AR051587A1 - METHODS TO TREAT VASCULAR INJURIES AND IMPLANTABLE DEVICE - Google Patents

METHODS TO TREAT VASCULAR INJURIES AND IMPLANTABLE DEVICE

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Publication number
AR051587A1
AR051587A1 ARP050104336A ARP050104336A AR051587A1 AR 051587 A1 AR051587 A1 AR 051587A1 AR P050104336 A ARP050104336 A AR P050104336A AR P050104336 A ARP050104336 A AR P050104336A AR 051587 A1 AR051587 A1 AR 051587A1
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Argentina
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heterocycloalkyl
alkyl
cycloalkyl
heteroaryl
arylalkyl
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ARP050104336A
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Spanish (es)
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Biogen Idec Inc
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Publication of AR051587A1 publication Critical patent/AR051587A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives

Abstract

Uso de compuestos y dispositivos implantables que incluyen aquellos compuestos para tratar, prevenir o reducir el engrosamiento de la íntima, la remodelacion vascular, la reestenosis (por ejemplo, la reestenosis coronaria, periférica y carotídea), vasculopatías (por ejemplo, relacionadas con transplantes de organos, cardíacas, pulmonares y renales) y la hipertension (por ejemplo, la hipertension primaria o secundaria, la hipertension sistolica, la hipertension pulmonar y la remodelacion vascular inducida por la hipertension que produce dano a los organos afectados). Reivindicacion 2: El método de la reivindicacion 1, en donde el inhibidor tiene la estructura indicada en la formula (1), o un N-oxido o una de sus sales farmacéuticamente aceptables en donde: RI-1 es arilo, heteroarilo, arilalquilo o heteroarilalquilo; cada RI-a es independientemente alquilo, alquenilo, alquinilo, alcoxilo, acilo, halogeno, hidroxilo, amino, nitro, oxo, tioxo, ciano, guanadino, amidino, carboxilo, sulfo, mercapto, alquilsulfanilo, alquilsulfinilo, alquilsulfonilo, aminocarbonilo, alquilcarbonilamino, alquilsulfonilamino, alcoxicarbonilo, alquilcarboniloxilo, urea, tiourea, sulfamoilo, sulfamida, carbamoilo, cicloalquilo, cicloalquiloxilo, cicloalquilsulfanilo, heterocicloalquilo, heterocicloalquiloxilo, heterocicloalquilsulfanilo, arilo, ariloxilo, arilsulfanilo, aroilo, heteroarilo, heteroariloxilo, heteroarilsulfanilo o heteroaroilo; XI-1 es cicloalquilo o heterocicloalquilo; YI-1 es un enlace -C(O)-, -C(O)-O-, -O-C(O)-, -S(O)p-O-, -O-S(O)p-, -C(O)-N(Rb)-, -N(Rb)-C(O)-, -O-C(O)-N(Rb)-, -N(Rb)-C(O)-O-, -O-S(O)p-N(Rb)-, -N(Rb)-S(O)p-O-, -N(Rb)-C(O)-N(Rc)-, -N(Rb)-S(O)p-N(Rc)-; -C(O)-N(Rb)-S(O)p-, -S(O)p- N(Rb)-C(O)-, -C(O)-N(Rb)-S(O)p-N(Rc)-, -C(O)-O-S(O)p-N(Rb)-, -N(Rb)-S(O)p-N(Rc)-C(O)-, -N(Rb)-S(O)p-O-C(O)-, -S(O)p-N(Rb)-, -N(Rb)-S(O)p-, -N(Rb)-, -S(O)p-, -O-, -S- o -(C(Rb)(Rc))q-; en donde cada Rb y Rc es independientemente hidrogeno, hidroxilo, alquilo, alcoxilo, amino, arilo, arilalquilo, heterocicloalquilo, heteroarilo o heteroarilalquilo; en donde p es 1 o 2 y q es 1-4; RI-2 es hidrogeno, alquilo, alquenilo, alquinilo, cicloalquilo, (cicloalquil)alquilo, cicloalquenilo, (cicloalquenil)alquilo, arilo, arilalquilo, arilalquenilo, heterocicloalquilo, (heterocicloalquil)alquilo, heterocicloalquenilo, (heterocicloalquenil)alquilo, heteroarilo, heteroarilalquilo o (heteroaril)alquenilo; cada AI-1 y AI-2, independientemente, es O, S, N o NRb, a condicion de que por lo menos uno entre AI-1 y AI-2 sea N; y m es 0, 1, 2 o 3 y cuando m es mayor igual 2, dos grupos RI-a adyacentes opcionalmente se pueden unir entre sí para formar un grupo cíclico de 4 a 8 miembros, opcionalmente sustituido. Reivindicacion 3: El método de la reivindicacion 1, en donde el inhibidor tiene la estructura indicada en la formula (2), o una de sus sales farmacéuticamente aceptables o uno de sus N-oxidos, en donde cada XII- 1, XII-2, XII-3 y XII-4 es independientemente CRx o N, a condicion de que no más de dos de XII-1, XII-2, XII-3 y XII-4 sean N simultáneamente; cada YII-1 y YII-2 es independientemente CRy o N, a condicion de que por lo menos uno entre YII-1 y YII-2 sea N; cada RII-1 es independientemente alquilo, alquenilo, alquinilo, alcoxilo, acilo, halogeno, hidroxilo, amino, nitro, ciano, guanadino, amidino, carboxilo, sulfo, mercapto, alquilsulfanilo, alquilsulfinilo, alquilsulfonilo, aminocarbonilo, alquilcarbonilamino, alquilsulfonilamino, alcoxicarbonilo, alquilcarboniloxilo, urea, tiourea, sulfamoilo, sulfamida, carbamoilo, cicloalquilo, cicloalquiloxilo, cicloalquilsulfanilo, heterocicloalquilo, heterocicloalquiloxilo, heterocicloalquilsulfanilo, arilo, ariloxilo, arilsulfanilo, aroilo, heteroarilo, heteroariloxilo, heteroarilsulfanilo o heteroaroilo; cada RII-2 es independientemente alquilo, alquenilo, alquinilo, acilo, halogeno, hidroxilo, -NH2, -NH(alquilo), - N(alquilo)2, -NH(cicloalquilo), -N(alquilo)(cicloalquilo), -NH(heterocicloalquilo), -NH(heteroarilo), -NH-alquil-heterocicloalquilo, -NH-alquil-heteroarilo, -NH(arilalquil), cicloalquilo, (cicloalquil)alquilo, arilo, arilalquilo, aroilo, heterocicloalquilo, (heterocicloalquil)alquilo, heteroarilo, heteroarilalquilo, heteroaroilo, nitro, ciano, guanadino, amidino, carboxilo, sulfo, mercapto, alcoxilo, cicloalquiloxilo, cicloalquil-alcoxilo, ariloxilo, arilalcoxilo, heterocicloalquiloxilo, (heterocicloalquil)alcoxilo, heteroariloxilo, heteroarilalcoxilo, alquilsulfanilo, cicloalquilsulfanilo, (cicloalquil)alquilsulfanilo, arilsulfanilo, arilalquilsulfanilo, heterocicloalquilsulfanilo, (heterocicloalquil)alquilsulfanilo, heteroarilsulfanilo, heteroarilalquilsulfanilo, alquilsulfinilo, alquilsulfonilo, aminocarbonilo, aminosulfonilo, alquilcarbonilamino, cicloalquilcarbonilamino, (cicloalquil)alquilcarbonilamino, arilcarbonilamino, arilalquilcarbonilamino, (heterocicloalquil)carbonilamino, (heterocicloalquil)alquilcarbonilamino, heteroarilcarbonilamino, heteroarilalquilcarbonilamino, alcoxicarbonilaminoalquilamino, (heteroaril)arilcarbonilaminoalquilamino, heteroarilalquilcarbonilaminoalquilamino, (heteroaril)arilsulfonilaminoalquilcarbonilaminoalquilamino, arilsulfonilaminoalquilamino, alcoxicarbonilo, alquilcarboniloxilo, urea, tiourea, sulfamoilo, sulfamida o carbamoilo; m es 0, 1, 2, 3 o 4 y cuando m es mayor igual 2, dos grupos R1 adyacentes opcionalmente pueden unirse para formar un grupo cíclico de 4 a 8 miembros, opcionalmente sustituido; n es 0, 1, 2 o 3 y cuando n es mayor igual 2, dos grupos R2 adyacentes opcionalmente pueden unirse para formar un grupo cíclico de 4 a 8 miembros, opcionalmente sustituido; y cada Rx y Ry es independientemente hidrogeno, alquilo, alquenilo, alquinilo, alcoxilo, acilo, halogeno, hidroxilo, amino, nitro, ciano, guanadino, amidino, carboxilo, sulfo, mercapto, alquilsulfanilo, alquilsulfinilo, alquilsulfonilo, cicloalquilcarbonilo, (cicloalquil)alquilcarbonilo, aroilo, arilalquilcarbonilo, heterocicloalquilcarbonilo, (heterocicloalquil)acilo, heteroaroilo, (heteroaril)acilo, aminocarbonilo, alquilcarbonilamino, (amino)aminocarbonilo, alquilsulfonilaminocarbonilo, alquilsulfonilamino, cicloalquilcarbonilamino, cicloalquilsulfonilamino, (cicloalquil)alquilcarbonilamino, (cicloalquil)alquilsulfonilamino, arilcarbonilamino, arilsulfonilamino, arilalquilcarbonilamino, arilalquilsulfonilamino, (heterocicloalquil)carbonilamino, (heterocicloalquil)sulfonilamino, (heterocicloalquil)alquilcarbonilamino, (heterocicloalquil)alquilsulfonilamino, heteroarilcarbonilamino, heteroarilsulfonilamino, heteroarilalquilcarbonilamino, heteroarilalquilsulfonilamino, alcoxicarbonilo, alquilcarboniloxilo, urea, tiourea, sulfamoilo, sulfamida, carbamoilo, cicloalquilo, cicloalquiloxilo, cicloalquilsulfanilo, (cicloalquil)alquilo, (cicloalquil)alcoxilo, (cicloalquil)alquilsulfanilo, heterocicloalquilo, heterocicloalquiloxilo, heterocicloalquilsulfanilo, (heterocicloalquil)alquilo, (heterocicloalquil)alcoxilo, (heterocicloalquil)alquilsulfanilo, arilo, ariloxilo, arilsulfanilo, arilalquilo, arilalquiloxilo, arilalquilsulfanilo, arilalquenilo, arilalquinilo, heteroarilo, heteroariloxilo, heteroarilsulfanilo, heteroarilalquilo, (heteroaril)alcoxilo o (heteroaril)alquilsulfanilo. Reivindicacion 4: El método de la reivindicacion 1, en donde el inhibidor tiene la estructura indicada en la formula (3), o una de sus sales farmacéuticamente aceptables o un N-oxido, en donde: en donde cada XIII-1, XIII-2, XIII-3 y XIII-4 es independientemente CRIII- x o N, a condicion de que no más de dos de XIII-1, XIII-2, XIII-3 y XIII-4 sean N simultáneamente; cada YIII-1 y YIII-2 es independientemente CRIII-y o N, a condicion de que por lo menos uno entre YIII-1 y YIII-2 sea N; cada RIII-1 es independientemente alquilo, alquenilo, alquinilo, alcoxilo, acilo, halogeno, hidroxilo, amino, nitro, ciano, guanadino, amidino, carboxilo, sulfo, mercapto, alquilsulfanilo, alquilsulfinilo, alquilsulfonilo, aminocarbonilo, alquilcarbonilamino, alquilsulfonilamino, alcoxicarbonilo, alquilcarboniloxilo, urea, tiourea, sulfamoilo, sulfamida, carbamoilo, cicloalquilo, cicloalquiloxilo, cicloalquilsulfanilo, heterocicloalquilo, heterocicloalquiloxilo, heterocicloalquilsulfanilo, arilo, ariloxilo, arilsulfanilo, aroilo, heteroarilo, heteroariloxilo, heteroarilsulfanilo o heteroaroilo; cada RIII-2 es independientemente alquilo, alquenilo, alquinilo, acilo, halogeno, hidroxilo, -NH2, -NH(alquilo), -N(alquilo)2, -NH(cicloalquilo), - N(alquil)(cicloalquilo), -NH(heterocicloalquilo), -NH(heteroarilo), -NH-alquil-heterocicloalquilo, -NH-alquil-heteroarilo, -NH(arilalquilo), cicloalquilo, (cicloalquil)alquilo, arilo, arilalquilo, aroilo, heterocicloalquilo, (heterocicloalquil)alquilo, heteroarilo, heteroarilalquilo, heteroaroilo, nitro, ciano, guanadino, amidino, carboxilo, sulfo, mercapto, alcoxilo, cicloalquiloxilo, (cicloalquil)alcoxilo, ariloxilo, arilalcoxilo, heterocicloalquiloxilo, (heterocicloalquil)alcoxilo, heteroariloxilo, heteroarilalcoxilo, alquilsulfanilo, cicloalquilsulfanilo, (cicloalquil)alquilsulfanilo, arilsulfanilo, arilalquilsulfanilo, heterocicloalquilsulfanilo, (heterocicloalquil)alquilsulfanilo, heteroarilsulfanilo, heteroarilalquilsulfanilo, alquilsulfinilo, alquilsulfonilo, aminocarbonilo, aminosulfonilo, alquilcarbonilamino, cicloalquilcarbonilamino, (cicloalquil)alquilcarbonilamino, arilcarbonilamino, arilalquilcarbonilamino, (heterocicloalquil)carbonilamino, (heterocicloalquil)alquilcarbonilamino, heteroarilcarbonilamino, heteroarilalquilcarbonilamino, alcoxicarbonilaminoalquilamino, (heteroaril)arilcarbonilaminoalquilamino, heteroarilalquilcarbonilaminoalquilamino, (heteroaril)arilsulfonilaminoalquilcarbonilaminoalquilamino, arilsulfonilaminoalquilamino, alcoxicarbonilo, alquilcarboniloxilo, urea, tiourea, sulfamoilo, sulfamida o carbamoilo; m es 0, 1, 2, 3 o 4 y cuando m es mayor igual 2, dos grupos RIII-1 adyacentes opcionalmente pueden unirse para formar un grupo cíclico de 4 a 8 miembros, opciUse of implantable compounds and devices that include those compounds to treat, prevent or reduce intimal thickening, vascular remodeling, restenosis (for example, coronary, peripheral and carotid restenosis), vasculopathies (for example, related to transplants of organs, cardiac, pulmonary and renal) and hypertension (for example, primary or secondary hypertension, systolic hypertension, pulmonary hypertension and vascular remodeling induced by hypertension that causes damage to the affected organs). Claim 2: The method of claim 1, wherein the inhibitor has the structure indicated in formula (1), or an N-oxide or a pharmaceutically acceptable salt thereof wherein: RI-1 is aryl, heteroaryl, arylalkyl or heteroarylalkyl; Each RI-a is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halogen, hydroxyl, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxyl, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocicloalquiloxilo, heterocicloalquilsulfanilo, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; XI-1 is cycloalkyl or heterocycloalkyl; YI-1 is a -C (O) -, -C (O) -O-, -OC (O) -, -S (O) pO-, -OS (O) p-, -C (O) link -N (Rb) -, -N (Rb) -C (O) -, -OC (O) -N (Rb) -, -N (Rb) -C (O) -O-, -OS (O) pN (Rb) -, -N (Rb) -S (O) pO-, -N (Rb) -C (O) -N (Rc) -, -N (Rb) -S (O) pN (Rc) -; -C (O) -N (Rb) -S (O) p-, -S (O) p- N (Rb) -C (O) -, -C (O) -N (Rb) -S (O ) pN (Rc) -, -C (O) -OS (O) pN (Rb) -, -N (Rb) -S (O) pN (Rc) -C (O) -, -N (Rb) - S (O) pOC (O) -, -S (O) pN (Rb) -, -N (Rb) -S (O) p-, -N (Rb) -, -S (O) p-, - O-, -S- or - (C (Rb) (Rc)) q-; wherein each Rb and Rc is independently hydrogen, hydroxyl, alkyl, alkoxy, amino, aryl, arylalkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl; where p is 1 or 2 and q is 1-4; RI-2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, aryl, arylalkyl, arylalkenyl, heterocycloalkyl, (heterocycloalkyl) alkyl, heterocycloalkenyl, (heterocycloalkenyl, heteroarylalkyl, heteroarylalkyl, heteroarylalkyl, alkyl, heteroaryl or alkynyl) (heteroaryl) alkenyl; each AI-1 and AI-2, independently, is O, S, N or NRb, provided that at least one between AI-1 and AI-2 is N; and m is 0, 1, 2 or 3 and when m is equal equal to 2, two adjacent RI-a groups may optionally be joined together to form a cyclic group of 4 to 8 members, optionally substituted. Claim 3: The method of claim 1, wherein the inhibitor has the structure indicated in formula (2), or a pharmaceutically acceptable salt thereof or one of its N-oxides, wherein each XII-1, XII-2 , XII-3 and XII-4 is independently CRx or N, provided that no more than two of XII-1, XII-2, XII-3 and XII-4 are N simultaneously; each YII-1 and YII-2 is independently CRy or N, provided that at least one between YII-1 and YII-2 is N; Each RII-1 is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halogen, hydroxyl, amino, nitro, cyano, guanadino, amidino, carboxyl, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonylamino, alkoxycarbonylamino alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocicloalquiloxilo, heterocicloalquilsulfanilo, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; each RII-2 is independently alkyl, alkenyl, alkynyl, acyl, halogen, hydroxy, -NH2, -NH (alkyl), - N (alkyl) 2, -NH (cycloalkyl), -N (alkyl) (cycloalkyl), - NH (heterocycloalkyl), -NH (heteroaryl), -NH-alkyl-heterocycloalkyl, -NH-alkyl-heteroaryl, -NH (arylalkyl), cycloalkyl, (cycloalkyl) alkyl, aryl, arylalkyl, aroyl, heterocycloalkyl, (heterocycloalkyl) alkyl , heteroaryl, heteroarylalkyl, heteroaroyl, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkoxy, cycloalkyloxy, cycloalkyl-alkoxy, aryloxy, arylalkoxy, heterocicloalquiloxilo, (heterocycloalkyl) alkoxy, heteroaryloxy, heteroarylalkoxy, alkylsulfanyl, cycloalkylsulfanyl, (cycloalkyl ) alkylsulfanyl, arylsulfanyl, arylalkyl sulfanyl, heterocycloalkylsulfanyl, (heterocycloalkyl) alkylsulfanyl, heteroarylsulfanyl, heteroarylalkyl sulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, alkylcarbonylamino, cycloalkylcarbonylamino or, (cycloalkyl) alkylcarbonylamino, arylcarbonylamino, arylalkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkyl) alkylcarbonylamino, heteroarylcarbonylamino, heteroarylalkycarbonylamino, alkoxycarbonylaminoalkylamino, (heteroaryl) arilcarbonilaminoalquilamino, heteroarilalquilcarbonilaminoalquilamino, (heteroaryl) arilsulfonilaminoalquilcarbonilaminoalquilamino, arylsulfonylaminoalkylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl , sulfonamide or carbamoyl; m is 0, 1, 2, 3 or 4 and when m is equal equal to 2, two adjacent R1 groups can optionally be joined to form a cyclic group of 4 to 8 members, optionally substituted; n is 0, 1, 2 or 3 and when n is equal equal to 2, two adjacent R2 groups may optionally be joined to form a cyclic group of 4 to 8 members, optionally substituted; and each Rx and Ry is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, halogen, hydroxyl, amino, nitro, cyano, guanadino, amidino, carboxyl, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, cycloalkylcarbonyl, (cycloalkyl) alkylcarbonyl, aroyl, arylalkylcarbonyl, heterocycloalkylcarbonyl, (heterocycloalkyl) acyl, heteroaroyl, (heteroaryl) acyl, aminocarbonyl, alkylcarbonylamino, (amino) aminocarbonyl, alkylsulfonylaminocarbonyl, alkylsulfonylamino, cycloalkylcarbonylamino, cycloalkylsulfonylamino, (cycloalkyl) alkylcarbonylamino, (cycloalkyl) alkylsulfonylamino, arylcarbonylamino, arylsulfonylamino , arylalkylcarbonylamino, arylalkyl sulfonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkyl) sulfonylamino, (heterocycloalkyl) alkylcarbonylamino, (heterocycloalkyl) alkylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfonylamino, heteroarylalkylcarbonylamino, alkoxycarbonylamino, alkylaminocarbonylamino, alkoxycarbonylamino, alkoxycarbonylamino, alkoxycarbonylamino, alkoxycarbonylamino, alkylaminocarbonylamino, alkylaminocarbonylamino alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulphonamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, (cycloalkyl) alkyl, (cycloalkyl) alkoxy, (cycloalkyl) alkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkyl (heterocycloalkyl) alkylocycloalkyl (heterocycloalkyl) alkyl (alkyl) alkyl heterocycloalkyl) alkylsulfanyl, aryl, aryloxy, arylsulfanyl, arylalkyl, arylalkyl, arylalkyl sulfanyl, arylalkyl, arylalkyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, heteroarylalkyl, (heteroaryl) alkoxy) (heteroaryl) alkoxy Claim 4: The method of claim 1, wherein the inhibitor has the structure indicated in formula (3), or a pharmaceutically acceptable salt thereof or an N-oxide, wherein: wherein each XIII-1, XIII- 2, XIII-3 and XIII-4 is independently CRIII-N or N, provided that no more than two of XIII-1, XIII-2, XIII-3 and XIII-4 are N simultaneously; each YIII-1 and YIII-2 is independently CRIII-y or N, provided that at least one between YIII-1 and YIII-2 is N; Each RIII-1 is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halogen, hydroxyl, amino, nitro, cyano, guanadino, amidino, carboxyl, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkylsulfonylamino, alkylsulfonylamino alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocicloalquiloxilo, heterocicloalquilsulfanilo, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; each RIII-2 is independently alkyl, alkenyl, alkynyl, acyl, halogen, hydroxy, -NH2, -NH (alkyl), -N (alkyl) 2, -NH (cycloalkyl), - N (alkyl) (cycloalkyl), - NH (heterocycloalkyl), -NH (heteroaryl), -NH-alkyl-heterocycloalkyl, -NH-alkyl-heteroaryl, -NH (arylalkyl), cycloalkyl, (cycloalkyl) alkyl, aryl, arylalkyl, aroyl, heterocycloalkyl, (heterocycloalkyl) alkyl , heteroaryl, heteroarylalkyl, heteroaroyl, nitro, cyano, guanadino, amidino, carboxyl, sulfo, mercapto, alkoxy, cycloalkyloxy, (cycloalkyl) alkoxy, aryloxy, arylalkoxy, heterocycloalkyloxy, (heterocycloalkyl) alkoxy, heteroaryloxylalkyl, heteroaryloxylalkyl, heteroaryloxylalkyl, heteroaryloxylalkyl, heteroaryloxylalkyl, heteroaryloxylalkyl cycloalkyl) alkylsulfanyl, arylsulfanyl, arylalkyl sulfanyl, heterocycloalkylsulfanyl, (heterocycloalkyl) alkylsulfanyl, heteroarylsulfanyl, heteroarylalkyl sulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, alkylcarbonylamino, cycloalkylcarbonylamino ino, (cycloalkyl) alkylcarbonylamino, arylcarbonylamino, arylalkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkyl) alkylcarbonylamino, heteroarylcarbonylamino, heteroarylalkycarbonylamino, alkoxycarbonylaminoalkylamino, (heteroaryl) arilcarbonilaminoalquilamino, heteroarilalquilcarbonilaminoalquilamino, (heteroaryl) arilsulfonilaminoalquilcarbonilaminoalquilamino, arylsulfonylaminoalkylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl , sulfonamide or carbamoyl; m is 0, 1, 2, 3 or 4 and when m is equal equal to 2, two adjacent RIII-1 groups can optionally join to form a cyclic group of 4 to 8 members, option

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