CO5021223A1 - CALCILITICAL CALCILITICAL COMPOUNDS - Google Patents

CALCILITICAL CALCILITICAL COMPOUNDS

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Publication number
CO5021223A1
CO5021223A1 CO99020600A CO99020600A CO5021223A1 CO 5021223 A1 CO5021223 A1 CO 5021223A1 CO 99020600 A CO99020600 A CO 99020600A CO 99020600 A CO99020600 A CO 99020600A CO 5021223 A1 CO5021223 A1 CO 5021223A1
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Colombia
Prior art keywords
alkyl
group
oso2
ocf3
cycloalkyl
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CO99020600A
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Spanish (es)
Inventor
Kumar Bhatnagar Pradip
Maria Amparo Lago
James Francis Callahan
Mar Eric G Del
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Smithkline Beecham Corp
Nps Pharma Inc
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Application filed by Smithkline Beecham Corp, Nps Pharma Inc filed Critical Smithkline Beecham Corp
Publication of CO5021223A1 publication Critical patent/CO5021223A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals

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  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Physical Education & Sports Medicine (AREA)
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  • Orthopedic Medicine & Surgery (AREA)
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  • Diabetes (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Quinoline Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Furan Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Un compuesto según la fórmula (I) que figura a continuación:en la que: Y1 es un enlace covalente, alquileno o alquenileno de hasta 4 átomos de carbono, sin sustituir o sustituido con alquilo de C1-4 u O; Y2 es metileno, sin sustituir o sustituido con alquilo o haloalquilo de C1-4 ; Y3 es un enlace covalente u O, S, N-RIV o alquileno de C1-4 -O, alquileno de C1-4 -S, o alquileno de C1-4 -N-RIV ; RIV se selecciona entre el grupo que consta de H, alquilo de C1-4 , o cicloalquilo de C3-6 ; R3 y R4 son, independientemente, metilo o etilo, o, juntos, forman ciclopropilo; R5 es heteroarilo o heteroarilo fusionado; en el que el anillo heterocíclico contiene N, O o S, y es aromático, dihidro o tetrahidro, sin sustituir o sustituido con cualesquiera sustituyentes seleccionados entre el grupo que consta de OH, OCH3 , CH(CH3 )2 , halógeno, alquilo de C1-4 , alcoxi de C1-4 , cicloalquilo de C3-6 , OSO2 RIV , CN, NO2 , OCF3 , CF3 , CH2 CF3 , (CH2 )n CO2 H, (CH2 )n CO2 RIV , y O-(CH2 )n CO2 RIV ; n es un número entero de 0 a 3; G es un enlace covalente, CHR6 o C-R6 , en cuyas fórmulas R6 es H, OH u O (formando una cetona); R7 es H, OH, u O-alquilo de C1-4 ; - 2 -R8 es H o alquilo de C1-4 ; o R7 y R8 juntos forman una cetona; A y B se seleccionan independientemente entre el grupo que consta de un enlace, CH2 , NH, O, S y C=O, con tal que o bien A o B se seleccione entre CH2 y NH; o A y B juntos forman un enlace; o el resto A-B está representado por CH=CH o CºC; X se selecciona entre las subfórmulas (Ia) a (Ie) que se indican a continuación; en las que: W se selecciona entre el grupo que consta de R1 , SO2 R1 , C(O)R1 , SO2 NR1 R1 ´, C(O)NR1 R1 ´, C(O)OR1 , y SO3 R1 ´, en cuyas fórmulas R1 y R1 ´ se seleccionan independientemente entre el grupo que consta de hidrógeno, alquilo de C1-4 , cicloalquilo de C3-6 , alquenilo de C2-5 , alquinilo de C2-5 , heterocicloalquilo, arilo y aril-alquilo de C1-4 ; o R1 y R1 ´ juntos forman un anillo heterocíclico de 3 a 7 miembros opcionalmente sustituido; en el que cualesquiera sustituyentes se seleccionan entre el grupo que consta de CN, arilo, CO2 R, CO2 NHR, OH, OR, NH2 , halo, CF3 , OCF3 y NO2 ; en cuyas fórmulas R representa alquilo de C1-4 o cicloalquilo de C3-6 ; X1 se selecciona entre el grupo que consta de CN, NO2 , Cl, F, Br, I, H, R´, OR´. CF3 , OCF3 y OSO2 R´, en cuyas fórmulas R´ representa alquilo de C1-4 o cicloalquilo de C3-6 ; X2 , X3 y X4 se seleccionan, independientemente, entre el grupo que consta de CN, NO2 , Cl, F, Br, I, H, R", OR", CF3 , OCF3 y OSO2 R", con tal que o bien X1 o X3 sea H, en cuyas fórmulas R" es alquilo o haloalquilo de C1-4 ; o X1 y X2 juntos forman un anillo arílico o heteroarílico, sustituido o sin sustituir, en el que el heteroátomo se selecciona entre N, S y O; y cualesquiera sustituyentes se seleccionan entre el grupo que consta de halo, alquilo de C1-4 , OCF3 , CF3 , OMe, CN, OSO2 R ´ y NO2 ; o X3 y X4 , independientemente, representan C(O)R1 ; y R2 se selecciona entre el grupo que consta de hidrógeno, alquilo de C1-4 , cicloalquilo de C3-6 , alquenilo de C2-5 , alquinilo de C2-5 , heterocicloalquilAND#8209;arilo y arilAND#8209;alquilo de C1-4 ; X1 " se selecciona entre el grupo que consta de CN, NO2 , Cl, F, Br, I, H, R, OR, CF3 , OCF3 y OSO2 R, en cuyas fórmulas R representa alquilo de C1-4 o cicloalquilo de C3-6 ; X2 ", X3 " y X4 " se seleccionan, independientemente, entre el grupo que consta de CN, NO2 , Cl, F, Br, I, H, R´, OR´. CF3 , OCF3 y OSO2 R´. con tal que o bien X"1 o X"3 sea H, en cuyas fórmulas R´ es alquilo o haloalquilo de C1-4 ; o X1 " y X2 " juntos forman un anillo arílico o heteroarílico, sustituido o sin sustituir, en el que el heteroátomo se selecciona entre N, S y O, y cualesquiera sustituyentes se seleccionan entre el grupo que consta de halo, alquilo de C1-4 , OCF3 , CF3 , OMe, CN, OSO2 AND#8209;alquilo de C1-4 , OSO2 AND#8209;cicloalquilo de C3-6 y NO2 ; o X3 " y X4 ", independientemente, representan C(O)R1 ; y R1 " y R2 " se seleccionan, independientemente, entre el grupo que consta de hidrógeno, alquilo de C1-4 , cicloalquilo de C3-6 , alquenilo de C2-5 , alquinilo de C2-5 , heterocicloalquilo y arilo; o R1 " y R2 " juntos forman un anillo heterocíclico de 3 a 7 miembros opcionalmente sustituido; en el que cualesquiera sustituyentes se seleccionan entre el grupo que consta de CN, arilo, CO2 R", CO2 NHR", OH, OR", NH2 , halo, CF3 , OCF3 y NO2 ; en cuyas fórmulas R" representa alquilo de C1-4 o cicloalquilo de C3-6 ; X1 "´ se selecciona entre el grupo que consta de CN, NO2 , Cl, F, Br, I, H, R, OR, CF3 , OCF3 y OSO2 R, en cuyas fórmulas R representa alquilo de C1-4 o cicloalquilo de C3-6 ; X2 "´, X3 "´ y X4 "´ se seleccionan, independientemente, entre el grupo que consta de CN, NO2 , Cl, F, Br, I, H, R´, OR´. CF3 , OCF3 y OSO2 R´. con tal que o bien X"´1 o X"´3 sea H, en cuyas fórmulas R´ es alquilo o haloalquilo de C1-4 ; o X1 "´ y X2 "´ juntos forman un anillo arílico o heteroarílico, sustituido o sin sustituir, en el que el heteroátomo se selecciona entre N. S y O y los sustituyentes se seleccionan entre el grupo que consta de halo, alquilo de C1-4 , OCF3 , CF3 , OMe, CN, OSO2 AND#8209;alquilo de C1-4 , OSO2 AND#8209;cicloalquilo de C3AND#8209;6 y NO2 ; o X3 "´ y X4 "´ representan, independientemente, C(O)R1 ; R1 "´ y R2 "´ se seleccionan, independientemente, entre el grupo que consta de hidrógeno, alquilo de C1-4 , cicloalquilo de C3-6 , alquenilo de C2-5 , alquinilo de C2-5 , heterocicloalquilo y arilo; o R1 "´ y R2 "´ juntos forman un anillo heterocíclico de 3 a 7 miembros, opcionalmente sustituido, en el que los sustituyentes se seleccionan entre el grupo que consta de CN, arilo, CO2 R", CO2 NHR", OH, OR", NH2 , halo, CF3 , OCF3 y NO2 , en cuyas fórmulas R" representa alquilo de C1-4 o cicloalquilo de C3-6 ; D se selecciona entre el grupo que consta de H, CN, NO2 , Cl, F, Br, I, R, OR, SR, CF3 , OCF3 y OSO2 R, en cuyas fórmulas R representa alquilo de C1-4 , cicloalquilo de C3-6 o arilo o heteroarilo de C1-10 , en el que el heteroátomo se selecciona entre N, S y O y los sustituyentes se seleccionan entre el grupo que consta de halo, alquilo de C1-4 , OCF3 , CF3 , OMe, CN, O SO2 AND#8209;alquilo de C1-4 , OSO2 AND#8209;cicloalquilo de C3-6 y NO2 ; n es el número entero 1 ó 2; cada E es independientemente C o N, con tal que no más de dos restos E sean N; con tal que, además, cuando n es 2. cada E es C; a y b son opcionalmente enlaces presentes; R1 IV se selecciona entre el grupo que consta de (CH2 )n CO2 R´, (CH2 )n CO2 H, (CH2 )n CONR´2 , (CH2 )n CH2 OR´, OR´. SR´. CN, NO2 , Cl, F, Br, I, H, CF3 , OCF3 , OSO2 R´, R´ y H, en cuyas fórmulas R´ representa alquilo de C1-4 o cicloalquilo de C3-6 ; o R1 IV es O, formando una cetona tal que YR1 IV representa AND#8209;C=O; R21 IV se selecciona entre el grupo que consta de hidrógeno, CN, NO2 , Cl, F, Br, I, H, R" OR", CF3 , OCF3 y OSO2 R", en cuyas fórmulas R" representa alquilo de C1-4 o cicloalquilo de C3-6 .Y se selecciona entre el grupo que consta de C, CH, O, N y S, con tal que cuando Y es S, R1 IV es O o no está presente; con tal que, además, cuando Y es O, R1 IV no está presente; X´ se selecciona entre el grupo que consta de CH2 , NH, O y S. R9 se selecciona entre el grupo que consta de OAND#8209;alquilo, OAND#8209;CH2 AND#8209;arilo y OAND#8209;arilo; X1 "" se selecciona entre el grupo que consta de CN, NO2 , Cl, F, Br, I, H, R, OR, CF3 , OCF3 y OSO2 R, en cuyas fórmulas R representa alquilo de C1-4 o cicloalquilo de C3-6 ; X2 "", X3 "" y X4 "" se seleccionan, independientemente, entre el grupo que consta de CN, NO2 , Cl, F, Br, I, H, R´, OR´, CF3 , OCF3 y OSO2 R´, con tal que o bien X""1 o X""3 sea H, en cuyas fórmulas R´ es alquilo o haloalquilo de C1-4 ; o X1 "" y X2 "" juntos forman un anillo arílico o heteroarílico, sustituido o sin sustituir, en el que el heteroátomo se selecciona entre N, S y O y los sustituyentes se seleccionan entre el grupo que consta de halo, alquilo de C1-4 , OCF3 , CF3 , OMe, CN, OSO2 AND#8209;alquilo de C1-4 , OSO2 AND#8209;cicloalquilo de C3-6 y NO2 ; o X2 "" y X4 "", independientemente, representan C(O)R1 ; y sus sales y complejos farmacéuticamente aceptables.A compound according to formula (I) below: in which: Y1 is a covalent, alkylene or alkenylene bond of up to 4 carbon atoms, unsubstituted or substituted with C1-4 or O alkyl; Y2 is methylene, unsubstituted or substituted with C1-4 alkyl or haloalkyl; Y3 is a covalent bond or O, S, N-RIV or C1-4 -O alkylene, C1-4 -S alkylene, or C1-4 -N-RIV alkylene; RIV is selected from the group consisting of H, C1-4 alkyl, or C3-6 cycloalkyl; R3 and R4 are, independently, methyl or ethyl, or, together, form cyclopropyl; R5 is fused heteroaryl or heteroaryl; wherein the heterocyclic ring contains N, O or S, and is aromatic, dihydro or tetrahydro, unsubstituted or substituted with any substituents selected from the group consisting of OH, OCH3, CH (CH3) 2, halogen, C1 alkyl -4, C1-4 alkoxy, C3-6 cycloalkyl, OSO2 RIV, CN, NO2, OCF3, CF3, CH2 CF3, (CH2) n CO2 H, (CH2) n CO2 RIV, and O- (CH2) n CO2 RIV; n is an integer from 0 to 3; G is a covalent bond, CHR6 or C-R6, in which formulas R6 is H, OH or O (forming a ketone); R7 is H, OH, or C1-4 O-alkyl; - 2 -R8 is H or C1-4 alkyl; or R7 and R8 together form a ketone; A and B are independently selected from the group consisting of a bond, CH2, NH, O, S and C = O, provided that either A or B is selected from CH2 and NH; or A and B together form a bond; or the remainder A-B is represented by CH = CH or C; X is selected from the sub-formulas (Ia) to (Ie) indicated below; in which: W is selected from the group consisting of R1, SO2 R1, C (O) R1, SO2 NR1 R1 ´, C (O) NR1 R1 ´, C (O) OR1, and SO3 R1 ´, in whose formulas R1 and R1 'are independently selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl, aryl and C1- aryl-alkyl 4 ; or R1 and R1 'together form an optionally substituted 3- to 7-membered heterocyclic ring; wherein any substituents are selected from the group consisting of CN, aryl, CO2 R, CO2 NHR, OH, OR, NH2, halo, CF3, OCF3 and NO2; in whose formulas R represents C1-4 alkyl or C3-6 cycloalkyl; X1 is selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R´, OR´. CF3, OCF3 and OSO2 R ', in which formulas R' represents C1-4 alkyl or C3-6 cycloalkyl; X2, X3 and X4 are independently selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R ", OR", CF3, OCF3 and OSO2 R ", provided that either X1 or X3 is H, in which formulas R "is C1-4 alkyl or haloalkyl; or X1 and X2 together form an aryl or heteroaryl ring, substituted or unsubstituted, in which the heteroatom is selected from N, S and O; and any substituents are selected from the group consisting of halo, C1-4 alkyl, OCF3, CF3, OMe, CN, OSO2 R 'and NO2; or X3 and X4, independently, represent C (O) R1; and R2 is selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkylAND # 8209; aryl and arylAND # 8209; C1- alkyl 4 ; X1 "is selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R, OR, CF3, OCF3 and OSO2 R, in which formulas R represents C1-4 alkyl or C3 cycloalkyl- 6; X2 ", X3" and X4 "are independently selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R´, OR´. CF3, OCF3 and OSO2 R´. provided that either X "1 or X" 3 is H, in which formulas R 'is C 1-4 alkyl or haloalkyl; or X1 "and X2" together form an aryl or heteroaryl ring, substituted or unsubstituted, in which the heteroatom is selected from N, S and O, and any substituents are selected from the group consisting of halo, C1- alkyl 4, OCF3, CF3, OMe, CN, OSO2 AND # 8209; C1-4 alkyl, OSO2 AND # 8209; C3-6 and NO2 cycloalkyl; or X3 "and X4", independently, represent C (O) R1; and R1 "and R2" are independently selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl and aryl; or R1 "and R2" together form an optionally substituted 3- to 7-membered heterocyclic ring; wherein any substituents are selected from the group consisting of CN, aryl, CO2 R ", CO2 NHR", OH, OR ", NH2, halo, CF3, OCF3 and NO2; in whose formulas R" represents C1- alkyl 4 or C3-6 cycloalkyl; X1 "´ is selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R, OR, CF3, OCF3 and OSO2 R, in which formulas R represents C1-4 alkyl or C3 cycloalkyl -6; X2 "´, X3" ´ and X4 "´ are independently selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R´, OR´. CF3, OCF3 and OSO2 R´. provided that either X "´1 or X" ´3 is H, in whose formulas R´ is C1-4 alkyl or haloalkyl; or X1 "´ and X2" ´ together form an aryl or heteroaryl ring, substituted or unsubstituted, in which the heteroatom is selected from N. S and O and the substituents are selected from the group consisting of halo, C1 alkyl -4, OCF3, CF3, OMe, CN, OSO2 AND # 8209; C1-4 alkyl, OSO2 AND # 8209; C3AND cycloalkyl # 8209; 6 and NO2; or X3 "´ and X4" ´ represent, independently, C (O) R1; R1 "´ and R2" ´ are independently selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl and aryl; or R1 "´ and R2" ´ together form an optionally substituted 3 to 7-membered heterocyclic ring, in which the substituents are selected from the group consisting of CN, aryl, CO2 R ", CO2 NHR", OH, OR ", NH2, halo, CF3, OCF3 and NO2, in whose formulas R" represents C1-4 alkyl or C3-6 cycloalkyl; D is selected from the group consisting of H, CN, NO2, Cl, F, Br, I, R, OR, SR, CF3, OCF3 and OSO2 R, in which formulas R represents C1-4 alkyl, C3 cycloalkyl -6 or C1-10 aryl or heteroaryl, wherein the heteroatom is selected from N, S and O and the substituents are selected from the group consisting of halo, C1-4 alkyl, OCF3, CF3, OMe, CN , O SO2 AND # 8209; C1-4 alkyl, OSO2 AND # 8209; C3-6 and NO2 cycloalkyl; n is the integer 1 or 2; each E is independently C or N, provided that no more than two residues E are N; provided, in addition, when n is 2. each E is C; a and b are optionally present links; R1 IV is selected from the group consisting of (CH2) n CO2 R´, (CH2) n CO2 H, (CH2) n CONR´2, (CH2) n CH2 OR´, OR´. MR. CN, NO2, Cl, F, Br, I, H, CF3, OCF3, OSO2 R´, R´ and H, in whose formulas R´ represents C1-4 alkyl or C3-6 cycloalkyl; or R1 IV is O, forming a ketone such that YR1 IV represents AND # 8209; C = O; R21 IV is selected from the group consisting of hydrogen, CN, NO2, Cl, F, Br, I, H, R "OR", CF3, OCF3 and OSO2 R ", in whose formulas R" represents C1-4 alkyl or C3-6 cycloalkyl .Y is selected from the group consisting of C, CH, O, N and S, provided that when Y is S, R1 IV is O or not present; provided, in addition, when Y is O, R1 IV is not present; X 'is selected from the group consisting of CH2, NH, O and S. R9 is selected from the group consisting of OAND # 8209; alkyl, OAND # 8209; CH2 AND # 8209; aryl and OAND # 8209; aryl; X1 "" is selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R, OR, CF3, OCF3 and OSO2 R, in which formulas R represents C1-4 alkyl or C3 cycloalkyl -6; X2 "", X3 "" and X4 "" are independently selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R´, OR´, CF3, OCF3 and OSO2 R´, provided that either X "" 1 or X "" 3 is H, in which formulas R 'is C 1-4 alkyl or haloalkyl; or X1 "" and X2 "" together form an aryl or heteroaryl ring, substituted or unsubstituted, in which the heteroatom is selected from N, S and O and the substituents are selected from the group consisting of halo, C1 alkyl -4, OCF3, CF3, OMe, CN, OSO2 AND # 8209; C1-4 alkyl, OSO2 AND # 8209; C3-6 and NO2 cycloalkyl; or X2 "" and X4 "", independently, represent C (O) R1; and its pharmaceutically acceptable salts and complexes.

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