AR057985A1 - BETA-SECRETASE HETEROCICLICAL MODULATORS, PHARMACEUTICAL COMPOSITIONS AND USES. - Google Patents

BETA-SECRETASE HETEROCICLICAL MODULATORS, PHARMACEUTICAL COMPOSITIONS AND USES.

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Publication number
AR057985A1
AR057985A1 ARP060105083A ARP060105083A AR057985A1 AR 057985 A1 AR057985 A1 AR 057985A1 AR P060105083 A ARP060105083 A AR P060105083A AR P060105083 A ARP060105083 A AR P060105083A AR 057985 A1 AR057985 A1 AR 057985A1
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Argentina
Prior art keywords
heteroatoms
alkyl
alkynyl
alkenyl
nr7c
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ARP060105083A
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Spanish (es)
Inventor
Vinod F Patel
Thomas Nguyen
Thomas Nixey
Lewis Pennington
Matthew Weiss
Qiufen Xue
Bryant Yang
Yuan Cheng
Stuart Charles Chafee
Michael Groghan
Russell Graceffa
Dean Hickman
Wenge Zhong
Stephen Hitchcock
Brian K Albrecht
Michael Bartberger
Dan Horne
Randall W Hungate
Matthew Kaller
Charles Kreiman
Daniel La
Patricia Lopez
Holger Monenschein
James Brown
Scott Harried
Ted Judd
Craig Masse
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Amgen Inc
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=39708735&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=AR057985(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Amgen Inc filed Critical Amgen Inc
Publication of AR057985A1 publication Critical patent/AR057985A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • C07D405/02—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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Furan Compounds (AREA)

Abstract

Reivindicacion 1: Un compuesto de la formula (1), o su estereoisomero, tautomero, solvato, sal farmacéuticamente aceptable, derivado o profármaco, donde A es alquilo C1-10, alquenilo C2-10, alquinilo C2-10, R1-alquilo C1-10-, R1-alquenilo C2-10- o R1-alquinilo C2-10-, donde 1, 2 o 3 átomos de carbono de (a) dichos alquilo C1-10, alquenilo C2-10, alquinilo C2-10 o (b) dichos alquilo C1-10, alquenilo C2-10, alquinilo C2-10 de R1-alquilo C1-10-, R1-alquenilo C2-10- o R1-alquinilo C2-10-, se reemplazan opcionalmente con un heteroátomo que se selecciona de O, S, S(O), S(O)2 y N, y están opcionalmente sustituidos, en forma independiente, con uno o más sustituyentes de R9 y R1 es un sistema de anillos totalmente saturado o parcial o totalmente insaturado monocíclico de 4 a 8 miembros, bicíclico de 6 a 12 miembros o tricíclico de 7 a 14 miembros; dicho sistema de anillos está formado de átomos de carbono y opcionalmente incluye 1 a 3 heteroátomos si es monocíclico, 1 a 6 heteroátomos si es bicíclico o 1 a 9 heteroátomos si es tricíclico; dichos heteroátomos se seleccionan de O, N o S, donde dicho sistema de anillos está sustituido, en forma independiente, con uno o más sustituyentes de oxo, R7, R8, R9, NR7R7, NR7R8, OR7, SR7, OR8, SR8, C(O)R7, OC(O)R7, COOR7, C(O)R8, OC(O)R8, COOR8, C(O)NR7R7, C(S)NR7R7, NR7C(O)R7, NR7C(S)R7, NR7C(O)NR7R7, NR7C(S)NR7R7, NR7(COOR7), OC(O)NR7R7, C(O)NR7R8, C(S)NR7R8, NR7C(O)R8, NR7C(S)R8, NR7C(O)NR7R8, NR7C(S)NR7R8, NR7(COOR8), OC(O)NR7R8, S(O)2NR7R7, NR7S(O)2NR7R7, NR7S(O)2R7, S(O)2R8, S(O)2NR7R8, NR7S(O)2NR7R8 o NR7S(O)2R8; W es -C(=O)-, -OC(=O)-, -NHC(O)-, -S(=O)b- o -NHS(=O)b-, donde b es 1 o 2; B es R2-(CR2aR2a)h-, R2-O-(CR2aR2a)h-, R2-S-(CR2aR2a)h- o R2-N(R2a)- (CR2aR2a)h-, donde R2 es alquilo C1-10, haloalquilo C1-10, alquenilo C2-10, alquinilo C2-10 o un sistema de anillos parcial o totalmente saturado o insaturado monocíclico de 3 a 8 miembros, bicíclico de 6 a 12 miembros o tricíclico de 7 a 14 miembros; dicho sistema de anillos está formado de átomos de carbono que opcionalmente incluyen 1 a 3 heteroátomos si es monocíclico, 1 a 6 heteroátomos si es bicíclico o 1 a 9 heteroátomos si es tricíclico; dichos heteroátomos se seleccionan de O, N o S, donde dicho alquilo C1-10, alquenilo C2-10, alquinilo C2-10 está opcionalmente sustituido, en forma independiente, con uno o más sustituyentes de R9, y dicho sistema de anillos está opcionalmente sustituido, en forma independiente, con uno o más sustituyentes de oxo, R7, R8, R9, NR7R7, NR7R8, OR7, SR7, OR8, SR8, C(O)R7, OC(O)R7, COOR7, C(O)R8, OC(O)R8, COOR8, C(O)NR7R7, C(S)NR7R7, NR7C(O)R7, NR7C(S)R7, NR7C(O)NR7R7, NR7C(S)NR7R7, NR7(COOR7), OC(O)NR7R7, C(O)NR7R8, C(S)NR7R8, NR7C(O)R8, NR7C(S)R8, NR7C(O)NR7R8, NR7C(S)NR7R8, NR7(COOR8), OC(O)NR7R8, S(O)2NR7R7, NR7S(O)2NR7R7, NR7S(O)2R7, S(O)2R8, S(O)2NR7R8, NR7S(O)2NR7R8 o NR7S(O)2R8; cada R2a, en forma independiente, es H, OH, NO2, CN, NH2, alquilo C1-10, alcoxilo C1-10 o haloalquilo; y h es 0, 1, 2 o 3; i es 1, 2 o 3; j es 0, 1 o 2; cada R3, en forma independiente, es H, haloalquilo, CN, alquilo C1-10, alquenilo C2-10, alquinilo C2-10, cicloalquilo C3-10 o cicloalquenilo C4-10, cada uno de alquilo C1-10, alquenilo C2-10, alquinilo C2-10, cicloalquilo C3-10 y cicloalquenilo C4-10 opcionalmente comprende 1 a 4 heteroátomos seleccionados de N, O y S, y está opcionalmente sustituido con 1 a 5 sustituyentes de R8 o R9; R4 es H, haloalquilo, CN, alquilo C1-10, alquenilo C2-10, alquinilo C2-10, cicloalquilo C3-10, o cicloalquenilo C4-10, cada uno de alquilo C1-10, alquenilo C2-10, alquinilo C2-10, cicloalquilo C3-10 y cicloalquenilo C4-10 opcionalmente comprende 1 a 4 heteroátomos seleccionados de N, O y S, y está opcionalmente sustituido con 1 a 5 sustituyentes de R8 o R9; R5 es una estructura del grupo de formulas (2), donde X1 es CR12, O, S o NR12; cada X2, en forma independiente, es CR12R12; cada uno de Y1, Y2 e Y3, en forma independiente, es CR12R12, O, S o NR12 m es 0, 1 o 2; y o es 0, 1, 2, 3, 4 o 5; siempre que (a) no más de dos de Y1, Y2 e Y3 sean O, S o NR12 y (b) cuando o es 0, cada uno de Y1 e Y2 es CR12R12; R7 es H, alquilo C1-10, alquenilo C2-10, alquinilo C2-10, cicloalquilo C3-10 o cicloalquenilo C4-10, cada uno de alquilo C1-10, alquenilo C2-10, alquinilo C2-10, cicloalquilo C3-10 y cicloalquenilo C4-10 opcionalmente comprende 1 a 4 heteroátomos seleccionados de N, O y S, y está opcionalmente sustituido con 1 a 5 sustituyentes de NR8R9, NR9R9, OR8, SR8, OR9, SR9, C(O)R8, OC(O)R8, COOR8, C(O)R9, OC(O)R9, COOR9, C(O)NR8R9, C(O)NR9R9, NR9C(O)R8, NR9C(O)R9, NR9C(O)NR8R9, NR9C(O)NR9R9, NR9(COOR8), NR9(COOR9), OC(O)NR8R9, OC(O)NR9R9, S(O)2R8, S(O)2NR8R9, S(O)2R9, S(O)2NR9R9, NR9S(O)2NR8R9, NR9S(O)2NR9R9, NR9S(O)2R8, NR9S(O)2R9, R8 o R9; R8 es un sistema de anillos parcial o totalmente saturado o insaturado monocíclico de 5 a 8 miembros, bicíclico de 6 a 12 miembros o tricíclico de 7 a 14 miembros, dicho sistema de anillos está formado de átomos de carbono que opcionalmente incluyen 1 a 3 heteroátomos si es monocíclico, 1 a 6 heteroátomos si es bicíclico o 1 a 9 heteroátomos si es tricíclico, dichos heteroátomos se seleccionan de O, N o S, y donde dicho sistema de anillos está opcionalmente sustituido, en forma independiente, con 1 a 5 sustituyentes de R9, oxo, NR9R9, OR9; SR9, C(O)R9, o un anillo de átomos de carbono parcial o totalmente saturado o insaturado de 5 a 6 miembros que opcionalmente incluyen 1 a 3 heteroátomos que se seleccionan de O, N o S, y está opcionalmente sustituido, en forma independiente, con 1 a 5 sustituyentes de R9; R9 es H, halo, haloalquilo, CN, OH, NO2, NH2, acetilo, alquilo C1-10, alquenilo C2-10, alquinilo C2-10, cicloalquilo C3-10, cicloalquenilo C4-10, alquilamino C1-10-, dialquilamino C1-10-, alcoxilo C1-10, tioalcoxilo C1-10 o un sistema de anillos saturado o parcial o totalmente insaturado monocíclico de 5 a 8 miembros o bicíclico de 6 a 12 miembros, dicho sistema de anillos está formado de átomos de carbono que opcionalmente incluyen 1 a 3 heteroátomos si es monocíclico o 1 a 6 heteroátomos si es bicíclico, dichos heteroátomos se seleccionan de O, N o S, donde cada uno de alquilo C1-10, alquenilo C2-10, alquinilo C2-10, cicloalquilo C3-10, cicloalquenilo C4-10, alquilamino C1-10-, dialquilamino C1-10-, alcoxilo C1-10, tioalcoxilo C1-10 y anillo de dicho sistema de anillos está opcionalmente sustituido, en forma independiente, con 1 a 5 sustituyentes de halo, haloalquilo, CN, NO2, NH2, OH, oxo, metilo, metoxilo, etilo, etoxilo, propilo, propoxilo, isopropilo, isopropoxilo, ciclopropilo, ciclopropilmetoxilo, butilo, butoxilo, isobutoxilo, ter-butoxilo, isobutilo, sec-butilo, ter-butilo, ciclobutilo, pentilo, ciclopentilo, hexilo, ciclohexilo, alquilamino C1-10-, dialquilamino C1-10-, tioalcoxilo C1-10, bencilo o fenilo; R10 es H, halo, haloalquilo, CN, OH, NO2,NH2, acetilo, alquilo C1-10, alquenilo C2-10, alquinilo C2-10, cicloalquilo C3-10, cicloalquenilo C4-10, alquilamino C1-10-, dialquilamino C1-10-, alcoxilo C1-10, tioalcoxilo C1-10 o un sistema de anillos saturado o parcial o totalmente insaturado monocíclico de 5 a 8 miembros o bicíclico de 6 a 12 miembros, dicho sistema de anillos está formado de átomos de carbono que opcionalmente incluyen 1 a 3 heteroátomos si es monocíclico o 1 a 6 heteroátomos si es bicíclico, dichos heteroátomos se seleccionan de O, N o S, donde cada uno de alquilo C1-10, alquenilo C2-10, alquinilo C2-10, cicloalquilo C3-10, cicloalquenilo C4-10, alquilamino C1-10-, dialquilamino C1-10-, alcoxilo C1-10, tioalcoxilo C1-10 y anillo de dicho sistema de anillos está opcionalmente sustituido, en forma independiente, con 1 a 5 sustituyentes de halo, haloalquilo, CN, NO2, NH2, OH, oxo, metilo, metoxilo, etilo, etoxilo, propilo, propoxilo, isopropilo, isopropoxilo, ciclopropilo, ciclopropilmetoxilo, butilo, butoxilo, isobutoxilo, ter-butoxilo, isobutilo, secbutilo, ter-butilo, ciclobutilo, pentilo, ciclopentilo, hexilo, ciclohexilo, alquilamino C1-10, dialquilamino C1-10-, tioalcoxilo C1-10, bencilo o fenilo; R11 es H, halo, haloalquilo, CN, OH, NO2, NH2, acetilo, alquilo C1-10, alquenilo C2-10, alquinilo C2-10, cicloalquilo C3-10, cicloalquenilo C4-10, alquilamino C1-10-, dialquilamino C1-10-, alcoxilo C1-10, tioalcoxilo C1-10 o un sistema de anillos saturado o parcial o totalmente insaturado monocíclico de 5 a 8 miembros o bicíclico de 6 a 12 miembros, dicho sistema de anillos está formado de átomos de carbono que opcionalmente incluyen 1 a 3 heteroátomos si es monocíclico o 1 a 6 heteroátomos si es bicíclico, dichos heteroátomos se seleccionan de O, N o S, donde cada uno de alquilo C1-10, alquenilo C2-10, alquinilo C2-10, cicloalquilo C3-10, cicloalquenilo C4-10, alquilamino C1-10-, dialquilamino C1-10-, alcoxilo C1-10, tioalcoxilo C1-10 y anillo de dicho sistema de anillos está opcionalmente sustituido, en forma independiente, con 1 a 5 sustituyentes de halo, haloalquilo, CN, NO2, NH2, OH, oxo, metilo, metoxilo, etilo, etoxilo, propilo, propoxilo, isopropilo, isopropoxilo, ciclopropilo, ciclopropilmetoxilo, butilo, butoxilo, isobutoxilo, ter-butoxilo, isobutilo, sec-butilo, ter-butilo, ciclobutilo, pentilo, ciclopentilo, hexilo, ciclohexilo, alquilamino C1-10-, dialquilamino C1-10-, tioalcoxilo C1-10, bencilo o fenilo; como alternativa, R10 y R11 tomados en conjunto con los átomos de carbono o de nitrogeno a los cuales están unidos, forman un segundo anillo de átomos de carbono parcial o totalmente saturado o insaturado de 5 a 6 miembros, que opcionalmente incluyen 1 a 3 heteroátomos que se seleccionan de O, N o S, el segundo anillo está opcionalmente sustituido, en forma independiente, con 1 a 5 sustituyentes de R12, R13, R14 o R15 y está opcionalmente fusionado con un tercer anillo de 4 a 7 miembros, el tercer anillo está formado de átomos de carbono que opcionalmente incluyen 1 a 3 heteroátomos que se seleccionan de O, N o S, y está opcionalmente sustituido, en forma independiente, con 1 a 5 sustituyentes de R12, R13, Claim 1: A compound of the formula (1), or its stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, derivative or prodrug, wherein A is C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, R1-C1 alkyl -10-, R1-C2-10 alkenyl or R1-C2-10 alkynyl, wherein 1, 2 or 3 carbon atoms of (a) said C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or ( b) said C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl of R1-C1-10 alkyl, R1-C2-10 alkenyl or R1-C2-10 alkynyl, are optionally replaced with a heteroatom which is selects from O, S, S (O), S (O) 2 and N, and are optionally substituted, independently, with one or more substituents of R9 and R1 is a fully saturated or partial or fully unsaturated monocyclic ring system 4 to 8 members, bicyclic of 6 to 12 members or tricyclic of 7 to 14 members; said ring system is formed of carbon atoms and optionally includes 1 to 3 heteroatoms if it is monocyclic, 1 to 6 heteroatoms if it is bicyclic or 1 to 9 heteroatoms if it is tricyclic; said heteroatoms are selected from O, N or S, wherein said ring system is independently substituted with one or more oxo substituents, R7, R8, R9, NR7R7, NR7R8, OR7, SR7, OR8, SR8, C (O) R7, OC (O) R7, COOR7, C (O) R8, OC (O) R8, COOR8, C (O) NR7R7, C (S) NR7R7, NR7C (O) R7, NR7C (S) R7 , NR7C (O) NR7R7, NR7C (S) NR7R7, NR7 (COOR7), OC (O) NR7R7, C (O) NR7R8, C (S) NR7R8, NR7C (O) R8, NR7C (S) R8, NR7C ( O) NR7R8, NR7C (S) NR7R8, NR7 (COOR8), OC (O) NR7R8, S (O) 2NR7R7, NR7S (O) 2NR7R7, NR7S (O) 2R7, S (O) 2R8, S (O) 2NR7R8 , NR7S (O) 2NR7R8 or NR7S (O) 2R8; W is -C (= O) -, -OC (= O) -, -NHC (O) -, -S (= O) b- or -NHS (= O) b-, where b is 1 or 2; B is R2- (CR2aR2a) h-, R2-O- (CR2aR2a) h-, R2-S- (CR2aR2a) h- or R2-N (R2a) - (CR2aR2a) h-, where R2 is C1-10 alkyl , C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl or a partially or fully saturated or unsaturated monocyclic ring system of 3 to 8 members, bicyclic of 6 to 12 members or tricyclic of 7 to 14 members; said ring system is formed of carbon atoms that optionally include 1 to 3 heteroatoms if it is monocyclic, 1 to 6 heteroatoms if it is bicyclic or 1 to 9 heteroatoms if it is tricyclic; said heteroatoms are selected from O, N or S, wherein said C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl is optionally substituted, independently, with one or more R9 substituents, and said ring system is optionally independently substituted with one or more oxo substituents, R7, R8, R9, NR7R7, NR7R8, OR7, SR7, OR8, SR8, C (O) R7, OC (O) R7, COOR7, C (O) R8, OC (O) R8, COOR8, C (O) NR7R7, C (S) NR7R7, NR7C (O) R7, NR7C (S) R7, NR7C (O) NR7R7, NR7C (S) NR7R7, NR7 (COOR7) , OC (O) NR7R7, C (O) NR7R8, C (S) NR7R8, NR7C (O) R8, NR7C (S) R8, NR7C (O) NR7R8, NR7C (S) NR7R8, NR7 (COOR8), OC ( O) NR7R8, S (O) 2NR7R7, NR7S (O) 2NR7R7, NR7S (O) 2R7, S (O) 2R8, S (O) 2NR7R8, NR7S (O) 2NR7R8 or NR7S (O) 2R8; each R2a, independently, is H, OH, NO2, CN, NH2, C1-10 alkyl, C1-10 alkoxy or haloalkyl; and h is 0, 1, 2 or 3; i is 1, 2 or 3; j is 0, 1 or 2; each R3, independently, is H, haloalkyl, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl or C4-10 cycloalkenyl, each of C1-10 alkyl, C2- alkenyl 10, C2-10 alkynyl, C3-10 cycloalkyl and C4-10 cycloalkenyl optionally comprises 1 to 4 heteroatoms selected from N, O and S, and is optionally substituted with 1 to 5 substituents of R8 or R9; R4 is H, haloalkyl, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, or C4-10 cycloalkenyl, each of C1-10 alkyl, C2-10 alkenyl, C2- alkynyl 10, C3-10 cycloalkyl and C4-10 cycloalkenyl optionally comprises 1 to 4 heteroatoms selected from N, O and S, and is optionally substituted with 1 to 5 substituents of R8 or R9; R5 is a structure of the group of formulas (2), where X1 is CR12, O, S or NR12; each X2, independently, is CR12R12; each of Y1, Y2 and Y3, independently, is CR12R12, O, S or NR12 m is 0, 1 or 2; and o is 0, 1, 2, 3, 4 or 5; provided that (a) no more than two of Y1, Y2 and Y3 are O, S or NR12 and (b) when or is 0, each of Y1 and Y2 is CR12R12; R7 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl or C4-10 cycloalkenyl, each of C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3- cycloalkyl 10 and C4-10 cycloalkenyl optionally comprises 1 to 4 heteroatoms selected from N, O and S, and is optionally substituted with 1 to 5 substituents of NR8R9, NR9R9, OR8, SR8, OR9, SR9, C (O) R8, OC ( O) R8, COOR8, C (O) R9, OC (O) R9, COOR9, C (O) NR8R9, C (O) NR9R9, NR9C (O) R8, NR9C (O) R9, NR9C (O) NR8R9, NR9C (O) NR9R9, NR9 (COOR8), NR9 (COOR9), OC (O) NR8R9, OC (O) NR9R9, S (O) 2R8, S (O) 2NR8R9, S (O) 2R9, S (O) 2NR9R9, NR9S (O) 2NR8R9, NR9S (O) 2NR9R9, NR9S (O) 2R8, NR9S (O) 2R9, R8 or R9; R8 is a partially or fully saturated or unsaturated monocyclic ring system of 5 to 8 members, bicyclic of 6 to 12 members or tricyclic of 7 to 14 members, said ring system is formed of carbon atoms that optionally include 1 to 3 heteroatoms if it is monocyclic, 1 to 6 heteroatoms if it is bicyclic or 1 to 9 heteroatoms if it is tricyclic, said heteroatoms are selected from O, N or S, and where said ring system is optionally substituted, independently, with 1 to 5 substituents from R9, oxo, NR9R9, OR9; SR9, C (O) R9, or a ring of partially or fully saturated or unsaturated carbon atoms of 5 to 6 members that optionally include 1 to 3 heteroatoms that are selected from O, N or S, and is optionally substituted, in the form independent, with 1 to 5 R9 substituents; R9 is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, C1-10 alkylamino, dialkylamino C1-10-, C1-10 alkoxy, C1-10 thioalkoxy or a 5 to 8 membered monocyclic or partially or fully unsaturated monocyclic ring system or 6 to 12 membered bicyclic ring, said ring system is formed of carbon atoms that optionally they include 1 to 3 heteroatoms if it is monocyclic or 1 to 6 heteroatoms if it is bicyclic, said heteroatoms are selected from O, N or S, where each of C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3 cycloalkyl -10, C4-10 cycloalkenyl, C1-10 alkylamino-, C1-10 dialkylamino, C1-10 alkoxy, C1-10 thioalkoxy and ring of said ring system is optionally substituted, independently, with 1 to 5 substituents of halo, haloalkyl, CN, NO2, NH2, OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclic opropyl, cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C1-10- alkylamino, C1-10- dialkylamino, C1-10 thioalkoxy , benzyl or phenyl; R10 is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, C1-10 alkylamino, dialkylamino C1-10-, C1-10 alkoxy, C1-10 thioalkoxy or a 5 to 8 membered monocyclic or partially or fully unsaturated monocyclic ring system or 6 to 12 membered bicyclic ring, said ring system is formed of carbon atoms that optionally they include 1 to 3 heteroatoms if it is monocyclic or 1 to 6 heteroatoms if it is bicyclic, said heteroatoms are selected from O, N or S, where each of C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3 cycloalkyl -10, C4-10 cycloalkenyl, C1-10 alkylamino-, C1-10 dialkylamino, C1-10 alkoxy, C1-10 thioalkoxy and ring of said ring system is optionally substituted, independently, with 1 to 5 substituents of halo, haloalkyl, CN, NO2, NH2, OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclic opropyl, cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C1-10 alkylamino, C1-10- dialkylamino, C1-10 thioalkoxy, benzyl or phenyl; R11 is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, C1-10 alkylamino, dialkylamino C1-10-, C1-10 alkoxy, C1-10 thioalkoxy or a 5 to 8 membered monocyclic or partially or fully unsaturated monocyclic ring system or 6 to 12 membered bicyclic ring, said ring system is formed of carbon atoms that optionally they include 1 to 3 heteroatoms if it is monocyclic or 1 to 6 heteroatoms if it is bicyclic, said heteroatoms are selected from O, N or S, where each of C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3 cycloalkyl -10, C4-10 cycloalkenyl, C1-10 alkylamino-, C1-10 dialkylamino, C1-10 alkoxy, C1-10 thioalkoxy and ring of said ring system is optionally substituted, independently, with 1 to 5 substituents of halo, haloalkyl, CN, NO2, NH2, OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyc lopropyl, cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C1-10- alkylamino, C1-10- dialkylamino, C1-10 thioalkoxy , benzyl or phenyl; alternatively, R10 and R11 taken in conjunction with the carbon or nitrogen atoms to which they are attached, form a second ring of partially or fully saturated or unsaturated carbon atoms of 5 to 6 members, which optionally include 1 to 3 heteroatoms which are selected from O, N or S, the second ring is optionally substituted, independently, with 1 to 5 substituents of R12, R13, R14 or R15 and is optionally fused with a third ring of 4 to 7 members, the third ring is formed of carbon atoms that optionally include 1 to 3 heteroatoms that are selected from O, N or S, and is optionally substituted, independently, with 1 to 5 substituents of R12, R13,

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