE and RF are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, cycloalkyl, heteroarylalkyl, and hydroxyalkyl; ??, X3, and X4 are independently selected from the group consisting of CH and N; X2 is selected from the group consisting of CH (R7), C (R7) (R8), C = 0, N (R3); X5 is selected from the group consisting of C and N; R7 is selected from the group consisting of hydrogen, alkoxy, alkyl, hydroxy, lower alkoxy, lower alkyl, and hydroxyalkyl; and R8 is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, and hydroxyalkyl. In another embodiment, the present invention relates to pharmaceutical compositions comprising a compound of the formula (I), or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier. In another embodiment, the present invention relates to a method for inhibiting protein kinases in a patient with the recognized need for said treatment, comprising administering to the patient a therapeutically effective amount of a compound of the formula (I), or a therapeutically salt thereof. acceptable of it. In another embodiment, the present invention relates to a method for the treatment of cancer in a patient with the The recognized need for said treatment, which comprises administering to the patient a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION In the main embodiment, the present invention relates to compounds of the formula (I): (0. or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, wherein: or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, wherein: Ri and R2 are independently selected from the group consisting of hydrogen, alkenyl, alkenyloxy alkoxy, alkoxyalkoxy, alkoxyalkoxyalkynyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, arylsulfinyl, arylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cycloalkenylalkoxy, cycloalkylalkoxy, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkyloxy, formyl, haloalkoxy, haloalkoxyalkynyl, haloalkyl, halogen, heteroarylalkoxy, heteroarylalkoxyalkoxy, heteroarylalkyl, heteroarylalkynyl, heteroaryloxyalkyl, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbony, heterocycle, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, hydroxysulfonyl, hydroxysulfonylalkyl, mercapto, mercaptoalkyl, nitro, -NRARB >; (NRARB) alkoxy, (NRARB) alkyl, (NRARB) alkynyl, (NRARB) carbonyl, (N RARB) carbonylalkoxy, (N RARB) carbonylalkyl, and (NRGRH) alkoxy; or R'i and R2 together with the carbon atoms to which they are attached form a non-aromatic ring of 5, 6, 7 or 8 members, wherein the ring contains 0, 1 or 2 heterogeneous atoms selected from the group consisting of O, N (RC), and N (RD) wherein the non-aromatic ring is substituted with 0, 1 or 2 substituents selected from the group consisting of alkyl and hydroxy; R3 is selected from the group consisting of hydrogen, alkenyl, alkenyloxy, alkoxy, alkoxyalkyl, alkoxycarbonyl, akoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NRERF, (NRERF) alkyl, (NRERF) carbonyl, and (NRERF) carbonylalkyl; R 4 is selected from the group consisting of hydrogen, alkoxycarbonyl, alkylcarbonylalkoxy, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, halogen, heteroaryl, heteroarylalkoxy, heteroarylalkyl, heteroaryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocycleoxy, hydroxy, -NRERF, and (NRERF) carbonyl; R5 is absent or selected from the group hydrogen, alkoxycarbonyl, carboxy, halogen, heteroaryl, hydroxy, nitro, -NRERF, and (NRERF) carbonyl; or 4 and 5, together with the atoms to which they are attached, form a phenyl ring optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl , alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NRGRH, (NRGRH) alkoxy, (NRGRH) alkyl, (NRGRH) carbonium, and (NRGRH) sulfonyl; or R4 and R5. together with the carbon atoms to which they are attached, they form a heterocycle optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy , cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, -NRGRH, (NRGRH) alkoxy, (NRGRH) alkyl, and (NRGRH) carbonyl; provided that when R5 is hydrogen, R4 is different from hydrogen; R6 is selected from the group consisting of hydrogen, lower alkoxy, lower alkyl, halogen, hydroxy, and -NRERF; RA and RB are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkylcarbonyl, alkoxysulfonyl, alkoxysulfonylalkyl, alkoxysulfonylalkylcarbonyl, alkyl, alkylcarbonyl, alkynyl, aryl, carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkylcarbonyl, cycloalkylcarbonyl, carbonylalkyl cycloalkyl, cicloalquilcarbonilalquilcarbonilo, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, heterocycloalkylcarbonyl, heterocyclecarbonyl, heterocyclecarbonylalkyl, heterociclocarbonilalquilcarbonilo, hydroxyalkyl, hydroxyalkylcarbonyl, hydroxysulfonyl, hidroxisulfonilalquilo, hidroxisulfonilalquilcarbonilo, (RERF) alkyl, (RERF) alkylcarbonyl, (NRERF) carbonyl, (NRERF ) carbonylalkyl, (NRERF) carbonylalkylcarbonyl, (NRERF) sulfonyl, (N RERF) sulfonylalkyl, and (NRERF) sulfonylalkylcarbonyl; Re and RD are independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, and alkylcarbonyl; E and RF are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, cycloalkyl, heteroarylalkyl, and hydroxyalkyl; X, X3, and X4 are independently selected from the group that consists of CH and N; X2 is selected from the group consisting of CH (R7), C (R7) (R8), C = 0, N (R8); X5 is selected from the group consisting of C and N; R7 is selected from the group consisting of hydrogen, alkoxy, alkyl, hydroxy, lower alkoxy, lower alkyl, and hydroxyalkyl; and R8 is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, and hydroxyalkyl. In another embodiment, the present invention relates to a compound of the formula (I) wherein Xi, X3, and X4 are CH; X2 is CH (R); X5 is C; R-, and R2 are independently selected from the group consisting of hydrogen, alkenyloxy, alkoxy, alkoxyalkyl, heterocycloalkyl, hydroxy, hydroxyalkyl, (NRARB) alk, and (NRARB) carbonyl; R3 is hydrogen; R 4 is selected from the group consisting of hydrogen, alkoxycarbonyl, aryl, carboxy, cyano, heteroaryl, hydroxy, -NRERF >; and (NRERF) carbonyl; R5 is selected from the group consisting of hydrogen and -NRERF; Re is hydrogen; R7 is hydrogen; RA is selected from the group consisting of hydrogen and alkyl; RB is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroarylalkyl, heterocycle, and hydroxyalkyl; RE is selected from the group consisting of hydrogen and alkyl; and RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl. In another embodiment, the present invention relates to a compound of the formula (1) wherein X-i, X3, and X4 are CH; X2 is CH (R7); X5 is C; R-? and R2 are independently selected from the group consisting of hydrogen, alkenyloxy, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, (NRARB) alkyl, (NRARB) carbonyl, and heterocycloalkyl, wherein the heterocycloalkyl heterocycle is selected from the group consisting of 4-morpholinyl and 4-hydroxy-1-piperidinyl; R3 is hydrogen; R 4 is selected from the group consisting of hydrogen, alkoxycarbonyl, carboxy, cyano, heteroaryl, hydroxy, -NRERF (NRERF) carbonyl, and aryl, wherein the aryl is phenyl substituted with 1, 2 or 3 substituents selected from the group consisting of alkoxy, formyl, halogen, hydroxy, hydroxyalkyl, and -NRQRH; R5 is selected from the group consisting of hydrogen and NRERFI R6 is hydrogen; R7 is hydrogen; RA is selected from the group consisting of hydrogen and alkyl; RB is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, and cycloalkyl, wherein the cycloalkyl is cyclohexyl substituted with a substituent selected from the group consisting of alkyl and hydroxy; RE is selected from the group consisting of hydrogen and alkyl; and RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl. In another embodiment, the present invention relates to a compound of the formula (I) wherein X, X3, and X4 are CH; X2 is CH (R7); X5 is C; R-i, R3, R5, and R6 are hydrogen; R2 is selected from the group consisting of alkenyloxy, alkoxyalkyl, hydroxy, hydroxyalkyl, (NRARB) alkyl, (NRARB) carbonium, and heterocycloalkyl, wherein the heterocycle of the heterocycloalkyl is selects from the group consisting of 4-morpholinyl and 4-hydroxy-1-piperidinyl; R 4 is selected from the group consisting of alkoxycarbonyl, carboxy, cyano, hydroxy, and (NRERF) carbonyl; R7 is hydrogen; RA is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl, wherein the cycloalkyl is cyclohexyl substituted with a substituent selected from the group consisting of alkyl and hydroxy; and RB, RE and RF are hydrogen. In another embodiment, the present invention relates to a compound of the formula (I) wherein X x, X 3, and X 4 are CH; X2 is CH (R7); X5 is C; R R3, R5, and R6 are hydrogen; R2 is selected from the group consisting of hydrogen, alkenyloxy, alkoxyalkyl, hydroxy, hydroxyalkyl, (NRARB) alkyl, (NRARB) carbonyl, and heterocycloalkyl, wherein the heterocycle of the heterocycloalkyl is selected from the group consisting of 4-morpholinyl and 4- hydroxy-1-piperidinyl; R 4 is aryl wherein the aryl is phenyl substituted with 1,2, or 3 substituents selected from the group consisting of alkoxy, formyl, halogen, hydroxy, hydroxyalkyl, and -NRGRH; R7 is hydrogen; RA is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl, wherein the cycloalkyl is cyclohexyl substituted with 1 substituent selected from the group consisting of alkyl and hydroxy: and RB, RE, and F are hydrogen. In another embodiment, the present invention relates to a compound of the formula (I) wherein X X3, and X4 are CH; X2 is CH (R7); X5 is C; R-i, R3, R5, and R6 are hydrogen; R2 is selected from the group consisting of hydrogen, alkenyloxy, alkoxyalkyl, hydroxy, hydroxyalkyl, (NRA B) alkyl, (NRARB) carbonyl, and heterocycloalkyl, wherein the heterocycloalkyl heterocycle is selected from the group consisting of 4-morpholinyl and 4-hydroxy-1-piperidinyl; R 4 is heteroaryl; R7 is hydrogen; RA is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl, wherein the cycloalkyl is cyclohexyl substituted with 1 substituent selected from the group consisting of alkyl and hydroxy; and RB is selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention relates to a compound of the formula (I) wherein X3, and X4 are CH; X2 is CH (R7); X5 is C; R-, R3, R5, and R6 are hydrogen; R2 is alkenyloxy; R is heteroaryl wherein the heteroaryl is tetraazolyl; and R7 is hydrogen. In another embodiment, the present invention relates to a compound of the formula (I) wherein Xi, X3, and X4 are CH; X2 is CH (R7); X5 is C; R ,, R3, and R6 are hydrogen; R 2 is selected from the group consisting of alkenyloxy, alkoxyalkyl, hydroxy, hydroxyalkyl, (NRARB) alkyl, (NRARB) carbonyl, and heterocycloalkyl, wherein the heterocycle of the heterocycloalkyl is selected from the group consisting of 4-morpholinyl and 4-hydroxy 1-piperidinyl; R is selected from the group consisting of hydrogen, carboxy, and cyano; R5 is selected from the group consisting of alkoxycarbonyl, carboxy, hydroxy, hydroxyalkyl, -NRERF, and (NRERF) carbonyl; R7 is hydrogen; RA is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl, wherein the cycloalkyl is cyclohexyl substituted with 1; substituent selected from the group consisting of alkyl and hydroxy; RB is selected from the group consisting of hydrogen and alkyl; RE is selected from the group consisting of hydrogen and alkyl; and RF is selected from the group consisting of hydrogen, alkyl, and alkyl carbonyl. In another embodiment, the present invention relates to a compound of the formula (I), wherein X x, X 3, and X 4 are CH; X2 is CH (R7); X5 is C; R1: R3, and R6 are hydrogen; R2 is selected from the group consisting of alkenyloxy, alkoxyalkyl, hydroxy, hydroxyalkyl, (NRAREs) alkyl, (NRARB) carbonyl, and heterocycloalkyl, wherein the heterocycloalkyl heterocycle is selected from the group consisting of 4-morpholinyl and 4-hydroxy 1-piperidinyl; R4 is selected from the group consisting of hydrogen, carboxy, and cyano; R5 is -NRERF; RA is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl, wherein the cycloalkyl is cyclohexyl substituted with 1 substituent selected from the group consisting of alkyl and hydroxy; RB is selected from the group consisting of hydrogen and alkyl; RE is selected from the group consisting of hydrogen and alkyl; and RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl. In another embodiment, the present invention relates to a compound of the formula (I) wherein Xi, X3, and X4 are CH; X2 is CH (R7); X5 is C; R2, Rs, Rs, and Re are hydrogen; R1 is selected from the group consisting of alkenyloxy, alkoxyalkyl, hydroxy, hydroxyalkyl, (NRARB) alkyl, (NRARB) carbonyl, and heterocycloalkyl, wherein the heterocycloalkyl heterocycle is selected from the group consisting of 4-morpholinyl and 4-hydroxy-1-piperidinyl; R 4 is selected from the group consisting of alkoxycarbonyl, carboxy, cyano, hydroxy, hydroxyalkyl, -NRERF, and (NRERF) carbonyl; R7 is hydrogen; RA is selected from the group consisting of alkyl, hydroxyalkyl, and cycloaikyl, wherein the cycloaikyl is cyclohexyl substituted with 1 substituent selected from the group consisting of alkyl and hydroxy; RB is selected from the group consisting of hydrogen and alkyl; RE is selected from the group consisting of hydrogen and alkyl; and RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl. In another embodiment, the present invention relates to a compound of the formula (I) wherein Xi, X3, and X4 are CH; X2 is CH (R7); X5 is C; R2, R3, R5, and Re are hydrogen; R- is selected from the group consisting of alkenyloxy, alkoxyalkyl, hydroxy, hydroxyalkyl, (NRARB) alkyl, (NRARB) carbonyl, and heterocycloalkyl, wherein the heterocycloalkyl heterocycle is selected from the group consisting of 4-morpholinyl and 4- hydroxy-1-piperid'mile; R 4 is aryl wherein the aryl is phenyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkoxy, formyl, halogen, hydroxy, hydroxyalkyl, and -NRGRH; R7 is hydrogen; RA is selected from the group consisting of alkyl, hydroxyalkyl, and cycloaikyl, wherein the cycloaikyl is cyclohexyl substituted with 1 substituent selected from the group consisting of alkyl and hydroxy; RB is selected from the group consisting of hydrogen and alkyl; RE is selected from the group consisting of hydrogen and alkyl; and RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl. In another embodiment, the present invention relates to a compound of the formula (I) wherein X-, X3, and X4 are CH; X2 is CH (R7); X5 is C; R2, R3, and F6 are hydrogen; Ri is selected from the group consisting of alkenyloxy, alkoxyalkyl, hydroxy, hydroxyalkyl, (NRARB) alkyl, (NRARB) carbonyl, and heterocycloalkyl, wherein the heterocycle of the heterocycloalkyl is selected from the group consisting of 4-morpholinyl and 4-hydroxy 1-piperidinyl; R4 is selected from the group consisting of hydrogen, carboxy, and cyano; R5 is selected from the group consisting of alkoxycarbonyl, carboxy, hydroxy, hydroxyalkyl, -NRERF, and (NRERF) carbonyl; R7 is hydrogen; RA is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl, wherein the cycloalkyl is cyclohexyl substituted with 1 substituent selected from the group consisting of alkyl and hydroxy; RB is selected from the group consisting of hydrogen and alkyl; RE is selected from the group consisting of hydrogen and alkyl; and RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl. In another embodiment, the present invention relates to a compound of the formula (I) wherein X (, X3, and X4 are CH; X2 is CH (R7); X5 is C; R-, and R2 are alkoxy; and R6 are hydrogen, R is selected from the group consisting of alkoxycarbonyl, carboxy, cyano, hydroxy, -NRERF &Y (NRERF) carbonyl; R5 is selected from the group it consists of hydrogen and carboxy; R7 is hydrogen; RE is selected from the group consisting of hydrogen and alkyl; and RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl. In another embodiment, the present invention relates to a compound of the formula (I) wherein X-i, X3, and X4 are CH; X2 is CH (R7); X5 is C; R1 and R2 are alkoxy; R3, R5, and R6 are hydrogen; R 4 is aryl wherein the aryl is phenyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkoxy, formyl, halogen, hydroxy, hydroxyalkyl, and -NRGRH; R7 is hydrogen; RE is selected from the group consisting of hydrogen and alkyl; and RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl. In another embodiment, the present invention relates to a compound of the formula (I) wherein X1f X3, and X4 are CH; X2 is CH (R7); X5 is C; R1 and R2 are alkoxy; R3, R5, and Re are hydrogen; R 4 is heteroaryl; and R7 is hydrogen. In another embodiment, the present invention relates to a compound of the formula (I) wherein X-, X3, and X4 are CH; X2 is CH (R7); X5 is C; R, and R2 are alkoxy; R3, R5, and R6 are hydrogen; R 4 is heteroaryl wherein the heteroaryl is tetraazolyl; and R7 is hydrogen. In another embodiment, the present invention relates to a compound of the formula (I) wherein X X3, and X4 are CH; X2 is CH (R7); X5 is C; R ^ R2, R3, R5. and Re are hydrogen; R4 is selected from the group consisting of alkoxycarbonyl, carboxy, cyano, hydroxy, hydroxyalkyl, -NRERF, and (NRERF) carbonyl; and R7 is selected from the group consisting of alkoxy and hydroxy. In another embodiment, the present invention relates to a compound of the formula (I) wherein Xi is CH; X2 is CH (R7); X3 is N; X4 is CH; X5 is C; R-i, R3, R5, and R6 are hydrogen; R2 is selected from the group consisting of alkenyloxy, alkoxyalkyl, hydroxy, hydroxyalkyl, (NRARB) alkyl, (NRARB) carbonyl, and heterocycloalkyl, wherein the heterocycle of the heterocycloalkyl is selected from the group consisting of 4-morpholinyl and 4-hydroxy 1-piperidinyl; R 4 is selected from the group consisting of hydrogen, alkoxycarbonyl, carboxy, cyano, hydroxy, hydroxyalkyl, -NRERF, and (NRERF) carbonyl; R7 is hydrogen; RA is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl, wherein the cycloalkyl is cyclohexyl substituted with 1 substituent selected from the group consisting of alkyl and hydroxy; RB is selected from the group consisting of hydrogen and alkyl; RE is selected from the group consisting of hydrogen and alkyl; and RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl. In another embodiment, the present invention relates to a compound of the formula (I) wherein X x, X 3, and X 4 are CH; X2 is CH (R7); X5 is C; and R2 together with the carbon atoms to which they are attached form a non-aromatic 5 or 6 membered ring, wherein the ring contains 0, 1, or 2 heterogeneous atoms selected from the group consisting of O, N (RC) , and N (RD); 3, R5, and R6 are hydrogen; R is selected from the group consisting of hydrogen, alkoxycarbonyl, carboxy, cyano, hydroxy, hydroxyalkyl, -NRERF, and (NRERF) carbonyl; R7 is hydrogen; RA is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl, wherein the cycloalkyl is cyclohexyl substituted with 1 substituent selected from the group consisting of alkyl and hydroxy; RB is selected from the group consisting of hydrogen and alkyl; RE is selected from the group consisting of hydrogen and alkyl; RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl; and RC and RD are as defined in formula (I). In another embodiment, the present invention relates to a compound of the formula (I) wherein Xi, X3, and X4 are CH; X2 is CH (R7); X5 is C; R- and R2 together with the carbon atoms to which they are attached form a non-aromatic 5- or 6-membered ring, wherein the ring contains two heterogeneous atoms selected from the group consisting of O, N (RC), and N (RD); R3, R5, and R6 are hydrogen; R 4 is selected from the group consisting of hydrogen, alkoxycarbonyl, carboxy, cyano, hydroxy, hydroxyalkyl, -NRERF, and (NRERF) carbonyl; R7 is hydrogen; RA is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl, wherein the cycloalkyl is cyclohexyl substituted with 1 substituent selected from the group consisting of alkyl and hydroxy; RB is selected from the group consisting of hydrogen and alkyl; RE is selected from the group consisting of hydrogen and alkyl; RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl; and RC and RD are as defined in formula (I).
In another embodiment, the present invention relates to a compound of the formula (I) wherein X, X3 > and X are CH; X2 is CH (R7); X5 is C; -iy R2 together with the carbon atoms to which they are attached form a non-aromatic 5 or 6 membered ring, wherein the ring contains 0, 1, or 2 heterogeneous atoms selected from the group consisting of O, N (RC) , and N (RD); 3, R5, and R6 are hydrogen; R 4 is aryl wherein the aryl is phenyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkoxy, formyl, halogen, hydroxy, hydroxyalkyl, and -NRGRH; R7 is hydrogen; RA is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl, wherein the cycloalkyl is cyclohexyl substituted with 1 substituent selected from the group consisting of alkyl and hydroxy; RB is selected from the group consisting of hydrogen and alkyl; RE is selected from the group consisting of hydrogen and alkyl; and RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl; and RC and RD are as defined in formula (I). In another embodiment, the present invention relates to a compound of the formula (I) wherein X3, and X4 are CH; X2 is CH (R7); X5 is C; R1 and R2 together with the carbon atoms to which they are attached, form a non-aromatic ring of 5 to 6 members, wherein the ring contains two heterogeneous atoms selected from the group consisting of O, N (RC), and N ( RD); R3, R5, and R6 are hydrogen; R4 is aryl, wherein the aryl is phenyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkoxy, formyl, halogen, hydroxy, hydroxyalkyl, and -NRGRH; R7 is hydrogen; RA is selected from the group consisting of alkyl, hydroxyalkyl, and cycloaikyl, wherein cycloaikyl is cyclohexyl substituted with 1 substituent selected from the group consisting of alkyl and hydroxy; RB is selected from the group consisting of hydrogen and alkyl; RE is selected from the group consisting of hydrogen and alkyl; and RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl; and Re and RD are as defined in formula (I). In another embodiment, the present invention relates to a compound of the formula (I) wherein X-i, X3, and X4 are CH; X2 is CH (R7); X5 is C; R-, is selected from the group consisting of hydrogen, alkoxy, alkyl, hydroxyalkoxy, and hydroxyalkyl; R 2 is selected from the group consisting of alkoxy, alkoxyalkoxyalkynyl, alkyl, haloalkoxyalkinyl, heteroarylalkoxy, heteroarylalkynyl, heteroaryloxyalkyl, heteroaryloxy, heterocycloalkoxy, heterocyclecarbonyl, heterocycleoxy, heterocycleoxyalkyl, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, (NRARB) alkynyl, and (NRARB) carbonyl; R3 is selected from the group consisting of hydrogen, -NRERF, and hydroxyalkyl; R 4 is aryl wherein the aryl is phenyl substituted with 1 or 2 substituents selected from the group consisting of alkoxy, carboxy, cyano, halogen, and hydroxy; R7 is selected from the group consisting of hydrogen, lower alkoxy, lower alkyl, and hydroxy; RE and RF are independently selected from the group consisting of hydrogen, alkyl and alkylcarbonyl; and RA and RB are as defined in formula (I). In another embodiment, the present invention relates to a compound of the formula (I) wherein Xi, X3, and X4 are CH; X2 is C = 0; X5 is C; R-i is selected from the group consisting of hydrogen, alkoxy, alkyl, hydroxychoxy, and hydroxyalkyl; R 2 is selected from the group consisting of alkoxy, alkoxyalkoxyalkynyl, alkyl, haloalkoxyalkynyl, heteroarylalkoxy, heteroarylalkynyl, heteroaryloxyalkyl, heteroaryloxy, ethercycloalkoxy, heterocyclecarbonyl, heterocycleoxy, heterocycleoxyalkyl, hydroxychoxy, hydroxyalkyl, hydroxyalkynyl, (NRARB) alkynyl, and (NRAREs) carbonyl; R3 is selected from the group consisting of hydrogen, -NRERF, and hydroxyalkyl; R 4 is aryl wherein the aryl is phenyl substituted with 1 or 2 substituents selected from the group consisting of alkoxy, carboxy, cyano, halogen, hydroxy; R5 and R6 are hydrogen; RE and F are independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl; and RA and RB are as defined in formula (I). In another embodiment, the present invention relates to a compound of the formula (I) wherein Xi and X4 are CH; X2 is CH (R7); X3 is N; X5 is C; R-i is selected from the group consisting of hydrogen, alkoxy, alkyl, hydroxychoxy, and hydroxyalkyl; R 2 is selected from the group consisting of alkoxy, alkoxyalkoxyalkynyl, alkyl, haloalkoxyalkynyl, heteroarylalkoxy, heteroarylalkynyl, heteroaryloxyalkyl, heteroaryloxy, heterocycloalkoxy, heterocyclecarbonyl, heterocycleoxy, heterocycleoxyalkyl, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, (NRARB) alkynyl, and (NRARB) carbonyl; R3 is selected from the group consisting of hydrogen, -NRERF, and hydroxyalkyl; R 4 is selected from the group consisting of cyano, halogen, and aryl wherein the aryl is phenyl optionally substituted with 1 or 2 substituents independently selected from alkoxy and hydroxy; R5 and R6 are hydrogen; R7 is selected from the group consisting of hydrogen, lower alkoxy, lower alkyl and hydroxy; RE and RF are independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl; and RA and RB are as formula (I) was defined. In another embodiment, the present invention relates to a compound of the formula (I) wherein X1 and X4 are CH; X2 is C = 0; X3 is N; X5 is C; R-, is selected from the group consisting of hydrogen, alkoxy, alkyl, hydroxyalkoxy, and hydroxyalkyl; R 2 is selected from the group consisting of alkoxy, alkoxyalkoxyalkynyl, alkyl, haloalkoxyalkynyl, heteroarylalkoxy, heteroarylalkynyl, heteroaryloxyalkyl, heteroaryloxy, heterocycloalkoxy, heterocyclecarbonyl, heterocycleoxy, heterocycleoxyalkyl, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, (NRAREs) alkynyl, and (NRARB) carbonyl; R3 is selected from the group consisting of hydrogen, -NRERF, and hydroxyalkyl; R 4 is selected from the group consisting of cyano, halogen, and aryl wherein the aryl is phenyl optionally substituted with 1 or 2 substituents independently selected from alkoxy and hydroxy; R5 and e are hydrogen; RE and RF are independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl; and RA and RB are as defined in formula (l). In another embodiment, the present invention relates to a compound of the formula (I) wherein and X3 are CH; X2 is CH (R7); X is N; X5 is C; R ^ is selected from the group consisting of hydrogen, alkoxy, alkyl, hydroxyalkoxy, and hydroxyalkyl; R 2 is selected from the group consisting of alkoxy, alkoxyalkoxyalkynyl, alkyl, haloalkoxyalkynyl, heteroarylalkoxy, heteroarylalkynyl, heteroaryloxyalkyl, heteroaryloxy, heterocycloalkoxy, heterocyclecarbonyl, heterocycleoxy, heterocycleoxyalkyl, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, (NRARe) alkynyl, and (NRARB) carbonyl; R3 is selected from the group consisting of hydrogen, -NRERF, and hydroxyalkyl; R 4 is selected from the group consisting of cyano, halogen, and aryl wherein the aryl is phenyl optionally substituted with one or two substituents independently selected from alkoxy and hydroxy; R5 and R6 are hydrogen; R7 is selected from the group consisting of hydrogen, lower alkoxy, lower alkyl, and hydroxy; RE and RF are independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl; and RA and RB are as defined in formula (I).
In another embodiment, the present invention relates to a compound of the formula (I) wherein X- and X3 are CH; X2 is C = 0; X4 is N; X5 is C; R, is selected from the group consisting of hydrogen, alkoxy, alkyl, hydroxyalkoxy, and hydroxyalkyl; R2 is selected from the group consisting of alkoxy, alkoxyalkoxyalkynyl, alkyl, haloalkoxyalkynyl, heteroarylalkoxy, heteroaryla! quinyl, heteroaryloxyalkyl, heteroaryloxy, heterocycloalkoxy, heterocyclecarbonyl, heterocycleoxy, heterocycleoxyalkyl, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, (NRARB) alkynyl, and (NRARB) carbonyl; R3 is selected from the group consisting of hydrogen, -NRERF, and hydroxyalkyl; R 4 is selected from the group consisting of cyano, halogen, and aryl wherein the aryl is phenyl optionally substituted with 1 or 2 independent substituents selected from alkoxy and hydroxy; R5 and R6 are hydrogen; RE and RF are independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl; and RA and RB are as defined in formula (I). In another embodiment, the present invention relates to a compound of the formula (I) wherein and X3 are CH; X2 is CH (R7); X4 and X5 are N; R1 is selected from the group consisting of hydrogen, alkoxy, alkyl, hydroxyalkoxy, and hydroxyalkyl; R 2 is selected from the group consisting of alkoxy, alkoxyalkoxyalkynyl, alkyl, haloalkoxyalkynyl, heteroarylalkoxy, heteroarylalkynyl, heteroaryloxyalkyl, heteroaryloxy, heterocycloalkoxy, heterocyclecarbonyl, heterocycleoxy, heterocycleoxyalkyl, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, (NRARB) alkynyl, and (NRARB) carbonyl; R3 is selected from the group consisting of hydrogen, -NRERF, and hydroxyalkyl; R is selected from the group consisting of cyano, halogen, and aryl wherein the aryl is phenyl optionally substituted with 1 or 2 substituents independently selected from alkoxy and hydroxy; R5 is absent; R6 is hydrogen; R7 is selected from the group consisting of hydrogen, lower alkoxy, lower alkyl, and hydroxy; RE and RF are independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl; and RA and RB are as defined in formula (1). In another embodiment, the present invention relates to a compound of the formula (I) wherein Xi and X4 are CH; X2 is CH (R7); 3 and X5 are N; R1 is selected from the group consisting of hydrogen, alkoxy, alkyl, hydroxyalkoxy, and hydroxyalkyl; R2 is selected from the group consisting of alkoxy, alkoxyalkoxyalkynyl, alkyl, haloalkoxyalkynyl, heteroarylalkoxy, heteroarylalkynyl, heteroaryloxyalkyl, heteroaryloxy, heterocycloalkoxy, heterocyclecarbonyl, heterocycleoxy, heterocycleoxyalkyl, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, (NRARB) alkynyl, and (NRARB) carbonyl; R3 is selected from the group consisting of hydrogen, -NRERF, and hydroxyalkyl; R 4 is selected from the group consisting of cyano, halogen, and aryl wherein the aryl is phenyl optionally substituted with 1 or 2 substituents independently selected from alkoxy and hydroxy; R5 is absent; RE is hydrogen; R7 is selected from the group consisting of hydrogen, lower alkoxy, lower alkyl, and hydroxy; RE and RF are independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl; and RA and RB are as defined in formula (I). In another embodiment, the present invention relates to a compound of the formula (I) wherein X1 and X4 are CH; X2 is C = 0; X3 and X5 are N; R-i is selected from the group consisting of hydrogen, alkoxy, alkyl, hydroxyalkoxy, and hydroxyalkyl; R 2 is selected from the group consisting of alkoxy, alkoxyalkoxyalkynyl, alkyl, haloalkoxyalkynyl, heteroarylalkoxy, heteroarylalkynyl, heteroaryloxyalkyl, heteroaryloxy, heterocycloalkoxy, heterocyclecarbonyl, heterocycleoxy, heterocycleoxyalkyl, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, (NRARB) alkynyl, and (NRARB) carbonyl; R3 is selected from the group consisting of hydrogen, -NRERF, and hydroxyalkyl; R 4 is selected from the group consisting of cyano, halogen, and aryl wherein the aryl is phenyl optionally substituted with 1 or 2 substituents independently selected from alkoxy and hydroxy; R5 is absent; R6 is hydrogen; RE and F are independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl; and RA and RB are as defined in formula (I). In another embodiment, the present invention relates to a compound of the formula (I) wherein X-i, X3, and X4 are CH; X2 is CH (R7); X5 is C; R-, is selected from the group consisting of hydrogen, alkoxy, alkyl, hydroxyalkoxy, and hydroxyalkyl; R 2 is selected from the group consisting of alkoxy, alkoxyalkoxyalkynyl, alkyl, haloalkoxyalkynyl, heteroarylalkoxy, heteroarylalkynyl, heteroaryloxyalkyl, heteroaryloxy, heterocycloalkoxy, heterocyclecarbonyl, heterocycleoxy, heterocycleoxyalkyl, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, (NRARB) alkyne, and (NRARB) carbonyl; R3 is selected from the group consisting of hydrogen, -NRERF, and hydroxyalkyl; R4 and R5, together with the atom to which they are attached form a phenyl ring optionally substituted with 1 or 2 substituents independently selected from alkoxy, carboxy, cyano, halogen, and hydroxy; R7 is selected from the group consisting of hydrogen, lower alkoxy, lower alkyl, and hydroxy; RE and RF are independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl; and RA and RB are as defined in formula (I). In another embodiment, the present invention relates to a compound of the formula (I) wherein X x, X 3, and X 4 are CH; X2 is C = 0; X5 is C; R1 is selected from the group consisting of hydrogen, alkoxy, alkyl, hydroxyalkoxy, and hydroxyalkyl; R 2 is selected from the group consisting of alkoxy, alkoxyalkoxyalkynyl, alkyl, haloalkoxyalkynyl, heteroarylalkoxy, heteroarylalkynyl, heteroaryloxyalkyl, heteroaryloxy, heterocycloalkoxy, heterocyclocarbonyl, heterocycloxy, heterocycleoxalkyl, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, (NRARB) alkynyl, and (NRARB) carbonyl; R3 is selected from the group consisting of hydrogen, -NRERF, and hydroxyalkyl; R 4 is selected from the group consisting of cyano, halogen, and aryl wherein the aryl is phenyl optionally substituted with 1 or 2 substituents independently selected from alkoxy and hydroxy; R5 is absent; R6 is hydrogen; RE and R-F are independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl; and RA and RB are as defined in formula (I).
Definition of Terms As used throughout this specification and the appended claims, the following terms have the following meanings. The term "alkenyl" as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl (allyl), 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1. -hepteniio, and 3-decenyl.
The term "alkenyloxy" as used herein, means an alkenyl group, as defined herein, appended to the molecular portion of origin through an oxygen atom. Representative examples of alkenyloxy include, but are not limited to, allyloxy, 2-butenyloxy and 3-butenyloxy. The term "alkoxy" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. The term "alkoxyalkoxy" as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of alkoxyalkoxy include, but are not limited to, 2- (methoxy) ethoxy, 2- (ethoxy) ethoxy, 2- (tert-butoxy) ethoxy, and 3- (methoxy) butoxy.
The term "alkoxyalkoxyalkynyl" as used herein means an alkoxyalkoxy group, as defined herein, appended to the moiety portion of origin through an alkynyl group, as defined herein. Representative examples of alkoxyalkoxyalkynyl include, but are not limited to, 3- (2-isopropoxyethoxy) prop-1-indole, 3- (2-methoxyethoxy) prop -inyl, and 4- (2-isopropoxyethoxy) but- -inyl . The term "alkoxyalkyl" as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, methoxymethyl, ethoxymethyl, 2-ethoxyethyl, tert-butoxymethyl, and 2-methoxyethyl. The term "alkoxyalkylcarbonyl" as used herein means an alkoxyalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxyalkylcarbonyl include, but are not limited to, 3-methoxypropanoyl and 5-methoxypentanoyl. The term "alkoxycarbonyl" as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl. The term "alkoxycarbonylalkyl" as used herein, means an alkoxycarbonyl group, as defined herein, appended to the molecular origin through an alkyl group, as defined herein. Representative examples of alkoxycarbonylalkyl include, but are not limited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and 2-tert-butoxycarbonylethyl. The term "alkoxycarbonylalkylcarbonyl" as used herein, means an alkoxycarbonylalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonylalkylcarbonyl include, but are not limited to, 5-methoxy-5-oxopentanoyl, 5-ethoxy-5-oxopentanoyl, and 4-methoxy-4-oxobutanoyl.
The term "alkoxysulfonyl" as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a sulfonyl group as defined herein. Representative examples of alkoxysulfonyl include, but are not limited to, methoxysulfonyl, ethoxysulfonyl and propoxysulfonyl. The term "alkoxysulfonylalkium" as used herein means an alkoxysulfonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxysulfonylalkium include, but are not limited to, 3- (methoxysulfonyl) propyl, 3- (ethoxysulfonyl) propyl, and 2- (methoxysulfonyl) ethyl. The term "alkoxysulfonylalkylcarbonyl" as used herein, means an alkoxysulfonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxysulfonyl alkylcarbonyl include, but are not limited to, 3- (methoxysulfonyl) propanoyl, 3- (ethoxysulfonyl) propanoyl, and 4- (methoxysulfonyl) butanoyl. The term "alkyl" as used herein means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, it-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n -hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. The term "alkylcarbonyl" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1 -oxopentyl. The term "alkylcarbonylalkoxy" as used herein, means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of alkylcarbonylalkoxy include, but are not limited to, acetyl, 2-oxopropoxy, 2-oxobutoxy, and 3-oxobutoxy, 4-oxopentyloxy. The term "alkylcarbonyloxy" as used herein, means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Examples Representative of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy. The term "alkylsulfyl" as used herein, means an alkyl group, as defined herein, appended to the molecular moiety of origin via a sulfinyl group as defined herein. Representative examples of alkylsulfinyl include, but are not limited to, methylsulfinyl and ethylsulphyl. The term "alkylsulfonyl" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl. The term "alkylthio" as used herein, means an alkyl group, as defined herein, appended to the molecular portion of origin through a sulfur atom. Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio. The term "alkylthioalkyl" as used herein, means an alkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylthioalkyl include, but are not limited to, methylthiomethyl and 2- (ethylthio) ethyl. The term "alkynyl" as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one triple bond of carbon-carbon. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and -butynyl. The term "aryl" as used herein means a monocyclic ring system or a bicyclic fused ring system wherein one or more of the fused rings are aromatic. Representative examples of aryl include, but are not limited to, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. The aryl groups of the present invention are substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from aikenium, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonium, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkylthioalkyl alkynyl, carboxy, carboxyalkyl, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkyl, mercapto, nitro, -NRGRH, (NRGRH) alkoxy, (NRGRH) alkyl, (NRGRH) carbonyl, and (NRGRH) sulfonyl. The aryl groups of the present invention can be optionally substituted with heterocycle, as defined herein. The heterocycle can optionally be substituted with 1, 2, 3, 4 or 5 substituents independently selected from aikenium, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonium, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NRGRH, (NRGRH) alkoxy, (NRc h alkyl, (NRGRH) carbonyl, and (NRGRH) sulfonyl The term "aryloalkoxy" as used herein, means an aryl group, as defined herein, appended to the molecular portion of origin through an alkoxy group, as defined herein, Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3-phenylpropoxy, and 5-phenylpentyloxy The term "arylalkyl" as used herein, means an aryl group, as defined herein, attached to the molecular portion of origin through an alkyl group, as defined herein Representative examples of arylalkyl include, but are not limited to, 4-carboxyphenylmethyl, 2- (4-hydroxyphenyl) ethyl, and 3- (4- carboxyiphenyl) propyl The term "aryloxy" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of aryloxy include, but are not limited to, , 4-carboxyphenoxy, 4-hydroxyphenoxy, and 3,4-dihydroxy phenoxy The term "carboxy" as used herein means a group -C02H. The term "carboxyalkyl" as used herein, means a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl, and 3-carboxypropyl. The term "carboxyalkylcarbonyl" as used herein, means a carboxyalkyl group, as defined herein, appended to the molecular portion of origin through a carbonyl group, as defined herein. Representative examples of carboxyalkylcarbonyl include, but are not limited to, 4-carboxybutanoyl, 3-carboxypropanoyl, and 5-carboxypentanoyl. The term "cyano" as used herein means a group -CN.
The term "cycloalkyl" as used herein, means a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloctyl. The cycloalkyl groups of the present invention are substituted with 0, 1, 2, 3, or 4 substituents selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen , hydroxy, hydroxyalkyl, -NRG H, (NRGRH) alkoxy, (NRGRH) alkyl, and (NRGRH) carbonyl. The term "cycloalkenyl" as used herein, means a monocyclic, bicyclic, or tricyclic, non-aromatic, partially unsaturated ring system having 4 to 8 carbon atoms and zero heterogeneous atoms. Representative examples of cycloalkenyl groups include, but are not limited to, cyclohexenyl and cyclopentenyl. The term "cycloalkenylalkoxy" as used herein, means a cycloalkenyl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined here. The term "cycloalkylalkoxy" as used herein, means a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of cycloalkylalkoxy include, but are not limited to, cyclopropylmethoxy, 2-cyclobutylethoxy, cyclopentylmethoxy, cyclohexylmethoxy, 2-cyclohexylethoxy, 3-cyclohexylpropoxy, 4-cyclohexylbutoxy, 4- (4-aminociclohexyl) butoxy, 4- (4-dimethylaminocyclohexyl) butoxy, 4- (4-hydroxycyclohexyl) butoxy, and 4-cycloheptylbutoxy. The term "cycloalkylalkyl" as used herein means a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, 4-cyclohexylbutyl, 4- (4-aminocyclohexyl) butyl, 4- (4-dimethylaminocyclohexyl) butyl, 4- (4-hydroxycyclohexyl) butyl, and 4-cycloheptylbutyl. The term "cycloalkylalkylcarbonyl" as used herein means a cycloalkylalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of cycloalkylalkylcarbonyl include, but are not limited to, 4-cyclohexylbutanoyl, 3-cyclohexylpropanoyl, and 5-cyclohexylpentanoyl.
The term "cycloalkylcarbonyl" as used herein, means a cycloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of cycloalkylcarbonyl include, but are not limited to, cyclohexylcarbonyl and cyclopentylcarbonyl. The term "cycloalkyloxy" as used herein, means a cycloalkyl group, as defined herein, appended to the molecular portion of origin through an oxygen atom. Representative examples of cycloalkyloxy include, but are not limited to, cyclohexyloxy and cyclopentyloxy. The term "cycloalkylcarbonylalkyl" as used herein, means a cycloalkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylcarbonylalkyl include, but are not limited to, 4-cyclohexyl-4-oxobutyl and 3-cyclohexyl-3-oxopropyl. The term "cycloalkylcarbonylalkylcarbonyl" as used herein, means' a cycloalkylcarbonylalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Exemplary examples of cycloalkylcarbonylalkylcarbonyl include, but are not limited to, 4-cyclohexyl-4-oxobutanoyl and 3-cyclohexyl-3-oxopropanoyl. The term "formyl" as used herein means a group -C (0) H. The term "halo" or "halogen" as used herein, means -C !, -Br, -I or -F. The term "haloalkoxy" as used herein means at least one halogen, as defined herein, appended to the molecular portion of origin through an alkoxy group, as defined herein. In addition, the alkyl group may optionally be substituted with at least one halogen atom. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, pentafluoroethoxy, and 3-chloro-2- (hydroxymethyl) -2-methylpropoxy. The term "haloalkoxyalkynyl" as used herein, means a haloalkoxy group, as defined herein, appended to the parent molecular moiety through a group alkynyl group, as defined herein. Representative examples of haloalkoxyalkynyl include, but are not limited to, 3- (2,2,2-trifluoroethoxy) prop-1 -i n i lo 3- (trifluoromethoxy) prop-1-ylo. The term "haloalkyl" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl. The term "heteroaryl" as used herein, refers to an aromatic 5 or 6 membered ring, wherein 1, 2, 3, or 4 heterogeneous atoms are independently selected from N, O, or S. The 5-membered rings they have two double bonds and the rings of 6 members have 3 double links. Heteroaryl groups are connected to the molecular portion of origin through a carbon or nitrogen atom. The term "heteroaryl" also includes bicyclic systems, wherein a heteroaryl ring is fused to a phenyl group or an additional heteroaryl group. Representative examples of heteroaryl include, but are not limited to, benzothienyl, benzoxadiazolyl, cinolinyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl. , pyrrolyl, quinolinyl, tetraazolyl, thiadiazolyl, thiazolyl, thienopyridinyl, thienyl, triazo I, and triazinyl. The heteroaryl groups of the present invention are substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NRGRH, (NRGRH) alkoxy, (NRGRH) alkyl, (GRH) carbonyl , and (NRGRH) sulfonyl. The term "heteroarylalkoxy" as used herein, means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of heteroarylalkoxy include, but are not limited to, 5-hydroxy-2-pyridinylmethyl, 2- (5-hydroxy-2-pyridinyl) ethyl, and 5-Hydroxy-2-pyrimidinylmethyl. The term "heteroarylalkoxyalkoxy" as used herein means a heteroarylalkoxy group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. The term "heteroarylalkyl" as used herein, means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heteroarylalkyl include, but are not limited to, 5-carboxy-2-pyridinylmethyl, 5-hydroxy-2-pyridinylmethyl, 2- (5-hydroxy-2-pyridinyl) ethyl, and 3- (5 -hydroxy-2-pyridinyl) propyl. The term "heteroarylalkyl" as used herein, means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an alkynyl group, as defined herein. Representative examples of heteroarylalkynyl include, but are not limited to, pyridin-2-ylethynyl, pyridin-3-ylkynyl, 4-pyridin-2-ylbut-1-ynyl, and 4-pyrazin-2-ylpent-1-ynyl. The term "heteroaryloxy" as used herein, means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of heteroaryloxy include, but are not limited to, 5-carboxy-2-pyridinyloxy, 5-hydroxy-2-pyridinyloxy, and 5-hydroxy-2-pyrimidinyloxy. The term "heteroaryloxyalkyl" as used herein means a heteroaryloxy group, as defined herein, appended to the molecular origin through an alkyl group. Representative examples of heteroaryloxyalkyl include, but are not limited to, pyridinyl-5-carboxy-2-pyridinyloxymethyl, 5-hydroxy-2-pyridinyloxymethyl, and 5-hydroxy-2-pyrimidyloxy. The term "heterocycle" as used herein, refers to a 3, 4, 5, 6, 7 or 8 member ring containing 1, 2, or 3 heterogeneous atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The 3-member ring has zero double bonds. The 4 and 5 member rings have zero or a double bond. The 6 member ring has 0, 1 or 2 double bonds. The 7 and 8 member rings have 0, 1, 2 or 3 double bonds. The heterocycle groups of the present invention can be attached to the molecular portion of origin through a carbon atom and a nitrogen atom. Representative examples of heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, azocanyl, 1,4-diazepane-2-yl, 1,4-dioxanyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl, and 1,1 -dioxidothiomorpholinyl. The heterocycles of the present invention are substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkyiocarbonium, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl , halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, -NRG H. (NRGRH) alkoxy, (NRGRH) alkyl, and (NRGRH) carbonyl. The heterocycles of the present invention optionally they can be substituted with an aryl group, as defined herein. The aryl group may be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl , carboxy, carboxyaikyl, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NRGRH, (NRGRH) alkoxy, (NRGRH) alkyl, (NRGRH) carbonyl, and (NRGRH) sulfonyl. The term "heterocycloalkoxy" as used herein, means a heterocycle, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of heterocycloalkoxy include, but are not limited to, 4-morpholinylmethoxy, 2- (4-morpholinyl) ethoxy, 4-thiomorpholinylmethoxy, 2- (4-thiomorpholinyl) ethoxy, 1-piperidinylmethoxy, 2- (1-piperidinyl) ethoxy, 4-hydroxy-1-piperidinylmethoxy, 2- (4-hydroxy-1-piperidinyl) ethoxy, 3-hydroxy-1 -pyrrolidinylmethoxy, 3-hydroxy-1-azetidinylmethoxy, and 4-hydroxy-1-azelanylmethoxy. The term "heterocycloalkyl" as used herein, means a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocycloalkyl include, but are not limited to, 4-morpholinylmethyl, 2- (4-morpholinyl) ethyl, 4-thiomorpholinylmethyl, 2- (4-thiomorpholinyl) ethyl, 1-piperidinylmethyl, 2- (1-piperidinyl) ethyl , 4-hydroxy- 1 - . 1-ethylpipe ndinilm, 2- (4-hydroxy-1-piperidinyl) ethyl, 3-hydroxy-1-pyrrolidinylmethyl, 3-hydroxy-1-azetidinylmethyl, 3-hydroxy-1-azepanylmethyl, and 4-hydroxy-1 -azepanylmethyl. The term "heterocycloalkylcarbonyl" as used herein, means a heterocycloalkyl, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of heterocycloalkylcarbonyl include, but are not limited to, 4- (1-piperidinyl) butanoyl, 3- (1-piperidinyl) propanoyl, 4- (4-morpholinyl) butane, and 3- (4-morfoinyl) propanoyl. . The term "heterocyclecarbonyl" as used herein, means a heterocycle, as defined herein, appended to the molecular portion of origin through a carbonyl group, as defined herein. Representative examples of heterocyclocarbonyl include, but are not limited to, 4-morpholinylcarbonyl, 4-thiomorpholylcarbonyl, 1-piperidinylcarbonyl, (4-hydroxy-1-piperidinyl) carbonyl, and 3-hydroxy-1-pyrrolidinylcarbonyl. The term "heterocyclocarbonylalkyl" as used herein, means a heterocyclocarbonyl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclocarbonylalkyl include, but are not limited to, 2- (4-morfo! Inyl) -2-oxoethyl, 3- (4-morpholinyl) -3-oxopropyl, and 2- (1-piperidinyl) -2-oxoethyl. . The term "heterocyclocarbonylalkylcarbonyl" as used herein, means a heterocyclecarbonylalkyl, as defined herein, attached to the molecular portion of origin through a carbonyl group, as defined herein. Representative examples of heterocyclocarbonylalkylcarbonyl include, but are not limited to, 5- (4-morpholinyl) -5-oxopentanoyl, 4- (4-morpholinyl) -4-oxobutanoyl, and 5- (1-piperidinyl) -5-oxopentanoyl. The term "heterocyclooxy" as used herein means a heterocycle group, as defined herein, appended to the molecular portion of origin through an oxygen atom. Representative examples of heterocyclooxy include, but are not limited to, 4-piperidinyloxy, 3-pyrrolidinyloxy, 3-azetidinyloxy, and tetrahydrofuran-3-yloxy. The term "hydroxy" as used herein, means a group -OH The term "hydroxyalkoxy" as used herein, means at least one hydroxy group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of hydroxyalkoxy include, but are not limited to, 2-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxypropoxy, 2,3-dihydroxypentoxy, and 3-hydroxy-2,2-dimethylpropoxy. The term "hydroxyalkyl" as used herein means at least one hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2,3-dihydroxypentyl, 2-ethyl-4-hydroxyheptyl, and 3- hydroxy-2,2-dimethyl pro ilo. The term "hydroxyalkynyl" as used herein, means at least one hydroxy group, as defined herein, appended to the parent molecular moiety through an alkynyl group, as defined herein. Representative examples of hydroxyalkynyl include, but are not limited to, 4-hydroxy-4-methylpent-1-ynyl, 4-hydroxybut-1-ynyl, and 3-hydroxyprop-1-inyl. The term "hydroxyalkylcarbonyl" as used herein means a hydroxyalkyl group, as defined herein, is attached to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of hydroxyalkylcarbonyl include, but are not limited to, glycolyl, 3-hydroxypropanoyl, and 4-hydroxybutanoyl. The term "hydroxysulfonyl" as used herein, means a HOS (0) 2- group. The term "hydroxysulfonylalkyl" as used herein, means a hydroxysulfonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined here. Representative examples of hydroxysulfonylalkyl include, but are not limited to, 4-sulfobutyl, 3-sulfopropyl, and 2-sulfoethyl. The term "hydroxysulfonylalkylcarbonyl" as used herein, means a hydroxysulfonylalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of hydroxysulfonyl alkylcarbonyl include, but are not limited to, 4- sulfobutanoyl and 3-sulfopropanoyl. The term "lower alkoxy" as used herein, is a subgroup of alkoxy as defined herein and means an alkyl group, as defined herein, appended to the parent molecular portion through an oxygen atom, as defined herein . Representative examples of lower alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, and 2-propoxy. The term "lower alkyl" as used herein, is a subgroup of alkyl as defined herein and means a straight or branched chain hydrocarbon group containing from 1 to 3 carbon atoms. Examples of lower alkyl are methyl, ethyl, n-propyl, and isopropyl. The term "mercapto" as used here, means a group -SH. The term "mercaptoalkyl" as used herein, means a mercapto group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of mercaptoalkyl include, but are not limited to, hydroxymethyl, 2-mercaptoethyl, 3-mercaptopropyl, and 4-mercaptobutyl. The term "nitro" as used herein, means a group -N02. The term "-NRA B" as used herein, means two groups, RA and RB > which are attached to the molecular portion of origin through a nitrogen atom. RA and RB are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alcoxicarbonilal Uilo, alcoxicar onilalquilcarbonilo, alkoxysulfonyl, alcoxisulfonilalquilo, alcoxisulfonilalquilcarbonilo, alkyl, alkylcarbonyl, alkynyl, aryl, carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkylcarbonyl, cycloalkylcarbonyl, cicloalquilcarbonilalquilo, cicloalquilcarbonilalquilcarbonilo, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, heterocycloalkylcarbonyl, cycloalkyl, heterocyclecarbonylalkyl, heterocyclecarbonylalkylcarbonyl, hydroxyalkyl, hydroxyalkylcarbonyl, hydroxysulfonyl, hydroxysulfonylalkyl, hydroxysulfonyl alkylcarbonyl, (NRERF) alkyl, (NRERF) alkylcarbonyl, (NRERF) carbonyl, (RERF) carbonylalkyl, (NRERF) carbonylalkylcarbonyl, (NRERF) ) sulfonyl, (NRERF) sulfonylalkyl, and (NR RF) sulfonylalkylcarbonyl. Representative examples of -NRARB include, but are not limited to, amino, methylamino, dimethylamino, cyclohexylamino, (trans) -4-methylcyclohexylamino, (cis) -4-methylcyclohexylamino, (trans) -4-hydroxycyclohexylamino, and (cis) - 4-hydroxycyclohexylamino. The term "(NRARB) alkoxy" as used herein, means a group -NRARB, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of (NRARB) alkoxy include, but are not limited to, aminomethoxy, 2-aminoethoxy, methylaminomethoxy, 2- (methylamino) ethoxy, dimethylaminomethoxy, 2- (dimethylamino) ethoxy, cyclohexylaminomethoxy, (trans) -4-methy1cyclohexylaminomethoxy, (cis) -4-methylcyclohexylaminomethoxy, (trans) -4-hydroxycyclohexylaminomethoxy, and (cis) -4-hydroxycyclohexylaminomethoxy. The term "(N RARB) alkyl" as used herein means a group -NRARB, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
Representative examples of (NRARB) alkyl include, but are not limited to aminomethyl, 2-aminoethyl, methylaminomethyl, 2- (methylamino) ethyl, dimethylaminomethyl, 2- (dimethylamino) ethyl, cyclohexylaminomethyl, (trans) -4-methylcyclohexylaminomethyl, (cis ) -4-methylcyclohexylaminomethyl, (trans) -4-h idroxycyclohexylaminomethyl, and (cis) -4- id idroxycyclohexylaminomethyl. The term "(NRARB) alkynyl" as used herein, means a group -NRARB, as defined herein, appended to the parent molecular moiety through an alkynyl group, as defined herein.
Representative examples of (NRARB) alkynyl include, but are not limited to, 3-aminoprop-1-ynyl, 3- (dimethylamino) prop-1-innyl, and 4-aminopent-1-i n i I o. The term "(NRARB) carbonyl" as used herein, means a group -NRARB, as defined herein, appended to the molecular portion of origin through a carbonyl group, as defined herein.
Representative examples of (NRARB) carbonyl include, but are not limited to, aminocarbonyl, (methylamino) carbonyl, (dimethylamino) carbonyl, and (ethylmethylamino) carbonyl. The term "(NRARB) carbonylalkyl" as used herein, means a group (NRARB) carbonyl, as defined herein, appended to the molecular portion of origin through an alkyl group, as defined herein. Representative examples of (NRARB) carbonylalkyl include, but are not limited to, aminocarbonylmethyl, (methylamino) carbonylmethyl, (dimethylamino) carbonylmethyl, and (ethylmethylamino) carbonylmethyl. The term "-NRERF" as used herein, means two groups, RE and RF, which are attached to the molecular portion of origin through a nitrogen atom. RE and F are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, cycloalkyl, heteroarylalkyl, and hydroxyalkyl. Representative examples of -NRERF include, but are not limited to, amino, methylamino, dimethylamino, acetylamino, and acetylmethylamino. The term "(NRERF) alkoxy" as used herein, means a group -NRERF, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of (NRERF) alkoxy include, but are not limited to, aminomethoxy, 2-aminoethoxy, methylaminomethoxy, 2- (methylamino) ethoxy, dimethylaminomethoxy, and 2- (dimethylamino) ethoxy. The term "(N RERF) alkyl" as used herein, means a group -NRERF. as defined herein, appended to the molecular moiety of origin through an alkyl group, as defined herein. Representative examples of (NRERF) alkyl include, but are not limited to aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl, 2- (methylamino) ethyl, dimethylaminomethyl, and 2-ethyl.
The term "(NRERF) alkylcarbonyl" as used herein, means a group (NRERF) alkyl, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NRERF) alkylcarbonyl include, but are not limited to aminoacetyl, 3-aminopropanoyl, 3-dimethylaminopropanoyl, and 4-aminobutanoyl. The term "(N-RERF) carbonyl" as used herein means a group -NRERF, as defined herein, appended to the molecular portion of origin through a carbonyl group, as defined herein. Representative examples of (NRERF) carbonyl. include, but are not limited to, aminocarbonyl, (methylamino) carbonyl, (dimethylamino) carbonyl, and (ethylmethylamino) carbonyl. The term "(NRERF) carbonylalkyl" as used herein, means a group (NRERF) carbonyl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (NRERF) carbonylalkyl include, but are not limited to, 2-amino-2-oxoethyl, 3-amino-3-oxopropyl, and 4-amino-4-oxobutyl. The term "(NRERF) carbonylalkylcarbonyl" as used herein, means a group (NRERF) carbonylalkyl, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. "Representative examples of (NRERF) carbonylalkylcarbonyl include, but are not limited to, 3-amino-3-oxopropanoyl and 4-amino-4-oxobutanoyl The term" (NRERF) sulfonyl "as used herein, means a -NRERp group, as defined herein, appended to the molecular portion of origin through a sulfonyl group, as defined herein. Representative examples of (NRERF) sulfonyl include, but are not limited to, aminosulfonyl, (methylamino) sulfonyl, (dimethylamino) sulfonyl, and (ethylmethylamino) sulfonyl. The term "(NRERF) sulfonylalkyl" as used herein, means a group (NRERF) sulfonyl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (NRERF) sulfonylalkyl include, but are not limited to, 2- (aminosulfonyl) ethyl, 2- (methylaminosulfonyl) ethyl, 3- (dimethylaminosulfonyl) propyl., and 4- (ethylmethylaminosulfonyl) butyl. The term "(NRERF) sulfonylalkylcarbonyl" as used herein, means a group (NRERF) sulfonylalkyl, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NRERF) sulfonylalkylcarbonyl include, but are not limited to, 3- (aminosulfonyl) propanoyl, 4- (methylaminosulfonyl) butanoyl, 4- (dimethylaminosulfonyl) butanoyl, and 4- (ethylmethiaminosulfonyl) butanoi! O. The term "-NRGRH" as used herein, means two groups, RG and RH. which are attached to the molecular portion of origin through a nitrogen atom. RG and RH are each independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl. Representative examples of -NRGRH include, but are not limited to, amino, methylamino, dimethylamino, acetylamino, and acetylmethylamino. The term "(NRGRH) alkoxy" as used herein, means at least one group -NRGRH, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of (RSRH) alkoxy include, but are not limited to, aminomethoxy, 2-aminoethoxy, methylaminomethoxy, 2- (methylamino) ethoxy, dimethylaminomethoxy, 2- (dimethylamino) ethoxy, and 2- (dimethylamino) -1. - [(d-methylamino) met i lo] ethoxy. The term "(NRGRH) alkyl" as used herein, means a group -NRGRH, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (NRGRH) alkyl include, but are not limited to, aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl, 2- (methylamino) ethyl, dimethylaminomethyl, and 2- (dimethylamino) ethyl. The term "(NRGRH) carbonyl" as used herein, means a group -NRGRH, as defined herein, appended to the molecular portion of origin through a carbonyl group, as defined herein. Representative examples of (NRGRH) carbonyl include, but are not limited to, aminocarbonyl, (methylamino) carbonyl, (dimethylamino) carbonyl, and (ethylmethylamino) carbonyl. The term "(NRGRH) sulfonyl" as used herein, means a group -NRGRH, as defined herein, appended to the molecular portion of origin through a sulfonyl group, as defined herein. Representative examples of (NRGRH) sulfonyl include, but are not limit aminosulphonyl, (methylamino) sulfonyl, (dimethylamino) sulfonyl, and (ethylenemethylamino) sulfonyl. This invention is intended to encompass compounds having the formula (I) when prepared through synthetic procedures or through metabolic processes. The preparation of the compounds of the invention through metabolic processes includes those that exist in the human or animal body (in vivo) or procedures that occur in vitro. The compounds of the present invention can exist as therapeutically acceptable salts. The term "therapeutically acceptable salt" as used herein, represents salts or zwitterionic forms of the compounds of the present invention, which are soluble in water or oil, or dispersible, are suitable for the treatment of diseases without undue toxicity, irritation and allergic response; which are in accordance with a reasonable benefit / risk ratio and are effective for their intended use. The salts can be prepared during the final isolation and purification of the compounds, or separately by reacting an amino group with suitable acid. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethane sulfonate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylene sulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate, and undecanoate. Also, the amino groups of the compounds of the present invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; chlorides, bromides and iodides of decyl, lauryl, myristyl and stearyl; and benzyl and phenethyl bromides. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric; and organic acids such as oxalic, maleic, succinic and citric. Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate or bicarbonate of a metal cation or with ammonia or a primary, secondary or tertiary organic amine . Cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine. ,?,? - dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine,?,? - dibenzymphenethylamine, 1-efenamine and?,? '- dibenzylethylenediamine. Other useful representative organic amines for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine and piperazine.
The compounds of the present may also exist as therapeutically acceptable prodrugs. The term "therapeutically acceptable prodrug" refers to those prodrugs that are suitable for use in contact with the tissues of patients without undue toxicity, irritation and allergic response, are in accordance with a reasonable benefit / risk ratio, and are effective for use alleged. The term "prodrug" refers to compounds that are rapidly transformed to compounds of origin of the formula (I), for example, by hydrolysis in the blood. A representative example of a prodrug of the present invention includes, but is not limited to 1,4'-bipiperidin-1 '-carboxylic acid 4' - (6,7-dimethoxy-1,4-dihydroindene [1, 2-c] ] pyrazol-3, il) -1,1 '-biphenyl-4-yl. Asymmetric centers exist in the compounds of the present invention. These centers are designated by the symbols "R" or "S", depending on the configuration of the substituents around the chiral carbon atom. It should be understood that the invention encompasses all isomeric stereochemical forms or mixtures thereof, which possess the ability to inhibit protein kinases. Individual stereoisomers of the compounds can be prepared, synthetically from commercially available starting materials containing polyacrylamic centers or through the preparation of mixtures or enantiomeric products followed by such separation. as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of enantiomers in chiral chromatographic columns. The starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. According to methods of treatment and pharmaceutical compositions of the invention, the compounds can be administered alone or in combination with other anti-cancer agents. When the compounds are used, the specific therapeutically effective dose level for any particular patient will depend on factors such as the disorder to be treated and the severity of the disorder; the activity of the particular compound used; the specific composition employed; age, body weight, general health, sex and the patient's diet; the time of administration; the administration route; the rate of excretion of the compound used, the duration of the treatment; and drugs used in combination with or coincidentally with the compound used. The compounds may be administered orally, parenterally, osmotically (nasal sprays), rectally, vaginally or topically in unit dose formulations containing carriers, auxiliaries, diluents, carriers or combinations thereof. The term "parenteral" includes infusion as well as subcutaneous, intravenous, intramuscular and intraessternal injection. Aqueous or oleaginous suspensions parenterally administered compounds can be formulated with dispersing, wetting or suspending agents. The injectable preparation can also be an injectable solution or suspension in a diluent or solvent. Among the acceptable diluents or solvents employed are water, saline, inger solution, pH regulators, monoglycerides, diglycerides, fatty acids such as oleic acid, and fixed oils such as monoglycerides or diglycerides. The anticancer effect of the parenterally administered compounds can be prolonged by reducing their absorption. One way to reduce the absorption of a particular compound is to administer injectable depot forms comprising suspensions of crystalline, amorphous or otherwise insoluble forms of the compound in water. The rate of absorption of the compound depends on its rate of dissolution that, in turn, depends on your physical state. Another way to reduce the absorption of a particular compound is to administer injectable depot forms comprising the compound as an oleaginous solution or suspension. Yet another way to reduce the absorption of a particular compound is to administer injectable depot forms comprising microcapsule matrices of the entrapped compound within liposomes, microemulsions or biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides. Depending on the ratio of drug to polymer and the composition of the polymer, the rate of release of the drug may be controlled The transdermal patches also provide controlled delivery of the compounds. The rate of absorption can be reduced by using speed control membranes or by trapping the compound within a polymer or gel matrix. Conversely, absorption enhancers can be used to increase absorption. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dose forms, the active compound may optionally comprise diluents such as sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, tablet-forming lubricants, and tablet-forming auxiliaries such such as magnesium stearate or microcrystalline cellulose. Capsules, tablets and pills also comprise pH regulating agents, and tablets and pills can be prepared with enteric shells or other release control covers. The powders and sprays may also contain excipients such as talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder or mixtures thereof. The sprays may also contain customary propellants such as chlorofluorohydrocarbons or substituents therefor. Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups and elixirs comprising inert diluents such as water. These compositions may also comprise auxiliaries such as wetting, emulsifying, suspending, sweetening, flavoring, and sizing agents. Topical dosage forms include ointments, pastes, creams, lotions, gels, or powders, solutions, sprays, inhalants, and transdermal patches. The compound can be mixed under sterile conditions with a vehicle and any necessary preservative or pH regulator. These dosage forms may also include excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Suppositories can be prepared for rectal or vaginal administration by mixing the compounds with a suitable non-irritating excipient, such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina. Also contemplated within the scope of this invention are ophthalmic formulations comprising eye drops, eye ointments, powders and solutions. The total daily dose of the compounds administered to a host in single or divided doses may be in amounts of about 0.1 to about 200 mg / kg of body weight or preferably from about 0.25 to about 100 mg / kg of body weight. The individual dose compositions may contain these amounts or submultiples of them to form the daily dose.
Determination of Biological Activity The Chk1 enzyme assay was performed using the recombinant Chk1 kinase domain protein that covers amino acids from residue 1 to 289 and a polyhistidine tag at the C-terminal end. The human peptide substrate cdc25c contained a sequence from amino acid residue 204 to 225. The reaction mixture contained 25 mM HEPES at pH 7.4, 10 mM MgCl 2, 0.08 mM Triton X-100, 0.5 mM DTT, 5 μ? ATP, 4 nM 33P ATP, 5 μ? peptide substrate cdc25c and 6.3 nM of the recombinant Chk1 protein. The DMSO vehicle of the compound was maintained at 2% in the final reaction. After 30 minutes at room temperature, the reaction was stopped by the addition of an equal volume of 4 M NaCl and 0.1 M EDTA, pH 8. A 40 pl aliquot of the reaction was added to a well of a plate ( NEN Life Science Products, Boston, MA), containing 160 μ? of saline regulated in its pH with phosphate (PBS) without calcium chloride and magnesium chloride and incubated at room temperature for 10 minutes. The plate was then washed 3 times in PBS with 0.05% Tween-20 and counted in a Packard TopCount counter (Packard BioScience Compani, Meriden, CT). The compounds of the present invention inhibited Chk1 at IC50 values of between about 0.1 nM and about 10.0000 nM. Preferred compounds inhibited Chk1 at values of IC 50 of between about 0.1 n and about 250 nWl. Highly preferred compounds inhibited Chk1 at IC50 values of between about 0.1 nM and about 50 nM. In this manner, the compounds of the invention are useful for treating disorders that are caused or exacerbated by increased levels of protein kinase. The compounds of the invention, including but not limited to those specified in the examples, possess the ability to inhibit protein kinases. As protein kinase inhibitors, such compounds are useful in the treatment of both primary and metastatic solid tumors, including carcinomas of the breast, colon, rectum, lung, oropharynx, hypopharynx, esophagus, stomach, pancreas, liver, gall bladder and two biliary, small intestine, urinary tract (including kidney, bladder and urothelium), female genital tract (including cervix, uterus and ovaries as well as choriocarcinoma and gestational trophoblastic disease), male genital tract (including prostate, seminal vesicles, testes and germ cell tumors) , endocrine glands (including thyroid, adrenal and pituitary glands), and skin, as well as hemangiomas, melanomas, sarcomas (including those arising from bones and soft tissues as well as Kaposi's sarcoma) and tumors of the brain, nerves, eyes and meninges (including astrocytomas, gliomas, glioblastomas, retinoblastomas, neuromas, neuroblastomas, Schwannomas, and meningiomas) . Said compounds may also be useful for treating solid tumors arising from hematopoietic malignancies such as leukemias (ie, chloromas, plasmacytomas and plaques and tumors of psychotic fungicides and cutaneous T cell lymphoma / leukemia) as well as in the treatment of lymphomas (both Hodgkin's and non-Hodgkin's lymphomas). In addition, these compounds may be useful in the prevention of metastasis of the tumors described above, either when used alone or in combination with radiotherapy and / or other chemotherapeutics.
Synthetic Models The abbreviations that have been used in the descriptions of the schemes and the examples that follow are: Bu for CHaCHaCh CHz-; Et for CH3CH2-; I for CH3-; PPh3 for triphenylphosphine; PCy3 for tricyclohexylphosphine; dba for dibenzylidenacetone; EDC or EDCI for 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; DCC for 1,3-dicyclohexylcarbodiimide; HOBt for 1-hydroxybenzotriazole; DMSO for dimethyl sulfoxide; DME for 1,2-dimethoxyethane; THF for tetrahydrofuran; D F for?,? - dimethylformamide; TFA for trifluoroacetic acid; dppf for diphenylphosphinoferrocene; Ac for -C (O) CH 3, TMS for trimethylsilyl; SEM for [2- (trimethylsilyl) ethoxy] methyl; DMA for dimethylacetamide; and DIEA for diisopropylethylamine. The compounds and methods of the present invention will be better understood in conjunction with the following synthetic schemes, which illustrate the methods by which they can be used. prepare the compounds of the invention. Starting materials can be obtained from commercial sources or prepared through well-established literature methods known to those skilled in the art.
SCHEME 1 3,6-disubstituted 1,4-dihydroxy [1,2-c] prazoles of the general formula (5) and (6) can be prepared, wherein RA, RB, R4, R5. and Re are as defined in formula (I), as described in Scheme 1. 1,4-Dihydroindeno [1,2-c] pyrazole-6-carbaldehyde, prepared using the procedure described in the US patent 6,297,238, incorporated herein by reference, can be treated with N-iodosuccinimide to provide 3-iodo-1,4-dihydroindeno [1,2-c] pyrazole-6-carbaldehyde. 3-Iodo-1,4-dihydroindeno [1,2-c] pyrazole-6-carbaldehyde can be treated with amines of the general formula (1) (or H2NOH) and a reducing agent, including, but not limited to , sodium borohydride or sodium cyanoborohydride to provide amines of the general formula (2). The amines of the general formula (2) can be treated with boronic acids of the general formula (4) (or, 4,5,5-tetramethyl-1, 3,2-dioxaborolanes), a base, including, but not limited to, cesium carbonate, sodium carbonate or potassium carbonate, and a metal catalyst including, but not limited to, , tetrakis (triphenylphosphine) palladium or bis (triphenylphosphine) palladium (II) chloride to provide 3,4-disubstituted 1,4-dihydroindene [1, 2-c] pyrazoles of the formula (5). 3-Iodo-1,4-dihydroindeno [1,2-c] pyrazole-6-carbaldehyde can also be treated with nitrogen containing heterocycles, including, but not limited to, azetidine, azepam, aziridine, azocan, morpholine, mono-piperazine. protected, piperidine, 4-hydroxypiperidine, pyrroiidine, thiomorpholine, or 1, -dioxidothiomorpholine, for example, to provide the compounds of the general formula (3). The compounds of the general formula (3) can be treated with boronic acids of the general formula (4), a base, including, but not limited to, cesium carbonate, sodium carbonate or potassium carbonate, and a metal catalyst, which includes, but is not limited to, tetrakis (triphenylphosphine) palladium or bis (triphenylphosphine) palladium chloride to provide 3,4-di-disubstituted 1,4-dihydroindeno [1, 2-c] pyrazoles of the general formula ( 6). It should be understood that the 1,4-disubstituted 1,4-dihydroindene [1, 2c] pyrazoles can be prepared from 1,4-dihydroindeno [1,2-c] pyrazole-7-carbaldehyde using the methodology described in Scheme 1 SCHEME 2 The compounds of the general formula (10), wherein X-, X3, Ri, R2, R3, R4, R5, and Re are as defined in the formula (I), can be prepared as described in the Scheme 1. The 1- indanones or 5,6-dihydro-7H-cyclopenta [b] pyridin-7-ones, purchased or prepared using the methodology known to those skilled in the art, can be treated with esters of the general formula (8),, 1'-carbonyldiimidazole, and a base, including, but not limited to, lithium diisopropylamide, to provide the compounds of the general formula (9). The compounds of the general formula (9) can be treated with hydrazine and an acid, including, but not limited to, acetic acid, with heat to provide compounds of the general formula (10).
SCHEME 3 The 1,4-dihydroindeno [1,2-c] pyrazoles of the general formula (13), wherein X3, R4, R5, and R6 are as defined in the formula (I) can be prepared as described in Scheme 3. 5,6-Dimethoxy-1-indanone, purchased from Aldrich Chemical Co., may be treated with sodium cyanide to provide 5-hydroxy-6-methoxy-1-indanone. The 5-hydroxy-6-methoxy-1-indanone can be treated with nitric acid and sodium nitrite to provide 5-h idroxy-6-methoxy-4-n-tro-1-indanone. The 5-hydroxy-6-methoxy-4-nitro-1-indanone can be treated with iodomethane and then with the methodology described in Scheme 2 to provide the compounds of the general formula (12). The compounds of the general formula (12) can be treated with a reducing agent, including an iron metal in the presence of acetic acid to provide the amines of the general formula (13). The compounds of the general formula (13) wherein R 4 is chloro, bromo or iodo can further be worked up under the conditions of Heck, Suzuki, or Stille to provide the compounds of the formula (13), wherein it is aryl or heteroaryl, as defined here. An example of suitable Suzuki conditions is described in Example 1D of the present or Suzuki conditions as described in N. Miyaura, A. Suzuki, Chem. Rev., 2457-2483: 95 (1995); A. Suzuki, J. Organomet. Chem., 147-168: 576 (1999), N. Miyaura, In Advances in Metal-Organic Chemestry, L. S. Liebeskind, Ed., JAI: London, 1998; Vol. 6, pgs. 187-243; and A. Suzuki, In Metal-Catalyzed Cross-Coupling Reactions, F. Diederich, P. J. Stang, Eds. , Wilei-VCH: New York, 1998; Episode 2; S. P. Stanfort, Tetrahedron, 263-303: 54 (1998); it can be used to prepare the compounds, including but not limited to 4 '- (5-amino-6,7-dimethoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -1, 1'-biphenyl-4-ol. The boronic esters and aryl and heteroarylboronic acids are commercially available or can be prepared as described in the scientific literature of synthetic organic chemistry as described in Example 11 herein. Compounds of the general formula (13), wherein R 4 is chlorine, bromine or iodine, can be treated with standard aryl or heteroaryl steanen (Me 3SnR, Bu 3 SnR 4), purchased or prepared using known methodology, a source of palladium such as tris (dibenzylidene acetone) dipalladium or palladium diacetate, and a tai ligand such as tris (2-furyl) phosphine or triphenylarcin in a solvent such as DMF at 25-150 ° C (Stille conditions) to provide compounds of the general formula (13 ), wherein R 4 is aryl or heteroaryl as defined herein. Organotin reagents can be prepared from arylhalides, aryltriflates, heteroaryl halides or heteroaryltriflates through the reaction with distanannes such as (Me 2 Sn) 2 (distanose hememethyl) in the presence of a palladium source such as Pd (Ph 3 P) 4 as described by Kresche, Lehn, et al., Helvética Chimica Acta, 1909-1920: 81 (11) (1998) and in Benagiia, et al., Tetrahedron Letters, 4737-4740: 38 (1997) 38. Compounds of the general formula (13 ), where R4 is chlorine, bromine or iodine, can be treated with aryl or heteroaryl halides, purchased or prepared using known methodology under Heck conditions as described in Tetrahedron 3327: 36 (1980) to provide the compounds of the general formula (13), wherein R 4 is aryl or heteroaryl, as defined herein.
SCHEME 4 1,4,7,8-Tetrahydro [, 4] dioxino [2 ', 3', 5,6] -indeno [1, 2-c] pyrazoles of the general formula (17) can be prepared, wherein X 3, 3 > R4, R5 and R6 are as defined in formula (I), as described in Scheme 4. The 5,6-dimethoxy indanones of the general formula (15), purchased or prepared using known methodology, can be treated with tribromoborane and then with 1,2-iodoethane to provide 2,3,7,8-tetrahydro-6H-indene [5,6- b] [1,4] dioxin-6-ones of the general formula (16). 2,3,7,8-tetrahydro-6H-indene [5,6-b] [1,4] dioxin-6-ones of the general formula (16) can be treated under conditions such as those described in Scheme 2 to provide 1,4,7,8-tetrahydro [1,4] dioxino [2 ', 3', 5,6] indene [1, 2-c ] pyrazoles of the general formula (17), including, but not limited to 4 '- (1, 4,7,8-tetrahydro [1,4] dioxin [2 \ 3 \ 5,6] indene [1, 2- c] pyrazol-3-yl) -1, 1 '-biphenyl-4-ol. The present invention will now be described along with certain preferred embodiments, which are not intended to limit its scope. Otherwise, the present invention covers all alternatives, modifications and equivalents as being included within the scope of the claims. Thus, the following examples, which include the preferred embodiments, will illustrate the preferred practice of the present invention, it being understood that the examples are for purposes of illustration only of certain preferred embodiments and are presented to provide what is believed to be so. more useful and easily understood description of its procedures and conceptual aspects.
The compounds of the present invention were named by ACD / ChemSketch version 5.0 (developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada) or were given names according to the ACD nomenclature.
EXAMPLE 1 4- (6- (Trans-4-methylcyclohexinylamino) -1-, 4-dihydroindenoH, 2-p-I-3-yl) benzoic acid EXAMPLE 1A 1,4-Dihydro-indeneH, 2-pi-reazo-6-carb aldehyde To a solution of 6-bromo-1,4-dihydro-indene [1,2-c] pyrazole (0.100 g, 0.425 mmol, see US Patent 6297238 for preparation) in THF (3 mL) at 78 ° C was added 1.8 M PhLi in cyclohexane / ether (0.71 mL_, 1.28 mmol) followed by 1.3 M s-BuLi in cyclohexane (0.98 mL, 128 mmol) 30 minutes later. The reaction was stirred at -78 ° C for 60 minutes and DMF (0.33 mL, 4.25 mmol) was added. The dry ice bath was removed after 30 minutes. After 30 more minutes, the reaction was quenched with water. The reaction mixture was extracted with EtOAc, washed with 50% brine, dried over MgSO4, filtered, and concentrated. The concentrate was purified by flash chromatography eluted with EtOAc / hexane (7: 3 to 8: 2) to 0.053 g (68%) of the desired product as a brown solid. MS (DCI / NH3) m / z: 185.0 (M + H) +; 1 H NMR (300 Hz, CD 3 OD) d 3.76 (s, 2 H), 7.63 (s, 1 H), 7.62-7.97 (m, 2 H), 8.04 (s, 1 H), 10.00 (s, 1 H).
Example 1 B 3 -Yod or -1.4-dihydro-indeneM, 2-clirazole-6-carbaldehyde A suspension of Example 1A (7.90-, 0.0429 mole) and N- Yodosuccinimide (11.6 g, 0.0515 mol) in DMF (150 ml_) was heated at 80 ° C for 5.5 hours. The reaction was cooled and the solvent was evaporated. The catalyst was titrated with EtOAc and ether to give 7.20 g of a brown solid as the desired product. The filtrate was concentrated and purified by flash chromatography eluted with EtOAc / hexane (7: 3) to give 1.30 g of the desired product (combined yield: 64%). S (DCI / NH3) m / z: 310.9 (M + H) +; 1H NMR (300 MHz, DMSO-d6) d 3.63 (s, 0.8H), 3.68 (S.1.2H), 7.72 (d, J = 7.46Hz, 0.5H), 7.83 (d, J = 7.80 Hz, 0.5 H), 7.96 (m, 1H), 8.07 (m, 1H), 10.03 (s, 1H), 13.45 (s, 0.6H), 13.72 (s, 0.4H).
Example 1C N - [(3-Vodo-1,4-dihydroindenoM, 2-clirazol-6-inmetin-N- (trans-4-methylcyclohexo-T-amino and Nr (3-vodo-1,4-dihydroindenof 1,2-clPirazole- 6-yl) metin-N- (cis-4-methylcyclohexyl) amine To a suspension of Example 1B (7.18 g, 0.0232 mol) in EtOH (500 ml_) was added 4-methylcyclohexylamine hydrochloride (8.66 g, 0.0579 mol ) and potassium carbonate (4.81 g, 0.0348 mol) .The mixture was heated to reflux overnight and cooled to room temperature.To the previous yellow suspension was added NaBH4 (1.76 g, 0.0464 mol) in two portions and the The reaction mixture was stirred overnight.After filtration of the solid, the filtrate was concentrated and purified by flash chromatography eluted with EtOAc / MeOH / N H 4 OH (10: 0.2: 0.02 to 10: 1: 0.1 ) to give 2.20 g of the cis product (highest Rf) as a yellow solid and 3.60 g of the trans product as an amyl solid: MS (DCI / NH3) m / z: 408.0 (M + H) +; 1 H NMR (300 MHz, CD3OD) d 0.96 (d, J = 6.78Hz, 3H), 1.35-1.70 (m, 9H), 2.56 (m, 1H), 3.53 (s, 2H), 3.81 (s, 1H) ), 7.35 (d, J = 7.80 Hz, 1H), 7.54 (s, 1H), 7.58 (d, J = 7.46Hz, 1H). trans isomer: MS (DCI / NH3) m / z: 408.0 (M + H) +; 1H NMR (300 MHz, CD3OD) d 0.88 (d, J = 6.44Hz, 3H), 1.09-1.24 (m, 2H), 1.28-1.53 (m, 2H), 1.62 (m, 1H), 1.67-1.79 ( m, 2H), 1.93-2.05 (m, 2H), 2.48 (m, 1H), 3.53 (s, 2H), 3.84 (s, 2H), 7.34 (d, J = 7.80 Hz, 1H), 7.53 (s) , 1H), 7.58 (d, J = 7.80 Hz, 1H).
EXAMPLE 1 D Acid 4- (6- r (trans-4-methylcyclohexaneaminoTmethyl) -, 4- dihydronide, 2-clpyrazol-3-yl) benzoic A mixture of Example 1C (trans, 45.0 mg , 0.110 mmol), 4-carboxybenzene boronic acid (20.1 mg, 0.121 mmol), Na2CO3 (1 M, 0.26 mL, 0.264 mmol), and Pd (PPh3) 2C12 (7.70 mg, 0.0110 mmol) in DME / EtOH / H20 ( 7: 2: 3, 1.2 mL) in a 2 ml cap was heated at 160 ° C for 450 seconds on a Smith Synthesizer (300W) .The reaction was cooled using 2832 kg / cm2 of pressurized air. evaporated and the crude product was purified using preparative HPLC to give 25.0 mg (26%) of the desired product as a pale yellow colored foam.The purification was processed on a Waters Simmetri C8 column (particle size 25mm X 100mm, 7 gm ) using a gradient of 10% a 100% acetonitrile: 0.1% aqueous TFA for 8 min (10 min operation time) and at a flow rate of 40 mL / min. MS (DCI / NH3) m / z: 402.2 (M + H) +; 1H NMR (300 MHz, CD3OD) d 0.95 (d, J = 6.44Hz, 3H), 1.00-1.20 (m, 2H), 1.33-1.60 (m, 3H), 1.81-1.98 (m, 2H), 2.15- 2.30 (m, 2H), 3.15 (m, 1H), 3.96 (s, 2H), 4.31 (s, 2H), 7.52 (m, 1H), 7.71 (m, 1H), 7.81 (d, J = 7.80 Hz , 1H), 7.90 (d, J = 8.81Hz, 2H), 8.15 (d, J = 8.48Hz, 2H).
Example 2: 4- (6-. {F (cis-4-methylcyclohexyl) aminoTmethyl> -1,4-dihydroindenof1,2-cl pyrazol-3-yl) benzoic acid The product was prepared using the procedure of Example 1D replacing the trans product of Example 1C with the cis product of Example 1C. MS (DCI / NH3) m / z: 402 (M + H) +; 1 H NMR (300 MHz, CD 3 OD) d 1.04 (d, J = 7.12 Hz, 3 H), 1.50-1.98 (m, 9 H), 3.23 (m, 1 H), 3.98 (s, 2 H), 4.31 (s, 2 H) , 7.53 (d, J = 9.15Hz, 1H), 7.73 (s, 1H), 7.82 (d, J = 7.80 Hz, 1H), 7.91 (d, J = 8.81Hz, 2H), 8.15 (d, J = 8.48Hz, 2H).
Example 3 4- (6-fr (traps-4-methylcyclohexinaminolmethyl> -, 4-dihydroindene G1, ethyl 2-clirazole-3-inbenzoate To a degassed suspension of Example 1C (trans, 45.0 mg, 0.110 mmol) in DME / EtOH / H20 (7: 3: 2) 4- (4,4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -benzoic acid ethyl ester was added (31.8 μ? _, 0.121 mmol), Na 2 CO 3 (1M, 0.11 mL), and Pd (PPh 3) 2 Cl 2 (7.7 mg, 0.0110 mmol). The reaction mixture was heated overnight at 85 ° C in a sealed flask. The mixture was concentrated and the residue was extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified using preparative HPLC (see condition in Example 1D) to give 8.8 mg (12%) of the desired product as a white foam. MS (DCI / NH3) m / z: 430.2 (M + H) +; 1 H NMR (300 Hz, CD3OD) d 0.95 (d, J = 6.78Hz, 3H), 1.09 (m, 2H), 1.42 (t, J = 7.12Hz, 3H), 1.42-1.57 (m, 3H), 1.82-1.94 (m, 2H), 2.16-2.29 (m, 2H), 3.15 (m, 1H), 3.98 (s, 2H), 4.30 (s, 2H), 4.40 (q, J = 7.12Hz, 2H) , 7.52 (d, J = 7.80 Hz, 1H), 7.72 (s, 1H), 7.82 (d, J = 7.80 Hz, 1H), 7.92 (d, J = 8.82Hz, 2H), 8.15 (d, J = 8.48Hz, 2H).
EXAMPLE 4 4- (6-. {R (trans-4-idroxycyclohexyl) amino-1-yl-1, 4-dihydroindenoH, 2-c1pyrazol-3-yl) benzoic acid Example 4A trans-4-r (3-lodo-1,4-dihydro-indenof1,2-cT-irazol-6-ylmethyl) -aminol-cyclohexane The desired product was prepared by replacing 4-methylcyclohexylamine hydrochloride with trans-4 hydrochloride. -hydroxycyclohexylamine in Example 1C. MS (DCI / NH3) m / z: 410.0 (M + H) +; 1H NMR (300 MHz, CD3OD) 5 1.09-1.35 (m, 4H), 1.82-2.08 m, 4H), 2.48 (m, 1H), 3.47-3.58 (m, 3H), 3.82 (s, 2H), 7.34 (m, 1H), .52 (m, 1H), 7.58 (d, J = 7.80 Hz, 0.8H), 7.65 (d, J = 7.80 Hz, 0.2H).
Example 4B 4- (6- F (trans-4-hydroxycyclohexyl) aminomethyl] -1, 4-dihydroindenoM, 2-clpyrazol-3-yl) benzoic acid The desired product was prepared by replacing Example 1C with Example 4A in Example 1D. MS (DCI / NH3) m / z: 404.2 (M + H) +; 1H NMR (300 MHz, CD3OD) d 1.27-1.61 (m, 4H), 2.02-2.16 (m, 2H), 2.18-2.32 (m, 2H), 3.07-3.25 (m, 1H), 3.50-3.66 (m , 1H), 3.97 (s, 2H), 4.30 (s, 2H), 7.51 (dd, J = 7.80, 1.36Hz, 1H), 7.71 (s, 1H), 7.81 (d, J = 7.80 Hz, 1H) , 7.91 (d, J = 8.48Hz, 2H), 8.15 (d, J = 8.48Hz, 2H).
Example 5 N- r3- (6-. {R (trans-4-hydroxycyclohexinylaminoTmetU.) -1 A- dihydroindenoM, 2-c1pyrazole-3-Qphenyllacet amide The desired product was prepared by replacing Example 1C and 4-acid. carboxybenzene boronic with Example 4A and 3-acetamidobenzene boronic acid in Example 1D MS (DCI / NH3) m / z: 417.2 (M + H) +; 1H NMR (300 MHz, CD3OD) d 1.28-1.69 ( m, 4H), 2.03-2.14 (m, 2H), 2.19 (s, 3H), 2.21-2.33 (m, 2H), 3.17 (m, 1H), 3.58 (m, 1H), 3.92 (s) , 2H), 4.29 (s, 2H), 7.34-7.59 (m, 4H), 7.70 (s, 1H), 7.80 (d, J = 8.14Hz, 1H), 8.24 (m, 1H).
Example 6 4- (6-. {F (trans-4-hydroxycyclohexinamino-methyl> -1.4- dihydroin den, 2-chloro-l-3-yl) benzamide The desired product was prepared by replacing Example 1C and acid 4-carboxybenzene boronic with Example 4A and 4- (4, 4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -benzamide in Example 1 D. MS (DCI / NH3) m / z: 403.3 (+ H) +; 1 H NMR (300 MHz, CD3CD) d 1.29-1.59 (m, 4H), 2.03-2.15 (m, 2H), 2.20-2.32 (m, 2H), 3.17 (m, 1H), 3.56 (m, 1H), 3.97 (s, 2H), 4.30 (s, 2H), 7.52 (dd, J = 7.80, 1.36Hz, 1H), 7.72 (s, 1H), 7.82 (d, J = 7.80 Hz , 1H), 7.90 (d, J = 8.48Hz, 2H), 8.02 (d, J = 8.48Hz, 2H).
EXAMPLE 7 4-R6- (4-morpholylmethyl) -1,4-d-hydrocarbonic acid, 2-c-thiazole-3-ylbenzoic acid Example 7A 3-Iodo-6-morpholin-4-ylmethyl-1,4-dihydro-indeneF 1, 2-clirazole A mixture of Example 1B (1.00 g, 3.22 mmol), morpholine (0.84 mL, 9.66 mmol), and TsOH H20 (61.2 mg, 0.322 mmol) in toluene (50 mL) was heated at reflux overnight. The solvent was evaporated. To the resulting residue were added EtOH (40 mL), THF (10 mL), and NaBH 4 (0.182 g, 4.83 mmol) at room temperature. The mixture was stirred overnight and the resulting solid was filtered. The concentrate was concentrated, treated with 1N HCl, and extracted with EtOAc. The layer aqueous was basified using 3N NaOH and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography eluted with EtOAc / MeOH (95: 5) to give 0.387 g (32%) of the desired product as a pale yellow solid. MS (DCI / NH3) m / z: 382.0 (M + H) +; 1H NMR (300 MHz, CD3OD) d 2.44-2.51 (m, 4H), 3. 53 (s, 2H), 3.57 (s, 2H), 3.66-3.72 (m, 4H), 7.34 (d, J = 8.14Hz, 1H), 7. 54 (s, 1H), 7.58 (d, J-7.80 Hz, 1H).
Example 7B 4-Re (4-morpholinylmethyl) -1,4-dihydroindeneM, 2-cTpirazol-3-H-benzoic acid The desired product was prepared by replacing Example 1C with Example 7A in Example 1D. MS (DCI / NH3) m / z: 376.1 (M + H) +; 1H NMR (500 MHz, DMSO-d6) d 3.06-3.17 (m, 2H,) 3.26 (d, J = 12.17Hz, 2H), 3.87 (t, J = 11.54Hz, 2H), 3.91-3.99 (m, 4H), 4.40 (d, J = 4.37Hz, 2H), 7.66 (d, J = 7.80 Hz, 1H), 7.75 (d, J = 7.80 Hz, 1H), 7.89 (s, 1H), 7.98 (d, J = 8.42Hz, 2H), 8.06 (d, J = 8.42Hz, 2H), 11.61 (s, 1 H).
Example 8 4-r6- (4-morpholinylmethyl) -1,4-dihydroindenoM, methyl 2-clirazole-3-methylbenzoate To Example 7B (28.8 mg, 0.0643 mmol) in McOH (3 mL) was added concentrated HCl ( 0.50 mL). The mixture was heated to 65 ° C and stirred for 3 days. The reaction mixture was concentrated and purified using HPLC. The TFA salt of the desired product was converted to HCl (17.0 mg, 81%) using the procedure in Example 7B. The HPLC condition is indicated as follows: a Dinamx C18 column (5 gm, 21.4250 mm) containing a Rainin Dinamax solvent supply system with a Dinamax UV-D II detector was used. The solvent used was 20% to 100% acetonitrile / water containing 0.1% linear gradient TFA. The elution rate was 10 mUmin and the UV detection wavelength was set at 254 nm). MS (DCI / NH3) m / z: 390 (M + H) +; 1H NMR (400 Hz, DMSO-d6) d 3.05-3.18 (m, 2H), 3.22-3.30 (m, 2H), 3.77-3.87 (m, 2H), 3.89 (s, 3H), 3.91-4.00 (m , 4H), 4.40 (d, J = 4.60 Hz, 2H), 7.63 (d, J = 7.98Hz, 1H), 7.75 (d, J = 7.67Hz, 1H), 7.86 (s, 1H), 7.99 (d , J = 8.29Hz, 2H), 8.08 (d, J = 8.28Hz, 2H), 11.29 (s, 1H).
Example 9 4-F6- (4-morpholinylmetin-1,4-dihydroindenor, 2-cTpirazol-3-ylbenzamide The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 7A and 4- (4, 4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -benzamide in Example 1D. The product was purified by flash chromatography eluted with EtOAc / MeOH / NH 4 OH (10: 1). : 0.1) .MS (DCIJNH3) m / z: 375.2 (M + H) +; 1 H NMR (300 MHz, DMSO-d6) d 2.34-2.44 (m, 4H), 3.53 (s, 2H), 3.56-3.63 (m, 4H), 3.91 (s, 2H), 7.31 (d, J = 7.46Hz, 1H), 7.42 (s, 1H), 7.52 (s, 1H), 7.64 (m, 1H), 7.87 (d, J = 7.80 Hz, 2H), 8.00 (d, J = 8.48Hz, 3H), 13.29 (s, 1H).
Example 10 N-r3-f6- (4-morp olinylmethyl) -1,4-dihydroindenofl.2-clirazol-3-illphenyl > acetamide The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 7A and 3-acetamidobenzene boronic acid in Example 1D. MS (DCI / NH3) m / z: 389.2 (M + H) *; 1 H NMR (400 MHz, DMSO-d 6) d 2.10 (s, 3 H), 3.06-3.17 (m, 2 H), 3.22-3.32 (m, 2 H), 3.78-3.90 (m, 4 H), 3.95 (d, J = 14.12Hz, 2H), 4.40 (d, J = 3.68Hz, 2H), 7.41 (t, J = 7.83Hz, 1H), 7.58 (m, 3H), 7.74 (d, J = 7.67Hz, 1H), 7.88 (s, 1H), 8.13 (s, 1H), 10.18 (s, 1H), 11.37 (s, 1H).
Example 11 2- (Acetylamino) -4-r6- (4-morpholinylmethyl) -1,4-dihydroindenoH, 2-cl p-I-3 -i? benzoic Example 11A N- (5-Bromo-2-methyl-phenyl) -acetamide To a solution of 3-bromo-6-methylaniline (1.00 g, 5.37 mmol) in pyridine (8 mL) was added acetylchloride (0.76 mL, 10.7 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour and concentrated. The residue was extracted with EtOAc, it was washed with 5% citric acid, dried over MgSO 4, concentrated, and titrated with ether to give 0.750 g (61%) of the desired product as an off-white crystal. MS (DCI / NH3) m / z: 227.9 (M + H) +, 229.9 (M + 2 + H) +; HN MR (300 MHz, CDCI3) d 2.21 (s, 6H), 6.90 (m, 1H), 7.04 (d, J = 8.14Hz, 1H), 7.20 (d, J = 7.80 Hz, 1H), 8.06 (s) , 1 HOUR).
Example 11 B 2-Acetylamino-4-bromo-benzoic acid To a solution of Example 11A (0.372 g, 1.63 mmol) in pyridine (6 mL) and H20 (6 mL) KMn04 (1.03 g, 6.52 mmol) was added in 2 portions at room temperature. The reaction mixture was heated at 90 ° C for 4 hours and filtered immediately. The filter cake was rinsed with hot H20. The filtrate was concentrated and treated with H20. The solid material was filtered and the filtrate was acidified with 10% HCl until having pH = 3. The precipitate was filtered, rinsed with H20, and dried in a vacuum oven to give 0.398 g (95%) of the desired product as a white solid. MS (DC1 / NH3) m / z: 257.9 (M + H) +, 259.9 (M + 2 + H) +; 1H NMR (300 MHz, CD3OD) d 2.20 (s, 3H), 7.30 (dd, J = 8.48, 2.03Hz, 111), 7.97 (d, J = 8.48Hz, 1H), 8.84 (d, J = 2.03Hz , 1 HOUR).
Example 11 C 2-Acetylamino-4- (4,4,5,5-tetramethyl-, 3,21 dioxaborolan-2-yl) -benzoic acid methyl ester To a solution of Example 11B (45.0 mg, 0.174 mmol) in CH2Cl2 / MeOH (2 mlJ 0.3 mL) was added TMSCHN2. After the disappearance of a strong bubbling, the reaction mixture was concentrated. The crude methyl ester product was taken in the next step without purification. A mixture of the previous crude product, Pd2 (dba) 3 (3.2 mg, 0.0034 mmol), PCi3 (3.9 mg, 0.014 mmol), KOAc (25.6 mg, 0.261 mmol), and bis (pinacolato) diboro (53.0 mg, 0.209 mmol) in 1.4- dioxane (1.5 mL) was heated at 85 ° C overnight in a stoppered flask. The solvent was evaporated and the residue was extracted with EtOAc, washed with a slammer, dried over MgSO4, filtered, concentrated, and purified by means of inanstaneous vapor chromatography eluted with hexane / EtOAc (8: 2 to 7: 3) to give 31.0 mg (56%) of the desired product as a whitish solid. MS (DCI / NH3) m / z: 320.1 (M + H) +; 1 H NMR (300 MHz, DMSO-d 5) d 1.31 (s, 12 H), 2.11 (s, 3 H), 3.85 (s, 3 H), 7.45 (d, J = 8.82 Hz, 1 H), 7.87 (d, J = 7.80 Hz, 1H), 8.42 (s, 1H), 10.42 (s, 1H).
Example 11D 2- (Acetylamino) -4-f 6- (4-morpholinylmethyl) -1,4-dihydroindene? , 2-Cli razo I-3-Inbenzoic The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 7A and Example 11C in Example 1D. The product was purified using the HPLC condition in Example 8. MS (DCI / NH3) m / z: 433.2 (M + H) +; H NMR (500 MHz, CD3OD) d 2.17 (s, 3H), 3.09-3.36 (m, 2H), 3.88 (s, 2H) 3.56-4.06 (in, 6H), 4.35 (s, 2H), 7.44 (d , J = 7.80 Hz, 1H), 7.50 (d, J = 6.55Hz, 1H), 7.65 (s, 1 H), 7.74 (d, J = 7.80 Hz, 1H), 7.83 (d, J = 8.73Hz, 1H), 8.09 (d, J = 8.11Hz, 1H) ), 8.99 (s, 1H).
EXAMPLE 12 Acid 4- (6-r (4-hydroxy-1-p.peridin-n-methyl-1,4-dihydro-n-nofof-1,2-c-pyrazol-3-yl> benzoic acid Example 12A 1 - (3-Iodo-, 4-dihydro-indenof 1,2-cli razo l-6-yl metí I) -pi per ¡din -4- _ [The desired product was prepared by replacing morpholine with 4- hydroxypiperidine in Example 7A. MS (DCI / NH3) m / z: 396.0 (M + H) +; 1 H NMR (300 MHz, CD 3 OD) d 1.48-1.65 (m, 2 H), 1.77-1.91 (m, 2 H), 2.12-2.31 (m, 2 H), 2.74-2.89 (m, 2 H), 3.54 (s, 2 H) ), 3.57-3.69 (m, IH), 3.57 (s, 2H), 7.33 (d, J = 9.15Hz, 1 H), 7.52 (s, 1H), 7.58 (d, J = 7.80 Hz, 1H).
Example 12B 4-6-R (4-Hydroxy-1-piperidinyl) metin-1,4-dihydroindenoH, 2-chloro I-3-yl) benzoic acid The desired product was prepared by replacing Example 1C with Example 12A in Example 1D. MS (DCI / NH3) m / z: 390.2 (M + H) +; 1H NMR (400 MHz, DMSO-d6) d 1.66-1.82 (m, 2H), 1.89-2.07 (m, 2H), 2.94 (m, 1H), 3.09-3.23 (m, 2H), 3.34 (m, 1H ), 3.64 (m, 1H), 3.97 (s, 2H), 4.34 (dd, J = 15.04, 4.60 Hz, 2H), 6.78-6.90 (m, 2H), 7. 56-7.67 (m, 0.5H), 7.71-7.81 (m, 2H) 7.84 (d, J = 13.81Hz, 0.5H,) 7.97 (d, J = 8.29Hz, 1H), 8.06 (d, J = 8.59 Hz, 1H), 10.55 (s, 1H).
Example 13 4-f ß-f (4-hydroxy-1-piperidinyl) methylene-1,4-dihydroindeneM. 2-c 1 irazol-3-yl benzamide The desired product was prepared by replacing Example 1C and 4-carboxybenzene acid. boronic acid with Example 12A and 4- (4, 4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -benzamide in Example 1D. S (DCI / NHg) m / z: 389.2 (M + H) +; H NMR (400 Hz, DMSO-d6) d 1.64-1.80 (m, 2H), 1.88-2.09 (m, 2H), 2.96 (m, 1H), 3.08-3.22 (m, 2H), 3.33 (m, 1H ), 3.63 (m, 1H), 3.95 (s, 2H), 4.33 (dd, J = 14.58, 5.06Hz, 2H), 7.40 (s, 1H), 7.62 (dd, J = 13.20.7.67Hz, 1H) , 7.74 (d, J = 7.67Hz, 1H), 7.84 (d, J = 13.20 Hz, 1H), 7.91 (d, J = 8.59Hz, 2H), 8.01 (m, 2H), 10.65 (s, 1H) .
EXAMPLE 14 N- (3-. {6-R (4-hydroxy-1-yl-dihnyi) -methin-1,4-dihydroindenori, 2-cl-irazol-3-yl) -phenyl) -acetamide The desired product was prepared by replacing the Example 1C and 4-carboxybenzene boronic acid with Example 12A and 3-acetamidobenzene boronic acid in Example 1D. MS (DCI / NH3) m / z: 403.2 (M + H) +; 1 H NMR (400 MHz, DMSO-d 6) d 1.65-1.80 (m, 2H), 1.88-2.04 (m, 2H), 2.95 (m, 1H), 3.09-3.23 (m, -2H), 3.35 (m, 1H), 3.62 (m, 1H), 3.88 (s, 2H) 4.33 (dd, J = 15.50, 5.06Hz, 2H), 7.41 (t, J = 7.83Hz, 1H), 7.50-7.64 (m, 3H), 7.73 (d, J = 7.67Hz, 1H), 7.84 (d, J = 14.12Hz, 1H), 8.13 (s, 1H), 10.15 ( s, 1H), 10.46 (s, 1H).
Example 15 4- (6-R (Neopentylamino) metin-1,4-dihydro-ndenori, 2-C 1 -Izolzol-3-yl.} -benzoic acid Example 5A (2.2-Dimethyl-propyl) - (3-iodo-, 4-dihydro-indenon, 2-c-pyrazol-6-ylmethyl) -amine The desired product was prepared by replacing morpholine with neopentylamine in Example 7A. MS (DCI / NH3) m / z: 382.1 (+ H) +; 1 H NMR (300 MHz, CD 3 OD) d 0.92 (s, 9 H), 2.34 (s, 2 H), 3.53 (s, 2 H), 3.82 (s, 2 H), 7.35 (d, J = 7.80 Hz, 1 H), 7.52 -7.61 (m, 2H).
Example 15B Acid 4-. { 6-r (neopentylamino) methyl-1-1,4-dihydro-indeneH, 2-chloro-I-3-I liberate the co-product The desired product was prepared by replacing Example 1C with Example 15A in Example 1D. MS (DCI / NH3) m / z: 376.2 (M + H) +; 1 H NMR (500 MHz, DMSO-d 6) S 0.98 (s, 9 H), 2.62-2.77 (m, 2 H), 3.96 (s, 2 H), 4.23 (s, 2 H), 7.62 (d, J = 7.80 Hz, 1H), 7.74 (d, J = 7.80 Hz, 1H), 7.83 (s, 1H), 7.96 (d, J = 8.42Hz, 2H), 8.06 (d, J = 8.42Hz, 2H), 8.94 (s, 1 HOUR).
Example 16 4-. { 6-f (neopentylamino) methyl-4-dihydroindene, 2-clpyrazol-3-ipbenzamide The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 5A and 4 (4,4,5,5- tetramethyl- [1,2,2] dioxaborolan-2-yl) -benzamide in Example 1D. MS (DCI / NH3) m / z: 375.2 (M + H) +; 1 H NMR (300 MHz, DMSO-d 6) d 0.97 (s, 9 H), 2.62-2.81 (m, 2 H), 3.97 (s, 2 H), 4.24 (s, 2 H), 7.42 (s, 1 H), 7.60 ( d, J = 8.48Hz, 1H), 7.74 (d, J = 7.80 Hz, 1H), 7.81 (s, 1H), 7.90 (d, J = 8.48Hz, 2H), 8.01 (d, J = 8.48Hz, 2H), 8.86 (s, 1H).
Example 17: 4- (6-f r (3-hydroxy-2,2-dimethylpropyl) amnolmethyl> -1.4- dihydroindenori, 2-cl irazol-3-yl) benzoic acid Example 17A 3-f (3-Iodo-1,4-dihydro-indeneM, 2-c1pyrazol-6-ylmethyl) -amino1-2,2-dimethyl-propan-1-ol The desired product was prepared by replacing morpholine with 3- amino-2,2-dimethyl-propanol in Example 7A. MS (DCI / NH3) m / z: 398.1 (M + H) +; 1H NMR (300 MHz, CD3OD) d 0.90 (s, 6H), 2.52 (s, 2H), 3.36 (s, 2H), 3.53 (s, 2H), 3.80 (s, 2H), 7.33 (d, J = 6.78Hz, 1H), 7.52 (s, 1H), 7.57 (d, J = 7.80 Hz, 1H).
Example 17B 4- (6- ^ r (3-Hydroxy-2,2-dimethylpropyl) aminolmethyl> -1.4- dihydroindenoH, 2-clpyrazol-3-yl) benzoic acid The desired product was prepared by replacing Example 1C with Example 17A in Example 1D. MS (DC / NH3) m / z: 391.3 (M + H) +; 1H NMR. (500 MHz, DMSO-d6) d 0.91 (s, 6H), 2.77 (m, 2H), 3.23 (S, 2H), 3.96 (s, 2H), 4.23 (s, 2H) 7.62 (d, J = 7.80 Hz, 1H), 7.73 (d, J = 7.80 Hz, 1H), 7.83 (s, 1H), 7.97 (d, J = 8.42Hz, 2H), 8.06 (d, J = 8.42Hz, 1H), 8.91 ( s, 2H).
Example 18 4- (6- { R (3-hydroxy-2,2-dimethylpropyl) amino-1-methyl-> 1,4-dihydroindene, 2-clpyrazol-3-yl) benzamide The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 17A and 4- (4, 4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -benzamide in Example 1D. MS (DCI / NHs) m / z: 391.2 (M + H) +; 1 H NMR (500 MHz, DMSO-d 6) 5 0.90 (s, 6 H), 2.82 (m, 2 H), 3.24 (d, J = 4.99 Hz, 2 H), 3.96 (s, 2 H), 4.23 (d, j = 17.47Hz, 2H), 7.49 (d, J = 8.42Hz, 0.5H) 7.54 (d, J = 8.11Hz, 0.5H), 7.66 (s, 1H), 7.75 (s, 1H), 7.90 (d, J = 8.42Hz, 1H), 8.01 (d, J = 8.11Hz, 3H), 8.53 (s, 2H).
Example 19 4-r6- (Hydroxymethin-1,4-dihydroindene, 2-dpyrazol-3-benzoic acid Example 19A (3 -Yod o- 1, 4-dihydro-indenof1,2-cTpirazol-6-n-methanol) To a suspension of Example 1B (0.500 g, 1.61 mmol) in a mixture of MeOH (9 mL) and TF (3 ml_) NaBH 4 (73.0 mg, 1.93 mmol) was added at room temperature The mixture was stirred for 2 hours and the solvent was evaporated The resulting concentrate was dissolved in hot CH 2 Cl 2 with a small amount of MeOH and the desired product was recrystallized to give 0.324 g (65%) of the desired product as a brown solid MS (DCI / NH3) rn / z: 312.9 (M + H) +; 1H NMR (300 MHz, CD3OD) d 3.54 (s, 2H) , 4.66 (s, 2H), 7.35 (d, J = 7.80 Hz, 1H), 7.55 (s, 1H), 7.59 (d, J = 7.80 Hz, 1H).
Example 19B 4-R6- (Hydroxymethyl) -1,4-dihydroindenof 1,2-clirazole-3-Mbenzoic acid The desired product was prepared by replacing Example 1C with Example 19A in Example 1D. MS (DC1 / NH3) miz: 307.1 (M + H) +; 1 H NMR (500 MHz, DMSO-d 6) d 3.90 (s, 2 H), 4.57 (s, 2 H), 7.33 (d, J = 7.49 Hz, 1 H), 7.54 (s, 1 H), 7.61 (d, J = 7.80 Hz, 1H), 7.94 (d, J = 8.42Hz, 2H), 8.05 (d, J = 8.42Hz, 2H).
EXAMPLE 20 4-r6- (hydroxymethyl) -1,4-dihydroindenori, 2-cTpyrazol-3-m benzamide The desired product was prepared by replacing Example IC and 4-carboxybenzene boronic acid with Example 19A and 4- (4,4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) -benzamide in the Example 1D. MS (DCI / NH3) m / z: 306.1 (M + H) +; 1 H NMR (500 Hz, DMSO-d 6) 5 3.90 (s, 2 H), 4.57 '(s, 2 H), 7.32 (d, J = 7.49 Hz, 1 H), 7.54 (s, 1 H), 7.61 (d, J = 7.80 Hz, 1H), 7.89 (d, J = 8.42Hz, 2H), 8.00 (d, J = 8.42Hz, 2H).
EXAMPLE 21 4-R6- (methoxymethyl) -1,4-dihydroindenon acid, 2-c1pyrazol-3-illbenzoic acid Example 21A 3-Iodo-6-methoxymethyl-1,4-dihydro-indenori, 2-chlororazole One, Example 19A (0.294 g, 0.942 mmol), LiBr (0.090 g, 1.04 mmol), and PBr3 (0.14 mL, 11.49 mmol) in DMF (5 mL) was stirred at room temperature for 2 hours. Ice was added to the reaction mixture and the resulting precipitate was filtered. The solid was suspended in MeOH and treated with Et 3 N (1 mL). The mixture was concentrated and purified by flash chromatography eluting with EtOAc / CH2Cl2 (2:98 to 5:95) to give 0.0422 g (12%) of the desired product. MS (DCI / NH3) m / z: 327.0 (M + H) +; 1 H NMR (500 MHz, CD 3 OD) d 3.38 (s, 3 H), 3.53 (s, 2 H), 4.50 (s, 2 H), 7.33 (d, J = 7.80 Hz, 1 H), 7.52 (s, 1 H), 7.59 (m, 1H).
Example 21 B 4-F6- (methoxymethin-1,4-dihydroindenof, 2-chlorozo-3-m benzoic acid) The desired product was prepared by replacing Example 1C with Example 21A in Example 1D.S (DCI / NH3) m / z: 321.0 (+ H) +; 1H NR (400 MHz, DMSO-d6) d 3.31 (s, 3H), 3.89 (s, 2H), 4.46 (s, 2H), 7.31 (d, J = 7.67Hz , 1H), 7.52 (s, 1H), 7.63 (d, J = 7.67Hz, 1H), 7.92 (d, J = 8.59Hz, 2H), 8.04 (d, J = 8.59Hz, 2H).
EXAMPLE 22 4-f6- (Alliloxin-1,4-dihydroindeneM, 2-c] pi-3-benzoic acid Example 22A 5-Allyloxy-indan-1-o na To a solution of 5-idroxy-1-indanone (4.27 g, 0.0288 mol) in THF / DMF (5 mL / 10 mL) at 0 ° C was added NaH (60 mL). %, 1.21 g, 0.0303 mol) followed by allyl bromide (2.7 mL, 0.0317 mol). The reaction was warmed to room temperature and stirred overnight. The reaction mixture was quenched with water and extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography eluted with EtOAc / hexane (1: 1) to give 4.29 g (79%) of the desired product as a brown oil. MS (DCI / NH3) m / z: 189.1 (M + H) +; 1H NMR (300 MHz, DMSO-d6) d 2.53-2.64 (m, 2H), 2.96-3.11 (m, 2H), 4.64-4.72 (m, 2H), 5.29 (dd, J = 10.51, 1.36Hz, 1H ), 5.42 (dd, J = 17.29, 1.70 Hz, 1H), 6.06 (m, 1H), 6.98 (dd, J = 8.48, 2.37Hz, 1H), 7.10 (d, J = 2.03Hz, 1H) 7.56 (d, J = 8.48Hz , 1 HOUR).
Example 22B 4-R (methyl 5- (allyloxy) -1-oxo-1,3-dihydro-2H-indon-2-ylidene) (hydroxy) metMlbenzoate To a solution of Example 22A (0.222 g, 1.18 mmol) in THF (5 ml_) at 78 ° C was added LDA (2.0M, 0.65 ml_, 1.30 mmol). After 40 minutes, a pre-mixed suspension of CDI (0.191 g, 1.18 mmol) and terephthalic acid monomethyl ester (0.213 g, 1.18 mmol) in THF / DMF (4 mL / mL) was added to the above reaction mixture. -78 ° C. The dry ice bath was removed after 15 minutes and the reaction mixture was stirred for 1 hour. The reaction was quenched with an NH 4 Cl solution and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated. The concentrate was titrated with ether to give 0.132 g (32%) of the desired product as a yellow solid. MS (DCI / NH3) m / z: 351.1 (M + H) +; 1 H NMR (300 MHz, CDCl 3) 8 3.90 (s, 2 H), 3.96 (s, 3 H), 4.60-4.69 (m, 2 H), 5.34 (dd, J = 10.51, 1.36 Hz, 1 H), 5.45 (dd, J = 17.29, 1.36Hz, 1H), 6.07 (m, 1H), 6.97-7.04 (m, 2H), 7.83 (d, J = 9.16Hz, 1H), 7.97 (d, J = 8.48Hz, 2H), 8.10-8.23 (m, 2H).
Example 22C 4-r6- (allyloxy) -1,4-dihydro-n-denon, methyl-2-clirazol-3-OH-benzoate A mixture of Example 22B (1.70 g, 4.85 mmol), hydrazine monohydrate (0.28 ml_, 5.82 mmol), and AcOH (0.33 ml_, 5.82 mmol) in EtOH (120 ml_) was heated at 90 ° C overnight. The reaction was cooled and the precipitate was filtered. The filter cake was rinsed with ether to give 1.56 g (93%) of the desired product as a white solid. S (DCI / NH3) m / z: 347.1 (M + H) +; 1 H NMR (300 MHz, D SO-d 6) d 3.88 (s, 5H), 4.58-4.67 (m, 2H), 5.28 (dd, J = 10.51, 1.36Hz, 1H), 5.43 (dd, J = 17.12, 1, 97Hz, 1H), 6.09 (m, 1H), 6.97 (d, J = 8.48Hz, 1H), 7.21 (s, 1H), 7.59 (d, J = 8.48Hz, 1H), 7.87-8.01 (m , 2H), 8.02-8.14 (m, 2H), 13.25 (s, 1H).
Example 22D Acid 4-f6- (allyloxy) -1,4-dihydroindenOn .2 - p i razo I - 3 - i I? benzoic A mixture of Example 22C (0.300 g, 0.866 mmol), LÍOH.H20 (0.109 g, 2.60 mmol) in THF / MeOH / H20 (20/5/3 mL) was heated at 60 ° C for 2 hours. After cooling, the reaction mixture was treated with TFA until it had a pH = 3. The solid material was filtered, rinsed with water, and dried in a vacuum oven to give 0.290 g (100%) of the desired product as a white solid. MS (DC / NH3) m / z: 333.1 (M + H) +; 1 H NMR (300 MHz, DMSO-de) d 3.87 (s, 2 H), 4.63 (d, J = 5.09 Hz, 2 H), 5.28 (dd, J = 10.51, 1.70 Hz, 1 H), 5.43 (dd, J = 17.12, 1.53Hz, 1H), 6.08 (m, 1H), 6.97 (dd, J = 8.48.2.37Hz, 1H), 7.21 (d, J = 2.37Hz, 1H), 7.56 (d, J = 8.48Hz, 1H), 7.91 (d, J = 8.48Hz, 2H), 8.04 (d, J = 8.48Hz, 2H) 13.11 (s, 1H).
Example 23 4-f6- (allyloxy) -1, 4-dihydroindenof1, 2-clirazol-3-yl-1-benzamide A mixture of Example 22D (50.0 mg, 0.150 mmol), HOBt (28.5 mg, 0.211 mmol), EDC (40.4 mg, 0.211 mmol), NH4CI (40.1 mg, 0.750 mmol) ), and Et3N (0.14 mL, 0.975 mmol) in DMF (3 mL) in a stoppered flask was stirred at room temperature for 24 hours. The reaction mixture was digested with EtOAc and washed with NaHCO 3 and brine. The organic layer was dried over MgSO4, filtered, concentrated, and titrated with EtOAc to give 28.6 mg (58%) of the desired product as a white powder. MS (DCI / NH3) m / z: 332.1 (M + H) +; 1 H NMR (300 MHz, DMSO-d 6) d 3.87 (s, 2 H), 4.54-4.69 (m, 2 H) 5.28 (dd, J = 10.51, 1.70 Hz, 1 H), 5.43 (dd, J = 17.29, 1.70 Hz , 1H), 6.09 (m, 1H), 6.97 (d, J = 8.48Hz, 1H), 7.20 (s, 1H), 7.41 (m, 1H), 7.58 (m, 1H), 7.79-7.92 (m, 2H), 4.94-8.06 (m, 3H), 13.15 (s, 1H).
EXAMPLE 24 Methyl 4- (6-hydroxy-1,4-dihydroindenof1,2-c-thorozol-3-yl) benzoate A suspension of Example 22C (0.200 g, 0.577 mmol) in THF (16 mL) was heated until a clear solution appeared and cooled to room temperature. To this solution was added Pd (PPh3) 4 (0.0130 g, 2%). A suspension of NaBH 4 in THF (2 mL) was added to the above reaction mixture in three portions at 0 ° C. the reaction was warmed to room temperature and stirred overnight. The reaction mixture was treated with acetone and the solvent was evaporated. The residue was treated with hot MeOH and the solid was filtered. The filtrate was concentrated and titered with hot EtOAc. After cooling, the solid was filtered and rinsed with EtOAc to give 0.179 g (100%) of the desired product as a yellow solid. MS (DCI / NH3) m / z: 307.0 (+ H) +; 1 H NMR (300 MHz, DMSO-ds) d 3.60 (s, 3 H), 3.86 (s, 2 H), 6.43 (d, J = 7.46 Hz, 1 H), 6.67 (s, 1 H), 7.17 (d, J = 8.14Hz, 1H), 7.89 (d, J = 8.48Hz, 2H), 7.99 (d, J = 8.48Hz, 2H).
Example 25 4- (6-Hydroxy-1,4-dihydroindenori, 2-c1pyrazol-3-yl) benzoic acid The desired product was prepared by replacing Example 22C with Example 24 in Example 22D. MS (DCI / NH3) m / z: 292.9 (M + H) +; H NUR (300 MHz, DMSO-d6) d 3.82 (s, 2H), 6.77 (dd, J = 8.14, 2.03Hz, 1H), 7.00 (s, 1H), 7.44 (d, J = 8.14Hz, 1H) , 7.90 (d, J = 8.48 Hz, 2H), 8.03 (d, J = 8.48Hz, 2H).
EXAMPLE 26 Acid 4- (6-. {R (trans-4-hydroxycyclohexane-1-carbonyl> -1,4-dihydroindene, 2-pi-I-3-yl) benzoic acid Example 26A 3-iodo-1,4-acid -dihydro-ndenori, 2-Cytl-l-6-carboxylic acid A mixture of Example 1B (3.00 g, 9.67 mmol), KH2P04 (5.26 g, 0.0387 mol), and H2NS03H (1.41 g, 0.0145 mol) in 1,4-doxane / H20 (100/30 mL) was stirred at 0 ° C for 15 minutes. To this mixture was added NaCl02 (1.14 g, 0.0126 mol) in H20 (15 mL) dropwise. The reaction mixture was stirred for 15 minutes at 0 ° C followed by the addition of NaHS03 (1.11 g, 0.0106 mol). The resulting suspension was warmed to room temperature and stirred for 1 hour. The reaction mixture was treated with a Na2S203 solution and concentrated under reduced pressure. The residue was treated with water and stirred for 1 hour. The mixture was filtered and the filter torat was rinsed with water and dried in a vacuum oven to provide the title compound, which was used in the next step without further purification. S (DCI / NH3) m / z: 327.0 (M + H) +; H NMR (300 MHz, D SO-d6) d 3.57 (s, 2H), 7.67 (m, 1H), 7.98 (d, J = 7.80 Hz, 1H), 8.10 (s, 1H).
Example 26B (3-iodo-1,4-dihydro-indenof, 2-cTpirazole-6-carboxylic acid 4-hydroxy-cyclohexyO-amide The desired product was prepared by replacing NH4CI and Example 22D with traps-4-amino-cyclohexanol and Example 26A in Example 23. MS (DCI / NH3) m / z: 424.0 (M + H) +; 1H NMR (300 MHz, DMSO-d6) d 1.12-1.48 (m, 4H), 1.71-1.93 (m, 4H), 3.41 (m, 1H), 3.55 (s, 0.5H), 3.60 (s, 0.5H), 3.74 (m, 1H), 4.55 (d, J = 4.41Hz, 1H), 7.56 ( d, J = 8.14Hz, 0.5H), 7.66 (d, J = 7.80 Hz, 0.5H), 7.86 (t, J = 7.97Hz, 1H), 8.01 (d, J = 5.76Hz, 1H), 8.20 ( d, J = 7.80 Hz, 1H).
Example 26C 4- (6- (trans-4-Hydroxycyclohexyl) aminolcarbonyl) -1,4-dihydroindenoM, 2-c1pyrazol-3-yl) benzoic acid The desired product was prepared by replacing Example 1C with Example 26B in Example 1D . MS (DCI / NH3) m / z: 418.2 (M + H) +; H NIMR (500 MHz, DMSO-d6) d 1.20-1.32 (m, 2H), 1.33-1.46 (m, 2H), 1.76-1.92 (m, 4H), 3.76 (m, 1H), 3.97 (s, 2H) ), 7.71 (d, J = 7.80 Hz, 1H), 7.88 (d, J = 7.18Hz, 1H), 7.95 (d, J = 8.11Hz, 2H), 8.03-8.08 (m, 3H), 8.20 (d) , J = 7.80 Hz, 1H).
Example 27: 4- acid. { 6-G (neo pe n ti lamí no) carbon i 11-1, 4-dihydroindenof1, 2-cT pirazol-3-il > benzoic Example 27A (3-iodo-1,4-dihydro-indenori, 2-chlororazole-6-carboxylic acid) -amide (2,2-dimethyl-propyl) -amide The desired product was prepared by replacing NH4CI and Example 22D with neopentylamine and Example 26A in Example 23. MS (DCl / NHg) m / z: 396.0 (M + H) +; 1 H NMR (300 MHz, DMSO-D 6) d 0.91 (s, 9 H), 3.12 (d, J = 6.44 Hz, 2 H), 3.59 (s, 2 H), 7.64 (m, 1 H), 7.88 (d, J = 8.14Hz, 1H), 8.06 (m, 1H), 8.37 (t, J = 6.27Hz, 1H).
Example 27B Acid 4-. { 6-r (neopentylamino) carbonin-1,4-dihydroindenoH, 2-cT pyrazole-3 ?} benzoic The desired product was prepared by replacing Example IC with Example 27A in Example 1D. MS (DCI / NH3) m / z: 390.1 (M + H) +; 1H NMR (500 ???, DMSO-D6) d 0.93 (s, 9H), 3.14 (d, J = 6.24Hz, 2H, 3.99 (s, 2H), 7.73 (d, J = 8.11Hz, 1H), 7.91 (d, J = 7.80 Hz, 1H), 7.96 (d, J = 8.42Hz 2H), 8.04-8.10 (m, 3H), 8.37- (t, J = 6.24, Hz 1H).
EXAMPLE 28 3-r4- (aminocarbonyl) phenNn-neopentyl-1,4-dihydroindenof, 2-chloro-l-6-carboxamide The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 27A and 4- (4, 4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -benzamide in Example 1D. MS (DCI / NH3) m / z: 389.2 (M + H) +; H NMR (300 MHz, DMSO-D6) d 0.93 (s, 9H), 3.14 (d, J = 6.10Hz, 2H) 3.99 (s, 2H), 7.41 (s, 1H), 7.73 (d, J = 8.14 Hz, 1H), 7.90 (d, J = 8.48Hz, 2H), 7.97-8.10 (m, 3H), 8.39 (t, J = 6.27Hz, 1H).
Example 29 4'-6-R (cis-4-methylcyclohexyl) aminolmethyl) -1,4-dihydroquinone? .2- c ^ p ^ razol-3-l) -1, 1 '-biphenl-4-ol Example 29A 4 '- (4,4.5.5-Tetramethyl-ri, 3,21d-oxaborolan-2-yl) -biphenyl-4-ol A mixture of 4'-bromo-biphenyl-4-ol (0.300 g, 1.20 mmol), bls (pinacolato) -diboron (0.336 g, 1.32 mmol), PdCI2 (dppf) .CH2CI2 (0.0293 g, 3%), dppf (0.0199 g, 3%), and KOAc (0.353 g, 3.60 mmol) in 1,4-dioxane (6 mL) was heated at 90 ° C overnight. The reaction mixture was concentrated and the residue was extracted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated, and purified by flash chromatography eluted with hexane / EtOAc (1: 1) to give 0.278 g (78%) of the desired product as a white foam. MS (DC / NH3) m / z: 296.1 (M + H) +; 1 H NMR (300 Hz, CDCl 3) d 1.36 (s, 12 H), 6.90 (d, J = 8.48 Hz, 2 H), 7.53 (d, J = 12.72, 8.65 Hz, 4 H), 7.85 (d, J = 8.14 Hz , 2H).
Example 29B 4 '- (6-. {F (cis-4-methylcyclohexyl) amino-1-methyl) -1,4-dihydroindene G1, 2-clpyrazol-3-yl) -1,1'-biphenl-4-ol The desired product was prepared by replacing Example 1C (trans) and 4-carboxybenzene boronic acid with Example 1C (cis) and Example 29A in Example 1D. MS (DCI (NH3) m / z: 450.2 (M + H) +; 1 H NMR (300 MHz, CD3OD) d 1.04 (d, J = 7.12Hz, 3H), 1.47-2.01 (m, 9H), 3. 28 (m, 1H), 3.96 (s, 2H), 4.31 (s, 2H), 6.89 (d, J = 8.82Hz, 2H), 7.46-7.59 (m, 3H), 7.67-7.76 (m, 3H) 7.78-7.89 (m, 3H).
Example 30 4 '- (6- (r (trans-4-hydroxycyclohexyl) aminomethyl] -1,4-dihydroindenoH, 2-c 1-irazol-3-yl) -3-methoxy-1,1' -biphenyl -4-ol Example 30A 4'-Bromo-3-methoxy-biphenyl-4-ol A mixture of 2-methoxy-4- (4, 4,5,5-tetramethyl- [1, 3,2] d-oxaborolan-2- il) -phenol (0.250 g, 1.00 mmol), 1,4-dibromo benzene (0.259 g, 1.10 mmol), Pd (PPh3) 4 (0.0580 g, 5%), and CsF (0.456 g, 3.00 mmol) in DME / MeOH (25 mL_, 1: 1) was heated at 70 ° C overnight. The reaction mixture was concentrated and the residue was extracted with CH2Cl2, washed with water, dried over gSO4, filtered, concentrated, and purified by flash chromatography eluted with hexane / CH2Cl2 (1: 9) to give 0.1518 (54%) of the desired product. MS (DCI / NH3) m / z: 279.9 (M + H) +; 1 H NMR (300 MHz, CD 3 OD) d 3.91 (s, 3 H), 6.86 (d, J = 8.14 Hz, 1 H), 7.06 (m, 1 H), 7.14 (d, J = 2.03 Hz, 1 H), 7.44-7.58 (m, 3H).
Example 30B 3-Methoxy-4 '- (4', 4,5,5-tetramethyl-ri, 3.21dioxaborolan-2-yl) -biphenyl-4 ° I The desired product was prepared by replacing 4'-bromo-biphenyl- 4-ol with Example 30A in Example 29A. MS (DCI / NH3) m / z: 326.1 (M + H) +; 1 H NMR (300 MHz, CD 3 OD) d 1.36 (s, 12 H), 3.92 (s, 3 H), 6.87 (d, J = 8.14 Hz, 1 H), 7.11 (d, J = 8.14 Hz, 1 H), 7.19 (d , J = 2.37 Hz, 1H), 7.57 (d, J = 8.14Hz, 2H), 7.76 (d, J = 8.48Hz, 2H).
Example 30C 4 '- (6-. {Rftrans-4-hydroxycyclohexyl) aminomethyl) -1,4-dihydroindenori, 2-c1pyrazol-3-iD-3-methoxy-1,1' -biphenyl-4 -ol The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 4A and Example 30B in Example 1D. MS (DC / NH3) m / z: 482.2 (M + H) +; H NMR (500 MHz, CD3OD) d 1.31-1.43 (m, 2H), 1.46-1.59 (m, 2H), 2.01-2.14 (m, 2H), 2.19-2.32 (m, 2H), 3.15 (m, 1H ), 3.59 (m, 1H), 3.93 (s, 5H), 4.28 (s, 2H), 6.89 (d, J = 8.11Hz, 1H), 7.14 (d, J = 8.11Hz, 1H), 7.22 (d) , J = 1.87Hz, 1H), 7.50 (d, J = 7.49Hz, 1H), 7.66-7.75 (m, 3H), 7.79-7.88 (m, 3H).
EXAMPLE 31 4 '- (6- (trans-4-hydroxycyclohexyl) aminomethyl> -1,4-dihydroindenoM, 2-cTpyrazol-3-yl) -3- (hydroxymethyl) -1, 1'-biphenyl-4-ol Example 31A 4"-Bromo-3-hydroxymethyl-biphenyl-4-ol The desired product was prepared by replacing 2-methoxy-4 (4,4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl); l) -phenol with 2-hydroxymethyl 4- (4,4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -phenol in Example 30A. MS (DCI / NH3) m / z: 278.0, 279.8 (M, M + 2). 1H NMR (500 MHz, CD3OD) d 4.61 (s, 2H), 6.75 (d, J = 8.42Hz, 1H), 7.26 (d, J = 10.92Hz, 1H), 7.37 (d, J = 8.42Hz, 2H ), 7.40-7.49 (m, 3H).
Example 31B 3-Hydroxymethyl-4 '- (4,4,5,5-tetramethyl-f 1, 3,21 dioxa boro lan-2-yl) -biphenyl-4-ol The desired product was prepared by replacing 4' -bromo-biphenyl-4-ol with Example 31A in Example 29A. MS (DC / NH3) m / z: 326.1 (M + 1) +; 1 H NMR (300 MHz, CD 3 OD) d 1.36 (s, 12 H), 4.71 (s, 2 H), 6.85 (d, J = 8.48 Hz, 1 H), 7.35-7.46 (m, 1 H), 7.54-7.62 (m, 3H) 7.76 (d, J = 8.14Hz, 2H).
Example 31C 4 '- (6- (. {(Trans-4-hydroxycyclohexyl) aminolmethyl> -1,4-dihydroindenor, 2-clpyrazol-3-yl) -3- (hydroxymethyl) -1,1' -bprienil-4-ol The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 4A and Example 31B in Example 1D. MS (EST) m / z: 482.0 (M + H) +; 1H NMR (500 MHz, CD3OD) d 1.30-1.43 (ra, 2H), 1.45-1.61 (m, 2H), 2.00-2.13 (m, 2H), 2.16-2.32 (m, 2H), 3.17 (m, 1H ), 3.58 (m, 1H), 3.93 (s, 2H), 4.27 (s, 2H), 4.73 (s, 2H), 6.88 (d, J = 8.42Hz, 1H), 7.40-7.52 (m, 2H) , 7.63 (s, 1H), 7.67-7.75 (m, 3H), 7.77-7.86 (m, 3H).
EXAMPLE 32 3-methoxy-4 '- ^ 6-r (neopentylamino) metm-1,4-dihydroindenori, 2-c1 pyrazol-3-yl -1, 1'-biphenyl-4-ol The desired product was prepared by replacing the Example 1C and 4-carboxybenzene boronic acid with Example 15A and Example 30B in Example 1D. MS (DCI / NH3) m / z: 454.2 (M + H) +; 1 H NMR (300 Hz, CD3OD) d 1.04. (s, 9H), 3.95 (s, 3H), 3.96 (s, 2H), 4.33 (s, 2H), 6.90 (d, J = 8.14Hz, 1H), 7.15 (dd, J = 8.31, 2.20 Hz, 1H), 7.23 (d, J = 2.03Hz, 1H), 7.56 (m, 1H), 7.69-7.77 (m, 3H), 7.80-7.88 (m, 3H).
EXAMPLE 33 4 '- (6-. {R (3-hydroxy-2,2-dimethylpropiDiamiromethyl) -1-, 4-dihydroindenori, 2-cTp -razol-3-n-3-methoxy-1, 1 '-biphenyl-4-ol The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 17A and Example 30B in Example 1D MS (DCI / NH3) m / z: 470.2 (M + H ) +; 1H NMR (300 MHz, CD3OD) d 1.02 (s, 6H), 3.00 (s, 2H), 3.45 (s, 2H), 3.95 (s, 5H), 4.30 (s, 2H), 6.89 (d , J = 8.14Hz, 1H), 7.15 (dd, J = 8.14, 2.03Hz, 1H), 7.23 (d, J = 2.03Hz, 1H), 7.50 (d, J = 1.36Hz, 1H), 7.68-7.76 (m, 3H) 7.78-7.91 (m, 3H).
EXAMPLE 34 3- (4'-Hydroxy-1,1 '-biphenyl-4-M) -1,4-dihydroquinone, 2-cl pyrazole-6-ol Example 34A 5- (Allyloxy) -2-r (4-bromophenin (idroxy) methylene-1 -inda none The desired product was prepared by replacing terephthalic acid monomethyl ester with 4-bromo-benzoic acid in Example 22 B. MS ( DCI / NH3) m / z: 371.4 (+ H) +; 1H NMR (300 MHz, CDCI3) d 3.86 (s, 2H), 4.64 (d, J = 5.43Hz 2H), - 5.29-5.52- (m, 2H) 6.08 (m, 1H), 6.92-7.04 (m, 2H), 7.63 (d, J = 8.82Hz, 2H), 7.73-7.86 (m, 3H).
Example 34B 6-Allyloxy-3- (4-bromo-phenyl) -1,4-dihydro-ir) denof1, 2-cl irazole The desired product was prepared by replacing Example 22B with Example 34A in Example 22C. MS (DC / NH3) m / z: 367.0 (+ 1) +, 367.9 (M + 1 + 2) +; 1 H NMR (400 MHz, CDCl 3) d 3.71 (s, 2 H), 4.59 (d, J = 5.22 Hz, 2 H), 5.24-5.53 (m, 2 H), 6.07 (m, 1 H), 6.90 (d, J = 8.29 Hz, 1H), 7.09 (m, 1H), 7.46-7.61 (m, 6H).
EXAMPLE 34C 3- (4'-Hydroxy-1,1'-biphenl-4-yl) -1,4-dihydroindenoH, 2-cl p-razo 1-6- or I The desired product was prepared by replacing Example IC and 4-carboxybenzene boronic acid with Example 34B and 4- (4,4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) -phenol in the Example 1D. MS (DCI / NHs) m / z: 341.1 (M + H) +; 1 H NMR (500 MHz, DMSO-d 6) d 3.80 (s, 2 H), 6.77 (d, J = 10.29 Hz, 1 H), 6.87 (d, J = 8.73 Hz, 2 H, 6.99 (s, 1 H), 7.45 ( d, J = 8.42Hz, 1H), 7.56 (d, J = 8.42Hz, 2H), 7.70 (d, J = 8.11Hz, 2H), 7.82 (d, J = 8.42Hz, 2H, 9.45 (s, 1H ), 9.57 (s, 1H).
Example 35 3- (4'-hydroxy-3'-methoxy-1,1'-biphen-4-yl) -1,4-clihydroindenori, 2-c1pyrazol-6-ol The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 34B and 2-methoxy-4- (4,4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -phenol in Example 1D. MS (DCI / NH3) m / z: 371.1 (M + H) +; 1 H NMR (500 MHz, CD 3 OD) d 3.88 (s, 2 H), 3.95 (s, 3 H), 6.78-6.98 (m, 2 H), 7.02-7.29 (m, 3 H), 7.55 (m, 1 H), 7.69 -7.89 (m, 4H).
EXAMPLE 36 4'-R6- (Hydroxymethyl) -1,4-dihydroindeneM, 2-clp-aceol-3-yn-1, 1'-biphenyl-4-ol The desired product was prepared by replacing Example 1C and 4-acid. -carboxybenzene boronic with Example 19A and 4- (4, 4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -phenol in Example 1D. MS (DCI / NH3) m / z: 355.1 (M + H) +; 1 H NMR (300 MHz, CD 3 OD) S 3.89 (s, 2 H), 4.68 (s, 2 H), 6.88 (d, J = 8.82 Hz, 2 H), 7.37 (d, J = 6.78 Hz, 1 H), 7.53 (d , J = 8.82Hz, 2H), 7.60 (s, 1H), 7.65-7.74 (m, 3H), 7.83 (d, J = 8.48Hz, 2H).
Example 37 4 '- (1, 4-dihydro-ndenori.2-cTpyrazol-3-in-1,1, -biphenyl-4-ol Example 37A A 3-Iodo-1,4-dihydro-indenof 1,2-clirazole The desired product was prepared by replacing Example 1A with 1,4-dihydro-indene [1,2-c] pyrazole prepared in accordance with the procedure described in the US patent 6297238, in Example 1B. MS (DCI / NH3) m / z: 282.9 (M + H) +; H N R (300 MHz, CD3OD) d 3.54 (s, 2H), 7.23-7.42 (m, 2H), 7.54 (d, J = 7.12Hz, 1H), 7.62 (d, J = 6.44Hz, 1H).
Example 37B 4 '- (1,4-dihydroindenoH, 2-clirazol-3-yl) -1, 1'-biphenyl-4-ol The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 37A and Example 29A in Example 1D. 1 AS (DCI / NH3) m / z: 325.1 (M + H) +; 1 H NMR (300 MHz, DMSO-de) d 3.90 (s, 2H), 6.87 (d, J = 8.82Hz, 2H), 7.23-7.45 (m, 2H), 7.53-7.63 (m, 3H), 7.65- 7.79 (m, 3H), 7.85 (d, J = 7.80 Hz, 2H), 9.60 (s, 1H), 13.22 (s, 1H).
Example 38 4'-r6- (hydroxymethyl) -1,4-dihydroindenoM, 2-clpyrazol-3-ill-3-methoxy-1,1'-biphenyl-4-ol The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 19A and Example 30B in Example 1D. MS (DCI / NH3) m / z: 385.1 (M + H) +; 1 H NMR (500 MHz, DMSO-d 6) d 3.88 (s, 5 H), 4.58 (s, 2 H), 6.88 (d, J = 8.11 Hz, 1 H), 7.16 (dd, J = 8.27, 2.03 Hz, 1 H) , 7.27 (d, J = 2.18Hz, 1H, 7.32 (d, J = 7.80 Hz, 1H), 7.55 (s, 1H), 7.62 (d, J = 7.49Hz, 1H), 7.76 (d, J = 8.42 Hz, 2H), 7.86 (d, J = 8.42Hz, 2H).
Example 39 3- (3'-Fluoro-4'-hydroxy-1,1'-biphenyl-4-e ') - 1,4-dihydroindenorri, 2-cl pyrazole-6-ol The desired product was prepared by replacing the Example 1C and 4-carboxybenzene boronic acid with Example 34B and 2-fluoro-4- (4,4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -phenol in Example 1D. MS (DCI / NH3) m / z: 359.0 (M + H) +; 1H NMR (400 MHz, CD3OD) d 3.84 (s, 2H), 6.83 (dd, J = 8.29.2.45Hz, 1H), 6.96-7.07 (m, 2H), 7.33 (m, 1H), 7.40 (dd, J = 12.27, 2.15Hz, 1H), 7.54 (d, J = 8.29Hz, 1H), 7.70 (d, J = 8.59Hz, 2H), 7.78-7.88 (m, 2H).
Example 40 3- (3'-amino-4'-hydroxy-1,1'-biphenyl-4-yl) -1,4-diriidroindenori.2-c1 pyrazole-6-ol Example 40A 2-Amino-4- (4,4,5,5-tetramethyl-M, 3,2T-dioxaborolan-2-yl) -phenol A mixture of Pd2 (dba) 3 (0.0765 g) and Ci-MAP (0.165 g) ) Degassed 1,4-dioxane (6 mL) was stirred at room temperature for 30 minutes. To the above mixture were added 2-amino-4-chloro-phenol (0.300 g, 2.09 mmol), bis (pinacolato) diboro (0.557 g, 2.19 nzmol), and KOAc (0.308 g, 3.14 mmol). The reaction mixture was heated at 85 ° C overnight, followed by cooling to room temperature, concentrated under reduced pressure and the residue treated with EtOAc. The ethyl acetate layer was washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes / EtOAc (7: 3 to 1: 1) to give 0.273g (69%) of the desired product as a brown solid. MS (DCI / NH3) m / z: 235.8 (M + H) +; 1 H NMR (300 MHz, DMSO-d 6) d 1.24 (s, 12 H), 3.92 (s, 1 H), 6.62 (d, J = 7.80 Hz, 1 H), 6.78 (dd, J = 7.63, 1.53 Hz, 1 H) , 6.96 (d, J = 1.36Hz, 1H).
Example 40B 3- (3'-amino-4'-hydroxy-1,1'-biphenyl-4-yl) -1,4-dihydroindenor, 2-c1pyrazol-6-ol The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 34B and 40A in Example 1D. MS (DCI / NH3) m / z: 356.1 (M + H) +; 1 H NMR (300 MHz, CD 3 OD) d 3.84 (s, 2 H), 6.83 (dd, J = 8.31, 2.20 Hz, 1 H), 7.05 (d, J = 2.37 Hz, 1 H), 7.12 (d, J = 8.48 Hz , 1H,) 7.53 (d, J = 8.14Hz, 1H), 7.60 (d, J = 2.37Hz, 1H), 7.63-7.68 (m, 1H), 7.71 (d, J = 8.48Hz, 2H), 7.87 (d, J = 8.48Hz, 2H).
Example 41 4-hydroxy-4'-f6- (hydroxymethyl) -1,4-dihydroindenori, 2-clirazol-3-yn-5-methoxy-1,1 '-biphenyl-2-carbaldehyde Example 41A 4'-B-rom 4-hi-hydroxy-5-methoxy-biphenyl-2-carb aldehyde A mixture of 2-bromo-5-hydroxy-4-methoxy-benzaldehyde (1.00 g, 4.32 mmol), acid 4-bromophenyl boronic acid (1.04 g, 5.18 mmol), Pd (PPh3) 4 (0.250 g), and CsF (1.97 g, 12.6 mmol) in DME / MeOH (1: 1, 65 mL) was heated at 70 ° C for the night. The mixture was diluted with CH2Cl2 and washed with water. The organic layer was dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexane / CH2Cl2 (1: 9) to give 0.809g (60%) of the desired product, which was taken to the next step without further purification. MS (DCI / NH3) m / z: 307.4 (M + H) +.
Example 41B 4-Hydroxy-5-methoxy-4 '- (4,4,5,5-tetramethyl-ri, 3,2-thioxaborolan-2-yl) -biphenyl-2-carbaldehyde The desired product was prepared by replacing 4'- bromo-biphenyl-4-ol with Example 41A in Example 29A. The product was taken to the next step without further purification. MS (DCI NH3) m / z: 372.2 (M + NH4) +.
Example 41C 4-hydroxy-4'-f6- (hydroxymethyl) -1,4-dihydroindenofl, 2-cl pyrazole-3-ill-5-m-ethoxy-1,1 '-bife nyl-2-carb aldehyde The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 19A and 41B in Example 1D. MS (DCI / NH3) m / z: 413.1 (M + H) +; 1 H NMR (500 MHz, DMSO-d 6) d 3.90 (s, 2 H), 3.94 (s, 3 H), 4.58 (s, 2 H), 7.03 (s, 1 H), 7.33 (d, J = 7.80 Hz, 1 H) , 7.36 (s, 1H), 7.55-7.58 (m, 3H), 7.62 (d, J = 7.80 Hz, 1H), 7.92 (d, J = 8.11Hz, 2H), 9.76 (s, 1H).
EXAMPLE 42 3- (4'-Hydroxy-1,1 '-biphenyl-4-yl) -N- (trans-4-hydroxycyclohexyl) -1,4-dihydro-n-dinori.2-c-pyrazole-6-carboxamide The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 26B and Example 29A in Example 1D. The microwave-assisted reaction was run for 450 to 2000 seconds at 160 to 180 ° C. MS (DCI / NH3) m / z: 466.2 (M + H) +; H NMR (300 MHz, CD3OD) d 1.38-1.52 (m, 4H), 1.93-2.10 (m, 4H), 3.58 (m, 1H), 3.883 (m, 1H), 3.94 (s, 2H), 6.88 ( d, J = 8.81Hz, 2H), 7.52 (d, J = 8.48Hz, 2H), 7.69 (d, J = 8.48Hz, 2H), 7.75-7.87 (m, 4H), 8.02 (s, 1H).
EXAMPLE 43 3- (4'-Hydroxy-1,1 '-bifinyl-4-in-N-neopentyl-1,4-dihydroindenoyl-1,2-clirazole-6-carboxamide The desired product was prepared by replacing Example 1C and 4- boronic carboxybenzene with Example 27A and Example 29A in Example 1D MS (DCI / NH3) m / z: 438.2 (M + H) +; 1H NMR (300 MHz, DMSO-d6) d 0.93 (s, 9H) , 3.14 (d, J = 6.10Hz, 2H), 3.97 (s, 2H), 6.88 (d, J = 8.48Hz, 2H), 7.58 (d, J = 8.82Hz, 2H), 7.73 (d, J = 8.48Hz, 3H), 7.83-7.96 (m, 3H), 8.07 (s, 1H), 8.39 (t, J = 6.44Hz, 1H), 9.60 (s, 1H).
Example 44 4-f7- (Hydroxymethyl) -1,4-dihydroindenori, 2-c-pyrazol-3-yl-1 benzoic acid Example 44A 1,4-Dihydroindenor, 2-Clpyrazole-7-carbaldehyde The desired product was prepared by replacing 6-bromo-1,4-dihydro-indene [1,2-c) pyrazole with 7-bromo-1,4-dihydro- indene [1, 2-c] pyrazole in Example 1A.
Example 44B 3 -Yod 0-1, 4-dihydroindenof1, 2-c1 irazol-7-carbaldehyde The desired product was prepared by replacing Example 1A with Example 44A in Example 1B. MS (DCI / NH3) m / z: 310.9 (M + H) +; 1H NMR (300 Hz, DMSO-d6) d 3.64 (s, 0.8H), 3.69 (s, 1. 2H), 7.78 (t, J = 8.82Hz, 1H), 7.88 (t, J = 7.97Hz, 1H), 8.02 (s, 0.4H), 8.11 (s, 0.6H), 10.08 (s, 1H).
Example 44C (3-Iodo-1, 4-dihydro-indenoiri, 2-c1-irazole-7-in-methanol The desired product was prepared by replacing Example 1B with Example 44B in Example 19A.MS (DCI / NH3) m / z: 312.9 (M + H) +; 1H NMR (300 MHz, CD3OD) d 3.52 (s, 2H), 4.67 (s, 2H), 7.30 (d, J = 9.49Hz, 1H), 7.51 (d, J = 7.80 Hz, 1H), 7.64 (s, 1H).
Example 44D 4-R7- (Hydroxymethi-1,4-dihydroindenon, 2-clpyrazole-3-benzoic acid The desired product was prepared by replacing Example 1C with Example 44C in Example 1D MS (DCI / NH3) m / z: 307.0 (M + H) +; H NMR (300 MHz, CD3OD) d 3.89 (s, 2H), 4.70 (s, 2H), 7.33 (d, J = 7.80 Hz, 1H), 7.56 (d, J = 8.48Hz, 1H), 7.74 (s, 1H), 7.91 (d, J = 8.81Hz, 2H), 8.09-8.18 (m, 3H).
EXAMPLE 45 4-f7- (hydroxymethyl) -1,4-dihydroquinone, 2-cl irazol-3-illbenzamide The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 44C and 4- (4, 4,5,5-tetramethyl- [1,2,2] d-oxaborolan-2-yl) -benzamide in Example 1D. MS (DCI / NHs) m / z: 306.0 (M + H) +; 1 H NMR (500 MHz, DMSO-d 6) d 3.88 (s, 2 H), 4.59 (s, 2 H), 5.22 (s, 1 H), 7.25 (d, J = 7.80 Hz, 1 H), 7.32-7.45 (m, 1H), 7.52 (d, J = 7.80 Hz, 1H), 7.65 (s, 1H), 7.88 (s, 2H), 7.99 (d, J = 7.80 Hz, 2H), 13.29 (s, 1H).
EXAMPLE 46 4'-f7- (Hydroxymethyl) -1,4-dihydroindenori, 2-clirazol-3-Ml-3-methoxy-1,1'-biphenyl-4-ol The desired product was prepared by replacing Example 1C and 4- boronic carboxybenzene with Example 44C and Example 30B in Example 1D. MS (DCI / NH3) m / z: 385.1 (M + H) +; 1 H NMR (300 MHz, DMSO-d 6) d 3.87 (s, 2 H), 3.88 (s, 3 H), 4.59 (s, 2 H), 6.88 (d, J = 8.14 Hz, 1 H) 7.16 (dd, J = 8.14 , 2.03Hz, 1H), 7.21-7.29 (m, 2H), 7.54 (m, 1H), 7.65 (s, 1H), 7.76 (d, J = 8.48Hz, 2H), 7.86 (d, J = 8.48Hz , 2H), 9.14 (s, brd, 1H).
Example 47 N- 3-f7- (hydroxymethyl) -1,4-dihydroindenori, 2-cTpyrazol-3-in phenylacetamide The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 44C and 3- acetamidobenzene acid boronic in Example 1D. MS (DCI / NH3) m / z: 320.0 (M + H) +; 1H NMR (300 MHz, CD3OD) d 2.18 (s, 3H), 3.86 (s, 2H), 4.69 (s, 2H), 7.34 (dd, J = 7.80, 1.36Hz, 1H), 7.42-7.47 (m, 2H, 7.52-7.58 (m, 2H), 7.73 (d, J = 0.68Hz, 1H), 8.15 (m, 1H).
EXAMPLE 48 4-R7- (4-morpholinylmethyl) -1,4-dihydroindenon. 2-clpyrazol-3-benzoic acid Example 48A 3-Iodo-7-morpholin-4-ylmethyl-1,4-dihydro-indenori, 2-cT irazole The desired product was prepared by replacing Example 1B with Example 44B in Example 7A. MS (DCI / NH3) m / z: 382.0 (M + H) +; 1H NMR (300 MHz, CD3OD) d 2.39-2.55 (m, 4H), 3.52 (s, 2H), 3.59 (s, 2H), 3.66-3.74 (m, 4H), 7.29 (dd, J = 7.80,1.70 Hz, 1H), 7.50 (d, J = 7.80 Hz, 1H), 7.63 (m, 1H).
Example 48B 4-R7- (4-morpholinylmethyl) -1,4-dihydroindenori, 2-clpyrazol-3-yl benzoic acid The desired product was prepared by replacing Example 1C with Example 48A in Example ID. MS (DCI / NH3) m / z: 376.2 (M + H) +; 1 H NMR (400 MHz, CD 3 OD) d 3.33-3.52 (m, 4 H), 3.65-3.86 (m, 2 H), 3.97 (s, 2 H), 3.99-4.14 (m, 2 H), 4.46 (s, 2 H), 7.47 (d, J = 7.67Hz, 1H), 7.73 (d, J = 7.67Hz, 1H), 7.82-7.96 (m, 3H), 8.14 (d, J = 8.59Hz, 2H).
Example 49 4-R7- (4-morpholinylmethyl) -1,4-dihydroindenori, 2-clirazol-3-benzamide The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 48A and 4- ( 4, 4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) -benzamide in Example 1D. MS (DCI / NH3) miz: 375.1 (M + H) +; 1 H NMR (400 MHz, CD 3 OD) d 3.21-3.33 (m, 2 H), 3.38-3.49 (m, 2 H), 3.67-3.81 (m, 2 H), 3.95 (s, 2 H), 4.01-4.12 (m, 2 H) ), 4.46 (s, 2H), 7.47 (dd, 1 = 7.67,1.53Hz, 1H), 7.72 (d, J = 7.98Hz, 1H), 7,847.91 (m, 3H), 8.00 (d, J = 8.29Hz, 2H).
Example 50: 4- (7-f f (2-Hydroxyethylamino-methyl> -1,4-dihydric acid, 2-d-prazole-3-yl) benzoic acid Example 50A 2-r (3-Iodo-1,4-dihydro-indenofl, 2-c] pyrazol-7-yltrnenyl) -amino] -ethanol The desired product was prepared by replacing Example 1B and morpholine with Example 44B and 2 -amino-ethanol in Example 7A. MS (DCI / NH3) m / z: 356.0 (M + H) +; 1H NMR (300 MHz, CD3OD) d 2.81 (t, J = 5.77Hz, 2H), 3.54 (s, 2H), 3.70 (t, J = 5.77Hz, 2H), 3.92 (s, 2H), 7.33 (dd) , J = 7.80, 1.70 Hz, 1H), 7.54 (d, J = 7.80 Hz, 1H), 7.64 (s, 1H).
Example 50B 4- (7- (2-Hydroxyethyl) amino-1-methyl) -1,4-dihydroindenone, 2-chlororazole-3-benzoic acid The desired product was prepared by replacing Example 1C with Example 50A in Example 1D . MS (DCI / NH3) m / z: 350.1 (M + H) +; 1H NMR (400 MHz, CD3OD) d 3.09 (t, J = 5.52Hz, 2H), 3.74 (t, J = 5.52Hz, 2H), 3.87 (s, 2H), 4.25 (s, 2H), 7.36 (dd, J = 7.67, 1.84Hz, 1H), 7.60 (d, J = 7.98Hz, 1H), 7.76 (d, J = 1.23Hz, 1H), 7.80 (d, J = 8.59Hz, 2H), 8.05 (d, J = 8.90 Hz, 2H).
Example 51 4'-r7- (hydroxymethyl) -1,4-dihydroindenoir, 2-c1 irazol-3-iM-1, 1'-biphenyl-4-ol The desired product was prepared by replacing Example 1C and 4-acid. -carboxybenzene boronic with Example 44C and Example 29A in Example 1D. MS (DC / NH3) m / z: 355.1 (M + H) +; 1 H NMR (500 MHz, DMSO-dg) d 3.86 (s, 2 H), 4.59 (s, 2 H), 6.87 (d, J = 8.42 Hz, 2 H), 7.24 (d, J = 7.80 Hz, 1 H), 7.52 (d J = 7.80 Hz, 1H), 7.57 (d J = 8.42Hz, 2H), 7.64 (s, 1H), 7.71 (d, J = 8.42Hz, 2H), 7.85 (d, J = 8.42Hz, 2H ), 9.56 (s, 1H).
EXAMPLE 52 4-7-f (neopentylamino) methylene-1,4-dihydroirthenoxy. 2-c1pyrazol-3-yl} benzamide Example 52A (2,2-Dimethyl-propyn- (3-vodo-1,4-dihydro-indenori, 2-clirazol-7-ylmethyl) -amine The desired product was prepared by replacing Example 1B and morpholine with Example 44B and neopentylamine in Example 7A.MS (DCI / NH3) m / z: 382.0 (+ H) +; 1H NMR (300 MHz, CD3OD) d 0.92 (s, 9H), 2.35 (s, 2H), 3.52 (s, 2H), 3.84 (s, 2H), 7.30 (dd, J = 7.80,1.70 Hz, 1H), 7.50 (d, J = 7.80 Hz, 1H), 7.62 (s, 1H).
Example 52B 4-f7-r (neopentylamino) metin-1,4-dihydroindenori, 2-cT pyrazole-3-yl} benzamide The desired product was prepared by replacing Example 1C and 4-carboxybenzene boronic acid with Example 52A and 4- (4, 4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) -benzamide in Example 1D. MS (DCI / NH3) m / z: 375.2 (M + H) +; H NMR (300 MHz, DMSO-d6) d 0.95 (s, 9H), 2.74 (s, 2H), 3.97 (s, 2H), 4.28 (s, 2H), 7.37-7.50 (m, 2H), 7.66 ( d, J = 7.80 Hz, 1H), 7.84-7.94 (m, 3H), 7.98-8.06 (m, 3H), 8.60 (s, brd, 1H).
Example 53 4'-. { 7-r (neopentylaminolmethyl-1,4-dihydroindenori .2-clpyrazol-3-yl-> 1,1'-biphenyl-4-ol The desired product was prepared by replacing Example 1C and 4-carboxybenzene acid. boronic acid with Example 52A and Example 29A in Example 1D MS (DCI / NH3) m / z: 424.2 (M + H) +; 1H NMR (300 Hz, D SO-d6) d 0.97 (s, 9H) , 2.67-2.81 (m, 2H), 3.95 (s, 2H), 4.20-4.38 (m, 2H), 6.88 (d, J = 8.48Hz, 2H), 7.46 (dd, J = 7.97, 1.53Hz, 1H ), 7.57 (d, J = 8.81Hz, 2H), 7.66 (d, J = 7.80 Hz, 1H), 7.73 (d, J = 8.48Hz, 2H), 7.82-7.88 (m, 2H), 7.91 (s) , 1H), 8.57 (s, brd, 1H).
Example 54: Acid 4-. { 7-r (methylamino) carbonin-1,4-di idroindenoi1, 2-clirazol-3-yl} benzoic Example 54A 3-Iodo-1 acid. 4-dihydro-indenori, 2-clirazole-7-carboxylic acid The desired product was prepared by replacing Example 2B with Example 44B in Example 26A. MS (DCI / NH3) m / z: 326.9 (M + H) +; H NMR (300 MHz, DMSO-d6) d 3.62 (s, 2H), 7.66 (d, J = 7.80 Hz, 1H), 7.90 (dd, J = 7.97, 1.53Hz, 1H, 8.12 (d, J = 1.36 Hz, 1H).
Example 54B Methyl 3-vodo-1,4-dihydro-indeneM. 2-d-prazol-7-carboxylic acid lamido The desired product was prepared by replacing Example 22D and NH4CI with Example 54A and methylamine in Example 23. MS (DCI / NH3) m / z: 339.9 (M + H) +; 1H NMR (300 MHz, DMSO-d6) d 2.79 (s, 1.2H), 2.81 (s, 1.8H), 3.55 (s, 0.8H), 3.60 (s, 1.2H), 7.60 (d, J = 7.12 Hz, 1H), 7.77 (m, 1H), 8.08 (m, 1H), 8.52 (d, J = 3.73Hz, 1H), 13.21 (s, 0.6H), 13.54 (s, 0.4H).
Example 54C Acid 4-. { 7-R (methylamino) carbonin-1,4-dihydroindenof1,2-cTpyrazole-3-yl) benzoic The desired product was prepared by replacing Example 1C with Example 54B in Example 1D. The microwave-assisted reaction was run for 900 seconds instead of 450 seconds in Example 1D. MS (DCI / NH3) m / z: 334.1 (M + H) +; 1 H NMR (500 MHz, DMSO-d 6) d 2.82 (d, J = 4.41 Hz, 3 H), 3.98 (s, 2 H), 7.66 (d, J = 7.80 Hz, 1 H), 7.81 (d, J = 8.73 Hz , 1H), 7.94 (d, J = 8.11Hz, 2H), 8.06 (d, J = 8.11Hz, 2H), 8.16 (s, 1H), 8.53 (d, J = 4.37Hz, 1H), 12.99 (s) , 0.4H), 13.49 (s, 0.6H).
Example 55 3-f4- (aminocarbonyl) phenin-N-metH-1,4-dihydroindenoy1,2-c1 pyrazole-7-carboxamide The desired product was prepared by replacing Example IC and 4-carboxybenzene boronic acid with Example 54B and 4 (4). , 4,5,5-tetramethyl- [3,2] dioxaborolan-2-yl) -benzamide in Example 1D. The assisted reaction with microwaves was run for 900 seconds instead of 450 seconds in Example 1D. MS (DCI / NH3) m / z: 333.6 (M + H) +; 1H N MR (500 MHz, DMSO-d6) d 2.82 (d, J = 4.41Hz, 3H), 3.98 (s, 2H), 7.65 (d, J = 7.80 Hz, 1H), 7.81 (dd, J = 7.80 , 1.56Hz, 1H), 7.89 (d, J = 8.42Hz, 2H), 8.00 (d, J = 8.42Hz, 2H), 8.16 (s, 1H), 8.53 (d, J = 4.68Hz, 1H).
EXAMPLE 56 3- (4'-Hydroxy-1,1'-b-phenyl-4-yl) -N-methyl-1,4-dihydroindenon, 2-cT pyrazole-7-carboxamide The desired product was prepared by replacing the Example 1C and 4-carboxybenzene boronic acid with Example 54B and Example 29A in Example 1D. The microwave-assisted reaction was run for 900 seconds instead of 450 seconds in Example 1D. MS (DCI / NHg) m / z: 382.1 (M + H) +; 1 H NMR (300 MHz, DMSO-d 6) S 2.82 (d, J = 4.41 Hz, 3 H), 3.96 (s, 2 H), 6.87 (d, J = 8.48 Hz, 2 H), 7.57 (d, J = 8.48 Hz , 2H), 7.65 (d, J = 7.80 Hz, 1H), 7.73 (d, J = 8.48Hz, 2H), 7.81 (d, J = 7.97,1.53Hz, 1H), 7.86 (d, J = 8.48Hz , 2H), 8.17 (s, 1H), 8.55 (d, J = 4.75Hz, 1H), 9.60 (s, brd, 1H).
Example 57 Acid 4-f 7-f (neopenti lamino) carbon IT -1. - dihydroindenoM, 2-c1 p i razol -3- l benzoic Example 57A (3-iodo-1,4-dihydro-indenon. 2-irazole-7-carboxylic acid) 57A (2,2-dimethyl-propyl) -amide The desired product was prepared by replacing Example 22D and NH4CI with Example 54A and neofentylamine in Example 23. MS (DCI / NH3) m / z: 396.0 (M + H) +; 1 H NMR (300 MHz, DMSO-d 6) d 0.92 (s, 9 H), 3.11 (s, 0.8 H), 3.13 (s, 1.2 H), 3.56 (s, 0.8 H), 3.61 (s, 12 H), 7.61 (d, J = 7.80 Hz, 1H), 7.79 (d, J = 7.80 Hz, 1H), 7.99 (s, 0.4H), 8.13 (s, 0.6H), 8.44 (s, brd, 1H), 13.22 (d, s, brd, 0.6H), 13.53 (s, brd, 0.4H).
Example 57B 4-f7-r (Neopentylamino) carbonyl-1, 4-d-hydroxydenorino-2-pi1-l-3-yl) benzoic acid The desired product was prepared by replacing Example 1C with Example 57A in the Example "1D.The microwave-assisted reaction was run for 900 seconds instead of 450 seconds in Example 1 D. MS (DCI / NH3) m / z: 390.1 (M + H) +; H NMR (300 MHz, DMSO- d6) d 0.93 (s, 9H), 3.15 (d, J = 6.44Hz, 2H), 3.99 (s, 2H), 7.66 (d, J = 8.14Hz, 1H), 7.76-7.90 (m, 1H), 7.95 (d, J = 8.14Hz, 2H), 8.06 (d, J = 8.14Hz, 2H), 8.18 (s, 1H), 8.47 (t, J = 6.44Hz, 1H).
Example 58 3- (4'-Idroxy-1,1'-biphenyl-4-in-N-neopentyl-1,4-dihydroindenoH, 2-chlororazole-7-carboxamide The desired product was prepared by replacing Example 1C and 4-carboxybenzene acid. boronic with Example 57A and Example 29A in Example 1 D. The microwave-assisted reaction was run for 900 seconds instead of 450 seconds in Example 1 D. MS (DCI / NHs) m / z: 438.2 (M + H) +; H MR (500 MHz, DMSO-d6) d 0.94 (s, 9H), 3.15 (d, J = 6.24Hz, 2H), 3.96 (s, 2H), 6.88 (d, J = 8.42Hz, 2H) , 7.57 (d, J = 8.74Hz, 2H), 7.65 (d, J = 8.11Hz, 1H), 7.73 (d, J = 8.11Hz, 2H), 7.82 (d, J = 9.36Hz, 1H), 7.86 (d, J = 8.42Hz, 2H), 8.19 (s, 1H), 8.45 (t, J = 6.24Hz, 1H), 9.57 (s, brd, 1H).
Example 59: 4- (7-f r (trans-4-hydroxyclohexyl) aminocarbonyl-1,4-dihydroindene-2-c-pyrazol-3-yl) benzoic acid Example 59A (Trans-4-hydroxy-cyclohexyl-3-vodo-1,4-dihydro-indenof-1,2-cTpirazole-7-carboxylic acid) The desired product was prepared by replacing Example 22D and NH4CI with the Example 54A and trans-4-amino-cyclohexanol in Example 23. MS (DCI / NH3) m / z: 424.0 (M + H) +; 1H MR (300 MHz, DMSO-d6) d 1.09-1.50 (m, 2H), 1.72-1.92 (m, 4H), 3.39 (m, 1H), 3.55 (s, 0.8H), 3.60 (s, 1.2H), 3.66-3.82 (m, 1H), 4.55 (d, J = 4.41Hz, 1H), 7.59 (m, 1H), 7.77 (t, J = 7.46Hz, 1H), 7.98 (s, 0.4H), 8.12 (s, 0.6H), 8.28 (d, J = 8.14Hz, 1H), 13.21 (s, 0.6H) 13.53 (s, 0.4H).
Example 59B Acid 4- (7-ff (t ra ns-4-hydroxy cyclohexylamolonyl carbon) -1,4-dihydroindenof 1,2-c1pyrazol-3-yl) benzoic acid The desired product was prepared by replacing Example 1C with Example 59A in Example 1D. The microwave-assisted reaction was run for 900 seconds instead of 450 seconds in Example 1D. MS (DCI / NH3) m / z: 418.1 (M + H) +; H NMR (500 MHz, DMSO-d6) d 1.20-1.32 (m, 2H), 1.35-1.47 (m, 2H), 1.79-1.90 (m, 4H), 3.36 (m, 1H), 3.76 (m, 1H ), 3.97 (s, 2H), 7.64 (d, J = 7.80 Hz, 1H), 7.81 (d, J = 7.80 Hz, 1H), 7.94 (d, J = 8.11Hz, 2H), 8.05 (d, J) = 8.42Hz, 2H), 8.17 (s, 1H), 8.29 (d, J = 7.80 Hz, 1H).
Example 60 6-f6- (allyloxy) -1,4-dihydroindenoM, 2-cl pyrazole-3-acid? nicotinic EXAMPLE 60A 6-rr5- (Allyloxy) -1-oxo-1,3-dihydro-2H-inden-2-ylidene (hydroxy) methyl1-methyl nicotinate The desired product was prepared by replacing monomethyl ester of terephthalic acid with acid 5- (methoxycarbonyl) -2-pyridinecarboxylic acid in Example 22B.
EXAMPLE 60B 6-R6- (Allyloxy) -, 4-dihydroindenon .2-C Myrzole-3-methyl-innicotinate The desired product was prepared by replacing Example 22B with Example 60A in Example 22C.
Example 60C 6-r6- (allyloxy) -1,4-dihydroldenyl-1, 2-chlororazole-3-nitnic acid The desired product was prepared by replacing Example 22C with Example 60B in Example 22D. MS (DCI / NH3) m / z: 334.0 (+ H) +; 1H NR (500 MHz, DMSO-d6) 5 3.88 (s, 2H), 4.63 (d, J = 4.99Hz, 2H), 5.28 (d, J = 10.61Hz, 1H), 5.43 (d, J = 17.47Hz , 1H), 6.08 (m, 1H), 6.97 (dd, J = 9.27, 2.03Hz, 1H), 7.22 (s, 1H), 7.56 (d, J = 8.11Hz, 1H), 7.94 (s, 1H) , 8.36 (d, J = 8.11Hz, 1H), 9.12 (s, 1H), 13.40 (s, brd, 1H).
Example 61 6- (6-Hydroxy-1,4-dihydroindene, 2-c1pyrazol-3-yl) nic acid Example 61A Methyl 6- (6-hydroxy-1,4-dihydroindenoH, 2-clpyrazol-3-yl) nicotinat The desired product was prepared by replacing Example 22C with Example 60B in Example 24.
EXAMPLE 61B 6- (6-Hydroxy-1,4-dihydroindeneM .2-cTp.razole-3-yl) nyl acid The desired product was prepared by replacing Example 22C with Example 61A in Example 22D. MS (DCI / NH3) m / z: 294.0 (M + H) +; H NMR (300 MHz, DMSO-d6) d 3.83 (s, 2H), 6.78 (dd, J = 8.14, 2.37Hz, 1H), 7.00 (d, J = 2.03Hz, 1H), 7.45 (d, J = 8.14Hz, 1H), 7.92 (d, J = 8.14Hz, 1H), 8.36 (dd, J = 8.14, 2.03Hz, 1H), 9.11 (d, J = 2.03Hz, 1H), 9.50 (s, brd, 1 HOUR).
EXAMPLE 62 6- (allox!) -3-r4- (1 H-tetraazole-5-l) f in ill-1,4-dihydroindene M, 2-c1 pyrazole Example 62A 4-rf5- (allyloxn-1-oxo-1,3-dihydro-2H-inden-2-ylidenehydroxy) methybenzonitrile The desired product was prepared by replacing monometilic ester of terephthalic acid with 4-cyanobenzoic acid in Example 22B.
Example 62B 4- (6-Allyloxy-1,4-dihydro-indenof, 2-cTpyrazol-3-iO-benzonitrile The desired product was prepared by replacing Example 22B with Example 62A in Example 22C.MS (DCI / NH3) m / z: 314.1 (M + H) +; 1H NMR (300 MHz, DMSO-d6) d 3.85 (S, 0.8H), 3.90 (s, 1. 2H), 4.46-4.68 (m, 2H), 5.28 (dd, J = 10.51, 1.70 Hz, 1H), 5.43 (dd, J = 17.29, 2.03Hz, 1H), 6.09 (m, 1H), 6.97 (m , 1H), 7.16-7.28 (m, 1H), 7.46-7.65 (d, J = 8.48Hz, 1H), 7.87-8.08 (m, 4H), 13.31 (s, brd, 1H).
Example 62C 6 - (??????) - 3-G4- (1 H-tetraazol-5-yl) fenin-1,4-dihydroindenofl, 2-cT pyrazole A mixture of Example 62B (61.5 mg, 0.196 mmol NaN3 (19.1 mg, 0.294 mmol), and Et3N.HCl (40.5 mg, 0.294 mmol) in DMF (2 mL) was heated at 140 ° C for 4 hours. To this mixture was added more NaN3 (60.0 mg) and Et3N.HCI (120 mg). The reaction mixture was stirred overnight, cooled, and concentrated. The crude material was purified using the HPLC condition in Example 8 to give 20.0 mg (29%) of the desired product product as a brown solid. MS (DCI / NHs) m / z: 357.1 (M + H) +; 1 H NMR (300 MHz, D SO-d 6) S 3.90 (s, 2H), 4.53-4.71 (m, 2H), 5.29 (dd, J = 10.51, .1.70 Hz, 1H), 5.44 (dd, J = 17.29, 2.03Hz, 1H), 6.07 (m, 1H), 6.98 (dd, J = 8.31, 2.20 Hz, 1H), 7.22 (d, J = 2.03Hz, 1H), 7.57 (d, J = 8.14Hz, 1H), 8.02 (d, J = 8.14Hz, 2H), 8.16 (d, J = 8.48Hz, 2H), 13.22 (s, brd, 1 HOUR).
Example 63 4- (6-yr (trans-4-methylcyclohexinamino-methyl> -1,4-dihydro-ndenori, 2-clpyrazole-3-yhphenol) The desired product was prepared by replacing 4-carboxybenzene boronic acid with 4- (4, 4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -phenol in Example 1D. MS (DCI / NH3) m / z: 374.2 (M + H) +; 1H NMR (300 MHz, CD3OD) d 0.95 (d, J = 6.44Hz, 3H), 1.00-1.18 (m, 2H), 1.35-1.56 (m, 3H), 1.81-1.95 (m, 2H), 2.15- 2.30 (m, 2H), 3.12 (m, 1H), 3.88 (s, 2H), 4.28 (s, 2H), 6.91 (d, J = 8.82Hz, 2H), 7.49 (d, J = 7.80 Hz, 1H ), 7.63 (d, J = 8.82Hz, 2H), 7.69 (s, 1H), 7.79 (d, J = 7.80 Hz, 1H).
Example 64 4 '- (6,7-dimethoxy-1,4-dihydroindenof 1,2-c1 irazol-3-yl) -1,1' -biphenyl-4-ol Example 64A 4-Bromophenyl) -imidazole-1-l-methanone 4-Bromobenzoic acid (10 g, 50 mmol) was treated in 50 ml of DMF with carbonyl-1,1 '-dlimidazole (18 g, 112.5 mmol ). The mixture was stirred for 3 hours and poured into water. The mixture was filtered and the filter cake was washed with water and dried to give the title compound. MS (DCI / NH3) m / z: 252.9 (M + H) +. 1H NMR (300 MHz, DMSO-D6) d ppm 7.17 (dd, J = 1.65, 0.81Hz, 1H) 7.69 (t, J = 1.48Hz, 1H) 7.77 (m, 2H) 7.83 (m, 2H) 8.21 ( dd, J = 1.36, 0.85Hz, 1H).
EXAMPLE 64B 2- (4-BromobenzoiD-5,6-dinoxy-indan-1 -one) 5,6-Dimethoxy-indan-1 -one (2 g, 10.4 mmol) in 25 mL of THF was treated with NaH (60 mL). %, 624 mg, 15.6 mmol) at 0 ° C. Then, the The suspension was stirred at room temperature for 1 hour, the mixture treated with Example 64A (2.61 g, 10.4 mmol) in 5 ml of THF dropwise. After stirring for 3 hours at room temperature, the mixture was poured into water and acidified with hydrochloric acid. The mixture was filtered and the filter cake was washed with water and recrystallized from ethanol to provide the title compound. MS (DCI / NH3) m / z: 375.0 (+ H) +.
Example 64C 3- (4-Bromophenyl) -6,7-dimethoxy-1,4-dihydroindenof 1,2-cT-irazole Example 64B (820 mg, 2.18 mmol), hydrazine monohydrate (0.127 mL, 2.63 mmol) were combined , and acetic acid (0.15 ml, 2.63 mmol) in 30 ml of ethanol and heated at 90 ° C for 6 hours. The mixture was allowed to cool to room temperature and filtered. The filter cake was dried to provide the title compound. MS (DCI / NH3) m / z: 373.0 (+ H) +. 1 H NMR (300 MHz, DMF-D7) d ppm. 3.84 (s, 2H), 3.89 (s, 3H), 3.93 (s, 3H), 7.31 (s, 1H), 7.34 (s, 1H), 7.71 (d, J = 8.48Hz, 2H), 7.89 (d , J = 8.48Hz, 2H), 13.17 (s, 1 H).
Example 64D 4 '- (6,7-dimethoxy-1,4-dihydroindenof 1,2-cT-pyrazole-3,1'-biphenyl-4-ol) Example 64C (50 mg, 0.14 mmol) was combined), 4-hydroxylphenyl boronic acid (23.3 mg, 0.17 mmol), Na 2 CO 3 (1 M, 0.3 mL), and Pd (PPh3) 2Cl2 (9.9 mg, 0.014 mmol) in DME: EtOH: H20 (7: 2: 3, 1.5 mL) in a 2 mL capped flask and heated at 160 ° C for 600 seconds on a Smith Synthesizer. The mixture was cooled using 2812 kg / cm2 of pressurized air, the solvents were evaporated, and the residue was purified using preparative HPLC (for conditions, see Example 1D) to provide the title compound. MS (DCI / NH3) m / z: 385.1 (+ H) +. 1H NR (500 MHz, DMSO-D6) d ppm 3.79 (s, 2H), 3.82 (s, 3H), 3.85 (s, 3H), 6.87 (d, J = 8.66Hz, 2H), 7.23 (s, 1H) ), 7.25 (s, 1H), 7.57 (d, J = 8.66Hz, 2H), 7.71 (d, J = 8.34Hz, 2H), 7.82 (d, J = 8.42Hz, 2H), 9.55 (s, 1H) ).
Example 65 6,7-D-methoxy-3-r4- (1 H-tetraazol-5-yl) phenyH-1,4-dihydroindene G, 2-chlororazole Example 64C (50 mg, 0.14 mmol)) was combined, zinc cyanide (17.4 mg, 1.48 mmol), and Pd (PPh3) 4 (15.6 mg, 0.014 mmol) in DMF (3 mL) in a capped vial of 5 mL vial and heated at 180 ° C for 300 seconds in a Smith Synthesizer. The mixture was cooled using 2812 kg / cm2 and then treated with sodium azide (105.3 mg, 1.62 mmol) and NH4CI (87 mg, 1.62 mmol). The bottle was recapped and heated to 220 ° C for 15 minutes. After the reaction mixture was cooled using 2.812 kg / cm2 of pressurized air, the solvent was removed and the residue was purified using preparative HPLC (for conditions, see Example 1D) to provide the title compound. MS (DCI / NH3) m / z: 361.0 (M + H) \ 1H NMR (500 Hz, DMSO-D6) d ppm 3.83 (s, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 7.24 (s, 1H), 7.26 (s, 1H), 8.01 (d, J = 8.42Hz, 2H), 8.15 (d, J = 8.42Hz, 2H).
Example 66 4- (6,7-Dimethoxy-1,4-dihydroindenoM, 2-cTpyrazol-3-yl) benzoic acid Example 64C, (78 mg, 0.21 mmol), PdCI2 (dppf) -CH2Cl2 (18 mg ), triethylamine (0.088 mL) in THF (98 mL) and H20 (1 mL) and stirred under a CO atmosphere (35.15 kg / cm2) at 120 ° C for 16 hours. The mixture was allowed to cool to room temperature, concentrated under reduced pressure and the residue was purified by HPLC (for conditions, see Example 1D) to provide the title compound. MS (DCI / NH3) m / z: 337.0 (M + H) +. 1H NMR (500 MHz, DMSO-D6) d ppm 3.81 (s, 2H), 3.82 (s, 3H), 3.84 (s, 3H), 7.23 (s, 1H), 7.25 (s, 1.H), 7.91 (d, J = 8.30Hz, 2H), 8.04 (d, J = 8.30 Hz, 2H).
Example 67 4- (4-Hydroxy-1,4-dihydroindenof 1,2-c1pyrazol-3-yl) benzoic acid Example 67A 2- (4-Bromobenzoyl) -1H-indene-1,3 (2H) -dione Methanol (8.5 ml) was treated with sodium (4.8 g) in benzene (90 mL). The reaction mixture was refluxed overnight, Cool to room temperature, and treat with phthalic dimethyl ester (38.84 g) and 1- (4-bromophenyl) ethanone (39.81 g) in benzene (50 ml). The distillation of the reaction mixture was carried out at 80 ° C overnight to remove the methanol. The reaction mixture was poured into dilute HCl and filtered. The filter cake was collected and recrystallized from ethanol to provide the title compound.
Example 67B 3- (4-Bromophenyl) indeneM, 2-clperazole-4- (1 H) -one Example 67A (5.8 g) and monohydrate hydrazine (0.982 ml, 20.24 mmol) in ethanol (300 rnL) were combined and refluxed at 90 ° C overnight. The mixture was allowed to cool to room temperature and filtered. The filter cake was dried to provide the title compound. MS (DCI / NH3) m / z: 327.3 (M + H) +.
Example 67C 4- (4-Oxo-1,4-dihydroindenof 1,2-cTpyrazol-3-in-benzoate butyl) Pd (OAc) 2 (3.5 mg), Ph3P (16 mg), DIEA (2.6 ml), and Example 67B (100 mg) in butanol were combined and treated with a CO vapor for 5 minutes. The mixture was stirred at 120 ° C overnight under a CO atmosphere. The mixture was allowed to cool to room temperature, concentrated, and the residue was purified through silica gel chromatography using a mixture of hexane and ethyl acetate as eluent to provide the title compound.
MS (DCI / NH3) m / z: 347.0 (M + H) +.
Example 67D 4- (4-Hydroxy-1,4-dihydroindenoM, 2-clpyrazol-3-yl) benzoic acid Example 67C (51 mg) in 2 ml of THF / MeOH (1: 1) was treated with NaBH 4 ( 5.6 mg) at 0 ° C. The reaction mixture was allowed to warm to room temperature and was stirred for 1 hour. The mixture was concentrated and the residue was suspended in THF (1 mL), MeOH (2 mL), and aqueous NaOH (1N, 1 mL). After stirring at 60 ° C for 2 hours, the mixture was concentrated and the residue was purified by HPLC to provide the title compound. MS (DCI / NH3) m / z: 293.3 (M + H) +. 1 H NMR (400 MHz, DMSO-De) d ppm 5.59 (d, J = 8.67Hz, 1H), 5.84 (d, J = 8.67Hz, 1H), 7.33 (m, 2H), 7.54 (d, J = 7.13 Hz, 1H), 7.59 (d, J = 7.29Hz, 1H), 8.03 (d, J = 8.44Hz, 2H), 8.10 (d, J = 8.44, 2H), 13.19 (s, 1H).
Example 68 4'-r6- (morpholin-4-ylmethyl) -1,4-dihydroindenoM, 2-clirazol-3-yl-1, 1'-biphenl-4-ol Example 68A 1,4-dihydroindenoyl, 2-clpirazole-6-carbaldehyde To a solution of 6-bromo-1,4-dihydro-indene [1,2-c] pyrazole (0.100 g, 0.425 mmol, see US Patent 6297238 for preparation) in THF (3 mL) at 78 ° C was added PhLi in cyclohexane / ether (1.8 M, 0.71 mL, 1.28 mmol) followed by s-BuLi in cyclohexane (1.3 M, 0.98 mL, 1.28 mmol) 30 minutes later. The reaction mixture was stirred at -78 ° C for 60 minutes and DMF (0.33 mL, 4.25 mmol) was added. The dry ice bath was removed after 30 minutes. After 30 more minutes, the reaction mixture was quenched with water. The reaction mixture was extracted with EtOAc, washed with 50% brine, dried over MgSO4, filtered, and concentrated. The concentrate was purified by flash chromatography eluted with EtOAc / hexane (7: 3 to 8: 2) to give 0.053 g (68%) of the desired product as a brown solid. S (DCI / NHg) m / z: 185.0 (M + H) +; 1H NR (300 Hz, CD3OD) d ppm 3.76 (s, 2H), 7.63 (s, 1H), 7.62-7.97 (m, 2H), 8.04 (s, 1H), 10.00 (s, 1H).
Example 68B 3-Vodo-1,4-dihydroindenof1,2-c1pyrazol-6-carbaldehyde A suspension of Example 68A (7.90 g, 0.0429 mol) and N-iodosuccinimide (11.6 g, 0.0515 mol) in DMF (150 mL) was heated at 80 ° C for 5.5 hours. The reaction was cooled and the solvent was evaporated. The concentrate was titrated with EtOAc and ether to give 7.20 g of a brown solid as the desired product. The filtrate was concentrated and purified by flash chromatography eluted with EtOAc / hexane (7: 3) to give 1.30 g of the desired product (combined yield: 64%). MS (DCI / NH3) m / z: 310.9 (M + H) +; 1H NMR (300 MHz, DMSO-D6) d ppm 3.63 (s, 0.8H), 3.68 (S, 1.2H), 7.72 (d, J = 7.46Hz, 0.5H), 7.83 (d, J = 7.80 Hz, 0.5H), 7. 96 (m, 1H), 8.07 (m, 1H), 10.03 (s, 1H), 13.45 (s, 0.6H), 13.72 (s, 0.4H).
Example 68C 3-iodo-6- (morpholin-4-ylmethyl) -1,4-dihydroindenoM, 2-chloro pyrazole A mixture of Example 68B (1.00 g, 3.22 mmol), morpholine (0.84 mL, 9.66 mmol), and TsOH H20 (61.2 mg, 0.322 mmol) in toluene (50 mL) was heated to reflux overnight. The solvent was evaporated. To the resulting residue were added EtOH (40 mC, THF (10 mL), and NaBH 4 (0.182 g, 4.83 mmol) at room temperature The mixture was stirred overnight and the solid filtered. with 1N HCl, and extracted with EtOAc The aqueous layer was basified using 3N NaOH and extracted with EtOAc The organic layer was dried over MgSO4, filtered, and concentrated The residue was purified through flash chromatography eluted with EtOAc / MeOH (95: 5) to give 0.387 g (32%) of the desired product as a pale yellow solid MS (DCI / NH3) m / z: 382.0 (+ H) +; HNR (300 MHz, CD3OD) d ppm 2.44-2.51 (m, 4H), 3.53 (s, 2H), 3.57 (s, 2H), 3.66-3.72 (rn, 4H), 7.34 (d, J = 8.14Hz, 1H), 7.54 (s, 1H), 7.58 (d, J = 7.80 Hz, 1H).
Example 68D 4 '- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) -1,1-biphenyl-4-ol A mixture of 4'-bromo-biphenyl-4 -ol (0.300 g, 1.20 mmol), bis (pinacolato) diboro (0.336 g, 1.32 mmol), PdCl2 (dppf) .CH2Cl2 (0.0293 g, 3%), dppf (0.0199 g, 3%), and ICOAc (0.353 g, 3.60 mmol) in 1,4-dioxane (6 mL) was heated at 90 ° C overnight. The reaction mixture was concentrated and the residue was extracted with EtOAc, washed with brine, dried over MgSO 4, filtered, concentrated, and purified by flash chromatography eluted with hexane / EtOAc (1: 1). to give 0.278 g (78%) of the desired product as a white foam. MS (DCI / NH3) m / z: 296.1 (M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 1.27 (s, 4 H), 1.36 (s, 8 H), 6.90 (d, J = 8.48 Hz, 2 H), 7.53 (dd, J = 12.72, 8.65 Hz, 4 H), 7.85 (d, J = 8.14Hz, 2H).
Example 68E 4'-6-morpholin-4-ylmethyl-1,4-dihydro-indenon, 2-cTptrazol-3-yl) -biphenyl-4-ol A mixture of Example 68C (60.0 mg, 0.157 mmol), Example 69 D (51.2 mg, 0.173 mmol), Na 2 CO 3 (1 M, 0.22 mL, 0.220 mmol), and Pd (PPh 3) 2 Cl 2 (11.0 mg, 0.0157 mmol) in DE / EtOH / H 2 O (7: 2: 3, 1.4 mL) in a 2 mL capped bottle was heated from 160 to 170 ° C for 450 to 600 seconds in a Smith Synthesizer (300W). The reaction was cooled using 2812 kg / cm2 of pressurized air. The solvents were evaporated and the crude product was purified using preparative HPLC to give 22.9 mg (22%) of the desired product as the TFA salt. The purification was processed on a Phenomenex® C18 column (250 mm X 21.2mm, 5 pm particle size) using a gradient from 0% to 70% acetonitrile: 0.1% TFA aqueous for 46 min at a flow rate of 25 mUmin. Examples 69 to 83, represented by Figure (1) and listed in Table 1 were synthesized in a manner similar to that described in Example 68E.
H Figure 1 TABLE 1 Example 84 Example 84A 3-Iodo-1,4-dihydroindenoH, 2-clirazole-6-carboxylic acid A mixture of Example 68B (3.00 g, 9.67 mmol), KH2P04 (5.26 g, 0.0387 mol), and H2NS03H (1.41 g, 0.0145 mol) in 1,4-dioxane / H20 (100/30 mL) was stirred at 0 ° C for 15 minutes. To this mixture was added NaCl02 (1.14 g, 0.0126 mol) in H20 (15 mL) dropwise. The reaction mixture was stirred for 15 minutes at 0 ° C followed by the addition of NaHS03 (1.11 g, 0.0106 mol). The resulting suspension was warmed to room temperature and stirred for 1 hour. The reaction mixture was treated with a Na2S203 solution and concentrated to remove most of the solvents. Water was added to the resulting slurry and the suspension was stirred for 1 hour. The solid material was filtered, rinsed with water, and dried in a vacuum oven to give 3.49 g of the desired product as a solid. yellow. This product was used in the next step without further purification. S (DCI / NH3) m / z: 327.0 (M + H) +; 1H N MR (300 Hz, DMSO-De) d ppm 3.57 (s, 2H), 7.67 (m, 1H), 7.98 (d, J = 7.80 Hz, 1H), 8.10 (s, 1H).
EXAMPLE 84B 3-iodo-6- (morpholin-4-ylcarbonyl) -1,4-dithiindrodon, 2-c1 pyrazole A mixture of Example 84A (0.210 g, 0.644 mmol), PiBOP (0.503 g, 0.966 mmol), morpholine (0: 084 mL 0.966 mmol), and diisopropylethylamine (0.39 mL, 2.25 mmol) in DMF (5 mL) was stirred at Room temperature during the night. The reaction mixture was diluted with EtOAc and washed with and NaHCO 3. The organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography eluted with EtOAc to give 0.122 g (48%) of the desired product as a red solid. MS (DCI / NH3) m / z: 396.0 (M + H) +; 1H NMR (300 MHz, DMSO-D6) S ppm 3.46-3.67 (m, 10H) 7.41 (m, 1H) 7.59 (s, brd, 1.5H) 7.67 (d, J = 7.46Hz, 0.5H).
Example 84C '1, 1' -biphenyl-4-ol The desired product was prepared by replacing Example 68C with Example 84B in Example 68E. The reaction temperature and time were raised to 180 ° C and 1000 seconds, respectively.
EXAMPLE 85 N-Cyclohexyl-3- (4'-idroxy-1,1'-biphenyl-4-yn-1,4-dihydroindenoyl. 2-chloro-l-6-carboxam ida Example 85A N-cyclohexyl-3-vodo-1,4-dihydroindenor, 2-dirazole-6-carboxamide Ua mixture of Example 84A (0.359 g, 1.07 mmol), HOBt (0.218 g, 1.61 mmol), EDC (0.308) 1.61 mmol), cyclohexylamine (0.18 mL, 1.61 mmol), and Et3N (0.22 mL 1.61 mmol) in DMF (8 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with NaHCO 3 and brine. The organic layer was dried over MgSO4, filtered, concentrated, and titrated with ether to give 0.216 g (50%) of the desired product as a yellow solid. MS (DCI / NH3) m / z: 408.0 (M + H) +; H NMR (300 MHz, DMSO-D6) d ppm 1.09-1.44 (m, 5H) 1.58-1.91 (m, 5H) 3.48-3.67 (m, 2H) 3.77 (m, 1H) 7.61 (m, 1H) 7.86 ( d, J = 7.46Hz, 1H) 8.02 (s, 1H) 8.23 (d, J = 8.14Hz, 1H) 13.27 (s, 0.5H) 13.58 (s, 0.5H).
Example 85B N-Cyclohexyl-3- (4'-hydroxy-1,1'-biphenyl-4-yl) -1,4-dihydroindenofl-2-c-thirazole-6-carboxamide The desired product was prepared by replacing Example 68C with the Example 85A in Example 68E. The reaction temperature and time were raised to 180 ° C and 1000 seconds, respectively.
Examples 86 to 97, represented by Figure (II) listed in Table 2, were synthesized in a manner similar to that described in Example 84C or 85B.
Figure (II) TABLE 2 EXAMPLE 98 N-R 3 -'4'-Hydroxy-1, R-Biphenyl-4-N-1,4-Dihydro-N-Denon-2-Clprazol-6-ill-2-morphine-4-ylacetamide EXAMPLE 98A 6-Bromo-1-fr2- (trimethylsilyl) ethoxymethyl} -1,4-dihydroindenori, 2-c1 pyrazole and 6-bromo-2-. { r2- (trimethylsilyl) ethoxymethyl} -2,4- dihydroindeno [1,2-cTpirazole To a solution of 6-bromo-1,4-dihydro-indene [1,2-c] pyrazole (4.08 g, 0.0174 mol, see US Patent 6297238 for preparation) in DMF (100 mL) at 0 ° C was added NaH (60%, 0.764 g, 0.0191 mol). After 20 minutes, SE CI (3.4 mL, 0.0191 mol) was added to the above mixture and the ice bath was removed. The reaction mixture was quenched with water 3.5 hours later. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over MgSO4, filtered, concentrated, and purified through flash chromatography eluted with EtOAc / hexane (2: 8) to give 5.14 g (81%) of the desired product as a brown oil. . S (DCI / NH3) m / z: 365.0 (M + H) +; 1H MR (300 MHz, CDCl 3) d ppm. 0.00-0.02 (m, 9H) 0.89-0.98 (m, 2H) 3.59-3.68 (m, 4H) 5.52 (s, 1.3H) 5.68 (s, 0.7H) 7.51 (m, 2.4H) 7.67 (m, 1.6 H).
Example 98B N-M -. { r 2 - (trimethylsilyl) ethoxymethyl} -1,4-dihydroindenoyl, 2-cl pyrazole-6-yl) -acetamide To a solution of Example 98A (5.77 g, 0.0158 mol) in degassed 1,4-dioxane (50 ml_) is gregaron Pd (OAc) 2 (70.9 mg, 2 mol%), Xantphos (274. mg, 3 mol%), CS2C03 (7.72 g, 0.0237 mol), and acetamide (1.12 g, 0.0190 mol). The mixture was heated to 100 ° C overnight and cooled. The solvent was evaporated and the residue was extracted with EtOAc, washed with water, brine, NaHCO 3, dried over MgSO 4, filtered, concentrated, and purified by flash chromatography eluted with EtOAc / hexane (6: 4 to 8: 2) to give 4.06 g (75%) of the desired product as a yellow solid. MS (DCI / NH3) m / z: 344.1 (M + H) +; H NMR (300 MHz, CDCIg) d ppm 0.00-0.02 (m, 9H) 0.94 (dd, J = 16.44, 8.31Hz, 2H) 2.23 (s, 3H) 3.60-3.68 (m, 4H) 5.51 (s, 1.3 H) 5.67 (s, 0.7H) 7.35 (m, 1H) 7.45 (d, J = 7.46Hz, 1H) 7.60 (d, J = 8.14Hz, 0.4H) 7.73 (d, J = 8.14Hz, 0.6H) 7.91 (d, J = 12.21Hz, 1H) Example 98C, 4-dihydroindenoH, 2-clirazol-6-amine To a solution of Example 99B (1.96 g, 5.71 mmol) in EtOH (25 ml_) conc. HCl was added. (1.5 ml_). The mixture was heated at 80 ° C for 7 hours and cooled. The solvent was evaporated and the residue was dissolved in water and washed with EtOAc. The aqueous layer was basified with 3N NaOH until pH = 9 and extracted with EtOAc (2X). The The combined organic layers were dried and concentrated to give the desired product (0.920 g, quantitative yield) as a white foam. MS (DC1 / NH3) m / z: 172.0 (M + H) +; 1 H NMR (300 MHz, DMSO-D 6) S ppm: 3.44 (s, 2 H) 5; 10 (s, 2 H) 6.52 (dd, J = 8.14 2.03 Hz, 1 H) 6.71 (s, 1 H) 7.26 (d, J = 8.14Hz, 1H) 7.48 (s, 1H) 12.27 (s, 1H).
EXAMPLE 98D 2-Chloro-N-1,4-dihydroindeno [1,2-clirazol-6-ylacetamide To a solution of Example 98C (0.250 g, 1.46 mmol) in acetone (10 ml_) was added a solution of saturated NaHCO3 ( 5 ml_) and chloroacetyl chloride (0.13 mL, 1.61 mmol). The mixture was heated at 50 ° C for 90 minutes and cooled. The solvent was partially evaporated and water was added to the suspension. The solid was filtered, washed with water, and dried to give the desired product (0.280 g, 78%) as an off-white solid. A small amount of the product (30 mg) was further purified using reverse phase HPLC to give an analytical sample. MS (DCI / NH3) m / z: 248.0 (M + H) +; 1 H NMR (500 MHz, DMSO-De) d ppm 3.62 (s, 2 H) 4.27 (s, 2 H) 7.52 (d, J = 8.42 Hz, 1 H) 7.58 (m, 1 H) 7.61 (s, 1 H) 7.85 (s) , 1H) 10.34 (s, 1H).
Example 98E 2-Chloro-N- (3-iodo-4-dihydroindenof, 2-cl-irazol-6-yl) -acetamide To a solution of Example 98D (0.140 g, 0.565 mmol) in DMF (3 mL) was added NIS (0.153 g, 0.678 mmol) and the. The mixture was heated at 80 ° C for 4 hours and cooled. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried, filtered and concentrated, and purified by flash chromatography eluted with EtOAc / hexane (7: 3 to 9: 1) to give 47 mg of the desired product like a solid coffee. MS (DCI / NH3) m / z: 373.9 (M + H) +; H NM (300 MHz, DMSO-D6) d ppm 3.53 (s, 2H) 4.26 (s, 2H) 7.52 (s, brd, 2H) 7.87 (s, 1H) 10.38 (s, 1H).
EXAMPLE 98F N- (3-yod 0-1, 4-dihydroindenori, 2-c 1p -razol-6-yl) -2-morph or in-4-ylacetamide To a solution of Example 98E (44.5 mg, 0.119 mmol) in EtOH (2 mL) was added morpholine (31.3 μ?). The mixture was heated at 60 ° C for 4 hours and cooled. The solvent was evaporated and the residue was purified by flash chromatography eluting with EtOAc to give 39.5 mg (78%) of the desired product as a yellow foam. MS (DCI / NH3) m / z: 425.0 (M + H) +; 1H NMR (300 MHz, DMSO-D6) d ppm 2.51-2.53 (m, 4H) 3.14 (s, 2H) 3.51 (s, 2H) 3.64 (m, 4H) 7.50 (m, brd, 1H) 7.59 (m, 1H) 7.90 (s, 1H) 9.81 (s, 1H).
Example 98G N-r3- (4'-hydroxy-1, 1'-biphenyl-4-in-1,4-dihadroindenoM, 2-d pyrazol-6-n-2-morpholin-4-ylacetamide The desired product was prepared by substituting Example 68C with Example 98F in Example 68E.
Examples 99 to 103, represented by Figure (III) and listed in Table 3, were synthesized in a manner similar to that described in Example 98G.
Figure (III) TABLE 3 EXAMPLE 104 3- (4'-Hydroxy-1,1'-biphenyl-4-in-7-methoxy-N- (pyridin-4-ylmethyl) -1,4-dihydroindenoM, 2-c1pyrazole-6-carboxamide Example 104A 2- (Hydroxymethylene) -6-methoxy-indan-1 -o na To a mixture of ethyl formate (15.75 mL, 0.195 mol) and NaH (60%, 7.80 g, 0.195 mol) in benzene (550 mL) A suspension of 6-methoxy-indan-1 -one (15.81 g, 0.0974 mol) in benzene (150 mL) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature overnight and treated with water. The solid was filtered, washed with water, and dried in an oven to give the desired product (16.86 g, 91%). The product may exist in the form of a sodium salt, however, it was carried to the next reaction without additional characterization). MS (DCI / NH3) m / z: 191.1 (M + H) +; 1 H NMR (300 Hz, DMSO-D 6) 8 ppm 3.50 (s, 2 H) 3.80 (s, 3 H) 7.13-7.20 (m, 2 H) 7.47 (d, J = 8.14 Hz, 1 H) 7.74 (s, brd, 1 H ).
EXAMPLE 104B 7- Eto-1, 4-dihydrolndeneM, 2-cl irazole A mixture of Example 104A (16.86 g, 0.0886 mol), hydrazine monohydrate (5.2 mL, 0.106 mol), and AcOH (6.1 mL, 0.106 mol) in EtOH (375 mL) was heated at 90 ° C for 2 hours. The solvent was evaporated and the residue was titrated with water and filtered. The filter cake was again titrated with a NaHCO3 solution, filtered, washed with water, and dried in an oven to give the desired product (13.9 g, 84%). MS (DCI / NH3) m / z: 187.0 (M + H) +; 1 H NMR (300 MHz, DMSO-D 6) d ppm 3.52 (s, 2 H) 3.81 (s, 3 H) 6.81 (dd, J = 8.31, 2.54 Hz, 1 H) 7.17 (s, 1 H) 7.40 (d, J = 8.14 Hz, 1H) 7.62 (s, 1H) 12.71 (s, 1H).
Example 104C 6-Bromo-7-methoxy-1,4-dihydroindenof1, 2-clirazole To a solution of Example 104B (8.91 g, 0.0478 mol) in AcOH (150 mL) was added Br2 (3.43 mL, 0.0669). The reaction mixture was concentrated after 5 minutes and the residue was titrated in EtOAc and hexane, and then filtered. The solid was stirred in a NaHCO 3 solution and filtered, washed with water, and dried in an oven to give the desired product (11.99 g, 95%). The material with a slight impurity was used in the next step without further purification. MS (DCI / NHa) m / z: 265.0 (M + H) +; 266.9 (M + H + 2) +.
Example 104D 7-Methoxy-1,4-dihydro-thirthenoxy, 2-c1pyrazole-6-carb aldehyde To a suspension of Example 104C (5.49 g, 0.0207 mol) in THF (300 mL) was added PhLi (1.9 M, 21.8 mL, 0.0414 mol) at -78 ° C. S-BuLi (1.4 M, 29.6 mL, 0.0414 mol) and DMF (12.8 mL, 0.166 mol) were added to the reaction mixture after 30 and 60 minutes, respectively. The mixture was stirred at -78 ° C for 1 hour and the cold bath was removed. The reaction was extinguished with a solution of saturated NH4CI after 1 hour at room temperature. The mixture was extracted with EtOAc, washed with water, brine, dried over MgSO4, filtered, concentrated, and titrated with ether to give 3.62 g (81%) of the desired product. S (DCI / NH3) m / z: 215.1 (M + H) +; 1 H NMR (300 MHz, D SO-D 6) d ppm 3.62 (s, 2 H) 4.01 (s, 3 H) 7.45 (s, 1 H) 7.73 (s, 1 H) 7.80 (s, 1 H) 10.37 (s, 1 H) 13.07 (s, 1H).
EXAMPLE 104E 3 -Oo d or -7- methoxy-1, 4-dihydroxyden, 2-c1pyrazol-6-carbaldehyde The desired product was prepared by replacing Example 68A with Example 104D in Example 68B. After the reaction, the solvent was evaporated and the residue was titrated with ether to give the crude product, which was used in the next step without further purification. MS (DC1 / NH3) m / z: 340.9 (M + H) +.
Example 104F 3-Iodo-7-methoxy-1,4-dihydroindene, 2-cl-irazole-6-carboxylic acid The desired product was prepared by replacing Example 68B with Example 104E in Example 84A. The crude product was used in the next step without further purification. MS (DCI / NH3) m / z: 374.0 (M + NH4) +.
Example 104G The desired product was prepared by substituting Example 84A and cyclohexylamine with Example 104F and 4- (aminometii) pyridine in Example 85A. The slightly impure product was used in the next step without further purification. MS (DCI / NH3) m / z: 447.0 (M + H) +. The formation of tertiary amides in this step towards corresponding final compounds listed in Table 4 was performed following the protocol in Example 84B.
EXAMPLE 104H 3- (4-Hydroxy-1,1'-b-phenyl-4-yl) -7-methoxy-N- (pyridin-4-ylmethyl) -, 4- di idroindenofl, 2- c1pyrazol-6-carboxamide The desired product was prepared by substituting Example 68C with Example 104G in Example 68E.
Example 105 4 '- (6- { Rf2-Hydroxyethyl) amino1methyl > -7-methoxy-1,4-dihydroindenon, 2-clpyrazol-3-yl) -1, 1'-biphenyl-4-ol Example 105A 2-f (3-Iodo-7-methoxy-1,4-dihydro-indeneM, 2-cTp -razol-6-ylmethyl) -aminol-ethanol The desired product was prepared by substituting Example 68B and morphillin with Example 104D and 2-aminoethanol in Example 68C. The slightly impure product was used in the next step without further purification. MS (DCI / NH3) m / z: 386.0 (M + H) +.
Example 105B 4 '- (6-. {R (2-H -droxyethyl) amino-1-methyl-7-methoxy-1,4-dihydroindenori, 2-clpyrazol-3-yl) -1, 1'-biphenyl-4-ol The product desired was prepared by substituting Example 68C with Example 105A in Example 68E.
Examples 106 to 116, represented by Figure (IV) and listed in Table 4, were synthesized in a manner similar to that described in Example 104H or Example 105B.
Figure (IV) TABLE 4 Example 117 3-Fluoro-4 '- [6- (hydroxymethyl) -1,4-dihydroindenor, 2-cTpyrazole-3-in- 1.1'-biphenyl-4-ol Example 117A (3-iodo-, 4-dihydroindenof1.2-c1pyrazol-6-yl) methanol To a suspension of Example 68B (0.500 g, 1.61 mmol) in a mixture of MeOH (9 mL) and THF (3 mL) was NaBH 4 (73.0 mg, 1.93 mmol) was added at room temperature. The mixture was stirred for 2 hours and the solvent was evaporated. The desired product (0.324 g, 65%) recrystallized from warm CH2CI2 with a small amount of MeOH. MS (DCI / NH3) m / z: 312.9 (M + H) +; 1 H NMR (300 MHz, CD 3 OD) d ppm 3.54 (s, 2 H), 4.66 (s, 2 H), 7.35 (d, J = 7.80 Hz, 1 H), 7.55 (s, 1 H), 7.59 (d, J = 7.80 Hz, 1H).
EXAMPLE 117B 3-Fluoro-4'-r6- (hydroxymethyl) -1,4-dihydroindenoH, 2 -prazole! -3-H- 1.1'-bp-phenyl-4-ol The desired product was prepared by substituting Example 68C and Example 68D with Example 117A and 2-fluoro-4- (4,4,5,5 -tetramethyl- [1,2,2] dioxaborolan-2-yl) -phenol respectively in Example 68E. MS (DCI / NH3) m / z: 373.1 (M + H) +; 1H NMR (400 MHz, DMSO-D6) d ppm 3.89 (s, 2H) 4.57 (s, 2H) 7.05 (t, J = 8.00 Hz, 1H) 7.32 (d, J = 7.36Hz, 1H) 7.41 (d, J = 8.29Hz, 1H) 7.54-7.59 (m, 2H) 7.61 (d, J = 7.67Hz, 1H) 7.76 (d, J = 8.29Hz, 2H) 7.86 (d, J = 12.0 Hz, 2H) 10.00 ( s, brd, 1H). The intermediates leading to the compounds represented by Figure V and shown in Table 5 were prepared in a similar manner as the examples shown in Table 1, Table 2 or Table 4. The final Suzuki coupling reaction was carried out in the form similar to the procedure described in Example 117B.
Figure (V) TABLE 5 Example 123 5-6-r (4-Methylpiperazin-1-ylmethyl-T-1,4-dihydroindenof1,2-c1-irazol-3-yl}. Pyridine-2-carbonitrile Example 123A 3-Iodo-1 -. r2- (trimethylsilyl) ethoxymethyl> -1,4-dihydroindenori, 2-cT pyrazole-6-carbaldehyde To a mixture of Example 68A (1.00 g, 3.22 mmol) and NaH (60%, 0. 142 g, 3.55 mmol) in DMF (20 mL) was added SEMCI (0.63 mL, 3.55 mmol). After 4 hours, the reaction was quenched with water and extracted with EtOAc. The organic layer was washed with NaHCO 3, dried over MgSO 4, filtered, concentrated, and purified by flash chromatography eluted with hexane / EtOAc (8: 2 to 1: 1) to give 0.887 g (63%). of the desired product as a yellow solid. MS (DCI / NH3) m / z: 440.9 (M + H) +; 1 H NM (300 MHz, CDCl 3) d ppm -0.01 (m, 9 H) 0.75-1.10 (m, 2 H) 3.46-3.76 (m, 2 H) 5.61 (s, 1 H) 5.68 (s, 1 H) 7.80 (d, J = 7.80 Hz, 0.5H) 7.87-7.97 (m, 1.5H) 8.03 (d, J = 5.76Hz, 1H) 10.06 (s, 1H).
EXAMPLE 123B 3-Iodo-6-r (4-methylpiperazin-1-immethyl-1 - { F2- (trimethyl) vU ethoxymethyl., -, 4-dihydroindenof 1,2-c-thirazole The desired product is prepared by substituting Example 68B and morpholine with Example 123A and 1-methylpiperazine respectively in Example 68 C. MS (EST) m / z: 525.1 (M + H) +.
Example 123C 6-Fluoropyridin-3-illboronic acid To a mixture of 5-bromo-2-fluoro-pyridine (1.71 g, 6.20 mmol) in dry ether (100 mL) was added n-BuLi (1.6 M in hexane, 41.4 mL, 0.0663 mol) at -78 ° C. After 30 minutes, trimethyl borate (8.2 mL, 0.0722 mol) was added to the above mixture and the reaction was warmed to room temperature and stirred overnight. The reaction was quenched with water and brine and acidified with 10% HCl until pH = 8. The mixture was extracted with EtOAc, washed with 50% brine, dried over MgSO4, filtered, concentrated to give 5.1 g. (60%) of the desired product. The crude product was used in the next step without further purification.
Example 123D 3- (6-Fluoropyridn-3-yl) -6-r (4-methylazin-1-Dmethyl-1 -. {2- (trimethylsilyl) ethoxymethyl}. -1,4-dihydroindene, 2-cl irazole The desired product was prepared by substituting Example 68C and Example 68D with Example 123B and Example 123C in Example 68E. The product was purified by flash chromatography instead of reverse phase HPLC. MS (ESI) m / z: 494.3 (M + H) +.
Example 123E 5-. { 6-R (4-ethylpiperazin-1-yl) metin-1,4-dihydroindenori, 2-c1pyrazol-3-yl} pyridine-2-carbonitrile A mixture of Example 123D (70.6 mg, 0.142 mmol) and NaCN (9.7 mg, 0.199 mmol) in DF (1.2 mL) in a stoppered flask, was heated at 210 ° C for 1200 seconds in a synthesizer Smith (300W). The reaction was cooled using 2812 kg / cm2 of pressurized air. The mixture was extracted with EtOAc and the organic layer was washed with 50% brine, NaHCO3, dried over MgSO4, filtered, concentrated. The crude product was treated with HCl (conc, 2 drops) and EtOH (3 mL) and the mixture was heated at 75 ° C for 2.5 hours. The solvent was evaporated and the residue was purified using reverse phase HPLC to give 7.5 mg of the desired product as the TFA salt.
Example 124 3- (6-Cyano-pyridin-3-yl) -N-fpyridin-2-ylmethyl) -1,4-d-hydroquinide, 2-clpyrazole-6-carboxamide Example 124A 3-Iodo-N- (pyridin-2-ylmethyl) -1,4-dihydroindenon, 2-clirazole-6-carboxamide The desired product was prepared by replacing cyclohexylamine with 2- (aminomethyl) pyridine in Example 85A. CH2CI2 was used for the titration. MS (DCI / NH3) m / z: 417.0 (M + H) +; 1 H NMR (300 MHz, DMSO-D 6) d ppm 3.58 (s, 1 H) 3.63 (s, 1 H) 4.58 (d, J = 5.76 Hz, 2 H) 7.26 (m, 1 H) 7.33 (d, J = 7.80 Hz, 1H) 7.60 (d, J = 8.14Hz, 0.5H) 7.74 (m, 1.5H) 7.95 (t, J = 7.97Hz, 1H) 8.10 (d, J = 5.42Hz, 1H) 8.50 (m, 1H) 9.14 (t, J = 5.93Hz, 1H) 13.29 (s, 0.4H) 13.61 (s, 0.6H).
Example 124B 1-rBis-4-methoxyphenyl) methyl-3-iodo-N- (iridin-2-ylmetin-1,4-dihydroindene, 2-c1-irazole-6-carboxamide A mixture of Example 124A (0.176 g, 0.423 mmol ), bis- (4-methoxy-phenyl) -methyl chloride (0.122 g, 0.465 mmol), and Et3N (71 pL, 0.507 mmol) in DF (2.0 mL) was stirred at room temperature During 4 hours. The reaction mixture was diluted with 50% brine and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, concentrated, and purified by flash chromatography eluting with EtOAc to give 0.166 g (61%) of the desired product as a pale yellow colored solid. . MS (ESI) m / z: 643.1 (M + H) +.
Example 124C 1-rBis (4-methoxyphenyl) methyl-3- (6-fluoropyridin-3-yn-N- (pyridin-2-ylmethyl) -1,4-dihydroindenoH. 2-c1pyrazole-6-carboxamide The product desired was prepared by substituting Example 68C and Example 68D with Example 124B and Example 123C in Example 67E.The product was purified via flash chromatography instead of reverse phase HPLC MS (ESI) m / z : 612.2 (M + H) +.
Example 124D 3- (6-Cyano-pyridin-3-yl) -N- (pyridin-2-ylmethyl) -1,4-dydrohydronide, 2- cTpyrazole-6-carboxamide desired product was prepared by replacing Example 123D with Example 124C in Example 123E. Acid deprotection was performed in EtOH and, 1,4-dioxane at 40 ° C overnight.
Examples 125 to 129, represented in Figure (VI) and shown in Table 6, were synthesized in a manner similar to the described in Example 123E or Example 124D. The pyrazole nitrogen of the intermediates can also be protected by the SEM group.
Figure (VI) TABLE 6 EXAMPLE 130-f6- (Hydroxymethyl) -1,4-dihydroindenof1,2-c1pyrazol-3-n-pyridine-2-carbonitrile EXAMPLE 130A (3-Iodo-1-fr2- (tr.methylsilyl) ethoxymethyl.) -1,4-dihydroindenof 1,2-cl pyrazol-6-yl) methanol To a solution of Example 123A (1500 g, 3.41 mmol) in MeH (18 mL) and THF (14 mL) was added NaBH4 (64.5 mg, 1.70 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 90 minutes and quenched with water. The solvents were evaporated and the residue was extracted with EtOAc, washed with NaHCO 3, dried over MgSO 4, filtered, concentrated, and purified by flash chromatography eluted with EtOAc / hexane (1: 1) to give 1195 g (79%) of the desired product as an off-white solid. MS (ESI) m / z: 443.0 (M + H) +.
EXAMPLE 130B 3- (6-Fluoropyridin-3-yn-1- (r2- (trimethylsilylethoxymethyl> -1,4-dihydroxyind in of 1,2-clirazole-6-yl) methanol The desired product is prepared by substituting Example 68C and Example 68D with Example 130A and Example 123C in Example 68E.The product was purified through flash chromatography instead of reverse phase HPLC MS (ESI) m / z: 412.1 (M + H) '.
Example 130C 5-r6- (Hydroxymethyl), 4-dihydroindenofl, 2-c1pyrazol-3-pyridin-2-carbonitrile The desired product was prepared by replacing Example 123D with Example 130B in Example 123E. MS (ESI) m / z: 289.0 (M + H) +. 1H NMR (300 MHz, DMSO-Ds) d ppm 3.95 (s, 2H) 4.57 (s, 2H) 7.34 (d, J = 7.80 Hz, 1H) 7.56 (s, 1H) 7.62 (m, 1H) 8.17 (m , 1H) 8.39 (dd, J = 8.14, 2.37Hz, 1H) 9.18 (s, 1H).
Example 131 5-. { 6-R (Pyridin-3-yloxy) metin-1,4-dihydroindenofl, 2-c1pyrazol-3-yl > pyridine-2-carbonitrile EXAMPLE 131A 5- (6- (hydroxymethyl) -1- (r2- (tr ymethylsilyl) ethoxymethyl> -1,4-dihydroindenof1,2-c1pyrazol-3-yl) pyridin-2 -carbonitrile The desired product was prepared by replacing Example 123D with Example 130B in Example 123E except that the final removal of SEM protecting group using HCI was not performed MS (ESI) m / z: 419.1 (M + H) +.
Example 131B 5-6-r (Pyridin-3-yloxy) methyl-1,4-dihydro-n-nofofl, 2-c1pyrazol-3-yl > pyridine-2-carbonitrile A mixture of Example 131A (60.0 mg, 0.143 mmol), di-t-butyl azodicarboxylate (39.6 mg, 0.172 mmol), P 3P on a solid support (3mmo1 / g, 57.3 mg, 0.172 mmol) , and 3-hydroxypyridine (16.4 mg, 0.172 mmol) in THF (2 ml_) was stirred at room temperature overnight. The solid was filtered and the solvent was evaporated. The crude product was treated with HCl (concentrate, 4 drops) and EtOH (4 ml_). The mixture was heated in a bottle capped at 75 ° C for 2 hours. The solvent was evaporated and the residue was purified using reverse phase HPLC to give the desired product (12.4 mg) as the TFA salt. MS (ESI) m / z: 366.0 (M + H) +. 1 H NMR (300 MHz, D SO-D 6) S ppm 4.01 (s, 2 H) 5.83 (s, 2 H) 7.58 (d, J = 7.80 Hz, 1 H) 7.74 (m, 1 H) 7.80 (s, 1 H) 7.93- 8.05 (m, 2H) 8.18 (d, J = 8.14Hz, 1H) 8.40 (dd, J = 8.14, 2.37Hz, 1H) 8.62-8.84 (m, 2H) 9.19 (s, 1H) 12.14 (s, 1H) .
EXAMPLE 132 5- (6-R (Pyridin-4-yloxy) methylene-1,4-dihydroindenori, 2-c1pyrazol-3-yl.) Pyrridin-2-carbonitrile The desired product was prepared by substituting 3-hydroxypyridine for 4-hydroxypyridine in Example 131 B. MS (ESI) m / z: 366.0 (M + H) +. 1 H NMR (300 MHz, DMSO-D6) d ppm 3.99 (s, 2H) 5.56 (s, 2H) 7.10 (d, J = 7.46Hz, 2H) 7.46 (d, J = 7.80 Hz, 1H) 7.67-7.83 (m, 2H) 8.17 (d, J = 8.14Hz, 1H) 8.39 (dd, J = 8.14, 2.03Hz , 1H) 8.62 (d, J = 7.12Hz, 2H) 9.18 (d, J = 2.03Hz, 1H).
Example 133 3- (6-Fluoro-iridin-3-yl) -7-methoxy-4,4-dimethyl-1,4-dihydroindene M, 2-c] pyrazol-6-ol Example 133A 6-Methoxy- 3,3-dimethyl-5- (r2- (trimethylsilyl) ethoxy-1-methoxy-1 -indane-1-one To a solution of 5-hydroxy-6-methoxy-3,3-dimethyl-indan-1 -one (40.0 g, 0.194 mol, see preparation in J. Chem. Soc. Perkin Trans. 11982, p2013-2017) in CH2CI2 (400 ML) were added diisopropylethylamine (35.5 mL, 0.204 mol) and SEMCI (34.9 mL, 0.198 mol) ). The reaction mixture was stirred at room temperature for 3 hours and concentrated. The residue was purified by flash chromatography eluted with EtOAc / hexane (2: 8) to give 60.5 g (93%) of the desired product as a brown oil. MS (DCI / NH3) m / z: 337.1 (M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 0.00 (s, 9 H) 0.96 (t, J = 8.10 Hz, 2 H) 1.39 (s, 6 H) 2.56 (s, 2 H) 3.83 (t, J = 8.10 Hz, 2 H) 3.90 (s, 3H) 5.39 (s, 2H) 7.15 (s, 1 H) 7.20 (s, 1H).
Example 133B 2- (Hydroxymethylene) -6-methoxy-3,3-dmethyl-5-. { r2- (trimethylsilyl) ethoxy methoxy} indan-1-one To a solution of Example 133A (2.41 g, 7.15 mmol) in THF (15 mL) was added NaH (60%, 0.343 g, 8.58 mmol) at 0 ° C. After 1 hour, ethyl formate (0.73 mL, 8.58 mmol) was added. The reaction mixture was heated at 50 ° C for 2 hours, cooled, quenched with water, and extracted with EtOAc. The organic layer was washed with 5% citric acid, brine, dried over MgSO4, filtered, concentrated, and purified by flash chromatography eluted with EtOAc / hexane (1: 1) to give 1.17 g of the desired product as a purple gel. MS (DCI / NH3) m / z: 365.2 (M + H) +. 1 H NMR (300 MHz, CDCl 3) d ppm 0.00 (s, 9H) 0.96 (t, J = 8.10Hz, 2H) 1.43 (s, 6H) 3.83 t, t, J = 8.10Hz, 2H) 3.93 (s, 3H), 7.18 (s, 1 H) 7.27 (d, J = 2.37Hz, 2H) .
Example 133C 7-Methoxy-4,4-dimethyl-6-r 2 - (trimethylsilyl) ethoxymethoxy > -1 A- dihydroindenoM, 2-clirazole A mixture of Example 133B (0.886 g, 2.43 mol), hydrazine monohydrate (0.14 mL, 2.92 mol), and AcOH (38 g, 0.729 mmol) in EtOH (20 mL) was heated at 85 ° C for 1.5 hours. The solvent was evaporated and the residue was purified by flash chromatography eluted with EtOAc / hexane (1: 1) to give 0.865 g of the desired product as a yellow solid. MS (DCI / NH3) m / z: 362.1 (M + H) +; 1H NR (300 MHz, DMSO-D6) d ppm 0.00 (s, 9H) 0.91 (t, J = 8.10Hz, 2H) 1.40 (s, 6H) 3.78 (t, J = 8.10Hz, 2H) 3.84 (s, 3H) 5.22 (s, 2.H) 7.17 (s, 1H) 7.20 (s, 1H) 7.53 (s, 1H).
Example 133D 3-Iodo-7-methoxy-4,4-dimethyl-6- 2- (trimethylsilyl) ethoxy-1-methoxy) -1,4-dihydroindenoM.2-c1pyrazole A suspension of Example 133C (10.4 g, 0.0290 mol) and N- Iodosuccinimide (7.82 g, 0.0348 mol) in 1,4-dioxane (300 mL) was heated at 90 ° C for 7.5 hours. The reaction was cooled and the solvent was evaporated. The concentrate was purified via flash chromatography eluted with EtOAc / hexane (1: 1) to give 8.79 g of the desired product. MS (DCI / NH3) m / z: 487.1 (M + H) +; 1 HOUR NMR (300 MHz, CDCI3) d ppm 0.00 (s, 9H) 0.97 (t, J = 8.10Hz, 2H) 1.48 (s, 6H) 3.85 (t, J = 8.10Hz, 2H) 3.92 (s, 3H) 5.32 (s, 2H) 7.21 (s, 1 H) 7.22 (s, 1 H).
Example 133E 3- (6-Fluoropyridin-3-yl) -7-methoxy-4,4-dimethyl-1,4-dihydroindenon, 2-clpyrazole-6-ol The desired product was prepared by replacing Example 68C and Example 68D with Example 133D and Example 123C in Example 68E. The product was purified by flash chromatography instead of reverse phase HPLC. This intermediate was treated with HCl (concentrate, 3 drops) and EtOH (2 mL). The mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified using reverse phase HPLC to give the desired product (13.0 mg) as the TFA salt. S (ESI) m / z: 326.0 (M + H) +. 1H NMR (300 MHz, CD3OD) d ppm 1.52 (s, 6H) 3.93 (s, 3H) 6.93 (s, 1H) 7.14-7.31 (m, 2H) 8.16 (m, 1H) 8.56 (d, J = 1.70 Hz , 1 HOUR).
EXAMPLE 134 5- (6-H! -hydroxy-7-methoxy-4,4-dimethyl-1,4-dihydroindenori. 2 -prazo I-3-yl) pyridine-2-carbonitrile Example 134A 3-Iodo-7-methoxy-4,4-dimethyl-6-. { r2- (tr.methyl) ethyl) ethoxyl methoxy) -1-. { r2-ftr-methylsilyl) ethoxylmethyl} -1,4-dihydroxydoH, 2-clirazole To a mixture of Example 133D (0.475 g, 0.977 mmol) and NaH (60%, 0.043 g, 1.07 mmol) in THF (10 mL) was added SEMCI (0.19 mL). 1.07 mmol). After 2 hours, the reaction was quenched with water and extracted with EtOAc. The organic layer was washed with NaHCO 3, dried over MgSO 4, filtered, concentrated, and purified by flash chromatography eluted with hexane / EtOAc (8: 2) to give 0.455 g (75%) of the desired product like a yellow gel. MS (DCI / NH3) m / z: 617.2 (M + H) +.
Example 134B 3-Iodo-7-methoxy-4,4-dimethyl-1 -. { 2- (trimethylsilyl-methoxy-methyl) -1-, 4-dihydroindenof-1,2-cl-irazol-6-ol A mixture of Example 134A (0.450 g, 0.730 mmol) and HCl (concentrated, 0.4 mL) in EtOH (10 mL) was stirred at room temperature for 3 hours. The solvent was evaporated at room temperature and the residue was purified by flash chromatography eluted with hexane / EtOAc / CH2Cl2 (7: 3: 1 to 1: 1: 0) to give 0.321 g (90%) of the desired product a yellow gel pale. MS (DC / NH3) m / z: 487.1 (M + H) +.
Example 134C 3- (6-Fluoropyridin-3-yl) -7-methoxy-4,4-dimethyl-1 - (G 2 - (trimethylsilyl) ethoxymethyl) -, 4-dihydroindenori, 2-c 1 irazole -6-ol The desired product was prepared by substituting Example 68C and Example 68D with Example 134B and Example 123C in Example 68E.The product was purified through flash chromatography instead of reverse phase HPLC MS (ESI). ) m / z: 456.1 (M + H) +.
EXAMPLE 134D 5- (6-Hydroxy-7-methoxy-4,4-dimethyl-1 - {T2- (trimethylsilyl) ethoxy-1-methyl) -1,4-dihydro-ndenori, 2-c-pyrazole-3-d! l) pyridine-2-carbonitrile The desired product was prepared by replacing Example 123D with Example 134C in Example 123E. The product was purified by flash chromatography instead of reverse phase HPLC. MS (ESI) m / z: 463.1 (M + H) +.
Example 134E 5- (6-Hydroxy-7-methoxy-4,4-dimethyl-1,4-dihydrolndenori, 2-cl-diol-3-yl) iridin-2-carbonitrile A mixture of Example 134D (23.0 mg, 0.0497 mmol ) and HCi (concentrate, 2 drops) in EtOH (2 mL) was stirred at 75 ° C for 1.5 hours. The solvent was evaporated and the residue was purified using Reverse phase HPLC to give the desired product (4.0 mg) as the TFA salt. MS (ESI) m / z: 333.0 (M + H) +; 1H NMR (300 MHz, CD3OD) d ppm 1.56 (s, 6H) 3.93 (s, 3H) 6.94 (s, 1H) 7.20 (s, 1H) 7.99 (d, J = 8.14Hz, 1H) 8.32 (dd, J = 8.14.2.37Hz, 1H) 9.11 (d, J = 2.37Hz, 1H).
EXAMPLE 135 5-R7-Methoxy-4,4-dimethyl-6- (pyridin-3-ylmethoxy) -1,4-dihydroindene G1, 2-clp-aceol-3-illpyridine-2-carbonitrile Example 135A 3-Iodo-7-methoxy-4,4-dimethyl-6- (pyridin-3-ylmethoxy) -1-2- (tr memethylsilyl) ethoxylmethyl > -1,4-dihydroindenof 1,2-cT-irazole A mixture of Example 134B (200.0 mg, 0.411 mmol), di-t-butyl azodicarboxylate (0.189 g, 0.822 mmol), Ph3P on solid support (3mmol / g, 0.274). g, 0.822 mmol), and 3-pyridylcarbinol (80 μ? _, 0.822 mmol) in THF (3 mL) was stirred at room temperature overnight. The solid was filtered and the solvent was evaporated. The crude product was purified via flash chromatography eluted with EtOAc to give 0.2428 (100%) of the desired product as a yellow gel. MS (DCL / NH3) m / z: 578.1 (M + H) +.
Example 135B 3- (6-Fluoropyridin-3-yl) -7-methoxy-4,4-dimethyl-6- (pyridin-3-ylmethoxy) -1-. { f2- (trimethylsilyl) ethoxylmethyl) -1,4-dihydroindenori, 2-cl irazole The desired product was prepared by substituting Example 68C and Example 68D with Example 135A and Example 123C in Example 68E. The product was purified by flash chromatography instead of reverse phase HPLC. MS (ESI) m / z: 547.2 (M + H) +.
Example 135C 5-R7-methoxy-4,4-dimethyl-6- (pyridin-3-ylmethoxy-1, 4-dihydroindeneM, 2-clp-aceol-3-n-pyridine-2-carbonitrile The desired product was prepared replacing Example 123D with Example 135B in Example 123E.
Examples 136 to 142, represented by Figure (VII) and mosatrates in Table 7, were synthesized in a manner similar to that of Example 135C.
Figure (VII) TABLE 7 EXAMPLE 143 5-R7-Methoxy-6- (pyridin-2-ylmethoxy) -1,4-dihydro-1,3-diol-1,2-clirazole-3-ylpyridin-2-carbonitrile Example 143A 6-Methoxy-5-f2- (tr.methylsilyl) ethoxyl methoxy} indan-1 -one To a solution of 5-hydroxy-6-methoxy-indan-1 -one (21.1 g, 0.118 mol, see preparation in J. Org. Chem. 57.1992.589-594) and N, N -diisopropylethylamine (21.6 mL, 0.124 mol) in CH2Cl2 (200 mL) was added SEMCI (21.3 mL, 0.121 mol). The mixture was stirred at room temperature for 2 hours and diluted with a solution of NaHCO3. After separation, the organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography eluted with EtOAc / hexane (3: 7 to 1: 1) to give 26.3 g (72%). ) of the desired product as a brown oil. MS (ESI) m / z: 309.0 (M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm -0.01 (s, 9 H) 0.96 (t, J = 8.25 Hz, 2 H) 2.66 (t, J = 5.70 Hz, 2 H) 3.03 (t, J = 5.70 Hz, 2 H) 3.80 (t, J = 8.25Hz, 2H) 3.90 (s, 3H) 5.36 (s, 2H) 7.20 (s, 1 H) 7.22 (s, 1 H).
Example 143B Phenyl 6-chloronicotinate A mixture of 6-chloronicotinic acid (68.0 g, 0.431 mol), phenol (40.6 g, 0.431 mol), DCC (93.6 g, 0.453 mol), and DMAF (1.60 g, 0.0129 mol) in ether (1 L) was stirred at room temperature overnight. The solvent was evaporated and the residue was stirred in CH2Cl2. The solid was filtered and the filtrate was purified by flash chromatography eluted with CH2Cl2 to give 88.0 g (88%) of the desired product. MS (DCI / NH3) m / z: 234.0 (M + H) +; H NMR (300 MHz, CDCl 3) d ppm 7.22 (d, J = 8.14Hz, 2H) 7.31 (t, J = 7.29Hz, 1H) 7.47 (dd, J = 17.12, 7.97Hz, 3H) 8.40 (m, 1H ) 9.17 (d, J = 1.70 Hz, 1H).
EXAMPLE 143C 3- (6-Chloropyridn-3-yl) -7-methoxy-6-f-2- (trimethylsilyl) ethoxymethyl} 1,4-dihydroindenoyl, 2-cTpyrazole To a solution of Example 143A (24.1 g, 0.0781 mol) in THF (400 mL) was added NaH (60%, 9.37 g, 0.234 mol) in 2 portions at room temperature. After 20 minutes, Example 143B (21.0 g, 0.0898 mol) was added. The reaction mixture was stirred for 3 hours, treated with EtOH, and concentrated. To the resulting residue was added EtOH (400 mL), glacial acetic acid (22.4 mL, 0.391 mol), and hydrazine monoohydrate (11.4 mL, 0.234 mol). The mixture was heated at 90 ° C for 2 hours, cooled, and concentrated. The residue was extracted with EtOAc and washed with NaHCQ3. The organic layer was dried over MgSO4, filtered, concentrated, and titrated with ether to give 23.8 g (69%) of the desired product an off-white solid. MS (ESI) m / z: 444.1 (M + H) +; 1H NMR (300 MHz, DMSO-D6) d ppm 0.00 (s, 9H) 0.92 (t, J = 8.09Hz, 2H) 3.77 (m, J = 7.94Hz, 2H) 3.86 (s, 3H) 5.24 (s, 2H) 6.70 (m, 1H) 7.30 (d, J = 10.51Hz, 2H) 7.66 (d, J = 8.14 Hz, 1 H) 8.23 (dd, J = 8.31, 2.54 Hz, 1 H) 8.83 (d, J = 3.05 Hz, 1 H).
Example 143D 3- (6-Chloropyridin-3-yl) -7-methoxy-6-. { [2- (trimethylsilyl) ethoxy-methoxy) -1-fr2- (trimethyl-silyl) -ethoxymethyl > -1,4-dihydroindenof1,2-clirazole The desired product was prepared by replacing Example 684 with Example 143C in Example 123A. MS (ESI) m / z: 574.2 (M + H) +.
Example 143E 5- (7-Ethoxy-6- { R 2 - (trimethylsilyl) ethoxymethoxy) -1- r 2 - (trimethylsilyl) ethoxymethyl > -1,4-dihydroindenor, 2-clirazol-3-yl) pyridine-2-carbonitrile A mixture of Example 143D (1,500 g, 2.61 mmol), Pd 2 (dba) 3 (71.7 mg, 3 mol%), dppf (86.8 mg, 6 mol%), Zn (20.5 mg, 12 mol%), and Zn (CN) 2 (0.460 g, 3.92 mmol) in N, N-dimethylacetamide (40 ml_) was degassed and heated to 120 ° C overnight. The mixture was cooled and filtered through celite. The filtrate was diluted with 50% brine and extracted with EtOAc twice. The combined organic layers were washed with NaHCO 3 and brine, dried over MgSO 4, filtered, concentrated, and purified by flash chromatography eluted with EtOAc / hexane (4: 6) to give 1.17 g (80%) of the desired product as a yellow solid. MS (ESI) m / z: 565.2 (M + H) +.
Example 143F 5- (6-Hydroxy-7-methoxy-1- { R 2 - (trimethylsilyl) ethoxylmethyl> -1,4-dihydroindenof 1,2-cT-razol-3-yl) pyridn-2 - Carbon A mixture of Example 143E (9.96 g, 0.0176 mmol) and HCl (concentrated, 4.0 mL) in MeOH (200 mL) and CH2Cl2 (100 mL) was stirred at room temperature for 1.5 hours. Most of the solvents were evaporated at room temperature. The residue was extracted with EtOAc, washed with NaHCO 3, dried over MgSO 4, filtered, concentrated to give 7.63 g (quantitative yield) of the desired product as a pale yellow solid. MS (ESI) m / z: 435.2 (M + H) +.
Example 143G 5-r7-ethoxy-6- (pyridin-2-ylmethoxy) -1,4-dihydroindenon. 2-clPyrazol-3-M-pyridin-2-carbonitrile The desired product was prepared substituting Example 134B and 3-pyrid Mcarbinol with Example 143F and 2-pyridylcarbinol in Example 135A. The intermediate was treated with HCl and EtOH at about 75 ° C for about 2 hours. The suspension was cooled and the solid filtered, washed with ether, and dried to give the desired product as the HCI salt. Alternatively, the intermediate after the acid treatment was purified using reverse phase HPLC to give the desired product as the TFA salt.
Example 144 5-. { 7-R (6-Chloropyridin-3-yl) methoxy-6-methoxy-1,4-dihydroindenoH, 2-clpyrazol-3-yl} pridin-2-carbonitrile Example 144A 5,6-Dihydroxyindan-1-one To a solution of 5,6-dimethoxy-indan-1 -one (40.0 g, 0.208 mol) in CH 2 Cl 2 (800 mL) at -78 ° C was added BBr 3 (59.0 mL, 0.624 mol) drop by drop. The dry ice bath was removed after the addition.
The mixture was stirred at room temperature for 1 hour and emptied into a large amount of ice / water and vigorously stirred. The pink solid was filtered, washed with water, and dried in a vacuum oven to give 33.3 g (98%) of the desired product. MS (DCI / NH3) m / z: 165.0 (M + H) +; H NMR (300 MHz, CD3OD) d ppm 2.58-2.61 (m, 2H) 2.98 (t, J = 5.55Hz, 2H) 6.85 (s, 1H) 7.04 (s, 1H).
Example 144B 6-Hydroxy-5-methoxyindan-1-one A mixture of Example 144A (28.5 g, 0.173 mol), Mel (27.0 ml_, 0.433 mol), and Li2C03 (32.0 g, 0.519 mol) in DMF (800 ml_) it was heated at 55 ° C overnight. The DMF was evaporated and the residue treated with water (1 L) and HCl (concentrated, 60 mL). The solid was filtered, washed with water until the filtrate became neutral, and dried to give 21.0 g (68%) of the desired product. MS (DC / NH3) m / z: 179.0 (M + H) +; 1H NMR (300 MHz, CD3OD) d ppm 2.58-2.67 (m, 2H) 3.05 (t, J = 5.55Hz, 2H) 3.96 (s, 3H) 7.04 (s, 2H).
Example 144C 5- (7-R (6-Chloropyridin-3-yl) methoxy-6-methoxy-1,4-dihydroindenofl-2, 2-irazol-3-yl}. Pyridine-2-carbonyltrile The desired product was prepared substituting 6-hydroxy-5-methoxyindan-1 -one with Example 144B in Example 143A followed by similar procedures in Examples 143C, 143D, 143E, 143F, and 143G.
Examples 145 to 163 represented by Figure (Vlll) and shown in Table 8 were synthesized in a manner similar to that described in Example 143G or 144C.
H Figure (Vlll) TABLE 8 Example 164 4W6,7-Dimethoxy-1,4-dihydroxydene, 2-clpyrazol-3-yl) -3-methoxy-1,1'-biphenyl-4-ol Ei Example 64C (50 mg, 0.14 mmol ), 2-methoxy-4- (4,4,5,5-tetramethyl [1, 3,2] dioxaborolan-2-yl) -phenol (42.3 mg, 0.17 mmol), Na 2 CO 3 (1 M, 0.3 mL), and Pd (PPh 3) 2 C 12 (9.9 mg, 0.014 mmol) were combined in DE / EtOH / H 2 O (7: 2: 3, 15 mL) in a 2 mL capped flask and heated at 160 ° C for 600 seconds on a Smith Synthesizer. The reaction was cooled using 2.812 kg / cm2 of pressurized air, the solvents were evaporated, and the residue was purified using preparative HPLC. MS (DCI / NH3) m / z: 415.06 (M + H) +. H NMR (500 MHz, DMSO-D6) d ppm 3.79 (s, 2H) 3.82 (s, 3H) 3.85 (s, 3H) 3.88 (s, 3H) 6.87 (d, J = 8.11Hz, 1H) 7.16 (dd , J = 8.11, 2.18Hz, 1H) 7.23 (s, 1H) 7.25 (s, 1H) 7.27 (d, J = 1.87Hz, 1H) 7.75 (d, J = 8.42Hz, 2H) 7.83 (d, J = 8.42Hz, 2H).
Example 165 4- (6,7-Dimethoxy-1,4-dihydroindenori, 2-clpyrazol-3-yl) phenol Example 165A 4-Benzyloxybenzoic acid (2 g, 8.76 mmol) and 1,1'-carbonyldiimidazole (2.3 g, 14 mmol) were combined in DMF. The reaction mixture was stirred overnight and was poured into ice-water. The resulting precipitate was collected through filtration, washed with water, and dried. The product of the title (2.4 g) was obtained at a rate of 99%. MS (DC1 / NH3) m / z: 279.08 (M + H) +.
Example 165B 2-r 4 - (Benzyloxy) benzoin-5,6-dimethoxydandan-1-one 5,6-dimethoxyindanone (1 g, 5.2 mmol) in 45 mL of THF was treated. with NaH (60%, 312 mg, 7.8 mmol). After the addition of Example 165A (1.45 g, 5.2 mmol), the reaction mixture was stirred overnight and emptied in ice / water. The resulting mixture was acidified with concentrated HCl. The yellow solid was collected through filtration, washed with water and hot ethanol. The title product (1.2 g) was obtained at a yield of 57%. MS (DCI / NH3) m / z: 403.11 (M + H) +.
Example 165C 3-r4- (Benzylloxy) phenan-6,7-dimethoxy-1,4-dihydro-ndenori, 2-clirazole Example 165B (500 mg, 1.24 mmol), hydrazine monohydrate (72 gL), and acetic acid (85 μ? _) Were combined in 20 measure ethanol, heated at 90 ° C overnight and cooled. The precipitates were collected through filtration to give the title compound. MS (DCI / NH3) m / z: 399.11 (M + H) +. 1 H NMR (500 MHz, DMSO-D 6) d ppm 3.73 (s, 2 H) 3.81 (s, 3 H) 3.84 (s, 3 H) 5.17 (s, 2 H) 7.14 (d, J = 7.49 Hz, 2 H) 7.21 (d , J = 8.11Hz, 2H) 7.34 (t, J = 7.18Hz, 1H) 7.41 (t, J = 7.49Hz, 2H) 7.48 (d, J = 7.18Hz, 2H) 7.71 (d, J = 8.11Hz, 2H) 12.85 (s, 1H).
Example 165D 4- (6,7-Dimethoxy-1,4-dihydroindenoyl-1,2-c1pyrazol-3-yl) phenol Example 165C (57 mg, 0.14 mmol) and Pd / C (10%, 15.2 mg) in THF were combined (20 mL) and stirred under a hydrogen atmosphere for 24 hours. The Pd / C was removed by filtration and the filtrate was concentrated. The residue was purified by HPLC to give title compound. S (DCI / NH3) m / z: 309.03 (M + H) +. H NMR (400 MHz, DMSO-D6) d ppm 3.71 (s, 2H) 3.81 (s, 3H) 3.83 (s, 3H) 6.87 (d, J = 8.59Hz, 2H) 7.20 (s, 1H) 7.22 (s) , 1H) 7.60 (d, J = 8.59Hz, 2H) Example 166 3- (4'-Hydroxy-1,1'-biphenyl-4-in-1,4-dihydroindenoyl, 2-cl pyrazole-6,7-diol EXAMPLE 166A 3- (4-Bromophenyl) -1,4-dihydroindenofl, 2-cl-irazole-6,7-diol Example 64C (142 mg, 0.38 mmol) in 1,2-dichloroethane (50 mL) was treated. with BBr3'SMe2 (597 mg, 1.91 mmol), it was heated at 80 ° C for 30 hours and cooled. The reaction was quenched with water (20 mL), and the resulting mixture was treated with ether (100 mL). The precipitate was collected by filtration and further purified by HPLC. MS (DCI / NH3) m / z: 344.94 (M + H) +.
EXAMPLE 166B 3- (4'-Hydroxy-1,1'-phenyl-4-yl) -1,4-dihydroindeneM-2-clirazole-6,7-diol Example 166A (35 mg, 0.10 mmol) was combined , 4-hydroxyphenyl-boronic acid (18 mg), Na 2 CO 3 (1 M, 0.25 mL), y-Pd (PPh 3) 2 Cl 2 (9.9 mg, 0.014 mmol) in DME / EtOH / H 2 O (7: 2: 3, 1.5 mL ) in a 2 mL capped flask and heated at 160 ° C for 600 seconds on a Smith Synthesizer. The reaction was cooled using 2812 kg / cm2 of pressurized air, the solvents were evaporated, and the residue was purified using preparative HPLC to give the title compound. MS (DCI / NH3) m / z: 357.04 (M + H) +. 1 H NMR (500 MHz, DMSO-D6), d ppm. 3.69 (s, 2H) 6.87 (d, J = 8.54Hz, 2H) 6.96 (s, 1H) 7.04 (s, 1H) 7.56 (d, J = 8.54Hz, 2H) 7.70 (d, J = 8.54Hz, 2H ) 7.81 (d, J = 8.54Hz, 2H).
Example 167 4- (6,7-D-methoxy-1,4-dihydroindenoH, 2-clpyrazol-3-yl) benzonitrile A mixture of Example 64C (50 mg, 0.14 mmol), zinc cyanide (17.4 mg, 1.48 mmol), Pd (PPh3) 4 (15.6 mg, 0.014 mmol) in DMF (3 mL) in a capped flask of 5 mL was added. heated at 180 ° C for 300 seconds on a Smith Synthesizer. The reaction was cooled using 2.812 kg / cm2 of pressurized air, and the solvent was evaporated. The residue was purified by HPLC preparation to give the title product. MS (DCI / NH3) m / z: 318.04 (M + H) +. 1 H NMR (500 MHz, DMSO-D 6) d ppm 3.81 (s, 2 H) 3.82 (s, 3 H) 3.84 (s, 3 H) 7.23 (s, 1 H) 7.25 (s, 1 H) 7.96 (s, 4 H).
Example 168 3- (6-Hydroxy-2-naphthyl) -1,4-dihydroindenoM .2-cTpirazol-6-ol Example 168A 1- (6-Methoxy-2-naphtho-1H-imidazole) 6-methoxy-naphthalene-2-carboxylic acid (2 g, 9.9 mmol) and 1 '1' -carbonyldiimidazole (2.4 g, 14.8 mmol) were combined DMF (10 mL) and stirred overnight The white solid was collected by filtration, washed with water and dried to give the title compound.
EXAMPLE 168B 5- (Benzyloxy) -2- (6-methoxy-2-naphthoandan-1 -o na 5-benzyloxydandanone (1.5 g, 6.29 mmol) was treated with NaH (60%, 377 mg) in THF (50 mL), and then Example 168A (1.59 g) was added.The reaction was stirred for 6 hours at room temperature.Precipitates were collected through filtration and dissolved in water, acidified with concentrated HCl, and the Resulting precipitates were collected, washed with water and dried to give the title compound.
Example 168C 6- (Benzyloxy) -3- (6-methoxy-2-naphthyl) -1,4-diriidroindenori.2-clpira2ol The desired product was prepared using the procedure of Example 165C by replacing Example 165E with Example 168B.
MS (DCI / NH3) m / z: 419.14 (M + H) +.
Example 168D 3- (6-Hydroxy-2-naphthin-1-4-dihydroindenon, 2-cl irazol-6-ol The desired product was prepared using the procedure of Example 166A replacing Example 64C with Example 168C. MS (DCI / NH3) m / z: 315.04 (M + H) +. 1H NMR (500 MHz, DMSO-D6) d ppm 3.89 (s, 2H) 6.84 (dd, J = 8.24, 2.14Hz, 1H) 7.07 (d, J = 1.53Hz, 1H) 7.13-7.14 (m, 2H) 7.54 (d, J = 8.24Hz, 1H) 7.75-7.79 (m, 2H) 7.82 (d, J = 9.76Hz, 1H) 8.14 (s, 1H).
Example 169 6,7-Dimethoxy-3-r4- (1 H-pyrrol-2-yl) phen-1,4-dihydroindene, 2-py pyrazole The desired product was prepared using the procedure of Example 164 replacing 2-methoxy-4- (4,4,5,5-tertramethyl [1, 3,2] dioxaborolan-2-yl) -phenol with 1-tert-Bocpyrrolyl-2-boronic acid. MS (DCI / NH3) m / z: 358.12 (M + H) +. 1 H NMR (400 MHz, DMSO-D6) d ppm 3.79 (s, 2H) 3.82 (s, 3H) 3.84 (s, 3H) 6.14 (q, J-2.35Hz, 1H) 6.59 (s, 1H) 6.88 ( s, 1H) 7.23 (d, J = 9.21Hz, 2H) 7.72-7.77 (m, 4H) 11.32 (s, 1H) Example 170 6,7-Dimethoxy-3-r4-M H -pyrazol-4-yl) phenyl-4-dihydroindene M.2-c1 pyrazole Example 170A 1-f Chloro (4-methoxyphenyl) metin-4-methoxybenzene Bis (4-methoxyphenii) methanol (30 g) was treated with thionyl chloride (40 mL). The resulting mixture was refluxed for 2.5 hours and concentrated to give the desired product.
Example 170B 1 -f Bis (4-methoxyphenyl) methyH-4-iodo-1 H-pyrazole 4-iodo-1 H-pyrazole (1 g, 5.15 mmol), Example 170A (1.49 g, 5.67 mmol) was combined, and triethylamine (0.79 mL) in THF (20 mL), and refluxed for 1.5 hour. The inorganic salts were removed by filtration, and the filtrate was concentrated. The residue was recrystallized from a mixture of ethyl acetate and hexane to give 1.56 g of the product in a yield of 72%. MS (DCI / NHs) m / z: 420.0 (M + H) +. 1H NMR (400 MHz, DMSO-D6) d ppm 3.72 (s, 6H) 6.78 (s, 1H) 6.90 (d, J = 8.59Hz, 4H) 7.06 (d, J = 8.59Hz, 4H) 7.58 (s, 1 H) 7.81 (s, 1H) EXAMPLE 170C 1-rBis (4-methoxyphenii) metin-3- (4-bromophenin-6,7-dimethoxy-1,4-dihydroindenoH, 2-chlororazole The desired product was prepared using the procedure of Example 170B by replacing 4-iodo- 1 H-pyrazole with Example 64. The title product (2.0 g) was obtained at a yield of 83% MS (DCI / NH3) m / z: 597.12 (M + H) +. 1 H NMR (400 MHz, DMSO-D6) d ppm 3.60 (s, 3H) 3.73 (s, 6H) 3.75 (s, 2H) 3.78 (s, 3H) 6.61 (s, 1H) 6.94 (d, J = 8.59Hz, 4H) 7.14 (s) , 1H) 7.20 (s, 1H) 7.25 (d, J = 8.59Hz, 4H) 7.62 (d, J = 8.59Hz, 2H) 7.72 (d, J = 8.59Hz, 2H).
EXAMPLE 170D 1 -FBis (4-methoxyphenyl) methyH-1 -6,7-dimethoxy-3-r4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) phenyl-4-dihydroindenori , 2-cl irazole Example 170C (1 g, 1.67 mmol), bis (pinacolato) diborane (467 mg, 1.84 mmol), PdCI2 (dppf) * CH2Cl2 (41 mg, 0.05 mmol), dppf (28 mg) were combined. , and K20Ac in 1,4-dioxane (35 ml_) and were purged with a stream of nitrogen. The reaction was heated to 90 ° C overnight and concentrated. The residue was purified by flash chromatography eluting with hexane: ethyl acetate (2: 1). The desired product (950 mg) was obtained at a yield of 88%. 1 H NMR (500 MHz, DMSO-D 6) d ppm 1.31 (s, 12 H) 3.58 (s, 3 H) 3.73 (s, 6 H) 3.77 (s, 2 H) 3.78 (s, 3 H) 6.54 (s, 1 H) 6.95 (s, d, J = 8.73Hz, 4H) 7.14 (s, 1H) 7.22 (s, 1H) 7.24 (d, J = 8.73Hz, 4H) 7.74 (d, J = 8.11Hz, 2H) 7.80 (d, J = 8.11 Hz, 2H).
Example 170E 1 -fBis (4-methoxyphenyl) metin-3- (4- (bis (4-methoxyphenyl) metin-1 H-pyrrazol-4-yl} phenyl) -6,7-dimethoxy-1, 4-dihydroquinone, 2-c1 pyrazole Example 170B (67 mg, 0.159 mmol), Example 170D (84 mg, 0.13 mmol), Na 2 CO 3 (1 M, 0.3 mL), and Pd (PPh 3) 2 Cl 2 (9.9 mg, 0.014 mmol) in DME / EtOH / were combined. H20 (7: 2: 3, 1.5 mL) in a capped 2 mL bottle and heated at 160 ° C for 1000 seconds on a Smith Synthesizer. The reaction was cooled using 2.812 kg / cm2 of pressurized air, the solvents were evaporated, and the residue was purified using flash chromatography eluting with hexane: ethyl acetate (1: 1). The title product (84 mg) was obtained in a 65% yield. MS (DCI / NH3) m / z: 811.37 (M + H) +. 1H NMR (400 MHz, DMSO-D6) d ppm 3.57 (s, 3H) 3.73 (s, 6H) 3.75 (s, 6H) 3.76 (s, 2H) 3.78 (s, 3H) 6.51 (s, 1H) 6.79 ( s, 1H) 6.92-6.96 (m, 8H) 7.12 (s, 1H) 7.14 (d, J = 8.90 Hz, 4H) 7.21 (s, 1H) 7.25 (d, J = 8.59Hz, 4H) 7.64 (d, J = 8.29Hz, 2H) 7.75 (d, J = 8.59Hz, 2H) 7.99 (s, 1 H) 8.14 (s, 1H).
EXAMPLE 170F 6,7-Dimethoxy-3-r 4 - (1 H-irazol-4-n-phenylH-1,4-dihydroxydene, 2-d pyrazole Example 170E (60 mg, 0.078 mmol) was treated with 4 M HCl in dioxane (5 mL) The reaction was stirred overnight and concentrated The residue was washed with a mixture of hexane and ethyl acetate to give a light yellow product MS (DCI / NH3) m / z: 359.07 (M + H) +. 1 H NMR (400 MHz, DMSO-D 6) d ppm 3.82 (s, 2 H) 3.83 (s, 3 H) 3.85 (s, 3 H) 7.25 (s, 1 H) 7.27 (s, 1 H) 7.76 (d, J = 8.29 Hz , 2H) 7.81 (d, J = 8.29Hz, 2H) 8.16 (s, 2H).
Example 171, 4'-B1piperidin-1'-carboxylate of 4"- (6,7-dimethoxy-1,4-dihydroindenof1,2-c-thirazol-3-n-, 1'-biphenyl-4-yl) Example 17 A 4 '- (1-rBis (4-methoxyphenyl) metin-6,7-dimethoxy-, 4-dihydroindenof1,2-clirazol-3-yl.} -, 1'-biphenyl-4-ol The product The desired product was prepared using the procedure of Example 166B replacing Example 166A with Example 170C, however, the product was purified by flash chromatography instead of HPLC.The title product (168 mg) was obtained in a yield 82% MS (DCI / NH3) m / z: 611.24 (M + H) +.
Example 171B 1,4'-Bi-4-1-fbis (4-methoxyphenyl) methan-6,7-dimethoxy-1,4-dihydroindenof 1,2-c1-carboxylate irazol-3-il > -, 1 '-biphenyl-4-yl Example 171A (150 mg, 0.25 mmol) in pyridine (4 ml) was treated with [, 4 '] bipiperidinyl-1-carbonyl chloride (190 mg, 3 mmol) and stirred for 3 days. The reaction mixture was poured into water and extracted with dichloromethane and ethyl acetate. The organic layer of dried MgS04 copper, and evaporated. The residue was purified by flash chromatography eluting with ethyl acetate: eOH: NH 4 OH (100: 5: 0.5). The title compound (160 mg) was obtained in an 81% yield.
Example 171C 1, 4'-Bipiperidin-1 '-carboxylic acid 4' - (6,7-dimethoxy-1,4-dihydroindenol, 2-c1pyrazol-3-yl) -1, 1'-biphenyl-4-Mo treated Example 171B (90 mg, 0.11 mmol) in dichloromethane with TFA (4.5 ml_), and the reaction was stirred overnight and concentrated. The residue was purified by HPLC preparation. The title product (50 mg) was obtained in a yield of 56%. MS (DCI / NH3) m / z: 579.30 (+ H) +. H NMR (500 MHz, DMSO-D6) d ppm. 1.65-1.73 (m, 6H) 1.86-1.89 (m, 2H) 2.08-2.10 (m, 2H) 2.93-3.02 (m, 4H) 3.09 (m, 1H) 3.43-3.49 (m, 4H) 3.81 (s, 2H) 3.83 (s, 3H) 3.85 (s, 3H) 7.23-7.26 (m, 4H) 7.77 (d, J = 8.54Hz, 2H) 7.81 (d, J = 8.54Hz, 2H) 7.89 (J = 8.86Hz , 2H) 9.11 (s, 1H).
Example 172 3- (4-Bromophenol) -7-methoxy-1,4-dihydroindenofl-2-clirazole-6-ol Example 172A 5-Hydroxy-6-methoxyindan-1-one 5,6-Dimethoxy-1-indanone (1 g, 5.20 mmol) and NaCN (2.55 g, 52 mmol) were combined in DMSO (10 mL). The reaction was stirred to 100 ° C for two days, cooled, diluted with water and extracted with dichloromethane. The aqueous solution was acidified with concentrated HCl, and extracted with dichloromethane. The organic layer was dried over MgSO4 and evaporated to give the title compound (500 mg). MS (DCI / NH3) m / z: 178.99 (M + H) +. 1 H NMR (500 Hz, CD 2 Cl 2) d ppm 2.59 (t, J = 5.62 Hz, 2 H) 3.01 (t, J = 5.62 Hz, 2 H) 3.93 (s, 3 H) 6.33 (s, 1 H) 6.95 (s, 1 H) 7.17 (s, 1H).
Example 172B 6- Ethoxy-5-f (4-methoxybenzyl) oxnindan-1 -o na Example 172A (1.4 g, 7.86 mmol), 4-methoxybenzyl chloride (2.13 g, 15.72 mmol), Na 2 CO 3 (1.67 g) were combined. , 15.72) and sodium iodide (1.18 g, 7.86) in acetone (50 mL). The reaction was stirred for 3 days, and then the solvent was removed. The residue was mixed with water (300 mL) and ethyl acetate (100 mL). The precipitate was collected by filtration, washed with a mixture of hexane and ethyl acetate (2: 1) and dried to give the title product (1.4 g). MS (DCI / NH3) m / z: 299.14 (M + H) +.
EXAMPLE 172C 2- (4-Bromobenzoyl) -6-methoxy-5-r (4-methoxybenzyl) oxyTindan-1 - or na Example 172B (1.2 g, 4.0 mmol) was treated in 40 mL of THF with NaH (60%, 240 mg, 6.0 mmol). After the addition of Example 64A (1.31 g), the reaction mixture was stirred overnight and emptied in ice / water. The resulting mixture was acidified with HCI •concentrated. The precipitate was collected by filtration and recrystallized from ethanol. The title product (1.7 g) was obtained in a yield of 88%. MS (DC1 / NH3) m / z: 481.04 (M + H) +.
Example 172D 3- (4-Bromophenyl) -7-methoxy-6-r (4-methoxybenzyl) -1, 4-dihydroxy-2-chlorozole The desired product was prepared using the procedure of Example 165C replacing Example 165E with Example 172C The title compound (1.45 g) was obtained in a yield of 92% MS (DCI / NH3) m / z: 479.05 (M + H) +.
Example 172E 3- (4-Bromophenyl) -7-methoxy-1,4-dihydroindenof 1.2-clpyrazol-6-ol Example 172D (280 mg, 0.59 mmol) in HOAc (35 ml_) was heated at 90 ° C for 24 hours. hours, and the solvent evaporated. The residue was titrated with a mixture of hexane and ethyl acetate to give the title product (220 mg) in 90% yield. MS (DCI / NH3) m / z: 357.98 (M + H) +. 1 H NMR (500 MHz, DMSO-D 6) d ppm 3.69 (s, 2 H) 3.85 (s, 3 H) 7.01 (s, 1 H) 7.20 (s, 1 H) 7.67 (d, J = 8.42 Hz, 2 H) 7.73 (d , J = 8.42Hz, 2H).
Example 173 3- (4 · - ?? € [G ??? - 1,1 '^ ????? 1-4-? 1) -7 - ?? T ???? - 1,4-? The desired product was prepared using the procedure of Example 166B replacing Example 166A with Example 172E.S (DCI / NH3) m / z: 371.14 (M + H) +. 1 H NMR (400 MHz, DMSO-D6) d ppm 3.72 (s, 2H) 3.84 (s, 3H) 6.86 (d, J = 8.59Hz, 2H) 7.00 (s) , 1H) 7.20 (s, 1H) 7.55 (d, J = 8.59Hz, 1H) 7.69 (d, J = 8.59Hz, 2H) 7.80 (d, J = 8.59Hz, 2H) 8.96 (s, 1H) 9.53 ( s, 1H).
EXAMPLE 174 3- (4'-Hydroxy-3'-methoxy-1,1'-biphenyl-4-yl) -7-methoxy-1,4-dihydroindeneH, 2-clp-aceol-6-ol The desired product is prepared using the procedure of Example 164 replacing Example 64C with Example 172E. MS (DCI / NH3) m / z: 400.14 (M + H) +. 1 H NMR (500 MHz, DMSO-D 6) d ppm 3.73 (s, 2 H) 3.86 (s, 3 H) 3.88 (s, 3 H) 6.87 (d, J = 8.11 Hz, 1 H) 7.02 (s, 1 H) 7.15 (dd , J = 8.11, 2.18Hz, 1H) 7.21 (s, 1H) 7.26 (d, J = 1.87Hz, 1H) 7.74 (d, J = 8.4.2Hz, 2H) 7.81 (d, J = 8.42Hz, 2H) 9.00 (s, 1H) 9.12 (s, 1H) Example 175 4'-r7-Methoxy-6- (pyridin-2-ylmethoxy) -1,4-dihydroindenoM, 2-cTpirazol-3-in-1, r-biphenyl-4-ol Example 175A 5- (Benzyloxy) -6-methoxyindan-1-one Example 172A (15 g, 84.3 mmol), benzyl bromide (15 ml_, 126.3 mmol), and K2CO3 (23.25 g, 168.5 mmol) in acetone were combined. (50 mL). The reaction was stirred for 2 days, and the inorganic salt was removed by filtration. The concentrated filtrate was concentrated, and the residue was recrystallized from a mixture of hexane and ethyl acetate to give the title product (17.1 g) in 76% yield. S (DCI / NH3) m / z: 269.11 (M + H) +.
Example 175B 5- (Benzyloxy) -2- (4-bromobenzoyl) -6-methoxyindan-1-one The desired product was prepared using the procedure of Example 172C replacing Example 172B with Example 175A. MS (DCl / NHs) m / z: 450.98 (M + H) +.
Example 175C 6- (Benzyloxy) -3- (4-bromophenyl) -7-methoxy-1,4-dihydroindenori, 2-cTpyrazole The desired product was prepared using the procedure of Example 165C replacing Example 165B with Example 175B .
MS (DCI / NH3) m / z: 449.08 (M + H) +.
Example 175D 6- (Benzyloxy) -3- (4-bromophenyl) -7-methoxy-1-2- (trimethylsilyl) ethoxylmethyl-1, 4-dihydroindenon, 2-cT irazole To a suspension of NaH (60 %, 1.21 g, 30.25 mmol) in DMF (150 ml_) was added Example 175C (12.3 g, 27.50 mmol). The mixture was stirred for 30 min and then SEMCI (5.35 mL, 30.25 mmol) was added dropwise. The reaction was stirred for 2 hours and emptied in spin / water. The precipitate was collected through filtration and dried to give the title product (15.0 g) in 94% yield.
Example 175E 4 '- (6- (Benzyloxy) -7-methoxy-1-fr2- (trimethylsilyl) ethoxymethyl-1,4-dihydroindenoH, 2-c1 irazol-3-yl) -1, 1'-biphenyl -4-ol The desired product was prepared using the procedure of Example 166B replacing Example 166A with Example 175D. MS (DCI / NH3) m / z: 591.27 (M + H) +.
Example 175F 6- (Benzyloxy) -7-methoxy-3- (4'-2- (trimethylsilyl) ethoxymethoxy > -1, 1'-bif in yl-4-I) -1-. { r 2 - (trimethylsilyl) ethoxymethyl) -1,4-dihydroindene, 2-chlororazole Example 175E (2.97 g, 5.03 mmol) was treated with NaH (60%, 221 mg, 5.53 mmol) in DMF for 1 hour, and then SEMCI (0.98 mL, 5.53 mmol) was added dropwise. The reaction was stirred at room temperature for 1 hour, emptied in ice / water, and extracted with ethyl acetate. The organic layer was dried over MgSO4, and concentrated. The residue was purified by flash chromatography eluting with hexane: ethyl acetate (4: 1). The title product (3.02 g) was obtained in a yield of 88%. MS (DCI / NH3) m: 721.35 (M + H) +.
Example 175G 7-Methoxy-3- (4-Wr2- (tr'methyl) -yl-ethoxyl-methoxy '-biphenyl-1-yl-f-dimethylsilyl-Detoxy-Tethyl-1, 4-dihydroindene, 2-c1-pyrazole-6-ol Example 175F (3.0 g, 4.16 mmol) and Pd / C (10%, 443 mg, 0.416 mmol) in THF (350 mL) were combined and stirred under a hydrogen atmosphere for 4 days. The solid was removed by filtration through Celite. The filtrate was concentrated, and the residue was purified by flash chromatography eluting with hexane: ethyl acetate (2: 1). The title product (2.3 g) was obtained in a yield of 88%. MS (DC / NH3) m / z: 631.24 (M + H) +.
Example 175H 4'-r7-ethoxy-6- (pyridin-2-ylmethoxy) -1,4-dihydroindenof1,2-c1pyrazol-3-yn-1,1'-biphenyl-4-ol The Example 175G (50 mg, 0.0792 mmol), Cs2C03 (103 mg, 0.317 mmol) and 2-chloromethylpyridine «HCl (14.3 mg, 0.087 mmol) in DMF (2 mL). The reaction mixture was purged with a stream of nitrogen, stirred at 50 ° C under a nitrogen atmosphere overnight and concentrated. The residue was suspended in methanol (2 mL), treated with 4 N HCl in dioxane (2 mL) and heated at 50 ° C for 5 hours. The solvent was removed, and the residue was purified by preparative HPLC to give the title compound (11.6 mg, 2TFA salt) in a yield of 22.3%.
Examples 176-188 represented by Figure (IX) and shown in Table 9 were synthesized in a manner similar to that described in Example 175H, except that replacing the appropriate organic chloride or bromide with 2-chloromethylpindin'HCl.
Figure (IX) TABLE 9 25 25 EXAMPLE 189 4'-R7-Methoxy-6- (pyridin-3-ylmethoxy) -1,4-dihydroindenoM, 2-clp-aceol-3-yn-1,1'-biphenyl-4-ol Example 175G (50 mg, 0.0792 mmol), di-tert-butyl azodicarboxylate (44 mg, 0.19 mmol), supported polymer Ph3P (3 mmol / g, 63 mg, 0.19 mmol) and pyridin-3-yl-methanol (22 mg, 0.20 mmol) in THF (3 ml_). The reaction was stirred at room temperature for 3 days, and the insoluble material was removed by filtration and washed with THF thoroughly. The filtrate was concentrated, and the residue was suspended in methanol (2 mL), treated with 4 N HCl in dioxane (2 mL) and heated at 50 ° C for 5 hours. The precipitate was collected through filtration to give the title compound. The filtrate was concentrated, and the residue was purified through HFLC to give another portion of the title compound.
Examples 190 to 204 represented by Figure (X) and shown in Table 10 were synthesized in a manner similar to that described in Example 189, except that substituting the appropriate alcohol for pyridin-3-yl-methanol.
Figure (X) TABLE 10 4- (6-Hydroxy-7-methoxy-1,4-dihydroindenor, 2-cl-irazol-3-yl-benzonitrile Example 205A 6-Methoxy-5-. { r 2 -trimethylsilyl) ethoxy-1-methoxy} 1indan-1-one Example 172A (1 g, 5.62 mmol) and N, N-diisopropylethylamine (2.94 mL, 16.86 mmol) in dichloromethane were combined and treated with SEMCI (1.49 mL, 8.43 mmol). The reaction mixture was stirred for 1 hour, diluted with dichloromethane, washed with cold water and saturated NaHCO 3. The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash chromatography with hexane: ethyl acetate (2: 1). The title product (1.3 g) was obtained in a 75% yield. MS (DCI / NHs) miz: 309.1 (M + H) \ Example 205B 4- (1H-imidazol-1-ylcar onyl) benzonitrile The desired product was prepared using the procedure of Example 165A by replacing 4-benzyloxybenzoic acid with 4-cyanobenzoic acid.
EXAMPLE 205C 4- (6-Ethoxy-1-oxo-5- { F2- (trimethylsim) ethoxymethoxy.) -2,3-dihydro-1 I-linden-2 -Dicarbonylbenzonitrile Example 205A (5.4 g, 17.51 mmol) in 250 mL of THF was treated with NaH (60%, 1.06 g, 26.37 mmol) After the addition of Example 205B (5.2-g, 26 37 mmol), the reaction mixture The mixture was acidified with concentrated HCl, a yellow solid was collected, washed with water and dried MS (DCI / NH3) m / z: 438.17 (M + H ) + Example 205D 4- (7-Methoxy-6- (r2- (trimethylsilyl) ethoxylmethoxy.) -1,4-dihydroindene r, 2-c1pyrazol-3-yl) benzonitrile The desired product was prepared using the procedure of Example 165C replacing Example 165B with Example 205C. The title compound (6.5 g) was obtained in an 88% yield. MS (DCI / NH3) m / z: 434.19 (M + H) +. 1H NMR (500 MHz, D SO-D6) d ppm 0.00 (s, 9tf) 0.92 (t, J = 8.11Hz, 2H) 3.77 (t, J = 8.11Hz, 2H) 3.81 (s, 2H) 3.86 (s , 3H) 5.24 (s, 2H) 7.32 (s, 2H) 7.96 (s, 4H) 13.32 (s, 1 HOUR).
EXAMPLE 205E 4- (7-Methoxy-6-y2- (trimethylsilyl) ethoxylmetxoi> -1-fr2-ftrimethylsilyl) ethoxymethyl} -1,4-dihydroindenoyl, 2-c1pyrazol-3-yl) benzonitrile The desired product was prepared using the procedure of Example 175D by replacing Example 175C with Example 205D. The title compound (6.5 g) was obtained in a yield of 83%. S (DCI / NH3) m / z: 564.28 (M + H) +.
Example 205F 4- (6-Hydroxy-7-methoxy-1,4-dihydroxydenoride, 2-cT-estradiol-3-in-benzonitrile Example 205E (50 mg, 0.089 mmol) in ethanol (2 ml) was treated with 4-hydroxy-3-indoxybenzoate. N HCl in dioxane (2 ml_) and heated at 50 ° C for 5 hours The precipitate was collected through filtration to give the title compound (22 mg) in an 82% yield MS (DCI / NH3) m / z: 304.06 (M + H) +. H NMR (400 Hz, DMSO-D6) d ppm 3.74 (s, 2H) 3.84 (s, 3H) 7.01 (s, 1H) 7.20 (s, 1H) 7.93 ( s, 4H).
Example 206 4-f7-Methoxy-6-pyridin-2-ylmethoxy) -1,4-dihydroindenori, 2-clirazol-3-illbenzoriitrile Example 206A 4- (6-Hydroxy-7-methoxy-1-. {R2- (trimethylsilyl) ethoxyTmethyl> -1.4- dihydroindenon, 2-clpyrazol-3-yl) benzonitrile Example 205E (1.5 g, 2.66 mmol ) in ethanol (40 mL) was treated with 4 N HCl in dioxane (1 mL). The reaction was stirred at room temperature for 30 min. The precipitate was collected through filtration to give the title compound (0.98g) in an 85% yield. S (DCI / NH3) m / z: 434.21 (M + H) +.
EXAMPLE 206B 4-f7-Ethoxy-6- (iridin-2-ylmethoxy) -1,4-dihydroindenM, 2-cTpyrazole-3-illbenzonitrile Example 206A (50 mg, 0.115 mmol), di-ter azodicarboxylate were combined -butyl (53.1 mg, 0.23 mmol), Ph3P of supported polymer (3 mmol / g, 77 mg, 0.23 mmol) and pyridin-2-yl-methanol (25.2 mg, 0.23 mmol) in THF (3 mL). The reaction was stirred at room temperature overnight, and the insoluble material was removed by filtration and washed with THF thoroughly. The filtrate was concentrated, and the residue was suspended in methanol (2 mL), treated with 4 N HCl in dioxane (2 mL) and heated at 50 ° C for 5 hours. The reaction mixture was concentrated, and the residue was purified by HPLC preparation to give the title compound (32.4 mg) in a 71% yield.
Examples 207 to 219 represented by Figure (XI) in Table 11 were synthesized in a manner similar to that described in Example 206B, except that substituting the aporpiated alcohol for pyridin-3-yl-methanol.
Figure (XI) TABLE 11 EXAMPLE 220 3- (4-Cyano-phenyl) -N- (4-hydroxy-cyclohexyl) -7-methoxy-1,4-dihydroindene, 2-c-thiazole-6-carboxamide Example 220A 6-Methoxy-1-oxo-2,3-dihydro-1 H-inden-5-yl Example 172A (6 g, 33.67 mmol), 2,6-lutidine (5.88 mL, 50.52 mmol) was combined, and 4-dimethylaminopyridine (822 mg, 6.72 mmol) at -35 ° C ~ -30 ° C and then treated dropwise with triflic anhydride (8.52 mL, 50.64 mmol). The reaction mixture was slowly warmed to room temperature with stirring and concentrated. The residue was purified by flash chromatography eluting with hexane: ethyl acetate (2: 1). The product of the title (9.8 g) was obtained at a 94% yield. S (DCI / NH3) m / z: 328.01 (M + NH4) +.
Example 220B Methyl 6-methoxy-1-oxotndan-5-carboxylate Example 220A (5.7 g, 18.37 mmol), PdCI2 (dppf) 'CH2Cl2 (1.5 g) and triethylamine (7.7 mL) in methanol (50 mL) were combined. and were stirred for 16 hours at 110 ° C under an atmosphere of carbon monoxide (35.15 kg / cm2). The solvent was removed, and the residue was purified by flash chromatography eluting with hexane: ethyl acetate (2: 1). The title product (3.1 g) was obtained in a yield of 77%. MS (DCI / NH3) m / z: 221.02 (M + H) +.
Example 220C Methyl 2- (4-cyanobenzoyl) -6-methoxy-1-oxoindan-5-carboxylate The desired product was prepared using the procedure of Example 205C replacing Example 205A with Example 220B. S (DCI / NH3) m / z: 350.07 (M + H) +.
Example 22QD 3- (4-Cyanophenyl) -7-methoxy-1,4-dihydroindenof1,2-c1 pyrazole-6-methyl carboxylate The desired product was prepared using the procedure of Example 165C replacing Example 165B with Example 220C. The title compound (3.7 g) was obtained in an 81% yield. MS (DCI / NH3) m / z: 346.08 (M + H) +. HR (400 MHz, DMSO-D6) d ppm 3.80 (s, 3H) 3.90 (s, 2H) 3.91 (s, 3H) 7.44 (s, 1H) 7.83 (s, 1H) 7.95 (d, 1 = 8.59Hz, 2H) 7.99 (d, 3 = 8.59Hz, 2H) 13.69 (s, 1H).
Example 220E 3- (4-Cyanophenyl) -7-methoxy-1,4-dihydroindenori, 2-cT-irazole-6-carboxylic acid Example 220D (1 g, 2.90 mmol), 2 N NaOH (10 mL) were combined, THF (20 mL) and ethanol (20 mL) and stirred overnight. The reaction mixture was concentrated, diluted with water and acidified with HCl. The precipitate was collected through filtration to give the title product (905 mg) in an 85% yield. MS (DCI / NH3) m / z: 349.06 (M + NH4) +. 1H NR (500 MHz, DMSO-D5) S ppm 3.89 (s, 2H) 3.92 (s, 3H) 7.39 (s, 1H) 7.85 (s, 1H) 7.98 (s, 4H).
Example 220F 3- (4-Cyanofenyl) -N- (4-hydroxy-cyclohexyl) -7-methoxy-1A-dihydroindenofl, 2-clirazole-6-carboxamide Example 220E (50 mg, 0.15 mmol ), 4-aminocyclohexanol (52 mg, 0.45 mmol), the BOP reagent (100 mg, 0.23 mmol) and triethylamine (0.063 mL) in DMF (2.5 mL) and stirred overnight. The precipitate was collected through filtration to give the title compound (44 mg) in 68% yield. MS (DCI / NH3) m / z: 429.2 (M + H) +.
Examples 221 to 227 represented by Figure (Xil) and shown in Table 12 were synthesized in a manner similar to that described in Example 220F, except that substituting the appropriate amine for 4-aminocyclohexanol.
Figure (XII) TABLE 12 EXAMPLE 228 4- (6- { FTrans (4-Ri'-chlorocyclohexyl) aminoTmethyl> -7-methoxy-1,4-dihydroindenof1,2-clpyrazol-3-yl) benzonitrile Example 228A (Trans) 4-. { r (3-iodo-7-methoxy-1,4-dihydroindenoH, 2-clirazole-6-iQ methyl-amino) cyclohexanol Example 104E (150 mg, 0.44 mmol), trans-4-aminocyclohexanol hydrochloride ( 100 mg, 0.66 mmol) and K2CO3 (91 mg, 0.66 mmol) in ethanol (20 mL) were heated at 100 ° C for 3 hours and cooled. After the addition of NaBH 4 (16.6 mg, 0.44 mmol), the reaction was stirred at room temperature overnight and concentrated. The residue was purified through flash chromatography eluting with CH2Cl2: CH3OH: NH40H (100: 10: 1). The title compound (110 mg) was obtained in 57% yield. MS (ESI) m / z: 439.98 (M + H) +.
Example 228B 4- (6- { RTrans (4-Rihydroxy-8-chloroxy) -1-amino-1-methyl-7-methoxy-1,4-dihydroindene-2-cyclopyrazol-3-yl) benzonitrile Example 228A (40 mg, 0.091 mmol), 4-cyanophenylboronic acid (16 mg, 0.11 mmol), Na 2 CO 3 (1 M, 0.25 mL), and Pd (PPh 3) 2 Cl 2 (6.4 mg, 0.009 mmol) in DME / EtOH / H 2 O (7: 2: 3 , 1.5 mL) in a capped 2 mL bottle and heated at 160 ° C for 600 seconds on a Smit Synthesizer. The reaction was cooled using 2812 kg / cm 2 of preseurized air, the solvents were evaporated, and the residue was purified using preparative HPLC. The title compound (20 mg) was obtained in 36% yield (based on 2TFA salt). MS (DC / NH3) m / z: 415.19 (M + H) +. 1H N MR (500 MHz, DMSO-D6) d ppm 1.14-1.23 (m, 2H) 1.38-1.45 (m, 2H) 1.89-1.91 (m, 2H) 2.07-2.10 (m, 2H) 3.00-3.05 (m , 2H) 3.88 (s, 2H) 3.94 (s, 3H) 4.14-4.17 (m, 2H) 7.39 (s, 1H) 7.60 (s, 1H) 7.96 (d, J = 8.42Hz, 2H) 7.99 (d, J = 8.42Hz, 2H) 8.45 (s, 2H).
Example 229 4-G6- (1 H-imidazol-1-ylmethyl) -7-methoxy-1,4-dihydroindenoH, 2-cl pyrazole-3-illbenzonitrile Example 229A 3- (4-Cyanophenyl) -7-methoxy-1-fr2- (trimethylsilyl) ethoxyT methyl} -1,4-dihydroindenori, methyl 2-clirazole-6-carboxylate The desired product was prepared using the procedure of Example 175D by replacing Example 175C with Example 220D. The title compound (1.5 g) was obtained in a 91% yield. MS (DC / NH3) m / z: 476.20 (M + H) +.
Example 229B 4- (6-Hydroxymethyl) -7-methoxy-1 -. { r2- (trimethylsilyl) ethoxyl methyl) -1,4-dihydroindeneM, 2-cl pyrol l-3-yl) benzonitrile Example 229A (200 mg, 0.42 mmol) and NaBH 4 (160 mg, 4.2 mmol) were combined. ) in THF-MeOH (1: 1), warmed to 50 ° C overnight, and concentrated. The residue was purified by flash chromatography eluting with a mixture of ethyl acetate and hexane. MS (DC / NH3) m / z: 448.19 (M + H) +.
Example 229C 4-G6-? H-imidazole-1-Methylene) -7-methoxy-1,4-dihydro indeneH, 2-chlororazole-3-illbenzonitrile Example 229B (20 mg, 0.045 mmol) and 1.1'- were combined. carbonyldiimidazole (30 mg, 0.18 mmol) in acetonitrile (3 mL), heated at 80 ° C for 24 hours and concentrated. The residue was treated with ethanol (2 mL) and 4 N HCl in dioxane (2 mL), and the reaction mixture was stirred overnight. White precipitates were collected through filtration and dried to give the title compound (14.4 mg, HCl salt) in 80% yield. MS (DCI / NHg) m / z: 368.14 (+ H) +. 1 H NMR (400 MHz, DMSO-D 6) d ppm 3.86 (S, 2 H) 3.93 (s, 3 H) 5.43 (s, 2 H) 7.33 (s, 1 H) 7.39 (S, 1 H) 7.61 (s, 1 H) 7.67 ( s, 1H) 7.73 (s, 1H) 7.95-8.00 (m, 4H) 9.23 (s, 1H) EXAMPLE 230 3- (6-Chloropyridin-3-yl) -6,7-dimethoxy-1,4-dihydroindenori, 2-cT pyrazole Example 230A 2-Chloro-5- (1H-imidazol-1-ylcarbonyl) pyridine The desired product was prepared using the procedure of Example 165A by replacing 4-benzyloxybenzoic acid with 6-chloronicotinic acid.
Example 230B 2-r (6-Chloropyridin-3-yl) carbonn-5,6-dimethoxyindan-1-one The desired product was prepared using the procedure of Example 165E replacing Example 165A with Example 230A . MS (DCI / NH3) m / z: 331.98 (M + H) +.
Example 230C 3- (6-Chloropyridin-3-yl) -6,7-dimethoxy-1,4-dihydroindenon, 2-cl pyrazole The desired product was prepared using the procedure of Example 165C replacing Example 165B with Example 230B. The title product (937 mg) was obtained in a 95% yield. S (DC / NH3) m / z: 328.01 (M + H) +. 1 H NMR (400 MHz, DMSO-D 6) 8 ppm 3.80 (s, 2 H) 3.82 (s, 3 H) 3.84 (s, 3 H) 7.23 (s, 2 H) 7.65 (s, 1 H) 8.21 (d, J = 7.37 Hz , 1H) 8.82 (d, J = 2.45Hz, 1H) 13.22 (s, 1H).
Example 231 4- (5- (6,7-Dimethoxy-1,4-dihydroindenof 1,2-c1pyrazol-3-yl) iridin-2-illphenol The desired product was prepared using the procedure of Example 166B replacing Example 166A with Example 230C MS (DCI / NH3) m / z: 386.09 (M + H) +. 1 H NMR (500 MHz, DMSO-D6) d ppm 3.82 (s, 3H) 3.83 (s, 2H) 3.84 (s, 3H) 6.89 (d, J = 8.73Hz, 2H) 7.24 (d, J = 7.80 Hz, 2H) 7.98-8.01 (m, 3H) 8.23 (dd, J = 8.42.2.18Hz, 1H) 8.99 (d, J = 1.56Hz, 1H).
EXAMPLE 232 4-r5- (6,7-Dimethoxy-1,4-dihydroindene, 2-clp-aceol-3-yl) irdin-2-yl-2-methoxyphenol The title product was prepared using the procedure of Example 164 replacing Example 64C with Example 230C in a yield of 83%. MS (ESI) m / z: 416.08 (M + H) +. 1H NR (500 MHz, DMSO-D6) d ppm 3.82 (s, 3H) 3.83 (s, 2H) 3.84 (s, 3H) 3.88 (s, 3H) 6.89 (d, J = 8.42Hz, 1H) 7.24 (s) , 1H) 7.25 (s, 1H) 7.59 (dd, J = 8.26, 2.03Hz, 1H) 7.74 (d, J = 1.87Hz, 1H) 8.04 (d, J = 8.42Hz, 1H) 8.21 (dd, J = 8.42, 2.18Hz, 1H) 9.00 (d, J = 1.87Hz, 1H).
EXAMPLE 233 4-r5- (6,7-Dimethoxy-1,4-dihydroindenori. 2-clpyrazol-3-yl) pyridin-2-α-2-fluorophenol The desired product was prepared using the procedure of Example 232 replacing 2-methoxy-4- (4,4,5,5-tetramethyl [1, 3,2] dioxaborolan-2-yl) -phenol with 2-f luoro-4- (4,4,5,5 -tetramethyl [1,2,2] dioxaborolan-2-yl) -phenol. MS (ESI) m / z: 404.07 (M + H) +. 1 H NMR (500 MHz, DMSO-D 6) d ppm 3.83 (s, 3 H) 3.84 (s, 2 H) 3.85 (s, 3 H) 7.07 (t, J = 8.89 Hz, 1 H) 7.24 (s, 1 H) 7.26 ( s, 1H) 7.84 (dd, J = 8.42.1.87Hz, 1H) 7.94 (dd, J = 12.79, 2.18Hz, 1H) 8.04 (d, J = 8.42Hz, 1H) 8.21 (dd, J = 8.42, 2.18 Hz, 1H) 9.02 (d, J = 2.18Hz, 1H) Example 234 5- (6,7-Dimethoxy-1,4-dihydroindenori, 2-cT-irazol-3-yl) iridin-2-carbonitrile The desired product was prepared using the procedure of Example 167 by replacing Example 64C with Example 230C. MS (DCI / MHs) m / z: 319.06 (M + H) +. 1 H NMR (500 MHz, DMSO-D 6) d ppm 3.81 (s, 3 H) 3.83 (s, 5 H) 7.23 (s, 1 H) 7.24 (s, 1 H) 8.13 (d, J = 8.11 Hz, 1H) 8.34 (dd, J = 8.42, 2.18Hz, 2H) 9.14 (d, J = 1.56Hz, 1H) Example 235 6- (6,7-Dimethoxy-1,4-dihydroindenori, 2-cTpyrazol-3-yl) nicotinonitrile EXAMPLE 235A Methyl 5-Bromopyridine-2-carboxylate 2.5-Dibromopyridine (9.5 g, 40.10 mmol), PdCI2 (PPh3) 2 (844 mg), triethylamine (8.36 ml_), methanol (38 mL), and acetonitrile were combined. (114 mL), were heated under an atmosphere of carbon monoxide (5.2725 kg / cm2) at 60 ° C for 16 hours and concentrated. The residue was purified by flash chromatography eluting with 25% ethyl acetate in hexane. The title compound (5.02 g) was obtained in a 58% yield. MS (DCI / MH3) m / z: 215.95 (M + H) +. 1H NMR (500 MHz, D MSO-DB) d ppm 3.91 (s, 3H) 8.00 (d, J = 8.11Hz, 1H) 8.27 (dd, J = 8.42, 2.49Hz, 1H) 8.86 (d, J = 1.56 Hz, 1H).
EXAMPLE 235B 2-f (5-Bromopyrdin-2-iDcarbonyl-1-5,6-d-methoxydandan-1-one The desired product was prepared using the procedure of Example 165B replacing Example 165A with Example 235A. The title compound (1.65 g) was obtained in a 95% yield: MS (DCI / NH3) m / z: 375.98 (M + H) +.
EXAMPLE 235C 3- (5-Bromopyrdin-2-n-6,7-d-methoxy-1,4-dihydroindene, 2-cl pyrazole The desired product was prepared using the procedure of Example 165C replacing Example 165B with Example 235B The title compound (1.35 g) was obtained in an 85% yield MS (DCI / NHa) m / z: 373.94 (M + H) +. 1 H NMR (500 MHz, DMSO-D6) S ppm 3.76 (s, 2H) 3.80 (s, 3H) 3.83 (s, 3H) 7.20 (s, 1H) 7.25 (s, 1H), 7.72 (d, J = 8.42 Hz, 1H) 8.17 (d, J = 6.86 Hz, 1H) 8.76 (s, 1H) 13.25 (s, 1H) Example 235D 6- (6,7-Dimethoxy-1,4-dihydroindenori, 2-cl irazol-3-yl) nicotinonitrile The desired product was prepared using the procedure of Example 167 replacing Example 64C with Example 235C in a 70% yield. MS (DCI / MH3) m / z: 319.06 (M + H) +. 1 H NMR (500 MHz, DMSO-D 6) d ppm 3.81 (s, 2 H) 3.82 (s, 3 H) 3.84 (s, 3 H) 7.24 (s, 1 H) 7.26 (s, 1 H) 7.98 (s, 1 H) 8.39 ( d, J = 7.49 Hz, 1H) 9.08 (d, J = 1.25 Hz, 1H) EXAMPLE 236 4'-r6- (1-Hydroxy-1-methyl-ethyl) -1,4-dihydroindenoyl, 2-cl-irazol-3-iH-1,1'-blfenl-4-ol EXAMPLE 236A 1,4-DihydroindenoM, methyl 2-c1p-aceol-6-carboxylate The desired product was prepared using the procedure of Example 2208 by replacing Example 220A with 6-bromo-1,4-dihydro-indene [1, 2 -c] pyrazole (for preparation, see US patent 6297238). MS (DC1 / NH3) m / z: 215.05 (M + H) +.
EXAMPLE 236B 3-Iodo-1,4-dihydroindenori, methyl 2-c1pyrazol-6-carboxylate The desired product was prepared using the procedure of Example 688 by replacing Example 68A with 236A. MS (DCI / NH3) m / z: 340.92 (M + H) +.
Example 236C 2- (3-Iodo-1,4-dihydroindenoM, 2-cT-irazol-6-in-propan-2-ol To a solution of Example 236B (1 g, 2.94 mmoi) in THF (145 mL) was added drop by drop 1.4 M MeMgBr in THF-toluene (8.4 mL, 11.76 mmol) The reaction mixture was slowly warmed to room temperature, stirred for 24 hours, quenched with aqueous NH 4 Cl, and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated, the residue was purified through flash chromatography eluting with 50% ethyl acetate in hexane. The title compound (700 mg) was obtained in a 70% yield. MS (DCI / NH3) m / z: 340.95 (M + H) +. 1 H NMR (500 MHz, DMSO-D g) d ppm 1.44 (s, 6 H) 3.48 (s, 2 H) 5.02 (s, 1 H) 7.44 (dd, J = 7.80, 1.25 Hz, 1 H) 7.48 (m, 1 H) 7.65 (s, 1H).
Example 236D 4'-r6- (1-Hydroxy-1-methylethin-4-dihydroxydenori, 2-c1pyrazol-3-yl-1-1,1'-biphenyl-4-ol Example 236C (45 mg, 0.13) was combined mmol), Example 68D (47 mg, 0.16 mmol), Na 2 CO 3 (1 M, 0.3 mL), and Pd (PPh 3) 2 Cl 2 (9.9 mg, 0.014 mmol) in DME / EtOH / H 2 O (7: 2: 3.1.5 mL ) in a 2 mL capped flask and heated at 160 ° C for 600 seconds in a Smit Synthesizer, the reaction was cooled using 2812 kg / cm2 of pressurized air, the solvents were evaporated, and the residue was purified using HPLC preparation. The title compound (26.7 mg, TFA salt) was obtained in a yield of 42% MS (DCI / NHg) m / z: 383.1 (M + H) +. 1 H NMR (500 MHz, DMSO-D6) d PPM 1.47 (s, 6H) 3.86 (s, 2H) 6.86 (d, J = 8.73Hz, 2H) 7.45 (d, J = 8.11Hz, 1H) 7.55-7.58 (m, 3H) 7.69-7.72, (m, 3H) 7.84 (d, J = 8.42Hz, 2H) EXAMPLE 237 4-G6- (1-Hydroxy-1-methyl-ethyl) -1,4-dihydroindertoM, 2-cTp! Razo! -3-yl benzonitrile The desired product was prepared using the procedure of Example 236D replacing Example 68D with 4-cyanophenyl boronic acid. The title compound (27.8 g) was obtained in a 51% yield. MS (DCI / NH3) m / z: 316.09 (M + H) +. 1H NMR (500 MHz, DMSO-D6) d ppm. 1.47 (s, 6H) 3.89 (s, 2H) 7.47 (dd, J = 7.95, 1.40 Hz, 1 H) 7.57 (d, J = 8.11Hz, 1H) 7.69 (s, 1H) 7.95 (d, J = 8.42 Hz, 2H) 7.98 (d, J = 8.42Hz, 2H) Example 238 2-r3- (6-Chloropyridin-3-in-1,4-dihydroindenon, 2-clirazol-6-ill propan-2-ol EXAMPLE 238A 1-Methyl oxxo-5-carboxylate The desired product was prepared using the procedure of Example 220B by replacing Example 220A with 5-bromoindanone. The title product was obtained in a yield of 85%. MS (DCI / NH3) m / z: 208.06 (M + NH4) +. H NMR (400 MHz, DMSO-D6) S ppm 2.69-2.72 (m, 2H) 3.16-3.19 (m, 2H) 3.90 (s, 3H) 7.75 (d, J = 7.98 Hz, 1H) 7. 96 (dd , J = 7.98, 1.53 Hz, 1H) 8.15 (s, 1H) EXAMPLE 238B Methyl 2-F (6-chloropyridin-3-yl) carbonin-1-oxoindan-5-carboxylate Example 238A (2.7 g, 14.2 mmol) was treated in 45 mL of THF with NaH (60%, 1.14 g. 28.4 mmol). After the addition of Example 230A (7.4 g, 35.5 mmol), the reaction mixture was stirred overnight and emptied in ice / water. The reaction mixture was acidified with concentrated HCl. A yellow solid was collected through filtration, washed with water and hot ethanol. The title product (4.3 g) was obtained in a yield of 92%. MS (DCI / NH3) m / z: 330.01 (M + H) +.
EXAMPLE 238C 3- (6-Chloropyridin-3-yl) -1,4-dihydroindenoM, methyl 2-cTpirazole-6-carboxylate The desired product was prepared using the procedure of Example 165C replacing Example 165B with Example 238B. The title compound (600 mg) was obtained in a yield of 74%. MS (DCI / NH3) m / z: 325.98 (M + H) +. 1 H NMR (400 Hz, DMSO-DB) d ppm 3.88 (s, 3 H) 3.98 (s, 1 H) 4.01 (s, 1 H) 7.607.83 (m, 2 H) 8.00 (d, J = 8.29 Hz, 1 H) 8.14 (s, 1H) 8.25 (t, J = 9.97Hz, 1H) 8.85 (s, 1H) 13.66 (s, 1H) Example 238D 2-r3- (6-Chloropyridin-3-yl) -1,4-dihydroindenon, 2-cTpyrazol-6-in-propan-2-ol The desired product was prepared using the procedure of Example 236C replacing Example 2368 with Example 238C. The title compound (250 mg) was obtained in a yield of 83%. MS (ESI) m / z: 326.02 (M + H) +. 1H NMR (300 MHz, DMSO-D6) d PPM 1. 47 (s, 6H) 3.89 (s, 2H) 5.06 (s, 1H) 7.48 (d, J = 8.48Hz, 1H) 7.58 (d, J = 7.80 Hz, 1H) 7.66 (d, J = 7.80 Hz, 1H ) 7.70 (s, 1H) 8.24 (dd, J = 8.48, 2.37Hz, 1H) 8.85 (d, J = 2.03Hz, 1H) 13.37 (s, 1H) Example 239 4-f5-f 6- (1-Hydroxy-1-methyl-ethyl) -1,4-dihydroindenori, 2-c] pyrazol-3-n-pyridin-2-yl > phenol The desired product was prepared using the procedure of Example 166E replacing Example 166A with Example 238D. The title compound (25.1 mg) was obtained in a 28% yield. S (DCI / NH3) m / z: 384.2 (M + H) +. 1 H NMR (500 Hz, DMSO-D6) d PPM 1.49 (s, 6H) 3.93 (s, 2H) 6.92 (d, J = 8.73Hz, 2H) 7.49 (dd, J = 8.11, 1.56Hz, 1H) 7.60 (d, J = 8.11Hz, 1H) 7.72 (s, 1H) 8.00 (d, J = 9.04Hz, 2H) 8.04 (d, J = 8.42Hz, 1H) 8.29 (dd, J = 8.42, 2.18Hz, 1H ) 9.03 (d, J = 1.56Hz, 1 H).
EXAMPLE 240 3- (5,6-Dichloropyridin-3-yl) -6,7-dimethoxy-1,4-dihydro-ndenori, 2-cT pyrazole Example 240A 2,3-Dichloro-5- (1H-imidazol-1-ylcarbonyl) pyridine The desired product was prepared using the procedure of Example 165A by replacing 4-benzyloxybenzoic acid with 5,6-chloronicotinic acid.
Example 240B 2-r (5,6-Dichloropyridin-3-yl) carbonill-5,6-dimethoxyindan-1-one The desired product was prepared using the procedure of Example 165B replacing Example 165A with Example 240A.
Example 240C 3- (5,6-Dichloropyridin-3-yl) -6,7-dimethoxy-1,4-dihydroindenof 1,2-the pyrazole The desired product was prepared using the procedure of Example 165C replacing Example 165B with the Example 24QB. MS (DCI / NH3) m / z: 361.98 (M + H) +. 1 H NMR (400 MHz, DMSO-D 6) d ppm 3.82 (s, 3 H) 3.83 (s, 2 H) 3.84 (s, 3 H) 7.23 (s, 1 H) 7.24 (s, 1 H) 8.42 (d, J = 2.15 Hz, 1H) 8.78 (d, J = 2.15Hz, 1H).
Example 241 2-r3- (6-Fluoropyridin-3-yl) -1,4-dihydroindenoH, 2-cl pyrazole-6-ill propan-2-ol The desired product was prepared using the procedure of Example 236D replacing Example 68D with 6-fluoronicotinic-boronic acid. The title compound (350 g) was obtained in 96% yield. MS (DCI / NH3) m / z: 310.08 (M + H) +. 1H NMR (500 MHz, DMSO-D6) d ppm 1.48 (s, 6H) 3.88 (s, 2H) 5.07 (s, 1H) 7.35 (d, J = 6.71Hz, 1H) 7.48 (d, J = 7.93Hz, 1H) 7.58 (d, J = 6.71Hz, 1H) 7.70 (s, 1H) 8.38 (m, 1H) 8.67 (d, J = 2.14Hz, 1H) 13.31 (s, 1H) Example 242 6,7-D-methoxy-3-pyrazin-2-yl-1,4-dihydroindenori, 2-clirazole Example 242A 5,6-Dimethoxy-2- (irazin-2-alkylcarbonyl) indan-1 -o na The desired product was prepared using the procedure of Example 165B by replacing Example 165A with methyl pyrazin-2-carboxylate. MS (DCI / NH3) m / z: 299.06 (M + H) +.
Example 242B 6,7-Dimethoxy-3-pyrrazin-2-yl-1,4-dihydro-ndenori, 2-cTpyrazole The desired product was prepared using the procedure of Example 165C replacing Example 1658 with Example 242A. MS (DCI / NH3) m / z: 295.05 (M + H) +. H NMR (500 Hz, DMSO-D6) d ppm 3.82 (s, 3H) 3.85 (s, 5H) 7.23 (s, 1H) 7.28 (s, 1H) 8.59 (s, 1H) 8.72 (s, 1H) 9.05 ( s, 1H) 13 41 (s, 1H).
Example 243 6,7-Dimethoxy-3-pyridin-3-yl-1,4-dihydroindene, 2-clirazole Example 243A 6,7-Dimethoxy-1,4-dihydro-n-nofofl-1, 1-pyrazol A mixture of 5,6-dimethoxyindanone (6.0 g, 31 mmol), formic acid ethyl ester (5.04 mL, 62 mmol), 95 % NaH (2.35 g, 93 mmol) and benzene (100 mL) was stirred at room temperature for the night. The solvent was removed. To the residue was added slowly ethanol (200 mL), acetic acid (20 mL) and hydrazine monohydrate (20 mL). The mixture was refluxed for 3 hours and cooled. The solvents were removed. The residue was suspended in water (100 mL), and the solid was collected through filtration, washed with water (100 mL) and CCI 4 (100 mL), and dried to give the desired product as a powder of light yellow color (5.80 g, 87%). MS (ESI) m / z 217 (M + H) +. H NMR (300 MHz, D SO-D6) d ppm 3.51 (s, 2H) 3.79 (s, 3H) 3.82 (s, 3H) 7.17 (s, 1H) 7.20 (s, 1H) 7.56 (s, 1H) 12.51 (s, 1H).
Example 243B 3-Iodo-6,7-dimethoxy-4-dihydroindene, 2-dpirazoi Example 243A (5.80 g, 26.8 mmol), N-iodosuccinimide (7.84 g, 34.9 mmol), and anhydrous DMF (100 mL) were added. ), were stirred at 80 ° C for 4 hours and concentrated. The residue was dissolved in dichloromethane (200 mL), washed with water (200 mL x 3), dried over MgSO 4 and concentrated. The residue was purified by flash chromatography to give the title product as a brown solid (5.84 g, 64%). MS (ESI) m / z 343 (M + H) 1H NMR (300 MHz, DMSO-D6) d ppm 3.42 (s, 2H) 3.79 (s, 3H) 3.81 (s, 3H) 7.15 (s, 1H) 7.19 (s, 1H).
EXAMPLE 243C 6,7-D-methoxy-3-pyridin-3-yl-1,4-di idroindenon. 2 -drazo I Example 243B (100 mg, 0.29 mmol), pyridu-3-boronic acid ( 43 mg, 0.35 mmol), Na 2 CO 3 (1 M, 0.35 mL), and Pd (PPh 3) 2 Cl 2 (20 mg, 0.014 mmol) in DME / EtOH / H 2 O (7: 2: 3, 4 mL) in a stoppered flask. 5 ml_ and heated at 160 ° C for 600 seconds on a Smit Synthesizer. The reaction was cooled using 2.812 kg / cm2 of pressurized air, the solvents were evaporated, and the residue was purified using preparative HPLC. MS (DCI / NH3) m / z: 294.1 (M + H) +. H NMR (500 MHz, D SO-D6) d ppm 3.83 (s, 5H) 3.85 (s, 3H) 7.24 (s, 1H) 7.25 (s, 1H) 7.73 (dd, J = 7.95, 5.15 Hz, 1H) 8. 39 (d, J = 8. 11Hz, 1H) 8.65 (dd, J = 4. 99.1, 25 Hz, 1H) 9.07 (d, J = 1. 56 Hz, 1H).
EXAMPLE 244 6,7-Dimethoxy-3-pyrimidin-5-yl-1,4-dihydrin or G1, 2-cl irazole The desired product was prepared using the procedure of Example 243C replacing pyridyl-3-acid. boronic acid with pyrimidyl-5-boronic acid. MS (DCI / NH3) m / z: 295.06 (M + H) +. H NMR (500 MHz, DMSO-De) d ppm 3.82 (s, 3H) 3.85 (s, 5H) 7.24 (s, 1H) 7.25 (s, 1H) 9.16 (s, 1H) 9.20 (s, 2H).
Example 245 3- (6-Chloropyridin-3-yn-7-ethyl-6-methoxy-1,4-dihydroindene, 2-pyrazole Example 245A Trif luoromethanesulfonate of 6-methoxy-3-oxo-2,3-dihydro-1 H-inden-5-yle Example 144B (3.5 g, 19.64 mmol) and NaH (60%, 496 mg, 19.64 g) were combined. mmol) and stirred at 40 ° C until no bubbles left the reaction mixture. After the addition of N-phenyltrifluoromethanesulfonimide (8.41 g, 23.57 mmol), the reaction mixture was stirred additionally at 40 ° C for 30 min and concentrated. The residue was purified by flash chromatography eluting with 50% ethyl acetate in hexane. The title compound (5.5 g) was obtained in a 90% yield. MS (DCI / NH3) m / z: 327.99 (M + NH4) +. H NMR (400 MHz, DMSO-De) d ppm 2.65-2.68 (m, 2H) 3.11-3.14 (m, 2H) 4.01 (s, 3H) 7.52 (s, 1 H) 7.62 (s, 1 H).
Example 245B 5-Methoxy-6-vinylndan-1-one Example 245A (4.5 g, 14.5 mmol), tributylvinyltin (5.54 g, 17.4 mmol), Pd (PPh3) 2 Cl2 (1.02 g, 1.45 mmol) were combined and Lithium chloride (4.9 g, 116 mmol), in DMF (60 mL) and heated at 80 ° C for 2 hours, cooled. After the addition of saturated potassium fluoride (100 ml_), the resulting mixture was stirred for 30 min, and diluted with ethyl acetate (800 mL). The presyntates were removed by filtration, and the filtrate was washed with water extensively, then with 10% HCl. The organic layer was dried over gS04 and concentrated. The residue was purified by flash chromatography eluting with 30% ethyl acetate in hexane. The title compound (1.65 g) was obtained in a yield of 60%. MS (DCI / NH3) m / z: 189.04 (+ H) +. IH NMR (500 MHz, D SO-D6) S ppm 2.47-2.49 (m, 2H) 2.94-2.96 (m, 2H) 3.81 (s, 3H) 5.19 (dd, J = 11.23, 1.25Hz, 1H) 5.74 ( dd, J = 17.78, 1.25Hz, 1H) 6.83 (dd, J = 17.78, 11.23Hz, 1H) 7.06 (s, 1H) 7.60 (s, 1H).
Example 245C 6-Ethyl-5-methoxyindan-1-one Example 245E (1.59 g, 8.46 mmol) and Pd-C (10%, 159 mg) in THF (70 mL) were combined and stirred under an atmosphere of hydrogen. for 6 hours. The insoluble material was removed by filtration through Celite, the filtrate was evaporated to give the title product in a quantitative yield.
Example 245D 2-G (6-Chloropyridin-3-yl) carboniH-6-ethyl-5-methoxyindan-1 -o na The desired product was prepared using the procedure of Example 238B replacing Example 238A with Example 245C.
The title compound (325 mg) was obtained in a 71% yield.
Example 245E 3- (6-Chloropyridin-3-yl) -7-ethyl-6-methoxy-1,4-dihydroindene f1,2-c] pyrazole The desired product was prepared using the procedure of Example 165C replacing Example 165B with Example 245D. MS (DCI / NHg) m / z: 326.04 (m + H) +. 1H NMR (500 MHz, DMSO-D6) d ppm 1.04 (t, J = 7.49Hz, 3H) 2.50 (q, J = 7.49Hz, 2H) 3.69 (s, 2H) 3.71 (s, 3H) 7.06 (s, 1H) 7.27 (d, J = 8.42Hz, 1H) 7.48 (d, J = 8.42Hz, 1H) 8.07 (s, 1H) 8.67 (d, J = 2.18Hz, 1H) 13.04 (s, 1H).
Example 246 5- (7-Ethyl-6-methoxy-1,4-dihydroindeneM, 2-clp-aceol-3-yl) pyridine-2-carbonitrile The desired product was prepared using the procedure of Example 167 replacing Example 64C with Example 245E in a 65% yield. MS (DCI / NH3) m / z: 317.04 (M + H) +. 1H NMR (500 MHz, DMSO-D6) d ppm 1.18 (t, J = 7.48Hz, 3H) 2.64 (q, J = 7.63Hz, 2H) 3.86 (s, 3H) 3.89 (s, 2H) 7.23 (s, 1H) 7.43 (s, 1H) 8.15 (d, J-8.24HZ, 1H) 8.35 (dd, J = 8.24, 2.14Hz, 1H) 9.15 (d, J = 1.83Hz, 1H).
Example 247 3- (6-Chloropyridin-3-yl) -7-ethyl-6- (tetrahydro-2H-pyran-4-yloxy) -1,4-dihydroindenoH, 2-clirazole Example 247A 6-Ethyl-5-hydroxyindan-1-one Example 245C (1 g, 5.31 mmol) was treated in dichloromethane (25 mL) at -78 ° C with BBr 3 (2 mL_, 21.24 mmol). The reaction mixture was warmed to room temperature and stirred for 24 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over gS04 and concentrated. The residue was purified by flash chromatography eluting with 50% ethyl acetate in hexane. The compound of! Title (0.8 g) was obtained in a yield of 85%.
Example 247B 6-Ethyl-5- (tetrahydro-2H-pyran-4 -loxy) indan-1-or na Example 247A (150 mg, 0.85 mmol), Ph3P of supported polymer (3 mmol / g, 0.57) were combined. g, 1.7 mmol), di-tert-butyl azodicarboxylate (392 mg, 1.70 mmol) and tetrahydropyran-4-ol (174 mg, 1.70 mmol) in THF (4 mL) and stirred overnight. The insoluble material was removed by filtration, and the filtrate was concentrated. The residue was purified by flash chromatography eluting with a mixture of ethyl acetate and hexane. The title compound was obtained in a quantitative yield. MS (DCI / MH3) m / z: 261.1 (+ H) +.
Example 247C 2-r (6-Chloropyridin-3-carboncarnin-6-ethyl-5- (tetrahydro-2H-pyran-4-yloxhindan -one) The desired product was prepared using the procedure of Example 238B replacing Example 238A with Example 247B.
EXAMPLE 247D 3- (6-Cioropyridin-3-yl) -7-ethyl-6- (tetrahydro-2H-pyran-4-yloxy) -1,4-d-hydroquinide, 2-cT irazole The desired product is prepared using the procedure of Example 165C replacing Example 165B with Example 247C. MS (DCI / NH3) m / z: 396.1 (+ H) +. H MR (500 MHz, DMSO-D6) d ppm 1.19 (t, J = 7.49Hz, 3H) 1.61-1.68 (m, 2H) 1.99-2.01 (m, 2H) 2.66 (q, J = 7.49Hz, 2H) 3.51-3.55 (m, 2H) 3.81 (s, 2H) 3.84-3.87 (m, 2H) 4.63-4.68 (m, 1H) 7.26 (s, 2H) 7.42 (s, 1H) 7.63 (d, J = 8.11Hz , 1H) 8.20 (dd, J = 8.11, 2.49Hz, 1 H) 8.80 (d, J = 2.18Hz, 1H) 13.17 (s, 1H).
Example 248 4-. { 5-r7-Ethyl-6- (tetrahydro-2H-pyran-4-yloxy) -. 4-dihydroindene? 2-clirazol-3-inpyridin-2-yl) phenol The desired product was prepared using the procedure of Example 166B replacing Example 166A with Example 247D. The title compound (35.2 mg) was obtained in a yield of 43% MS (DCI / NH3) m / z: 454.17 (M + H) +. H NMR (500 Hz, DMSO-D6) d ppm 1.21 (t, J = 7.49Hz, 3H) 1.63-1.70 (m, 2H) 2.00-2.03 (m, 2H) 2.68 (q, J = 7.49Hz, 2H) 3.52-3.57 (m, 2H) 3.86 (s, 3H) 3.94-3.99 (m, 2H) 4.65-4. 69 (m, 1H) 6.90 (d, J = 8.73Hz, 2H) 7.28 (s, 1H) 7.45 (s, 1H) 8.00 (d, J = 8.73Hz, 3H) 8.22 (dd, J = 8.26, 2.03 Hz , 1 H) 9.00 (d, J = 2.18Hz, 1H).
Example 249 5-r7-Ethyl-6- (3-morpholin-4-ylpropoxy) -1,4-dihydroindenori, 2-cl pyrazole-3-illpyridine-2-carbonitrile Example 249A 6-Ethyl-5-. { r 2 - (trimethylsilyl) ethoxyl methoxy > Ndan-1 -one The desired product was prepared using the procedure of Example 205A replacing Example 172A with Example 247A.
Example 249B 2-r (6-Chloropyridin-3-yl) carbonyl-1-6-ethyl-5-. { (2- (Tr.methylsilyl) ethoxy-1-methoxy.) Ndan-1 -one The desired product was prepared using the procedure of Example 238B replacing Example 238A with Example 249A.
Example 249C 3- (6-Chloropyridin-3-yl-7-ethyl-6- 2- (trimethylsilyl-ethoxymethoxy> -1.4- dihydroindenoyl, 2-clirazole The desired product was prepared using the procedure of Example 165C replacing Example 165B with Example 249 B. The title compound (1.35 g) was obtained in a yield of 69% (for 3 steps).
Example 249D 3- (6-Chloropyridin-3-n-7-ethyl-6-. {R 2> (trimethylsilylethoxy-1-methoxy-1- (2- (trimethylsilyl) ethoxy-1-methyl-, 4-dihydroindene-f-1, 2-D-pyrazole The desired product was prepared using the procedure of Example 175D by replacing Example 175C with Example 249 C. The title compound (1.05 g) was obtained in an 81% yield.
Example 249E 5- (7-Ethyl-6- { R2- (trimethylsilyl-methoxy-1-methoxy> -1- { R2- (trimethylsilyl) ethoxy-1-methyl} -1,4-dihydroindeneM, 2-cT-irazol-3 -yl) pyridine-2-carbonitrile Example 249D (900 mg, 1.57 mmol), Pd2 (dba) 3 (36 mg, 0.039 mmol), dppf (43.5 mg, 0.078 mmol), zinc (204 mg, 0.39 mmol) were combined. ) and Zn (CN) 2 in DMA (75 mL), was heated at 130 ° C for 3 hours and concentrated, the residue was purified by flash chromatography eluting with 20% acetate of ethyl in hexane. The title product (872 mg) was obtained in a yield of 98.5%. MS (DCI / NH3) m / z: 563.26 (M + H) +.
Example 249F 5- (7-Ethyl-6-hydroxy-1-n2-ftrimethylsilyl) ethoxymethanol > -1.4- dihydroindenoyl, 2-cTpyrazol-3-yl) pyridine-2-carbonitrile The desired product was prepared using the procedure of Example 206A replacing Example 205E with Example 249E. The title compound (250 mg) was obtained in an 81% yield. MS (DCI / NH3) m / z: 433.19 (M + H) +.
Example 249G 5-r7-Ethyl-6- (3-morpholin-4-ylpropoxy) -1,4-dihydroxydene, 2-cl pyrazole-3-inpyridine-2-carbonitrile Example 249F (40 mg , 0.092 mmol), Ph3P in supported polymer (3 mmol / g, 46 mg, 0.139 mmol), di-tert-butyl azodicarboxylate (32 mg, 0.139 mmol) and 3-morpholin-4-ylpropan-1-ol (27 mg, 0.184 mmol) in THF (3 ml_) and stirred overnight. The insoluble material was removed by filtration, and the filtrate was concentrated. The residue was dissolved in a mixture of EtOH (5 mL) and CH2Cl2 (2 mL), treated with 4 N HCl in dioxane (0.5 mL), stirred at 50 ° C overnight and concentrated. The residue was purified by preparative HPLC. The title compound (33 mg) was obtained in 50% yield. MS (DCI / MH3) m / z: 430.2 (M + H) +.
Examples 250 to 254 represented by Figure (XIII) and shown in Table 13 were synthesized in a manner similar to that of Example 249G, except that substituting the appropriate alcohol for 3-morph olí-4-il clothes n-1 -ol.
Figure (XIII) TABLE 13 Example 255 5- (6,7-Diethyl-1,4-dihydroindenof 1.2-clpyrazol-3-yl) pyridyl-2-carbonitrile Example 255A Trifl or gold meta-sulfon ate 6-ethi 1-1 -oxo-2,3-dydro-1 H-inden-5-yl The desired product was prepared using the procedure of Example 245A replacing Example 144B with Example 247A. The title compound (8.5 g) was obtained in a yield of 72%. MS (DCI / NH3) m / z: 325.99 (+ NH4) +. H NMR (500 MHz, DMSO-De) d ppm 1.22 (t, J = 7.49Hz, 3H) 2.68-2.70 (m, 2H) 2.74 (q, J = 7.49Hz, 2H) 3.13-3.15 (m, 2H) 7.64 (s, 1H) 7.74 (s, 1H).
Example 255B 6-Ethyl-5-vinylindan-1 -o na The desired product was prepared using the procedure of Example 245B by replacing Example 245A with Example 255A. The title compound (430 mg) was obtained in a 52% yield. MS (DCI / NH3) m / z: 187.05 (M + H) +. 1H NMR (500 MHz, DMSO-D6) d ppm 1.13 (t, J = 7.63Hz, 3H) 2.60-2.63 (m, 2H) 2.74 (q, J = 7.43Hz, 2H) 3.05-3.08 (m, 2H) 5.49 (dd, J = 11.14, 1.07Hz, 1H) 5.90 (dd, J = 17.39,1.22Hz, 1H) 7.07 (dd, J = 17.39, 10.98Hz, 1H) 7.44 (s, 1H) 7.71 (s, 1H) ) Example 255C 2-r (6-Chloropyridin-3-yl) carbonin-6-ethyl-5-vinylindan-1-one The desired product was prepared using the procedure of Example 238B replacing Example 238A with Example 255B. The title compound was used directly for the preparation of Example 255D.
Example 255D 3- (6-Chloropyridin-3-yl) -7-ethyl-6-vinyl-1,4-dihydroindenor. 2-c 1 pyrazole The desired product was prepared using the procedure of Example 165C replacing Example 165B with Example 255C. The title compound (250 mg) was obtained in 46% yield (for 2 steps). MS (DCI / NH3) m / z: 322.04 (M + H) +. 1H NMR (500 Hz, DMSO-De) d ppm 1.19 (t, J = 7.64Hz, 3H) 2.77 (q, J = 7.49Hz, 2H) 3.88 (s, 2H) 5.34 (d, J = 12.17Hz, 1H ) 5.79 (d, J = 17.16Hz, 1H) 7.07 (dd, J = 17.31, 11.07Hz, 1H) 7.48 (s, 1H) 7.65 (d, J = 7.80 Hz, 1H) 7.74 (s, 1H) 8.24 ( dd, J = 8.42, 2.50 Hz, 2H) 8.84 (d, J = 2.50 Hz, 1H) 13.41 (s, 1H).
Example 255E 1-rBis (4-methoxyphenyl) methyH-3- (6-chloropyridin-3-yl) -7-ethyl-6-vinyl-1,4-dihydroindene, 2-pyrazole The desired product was prepared using the procedure of Example 170B replacing 4-iodo-1 H-pyrazole with Example 255D. The title product (220 mg) was obtained in a yield of 79%.
Example 255F 1-rBis (4-methoxyphenyl) methin-3- (6-chloropyridin-3-yl) -6,7-diethyl-1,4-dihydroindene, 2-c-thirazole Example 255E (130 mg) was combined and Pt / C (5%, 13 mg) in THF and stirred for 4 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was evaporated. The title compound was obtained in a quantitative yield.
Example 255G 5-f1-rBis (4-methoxyphenyl) methylene-6,7-diethyl-1,4-dihydroquinone G1. 2-Cl pyrazole-3-yl} pyridine-2-carbonitrile The desired product was prepared using the procedure of Example 167 by replacing Example 64C with Example 255F. The title product (62 mg) was obtained in a 67% yield.
Example 255H 5- (6,7-Diethyl-1,4-dihydroindenori, 2-cl-irazol-3-iQpyridin-2-carbonitrile t Example 255G (60 mg, 0.11 mmol) in a mixture of ethanol (10 ml_) ) and THF (5 mL) was treated with 4 N HCl in dioxane (1 mL) The reaction was stirred for 4 hours, and the precipitate was collected, dry. The title product (30 mg) was obtained in a yield of 86%. MS (DCI / NH3) m / z: 315.11 (M + H) +. 1 H NMR (500 MHz, DMSO-De) d ppm 1.20-1. 25 (m, 6 H) 2.66-2. 73 (m, 4 H) 3.87 (s, 2 H) 7.38 (s, 1H) 7.46 (s, 1 H) 8.14 (d, J = 8.11 Hz, 1 H) 8.37 (dd, J = 8.11, 2.18 Hz, 1H) 9.16 (d, J = 1. 56 Hz, 1H).
Example 256 3- (6-Chloropyridin-3-M) -6,7-bis (2-methoxyethoxy) -1,4-dihydroindene G, 2-clirazole Example 256A 5,6-Bis (2-methoxyethoxy) indan-1 -o na Example 144A (800 mg, 4.88 mmol), 2-bromoethyl methyl ether (8 ml_, 85.1 mmol), Cs2CO3 (9 g, 27.6 g) were combined. mmol) in DMF and heated at 100 ° C for 2 hours. The inorganic salts were removed by filtration, and the filtrate was concentrated. The residue was purified by flash chromatography eluting with 50% ethyl acetate in hexane. The title product (600 mg) was obtained in a yield of 44%. MS (DCI / NH3) m / z: 281.00 (M + H) +.
Example 256B 2-r (6-Chloropyridin-3-yl) carbonn-5,6-bis (2-methoxyethoxy) indan-1-one The desired product was prepared using the procedure of Example 238B replacing Example 238A with Example 256A.
Example 256C 3- (6-Chloropyridin-3-yl) -6,7-bys (2-methoxyethoxy) -1,4-dihydro-mannide G1, 2-clirazole The desired product was prepared using the procedure of Example 165C replacing Example 165B with Example 256B. The title compound (617 mg) was obtained in a yield of 82% (for 2 steps). MS (DCI / NH3) m / z: 416.1 (+ H) +. 1 H NMR (500 MHz, DMSO-D 6) d ppm 3.34 (s, 3 H) 3.35 (s, 3 H) 3.68-3.71 (m, 4 H) 3.78 (s, 2 H) 4.14-4.18 (m, 4 H) 7.24 (s, 1H) 7.26 (s, 1H) 7.64 (d, J = 7.80 Hz, 1H) 8.20 (dd, J = 8.42, 2.50 Hz, 1H) 8.81 (d, J = 2.18Hz, 1H) 13.22 (s, 1H).
Example 257 5-f6,7-Bis (2-methoxyethoxy) -1,4-dihydroindenofl, 2-clirazol-3-pyridine-2-carbonitrile The desired product was prepared using the procedure of Example 167 replacing Example 64C with Example 256C. The title product was obtained in a yield of 85%. MS (DCI / NH3) m / z: 424.16 (M + NH4) +. 1 H NMR (400 MHz, DMSO-D 6) d ppm 3.34 (s, 3 H) 3.35 (s, 3 H) 3.68-3.71 (m, 4 H) 3.85 (s, 2 H) 4.15-4.19 (m, 4 H) 7.26 (s, 1H) 7.27 (s, 1H) 8.14 (d, J = 8.29Hz, 1H) 8.35 (dd, J = 8.29, 2.15Hz, 1H) 9.15 (d, J = 1.53Hz, 1H).
Example 258 6-Hydroxy-3- (4'-hydroxy-1,1'-blfenyl-4-yl) -7-methoxyindenori-2-pyrazole-4 (1 H) -one EXAMPLE 258 A 6-Hydroxy-7-methoxy-3- (4'-U2- (trimethylsulfoxymethoxy > -1,1'-biphenyl-4-yl) -1- { R2- (trimethylsilyl) ethoxy-1-methy1indenori, 2-cl pyrazole-4 (1H) -one Example 175G (310 mg, 0.49 mmol) and CS2C03 (640 mg, 1.96 mmol) in DMF were combined and heated in air at 90 ° C for 24 hours. The inorganic salt was removed by filtration, and the filtrate was concentrated.The residue was purified by flash chromatography eluting with 33% ethyl acetate in hexane.The title product (282 mg) was obtained in 89% yield MS (DCI / NH3) m / z: 645.29 (M + NH4) +.
Example 258B 6-Hydroxy-3- (4'-hydroxy-1,1'-biphenyl-4-yl) -7-methoxyindenori, 2-c1pyrazole-4 (1 H) -one Example 258A (30 mg, 0.46 mmol) in ethanol (2 mL) was treated with 4 N HCl in dioxane (2 mL). The reaction mixture was heated at 50 ° C overnight and concentrated. The residue was purified by preparative HPLC. The title compound (19 mg) was obtained in an 85% yield. MS (DCI / NH3) m / z: 385.09 (M + NH4). 1H NMR (500 MHz, DMSO-D6) d ppm 3.92 (s, 3H) 6.88 (d, J = 8.73Hz, 2H) 7. 01 (s, 1H) 7.14 (s, 1H) 7.62 (d, J = 8.73 Hz, 2H) 7.78 (d, J = 8.42 Hz, 2H) 8.22 (d, J = 8.42 Hz, 2H) 9.53 (s, 1H) ) 9.63 (s, 1H) 13.46 (s, 1H) Example 259 3- (4'-Hydroxy-1, 1'-biphenyl-4-yl) -7-methoxy-6- (2-piperidin-1-ylethoxy) indeneM, 2-cli razo 1-4 (1 H ) -one Example 258A (40 mg, 0.0465 mmol), di-tert-butyl azodicarboxylate (21.4 mg, 0.093 mmol), Ph3P in supported polymer (3 mmol / g, 31 mg, 0.093 mmol) and 2- piperidin-1-ethanol (15 mg, 0.116 mmol) in THF (3 mL). The reaction was stirred at room temperature for 2 days, and the insoluble material was removed by filtration and washed with THF thoroughly. The filtrate was concentrated, and the residue was treated with 4 N HCl in dioxane (2 mL) and methanol (2 mL), and heated at 50 ° C for 3 hours and concentrated. The residue was purified by HPLC to give the title compound (14.4 mg) in 45% yield. MS (DCI / NH3) m / z: 496.2 (+ H) +.
Examples 260 and 261 represented by Figure (XIV) and shown in Table 14 were synthesized in a manner similar to that described in Example 259, except that substituting the appropriate alcohol for 2-piperidin-1-ylethanol.
Figure (XIV) TABLE 14 Example 262 4-. { 6-r3- (Dimethylamino) propoxyl-7-methoxy-4-oxo-1,4-dihydroindene G1, 2-clp-aceol-3-yl) benzonitrile EXAMPLE 262A 4- (7-Methoxy-4-oxo-6-r2- (trimethylsilyl) ethoxylmethoxy> 2- (trimethylsilyl) ethoxymethyl> -1,4-dihydroindenofl, 2-clpyrazole-3- il) benzonitrile Example 205E (1.8 g, 3.19 mmol) and Cs2CO3 (4.16 g, 12.76 mmol) in DMF (50 mL) were combined and heated under air at 50 ° C overnight. The inorganic salt was removed by filtration, and the filtrate was concentrated. The residue was purified by flash chromatography eluting with 25% ethyl acetate in hexane. The title product (1.82 g) was obtained in a yield of 99%. MS (DCI / NH3) m / z: 578.25 (+ H) +.
EXAMPLE 262B 4- (6-Hydroxy-7-methoxy-4-oxo-1- { R2- (trimemethyl) ethoxymethyl> -1, 4- dihydroindy in oH, 2-chlirazol-3-yl) benzonitrile The desired product was prepared using the procedure of Example 206A replacing Example 205E with Example 262A. The title compound was obtained in a quantitative yield.
Example 262C 4-6-f3- (Dimethylamino) propoxn-7-methoxy-4-oxo-1,4-dihydroindene G1, 2-c1pyrazol-3-yl} Benzonitrile Example 262B (40 mg, 0.089 mmol), di-tert-butyl azodicarboxylate (42 mg, 0.18 mmol), Ph3P in supported polymer (3 mmol / g, 60 mg, 0.18 mmol) and 3-dimethylaminopropanol ( 18.6 mg, 0.18 mmoi) in THF (3 mL). The reaction was stirred at room temperature overnight, and the insoluble material was removed by filtration and washed with THF thoroughly. The filtrate was concentrated, and the residue was treated with 4 N HCl in dioxane (2 mL) and methanol (2 mL), and heated at 50 ° C for 5 hours. The reaction mixture was concentrated, and the residue was purified by HPLC to give the title compound (41 mg) in a 77% yield. MS (DCI / NH3) m / z: 403.14 (M + H) +.
Example 263 4-f 6-Hydroxy-7-methoxy-4-oxo-1,4-dihydroindene, 2-clpyrazol-3-yl) benzonitrile The desired product was prepared using the procedure of Example 205F replacing Example 205E with the Example 262A. The title compound was obtained in a quantitative yield. MS (ESI) m / z: 315.99 (M-H) \ Examples 264 and 265 represented by Figure (XV) and shown in Table 15 were synthesized in a manner similar to the described in Example 262C, except that substituting the appropriate alcohol for 3-dimethylaminopropanol.
Figure (XV) TABLE 15 Example 266 3-l6-Chloropyridin-3-yl) -6,7-dimethoxy-4-methyl-1,4-dihydroindenone .2-c-thirazol-4-ol Example 266A 3- (6-Chloropyridin-3-yl) -67-dimethoxyindenori, 2-clpirazole 1-4 (1 H) -one Example 230C (300 mg, 0.91 mmol) and Cs2CO3 (1.5 g, 4.6 mmol) in DMF (30 ml_) were combined, heated in air at 90 ° C for 3 hours and concentrated. The residue was suspended in water, and the orange solid was collected through filtration and dried. The title product (287 mg) was obtained in a yield of 92%. MS (DCI / NH3) m / z: 342.20 (M + H) +. 1 H NMR (400 MHz, DMSO-D 6) d ppm 3.82 (s, 3 H) 3.90 (s, 3 H) 7.15 (s, 1 H) 7.16 (s, 1 H) 7.75 (d, J = 8.59 Hz, 1 H) 8.48 (dd) , J = 8.44, 2.30 Hz, 1H) 9.14 (d, J = 2.15Hz, 1H).
Example 266B 3- (6-Chloropyridin-3-yl) -6,7-dimethoxy-4-methyl-1,4-dihydroindene, 2-chlororazole-4-ol To a suspension of 266A (100 mg, 0.29 mmol) in THF (15 rnL) at 0 ° C was added 1.4 M CH3MgCI in toluene: THF (1: 1, 1.3 mL). The reaction was warmed to room temperature, stirred for 1 day, quenched with water and concentrated. The residue was purified by preparative HPLC. MS (DCI / NH3) m / z: 358.03 (M + H) +. 1 H NMR (500 MHz, DMSO-D 6) d ppm 1.57 (s, 3 H) 3.83 (s, 6 H) 3.86 (d, J = 2.81Hz, 1H) 7.10 (s, 1H) 7.17 (d, J = 3.74Hz, 1H) 7.69 (d, J = 8.4) Hz, 1H) 8.37 (dd, J = 8.42, 2.50 Hz, 1H) 9.01 (d, J = 2.50 Hz, 1, H).
Example 267 4'-f6-Methoxy-7- (2-pyrrolidin-1-ylethoxy) -1,4-dihydroindenof1,2-c1 pyrazole-3-n-1,1'-biphenyl-4-ol Example 267A 1- (4-Bromobenzoyl) -1 H-imidazole To a solution of 4-bromo-benzoic acid (19.55 g, 97.3 mmol) in DMF (100 ml_) was added 1,1 '-carbonyldiumazole (39.42 g, 243.2 mmol) slowly at room temperature under N2. After 2 hours, the reaction was complete and was poured into ice-water (1 L). The precipitate was filtered, washed with water (2 L), and dried under vacuum to give the desired product (16.7 g, 68%). MS (DCI / NH3) m / z 252 (M + H) +; H NMR (300 MHz, DMSO-D5) d ppm 7.02 (s, 1H) 7.17 (s, 1H) 7.63-7.90 (m, 4H) 8.21 (s, 1 H).
Example 267B 6- (Benzyloxy) -5-methoxyindan-1-na Example 144B (8.65 g, 48.5 mmol), benzyl bromide (12 mL, 97.1 mmol), K2CO3 (20.2 g, 146.2 mmol) and acetone were mixed. Anhydrous (500 ml_) and refluxed overnight. The acetone was removed, and the concentrate was treated with water (300 mL). The precipitate was filtered, washed with water (300 ml_x2), and dried to give the desired product (11.80 g, 91%). S (DCI / NH3) m / z 269 (M + H) +; 1H NMR (300 Hz, CD3OD) d ppm 2.61-2.67 (m, 2H) 3.04-3.10 (m, 2H) 3.95 (s, 3H) 5.12 (s, 2H) 7.10 (s, 1H) 7.21 (s, 1H) 7.28-7.39 (m, 3H) 7.41-7.47 (m, 2H) Example 267C 6- (Benzyloxy) -2- (4-bromobenzoyl) -5-methoxyandan-1 -na Na To a solution of Example 267B (11.50 g, 42.9 mmol) in anhydrous THF (200 mL) was added 95% NaH (3.25 g, 128.7 mmol). The mixture was stirred at room temperature for 0.5 hours. Example 267A (16.2 g, 64.35 mmol) in THF (50 mL) was added dropwise to the above mixture. The reaction was run overnight, and was poured into water (1.5 L). Concentrated hydrochloric acid (30 mL) was added dropwise to neutralize the mixture. The precipitate was filtered, recrystallized from ethanol (100 mL), and dried in vacuo to give the desired product (14.08 g, 73%). MS (APCI) m / z 451 (M + H) +; H NMR (300 MHz, CDCl 3) d ppm 3.82 (s, 2 H) 3.98 (s, 3 H) 5.21 (s, 2 H) 6.99 (s, 1 H) 7.30-7.42 (m, 5 H) 7.44-7.50 (m, 2 H) 7.59-7.65 (m, 2H) 7.74-7.81 (m, 2H).
EXAMPLE 267D 7- (Benzylloxy) -3- (4-bromophenyl) -6-methoxy-1,4-dihydroindene f 1, 2-cT pyrazole Example 267C (14.08 g, 31.2 mmol), hydrazine monohydrate were mixed (3.03 mL, 62.4 mmol), absolute ethanol (300 mL), and glacial acetic acid (3.57 ML, 62.4 mmol) and refluxed for 24 hours. The reaction cooled. The precipitate was filtered, washed with water (30 mL x 2), and ethanol (30 mL x 2), and dried under vacuum overnight to give the desired product (11.66 g, 84%). MS (ESI) m / z 448 (M + H) \ Example 267E 7- (Benzyloxy) -3- (4-bromophenyl) -6-methoxy-1-. { r2- (Trimethylsilyl) ethoxymethyl) -1,4-dihydroxydenof1,2-c1parazol To a mixture of Example 267D (11.66 g, 26.1 mmol) and DMF (500 mL) in an ice bath was added 95% NaH (0.69 g, 27.41 mmol). The mixture was stirred at room temperature for 0.5 hours and then cooled to 0 ° C. 2- (Trimethylsilyl) ethoxymethyl chloride (4.85 mL, 27.41 mmol) was added to the mixture. After 0.5 hours, the ice bath was removed. The reaction was run at room temperature for another hour, and then it was poured into water. Ethyl acetate (200 mLx3) was used to extract the product. The organic solution was dried with MgSO 4, concentrated, and purified by flash chromatography to give the desired product (10.84 g, 72%). MS (DCI / NH3) m / z 577 (M + H) + Example 267F 4 '- (7- (Benzyloxy) -6-methoxy-1 - (2- (trimethylsilyl) ethoxy-1-methyl) -1,4-dihydroindenoH, 2-c1pyrazol-3-yl) -1,1-biphenyl-4 -ol Example 267E (518 mg, 0.896) was mixed together mmol), dichlorobis (triphenylphosphine) palladium (II) (63 mg, 0.090 mmol), 4- (hydroxyphenyl) boronic acid (147.3 mg, 1.07 mmol), a solution of 1M Na2CO3 (1 mL), DME / EtOH / H20 ( 7: 2: 3, 3 mL) and a stir bar in a capped tube. The mixture was heated at 160 ° C for 5 minutes in a Smith Sintentizer. The reaction was repeated 19 times. The solution was combined, and concentrated. The residue was puirified by flash chromatography to give the desired product (4.69 g, 47%). MS (DCI / NH3) m / z 591 (M + H) + Example 267G 7- (Benzyloxy -6-methoxy-3 - ((2- (trimethylsilyl) ethoxy-1-methoxy> -1, 1'-biphenyl-4-yl) -1 -. {2- (trimethylsilyl) ethoxymethoxy} -1, 4-dihydroindenoyl, 2-c1 pyrazole To the solution of Example 267F (4.66 g, 7.9 mmol) in DMF (200 mL) was added 95% NaH (0.21 g, 8.28 mmol) The mixture was stirred at room temperature for 0.5 hours 2- (Trimethylsilyl) ethoxymethyl chloride (1.49 mL, 8.28 mmol) was added dropwise The reaction was stirred for 1 hour The DMF was removed The residue was treated with water (200 mL ) and extracted with ethyl acetate (200 mL) The organic phase was dried with MgSO 4, and purified by flash chromatography to give the desired product (4.31 g, 76%) MS (DCI / NH3) m / z 722 (M + H) + EXAMPLE 267H 6-Methoxy-3- (4'-fr2-ftrimethylsilyne-methoxymethoxy -1,1-biphenyl-4-in-1- { F2- (tr.methyl) ethyl) ethoxymethanol-1,4-dihydroindenofl 2-cl pyrazole-7-ol Example 267G (4.20 g, 5.82 mmol), 10% Pd / C (2.1 g, 2 mmol), and THF (100 mL) were mixed. The reaction was stirred under H2 (4218 kg / cm2) at room temperature for 3 days. Flash chromatography was used to purify the desired product (2.67 g, 71%). MS (DCI / NH3) m / z 631 (M + H) + Example 2671 4W6-ethoxy-7- (2-pyrrolidin-1-ylethoxy) -1,4-dihydroindene, 2-cl pyrazole-3-in-biphenyl-4-ol Example 267H (50 mg, 0.079 mmol) was mixed , 1- (2-chloroethyl) pyrrolidine hydrochloride (20 mg, 0.118 mmol), Cs2CO3 (77 mg, 0.238 mmol), and DMF (2 mL) in a bottle and shaken at 60 ° C overnight. The LC-MS indicated that the reaction was complete. The mixture was filtered and concentrated. To the residue was added ethanol (2 mL) and concentrated hydrochloric acid (2 mL). The reaction was heated at 50 ° C for 5 hours. The mixture was concentrated, and purified by HPLC to give the desired product.
Examples 268 and 284 represented by Figure (XVI) and shown in Table 16 were synthesized in a similar manner as described in Example 267.
H Figure (XVI) TABLE 16 25 Example 285 3- (4'-Hydroxy-1,1'-biphenyl-4-yl) -6-methoxy-1,4-dihydroindenoH, 2-cTpyrazol-7-ol To Example 267H (33.3 mg, 0.053 mmol ) were added ethanol (2 mL) and concentrated hydrochloric acid (2 mL). The reaction was stirred at 50 ° C for 5 hours. The mixture was concentrated, and purified by HPLC to give the desired product (18 mg, 57%). MS (ESI) m / z 371 (M + H) +; 1 H NMR (400 MHz, DMSO-D 6) 5 ppm 3.74 (s, 2 H) 3.82 (s, 3 H) 6.86 (d, J = 8.90 Hz, 2 H) 7.07 (s, 1 H) 7.16 (s, 1 H) 7.55 (d , J = 8.59Hz, 2H) 7.69 (d, J = 8.29Hz, 2H) 7.81 (d, J = 8.59Hz, 2H) 9.56 (s, 1H) EXAMPLE 286 3- (4'-Hydroxy-1, 1 '-biphenyl-4-yl) -6-methoxy-N-r2- (4-methylpiperazin-1-yl) etin-1,4-dihydroindenoyl, 2-c1p Razol-7-carboxamide EXAMPLE 286A 6-Methoxy-3- (4'-. {R2- (trimethylsirinetoxymethoxy> -1, 1'-biphenyl-4-yl) -1-f G2- (trimethyl-4-yl) trifluoromethanesulfonate ethoxymethyl) -1, 4-dihydroindenori, 2-cl irazol-7-yl To the solution of Example 267H (1.29 g, 2.04 mmol) in THF (10 mL) at room temperature was added 95% NaH % (51.6 mg, 2.04 mmol) The mixture was stirred for half an hour, and N-phenyltrifluoromethane sulfonamide (0.88 g, 2.45 mmol) was added.The reaction mixture was stirred at 40 ° C overnight. it was purified by flash chromatography to give the desired product (1.80 g, 100%) MS (APCI) m / z 763 (M + H) + EXAMPLE 286B 3- (4'-H -droxy-1, 1'-b-phenyl-4-yl) -6-methoxy-N-r2- (4-methylpiperazin-1-yl) etin-1.4- dihydroindenori, 2-c1pyrazole-7-carboxamide Example 286A (40 mg, 0.0524 mmol), 2- (4-methylpiperazin-1-yl) ethylamine (75 mg, 0.524 mmol), triethylamine (143 pL) were mixed. , 1.048 mmol), PdCI2 (dppf) (10 mg, 0.00132 mmol), and dichloromethane (5 mL) under CO (7.03 kg / cm2) at 100 ° C for 5 days. The reaction was cooled, and the pressure was released. The solution was concentrated. Ethanol (2 mL) and hydrochloric acid were added concentrated (2 ml_). The reaction was stirred at 50 ° C for 5 hours. The mixture was concentrated, and purified by HPLC to give the desired compound.
Examples 287 to 299 represented by Figure (XVII) and shown in Table 17 were synthesized in a manner similar to that described in Example 286B using the appropriate amine in place of 2- (4-methiipiperazin-1-yl) ethylamine .
Figure (XVII) TABLE 17 Example - i -R2 'H-NMR MS m / z Weight and Rend. 280 -. 280 H 1 H NMR (500 MHz, DMSO-MS 24 mg D ") d ppm 2.85 (s, 3H) (ESI) 87% 3.543.63 (m, 4H) 3.73-3.79 m / z 524 (m, 8H) 3.96 (s, 2H) 3.99 (s, (M + H) + 3H) 6.88 (d, J = 8.54 Hz, 2H) 7.44 (s, 1H) 7.57 (d, J = 8.54 Hz, 2H) 7.73 (d, J = 8.54Hz, 2H) 7.84 (d, J = 8.54Hz, 2H) 8.11 (s, 1H) 8.63 (s, 1H) 25 EXAMPLE 300 4'- 6-Methoxy-7-f (4-methylene-1,4-diazepan-1-yl) carbonyl-1, 4-dihydroindenon, 2-cTpyrazol-3-yl) -1, 1'-biphenyl -4-ol The title compound was synthesized in a manner similar to the decsrite in Example 286B using 1-methyl-1,4-diazepam instead of 2- (4-methylpiperazin-1-y)) ethylamine, 22 mg 85% yield. MS (ESI) m / z 495 (M + H) +; 1H NMR (500 MHz, DMSO-D6) d ppm 1.92-2.10 (m, 2H) 2.92 (s, 3H) 3.14-3.30 (m, 4H) 3.35-3.60 (m, 4H) 3.89 (s, 2H) 3.94 ( s, 3H) 6.88 (d, J = 8.42 Hz, 2H) 7.38 (s, 1H) 7.54-7.60 (m, 3H) 7.73 (d, J = 8.42 Hz, 2H) 7.84 (d, J = 8.42 Hz, 2H ) 9.69 (s, 1H).
EXAMPLE 301 6-Methoxy-3-. { 4-r3- (1-Methylpyrrolidin-2-yl-oxo-phenyl) -7- (2-piperidin-1-ylethoxy) -1,4-dihydroindenofl, 2-clirazole Example 301A 4- (benzyloxy) benzoate phenyl Phenyl ester of 4-hydroxy-benzoic acid ( 23. 3 mnol), benzyl bromide (5.54 mL, 46.7 mmol), K2C03 (9.6 g, 70.0 mmol), and anhydrous acetone (200 mL) and refluxed overnight. All the acetone was removed. Water (300 mL) was added to the mixture. The solid was filtered, washed with methanol (50 mLx3), and dried to give the desired compound (6.63 g, 93%). S (DCI) m / z 305 (M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 5.17 (s, 2 H) 7.30-7.09 (m, 2 H) 7.17-7.23 (m, 2 H) 7.27 (m, 1 H) 7.347.48 (m, 7 H) 8.13-8.19 ( m, 2H) Example 301B 5-Methoxy-6- (2-pyridin-1-ylethoxy) ndan-1-one Example 144B (5348, 30 mmol), 1- (2-chloro-ethyl) -piperidine hydrochloride were mixed. (11.0 g, 60 mmol), K2C03 (16.6 g, 120 mmol), and acetonitrile (150 mL) and refluxed for 3 days. The reaction mixture was filtered. The filtrate was concentrated, and purified by flash chromatography to give the desired product (6.92 g, 80%). MS (ESI) m / z 290 (M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 1.40-1.49 (m, 2H) 1.55-1.65 (m, 4H) 2.45-2.57 (m, 4. H) 2.63-2.70 (m, 2H) 2.84 (t, J = 6.27Hz, 2H) 3.013.08 (m, 2H) 3.94 (s, 3H) 4.18 (t, J = 6.44Hz, 2H) 6.88 (s, 1 H) 7.20 (s, 1H) Example 301C 3-r4- (Benzyloxy) phenin-6-methoxy-7- (2-piperidin-1-ylethoxy) -1,4-dihydroindene, 2-clirazole Example 301A (7.16 g, 24.00 mmol) was mixed, the example 301B (6.92 g, 23.92 mmo!), 95% NaH (1.82 g, 72 mmol) and benzene (100 mL) and refluxed overnight. The reaction mixture was cooled to room temperature, and the benzene was removed. Acetic acid (10 mL), ethanol (100 mL) and hydrazine monohydrate (10 mL) were added. The mixture was refluxed for 2 hours, and then cooled. All solvents were removed. The residue was treated with water (200 mL). The precipitate was filtered, washed with water (100 mL x 3) and ethyl acetate (100 mL x 3), and dried to give the desired product (7.71 g, 85%). MS (ESI) m / z 496 (M + h) +; 1H NMR (300 MHz, CD3OD) d ppm 1.44-1.55 (m, 2H) 1.59-1.70 (m, 4H) 2.60-2.67 (m, 4H) 2.87 (t, J = 5.76Hz, 2H) 3.75 (s, 2H ) 3.89 (s, 3H) 4.23 (t, J = 5.76Hz, 2H) 5.15 (s, 2H) 7.11 (d, J = 8.81Hz, 2H) 7.24 (s, 1H) 7.29-7.41 (m, 4H) 7.43 -7.48 (m, 2 M 7.69 (d, J = 9.15Hz, 2H) Example 301D 3-r4- (Benzyloxy-Henin-6-methoxy-7- (2-piperidin-1-ylethoxy) -1 -. {12- (trimethylsilyl) ethoxymethyl) -1,4-dihydroindenoH, 2-c] pyrazole To the solution of Example 301C (7.71 g, 15.56 mmol) in DMF (200 mL) was added 95% NaH (0.412 g, 16.34 mmol). After 0.5 hours, 2- (trimethylsilyl) ethoxymethyl chloride (2.89 mL, 16.34 mmol) was added dropwise. Then the reaction was run at room temperature for 2 hours. The entire DMF was removed. The residue was purified by flash chromatography to give the desired product (5.50 g, 56%). MS (APCI) m / z 626 (M + H) + EXAMPLE 301E 4- (6-Methoxy-7- (2-pyridin-1-ylethoxy-1-t r 2 - (tr ymethylsilyl) ethoxymethyl) -1,4- dihydroindenoH, 2-c1pyrazole-3 -il) phenol The mixture of Example 301D (5.50 g, 8.79 mmol) and 10% Pd / C (1.15 g, 1.09 mmol) in THF (100 mL) was treated with H2 (4218 kg / cm2) at room temperature for 2 hours. The mixture was filtered, the solution was concentrated, and purified by flash chromatography to give the desired product (4.0 g, 85%) MS (ESI) m / z 536 (+ H) + Example 301 F 6-Methoxy-3-f4-r3- (1-methylpyrrolidin-2-yl) -propoxylphenyl ') - 7- (2-piperidin-1-ylethoxy) -1,4-dihydroindenof 1,2- cTpirazole Example 301E (54 mg, 0.10 mmol), (1-methyl-pyrrolidin-2-yl) -propan-1 -ol (29 mg, 0.20 mmol), PPh3 of supported polymer (50 mg, 0.15 mmol) was mixed. , di tert-butyl azodicarboxylate (34.5 mg, 0.15 mmol), and THF (3 mL) and stirred at room temperature for 4 days. The resin was filtered, and the solution was concentrated. To the residue was added a solution of 2N HCl (1 mL) and ethanol (1 mL). The reaction was at 50 ° C for 8 hours, and concentrated. The residue was purified by HPLC to give the desired product (24 mg, 46%). MS (EST) m / z 517 (M + H) +; 1H MR (500 MHz, CD3OD) d ppm 1.58 (m, 1H) 1.79-1.91 (m, 5H) 1.96-2.05 (m, 3H) 2.06-2.20 (m, 3H) 3.08-3.15 (m, 3H) 3.35 ( s, 3H) 3.55-3.62 (m, 4H) 3.743.77 (m, 4H) 3.82 (s, 2H) 3.94-3.98 (m, 3H) 4.39-4.44 (m, 2H) 7.08-7.13 (m, 2H) 7.34 (s, 1H) 7.40 (s, 1H) 7.71-7.75 (m 2H) Example 302 1 -. { 4-r6-Methoxy-7- (2-piperidin-1-ylethoxy) -1,4-dihydroindenoM, 2-d pyrazole-3-inphenoxy} acetone Example 302 was synthesized in a lar manner as Example 30 F, substituting (1-methyl-pyrrolidin-2-yl) -propan-1 -ol with 1-hydroxy-propan-2-one (19 mg, 41%) . MS (ESI) m / z 462 (? +?) ?? NMR (500 MHz, CD3OD) d ppm 1.58 (m, 1H) 1.79-1.91 (m, 3H) 1.97-2.06 (m, 2H) 2.25 (s, 3H) 3.06-3.16 (m, 2H) 3.56-3.63 (m , 2H) 3.75 (d, J = 12.16Hz, 2H) 3.81 (s, 2H) 3.95 (s, 3H) 4.39-4.44 (m, 2H) 4.79 (s, 2H) 7.06 (d, J = 9.04Hz, 2H ) 7.33 (s, 1H) 7.40 (s, 1H) 7.71 (d, J = 8.73Hz, 2H) Example 303 r4- (6,7-Dimethoxy-1,4-dihydroindenori, 2-cT-irazol-3-yl) phenin methane! Example 243B (70 mg, 0.20 mmol), bis (triphenylphosphine) dichloropalladium (14.3 mg, 0.020 mmol), 3-hydroxymethyl-phenyl boronic acid (36 mg, 0.24 mmol), DME / EtOH / H20 (7: 2: 3, 3 mL), and a solution of 1M Na2CO (1 mL_) under N2. The reaction mixture was heated to 160 ° C for 600s on a Smith Synthesizer. After the reaction, the mixture was dried, and purified by HPLC to give the desired product (17 mg, 26%). MS (ESI) m / z 323 (M + H) +; 1 H NMR (400 MHz, DMSO-De) d ppm 3.76 (s, 2H) 3.82 (s, 3H) 3. 84 (s, 3H) 4.54 (s, 2H) 7.21 (s, 1H) 7.24 (s, 1H) 7.61 (d, J = 8.29Hz, 2H) 7.74 (d, J = 8.29Hz, 2H) EXAMPLE 304 3- (4-Cyanophenin-6-methoxy-N- (pyridin-4-methylmethyl) -1,4-dihydroindeneM, 2-c1pyrazol-7-carboxamide Example 304A Phenyl 4-C-benzoate 4-Cyano-benzoic acid (10.0 g, 68.0 mmol), phenol was mixed (6.40 g, 68.0 mmol), DCC (14.73 g, 71.4 mmol), DMAP (0.25 g, 2.04 mmol) and ether (200 mL), and stirred at room temperature for 3 days. The ether stirred. To the residue was added CH2Cl2 (200 mL). The solid was filtered. The filtrate was concentrated, and purified by flash chromatography to give the desired product (12.41 g, 82%). MS (DCI / NH3) m / z 224 (+ H) +; 1 H N R (300 Hz, CDCl 3) d ppm 7.19-7.25 (m, 2H) 7.31 (m, 1H) 7.41-7.50 (m, 2H) 7.80-7.85 (m, 2H) 8.29-8.34 (m, 2H) EXAMPLE 304B 6-Methoxy-3-oxo-2,3-dihydro-1 H-inden-5-yl trifluoromethanesulfonate trifluoromethanesulfonate To the solution of Example 144B (4.86 g, 27.3 mmol) in THF (136 mL) at room temperature 95% NaH (0.690 g, 27.3 mmol) was added. The temperature rose to 40 ° C. After 0.5 hours, N-Phenyltrifluoromethanesulfonimide (11.69 g, 27.3 mmol) was added. The temperature was maintained at 40 ° C overnight under N2. The THF was removed. The residue was purified by flash chromatography to give the title compound (8.47 g, 100%). MS (DCI / NHg) m / z 311 (+ H) +; 1 H NMR (300 Hz, CDCl 3) d ppm 2.69-2.76 (m, 2 H) 3.11-3.18 (m, 2 H) 4.01 (s, 3 H) 7.07 (s, 1 H) 7.60 (s, 1 H) Example 304C 6-Methoxy-3-o odandan-5-carboxylic acid Example 304B (8.47 g, 27.3 mmol), PdC12 (dppf) (0.21 g, 0.331 mmol), triethylamine (19.0 mL, 136.5 mmol), THF were mixed. (200 mL) and water (50 mL) and stirred at room temperature under N2 for 10 minutes. Then the reaction system was charged with CO (35.15 kg-cm2). The temperature was raised to 110 ° C for 16 hours. The solvents were removed, and the residue was purified by flash chromatography to give the desired product (5.35 g, 95%). MS (ESI) m / z 207 (M + H) +; 1H NMR (300 MHz, CD3OD) d ppm 2.63-2.69 (m, 2H) 3.10-3.16 (m, 2H) 3.99 (s, 3H) 6.99 (s, 1H) 8.26 (s, 1H) Example 304D Methyl 6-methoxy-3-oxoindan-5-carboxylate Example 304C (5.35g, 25.94 mmol) was dissolved in methanol (100 mL). Concentrated H2SO4 (10 drops) was added. The mixture It led to reflux during the night. The reaction was cooled, and the methanol was removed. A saturated solution of NaHCO 3 (100 ml_) and CH 2 Cl 2 (100 mL) was added. The organic layer was separated, and dried with MgSO4. The organic solution was concentrated, and purified by flash chromatography to give the desired product (3.00 g, 48%). MS (DCI / NH3) m / z 221 (M + H) +; H NMR (300 MHz, CD3OD) d ppm 2.66-2.73 (m, 2H) 3.15-3.22 (m, 2H) 3.87 (s, 3H) 3.98 (s, 3H) 7.26 (s, 1H) 8.05 (s, 1H) Example 304E 3- (4-Cyanophenyl) -6-methoxy-1,4-dihydroindenone, methyl 2-cl pyrazole-7-carboxylate Example 304D (0.92 g, 4.18 mmol), Example 304A (1.74 g, 6.27 mmol), 95% NaH (0.32 g, 12.54 mmol) and benzene (50 mL), and were heated to reflux overnight. The benzene was removed. Ethanol (50 mL), acetic acid (3 mL) and hydrazine monohydrate (3 mL) were added. The mixture was refluxed for 2 hours. The mixture was cooled, and the solvents were removed. Water (50 mL) was added to the residue. The precipitate was filtered, washed with water (10 mL x 3) and ethyl acetate (10 mL x 3), and dried to give the above intermediate (0.925 g, 64%). MS (ESI) m / z 346 (M + H) +; 1 H NMR (400 MHz, DMSO-D 6) d ppm 3.82 (s, 3 H) 3.90 (s, 3 H) 3.97 (s, 2 H) 7.44 (m, 1 H) 7.87-8.05 (m, 5 H) 13.42 (m, 1 H) Example 304F 3- (4-Cyanophenyl) -6-methoxy-1,4-dihydro-mannitolH, 2-clirazole-7-carboxylic acid Example 304E (0.925 g, 2.66 mmol) was dissolved in DMF (90 ml_). To this solution was added a solution of LiOH (1.28 g, 54 mmol) in water (10 ml_). The solution was stirred at room temperature for 4 days. All solvents were removed by a vacuum pump. A solution of 2N HCl was added until the pH was equal to 2. The yellow precipitate was filtered, washed with water (2 ml_x2), and dried to give the above intermediate (0.75 g, 72%). MS (ESI) m / z 332 (M + H) +; H NMR (500 MHz, DMSO-D6) d ppm 3.90 (s, 3H) 3.96 (s, 2H) 7.41 (s, 111) 7.92 (s, 1H) 7.94-8.00 (m, 4H) EXAMPLE 304G 3- (4-Cyanophenyl) -6-methoxy-N- (pyridin-4-ylmethin-1,4-dihydroindenon, 2-clp-aceol-7-carboxamide Example 304F (50 mg , 0.136 mmol), PiBrop (65.3 mg, 0.140 mmol), O-pyridin-4-yl-methylamine (15 mg, 0.14 mmol), DIEA (49 pL, 0.28 mmol) and DMF (2 mL) were mixed, and The mixture was stirred overnight, the solvent was removed, the residue was washed with water (2 mLx2), methanol (2 ml_x2) and ethyl acetate (2 ml_x2), and dried to give the title compound (20 mg, 35%). MS (ESI) m / z 422 (M + H) +; 1H NMR (500 MHz, DMSO-D6) d ppm 3.89 (s, 2H) 3.99 (s, 3H) 4.56 (d, J = 5.93Hz, 2H) 7.34 (d, J = 5.30 Hz, 2H) 7.45 (s, 1H) 7.948.00 (m, 5H) 8.52 (d, J = 4.05Hz, 2H) 8.86 (s, 1H) 13.39 (s, 1H) EXAMPLE 305 3- (4-Cyanophenyl) -N- (trans-4-hydroxy-cyclohexyl) -6-methoxy-1,4-dihydroindene, 2-c1pyrazole-7-carboxamide Example 305 was synthesized in one form similar to that of Example 304G, replacing O-pyridin-4-yl-methylamine with trans-4-amino-cyclohexanol (9 mg, 15%). MS (ESI) m / z 429 (M + H) +; 1H NMR (500 MHz, DMSO-D6) d ppm 1.22-1.40 (m, 4H) 1.81-1.93 (m, 4H) 3.43 (m, 1H) 3.75 (m, 1H) 3.90-4.05 (m, 5H) 7.40 ( m, 1H) 7,948.00 (m, 5H) 13.37 (m, 1H) Example 3Q6 4-r6-Methoxy-7- (pyridin-3-ylmethoxy) -1,4-dihydroindenori. 2-pyrazole-3-illbenzonitrile Example 306A Phenyl 4-Bromobenzoate 4-Bromo-benzoic acid (32.83 g, 163.3 mmol), phenol (15.37 g, 163.3 mmol), DCC (35.38 g, 171.46 mmol), DMAP (0.40 g, 4.9 mmol) were mixed and ether (500 ml_), and stirred at room temperature for 3 days. The ether stirred. CH2Cl2 (1 L) was added. The suspension was filtered. The filtrate was concentrated, and purified by flash chromatography to give the above intermediate (33.14 g, 73%). MS (DCI / NH) m / z 278 (M + H) +; H NMR (300 MHz, CDCl 3) d ppm 7.18-7.23 (m, 2H) 7.29 (d, J = 7.46Hz, 1H) 7.407.47 (m, 2H) 7.63-7.69 (m, 2H) 8.04-8.09 (m , 2H) Example 306B 5-Methoxy-6- (pyridin-3-ylmethoxy) indan-1-one Example 144B (1.00 g, 5.61 mmol), 3-chloromethyl-pyridine hydrochloride (1.84 g, 11.22 mmol), K2C03 ( 3.88 g, 28.10 mmol) and acetone (50 mL), were stirred, and were heated to reflux overnight. The reaction mixture was then filtered. The filtrate was concentrated, and purified by flash chromatography to give the above intermediate (1.23 g, 81%). MS (ESI) m / z 270 (M + M +); H NMR (300 Hz, CD3OD) d ppm 2.62-2.67 (m, 2H) 3.043.11 (m, 2H) 3.95 (s, 3H) 5.19 (s, 2H) 7.13 (s, 1H) 7.27 (s, 1H) 7.46 (dd, J = 7.80, 4.07Hz, 1H) 7.96 (m, 1H) 8.50 (dd, J = 4.92, 1.53Hz, 1H) 8.65 (d, J = 1.36Hz, 1H).
Example 306C 3- (4-Bromophenyl) -6-methoxy-7- (pyridin-3-ylmethoxy) -1,4-dihydroindenorM, 2-clirazole Example 306B (1.10 g, 4.08 mmol), Example 306A ( 2.26 g, 8.17 mmol), 95% NaH (0.41 g, 16.34 mmol) and benzene (100 mL), were stirred, and heated to reflux for 3 hours. The solvent was removed. Ethanol (100 mL), acetic acid (3 mL) and hydrazine monohydrate (3 mL) were added. The mixture was refluxed for another 2 hours. All solvents were removed. Water (100 mL) was added to the residue. The suspension was filtered, washed with water (30 mLx3), ethyl acetate (30 mLX3), and dried to give the above product (1.70 g, 93%). MS (ESI) m / z 449 (M + H) +; 1H NMR (400 MHz, DMSO-D6) d ppm. 3.76 (s, 2H) 3.83 (s, 3H) 5.22 (s, 2H) 7.25 (s, 1H) 7.35 (s, 1H) 7.43 (dd, J = 7.83, 4.76Hz, 1H) 7.60-7.80 (m, 4H ) 7.88 (d, J = 7.98Hz, 2H) 8.54 (dd, J = 4.91, 1.53Hz, 1H) 8.68 (d, J = 1.84Hz, 1 H) 13.08 (s, 1 H).
Example 306D 4-r6-Methoxy-7- (pyridin-3-ylmethoxy) -1,4-dihydroindenoM, 2-cl pyrazole-3-illbenzonitrile Example 306C (75 mg, 0.167 mmol), Pd (PPh3) (20 mg, 0.0167 mmol), Zn (CN) 2 (230 mg, 2.00 mmol) and DMF (4 mL), were pumped with N2, stirred, and heated at 180 ° C for 5 minutes on a Smith Synthesizer. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by HPLC to give the title compound (40.0 mg, 61%). MS (ESI) m / z 395 (M + H) +; 1H N MR (400 MHz, DMSO-DB) d ppm 3.84 (s, 2H) 3.86 (s, 3H) 5.36 (s, 2H) 7.30 (s, 1H) 7.41 (s, 1H) 7.92 (dd, J = 7.82 , 5.37Hz, 1H) 7.96 (s, 4H) 8.44 (d, J = 7.98Hz, 1H) 8.81 (d, J = 4.91Hz, 1H) 8.93 (s, 1H) Example 307 4-. { 7-r 2 - (Dimethylamino) ethoxy-1-6-methoxy-1,4-dihydroindenof 1,2-cl pyrazol-3-yl} benzonitrile Example 307A 6-r 2 - (Dimethylamino) ethoxy-5-methoxy-1-na-n Example 144B (1.00 g, 5.61 mmol), hydrochloride were mixed of (2-chloro-ethyl) -dimethyl-amine (1.62 g, 11.22 mmol), K2CO3 (3.88 g, 28.10 mmol) and acetone (50 mL) were stirred, and were heated to reflux overnight. The reaction mixture was then filtered. The filtrate was concentrated, and purified by flash chromatography to give the above intermediate (1.20 g, 86%). MS (ESI) m / z 250 (M + H) +; 1H NMR (300 MHz, CD3OD) d ppm 2.37 (s, 6H) 2.62-2.68 (m, 2H) 2.82 (t, J = 5.43Hz, 2H) 3.05-3.10 (m, 2H) 3.93 (s, 3H) 4.14 (t, J = 5.43Hz, 2H) 7.09 (s, 1H) 7.19 (s, 1H).
Example 307B N- (2-f r3- (4-Bromophenyl) -6-methoxy-1,4-dihydroindenon, 2-dpyrazol-7-haloxy) ethyl) -N, N-dimethanol Example 307A was mixed (0.678, 2.69 mmol), Example 306A (1498, 5.38 mmol), 95% NaH (0.27 g, 10.7 mmol) and benzene (100 mL) were stirred, and heated to reflux for 3 hours. The solvent was removed. Ethanol (100 mL), acetic acid (3 mL) and hydrazine monohydrate (3 mL) were added. The mixture was refluxed for another 2 hours. All solvents were removed through a vacuum pump. To the residue was added methanol (100 mL) and K2CO3 (10 g). The suspension was stirred for 1 hour, and filtered. The filtrate was concentrated, and purified by flash chromatography to give the above intermediate (0.94 g, 82%). MS (ESI) m / z 429 (M + H) +; 1H NMR (500 MHz, CD3OD) d ppm 2.39 (s, 6H) 2.83 (t, J = 5.46Hz, 2H) 3.71 (s, 2H) 3.88 (s, 3H) 4.18 (t, J = 5.61Hz, 2H) 7.20 (s, 1 H) 7.30 (s, 1H) 7.61 (d, J = 8.42Hz, 2H) 7.65 (d, J = 8.42Hz, 2H) Example 307C 4-. { 7-r2- (Dimethylamino) ethoxy-1-6-methoxy-1,4-dihydroindenoH, 2-cy1-pyrazol-3-yl} Benzonitrile Example 307B (73 mg, 0.170 mmol), Pd (PFh3) 4 (20 mg, 0.0167 mmol), Zn (CN) 2 (230 mg, 2.00 mmol) and DF (4 mL) were mixed with N2. , were shaken, and heated at 180 ° C for 5 minutes on a Smith Synthesizer. The reaction mixture was filtered. The filtrate was concentrated. The residue was purified by HPLC to give the title compound (38.0 mg, 60%). MS (ESI) m / z 375 (M + H) +; 1H NMR (400 MHz, CD3OD) d ppm 3.07 (s, 6H) 3.61-3.67 (m, 2H) 3.88 (s, 2H) 3.97 (s, 3H) 4.40-4.47 (m, 2H) 7.37 (s, 1H) 7.43 (s, 1H) 7.85 (d, J = 8.29 Hz, 2H) 7.94 (d, J = 8.29Hz, 2H) Example 308 4-r6-ethoxy-7- (irdin-4-ylmethoxy) -1,4-dihydroindenori, 2-c1-irazole-3-ylbenzonitrile EXAMPLE 308A 5-Methoxy-6- (pyridin-4-methoxy) ndan-1 -o na Example 144B (1.00 g, 5.61 mmol), 4-chloromethyl-pyridine hydrochloride (1.84 g, 11.22 mmol) were mixed. , K2CO3 (3.88 g, 28.10 mmol) and acetone (50 mL) were stirred, and heated to reflux overnight. The reaction mixture was then filtered. Filtering it was concentrated, and purified by flash chromatography to give the above intermediate (1.44 g, 95%). MS (ESI) m / z 270 (M + H) +; 1H NMR (300 MHz, CD3OD) d ppm 2.62-2.68 (m, 2H) 3.06-3.10 (m, 2H) 3.98 (s, 3H) 5.22 (s, 2H) 7.14 (s, 1H) 7.21 (s, 1H) 7.54 (d, J = 6.10Hz, 2H) 8.515.55 (m, 2H) Example 308B 3- (4-Bromophenyl) -6-methoxy-7- (pyridin-4-ylmethoxy) -1,4-dihydroindene, 2-clirazole Example 308A (0.54 g, 2.00 mmol) was mixed, Example 306A (1.11 g, 4.00 mmol), 95% NaH (0.38 g, 16.0 mmol) and benzene (70 mL) were stirred, and heated to reflux overnight. The solvent was removed. Ethanol (70 mL), acetic acid (3 mL) and hydrazine monohydrate (3 mL) were added. The mixture was refluxed for another 2 hours. All solvents were removed through a vacuum pump. Water (100 mL) was added to the residue. The suspension was filtered, washed with water (20 mL x 3) and ethyl acetate (20 mL x 3), and dried to give the above product (0.82 g, 91%). MS (ESI) m / z 449 (M + H) +; 1 H NMR (400 MHz, DMSO-D 6) d ppm 3.76 (s, 2 H) 3.87 (s, 3 H) 5.27 (s, 2 H) 7.25-7.33 (m, 2 H) 7.47 (d, J = 6.14 Hz, 2 H) 7.71 (s, 4H) 8.55-8.62 (m, 2H) 13.08 (s, 1H) EXAMPLE 308C 4-r6-Methoxy-7- (pyridin-4-methoxy) -1,4-dihydroindenoM, 2-cl-pyrazol-3-yl-1-benzonitrile Example 308B (75 mg, 0.167 mmol), Pd (PPh3) was mixed. 4 (20 mg, 0.0167 mmol), Zn (CN) 2 (0.230 g, 2.00 mmol) and DF (4 mL) were purged with N2, stirred, and heated at 180 ° C for 5 minutes on a Smith Synthesizer. The reaction mixture was filtered. The filtrate was concentrated. DMSO (2.5 mL) was added, and the suspension was stirred for 0.5 hour. The precipitate was then filtered, washed with water (5 mLx3) and ethyl acetate (5 mLx3), and dried in vacuo to give the title compound (35 mg, 53%). MS (ESI) m / z 395 (M + H) +; H NMR (300 MHz, DMSO-D6) d ppm 3.84 (s, 2H) 3.88 (s, 3H) 5.28 (s, 2H) 7.28 (s, 1H) 7.33 (s, 1H) 7.47 (d, J = 6.10Hz , 2H) 7.92-8.01 (m, 4H) 8.60 (d, J = 5.76Hz, 2H) 13.30 (s, 1H) EXAMPLE 309 4'-r6-Methoxy-7- (trifluoromethoxy) -1,4-dihydro-1,2-cl-irazol-3-n-1.1'-biphenyl-4-ol Example 309A 0- (6-Methoxy-3-oxo-2,3-dihydro-1 H-inden-5-yl) S-methyl dithiocarbonate To a stirred solution of Example 144E (1.18 g, 6.6 mmol) in DMF (60 mL ) 95% NaH (0.20 g, 7.95 mnol) at 0 ° C was slowly added. Then the resulting mixture was stirred at temperature At room temperature for 1 hour, CS2 (0.79 mL, 13.2 mmol) was added dropwise at 0 ° C. The resulting mixture was stirred for 10 hours at room temperature before adding iodomethane (0.49 mL, 7.92 mmol) dropwise to the reaction mixture at 0 ° C. The resulting mixture was stirred for 1 hour at room temperature. All solvents were removed. The residue was separated through flash chromatography to give the above intermediate (0.80 g, 45%). MS (DCI / NH3) m / z 269 (M + H) + ¡1H MR (300 Hz, CDCI3) d ppm 2.65-2.74 (m, 5H) 3.09-3.17 (m, 2H) 3.90 (s, 3H) 7.01 (s, 1H) 7.44 (s, 1H) EXAMPLE 309B 5- Ethoxy-6- (trifluoromethoxyndan-1-one) To the suspension of 1,3-dibromo-5,5-dimethylhydantoin (0.83 g, 2.91 mmol) in CH 2 Cl 2 in a flask dried with flames at -78 ° C 70% HF / pyridine (2 mL) was added dropwise to this mixture, Example 309A (0.26 g, 0.97 mmol) in dichloromethane (5 mL) was added, then the dry ice bath was replaced with a bath of an ice-cold NaCl solution The red-brown mixture was stirred for 0.5 hour and diluted with ethyl ether NaHS03 / NaHCO3 / NaOH was used to adjust the pH to 10. Ethyl ether (100 mL) was added. ) to extract the product The extraction solution was dried with concentrated MgSO4, and separated through flash chromatography to give the above intermediate (79.7 mg, 33%) MS (APCI) m / z 247 (M + H) + Example 309C 3- (4-Bromophenin-6-methoxy-7- (trifluoromethoxy-1,4-dihydroindene M, 2-clirazole) Example 309B (80 mg, 0.325 mmol), Example 306A (180 mg, 0.65 mmol), 95% NaH (66 mg, 2.60 mmol), and benzene (10 mL) were refluxed overnight, then all the solvent was removed, ethanol (10 mL), acid was added to the residue. acetic acid (2 mL), and hydrazine monohydrate (2 mL) The mixture was refluxed for 2 hours.The purification of flash chromatography was used to give the above intermediate (45.3 mg, 33%). ) m / z 425 (M + H) +; H NMR (300 MHz, DMSO-D6) d ppm 3.89 (s, 2H) 3.92 (s, 3H) 7.68-7.75 (m, 4H) 7.83-7.89 (m, 2H) Example 309D 4'-f6-Methoxy-7- (trifluoromethoxyH-j, 4-dihydroindenof, 2-cl pyrazol-3-ylM.1'-biphenyl-4-ol) Example 309C (41.6 mg, 0.098 mmol) was mixed , dichlorobis (triphenylphosphine) palladium (6.9 mg, 0.0098 mmol), (4-hydroxyphenyl) boronic acid (16.2 mg, 0.118 mmol), D ME / EtOH / H20 (7: 2: 3, 3 mL), and a solution of 1M Na 2 CO 3 (1 mL), were heated at 160 ° C for 10 minutes on a Smith Synthesizer, all solvents were removed, the residue was purified by HPLC to give the title compound (9.0 mg, 42%). (ESI) m / z 439 (M + H) +; 1H NMR (400 MHz, DMSO-D6) d ppm 3.88-3.95 (m, 5H) 6.87 (d, J = 8.90 Hz, 2H) 7.52 (s, 1H) 7.557.58 (m, 3H) 7.72 (d, J = 8.59Hz, 2H) 7.84 (d, J = 8.61Hz, 2H) Example 312 4 '- (6-orpholin-4-yl-1,4-dihydroindene, 2-c1pyrazol-3-yl) -1, 1'-bifenyl-4-? Example 312A 5-Morpholin-4-ylindan-1 -one A mixture of 5-bromo-1-indanone (0.76 g, 3.60 mmol), Cs2C03 (1.64 g, 5.04 mmol), Pd2 (dba) 3 (82 mg, 0.09 mmol), BINAP (112 mg, 0.18 mmol), morpholine (0.94 mL, 10.8 mmol) and THF (15 mL) was pumped with N2 for 0.5 hour and then heated to reflux overnight. The reaction mixture was concentrated, and purified by flash chromatography to give the above intermediate (0.40 g, 51.1%). MS (ESI) m / z 218 (M + H) +; H MR (300 MHz, CD3OD) d ppm. 2.59-2.65 (m, 2H) 3.03-3.10 (m, 2H) 3.34-3.40 (m, 4H) 3.79-3.85 (m, 4H) 6.95 (s, 1H) 6.99 (m, 1H) 7.57 (d, J = 8.48Hz, 1 H).
Example 312B 3- (4-Bromophenyl) -6-morpholin-4-yl-1,4-dihydroindenoH, 2-clirazole Example 312A (0.390 g, 1.80 mmol), Example 306A (0.746 g, 2.69 mmol), 95% NaH (0.136 g, 5.38 mmol) and bezene (40 mL) were mixed and refluxed for 3 hours. After everything the benzene was removed. To the residue were added ethanol (30 ml_), acetic acid (2.5 ml_) and hydrazine monohydrate (2.5 ml_). The mixture was refluxed for hours. Once again, all liquid reagents were removed using a vacuum pump. Water (50 mL) was added. The precipitate was washed with water (20 ml_x2) and ethyl acetate (10 mLx2), and dried under vacuum to give the above intermediate (0.464 g, 65%). MS (ESI) m / z 396 (M + H) +; H NMR (300 MHZ, DMS-D6) d ppm 3.13-3.20 (m, 4H) 3.73-3.81 (m, 6H) 6.95 (dd, J = 8.48, 2.37Hz, 1H) 7.19 (d, J = 2.03Hz, 1H) 7.49 (d, J = 8.14Hz, 1H) 7.68 (d, J = 8.48 Hz, 2H) 7.65-7.80 (m, 2H) 13.03 (s, 1H) Example 312C 4 '- (6-orpholin-4-yl-1,4-dihydroindenori, 2-clirazol-3-yn-1, 1'-biphenyl-4-ol Example 312B (60 mg, 0.151 mmol) was mixed , (4-hydroxyphenyl) boronic acid (25 mg, 0.182 mmol), Pd (PPh3) 2CI2 (10.6 mg, 0.015 mmol), DME / EtOH) H20 (7: 2: 3, 3 mL) and a solution of 1 M Na 2 CO 3 (1 mL) was capped, and heated at 160 ° C for 10 minutes on a Smith Synthesizer. All solvents were removed. The residue was purified by HPLC to give the title compound (29 mg, 47%). MS (ESI) m / z 410 (M + H) +; H NMR (500 MHz, DMSO-D6) d ppm 3.14-3.21 (m, 4H) 3.73-3.81 (m, 4H) 3.83 (s, 2H) 6.87 (d, J = 8.73Hz, 2H) 6.96 (dd, J = 8.42, 2.18Hz, 1H) 7.21 (s, 1H) 7.51 (d, J = 8.42Hz 1H) 7.56 (d, J = 8.73Hz, 2H) 7.71 (d, J = 8.42Hz, 2H) 7.82 (d, J = 8.42Hz, 2H) 9.56 (s, 1H).
Example 313 3-Methoxy-4 '- (6-morpholin-4-yl-1,4-dihydroindenof 1,2-cl pyrazolo-3-iQ-1,1'-biphenyl-4-ol Example 313 was synthesized in a form similar to that of Example 312C, substituting (4-hydroxyphenyl) boronic acid with 2-methoxy-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -phenol (41 mg, 62%) MS (ESI) m / z 440 (M + H) +; 1 H NMR (500 MHz, DMSO-D6) 5 ppm 3.14-3.21 (m, 4H) 3.73-3.81 (m, 4H) 3.83 (s, 2H) 3.88 (s, 3H) 6.87 (d, J = 8.11Hz, 1H) 6.97 (dd, J = 8.58, 2.03Hz, 1H) 7.16 (dd, J = 8.11, 2.18Hz, 1H) 7.21 (s, 1H) 7.26 (d, J = 1.87Hz, 1H) 7.52 (d, J = 8.42Hz, 1H) 7.75 (d, J = 8.42Hz, 2H) 7.83 (d, J = 8.42Hz, 2H).
Example 314 4- (6-Morph olin-4-tl-, 4-dihydroindenon, 2-cTpyrazol-3-in-benzonitrile Example 312B (60 mg, 0.151 mmol), Pd (PPh3) 4 (17.5 mg, 0.015 mmol), Zn (CN) 2 (213 mg, 1.82 mmol), and DMF (4 mL), and were purged with N2 for 10 minutes, the reaction mixture was capped, stirred, and heated at 18 ° C. 5 minutes on a Smith Synthesizer After the reaction, the reaction mixture was filtered, and the filtrate was concentrated The residue was purified by HPLC to give the title compound (33 mg, 64%) MS (ESI) ) m / z 343 (M + H) +; 1H NMR (500 MHz, DMSO-D6) d ppm 3.17-3.24 (m, 4H) 3. 74-3.82 (m, 4H) 3.85 (s, 2H) 7.00 (dd, J = 8.42, 1.87Hz, 2H) 7.23 (s, 1H) 7.52 (d, J = 8.42Hz, 1H) 7.908.01 (m, 4H).
EXAMPLE 315 4-R5- (6-Morpholin-4-yl-1,4-dichloride, 2-c1pyrazol-3-pyridin-2-ylphenol Example 315A 3- (6-Chloropyridin-3-yl) -6-morpholin-4-yl-, 4-dihydroindenolM, 2-c1pyrazole Example 312A (403 mg, 1.85 mmol), Example 230A (963 mg) was mixed. , 4.63 mmol), 95% NaH (187 mg, 7.40 mmol) and THF (20 ml_) and stirred under N2 overnight. The THF was removed. To the residue was added ethanol (60 ml_), acetic acid (3 ml_) and hydrazine monohydrate (3 ml). The mixture was refluxed for 2 hours, and then cooled. The reaction mixture was concentrated. Water (30 mL) was added. The light yellow precipitate was washed with water (20 mLx2) and ethyl acetate (5 mLx2), and vacuum dried to give the above intermediate (0.514 g, 79%). MS (ESI) m / z 353 (M + H) +; 1H NMR (400 MHz, D SO-D6) d ppm 3.13-3.19 (m, 4H) 3.72-3.78 (m, 4H) 3.82 (s, 2H) 6.95 (dd, J = 8.59, 1.53Hz, 1 H) 7.18 (s, 1H) 7.48 (s, 1H) 7.64 (s, 1H) 8.20 (d, J = 8.29Hz, 1H) 8.81 (d, J = 2.15Hz, 1H) 13.17 (s, 1H).
Example 315B 4-5 5 - (6-Morpholin-4-yl-1,4-dihydroindene, 2-cl-irazol-3-in-pyridin-2-illphenol Example 315A (60 mg, 0.151 mmol), acid (4 mg) was mixed. -hydroxyphenyl) boronic (25 mg, 0.182 mmol), Pd (PPh3) 2Cl2 (10.6 mg, 0.015 mmol), DME / EtOH / H20 (7/2/3, 3 mL) and 1M Na2C03 (1 mL) and warmed at 160 ° C for 10 minutes on a Smith Synthesizer The solvents were removed The residue was purified by HPLC to give the title compound (29 mg, 47%) MS (ESI) m / z 411 (M + H) +; 1H NMR (500 MHz, DMSO-D6) d ppm 3.14-3.21 (m, 4H) 3.73-3.81 (m, 4H) 3.88 (s, 2H) 6.90 (d, J = 8.73Hz, 2H) 6.98 (dd, J = 8.26, 2.03Hz, 1H) 7.23 (s, 1 H) 7.52. (d, J = 8.42Hz, 1H) 8.00 (t, J = 9.04Hz, 3H) 8.24 (dd, J = 8.42, 2. 8Hz, 1H) 9.00 (d, J = 1.87Hz, 1H) 9.85 (s, 1H).
Example 316 2- ethoxy-4-r5- (6-morpholin-4-yl-1,4-dihydroindenof1,2-c1 pi razo 1-3-ihpyridin-2-infenol Example 316 was synthesized in a similar manner as of Example 315B, substituting (4-hydroxyphenyl) boronic acid with 2-methoxy-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -phenol (76 mg, 61%) MS (ESI) m / z 441 (M + H) +; 1H NMR (500 MHz, DMSO-D6) d ppm 3.14-3.21 (m, 4H) 3.73-3.81 (m, 4H) 3.88 (s, 2H) 3.89 (s, 3H) 6.91 (d, J = 8.11Hz, 1H) 6.98 (dd, J = 8.42, 1.87Hz, 1H) 7.23 (s, 1H) 7.52 (d, J = 8.42Hz, 1H) 7.60 (dd, J = 8.26, 2.03Hz, 1H) 7.74 (d, J = 1.87Hz, 1H) 8. 05 (d, J = 8.42Hz, 1H) 8.23 (dd, J = 8.42, 2.18Hz, 1H) 9.01 (d, J = 2.18Hz, 1H).
Example 317 5- (6-Morpholin-4-yl-1,4-dihydroindenon, 2-c1-irazol-3-yl) pyridine-2-carbonitrile Example 315A (100 mg, 0.283 mmol), Pd (PPh3) were mixed. 4 (33 mg, 0.0283 mmol), Zn (CN) 2 (332 mg, 2.83 mmol), and DMF (4 mL) and pumped with N2 for 10 minutes. The reaction mixture was stirred, and heated at 180 ° C for 5 minutes on a Smith Synthesizer. After the reaction, the solution was filtered, and the solvent was removed. The residue was purified by HPLC to give the title compound (39 mg, 40%). S (ESI) m / z 344 (M + H) +; 1H NMR (500 MHz, DMSO-D6) d ppm 3.14-3.21 (m, 4H) 3.73-3.81 (m, 4H) 3.89 (s, 2H) 6.98 (dd, J = 8.42, 2.18Hz, 1H) 7.22 (d , J = 1.56Hz, 1H) 7.51 (d, J = 8.t Hz, 1H) 8.13 (d, J = 8.11Hz, 1H) 8.35 (dd, J = 8.11, 2.18Hz, 1H) 9.15 (d, J = 1.56Hz, 1H).
Example 318 5- (6,7-Diisopropoxy-1,4-dihydroinderium, 2-clpyrazol-3-in pyridine-2-carbonitrile Example 318A 5,6-Diisopropoxydandan-1-one Example 144A (0.445 g, 2.70 mmol), 2-bromo- Propane (0.64 mL, 6.77 mmol), Cs 2 CO 3 (2.20 g, 6.77 mmol) and DMF (20 mL) were stirred and heated at 60 ° C for 8 hours. The reaction mixture was then filtered. The solution was concentrated, and dried to give the desired intermediate (0.67g, 100%). S (DCI / NH3) m / z 249 (M + H) +; 1H NMR (300 MHz, CD3OD) 6 ppm 1.32 (d, J = 6.10Hz, 6H) 1.38 (d, 1 = 6.10Hz, 6H) 2.61-2.68 (m, 2H) 3.03-3.09 (m, 2H) 4.51 ( m, 1H) 4.75 (m, 1H) 7.08 (s, 1H) 7.18 (s, 1H).
EXAMPLE 318B 3- (6-Chloropyridin-3-yl) -6,7-diisopropoxy-1,4-dihydroxydene, 2-py pyrazole Example 318A (0.67 g, 2.70 mmol), Example 230A ( 1.12 g, 5.40 mmol), 95% NaH (0.26 g, 10.8 mmol) and benzene (30 mL) were stirred and heated to reflux for 4 hours. All the solvent was removed. To the residue were added ethanol (70 mL), acetic acid (5 mL) and hydrazine monohydrate (5 mL). The reaction mixture was heated to reflux for 2 hours. Then the solvents were removed. Water (50 mL) was added. The precipitate was filtered, washed with water (20 mL x 3) and ethyl acetate (20 mL x 3), and dried under vacuum to give the above intermediate (0.60 g, 58%). MS (ESI) m / z 384 (+ H) +; 1H NMR (500 MHz, DMSO-D6) d ppm 1.25-1.33 (m, 12H) 3.72-3.85 (m, 2H) 4.45-4.60 (m, 2H) 7.15-7.28 (m, 2H) 7.63 (m, 1H) 8.21 (m, 1H) 8.81 (s, 1H) 13.23 (s, 1H).
Example 318C 5- (6,7-Diisopropoxy-1,4-dihydroindene, 2-c1pyrazol-3-yl iridin-2-carbonitrile) Example 318B (100 mg, 0.261 mmol), Pd (PPh3) 4 (30.1 mg, 0.0261 mmol), Zn (CN) 2 (0.367 g, 3.126 mmol) and DMF (5 mL), purged with N2, stirred, and heated at 180 ° C for 5 minutes on the Smith Synthesizer. The solution was concentrated, DIVISO (2.5 mL) was added, the suspension was filtered, the precipitate was washed with ethyl acetate (2 mLx3), and dried to give the title compound (19.4 mg, 20%). (ESI) m / z 375 (M + H) +; 1H NR (500 Hz, D S-D6) d ppm 1.25-1.31 (m, 12H) 3.86 (s, 2H) 4.45-4.60 (m, 2H) 7.17 -7.30 (m, 2H) 88.13 (m, 1H) 8.34 (m, 1H) 9.13 (en, i H) 13.39 (m, 1H).
Example 319 4-f5- (6,7-Di-oxo-1,4-dihydroindenori, 2-cT-irazol-3-yl) pyridin-2-illphenol Example 318B (100 mg, 0.26 mmol) was mixed , (4-hydroxyphenyl) boronic acid (43 mg, 0.313 mmol), Pd (PP 3) 2CI2 (18 mg, 0.026 mmol), DME / EtOH / H20 (7: 2: 3, 3 mL) and a solution of 1 Na 2 CO 3 (1 mL), were capped, and heated at 160 ° C for 10 minutes on a Smith Synthesizer. Then all the solvents were removed. The residue was purified by HPLC to give the title compound (16.4 mg, 14%). MS (ESI) m / z 442 (M + H) +; 1H NMR (500 MHz, DMSO-D6) d ppm 1.24-1.31 (m, 12H) 3.81 (s, 2H) 4. 46-4.57 (m, 2H) 6.89 (d, J = 8.73Hz, 2H) 7.22 (d, J = 9.36Hz, 2H) 7.95-8.01 (in, 3H) 8.20 (dd, J = 8.42, 2.18Hz, 1H 8.99 (d, J = 1.87Hz, 1H) 9.80 (s, 1H).
Example 320 4-f5- (6,7-Diisopropoxy-1,4-dihydroindenori, 2-clpyrazol-3-yl) pyridin-2-n-2-methoxyphenol Example 320 was synthesized in a similar manner as Example 319, substituting (4-hydroxyphenyl) boronic acid with 2-methoxy-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -phenol (65.4 mg, 53%) . MS (ESI) m / z 472 (M + M +; 1H NMR (500 MHz, DMSO-D6) d ppm 1.23-1.30 (rn, 12H) 3.82 (s, 2H) 3.88 (s, 3H) 4.464.57 (m, 2H) 6.89 (d, J = 8.42Hz, 1H) 7.22 (d, J = 9.04Hz, 2H) 7.56-7.62 (m, 3H) 7.73 (d, J = 2.18Hz, 1H) 8.03 (d, J = 8.42Hz, 1H) 8.20 (dd, J = 8.42.2.18Hz, 1H) 8.99 (d, J = 2.18Hz, 1H).
Example 321 5-f6- (Tetrahydro-2H-pyran-4-noxn-1,4-dihydroindenof 1,2-cT pyrazole-3-inpyridin-2-carbonitrile Example 321A 5- (Tetrahydro-2H-pyran-4-yloxy) indan-1 -o na 5-Hydroxy-1-indanone (0.636 g, 4.30 mmol), tetrahydro-pyran-4-ol (1.22 mL, 12.80 g. mmol), PPh3 of supported polymer (2.864 g, 8.59 mmol), DBAD (1.978 g, 8.59 mmol) and THF (40 ml_), and stirred overnight. The mixture was filtered, and washed with THF (10 ml_x3). The filtrate was concentrated. The residue was purified by flash chromatography to give the above intermediate (0.85 g, 85%). MS (APCI) m / z 233 (+ H) +; 1H NMR (300 MHz, CD3OD) d ppm 1.79-1.89 (m, 2H) 2.01-2.12 (m, 2H) 2.62-2.69 (m, 2H) 3.07-3.15 (m, 2H) 3.85-4.00 (m, 4H) 4.75 (m, 1H) 6.97 (dd, J = 8.65.2.20 Hz, 1H) 7.08 (s, 1H) 7.63 (d, J = 8.48Hz, 1H) EXAMPLE 321 B 3- (6-Chloro-iridin-3-yl) -6- (tetrahydro-2H-pyran-4-Hoxy) -1,4-dihydroindeneM, 2-cl irazole Example 321A (0.85 g, 3.66 g. marble), Example 230A (1.52 g, 7.32 nmol), 95% NaH (0.37 g: 14.64 nmol) and benzene (40 ml_), was stirred, and heated to reflux for 4 hours. The mixture was concentrated. To the residue was added ethanol (40 mL), acetic acid (5 mL) and hydrazine monohydrate (5 mL). The reaction mixture was heated to reflux for 2 hours. All solvents were removed. Water (50 mL) was added to the residue. The precipitate was filtered, washed with water (30 mL x 3) and ethyl acetate (30 mL x 3), and dried in vacuo to give the desired intermediate (0.70 g, 28%). MS (ESI) m / z 368 (M + H) +; 1H NMR (400 MHz, DMSO-D6) d ppm 1.56-1.62 (m, 2H) 1.95-2.04 (m, 2H) 3.46-3.55 (m, 2H) 3.82-3.91 (m, 4H) 4.62 (m, 1H) 6.99 (dd, J = 8.59.2.15Hz, 1H) 7.23 (d, J = 1.84Hz, 1H) 7.54 (d, J = 7.98Hz, 1H) 7.64 (d, J = 8.29Hz, 1H) 8.22 (dd, J = 8.29.2.45Hz, 1H) 8.82 (d, J = 2.15Hz, 1H) 13.25 (s, 1H).
Example 321C 5- (Tetrahydro-2H-pyran-4-yloxy) -1,4-dihydroindenoH, 2-clirazol-3-illpyridin-2-carbonyl ester Example 321B (100 mg, 0.27 mmol), Pd ( PPh3) 4 (31 mg, 0.027 mmol), Zn (CN) 2 (0.383 g, 3.26 mmol) and DMF (5 mL), were purged with N2, stirred, and heated at 180 ° C for 5 minutes in a Smith synthesizer. The reaction mixture was filtered. The solution was concentrated. DMSO (2.5 mL) was added. The suspension was filtered. The precipitate was washed with ethyl acetate (2 mLx3), and dried to give the title compound (19.4 mg, 20%). MS (ESI) m / z 359 (+ H) +; 1H NMR (500 Hz, DMSO-D6) d ppm 1.56-1.62 (m, 2H) 1.94-2.03 (m, 2H) 3.46-3.54 (m, 2H) 3.82-3.91 (m, 4H) 4.62 (m, 1H) 7.00 (d, J = 7.49Hz, 1H) 7.23 (s, 1H) 7.52 (m, 1H) 8.10 (m, 1H) 8.35 (d, J = 7.49Hz, 1H) 9.14 (s, 1H) 13.42 (m, 1 HOUR).
Example 322 4-. { 5-r6- (Tetrahydro-2H-pyrn-4-yloxy) -1,4-dihydroquinone, 2-cTpyrazol-3-inpyrdin-2-yl} phenol Example 321B (100 mg, 0.27 mmol), (4-hydroxyphenyl) boronic acid (45 mg, 0.326 mmol), Pd (PPh3) 2 Cl2 (19 mg, 0.027 mmol), DME / EtOH / H20 (7: 2: 3, 3 mL) and 1M Na 2 CO 3 (1 mL), and heated at 160 ° C for 10 minutes on a Smith Synthesizer. All solvents were removed. The residue was purified through HPLC to give the title compound (31.7 mg, 28%). MS (ESI) m / z 426 (M + H) +; 1H NR (300 MHz, DMSO-D6) d ppm 1.57-1.64 (m, 2H) 1.95-2.04 (m, 2H) 3.47-3.54 (m, 2H) 3.82-3.91 (m, 4H) 4.63 (m, 1H) 6.87-6.71 (m, 2H) 6.99 (dd, J = 8.48, 2.37Hz, 1H) 7.24 (d, J = 2.03Hz, 1H) 7.55 (d, J = 8.14Hz, 1H) 7.948.02 (m, 3H ) 8.19 (dd, J = 8.48, 2.37Hz, 1H) 9.01 (d, J = 1.70 ??, '1H).
EXAMPLE 323 2-Methoxy-4-f5-re- (tetrahydro-2H-pyran-4-yloxy) -1,4-dihydroindene G1, 2-cT-irazol-3-yl-1-pyridin-2-yl} phenol Example 323 was synthesized in a similar manner as in Example 322, substituting (4-hydroxyphenyl) boronic acid with 2-methoxy-4- (4,4,5,5-tetramethyl-, 3,2-dioxaborolan-2- il) -phenol (56 mg, 46%). MS (ESI) m / z 456 (M + H) +; 1H NMR (300 MHz, DMSO-D6) d ppm 1.58 1.66 (m, 2H) 1.942.04 (m, 2H) 3.46-3.53 (m, 2H) 3,843.92 (m, 4H) 4.63 (m, 1H) 6.90 (d, J = 8.48Hz, 1H) 6.99 (dd, J = 8.48, 2.37Hz, 1H) 7.25 (d, J = 2.37Hz, 1H) 7.56 (d, J = 8.48Hz, 1H) 7.60 (dd, J = 8.14, 2.03Hz, 1H) 7.75 (d, J = 2.03Hz, 1H) 8.04 (d, J = 8.48Hz, 1H) 8.20 (dd, J = 8.65, 2.15Hz, 1H) 9.01 (d, J = 2.37 Hz, 1H) 9.35 (s, 1H).
Example 324 5- (6-lsopropoxy-1,4-di idroindenon .2-cTpyrazol-3-yl) pyridine-2-carbonitrile Example 324A Phenyl 6-chloronicotinate 6-chloro-nicotinic acid (31.67 g, 201 mmol), phenol (18.92 g, 201 mmol), DCC (43.55 g, 211 mmol), DMAP (0.737 g, 6.03 mmol) were mixed and ether (500 mL), and stirred under N2 at room temperature for 3 days. Then the ether was removed. CH2Cl2 (1000 mL) was added to the residue. The precipitate of urea was filtered. The solution was concentrated, and purified by flash chromatography to give the desired intermediate (37 g, 79%). MS (DCI / NH3) m / z 234 (M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 7.19-7.34 (m, 3 H) 7.41-7.53 (m, 3 H) 8.39 (dd, J = 8.14.2.37 Hz, 1 H) 9.17 (d, J = 2.03 Hz, 1 H).
Example 324B 5-lsopropoxyindan-1-one 5-hydroxy-indanone (0.665 g, 4.68 mmol), 2-bromo-propane (0.88 mL, 9.36 mmol), Cs2CO3 (3.05 g, 9.36 mmol) and DF (50 g) were mixed. mL), were stirred, and heated at 60 ° C overnight. The reaction was filtered. The solution was concentrated, and dried to give the above intermediate (0.89 g, 100%). MS (DCI / NH3) m / z 191 (M + H) +; 1 H NMR (300 MHz, CD 3 OD) d ppm. 1.35 (d, J = 6.10Hz, 6H) 2.62-2.69 (m, 2H) 3.07-3.15 (m, 2H) 4.75 (m, 1H) 6.91 (dd, J = 8.48, 2.03Hz, 1 H) 7.01 (s, 1H) 7.61 (d, J = 8.48Hz, 1H) .
Example 324C (A-833748. 0) 3- (6-Chloropyridin-3-yl-6-isopropoxy-1,4-dihydroindene, 2-pyrazole Example 324B (0.89 g, 4.68 mmol) was mixed, Example 324A (1.64 g, 7.02 mmol), 95% NaH (0.355 g, 14.64 mmol) and benzene (50 mL) were stirred and refluxed for 4 hours, the mixture was concentrated. added ethanol (150 mL), acetic acid (10 mL) and hydrazine monohydrate (10 mL) The reaction mixture was heated to reflux for 2 hours All the solvents were removed Water was added to the residue (100 mL) The precipitate was filtered, washed with water (30 mL x 3) and ethyl acetate (30 mL x 3), and dried under vacuum to give intermediate 58 C (1.01 g, 66%) MS (ESI) m / z 326 ( M + H) +; H NMR (500 MHz, DMSO-De) d ppm 1.30 (d, J = 6.24Hz, 6H) 3.85 (s, 2H) 4.66 (m, 1H) 6.93 (dd, J = 8.11, 2.18 Hz, 1H) 7.16 (d, J = 2.18Hz, 1H) 7.53 (d, J = 8.11Hz, 1H) 7.64 (d, J = 8. I 1Hz, 1H) 8.22 (dd, J = 8.11, 2.50 Hz, 1H) 8.82 (d, J = 2.50 Hz, 1H) 13.24 (s, 1 HOUR).
EXAMPLE 324D 5- (6-lsopropoxy-1,4-dihydroindenori, 2-cT-irazol-3-yl) iridin-2-carbonitrile Example 324C (100 mg, 0.31 mmol), Pd (PPh 3) 4 were mixed. (36 mg, 0.031 mmol), Zn (CN) 2 (0.43 g, 3.68 mmol) and D F (5 mL), were pumped with N2, stirred, and heated at 180 ° C for 5 minutes on the Smith Synthesizer. The reaction mixture was filtered. The filtrate was concentrated. DIVISO (2.5 mL) was added to the residue. The suspension was filtered. The precipitate was washed with ethyl acetate (2 mLx3), and dried to give the title compound (53.6 mg, 55%). MS (ESI) m / z 317 (M + H) +; 1H NMR (500 MHz, DMSO-D6) d ppm 1.30 (d, J = 6.24Hz, 6H) 3.89 (d, J = 14.66Hz, 2H) 4.67 (m, 1H) 6.94 (d, J = 8.11Hz, 1H ) 7.17 (s, 1H) 7.54 (s, 1H) 8.11 (s, 1H) 8.36 (dd, J = 8.11, 1.87Hz, 1H) 9.15 (s, 1H) 13.43 (s, 1H).
Example 325 4-r5- (6-lsopropoxy-1,4-dihydroindenof 1,2-clirazol-3-inpyridin-2-illphenol Example 324C (100 mg, 0.31 mmol), (4-hydroxyphenyl) boronic acid ( 51 mg, 0.37 mmol), Pd (PPh3) 2Cl2 (22 mg, 0.031 mmol), DE / EtOH / H20 (7/2/3, 3 mL) and 1 Na2C03 (1 mL), were capped, and heated to 160 ° C for 10 minutes on a Smith Synthesizer All solvents were removed The residue was purified by HPLC to give the title compound (43 mg, 36%) MS (ESI) m / z 384 (M + H) +; 1H NMR (500 MHz, DMSO-D6) d ppm 1.30 (d, J = 5.93Hz, 6H) 3.89 (s, 2H) 4.67 (m, 1H) 6.89 (d, J = 8.73Hz, 2H) 6.92 (dd, J = 8.11, 2.18Hz, 1H) 7.17 (s, 1H) 7.54 (d, J = 8.11Hz, 1H) 7.96 (d, J = 8.42Hz, 1H) 8.00 (d, J = 8.73Hz, 2H) 8.18 (dd, J = 8.26.2.34Hz, 1 H) 9.01 (d, J = 2.18Hz, 1H) 9.75 (s, 1H).
Example 326 4-r5- (6-lsopropoxy-1,4-dihydroindenoH, 2-cTp -razol-3-M) pyridin-2-l, 2-methoxyphenol Example 326 was synthesized in a similar manner as in Example 325, replacing (4-hydroxyphenyl) boronic acid with 2-methoxy-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -phenol (72 mg, 56%). MS (ESI) m / z 414 (M + H) +; 1 H NMR (500 MHz, D SO-D 6) d ppm 1.30 (d, J = 5.93Hz, 6H) 3.89 (s, 5H) 4.66 (m, 1H) 6.90 (d, J = 8.11Hz, 1H) 6.93 (dd) , J = 8.26, 2.34Hz, 1H) 7.17 (s, 1H) 7.55 (d, J = 8.42Hz, 1H) 7.60 (d, J = 8.26, 2.03Hz, 1 H) 7.74 (d, J = 2.18Hz, 1H) 8.03 (d, J = 8.42Hz, 1H) 8.21 (dd, J = 8.42, 2.18Hz, 1H) 9.01 (d, J = 2.18Hz, 1H) 9.35 (s, 1H).
Example 327 5- (6,7-Dietoxy-1,4-dihydroindenoM, 2-cTpyrazol-3-yl) pyridine-2-carbonitrile Example 327A 5.6-Dietoxündan-1 - or na Example 144A (0.56 g, 3.41 mmol), bromoethane were mixed. (2.55 mL, 34.1 mmol), Cs2C03 (3.33 g, 10.23 mmol) and DMF (20 mL), were stirred, and heated to 60 ° C in a capped tube at high pressure overnight. The reaction was then filtered. The solution was concentrated, and dried to give the desired intermediate (0.75 g, 100%). MS (APCl) m / z 221 (M + H) +.
EXAMPLE 327B 3- (6-Chloropyridin-3-yl) -6,7-diethoxy-1,4-dihydroindenoyl, 2 -prazole Example 327A (0.75 g, 3.41 mmol), Example 324A (1.60 g, 6.82 mmol), 95% NaH (0.344 g, 13.64 mmol) and benzene (50 mL) were mixed, stirred, and heated to reflux for 4 hours. The mixture was then concentrated. To the residue were added ethanol (150 mL), acetic acid (10 mL) and hydrazine monohydrate (10 mL). The reaction mixture was heated to reflux for 2 hours. All solvents were removed. Water (100 mL) was added to the residue. The precipitate was filtered, washed with water (30 mL x 3) and ethyl acetate (30 mL x 3), and dried under vacuum to give the above intermediate (0.57 g, 47%). MS (ESI) m / z 356 (+ H) +; 1H NMR (500 MHz, D SO-D6) d ppm 1.36 (q, J = 6.86Hz, 6H) 3.78 (s, 2H) 4.00-4.13 (m, 4H) 7.21 (d, J = 9.04Hz, 2H) 7.64 (d, J = 8.42Hz, 1H) 8.20 (dd, J = 8.27, 2.34Hz, 1H) 8.81 (d, J = 2.18Hz, 1H) 13.17 (s, 1H).
EXAMPLE 327C 5- (6,17-Dietoxy-1,4-dihydroindenori, 2-clpyrazol-3-yl) pyridine-2-carbonitrile. Example 327B (100 mg, 0.281 mmol) was mixed, Pd (PPh3) 4 (32 mg, 0.028 mmol), Zn (CN) 2 (0.40 g, 3.37 mmol) and. D F (5 mL), were pumped with N2, shaken, and heated at 180 ° C for 5 minutes on a Smith Synthesizer. The reaction mixture was filtered. The solution was concentrated. DIVISO (2.5 mL) was added to the residue. The suspension was filtered. The precipitate was washed with acetate of ethyl (2 ml_x3), and dried to give the title compound (82.1 mg, 84%). MS (ESI) m / z 347 (M + H) +; H NMR (400 MHz, DMSO-D6) d ppm 1.32-1.41 (m, 6H) 3.78-3.88 (en, 2H) 4.04-4.14 (m, 4H) 7.15-7.28 (m, 2H) 7.57 (m, 1H) 8.13 (m, 1H) 8.34 (t, J = 7.52Hz, 1H) 9.15 (m, 1H) 13.36 (s, 1H).
EXAMPLE 328 4-r5-α6,7-Dethoxy-1,4-dihydroquinone, 2-clpyrazol-3-yl) pyridin-2-yl phenol Example 327B (100 mg, 0.281 mmol) was mixed , (4-hydroxyphenyl) boronic acid (46 mg, 0.34 mmol), Pd (PPh3) 2 Cl2 (20 mg, 0.0281 mmol), DE / EtOH / H20 (7: 2: 3, .3 mL) and a solution of 1 NaC03 (1 mL), and heated at 160 ° C for 10 minutes on a Smith Synthesizer. All solvents were removed. The residue was purified by HPLC to give the title compound (34 mg, 29%). MS (ESI) m / z 414 (M + H) +; 1H NMR (400 MHz, DMSO-D6) S ppm 1.33-1.40 (m, 6H) 3.82 (s, 2H) 4.05-4.15 (m, 4H) 6.77-6.81 (m, 2H) 7.23 (d, J = 6.14Hz , 2H) 7.98-8.02 (m, 3H) 8.19 (dd, J = 8.29.2.46Hz, 1H) 9.00 (d, J = 1.53Hz, 1H) 11.13 (s, 1H).
Example 329 4-r5- (6,7-Dethoxy-1,4-dihydroindene, 2-cTpyrazol-3-yl) pyridin-2-n-2-methoxyphenol Example 329 was synthesized in a similar manner as in Example 328, substituting (4-idroxyphenyl) boronic acid with 2- methoxy-4- (4,4,5,5-tetramethyl-1, 3,2-d-oxaborolar-2-yl) -phenol (47 mg, 38%). MS (ESI) m / z 444 (M + H) +; 1H NMR (400 MHz, DMSO-D6) d ppm 1.33-1.40 (m, 6H) 3.82 (s, 2H) 3.89 (s, 3H) 4.05-4.15 (m, 4H) 6.90 (d, J = 8.29Hz, 114 ) 7.23 (d, J = 6.14Hz, 2H) 7.60 (d, J = 8.29, 2.15Hz, 1H) 7.72 (m, 1H) 8.03 (d, J = 8.29Hz, 1H) 8.19 (dd, J = 8.44, 2.30 Hz, 1H) 9.01 (d, J = 1, 84Hz, 1 H).
Example 330 5-f6,7-Bis (difluoromethoxy) -1,4-dihydroindenof 1,2-c1pyrazol-3-pyridine-2-carbonitrile Example 330A 5.6-Bis (difluoromethoxy) indan-1-one Example 144A (1266 g, 7.71 mmol), 2 CO 3 (4.26 g, 30.84 mmol) and DMF (100 mL) were mixed and stirred. CICHF2 (5,624 kg / cm2) was introduced to the reaction. The temperature was set at 85 ° C for 2 hours. After the reaction, the high pressure was released. The solvent was removed. The residue was purified by flash chromatography to give the above intermediate (1.10 g, 54%). MS (ESI) m / z 265 (M + H) +; H NMR (300 MHz, CD3OD) d ppm 2.69-2.76 (m, 2H) 3.133.20 (m, 2H) 6.61-7.27 (m, 2H) 7.46 (s, 1H) 7.55 (s, 1H).
Example 330B (A-835801. 0) 3-f6-Chloropyridin-3-yl) -6.7-bis (d-fluoro-methoxy) -1.4-dihydroindenofl, 2-clirazole Example 330A (0.55 g, 2.08 mmol) was mixed , Example 324A (0.974 g, 4.16 mmol), 95% NaH (0.21 g, 8.32 mmol) and benzene (50 mL) were stirred and refluxed for 4 hours, then the mixture was concentrated. they added ethanol (50 mL), acetic acid (5 mL) and hydrazine monohydrate (5 mL) The reaction mixture was heated to reflux for 2 hours All the solvents were removed Water was added to the residue (100 mL) The precipitate was filtered, and washed with water (30 mL x 3) .The solid was further purified by flash chromatography to give the above intermediate (89 mg, 11%) .S (ESI) m / z 400 (M + H) + Example 330C 5-r6,7-Bis (difluoromethoxy) -1,4-dihydroindene [1, 2-cl-irazol-3-in'-iridin-2-carbonitrile Example 330B (30 mg, 0.075 mmol) was mixed, Pd (PPh3) 4 (8.7 mg, 0.0075 mmol), Zn (CN) 2 (106 g, 0.901 mmol) and DMF (2 mL), were pumped with N2, stirred, and heated at 180 ° C for 5 minutes. in a Smith Synthesizer. The reaction mixture was filtered. The solution was concentrated. DIVISO (2.5 mL) was added to the residue. The suspension was filtered. The precipitate was purified by flash chromatography to give the title compound. title (22.7 mg, 78%). MS (ESI) m / z 400 (M + H) +; 1H NMR, (300 Hz, DMSO-D6) d ppm 4.02 (s, 2H) 6.99-7.57 (m, 2H) 7.62 (s, 2H) 8.18 (d, J = 7.80 Hz, 1H) 8.39 (dd, J = 8.14, 2.37Hz, 1 H) 9.18 (d, J = 2.03Hz, 1H) 13.74 (s, 1H).
Example 331 4- (5-r6,7-Bis (d-fluoro-methoxy) -1,4-dihydro-tri-N, 2-clirazol-3-yl-1-pyridin-2-yl} phenol Example 330B was mixed (30 mg, 0.075 mmol), (4-hydroxyphenyl) boronic acid (12.4 mg, 0.090 mmol), Pd (PPh3) 2 Cl2 (5.2 mg, 0.0075 mmol), DE / EtOH / H20 (7/2/3, 2.25 mL ) and 1M Na 2 CO 3 (0.75 mL), and heated at 160 ° C for 10 minutes on a Smith Synthesizer, all the solvents were removed, the residue was purified by HPLC to give the title compound (24 mg, 70%). MS (ESI) m / z 458 (M + H) +; 1H NMR (300 MHz, DMSO-D6) d ppm 3.99 (s, 2H) 6.85-6.92 (m, 2H) 6.98-7.57 (m, 2H ) 7.60-7.64 (m, 2H) 7.98-8.04 (m, 2H) 8.18 (m, 1H) 9.03 (d, J = 2.71Hz, 1H) 9.79 (s, 1H).
Example 332 5-G6-? H-1,2,4-triazol-1-methylmethyl) -1,4-dihydro-nitrile, 2-cTpyrazol-3-pyridine-2-carbonitrile Example 332A 5'-Bromo-2 ', 3'-dihydro-irof1,3-dioxolane-2,1'-indenol A mixture of 5-bromo-1-indanone (13.0 g, 61.8 mmol), acid p-Toluenesulfonic acid (23 mg, 0.12 mmol) and ethylene glycol (27.6 mL, 494.6 mmol) in benzene (140 mL) was refluxed for 24 hours, using a D.ean-Stark trap to remove the water. The mixture was cooled, poured into excess 5% sodium bicarbonate and extracted with toluene. The combined organic extracts were washed with brine, dried with MgSO 4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography using dichloromethane as the mobile phase to give the above intermediate. MS (DCWNH3): m / z 254, 256 () +.
EXAMPLE 332B 2 ', 3'-Dihydrospiro (1,3-dioxolan-2,1l-indenl-5'-yl methane) To a solution of Example 332A (13 g, 50.9 mmol) in tetrahydrofuran (150 mL) was added an solution of 2.5 n-butyl lithium in hexanes (30.5 mL, 76.4 mmol) dropwise at about -78 ° C. A solution of N, N-dimethylformamide (39.4 mL, 509.0 mmol) in tetrahydrofuran (40 mL) was then added. ) and the mixture was allowed to warm to room temperature.The mixture was poured into water and extracted with ethyl acetate.The combined organic extracts were washed with brine, dried over MgSO 4, filtered, and evaporated in vacuo. was redissolved in a mixture of tetrahydrofuran (15 mL) and methanoi (150 mL) and sodium borohydride (2.6 g, 68.7 mmol) was added in portions at about 0 ° C. The reaction mixture was stirred at room temperature. room temperature for about 2 hours, then the mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO 4), filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using hexane / ethyl acetate (2: 1) as the mobile phase to give the above intermediate. MS (DC1 / NH3): m / z 207 (+ H) *.
Example 332C 5- (Hydroxymethindan-1-one) A solution of Example 332B (8.0 g, 38.7 mmol) and p-toluenesulfonic acid (7.4 g, 38.7 mmol) in a mixture of water (20 mL) and acetone (85 mL) The mixture was concentrated in vacuo, diluted with water and neutralized through the careful addition of potassium carbonate (2.7 g, 19.4 nunol) .The precipitate was filtered, washed with a minimum of water and diethyl ether and dried under vacuum to give the above intermediate MS (DCI / NH3): m / z 180 (M + H) +.
EXAMPLE 332D (1-Oxo-2,3-dihydro-1 H-inden-5-yl) methyl methanesulfonate To a mixture of Example 332C (3.8 g, 23.6 mmol) and triethylamine (4.3 mL, 30.7 mmol) in tetrahydrofuran ( 50 mL) methanesulfonyl chloride (2.2 mL, 28.3 mmol) was added dropwise to about 0 ° C. After about 30 min of stirring at about 0 ° C, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO 4), filtered and evaporated under reduced pressure to give the above intermediate. MS (DCI / NH3): m / z 258 (M + NH4) +.
Example 332E 5- (1 H-1, 2,4-triazol-1-ylmethyl) indan-1 -o na To a suspension of Example 332D (5.6 g, 23.3 mmol) and potassium carbonate (6.4 g, 46.6 mmol) in ethanol (200 mL) was added 1-methylpiperazine (5.2 mL, 46.6 mmol) dropwise at about 0 ° C. The mixture was stirred at room temperature for about 3 hours, concentrated in vacuo, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried (MgSO 4), filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using dichloromethane / methanol (5: 1) as the mobile phase to give the above intermediate. MS (DCI / NH3): m / z 214 (M + H) +; 1H'NMR (500 MHz, CDCI3) d ppm 2.62 (t, J = 8Hz, 2H), 3.08 (t, J = 8Hz, 2H), 5.55 (s, 2H), 7.28 (d, J = 9Hz, 1H) , 7.42 (s, 1H), 7.63 (d, J = 9Hz, 1H), 8.01 (s, 1H), 8.75 (s, 1H).
Example 332F 3- (6-Chloropyridin-3-yl-6- (1H-1,2,4-triazol-1-methyl-1,4-dihydroindenon, 2-clirazole) Example 332E (250 mg. , 1.17 mmol), Example 324A (0.55 g, 2.35 mmol), 95% NaH (0.120 g, 4.69 mmol) and THF (50 mL), and stirred under N2 for 1 hour. The mixture was concentrated. To the residue was added ethanol (100 mL), acetic acid (5 mL) and hydrazine monohydrate (5 mL). The reaction mixture was refluxed for 2 hours, and then cooled to room temperature. All solvents were removed. Water (100 mL) was added to the residue. The precipitate was filtered, washed with water (30 mL x 3) and CCI 4 (30 mL x 3), and dried under vacuum to give the above intermediate (200.5 mg, 49%). MS (ESI) m / z 349 (M + H) +; 1 H NMR (400 MHz, D SO-D 6) d ppm 3.89 (s, 2 H) 5.47 (s, 2 H) 7.31 (d, J = 7.67 Hz, 1 H) 7.42 (m, 1 H) 7.50 (s, 1 H) 7.64 (d, J = 7.98Hz, 2H) 7.97 (d, J = 7.98Hz, 1H) 8.22 (dd, J = 8.44, 2.61Hz, 1H) 8.68 (s, 1H) 8.83 (d, J = 2.15Hz, 1 H).
Example 332G 5-f6- (H-1.2.4-triazol-1-ylmetin-1,4-dihydroindenon.2-c1pyrazol-3-illpyridin-2-carbonyl ester Example 332F (50 mg, 0.143 mmol), Pd was mixed (PPh3) 4 (16.5 mg, 0.0143 mnol), Zn (CN) 2 (0.200 g, 1.71 mmol) and DMF (2 mL), were pumped with N2, stirred, and heated at 180 ° C for 5 minutes in a Smith Synthesizer The reaction mixture was filtered. solution was concentrated. DMSO (2.5 mL) was added to the residue. The suspension was filtered. The precipitate was washed with ethyl acetate (2 ml_x3), and dried to give the title compound (33 mg, 68%). S (ESI) m / z 340 (M + H) +; 1H NMR (500 MHz, DMSO-D6) d ppm 3.91 (s, 2H) 5.45 (s, 2H) 7.28 (s, 1H) 7.45-7.65 (m, 3H) 7.95 (s, 1H) 8.33 (s, 1H) 8.65 (m, 1H) 9.11 (s, 1H) 13.60 (m, 1H).
EXAMPLE 333 4-f5-r6- (1H-1,2,4-triazol-1-ylmethin) -1,4-dihydroquinon-2-c1 pyrazol-3-inpyridin-2-yl} phenol Example 332F (50 mg, 0.143 mmol), (4-hydroxyphenyl) boronic acid (24 mg, 0.172 mmol), Pd (PPh3) 2 Cl2 (10 mg, 0.0143 mmol), DME / EtOH / H20 (7 / 2/3, 2 mL) and I NaC03 (1 mL), and heated at 160 ° C for 10 minutes on a Smith Synthesizer. All solvents were removed. The residue was purified by HPLC to give the title compound (29 mg, 50%). MS (ESI) m / z 407 (M + H) +; 1H NMR. (500 MHz, DMSO-D6) d ppm 3.93 (s, 2H) 5.48 (s, 2 H) 6.87-6.90 (m, 2H) 7.31 (d, J = 7.4.9Hz, 1H) 7.51 (s, 1H) 7.65 (d, J = 7.80 Hz, 1H) 7.968.01 (m, 4H) 8.20 (dd, J = 8.42, 2.18Hz, 1H) 8.69 (s, 1H) 9.01 (d, J = 2.18Hz, 1H) Example 334 4-r6-MH-1.2.4-tria2ol-1-ylmetin-1,4-dihydroindenori, 2-cT piarazol-3-illbenzonitrile Example 334A 3-4-Bromophenyl-6- (1H-1,2,4-tria2ol-1-ylmethyl-1,4-dihydroindenofl, 2-clirazole Example 332E (250 mg, 1.17 mmol) was mixed, phenyl brominated benzoate (0.65 g, 2.35 mmol), 95% NaH (0.120 g, 3. 4.69 mmol) and THF (50 mL), and stirred for 3 hours, the mixture was then concentrated. Ethanol (100 mL), acetic acid (5 mL) and hydrazine monohydrate (5 mL) The reaction mixture was heated to reflux for 2 hours, all the solvents were removed, water was added to the residue (100 mL). The precipitate was filtered, washed with water (30 mL x 3) and CCI 4 (30 mL x 3), and dried in vacuo to give the above intermediate (307 g, 67%) S (ESI) m / z 393 (+ H ) +; 1H NR (500 MHz, DMSO-D6) S ppm 3.85 (s, 2H) 5.48 (s, 2H) 7.30 (d, J = 7.80 Hz, 1H) 7.50 (s, 1H) 7.64 (d, J = 7.80 Hz, 1H) 7.69 (d, J = 8.11Hz, 2H) 7.76 (d, J = 8.11Hz, 2H) 7.99 (s, 1H) 8.68 (s, 1H) 13.30 (s, 1H).
Example 334B 4-G6-? H-1, 2,4-triazol-1-ylmethyl) -1,4-dihydroquinone H, 2-cl pyrazole-3-illbenzonitrile Example 334A (50 mg, 0.127 mmol), Pd (PPh3) were mixed. 4 (14.7 mg, 0.0127 mmol), Zn (CN) 2 (0.179 g, 1524 mmol) and D F (2 ml_), were purged with N2, stirred, and heated at 180 ° C for 5 minutes on a Smith Synthesizer. The reaction mixture was filtered. The solution was concentrated. DMSO (2.5 mL) was added to the residue. The suspension was filtered. The precipitate was washed with ethyl acetate (2 mLx3), and dried to give the title compound (40 mg, 93%). MS (ESI) m / z 339 (M + H) +; 1 H NMR (500 MHz, DMSO-D6) d ppm 3. 92 (s, 2H) 5.49 (s, 2H) 7.31 (m, 1H) 7.51 (m, 1H) 7.66 (m, 1H) 7. 86-8.03 (m, 5H) 8.70 (s, 1H) 13.49 (s, 1H). % Example 335835613 4'-r6- (1H-1.2.4-triazol-1-ylmethyl) -1,4-dihydroindenon, 2-cT pyrazole-3-in-1,1'-biphenol-4-ol Example 334A (50 mg, 0.127 mmol), (4-hydroxyphenyl) boronic acid (21 mg, 0.152 mmol), Pd (PPh3) 2 Cl2 (9 mg, 0.0127 mmol), DE / EtOH / H20 (7/2/3, 2). mL) and 1M Na2CO3 (1 mL), and heated at 160 ° C for 10 minutes in a Smith Slider. All solvents were removed. The residue was purified by HPLC to give the title compound (18 mg, 35%). MS (ESI) m / z 406 (M + H) +; 1 H NMR (500 MHz, DMSO-D 6) d ppm 3.88 (s, 2 H) 5.47 (s, 2 H) 6.84-6.88 (m, 2 H) 7.30 (d, J = 8.11 Hz, 1 H) 7.50 (s, 1 H) 7.547.57 (m, 2H) 7.64 (d, J = 7.17Hz, 1H) 7.70 (d, J = 8.42142, 2H) 7.83 (d, J = 8.42Hz, 2H) 7.99 (s, 1H) 8.68 (s, 1 HOUR).
Example 336 4-f 5-f6- (Diethyl lamine o) -1,4-dihydroindenori "2-c1pyrazol-3-pyridin-2-yl phenol Example 336A 5- (Diethylamino) i ndan-1 -o na 5-amino-indan-1 -one (408 mg, 2.77 mmol), iodoethane (0.89 mL, 11.1 mmol), Na 2 CO 3 (0.88 g, 8.31 mmol) were mixed. ) and water (10 mL), and stirred at 100 ° C in a high pressure tube for 1 night. The reaction was concentrated. The residue was purified by flash chromatography to give the intermediary above (0.40 g, 47%). MS (DCI / NH3) m / z 204 (M + H) +; † H NMR (300 MHz, CD3OD) d ppm 1.21 (t, J = 7.12Hz, 6H) 2.56-2.62 (m, 2H) 2.99 3.06 (m, 2H) 3.50 (q, J = 7.12Hz, 4H) 6.67 ( s, 1H) 6.73 (dd, J = 8.82, 2.37Hz, 1H) 7.52 (d, J = 8.82Hz, 1H) EXAMPLE 336B 3- (6-Chloropyridin-3-yl) -N, N-diethyl-, 4-dihydroindene, 2-cl-p-polyol-amine Example 336A (0.40 g, 1.97 mmol) was mixed, Example 324A (0.92 g, 3.94 mmol), 95% NaH (0.20 g, 7.88 mmol) and benzene (30 mL) were stirred and heated to reflux overnight. The mixture was concentrated. To the residue was added ethanol (100 mL), acetic acid (5 mL) and hodrazine monohydrate (5 mL). The reaction mixture was heated to reflux for 2 hours. All solvents are removed. Water (100 mL) was added to the residue. The precipitate was filtered, washed with water (30 mLx3) and ethyl acetate (30 ml_x3), and dried in vacuo to give the above intermediate (0.50 g, 75%). MS (ESI) m / z 339 (+ H) +; H NMR (300 MHz, DMSO-D6) d ppm 1.12 (t, J = 6.95Hz, 6H) 3.343.43 (m, 4H) 3.80 (s, 2H) 6.67 (dd, J = 8.65, 2.20 Hz, 1H) 6.90 (s, 1H) 7.43 (s, 11-1) 7.65 (s, 1H) 8.22 (s, 1H) 8.80 (d, J = 2.37Hz, 1H) 13.05 (s, 1H).
Example 336C 5-r6- (Diethylamino) -1,4-dihydroindenori.2-clirazole-3-inpyridine-2-carbonitrile Example 336B (100 mg, 0.294 mmol), Pd (PPh3) 4 (34 mg, 0.0294) were mixed. mmol), Zn (CN) 2 (0.416 g, 3.54 mmol) and DMF (5 mL), were pumped with N2, stirred, and heated at 180 ° C for 5 minutes on a Smith Synthesizer. The reaction mixture was filtered. The solution was concentrated. To the residue, DMSO (2.5 mL) was added. The suspension was filtered. The precipitate was washed with ethyl acetate (2 mLx3), and dried to give the title compound (71 mg, 73%). MS (ESI) m / z 330 (M + H) +; 1 H NMR (400 MHz, DMSO-De) d ppm 1.07 (t, J = 6.90 Hz, 6H) 3.33-3.37 (m, 4H) 3.75-3.84 (m, 2H) 6.63 (d, J = 8.59Hz, 1H) 6.86 (d, J = 1.23Hz, 1H) 7.34 (m, 1H) 8.07 (m, 1H) 8.27 (sT 1H) 9.09 (s, 1H) 13.22 (s, 1H).
Example 336D 4-. { 5-f6- (Diethylamino) -1,4-dihydroindenoM, 2-c1pyrazol-3-yl-1-pyridin-2-phenolene Example 336B (100 mg, 0.294 mmol), (4-hydroxyphenyl) boronic acid (49 mg, 0.0353 mmol),? (??? 3) 2 ?? 2 (21 mg, 0.0294 mmol), DME / EtOH / H20 (7/2/3, 3.5 mL) and 1M N4C03 (1.5 mL), and heated at 160 ° C for 10 minutes. minutes on a Smith Synthesizer. All solvents were removed. The residue was purified by HPLC to give the title compound (29 mg, 25%). MS (ESI) m / z 397 (+ H) +; H NMR (500 MHz, D SO-D6) d ppm 1.07 (t, J = 6.87Hz, 6H) 3.61 (s, 2H) 4.02 (s, 4H) 6.90 (d, J = 8.85Hz,, 2H) 7.998. 03 (m, 3H) 8.23 (dd, J = 8.54, 2.14Hz, 1H) 9.03 (s, 1H).
Example 337 4-. { 5-r6- (Diethylamino) -1,4-dihydro-n-nofofl, 2-clirazol-3-yl-1-pyridin-2-yl) -2-methoxyfenoi Example 337 was synthesized in a similar manner as in Example 336D, replacing acid ( 4-hydroxyphenyl) boronic with 2-methoxy-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -phenol (45 mg, 36%). MS (ESI) m / z 427 (M + H) +; 1H NMR (500 MHz, DMS> 0-D6) d ppm 1.03-1.12 (m, 6H) 3.60 (s, 2H) 3.89 (s, 3H) 3.93-4.06 (m, 4H) 6.90 (d, J = 8.24 Hz, 1H) 7.408.00 (m, 4H) 8.06 (d, J = 8.54Hz, 1H) 8.23 (dd, J = 8.39, 1.98Hz, 11-1) 9.03 (s, 1H) 9.41 (s, 1H) .
Example 338 5-r6- (Tetrahydrofuran-3-methoxy) -1,4-dihydroindeneM, 2-cT pyrazole-3-n-pyridine-2-carbonitrile Example 338A 1-rCloro (4-methoxy-phenyl) -methane-4-methoxy-benzene Bis- (4-methoxy-phenyl) -methanol (25 g, 102 mmol) and SOCI2 (60 mL, 823 mmol) were mixed, and they were heated to reflux for 4 hours. The reaction mixture was concentrated under vacuum pump, and dried completely to give the above intermediate (26.5 g, 99%). S (DCI / NH3) m / z 263 (M + H) +; H NMR (300 MHz, CDCl 3) d ppm 3.80 (s, 6H) 6.12 (s, 1H) 6.82-6.91 (m, 4H) 7.29-7.36 (m, 4H).
Example 338B 5- (Cyclohex-2-en-1-yloxy) indan-1 -o na 5-hydroxy-indan-1 -one (6.60 g, 46.4 mmol), cyclohex-2-enol (7.68 mL, 77.00 nunol), PPh3 of supported polymer (18.93 g, 56.79 mmol), DBAD (13.08 g, 56.80 mmol) and THF (300 mL), and stirred overnight. The reaction mixture was filtered. The solution was concentrated. The residue was purified by flash chromatography to give the above intermediate (6.75 g, 64%). MS (DCI / NH3) m / z 229 (M + H) +; 1H NMR (300 MHz, CD3OD) d ppm 1.70 (m, 1H) 1.77-1.91 (m, 2H) 1.99 (m, 1H) 2.042.15 (m, 2H) 2.62-2.68 (m, 2H) 3.07-3.14 (m, 2H) m, 2H) 4.99 (m, 1H) 5.85 (m, 1H) 6.00 (m, 1H) 6.93 (dd, J = 8.48.2.37Hz, 1H) 7.05 (d, J = 2.37Hz, 1H) 7.61 (d, J = 8.81Hz, 1H).
Example 338C 3- (6-Chloropyridin-3-iQ-6- (cyclohex-2-en-1-yloxy) -1,4-dihydroindene M, 2-clirazole Example 338B (6.70 g, 29.3 mmol) was mixed, Example 324A (13.7 g, 58.7 nunol), 95% NaH (3.71 g, 146.7 mmol) and benzene (200 mL) were stirred and refluxed overnight.The mixture was concentrated. He added ethanol (150 mL), acetic acid (25 mL) and hydrazine monohydrate (25 mL), the reaction mixture was heated to reflux for 3 hours, all solvents were removed, water was added to the residue (300 mL) The precipitate was filtered, washed with water (100 mL x 3) and ethyl acetate (50 mL x 3), and dried in vacuo to give the above intermediate (8.54 g, 80%) MS (ESI) m / z 364 (M + H) +; 1 H NMR (300 MHz, D SO-D6) S ppm 1.64 (m, 1H) 1.69-1.81 (m, 2H) 1.95 (m, 1H) 2.00-2.10 (m, 2H) 3.86 (s, 2H) 4.93 (s, 1H) 5.85 (m, 1H) 5.95 (m, 1H) 6.96 (m, 1 H) 7.20 (s, 1H) 7.54 (s, 1H) 7.67 (s, 1H) 8.22 ( dd, J = 8.48, 2.03Hz, 1H) 8.82 (d, J = 2.37Hz, 1H) 13.26 (s, 1H).
Example 338D 1 -FBis (4-methoxyphenyl) methy1-3- (6-chloropyridine-3-yl) -6- (hex-2-en-1-yloxy) -1 cycle, 4-dihydroindenoyl, 2-chlororazole Example 338C (8.54 g, 23.47 mmol), Example 338A (8.02 g, 30.51 mmol), triethylamine (6.54 mL, 46.94 mmol) and THF were mixed. (200 mL), were stirred, and heated at 60 ° C for 2 hours. The reaction mixture was cooled, filtered, and concentrated. The residue was purified by flash chromatography to give the above intermediate (12.96 g, 94%). MS (ESI) m / z 591 (M + H) +; H NMR (300 MHz, CDCl 3) d ppm 1.65 (m, 1H) 1.76-2.15 (m, 5H) 3.75 (s, 2H) 3.79 (s, 6H) 4.79 (m, 1H) 5.85 (m, 1H) 5.97 ( m, 1H) 6.66 (d, J = 8.48Hz, 1H) 6.72 (m, 114) 6.83-6.89 (m, 4H) 6.93 (s, 1 H) 7.11 (s, 1H) 7.19-7.25 (m, 4H) 7.34 (d, J = 8.14Hz, 1H) 8.16 (dd, J = 8.31, 2.20 Hz, 1H) 8.80 (d, J = 2.03Hz, 1H).
Example 338E 5-. { Bis (4-methoxyphenyl) methylene-6-hydroxy-1,4-dihydroindene G1, 2-cT pyrazol-3-yl > pyridine-2-carbonitrile were mixed from Example 338D (3.18 g, 5.39 mmol), Pd (PPh3) 4 (1.62 g, 0.147 mind), Zn (CN) 2 (7.59 g, 64.67 mmol) and DF (200 mL), they were pumped with N2, stirred, and heated to reflux for 6 hours. The reaction mixture was filtered. The filtrate was concentrated. The residue was purified by flash chromatography to give the above intermediate (2.06 g, 76%). MS (ESI) miz 501 (M + H) +; 1H NMR (500 MHz, DMSO-D6) d ppm 3.73 (s, 6H) 3.87 (s, 2H) 6.68 (dd, J = 8.11, 2.18Hz, 1H) 6.90-6.95 (m, J = 8.73Hz, 4H) 7.00 (d, J = 1.87Hz, 1H) 7.12 (s, 1H) 7.267.30 (m, 4H) 8.07 (d, J = 8.11Hz, 1H) &28 (dd, MA I, 2.18Hz, 1H) 9.09 (d, J = 1.25Hz, 1H) 9.66 (s, 1H).
Example 338F 5-r6- (Tetrahydrofuran-3-ylmethoxy) -1,4-dydroindenofl, 2-cTpyrazol-3-n-pyridine-2-carbonitrile Example 338E (100 mg, 0.20 mmol) was mixed, (tetrahydro-furan 3: 1) -methanol (82 mg, 0.80 mmol), DBAD (92 mg, 0.40 mmol), PPh3 of supported polymer (133 mg, 0.40 mmol) and THF (5 mL), and stirred for the night. The mixture was filtered. The filtrate was concentrated. To the residue was added methanol (8.0 mL) and 4N HCl in dioxane (0.50 mL). The mixture was stirred at room temperature for 8 hours. All solvents were removed. The residue was washed with ethyl acetate (10 mLx2), and dried to give the desired product (48 mg, 67%).
Examples 339 to 343 represented by Figure (XVIII) and shown in Table 18 were synthesized in a similar manner as described in Example 338F using the appropriate alcohol in place of (tetrahydro-furan-3-yl) -methanol.
Figure (XVIII) TABLE 18 Example 344 5-6-G (4-? Id roxy cyclohexyl) oxH-1,4-dihydroindenof, 2-cTpirazol-3-yl-pyridine-2-carbonitrile EXAMPLE 344A 4-r2- (Trimethylsilyl) et x-methoxy-cyclohexanol Cyclohexane-1,4-diol (4 g, 34.8 mmol) was dissolved in THF (200 ml_). To this solution was added 95% NaH (0.922 g, 36.6 mmol). The mixture was refluxed for 1 hour. Then the reaction cooled. SEMCI (6.44 mL, 36.6 mmol) was added dropwise. The reaction mixture was heated to reflux again overnight. The THF was removed. The residue was purified by flash chromatography to give the desired product (2.10 g, 16%). MS (DCI / NH3) m / z 247 (M + H) +; H NMR (400 MHz, CDCl 3) d ppm 0.02 (s, 9H) 0.87-0.95 (m, 2H) 1.30-1.38 (m, 2H) 1.57 (m, 1H) 1.641.70 (m, 2H) 1.80 (m, 1H) 1.91-2.01 (m, 2H) 3.50-3.70 (m, 4H) 4.69 (s, 2H).
Example 344B 5-f6-r (4-Hydroxycyclohexyl) oxyl-1,4-dihydroindenon, 2-clirazol-3-yOpyridine-2-carbonitrile Example 338E (20 mg, 0.040 mmol), Example 344A (20 mg , 0.080 mmol), DBAD (13.8 mg, 0.060 mmol), PPh3 of supported polymer (20 mg, 0.060 mmol) and THF (2 mL) and stirred during the night. The reaction mixture was filtered. The filtrate was concentrated. To the residue was added methanol (5 mL) and 4N HCl in dioxane (0.5 mL). After 4 hours, the reaction was complete. The solution was concentrated. The residue was purified by HPLC to give the title compound (4.0 mg, 27%). S (ESI) m / z 373 (M + H) +; 1H NMR (400 MHz, DMSO-Ds) d ppm 1.57-1.76 (m, 2H) 1.77-1.95 (m, 4H) 1.98-2.10 (m, 2H) 3.92 (s, 2H) 4.56 (s, 1H) 5.15 ( s, 1H) 7.01 (m, 1H) 7.25 (m, 1H) 7.56 (d, J = 8.29Hz, 1H) 8.14 (d, J = 8.29Hz, 1H) 8.36 (dd, J = 8.29, 2.15Hz, 1H ) 9.16 (s, 1H).
EXAMPLE 345 5-2- (4-Methyl-, 3-thiazol-5-yl) ethoxyl-1,4-dihydroindenoH, 2-cl-2-ylolol-3-ylpyridyl-2-carboxamide The Example 338E (100 mg, 0.192 mmol), 2- (4- methyl-thiazol-5-yl) -ethanol (55 mg, 0.384 mmol), DBAD (66 mg, 0.288 mmol), PPh3 of supported polymer (96 mg, 0.288 mmol) and THF (5 mL), and stirred during the night. The mixture was filtered. The filtrate was concentrated. To the residue was added 4N HCl in dioxane (4 mL). The mixture was stirred at room temperature overnight. All solvents were removed. The residue was purified by HPLC to give the title compound (18 mg, 22%). S (ESI) m / z 418 (M + H) +; 1 H NMR (400 MHz, DMSO-D 6) d ppm 2.38 (s, 3 H) 3.25 (t, J = 6.29 Hz, 2 H) 3.91 (s, 2 H) 4.22 (t, J = 5.98 Hz, 2 H) 6.96 (dd, J = 8.44, 1.99Hz, 1H) 7.20 (d, J = 1.53Hz, 1H) 7.56 (d, J = 8.29Hz, 1H) 7.65 (s, 1H) 8.13 (s, 1H) 8.15 (s, 1H) 8.33 (dd, J. = 7.98, 2.15Hz, 1H) 8.89 (s, 1H) 9.04 (d * .J = 1.53Hz, 1H).
Example 346 5- (6- (2-Hydroxyethyl-1,4-dihydroindenon. 2-c1pyrazol-3-pyridin-2-carbonitrile.
EXAMPLE 346A 5'-Bromo-2 ', 3'-dihydroes irot1.3-dioxolan-2.1'-indenol 5-Bromo-indan-1 -one (15 g, 71.1 mmol), ethylene glycol (19.8 mL, 355.2) were mixed. mmol), p-toluenesulfonic acid monohydrate (15 mg, 0.079 mmol) and benzene (400 mL), were stirred, and heated to reflux in a Dean Stark apparatus overnight. The mixture was poured into a saturated NaHC03 solution (200 mL) in a separatory separatory funnel, and stirred. The organic layer it was separated and dried on K2C03 powder. The solution was concentrated, and purified by flash chromatography to give the above intermediate (10.50 g, 60%). MS (DCI / NH3) m / z 256 (M + H) +; 1H NMR (300 MHz, CDCl 3) d ppm 2.24-2.34 (m, 2H) 2.93 (t, J = 6.95Hz, 2H) 4.04-4.20 (m, 4H) 7.22 (d, J = 8.48Hz, 1H) 7.35- 7.40 (m, 2H).
EXAMPLE 346B 5'-V'n'l-2 ', 3'-d-hydroespyri-3-oxoxne-2,1'-indene1 Example 346A (7.80 g, 30.58 mmol), tributy, were mixed. l (yin / l) tin (10.71 mL, 36.69 mmol), Pd (PPh3) 4 (3.52 g, 3.06 mmol) and DMF (100 mL), were pumped with N2 and heated at 80 ° C overnight. All solvents were removed. The residue was purified by flash chromatography to give the above intermediate (4.53 g, 66%). MS (DCI / NH3) m / z 203 (M + H) +; 1 H NMR (300 MHz, CDCl 3) d ppm 2.25-2.34 (m, 2H) 2.89-2.94 (m, 2H) 4.04-4.23 (m, 4H) 5.24 (d, J = 10.85 Hz, 1H) 5.74 (d, J = 17.63Hz, 1H) 6.72 (dd, J = 17.63, 10.85Hz, 1H) 7.297.31 (m, 2H) 7.39 (s, 1H).
EXAMPLE 346C 2- (2'.3'-Dihydrospron.3-dioxolan-2.1'-indenT-5'-ethanol) To a solution of Example 346B (4.53 g, 22.39 mmol) in anhydrous THF (100 mL) was added. 0.5M 9-BBN in THF (54 mL, 26.88 mmol) was added.The reaction was run at room temperature during the night. A solution of NaOH (1.08 g, 26.88 mmol) in water (5 mL) was added, followed by the dropwise addition of a solution of 30% H202 (3.05 nrtiL, 26.88 mmol). The mixture was stirred for 4 hours at room temperature. The reaction mixture was concentrated. Ethyl acetate (100 mL) and water (100 mL) were added to the residue. The organic layer was separated. To the water phase, ethyl acetate (100 mL × 5) was added. The organic layers were combined, dried over K2C03 powder, and concentrated. The residue was purified by flash chromatography to give the above intermediate (2.96 g, 60%). MS (DCI / NH3) m / z 221 (M + H) +; 1 HNMR (300 MHz, CD3OD) d ppm 2.21-2.29 (m, 2H) 2.78-2.92 (m, 4H) 3.73 (t, J = 7.12Hz, 2H) 4.01-4.19 (m, 4H) 7.0 &7.13 ( m, 2H) 7.25 (d, J = 8.14 Hz, 1 H).
Example 346D 5- (2-Hydroxyethyl) indan-1-one Example 346C (2.96 g, 13.43 mmol) was dissolved in THF (30 mL). To this solution was added a solution of 2N HCl (40 mL). The reaction mixture was stirred at room temperature overnight, concentrated, and extracted with ethyl acetate (50 mLx5). The organic solution was dried with MgSO 4, concentrated, and purified by flash chromatography to give the above intermediate (1.63 g, 69%). MS (DCI / NH3) m / z 177 (M + H) +; 1H NMR (300 MHz, CD3OD) d ppm 2.64-2.70 (m, 2H) 2.92 (t, J = 6.78Hz, 2H) 3.11-3.17 (m, 2H) 3.80 (t, J = 6.78Hz, 2H) 7.29 ( d, J = 7.80Hz, 1H) 7.43 (s, 1H) 7.63 (d, J = 7.80 Hz, 1H).
EXAMPLE 346E 5-r2- (Plridin-4-yloxy) etillindan-1-ona Example 346D (0.2933 g, 1646 mmol), pyridin-4-ol (0.156 g, 1646 mmol), PPh3 of supported polymer (1.097) were mixed. g, 3.292 mmol), DBAD (0.758 g, 3.292 mmol) and THF (15 mL), and stirred at room temperature overnight. The solution was filtered, concentrated, and purified by flash chromatography to give the above intermediate (213 mg, 51%). S (DCI / NHa) m / z 254 (M + H) +; 1H NMR (300 MHz, CD3OD) d * ppm 2.65-2.77 (m, 2H) 3.12-3.18 (m, 2H) 3.22 (t, J = 6.44Hz, 2H) 4.37 (t, J = 6.44Hz, 2H) 6.97 (dd, J = 4.92, 1.53Hz, 2H) 7.38 (d, J = 7.46Hz, 1H) 7.51 (s, 1H) 7.65 (d, J = 7.80 Hz, 1H) 8.31 (dd, J = 5.09, 1.70 Hz , 2H).
EXAMPLE 346F 2-f3-6-Chloropyridn-3-yl) -1,4-dihydroindenoH. 2-cTp-aceol-6-ethanol Example 346E (115.2 mg, 0.61 mmol), 324A was mixed. (360.0 mg, 1.53 mmol), 95% NaH (77 mg, 3.05 mmol) and benzene (20 mL) were stirred and refluxed for 3 hours. The mixture was then concentrated. To the residue was added ethanol (20 mL), acetic acid (2 mL) and hydrazine monohydrate (2 mL). The reaction mixture was heated to reflux for 2 hours. All the solvents were removed. Water (20 mL) was added to the residue. The precipitate was filtered, washed with water (10 ml_X3) and ethyl acetate (10 mLX3), and dried under vacuum to give the above intermediate (64 mg, 34%). MS (ESI) m / z 312 (M + H) +; 1H NR (400 MHz, DMSO-D6) d ppm 2.80 (t, J = 7.06Hz, 2H) 3.64-3.66 (m, 2H) 3.85-3.88 (m, 2H) 4.64 (t, J = 5.22Hz, 1H) 7.23 (s, 1H) 7.43 (s, 1H) 7.59 (d, J = 5.52Hz, 1H) 7.68 (m, 1H) 8.24 (m, 1H) 8.84 (s, 1H) 13.35 (s, 1H).
EXAMPLE 346G 5-r6- (2-Hydroxyethin-1,4-dihydroxy-1,2-cTpira2ol-3-inpyridine-2-carbonitrile) Example 346F (64 mg, 0.205 mmol), Pd (PPh3) 4 (24 mg, 0.0205 mmol), Zn (CN) 2 (0.29 g, 22.463 mmol) and DMF (4 mL), pumped with N2, stirred, and heated at 180 ° C for 5 minutes in a Smith Synthesizer. The reaction was filtered The filtrate was concentrated The residue was purified by HPLC to give the title product (30.5 mg, 49%) MS (ESI) m / z 303 (M + H) +; 1H NMR ( 400 MHz, DMSO-D6) d ppm, 2.80 (t, J = 7.06Hz, 2H) 3.66 (t, J = 7.06Hz, 2H) 3.92 (s, 2H) 4.65 (br. S, 1H) 7.24 (d, J = 7.36Hz, 1H) 7.45 (s, 1H) 7.57 (s, 1H) 8.16 (s, 1H) 8.38 (dd, J = 7.98.2.15Hz, 1H) 9.17 (s, 1H) 13.56 (s, 1H) .
Example 347 5-f6- (Difluoromethoxy) -7-methoxy-1,4-dihydroindertoM, 2-cl pyrazole-3-n-pyridin-2-carbon itriio Example 347A 5- (Difluoromethoxy-6-methoxyindan-1 -na) 5-Hydroxy-6-methoxy-indan-1 -one (0.78 g, 4.38 mmol), CICHF2 (7.0 g, 80.95 mmol), K2C03 (3.6 g, 26.04 mmol) and DMF (40 mL), and were heated at 100 ° C for 2 hours, the reaction mixture was filtered, the filtrate was concentrated, the residue was purified by flash chromatography to give the intermediate previous (0.59 g, 59%) MS (DCI / NH3) m / z 229 (M + H) +; 1 H NMR (300 MHz, CD3OD) d ppm 2.67-2.73 (m, 2H) 3.06-3.13 (m, 2H) 3.91 (s, 3H) 6.90 (t, J = 74.43Hz, 1H) 7.31 (s, 1H) 7.32 (s, 1H).
Example 347B 3- (6-Chloropyridin-3-yl) -6- (difluoromethoxy) -7-methoxy-1,4-dihydroindenofl ^ -c-thirazole Example 347A (0.59 g, 2.59 mmol) was mixed, Example 324A (1.21 g, 5.17 mmol), 95% NaH (0.26 g, 10.34 mmol) and anhydrous THF (30 mL), and stirred at room temperature for 1 hour. All solvents were removed. To the residue was added ethanol (50 mL), acetic acid (2 mL) and hydrazine monohydrate (2 mL). The mixture was refluxed for 2 hours, and cooled. All solvents were removed. Water was added to the residue (50 mL). The precipitate was filtered, washed with water (5 mLx3) and ethyl acetate (5 mLx3), and dried to give the above intermediate (0.64 g, 68%). MS (ESI) m / z 364 (M + H) +; 1H NMR (500 MHz, DMSO-D6) d ppm 3.83 (s, 2H) 3.91 (s, 3H) 7.06 (t, J = 74.87Hz, 1H) 7.40 (d, J = 7.49Hz, 2H) 7.64 (d, J = 8.42Hz, 1H) 8.20 (dd, J = 8.42, 1.87Hz, 1H) 8.81 (d, J = 1.56Hz, 1H) 13.41 (s, 1H).
EXAMPLE 347C 5-r6- (D-Fluoropomethoxy) -7-methoxy-1,4-dhydroindenoM.2-c1 pyrazole-3- i 11 pi di di-2-carbo nitrite Example 347B (10Q mg) was mixed. , 0.282 mmol), Pd (PPh3) 4 (33 mg, 0.0282 mmol), Zn (CN) 2 (0.331 g, 2.82 mmol) and DF (5 mL, were pumped with N2, stirred, and heated to 180 °. C for 5 minutes on a Smith Synthesizer The reaction mixture was filtered The filtrate was concentrated DIVISO (2.5 mL) was added to the residue The suspension was stirred for 0.5 hour The precipitate was then filtered, washed with water (5 mLx3) and ethyl acetate (5 mLx3), and dried in vacuo to give the title compound (32 mg, 32%) MS (ESI) m / z 355 (M + H) +; H NMR ( 500 MHz, DMSO-D6) d ppm 3.84-3.92 (m, 5H) 7.08 (t, J = 74.71Hz, 1H) 7.347.52 (m, 2H) 8.13 (m, 1H) 8.35 (s, 1H) 9.15 ( d, J = 1.87Hz, 1H).
Example 348 4-. { 5-G6- (Difluoromethoxy) -7-methoxy-1,4-dihydroindenori, 2-cl pyrazole-3-iHpyridin-2-MHenol Example 347B (100 mg, 0.275 mmol), acid (4-hydroxyphenyl) was mixed ) boronic (49 mg, 0.356 mmol), Pd (PPh3) 2 Cl2 (17 mg, 0.0237 mmol), DME / EtOH / H20 (7/2/3, 3.5 mL) and 1M N4C03 (1.5 mL), and heated at 160 ° C for 10 minutes on a Smith Synthesizer. All solvents were removed. The residue was purified by HPLC to give the title compound (42 mg, 36%). ^ MS (ESI) m / z 422 (M + H) +; HNR (500 Hz, D SO-D6) d ppm 3.89 (s, 2H) 3.93 (s, 3H) 6.89 (d, J = 8.73Hz, 2H) 7.08 (t, J = 74.87Hz, 1H) 7.43 (d, J = 12.17Hz, 2H) 7.988.02 (m, 3H) 8.20 (dd, J = 8.42, 2.18Hz, 1H) 9.02 (d, J = 2.18Hz, 1H). It will be apparent to someone skilled in the art that the present invention is not limited to the foregoing illustrative examples, and that it can be modalized into other specific forms without departing from its essential attributes. Therefore, it is desired that the examples be considered in all respects as illustrative and not restrictive, referring to the appended claims, instead of the foregoing examples, and that all the changes that come with the meaning and scale of equivalence of the claims, therefore, are intended to be encompassed with it.

Claims (7)

    CLAIMS composed of the formula (I) or a pharmaceutically acceptable ester, amide or prodrug salt thereof, wherein Ri and R 2 are independently selected from the group consisting of hydrogen, alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkynyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cicloalquenilalcoxi, cycloalkylalkoxy, cycloalkylalkyl, cicloalquiícarbonilo, cycloalkyloxy, formyl, haloalkoxy, haloalcoxialquinilo, haloalkyl, halogen, heteroarylalkoxy, heteroarilalcoxialcoxi, heteroarylalkyl, heteroarylalkynyl, heteroaryloxyalkyl, heterocycle, heterocycloalkoxy, heterocycloalkyl, heterocyccarbonylp, heterocyclypoxy, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, hydroxysulfonyl, hydroxysulfonylalkyl, mercapto, mercapto-alkyl, nitro, -NRARB, (NRARB) alkoxy, (NRARB) alkyl, ( NRARB) alkynyl, (NRARB) carbonyl, (NRARB) carbonylalkoxy, (NRARB) carbonylalkyl, and (NRGRH) alkoxy; or Ri and R2 together with the carbon atoms to which they are a non-aromatic ring of 5, 6, 7, or 8 members, wherein the ring contains 0, 1, or 2 heterogeneous atoms selected from the group consisting of O, N (RC), and N (RD), wherein the non-aromatic ring is substituted with 0, 1, or 2 substituents selected from the group consisting of alkyl and hydroxy; R3 is selected from the group consisting of hydrogen, alkenyl, alkenyloxy, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NRERF, (NRERF) alkoxy (NRERF) alkyl, (NRERF) carbonyl, and (NRERF) carbonylalkyl; R 4 is selected from the group consisting of hydrogen, alkoxycarbonyl, alkylcarbonylalkoxy, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, halogen, heteroaryl, heteroarylalkoxy, heteroarylalkyl, heteroaryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocycleoxy, hydroxy, -NRERF, and (NRERF) carbonyl; R5 is absent or selected from the group consisting of hydrogen, alkoxycarbonyl, carboxy, halogen, heteroaryl, hydroxy, nitro, -NRERF, and (NRERF) carbonyl; provided that when R5 is hydrogen, R4 is other than hydrogen; or R4. and R5, together with the carbon atoms to which they are bound, forms a phenyl ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of a-annyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkylthioalkyl alkynyl, carboxy, carboxyalkyl, siamino, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NRGRH, (NRGRH) alkoxy, (NRGRH) alkyl, (NRGRH) carbonyl, and (NRGRH) sulfonyl; or R4 and R5, together with the atoms to which they are attached, form a heterocycle optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of aikenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio , alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, -NRGRH, (NRGRH) alkoxy, (NRGRH) alkyl, and (NRGRH) carbonyl; R6 is selected from the group consisting of hydrogen, lower alkoxy, lower alkyl, halogen, hydroxy, and -NRERFI RA and RB, independently selected from the group consisting of hydrogen, anynyl, alkoxyalkyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoacarbonyl alkylcarbonyl, alkoxysulfonyl, alkoaisulfonylalkyl, alkoaisulfonylalkylcarbonyl, alkyl, alkylcarbonyl, alkynyl, aryl, carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonylalkylcarbonyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, heterocycloalkylcarbonyl, heterocyclecarbonyl, heterocyclecarbonylalkyl, heterocyclocarbonylalkylcarbonyl, hydroxyalkyl, hydroxyalkylcarbonyl, hydroxysulfonyl, hydroxysulfonyl alkyl, hydroxysulfonyl alkylcarbonyl, (NRERF) alkyl, (NRERF) aikylcarbonyl, (NRERF) carbonyl, (NRERF) carbonylalkyl, (NRERF) carboniyalkylcarbonyl,: (NRERF) sulfonyl, (NRERF) sülfonilaiquilo, and (NRERF) sulfonylalkylcarbonyl; RC and D independently are selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, and alkylcarbonyl; RE and F independently are selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, cycloalkyl, heteroarylalkyl, and hydroxyalkyl; ?? X3, and X4 independently are selected from the group consisting of CH and N; X2 is selected from the group consisting of CH (R7), C (R7) (R8), C = 0, N (R8); X5 is selected from the group consisting of C and N; R7 is selected from the group consisting of hydrogen, alkoxy, alkyl, hydroxy, lower alkoxy, lower alkyl, and hydroxyalkyl; and R8 is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, and hydroxyalkyl. 2. The compound according to claim 1, in where; X2 is CH (R7); XS is C; and R 2 independently are selected from the group consisting of hydrogen, alkenyloxy, alkoxy, alkoxyalkyl, heterocycloalkyl, hydroxy, hydroxyalkyl, (NRARB) alkyl, and (NRARB) carbonyl; R3 is hydrogen; R4 is selected from the group consisting of hydrogen,? alkoxycarbonyl, aryl, carboxy, cyano, heteroaryl, hydroxy, -NRERF, and (NRERF) carbonyl; R5 is selected from the group consisting of hydrogen and -NRERF; R6 is hydrogen; R7 is hydrogen; RA is selected from the group consisting of hydrogen and alkyl; RB is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroarylalkyl, heterocycle, and hydroxyalkyl; RE is selected from the group consisting of hydrogen and alkyl; and RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl. 3. The compound according to claim 1, wherein: Xlp X3, and X4 are CH; X2 is CH (R7); X5 is C; R-? and R 2 independently are selected from the group consisting of hydrogen, alkenyloxy, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, (NRARB) alkyl, (N RARB) carbonylo, and heterocycloalkyl, wherein the heterocycle of the heterocycloalkyl is selected from the group consisting of of 4-morpholinyl and 4-hydroxy-1-piperidinyl; R3 is hydrogen; R 4 is selected from the group consisting of hydrogen, alkoxycarbonyl, carboxy, cyano, hydroxy heteroaryl, -NRERF, (NRERF) carbonyl, and aryl, wherein the aryl is phenyl substituted with 1, 2, or 3 substituents selected from the group consisting of of alkoxy, formyl, halogen, hydroxy, hydroxyalkyl, and -NRGRH; RS is selected from the group consisting of hydrogen and -NRERF; R6 is hydrogen; R7 is hydrogen; RA is selected from the group consisting of hydrogen and alkyl; RB is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, and cycloalkyl, wherein the cycloalkyl is cyclohexyl substituted with 1 substituent selected from the group consisting of alkyl and hydroxy; RE is selected from the group consisting of hydrogen and alkyl; RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl. 4. The compound according to claim 1, wherein: X2 is CH (R7); Ri > R3. R5, and Re, are hydrogen; R2 is selected from the group consisting of alkenyloxy, 3 > alkoxyalkyl, hydroxy, hydroxyalkyl, (NRARB) carbonyl, and heterocycloalkyl, wherein the heterocycloalkyl heterocycle is selected from the group consisting of 4-morpholinyl and 4-hydroxy-1-piperidinyl; R 4 is selected from the group consisting of alkoxycarbonyl, carboxy, cyano, hydroxy, and (NRERF) carbonyl; R7 is hydrogen; RA is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl, wherein the cycloalkyl is cyclohexyl substituted with 1 substituent selected from the group consisting of alkyl and hydroxy; and RB, RE and RF are hydrogen. 5. The compound according to claim 4, selected from the group consisting of: 4- (6-. {[[(Trans-4-methylcyclohexyl) amino] methyl} -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl) benzoic acid; 4- (6-. {[[(cs-4-methyl-cyclohexyl) amino] methyl} -1,4-dihydro-mandene [1, 2-c] p-aceol-3-yl) benzoic acid; Ethyl 4- (6-. {[[Trans-4-methylcyclohexyl) amino] methyl} -1,4-dihydroindeno [1, 2-e] pyrazol-3-yl) benzoate; 4- (6-. {[[(trans-4-hydroxycyclohexyl) amino] methyl} -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl) benzoic acid; 4- (6- { [(Trans-4-hydroxycyclohexyl) amino] methyl) -, 4-dihydroindeno [1, 2-c] pyrazol-3-yl) benzamide; 4- [6- (4-morpholinihnethyl) -, 4-dihydroindeno [1, 2-c] pyrazol-3-yl] benzoic acid; 4- [6- (4-morpholinylmethyl) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] methyl benzoate; 4- [6- (4-morpholinylmethyl) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] benzamide; 4- acid. { 6 - [(4-hydroxy-1-piperidinyl) methyl] -1,4-dihydroindeno [1,2-e] pyrazol-3-yl} benzoic; and 4-. { 6 - [(4-hydroxy-1-piperidinyl) methyl] -1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide; 4- acid. { 6 - [(neopentylamino) methyl] -1,4-dihydroindeno [1,2-c] pyrazol-3-yl} benzoic; 4-. { 6 - [(neopentylamino) methyl] -, 4-dihydroindeno [1, 2-c] pyrazol-3-yl) benzamide; 4- (6-. {[[(3-hydroxy-2,2-dimethylpropyl) amino] methyl} -1,4-dihydroindeno [, 2-c] pyrazol-3-yl) benzoic acid; 4- (6- { [(3-hydroxy-2,2-dimethylpropyl) to mino] methyl.} - 1,4- dihydroindeno [1, 2-c] pyrazol-3-yl) benzamide; 4- [6- (hydroxymethyl) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl-benzoic acid; 4- [6- (hydroxymethyl) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] benzamide; 4- [6- (Methoxymethyl) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] benzoic acid; 4- [6- (Allyloxy) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] benzoic acid; 4- [6- (Allyloxy) -1,4-dihydroindeno [1,2- c] pyrazo] -3-] methylbenzoate; 4- [6- (allyl) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] benzamide; 4- (6-hydroxy-1,4-dihydroindeno [1, 2-c] pyrazol-3-yl) benzoate methyl; 4- (6-hydroxy-1,4-dihydroindeno [1, 2-c] pyrazol-3-yl) benzoic acid; 4- (6-. {[[(trans-4-hydroaicyclohexyl) amino] carbonyl] -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl) benzoic acid; 4- acid. { 6 - [(neopentylamino) carbonyl] -1,4-dihydroindeno [1,2-c] pyrazol-3-yl} benzoic; 3- [4- (aminocarbonyl) phenyl] -N-neopentyl-1,4-dihydroindeno [1,2-c] pyrazole-6-carboxamide; and 4- (6-. {[[(trans-4-methylcyclohexyl) amino] methyl) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol. 6. The compound according to claim 1, wherein: Xi, X3, and X4 are CH X2 is CH (R7); X5 is C; Ri, R3, 5, and e are hydrogen; R 2 is selected from the group consisting of hydrogen, alkenyloxy, alkoxyalkyl, hydroxy, hydroxyalkyl, (R ealkyl, (NRARB) carbonyl, and heterocycloalkyl, wherein the heterocycloalkyl heterocycle is selected from the group consisting of 4-morpholinyl and 4-hydroxy -1-piperidinyl, R4 is aryl, wherein arylene is phenyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkoxy, formyl, halogen, hydroxy, hydroxyalkyl, and -NRGRHÍ R7 is hydrogen; is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl, wherein the cycloalkyl is cyclohexyl substituted with 1 substituent selected from the group consisting of alkyl and hydroxy, and RB, RE, and F are hydrogen. with claim 6 selected from the group consisting of: 4, - (6- { [(cis-4-methylcyclohexyl) amino] methyl) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl ) -1, 1 '-biphenyl-4-ol; 4 '- (6- { [(Trans-4-hi droxiciclohe) il) to me no] meti l} -1,4-dihydroindeno [, 2-c] pyrazol-3-yl) -3-methoxy-1,1 '-biphenyl-4-ol; 4 '- (6- { [(Trans-4-hydroxycyclohexyl) amino] methyl.} -1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -3- (hydroxymethyl) -1 , 1 '-biphenyl-4-ol; 3-methyloxy-4'-. { 6 - [(neopentylamino) methyl] -1,4-dihydroindeno [1,2-c] irazol-3-yl} -1, 1 '-biphenyl-4-ol; 4, - (6- { [(3-hydroxy-2,2-dimethylpropyl) amino] methyl.} -1,4-di idroindenotl, 2-c] pyrazol-3-yl) -3-methoxy- 1, 1 '-biphenyl-4-ol; 3- (4'-Hydroxy-1,1'-biphenyl-4-yl) -1,4-dihydroindeno [1,2-c] pyrazol-6-ol; 3- (4'-hydroxy-3'-methoxy-1,1] -biphenl-4-yl) -1,4-dihydroindeno [1,2-c] pyrazol-6-ol; 4 '- [6- (hydroxymethyl) -1,4-dihydroxydo [1,2-c] pyrazol-3-yl] -1,1-biphenyl-4-ol; 4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -1,1' -biphenyl-4-ol;; 4 '- [6- (hydroxyethyl) -1,4-dihydroindeno [, 2-c] pyrazol-3-yl] -3-methoxy-1,1' -biphenyl-4-ol; 3- (3'-fluoro-4, -hydroxy-1,1'-b-phenyl-4-y- [-] -, 4-dihydroindeno [, 2-c] p¡razol-6-ol; 3- (3'-amino-4'-hydroxy-1,1'-biphenyl-4-yl) -1,4-dihydroindeno [1,2-c] pyrazol-6-ol; 4- hydroxy-4 '- [6- (hydroxymethyl) -1,4-dihydroindeno [, 2-c] pyrazol-3-yl] -5-methoxy-1,1' -biphenyl-2-carbaldehyde; 3- (4'-hydroxy-1) -1, -biphenyl-4-yl) -N- (trans-4-hydroxycyclohexyl) -1,4-dihydroindeno [1,2-c] pyrazole-6-carboxamide; and 3- (4'-hydroxy-1,1'-biphenyl-4-yl) -N-neopentyl-1,4-dihydroindeno [, 2-c] pyrazole-6-carboxamide. 8. The compound according to claim 1, wherein: X2 is CH (R7); X5 is C; R1, R3, R5, and 6 are hydrogen; R2 is selected from the group consisting of hydrogen, alkenyloxy, alkoxyalkyl, hydroxy, hydroxyalkyl, (NRARB) alkyl, (NRARB) carbonyl, and heterocycloalkyl, wherein the heterocycloalkyl heterocycle is selected from the group consisting of 4-morpholinyl and 4- hydroxy-1-piperidinyl; R 4 is heteroaryl; R7 is hydrogen; RA is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl, wherein the cycloalkyl is cyclohexyl substituted with 1 substituent selected from the group consisting of alkyl and hydroxy; and RB is selected from the group consisting of hydrogen and alkyl. 9. The compound according to claim 8, which is 6- (allyloxy) -3- [4- (1 H-tetraazol-5-yl) phenyl] -1,4-dihydroindeno [1,2-c] pyrazole. 10. The compound according to claim 1, wherein: X2 is CH (R7); X5 is C; R-i, R3, and e are hydrogen; R 2 is selected from the group consisting of alkenyloxy, alkoxyalkyl, hydroxy, hydroxyalkyl, (NRARB) alkyl, (NRARB) carbonyl, and heterocycloalkyl, wherein the heterocycloalkyl heterocycle is selected from the group consisting of 4-morpholinyl and 4-hydroxy-1-piperidinyl; R4 is selected from the group consisting of hydrogen, carboxy, and cyano; R5 is selected from the group consisting of alkoxycarbonyl, carboxy, hydroxy, hydroxyalkyl, -NRERF, and (NRERF) carbonyl; R7 is hydrogen; RA is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl, wherein the cycloalkyl is cyclohexyl substituted with 1 substituent selected from the group consisting of alkyl and hydroxy; RB is selected from the group consisting of hydrogen and alkyl; RE is selected from the group consisting of hydrogen and alkyl; and RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl. 11. The compound according to claim 10 selected from the group consisting of: N- [3- (6- {[[(trans-4-hydroxycyclohexyl) amino] methyl} -1,4-dihydroindene [1] , 2-c] pyrazol-3-yl) phenyl] acetamide; N-. { 3- [6- (4-morpholinylmethyl) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] phenyl) acetamide; 2- (Acetylamino) -4- [6- (4-morfoiinylmethyl) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] benzoic acid; and N- (3-. {6 - [(4-hydroxy-1-piperidinyl) methyl] -1,4-dilridro-quinone [1, 2-c] pyrazol-3-yl] phenyl) acetamide. 12. The compound according to claim 1, wherein: X2 is CH (R7); X5 is C; 'R2, R3 > R5, and Re are hydrogen; R-i is selected from the group consisting of alkenyloxy, alkoxyalkyl, hydroxy, hydroxyalkyo, (NRARB) alkyl, (NRARB) carbonyl, and heterocyanoalkyl, wherein the heterocycle heterocycle is selected from the group consisting of 4-morpholinyl and 4-hydroxy-1-piperidinyl; R 4 is selected from the group consisting of alkoxycarbonyl, carboxy, cyano, hydroxy, hydroxyalkyo, -NRERF, and (NRERF) carbonyl; R7 is hydrogen; RA is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl, wherein the cycloalkyl is cyclohexyl substituted with 1 substituent selected from the group consisting of alkyl and hydroxy; RB is selected from the group consisting of hydrogen and alkyl; RE is selected from the group consisting of hydrogen and alkyl; Y RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl. 13. The compound according to claim 12 selected from the group consisting of: 4- [7- (hydroxymethyl) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] benzoic acid; 4- [7- (hydroxymethyl) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] benzamide; 4- [7- (4-morfoinimethyl) -1,4-dihydroindeno [1,2-c] pyrazole-3? il] benzoic; 4- [7- (4-morpholinylmethyl) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] benzamide; 4- (7-. {[[(2-hydroxyethyl) amino] methyl} -1,4-dihydroindeno [1, 2-c] p-razo l-3-yl) benzoic acid; 4-. { 7 - [(neopentylamino) methyl] -1,4-dihydroindeno [1,2-c] pyrazol-3-ylbenzamide; 4- acid. { 7 - [(methylamino) carbonyl] -1,4-dihydroindeno [1,2-c] pyrazol-3-yl} benzoic; 3- [4- (aminocarbonyl) phenyl] -N-methyl-1,4-dihydroindeno [1,2-c] pyrazole-7-carboxamide; acid 4 -. { 7 - [(neopentylamino) carbonyl] -1,4-dihydroindeno [1,2-c] pyrazol-3-yl} benzoic; and 4- (7-. {[[(trans-4-hydroaicyclohexyl) amino] carbonyl} -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl) benzoic acid. 14. The compound according to [a claim 1, in where: X2 eis CH (R7); R2. R3, R5, and R6 are hydrogen; R is selected from the group consisting of alkenyloxy, alkoxyalkyl, hydroxy, hydroxyalkyl, (NRARB) alkyl, (NRARB) carbonyl, and heterocycloalkyl, wherein the heterocycloalkyl heterocycle is selected from the group consisting of 4-morpholinyl and 4-hydroxy-piperidinyl; R 4 is aryl wherein the aryl is phenyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkoxy, formyl, halogen, hydroxy, hydroxyalkyl, and NRGRH; R7 is hydrogen; RA is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl, wherein the cycloalkyl is cyclohexyl substituted with 1 substituent selected from the group consisting of alkyl and hydroxy; RB is selected from the group consisting of hydrogen and alkyl; RE is selected from the group consisting of hydrogen and alkyl; and RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl. 15. The compound according to claim 14 selected from the group consisting of: 4 '- [7- (hydroxymethyl) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] -3-methoxy-1,1'-biphenyl-4-ol; 4 '- [7- (hydroxymethyl) -1,4-dihydroindeno [1, 2-c] pi razol-3-yl] -1,1' -biphenyl-4-ol; 4'-. { 7 - [(neopentylamino) methyl] -1,4-dihydroindeno [1,2-c] pyrazol-3-yl} -1,1'-biphenyl-4-ol; 3- (4'-hydroxy-1, 1'-biphenyl-4-yl) -N-methyl-1,4-dihydroindeno [1,2-c] pyrazole-7-carboxamide; and 3- (4'-hydroxy-1,1'-biphenyl-4-yl) -N-neopentyl-1,4-dihydroindene% [1,2-c] pyrazole-7-carboxamide. 16. The compound according to claim 1, wherein: X2 is CH (R7); X5 is C; R2. R3, and R6 are hydrogen; R1 is selected from the group consisting of alkenyloxy, alkoxyalkyl, hydroxy, hydroxyalkyl, (NRARB) alkyl, (NRARB) carbonyl, and heterocycloalkyl, wherein the heterocycloalkyl heterocycle is selected from the group consisting of 4-morpholinyl and 4-hydroxy-1-piperidinyl; R4 is selected from the group consisting of hydrogen, carboxy, and cyano; R5 is selected from the group consisting of alkoxycarbonyl, carboxy, hydroxy, hydroxyalkyl, -NRERF, and (NRERF) carbonyl; R7 is hydrogen; RA is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl, wherein the cycloalkyl is cyclohexyl substituted with 1 substituent selected from the group consisting of alkyl and hydroxy; RB is selected from the group consisting of hydrogen and alkyl; RE is selected from the group consisting of hydrogen and alkyl; and. RF is selected from the group consisting of hydrogen, alkyl,? and alkylcarbonyl. 17. The compound according to claim 16 which is N { 3- [7- (hydroxymethyl) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] phenyl} acetamide. 18. The compound according to claim 1, wherein: X2 is CH (R7); X5 is C; 1 and R2 are alkoxy; R3 and R6 are hydrogen; R 4 is selected from the group consisting of alkoxycarbonyl, carboxy, cyano, hydroxy, -NRERF, and (NRERF) carbonyl; R5 is selected from the group consisting of hydrogen and carboxy; R7 is hydrogen; RE is selected from the group consisting of hydrogen and alkyl; and RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl. 19. The compound according to claim 18 which is 4- (6,7-dimethoxy-1,4-dihydroindeno [1, 2-c] pyrazol-3-yl) benzoic acid. 20. The compound according to claim 1, wherein: X, X3, and X4 are CH; X2 is CH (R7); X5 is C; Ri and R2 are alkoxy; 3, R5, and R6 are hydrogen; R 4 is aryl wherein the aryl is phenyl substituted with 1, 2, or 3 substituents selected from the group consisting of alkoxy, formyl, halogen, hydroxy, hydroxyalkyl, and NRGRH; R7 is hydrogen; RE is selected from the group consisting of hydrogen and alkyl; and RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl. 21. The compound according to claim 20 which is 4 '- (6,7-dimethoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -1, 1'-biphenyl-4 -ol. 22. The compound according to claim 1, wherein: X2 is CH (R7); X5 is C; Ri and R2 are alkoxy; R3. R5, and R6 are hydrogen; R 4 is heteroaryl; and R7 is hydrogen. 23. The compound according to claim 22 which is 6,7-dimethoxy-3- [4- (1 H-tetraazo.l-5-yl) phenyl] -1,4-dihydroindeno [1, 2-c] pyrazole 24. The compound according to claim 1, wherein: X2 is CH (R7); X5 is C; Ri, R2, R3, R5, and Re are hydrogen; R 4 is selected from the group consisting of alkoxycarbonyl, carboxy, cyano, hydroxy, hydroxyalkyl, -NRERF. and (RERF) carbonyl; and R7 is selected from the group consisting of alkoxy and hydroxy. 25. The compound according to claim 24 which is 4- (4-hydroxy-1,4-dihydroindeno [1, 2-c] pyrazol-3-yl) benzoic acid. 26. The compound according to claim 1, wherein: Xi is CH; X2 is CH (R7); X3 is N; X4 is CH; X5 is C; Ri, R3, R5, and Re are hydrogen; R2 is selected from the group consisting of alkenyloxy, alkoxyalkyl, hydroxy, hydroxyalkyl, (NRARB) alkyl, (NRARB) carbonyl, and heterocycloalkyl, wherein the heterocycloalkyl heterocycle is selected from the group consisting of 4-morpholinyl and 4-hydroxy-1-p-liperidinyl; R 4 is selected from the group consisting of hydrogen, alkoxycarbonyl, carboxy, cyano, hydroxy, hydroxyalkyl, -NRERF, and (NRERF) carbonyl; R7 is hydrogen; RA is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl, wherein the cycloalkyl is cyclohexyl substituted with 1 substituent selected from the group consisting of alkyl and hydroxy; RB is selected from the group consisting of hydrogen and alkyl; RE is selected from the group consisting of hydrogen and alkyl; and RF is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl. 27. The compound according to claim 26 selected from the group consisting of: 6- [6- (allyloxy) -1,4-dihydroindene |; i, 2-c] pyrazol-3-yl] nicotinic; and 6- (6-hydroxy-1,4-dihydro-mandene [1, 2-c] pyrazol-3-yl) nicotinic acid. 28. The compound according to claim 1 selected from the group consisting of: 4 '- [6- (morpholin-4-ylmethi) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] - 1,1'-biphenyl-4-ol; 4'-. { 5 - [(neopentylamino) rriethyl] -1,4-dihydroindeno [1,2-c] pyrazol-3-yl} -1,1'-biphenyl-4-ol; s. 4'-. { 6 - [(neopentylamino) methyl] -1,4-dihydroindeno [1,2-c] pyrazol-3-yl} -1, r-biphenyl-4-ol; 4 '- (5- { [(2-hydroxyethyl) amino] methyl.} -1,4-dihydroinderium [, 2-c] p¡razole-3-M) -1,1' -biphenyl-4 -ol; 4 '- (6- { [(2-hydroxyethyl) amino] methyl.} -1,4-dihydroindeno [1,2- c] pyrazol-3-yl) -1,1' -biphenyl-4- ol; 4 '- (7- { [(2-hydroxyethyl) amino] methyl.} -1,4-dihydroindeno [1,2- c] pyrazol-3-yl) -1,1' -biphenyl-4- ol; 4'-. { 6 - [(butylamino) methyl] -1,4-dihydroindeno [1,2-c] pyrazol-3-yl} -1, 1'-biphenyl-4-ol; 1-. { [3- (4, -hydroxy-1,1, -biphenyl-4-yl) -1,4-dihydroindeno [1,2-c] pyrazol-6-yl] methyl} piperidin-4-ol; 4'-. { 6 - [(4-methylpiperazin-1-yl) methyl] -1,4-dihydroindeno [1,2-c] pyrazol-3-yl} -1, 1 '-biphenyl-4-ol; 4'-. { 6 - [(pyridin-4-ylamino) methyl] -1,4-dihydroindeno [1, 2-c] pyrazol-3'-yl} -1,1'-biphenyl-4-ol; 4 '- (6- { [(3-hydroxy-2,2-dimethylpropyl) amino] methyl.} -1,4-dihydroxydene [1,2-c] pyrazol-3-yl) -1 , 1 '-biphenyl-4-ol; 1-. { [3- (4, -hydroxy-1,1'-biphenyl-4-yl) -1,4-dihydroindeno [1,2-c] pyrazol-6-yl] methyl} piperidine-4-carboxamide; 4 '- [6- ( { [(5-Methylpyrazin-2-yl) methyl] amino.} Methyl) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] -1, 1 '-biphenyl-4-??; 4 '- (6-. {[[(Pyridin-2-ylmethyl) amino] n-ethyl] -1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -1,1-biphenyl- 4-ol; 4 '- (7- { [. (2-pyrrolidin-1-ylethyl) amino] methyl.} -1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -1,1' -biphenyl-4-ol; 4 '- [6- (thiomorpholin-4-ylmethyl) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] -1,1'-biphenyl-4-ol; [3- (4'-idroxy-biphenyl-4-yl) -1,4-dihydro-indene [, 2-c] pyrazol-6-yl] -morpholin-4-ü-methanone; 4 '- [6- (morpholin-4-ylcarbonyl) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] -1,1'-biphenyl-4-ol; N-cyclohexyl-3- (4'-hydroxy-1,1'-biphenyl-4-yl) -1,4-dihydroindeno [1,2-c] pyrazole-6-carboxamide; 4 '- [7- (morpholin-4-ylcarbonyl) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] -1,1'-biphenyl-4-ol; 3- (4'-hydroxy-1,1'-biphenyl-4-yl) -N- (2-hydroxyethyl) -1,4-dihydroindeno [1,2-c] pyrazole-7-carboxamide; 1-. { [3- (4'-hydroxy-1,1'-biphenyl-4-yl) -1,4-dihydroindeno [, 2-c] pyrazol-6-yl] carbonyl} piperidin-4-ol; 4 '- [6- (piperazin-1-ylcarbonyl) -1,4-dihydroindeno [1,2-c] pyrazole-3- il] -1,1'-b-phenyl-4-ol; 4'-. { 6 - [(4-methylpiperazin-1-yl) carbonyl] -1,4-dihydroindeno [1,2-c] pyrazol-3-yl} -1, i * -biphenyl-4-ol; 3- (4, -hydroxy-1,1, -biphenyl! -4-yl) -N- (pyridin-4-ylmethyl) -1,4-dihydroindeno [1,2-c] pyrazole-6-carboxamido; 1-. { [3- (4'-Hydroai-1,1, -biphenyl-4-yl) -1,4-dihydroindeno [1, 2-c] pyrazol-6-yl] carbonyl} piperidine-4-carboxamide; 3- (4'-hydroxy-1,1, -b-phenyl-4-yl) -N - [(5-methylpyrazin-2-yl) methyl] -1,4-d-hydroin.deno [1, 2 -c] pyrazole-6-carboxamide; 3- (4'-Hydroxy-1,1'-b-phenyl-4-yl) -N- (pyridin-2-ylmethyl) -1,4-dihydroindeno [1,2-c] pyrazole- 6-carboxamide; 3- (4 * -hydroxy-1, 1 '-biphenyl-4-yl) -l \ J-. { [6- (trmuorometl) pirin-3 ^ i 1] meti I.}. - 1,4-dihydroindeno [1,2-c] irazole-6-carboxamide; N- [2- (dimethylamino) ethyl] -3- (4'-hydroxy-1,1, -biphenyl-4-y!) - 1,4-dihydroindeno [1,2-c] pyrazole-6-carboxam gives; 3- (4'-hydroxy-1,1, -biphenl-4-yl) -N- (pyridin-3-i [methyl) -1,4-dihydroindeno [1,2-c] ] p -razol-6-carboxamide; N- [3- (4'-hydroxy-1,1'-biphenyl-4-yl) -1,4-dihydroindeno [1,2-c] pyrazol-6-yl] -2-morpholin-4-ylacetamide; N- [3- (4'-Hydroa-1,1'-b-phenyl] -4-yl) -1,4-dihydroindeno [1,2-c] pyrazol-5-yl] acetamide; N- [3- (4'-hydroxy-1, 1'-b-phenyl-4-yl) -1,4-dihydroindeno [1,2- c] pyrazol-6-yl] -2 - [(pir ' idin-4-methyl] amino] acetamide; N- [3- (4'-hydroxy-1, 1'-biphenyl-4-yl) -1,4-dihydroxyde [1, 2-c] pyrazol-6-yl] -2- [trans- ( 4-hydroxycyclohexyl) amino] acetamide; 2- (butylamino) -N- [3- (4, -hydroxy-1,1, -biphenyl-4-yl) -1,4-dihydroindeno [1, 2-c] pyrazol-6-yl] acetamide; N- [3- (4'-hydroxy-1,1'-bifem'l-4-yl) -1,4-dihydroindeno [1,2-c] pyrazol-6-yl] -2 - [(2- hydroxyethyl) to mino] to ceta mide; 3- (4'-hydroxy-1,1'-biphenyl-4-yl) -7-methoxy-N- (pyridin-4-ylmethyl) -1,4-dihydroxydene [1,2-c3-pyrazole- 6-carboxamide; 4 '- (6- { [(2-hydroxyethyl) amino] methyl.} - 7-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -1,1' - biphenyl-4 - ??; 4'-. { 7-methoxy-6 - [(4-methylpiperazin-1-yl) carbonyl] -, 4-dihydroindeno [1,2-c] irazol-3-yl} -1, 1'-biphenyl-4-ol; 3- (4'-hydroxy-1, 1'-biphenyl-4-yl) -N- (trans-4-hydroxycyclohexyl) -7-methoxy-1,4-dihydroindeno [1,2-c] p. -6-carboxam ida; 4 '- [7-methoxy-6- (morpholin-4-iicarbonyl) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] -1,1' -biphenyl-4-ol; 1-. { [3- (4'-hydroxy-1, '-biphenyl-4-yl) -7-methoxy-1,4-dihydroindene [1, 2-c] pyrazol-6-yl] carbonyl} piperidine-4-carboxamide; 1-. { [3- (4'-hydroxy-, 1'-biphenyl-4-yl) -7-methoxy-1,4-dihydroindeno [1, 2-c] pyrazol-6-yl] carbonyl} piperidin-4-ol; 4'-. { 7-methoxy-6 - [(4-methyl-piperazin-1-yl) methyl] -1,4-dihydroindeno [1,2-c] pyrazol-3-yl} -1, 1 '-biphenyl-4-ol; 4 '- (7-methoxy-6-. {[[(2-pyrrolidin-1-ylethyl) amino] methyl} -1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -1 , 1 '-biphenyl-4-ol; 4 '- (6- { [(Trans-4- idroxycyclohexyl) amino] methyl.}. -7-methoxy-, 4-dihydroindeno [1, 2-c] p ira zol-3-ii) -1, 1 '-bife nil-4-ol; 4'-. { 7-methoxy-6 - [(pyridin-4-ylamino) methyl] -1,4-dihydroindeno [1, 2- c] pyrazole-3-yl} -1,1'-bifen-1-4-ol; 1-. { [3- (4, -hydroxy-1,1'-biphenyl-4-yl) -7-methoxy-1,4-dihydroindeno [1, 2-c] p¡razol-6-yl] methyl} piperidine-4-carboxamide; 1-. { [3- (4'-hydroxy-, '-biphenyl-4-yl) -7-methoxy-1,4-dihydroindeno [1, 2-c] pyrazol-6-yl] methyl} piperidine-4-carboxamide; 3-fluoro-4 '- [6- (hydroaimethyl) -, 4-dihydroindeno [1, 2-c] pyrazol-3-yl] -1,1' biphenyl-4-ol; 3-fluoro-4 '- (7-methoxy-6-. {[[(2-pyrrolidin-1-ylethyl) amino] methyl} -1,4-dihydroindeno [1,2- c] pyrazole- 3-l) -1, 1 '-biphenyl-4 -?!; 3-fluoro-4'-. { 6 - [(4-methylpiperazin-1-yl) methyl] -1,4-dthydroindeno [1, 2-c] pyrazol-3-yl) -, 1 '-biphenyl-4-ol; 3- (3'-fluoro-4, -hydroxy-1,1'-biphenyl-4-yl) -N- (pyridin-2-yl] methyl) -1,4-dihydroindene [1,2] -c] pyrazole-6-carboxarnide; 3-f! Uoro-4 '- (7-. {[[(2-pyrrolidin-1-ylethyl) amino] methyl} -1,4-dihydroindeno [1, 2-c] pyrazole-3 il) -1, 1 '-biphenyl-4-ol; 3-fluoro-4 '- [7-methoxy-6- (morpholin-4-ylcarbonyl) -, 4-dihydroindeno [1, 2-c] pyrazol-3-yl] -, 1' -biphenyl-4-ol; 5-. { 6 - [(4-methylpiperazin-1-yl) methyl] -1,4-dihydroindeno [1,2- c] pyrazol-3-yl) pyridine-2-carbonitrile; 3- (6-cyanopyridin-3-yl) -N- (pyridin-2-yhnetM) -1,4-dihydroindeno [1,2-c] pyrazole-6-carboxamide; 5-. { 6 - [(4-hydroxy-piperidin-1-yl) methyl] -1,4-dihydroindeno [1, 2-c] p-aceol-3-yl} pyridine-2-carbonyltryl; 5- (6- { [(Pyridin-2-ylmethyl) amino] methyl} -, 4-dihydroindeno [1, 2-c] pyrazol-3-yl) pyridin-2-carbonitrile; 5- (6- { [(Trans-4-hydroxyclocloxyl) amino] methyl} -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl) pyridine-2-carbonitrile; 3- (6-cyanopyridin-3-yl) -N- (trans-4-hydroxycyclohexyl) -1,4-dihydrodeoxy [1,2-c] pyrazole-6-carboxamide; 3- (6-cyanopyridin-3-yl) -N-. { [6- (trifluoromethyl) pyridin-3-yl] methyl} -1,4-dihydroindeno [1,2-c] pyrazole-6-carboxamide; 5- [6- (hydroxymethyl) -1,4-dihydroindeno [1, 2-c] p¡razol-3-yl] pyridin-2-carbonitrile; 5-. { 6 - [(pyridin-3-yloxy) metii] -1,4-dihydroindeno [1, 2"-c] pyrazol-3-yl}. Pyridine-2-carbonitrile; 5-. {6 - [(pyridin 4-yloxy) methyl] -1,4-di-idroindeno [, 2-c] p¡razol-3-yl.} Pyridine-2-carbonityl; 3- (6-f lu or ropyridin-3-yl) -7-methoxy-4,4-di methyl-1,4-dihydroindeno [1,2-c] pyrazol-6-ol; 5- (6-hydroxy-7-methoxy-4,4-dimethyl-1,4) -dihydroindeno [1, 2-c] pyrazol-3-yl) pyridine-2-carbonitrile; 5- [7-methoxy-4,4-dimethyl-6- (pyridin-3-ylmethoxy) -1, 4- dihydroindeno [1,2-c] pyrazol-3-yl] pyridin-2-carbonitrile; 5- [7-methoxy-4,4-dimethyl-6- (3-morfoiin-4-ylpropoxy) -1, 4 -dihydroindeno [1, 2-c] pyrazol-3-yl] pyridine-2-carbonitrile; 5- [7-methoxy-4,4-dimethyl-6- (tetrahydrofuran-3-yloxy) -, 4-dihydroindene [1] , 2-c] pyrazol-3-yl] pyridine-2-carbonitrile; 5- (6- { [(2R) -2,3-dihydroapropyl] oxy} -7-methoxy-4, 4-dimethyl-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) pyridine-2-carbonitrile; 5- [7-methoxy-4,4-dimethyl-6- (pyridin-2-ylmethoxy) -1, 4-dihydroindene [1, 2-c] pyrazol-3-yl] pyridin-2-carbonitrile; 5- [7-methoxy-4,4-d, methyl-6- (3-piperidin-1-ylpropoxy) -1,4-dihydroindeno [1,2- c] pyrazol-3-yl] pyridine- 2-carbonitrile; 5- (6,7-Dimethoxy-4,4-dimethyl-, 4-dihydroindeno [1,2-c] pyrazol-3-yl) pyridine-2-carbonitrile; 5- [7-methoxy-6- (pyridin-2-ylmethoxy) -1,4-dihydro-mandene [1, 2-c] pyrazol-3-yl] pyridine-2-carbonitrile; 5-. { 7 - [(6-chloropyridin-3-yl) methoxy] -6-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl} pyridine-2-carbonitrile; 5- [6-methoxy-7- (pyridin-2-ylmethoxy) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] pyridine-2-carbonitrile; 5- [6-me * toxi-7- (2-piperidin-1-ylethoxy) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] pyridine-2-carbonitrile; 5- [6-methoxy-7- (pyridin-3-ylmethoxy) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] pyridine-2-carbonitrile; 5- [6-methoxy-7- (2-morpholin-4-ylethoxy) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] pyridine-2-carbonitrile; 5-. { 6-methoxy-7- [2- (4-methyl-1,3-thiazol-5-yl) ethoxy] -, 4-dihydroindeno [1,2-c] pyrazol-3-i !} pyridine-2-carbonitrile; 5- [6-methoxy-7- (2-pyrrolidin-1-yletoai) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] pyridine-2-carbonitrile; 5-. { 6-methoxy-7- [2- (2-oxopyrrolidin-1-yl) ethoxy] -, 4-dihydroindeno [1,2-c] pyrazolo-3-yl} pyridine-2-carbonitrile; 5- [7- (2-Hydryl-oxyethoxy) -6-methoxy-1,4-dihydroquinone [1,2-c] pi-I-3-yl] pyridine-2-carbonitrile; 5-. { 7 - [(6-Bromopyridin-2-yl) methoxy] -6-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl} pyridine-2-carbonitrile; 5- [7-methoxy-6- (pyridin-3-ylmethoxy) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] pyridin-2-carbonitrile; 5- [7-methoxy-6- (3-morpholm-4-ylpropoxy'i) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] pyridine-2-carbonitrile; 5- [7-methoxy-6- (tetrahydrofuran-3-yloxy) -1,4-dihydroindeno [1,2-cJpyrazol-3-yl] pyridine-2-carbonitrile; 5-. { 6- [3- (dimethylamino) propoxy] -7-methyxy-1,4-dihydroindeno [1,2-c] pyrazoI-3-M} pyridine-2-carbonitrile; 5-. { 7-methoxy-6- [2- (4-methyl-1,3-thiazol-5-yl) ethoxy] -1,4-dihydroin-ene [1,2-c] pyrazol-3-yl} iri, din-2-carbonitrile; 5- [6- (2-hydroxyethoxy) -7-methoxy-1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] pyridine-2-carbonitrile; 5-. { 6 - [(6-Bromopyridin-2-yl) methoxy] -7-methoxy-1,4-dihydroindene [1, 2-c] pyrazol-3-yl} pyridine-2-carbonitrile; 5-. { 6 - [(6-chloropyridin-3-yl) methoxy] -7-methoxy-1,4-dihydroindeno [, 2-c] pyraz-3-yl} pyridine-2-carbonitrile; 5- [7-methoxy-6- (2-morpholin-4-ylethoxy) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] pyridine-2-carbonitrile; 5-. { 6- [2- (5-ethylpyridin-2-yl) ethoxy] -7-methoxy-, 4-dihydroindeno [, 2-c] pyrazol-3-yl} pyridine-2-carbonitrile; 4 '- (6,7-dimethoxy-1,4-dihydroindeno [1, 2-c] pyrazol-3-yl) -3-methoxy-1,1' -biphenyl-4-ol; 4- (6,7-dimethoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol; 3- (4'-hydroxy-1, 1'-biphenyl-4-yl) -, 4-dihydroindeno [1,2-c] p¡razole-6,7-diol; 4 (6,7-dimethoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzonitrile; 3- (6-hydroxy-2-naphthyl) -1,4-dihydroindeno [1,2-c] pyrazol-6-ol; 6,7-dimethoxy-3- [4- (1 H -pyrrol-2-yl) phenyl] -1,4-dihydroindeno [1,2-c] pyrazole; 6,7-dimethoxy-3- [4- (1 H -pyrazol-4-yl) phenyl] -1,4-dihydroindeno [1,2-c] pyrazole; 3- (4-bromophenyl) -7-methoxy-, 4-dihydroindeno [1,2-c] pyrazol-6-ol; 3- (4'-hydroxy-1,1'-biphenyl-4-yl) -7-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-6-ol; * 3- (4'-hydroxy-3'-methoxy-1,1'-biphenyl-4-yl) -7-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-6-ol; 4 '- [7-methoxy-6- (pyridin-2-ylmethoxy) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] -1, 1'-biphenyl-4-ol; 4 '- [7-methoxy-6- (pyridin-4-ylmethoxy) -1,4-dihydroindeno [1, 2-c] pyrazol-3-y!] -1,1' -biphenyl-4-ol; 4 '- (7-methoxy-6-. {3- [4- (2-methoxyphenyl) piperazin-1-yl] pro oxy} -1,4-dihydroindeno [1,2-c] pirazo! 3-yl) -1, 1'-biphenyl-4-ol; 4 '- (6- { 3- [4- (3-chlorophenol) piperazin-1-yl] propoxy.} - 7-methoxy-1,4-dihydroindeno [1,2-.c] pyrazole -3- jl.} -1, 1 '-biphenyl-4-ol; 4'-. {6- [2- (dimethylamino) ethoxy] -7-methoxy-1,4-dihydroindene [, 2-c] ] pyrazol-3-yl.} -1, 1'-bifenll-4-ol; 4 '- [7-methoxy-6- (2-piperidin-1-ylethoxy) -1,4-dihydroindene [1, 2] -c] pyrazol-3-yl] -1, 1 '-biphenyl-4-ol; 4, - [7-methoxy-6- (3-piperidin-1-ylpropoxy) -1,4-dihydroindenp [1, 2-c] pyrazol-3-yl] -1, 1 '-biphenyl-4-ol; 4'-. { 6- [2- (dimethylamino) -1-methoxy] -7-methoxy-1,4-dihydroxyde [1, 2-c] pyrrazol-3-yl) -1, 1'-biphenyl -4-ol; 4'-. { 7-methoxy-6- [2- (1-methylpyrrolidin-2-yl) ethoxy] -1,4-dihydroxydene [1, 2-c] pyrazol-3-yl} -1, 1'-biphenyl-4-ol; 4'-. { 6- [2- (1 H-imidazol-1-yl) e.toxy] -7-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl} -1, 1 '-biphenyl-4-ol; 4 '- [7-methoxy-6- (2-morfo1in-4-ylethoxy) -1,4-dihydroindeno [, 2-c] pyrazol-3-yl] -1,1' -biphenyl-4-ol; 4'-. { 6- [3- (dimethylamine) propoxy] -7-methioxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl} -1, 1 '-biphenyl-4-ol; 4 '- [7-methoxy-6- (2-pyrrolidin-1-ylethoxy) -1,4-dihydroindeno [, 2-c] pjrazol-3-yl] -1,1' -biphenyl-4-ol; 4.'-. { 6- [2- (diethylamino) ethoxy] -7-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl} -1, 1 '-biphenyl-4-ol; 4 '- [7-methoxy-6- (pyridin-3-ihnetoxy) -, 4-dihydroindeno [1, 2-c] pyrazol-3-yl] -1, 1' -biphenyl-4-ol; 4 '- [7-methoxy-6- (2-pyridin-2-ylethoai) -, 4-dihydroindeno [, 2-c] pyrazol-3-yl] -1, 1' -biphenyl-4-ol; 4'-. { 6- [2- (5-ethylpyridin-2-yl) ethoxy] -7-methoxy-1,4-dihydroindeno [1,2-c] irazol-3-yl} -1, 1 '-biphenyl-4-ol; 4 '- [7-methoxy-6- (2-pyridin-4-ylethoxy) -, 4-di idroindeno [, 2-c] pyrazol-3-yl] -1, 1' -biphenyl-4-ol; 2-. { [3- (4'-hydroxy-, 1'-biphenyl-4-yl) -7-methoxy-, 4-di idroindene [1, 2-c] pyrazol-6-yl] oxy} propane-1, 3-diol; (2S) -3-. { [3- (4'-Hydroai-1,1'-biphenyl-4-yl) -7-methoxy-1,4-dihydroindeno [1, 2-c] pyrazol-6-yl] oxy) propane-1, 2 -diol; (2R) -3-. { [3- (4, -hydroxy-1I1'-biphenyl-4-yl) -7-methoxy-1,4-dihydroindeno [1, 2-c] pyrazol-6-yl] oxy} propane-1,2-diol; 4 '- (7-methoxy-6- { 2- [3- (6-methylpyridin-2-yl) propoxy] ethoxy) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -, 1 '-biphenyl-4-ol; 4'-. { 6- [3-chloro-2- (hydroxymethyl) -2-methylpropoxy] -7-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl} -1, 1 '-biphenyl-4-ol; N, N-diethyl-2-. { [3- (4, -hydroxy-1,1'-biphenyl-4-M) -7-methoxy-1,4-dihydroindeno [1, 2-c] irazol-6-yl] oxy} to ceta mida; 4 '- [7-metoa-6- (tetrahydrofuran-3-ylmethoxy) -1,4-dihydroindeno [1,2-c] pyrazolo-3-yl] -1, 1'-biphenyl-4-ol; 4 '- [7-methoxy-6- (tetrahydro-2H-pyran-4-yloxy) -1,4-dihydroxyde [1,2-c] pyrazol-3-yl] -1,1-biphenyl-4 -ol; 4 '- [7-methoxy-6- (2-pyridin-3-ylethoxy) -1,4-dihydroindeno [1, 2-c] pyrazol-3-i (] - 1, 1'-biphenyl-4-ol; 4 '- [7-methoxy-6- (tetrahydrofuran-3-yloxy) -1,4-dihydroxyde [1,2-c] irazol-3-yl] -1,' -biphenyl-4-ol; '- [6- (cyclohex-3-en-1-ylmethoxy) -7-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl] -, 1' -biphenyl-4-ol; 4 '- [7-methoxy-6- (3-morpholin-4-ylpropoxy) -, 4-dihydroindeno [1, 2-c] pyrazol-3-yl] -, 1' -biphenyl-4-ol; (6-hydroxy-7-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzonitrile; 4- [7-methoxy-6- (pyridin-2-ylmethoxy) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] benzonitrile; 4- [7-methoxy-6- (pyridin-3-ylmethoxy) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] benzonitrile; 4- [7-methoxy-6- (pyridin-4-ylmethoxy) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] benzonitrile; 4- [7-methoxy-6- (tetrahydro-2H-pyran-4-Hoxy) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] benzonitrile; 4- [7-methoxy-6- (3-morpholin-4-ylpropoxy) -1,4-dihydro-malene [1,2-c] pyrazol-3-yl] benzonitrile; 4- (6- { [(2R) -2,3-dihydroxypropyl] oxy} -. 7-methoxy-1,4-dihydroindeno [1,2-c] pi-reazo-3-yl) benzonit ril; 4-. { 6- [2- idroxy-1 - (hydro) imetii) ethoxy] -7-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl} benzonitrile; 4-. { 6- [2- (5-ethylpyridin-2-yl) ethoxy] -7-methoxy-, 4-dihydroindeno [1, 2-c] pyrazol-3-yl) benzonitrile; 4-. { 7-methoxy-6- [2- (5-methyl-, 3-thiazol-4-yl) ethoxy] -1,4-dihydroindeno [1,2-c] pyrazol-3-yl} benzonitrile; 4-. { 6- [3- (dimethylamino) propoxy] -7-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl} benzonitriium; 4- [7-methoxy-6- (tetrahydrofuran-3-ylmethoxy) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] benzonitrile; 4- [7-methoxy-6- (tetrahydrofuran-3-yloxy) -, 4-dihydroindeno [1, 2-c] p irazol-3-yl] benzo nitrite; 4-. { 6- [2- (2,5-dioxopyrrolidin-1-yl) ethoxy] -7-methoxy-1, 4- dihydroindeno [1, 2-c] p¡razol-3-yl} benzonitrile; 4-. { 6- [2- (3,5-Dimethyl-1H-pyrazol-1-M) ethoxy] -7-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-iJ} benzonitrile; 3- (4-cyanophenyl) -N- (4-hydroxycyclohexyl) -7-methoxy-1,4-dihydroindeno [1,2-c] pyrazole-6-carboxamide; 3- (4-cyanophenyl) -7-methoxy-1,4-dihydroindeno [1,2-c] pyrazole-6-carboxylic acid; 3- (4-cyanophenyl) -7-methoxy-N- (pyridin-2-yl-ethyl) -, 4-dihydroindeno [1,2-c] pyrazole-6-carboxamide; 3- (4-cyanophenyl) -7-methoxy-N- (pyridin-3-ylmethyl) -1,4-dihydroindene [1, 2-c] pyrazole-6-carboxamide; 3- (4-cyanophenyl) -7-methoxy-N- (pyridin-4-ylmethyl) -1,4-dihydroindeno [1,2- c] pyrazo! -6-carboxamide; 3- (4-cyanophenyl) -7-methoxy-N- (4-morpholin-4-ylphenyl) -1,4-dihydroindeno [1,2-c] p-razo l-6-carboxamido; 3- (4-cyanophenyl) -7-methoxy-N- (2-pyrrolidin-1-ylethyl) -1,4-dihydroindeno [1,2-c] pyrazole-6-carboxamide; 3- (4-cyanophenyl) -7-methoxy-N- (2-piperidin-1-ylethyl) -1,4-dihydroindeno [1,2-c] pyrazole-6-carboxamide; 3- (4-cyanophenyl) -7-methoxy-N- (2-morpholin-4-ylethyl) -1,4-dihydroindeno [1,2-c] pi-azole-6-carboxamido; 4- (6- { [(4-hydroxycyclohexyl) amino] methyl) -7-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzonit; 4- [6- (1 H -imidazol-1-ylmethyl) -7-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl] benzonit; 3- (6-chloropifidin-3-yl) -6,7-dimethoai-1,4-dihydroindeno [1,2-c] pyrazole; 4- [5- (6,7-dimethoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) pyridin-2-ylphenol; 4- [5- (6,7-dimethoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) pyridin-2-yl] -2-methoxyphenol; 4- [5- (6,7-dimethoxy-1,4-dihydroindeno [1, 2-c] pyrazol-3-yl) pyridin-2-yl] -2-fluorophenol; 5- (6,7-dimethoxy-1,4-dihydroquinone of [1, 2-c] pyrazol-3-yl) pyridine-2-carbonit; 6- (6,7-dimethoxy-1,4-dihydroindeno [1, 2-c] p¡razol-3-yl) nicotinonit; 3- (5-Bromopyridin-2-yl) -6,7-dimethoxy-1,4-dihydro-mandene [1,2-c] pyrazole; 4, - [6- (1-Hydroxy-1-methylethyl) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] -1,1'-biphenyl-4-oi; 4- [6- (1-id roxi- -metí I eti I) -1,4-dih id roin den or [1, 2-c] pyrazol-3-yl] benzonit; 2- [3- (6-chloropyridin-3-yl) -1,4-dihydroindeno [1,2-c] pyrazol-6-yl] propan-2-ol; 4-. { 5- [6- (1-hydroxy-1-methylethyl) -1,4-dihydroindeno [1,2- c] pyraz! -3-yl] pyridin-2-yl) phenol; 3- (5,6-dichloropyridin-3-yl) -6,7-dimethoxy-1,4-dihydroquinone [1,2-c] pyrazole; 2- [3- (6-fluoropyridin-3-yl) -1,4-dihydroindeno [, 2-c] pyrazol-6-yl] propan-2-ol; 6,7-dimethoxy-3-pyrazin-2-yl-1,4-dihydroindeno [1,2-c] pirazoi; 6,7-dimethoxy-3-pyridin-3-yl-1,4-dihydroindeno [1,2-c] pyrazole; 6,7-dimethoxy-3-pyrimidin-5-yl-1,4-dihydroindeno [1,2-c] pyrazole; 3- (6-chloropyridin-3-yl) -7-ethyl-6-methoxy-1,4-dihydroindeno [1,2-c] pyrazole; 5- (7-ethyl-6-methoai-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) pyridine-2-carbonit; 3- (6-chloropyridin-3-yl) -7-ethylyl-6- (tetrahydro-2 H -pyran-4-yloxy) -1,4-dihydroindeno [1,2-c] pyrazole; 4- . { 5- [7-ethyl-6- (tetrahydro-2 H -pyran-4-yloxy) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] pyridin-2-yl} phenol; 5- [7-ethyl-6- (3-morpholin-4-ylpropoxy) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] pyridine-2-carbonit; 5- [7-ethyl-6- (tetrahydrofuran-3-ylmetoai) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] pyridine-2-carbonit; 5- [7-ethyl-6- (tetrahydrofuran-3-yloxy) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] pyridine-2-carbonit; 5-. { 7-ethyl-6 - [(4-hydroxycyclohexyl) oxy] -1,4-dihydroindeno [1,2-c] pyrazol-3-yl} pyridine-2-carbonit; 5- [7-ethyl-6- (tetrahydro-2 H -pyran-4-yloxy) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] pyridine-2-carbonit; 5- [7-Eiyl-6- (pyridin-2-ylmethoxy) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] pyridin-2-carbonyl ester; 5- (6,7-diethyl-1,4-dihydroindeno [1,2- c] pyrazol-3-yl) pyridin-2- coal itri lo; 3- (6-chloropyridin-3-yl) -6,7-bis (2-methoxyethoxy) -1,4-dihydroindeno [1,2-c] pyrazole; 5- [6,7-bis (2-methoxyethoxy) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] pyridine-2-carbonit; 6- hydroxy-3- (4'-hydroxy-1,1'-biphen-4-yl) -7-methoxyindeno [1,2-c] pyrazol-4 (1 H) -one; 3- (4'-hydroxy-1, 1 '-bifenii-4-yl) -7-methoxy-6- (2-piperidin-1-ylethoxy) -indeno [1,2-c] pi razo 1-4 ( 1 H) -one; * 3- (4'-hydroxy-1, 1'-biphenyl-4-yl) -7-methoxy-6 - [(1-methylpiperidin-3-y!) Methoxy] indene [1, 2-c] pyrazole-4 (1 H) -one; 6- { 3- [4- (3-chlorophenyl) piperazin-1-yl] pro oxy} -3- (4'-hydroxy-1, 1'-biphenyl-4-yl) -7-methoxy-indene [1, 2-c] -prazole 1-4 (1 H) -one; 4- . { 6- [3- (dimethylamino) ropoxy] -7-methoxy-4-oxo-1, 4- di idroindenot, 2-c] pyrazol-3-yl} benzonit; 4- (6-hydroxy-7-methoxy-4-oxo-, 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzonit; 4- [7-methoxy-4-oxo-6- (tetrahydrofuran-3-yloxy) -, 4-dihydroindeno [1,2-c] pyrazol-3-yi] benzo nitrite; 4- [7-methoxy-6- (3-morpholin-4-yipropoai) -4-oxo-1,4-dihydroindeno [1,2-c] pyrazol-3-yl] benzonit; 3- (6-chloropyridin-3-yl) -6,7-dimethoxy-4-methyl-1,4-di-idroindeno [1,2-c] pyrazol-4-ol; 4 '- [6-methoxy-7- (2-pyrrolidin-1-ylethoxy) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] -1,' -biphenyl-4-ol; 4 '- [6-methoxy-7- (2-morpholin-4-ifethoxy) -1,4-dihydroindeno [1,2-c] pyrazol-3-M] -1,1' -biphenyl-4-ol; 4'-. { 7- [2- (diethylamino) ethoxy] -6-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl} -1, 1'-biphenyl-4-ol; 4 '- [6-methoxy-7- (pyridin-3-ylmethoxy) -1,4-dihydroxyde [1,2-c] pyrazol-3-yl] -1,1-biphenyl-4-ol; 4 '- [6-methoxy-7- (pyridin-2-ylmethoxy) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] -1,1'-biphenyl-4-ol; 4 '- (7- { 3- [4- (3-chlorophenyl) piperazin-1-yl] proppxy.} - 6-methoxy-1,4-dihydroindeno [1,2-c] pyrazole-3 -yl) -1, 1 '-biphenyl-4-ol; 4 '- [6-methoxy-7- (pyridin-4-ihnetoxy) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] -1,1' -biphenyl-4-ol; 4'-. { 7- [2- (dimethylamino) ethoxy] -6-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl} -1, 1'-biphenyl-4-of; 4 '- [6-methoxy-7- (2-piperidin-1-ylethoxy) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] -1,' -biphenyl-4-ol; 4'-. { 7- [3- (dimethylamino) propoxy] -6-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl} -1, 1 '-biphenyl-4-ol; 4 '- [6-methoxy-7- (3-piperid'm-1-ylpropoxy) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] -1,' -biphenyl-4-ol; 4'-. { 7- [2- (dimethylamino) -1-methyletoai] -6-methoxy-, 4-dihydroindeno [1,2-c] pyrazol-3-yl} -1, 1 '-biphenyl-4-ol; 4 '- (7-. {2- (dimethylamino) -1 - [(dimethylamino) methyl] ethoxy.} - 6-methoxy-, 4-dihydroindeno [1,2- c] pyrazol-3-yl) - 1, 1 '-biphenyl-4-ol; 4'-. { 7 - [(1-ethylpiperidin-3-yl) oxy] -6-methoxy-1,4-dihydroindene [1, 2- c] pyrazol-3-yl} -1,1'-b-phenyl-4-ol; 4'-. { 7- [3- (dimethylamino) -2-methylpropoxy] -6-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl} -1, 1 * -biphenyl-4-ol; 4'-. { 6-methoxy-7- [2- (1-methylpyrrolidin-2-yl) ethoxy] -, 4-d i hydroindeno [1,2-c] pyrazol-3-yl} -1, 1 '-biphenyl-4-ol; 4"- { 7- [2- (1 H-imidazol-1-yl) ethoxy] -6-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl}. -1, 1'-biphenyl-4-ol; 4'-. {6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy] -1,4-dihydroindene [1, 2-c] ] irazol-3-yl.} -1, 1'-biphenyl-4-ol; 3- (4'-hydroxy-1, 1'-biphenyl-4-ii) -6-methoxy-1,4-dihydroindenol , 2-c] pyrazol-7-ol; 3- (4'-hydroxy-1,1 '-biphenyl-4-yl) -6-methoxy-N- [2- (4-methylpiperazin-1-yl) ethyl ] -1,4-dihydroindeno [1,2-c] pyrazole-7-carboxamide; 3- (4'-hydroxy-1,1-biphenyl-4-yl) -6-methoxy-N- (pyridine-2) -iimethyl) -1,4-dihydroindeno [1,2-c] pyrazole-7-carboxamide; 3- (4'-hydroxy-1,1'-biphenyl-4-yl) -6-methoxy-N- (pyridine -4-ylmethyl) -1,4-dihydroindeno [1,2-c] pyrazole-7-carboxamide; N- [2- (diethylamino) ethyl] -3- (4'-hydroxy-1, '-biphenyl-4 -iI) -6-methoxy-1,4-dihydroindeno [1,2-c] pyrazole-7-carboxamide; N- [3- (diethylamino) propyl] -3- (4 * -hydroxy-, 1, -b phenyl-4-yl) -6-methoxy-, 4-dihydroindeno [, 2-c] pyrazole-7-carboxamide; N- [4- (diethylamine) butyl] -3- (4'-hydroxy-1, 1 '-biphenyl-4-yl) -6-methoxy-1,4-dihydroxy ndeno [, 2-c] pyrazole-7-carboxamide; N- [2- (dimethylamino) ethyl] -3- (4'-hydroxy-1,1'-biphenyl-4-yl) -6-methoxy-1,4-dihydroindeno [1,2-c] pyrazole-7 -carboxamide; 3- (4'-hydroxy-, 1 '-biphenyl-4-H) -6-methoxy-N- (2-pyrrolidin-1-ethylthi) -1,4-dihydroindeno [1,2-c] pyrazole-7 -carboxamide; 3- (4 '- ??? (? G ??? - 1,1'- ?? ß ??? - 4 -?) - 6-? T? ß ???? -? - (3-? G ((α) -1- [[G (G)] -1,4-dihydroxydene [1,2-c] pyrazole-7-carboxamide; 3- (4"-hydroxy-1, 1'-biphenyl-4-ii) -6-methoxy-N- (2-piperidin-1-ethylthyl-1-dihydroindenotl, 2-c] pyrazole-7-carboxamide; 3- (4'-hydroxy) 1,1 '-biphenyl-4-yl) -6-methoxy-N- (3-piperidin-1-ylpropyl) -1,4-dihydroindeno [1,2-c] pyrazole-7-carboxamide; '-hydroxy-1, 1' -biphenyl-4-yl) -6-smetoxy-N- (2-morpholin-4-ylethyl) -1,4-dihydroindenol, 2-c] pyrazole-7-carboxamide; N- [2- (dimethylamino) ethyl] -3- (4'-hydroxy-1,1 '-biphenyl-4-yl) -6-methoxy-N-methyl-1,4-dihydroindeno [1,2-c] pyrazole -7-carboxamide; N- [3- (dimethylamino) propyl] -3- (4'-hydroxy-1,1'-biphenyl-4-yl) -6-methoxy-N-methyl-1,4-dihydroindene [ 1, 2-c] pyrazole-7-carboxamide; 4'-. {6-methoxy-7 - [(4-methyl-1,4-diazepan-1-yl) carbonyl] -1,4-dihydroindene [1 , 2-c] pyrazol-3-yl) -1, 1 '-biphenyl-4-ol; 6-methoxy-3-. {4- [3- (1-methylpyrrolidin-2-yl) propoxy] phenyl} -7- (2- i eridin-1-ylethoxy) -, 4-dihydroindeno [1, 2-c] pyrazole; 1 - { 4- [6- methoxy-7- (2-piperidin-1-ylethoxy) -1,4-dihydroindeno [, 2-c] pyrazol-3-yl] phenoxy} acetone; [4- (6,7-dimethoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-M) phenii] methanol; 3- (4-cyanophenyl) -6-methoxy-N- (pyridin-4-ylmethyl) -1,4-dihydroindeno [1,2-c] pyrazole-7-carboxamide; 3- (4-cyanophenyl) -6-methoxy-1,4-dihydroindeno [1,2-c] pyrazole-7- methyl carboxylate; 3- (4-cyanophenyl) -N- (trans-4-hydroxycyclohexyl) -6-methoxy-1,4-dihydroindeno [1,2-c] pyrazole-7-carboxamide; 4- [6-methoxy-7- (pyridin-3-ylmethoxy) -1,4-dihydro-mandene [1, 2-c] pyrazol-3-yl] benzonitrile; 4-. { 7- [2- (dimethylamino) ethoxy] -6-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzonitrile; 4- [6-methoxy-7- (pyridin-4-ylmethoxy) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] benzonitrile; a 3 > 4 '- [6-methoxy-7- (trifluoromethoxy) -1,4-dihydroxy [1,2-c] pyrazol-3-yl] -1,1-biphenyl-4-ol; 4 - [(6,7-dimethoxy] -1,4-dihydroindeno [1,2-c] pyrazol-3-yl) etiriyl] phenol; 4 - [(6,7-dimethoxy-1,4-dihydro-malene [1,2-c] pyrazol-3-yl) ethynyl] -2-methoxyphenol; 4 '- (6-morpholin-4-yl-1,4-dihydroindeno [1, 2-c] pyrazol-3-yl) -1, 1' -biphenyl-4-ol; 3-methoxy-4 '- (6-morpholin-4-yl-1,4-dihydro-mandene [1,2-c] pyrazol-3-yl) -1,1'-biphen
  1. I-4 ol; 4- (6-morpholin-4-yl-1,4-dihydroindeno [, 2-c] p¡razol-3-yl) benzonitrile; 4- t5- (6-morpholin-4-yl-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) pyridin-2-yl] phenol; 3- (6-chloropyridin-3-yl) -6-morpholin-4-yl-1,4-dihydroindeno [1,2-c] pyrazole;
  2. 2-methoxy-4- [5- (6-morpholin-4-yl-1,4-dihydroindeno [1, 2-c] pyrazol-3-yl) pyridin-2-yl] phenol; 5- (6-morpholin-4-y1-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) pyridin-2-carbonitrile; 5- (6,7-Diisopropoxy-1,4-d ihyd) ruthenium [1,2-c] pyrazolo-3-yl) pyridine-2-carbonitrile; 3- (6-chloropyridin-3-yl) -6,7-diisopropoxy-1,4-dihydroindeno [1,2-c] pyrazole; 4- [5- (6,7-diisopropoxy] -1,4-dihydroindeno [1,2-c] pyrazol-3-yl) & pyridin-2-yl] phenol; 4- [5- (6,7-diisopropoxy-1,4-dihydroxydeno [1,2-c] pyrazol-3-yl) pyridin-2-yl] -2-methoxy-phenol; 5- [6- (tetrahydro-2 H -pyran-4-yloxy) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] pyridine-2-carbonitrile; 3- (6-chloropyridin-3-yl) -6- (tetrahydro-2 H -pyran-4-yloxy) -1,4-dihydro-mandene [1,2-c] pyrazole; 4- . { 5- [6- (Tetrahydro-2H-pyran-4-yloxy) -1,4-dihydroxydene [1,2-c] pyrazol-3-yl] pyridin-2-yl} phenol; 2-methoxy-4-. { 5- [6- (Tetrahydro-2H-pyran-4-yloxy) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] pyridin-2-yl} phenol; 5- (6-α-Propoxy-1,4-dihydroindeno [1,2-c] pi-razo-l-3-yl) pyridin-2-carbonitrile; 5- (6-isopropoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) pyridine-2-carbonitrile; 4- [5- (6-isopropoxy-1,4-di idroindeno [1,2-c] pyrazol-3-yl) pyridin-2- il] phenol; 4- [5- (6-iso ropo) ri-1,4-dihydroindeno [1, 2-c] pyrazol-3-yl) pyridin-2-ii] -2-methoxyphenol; 5- (6,7-diethoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) pyridine-2-carbonitrile; 3- (6-chloropyridin-3-yl) -6,7-diethoi-1,4-dihydroindeno [1,2-c] pyrazole; 4- [5- (6,7-diethoxy-1,4-dihydroindeno [1, 2-c] pyrazol-3-yl) iridin-2-yl] phenol; i > 4- [5- (6,7-diethoxy-, 4-dihydroindeno [1, 2-c] pyrazol-3-yl) pyridin-2-yl] -2-methoxyphenol; 5- [6,7-bis (difluoromethoxy) -1,4-dihydroindromo [1,2-c] pyrazol-3-yl] pyridine-2-carbonitrile; 3- (6-chloropyridin-3-yl) -6,7-bis (difluoromethoxy) -1,4-dihydroindeno [, 2-c] pyrazole; 4- . { 5- [6,7-bis (difluoromethoxy) -1,4-dihydroindeno [1,2-c] irazol-3-yl] pyridin-2-yl} phenol; 5- [6- (1H-1, 2,4-triazol-1-ylmethyl) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] pyridine-2-carbonitrile; 3- (6-c! Oropyridin-3-yl) -6- (1H-1,2,4-triazol-1-ylmethyl) -1,4-dihydroindeno [1,2-c] pyrazole; 4-. { 5- [6- (1H-1,2,4-triazol-1-ylmethyl) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] pyridin-2-yl} phenol; 4- [6- (1 H-, 2,4-triazol-1-ylmethyl) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] benzonitrile;
  3. 3- (
  4. 4-bromophenyl) -6- (1H-1,2,4-triazol-1-ylmethyl) -1,4-dihydroindeno [1,2-c] pyrazole; 4 '- [6- (1H-1, 2,4-triazol-1-ylmethyl)) - 1,4-dihydroindeno [1,2-c] pyrazol-3-yl] -1,1-biphenyl 4- ol; 4-. {
  5. 5- [
  6. 6- (diethylamino) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] pyridin-2-yl) phenol; 3- (6-chloro-pyridin-3-yl) -N, N-diethyl-1,4-dihydroindeno [1,2-c] pyrazol-6-amine; 5- [6- (diethylamino) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] pyridine-2-carbonitrile; 4- . { 5- [6- (diethylamino) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] pyridin-2-yl} -2-methoxyphenol; 5- [6- (tetrahydrofuran-3-ylmethoxy) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] pyridine-2-carbonitrile; 5-. { 6 - [(3-methylcyclohexyl) oxy] -1,4-dihydroindeno [1,2-c] pyrazol-3-yl} pyridine-2-carbonitrile; 5- [6- (cyclohexylmethoxy) -1,4-dihydroindeno [1,2-c] pyrazol-3-yl] pyridine-2-carbonitrile; 5- [6- (pyridin-2-ylmethoxy) -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl] pyridine-2-carbonitrile; 5- [6- (2-pyridin-2-ylethoxy) -1,4-dihydroindeno [, 2-c] pyrazol-3-yl] pyridine-2-carbonitrile; 5- (6- { 2- [4- (dimethylamino) phenyl] ethoxy] -1,4-dihydroindeno [1, 2-c] pyrazol-3-yl) pyridine-2-carbonitrile; 5-. { 6 - [(4-hydroxycyclohexyl) oxy] -1,4-dihydroindeno [1,2-c] pyrazole-3- il} pyridine-2-carbonbonitrile; 5-. { 6- [2- (4-methyl-1,3-thiazo! -5-yl) ethoxy] -1,4-dihydroindeno [1,2-c] pyrazol-3-yl} pyridine-2-carboxamide; 5- [6- (2-hydroacetyl) -1,4-dihydro-mandene [1, 2-c] pyrazol-3-yl] pyridine-2-carbonitrile; 5- [6- (difluoromethoxy) -
  7. 7-methoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl] pyridin-2-carbonitrile; 3- (6-chloropyridyl-3-yl) -6- (difluoromethoxy) -7-methoxy-1,4-dihydroindeno [1,2-c] pyrazo I; and l 4-. { 5- [6- (difluorometoai) -7-methoxy-1,4-dihydro-mandene [1,2-c] p-aceol-3-yl] pyridine 2-yl} phenol. 29. A compound that is 1, ¾ '-bipi pe ri di n- 1' -carboxylic acid 4 '- (6,7-dimethoxy-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -1, 1'-biphenyl-4-yl. 30. A pharmaceutical composition comprising a compound of the formula (I) or a therapeutically acceptable salt thereof in combination with a therapeutically acceptable carrier. 31. A method for inhibiting protein kinases in a patient with the recognized need for such treatment, comprising a therapeutically acceptable amount of a compound of the formula (I) or a therapeutically acceptable salt thereof. 32. A method of treating cancer in a patient with the recognized need for such treatment, comprising administering to the patient a therapeutically effective amount of a compound of the formula (I) or a therapeutically acceptable salt thereof.
MXPA05009576A 2003-03-07 2004-03-04 Fused tri and tetra-cyclic pyrazole kinase inhibitors. MXPA05009576A (en)

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WO2005118543A1 (en) * 2004-06-03 2005-12-15 Ono Pharmaceutical Co., Ltd. Kinase inhibitor and use thereof
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US8853207B2 (en) 2012-04-12 2014-10-07 Development Center For Biotechnology Heterocyclic pyrazole compounds, method for preparing the same and use thereof
US9475816B2 (en) 2012-09-07 2016-10-25 Takeda Pharmaceutical Company Limited Substituted-1,4-dihydropyrazolo[4,3-b]indoles
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Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2969371A (en) * 1959-02-03 1961-01-24 Robert A Braun Substituted indeno [1, 2-c] pyrazole derivatives
US2969373A (en) * 1959-10-27 1961-01-24 Smith Kline French Lab Trifluoromethylpyrazoloindenone derivatives
US3004983A (en) * 1960-05-16 1961-10-17 Smith Kline French Lab 4-aminopyrazolo [3, 4-a] indene derivatives
BE789948A (en) * 1971-10-13 1973-04-11 Sandoz Sa NEW DERIVATIVES OF PYRAZOLE, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS
DD100256A5 (en) * 1971-10-13 1973-09-12
US3843665A (en) * 1973-04-11 1974-10-22 Sandoz Ag Process for preparing substituted indeno,naphtho and cyclohepta pyrazoles
US3843666A (en) * 1973-05-29 1974-10-22 Sandoz Ag Process for preparing substituted indeno,naphtho and cyclohepta pyrazoles
JPS60130521A (en) * 1983-12-19 1985-07-12 Morishita Seiyaku Kk Anticancer agent
DE69818083T2 (en) * 1997-10-06 2004-07-08 Abbott Gmbh & Co. Kg INDENO [1,2-c] -, NAPHTHO [1,2-C] AND BENZO [6,7] CYCLOHEPTA [1,2-c] PYRAZOLE DERIVATIVES
EP1021182A1 (en) * 1997-10-06 2000-07-26 Basf Aktiengesellschaft Indeno[1,2-c] pyrazole derivatives for inhibiting tyrosine kinase activity
IL142584A0 (en) * 1998-11-06 2002-03-10 Basf Ag Tricyclic pyrazole derivatives
US6462036B1 (en) * 1998-11-06 2002-10-08 Basf Aktiengesellschaft Tricyclic pyrazole derivatives
CA2368686A1 (en) * 1999-04-06 2000-10-12 Knoll Gmbh Substituted 1,4-dihydroindeno[1,2-c]pyrazoles as inhibitors of tyrosine kinase
US6297238B1 (en) * 1999-04-06 2001-10-02 Basf Aktiengesellschaft Therapeutic agents
US6670358B2 (en) * 2000-05-16 2003-12-30 Cephalon, Inc. Substituted thioacetamides

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