AR048088A1 - DERIVATIVES OF 1,6-NAFTIRIDINE AND 1,8-NAFTIRIDINE AND THEIR USE TO TREAT DIABETES AND RELATED DISORDERS - Google Patents

DERIVATIVES OF 1,6-NAFTIRIDINE AND 1,8-NAFTIRIDINE AND THEIR USE TO TREAT DIABETES AND RELATED DISORDERS

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AR048088A1
AR048088A1 ARP050100921A ARP050100921A AR048088A1 AR 048088 A1 AR048088 A1 AR 048088A1 AR P050100921 A ARP050100921 A AR P050100921A AR P050100921 A ARP050100921 A AR P050100921A AR 048088 A1 AR048088 A1 AR 048088A1
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heterocycloalkenyl
heterocycloalkyl
heteroatoms selected
cycloalkyl
heteroatoms
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ARP050100921A
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Bayer Pharmaceuticals Corp
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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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/10Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12Antidiuretics, e.g. drugs for diabetes insipidus

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  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Derivados de 1,6-naftiridina y 1,8-naftiridina, composiciones farmacéuticas que contienen tales derivados, y métodos para el tratamiento de la diabetes y trastornos relacionados. Reivindicacion 1: Un método para tratar o prevenir una enfermedad o afeccion seleccionada del grupo integrado por diabetes (tipo 1 o tipo 2), diabetes juvenil de inicio en la madurez (MODY); diabetes autoinmune del adulto (LADA); intolerancia a la glucosa (IGT); glucemia basal alterada (IFG), diabetes gestacional, y síndrome metabolico X, que comprende la administracion a un sujeto de una cantidad eficaz de un compuesto de formula (1), en la cual: R1 se selecciona de alquilo C1-8, alquenilo C2-8, alquinilo C2-8, y A-R9, o R1 se selecciona de arilo C6-10, heteroarilo C2-9 y 1-4 heteroátomos seleccionados de N, S(=O)0-2 y O, cicloalquilo C3-8, cicloalquenilo C4-8, heterocicloalquilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, y heterocicloalquenilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, donde dicho heterocicloalquilo y dicho heterocicloalquenilo además puede estar fusionado con fenilo o un heteroarilo de 5-6 miembros de C2-5 y 1-3 heteroátomos seleccionados de N, S(=O)0-2 y O, y/o donde uno o más de los átomos de carbono en dicho heterocicloalquilo o heterocicloalquenilo pueden estar oxidados a C(=O), todos los cuales pueden estar sustituidos con 1-3 de R10; R10 se selecciona de nitro, nitrilo, hidroxi, halogeno, acilo C1-6, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, haloalquilo C1-6, alcoxi C1-6, haloalcoxi C1-6, cicloalcoxi C3-6, arilo C6-10, heteroarilo C2-9 y 1-4 heteroátomos seleccionados de N, S(=O)0-2 y O, NR11R12, C(=O)OR11, C(=O)NHR11, NHC(=O)R13, NHS(=O)2R13, S(=O)0-2R13, S(=O)2NHR11, cicloalquilo C3-6, cicloalquenilo C3-6, heterocicloalquilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados de N S(=O)0-2 y O, y heterocicloalquenilo de 5-7 miembros C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, donde dicho heterocicloalquilo y dicho heterocicloalquenilo además puede estar fusionado con fenilo o un heteroarilo de 5-6 miembros de C2-5 y 1-3 heteroátomos seleccionados de N, S(=O)0-2 y O, y/o donde uno o más de los átomos de carbono en dicho heterocicloalquilo o heterocicloalquenilo pueden estar oxidados a C(=O); R13 se selecciona de alquilo C1-6, alquenilo C2-6, alquinilo C2-6, haloalquilo C1-6, cicloalquilo C3-6, y cicloalquenilo C4-6; R11 y R12 se seleccionan en forma independiente de hidrogeno, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, haloalquilo C1-6, cicloalquilo C3-6, y cicloalquenilo C4-6; A se selecciona de alquilo C1-8, alquenilo C2-8, alquinilo C2-8, y haloalquilo C1-8; R9 se selecciona de hidroxi, alcoxi C1-6, cicloalcoxi C3-6, O-A-R14, NR11R12; o R9 se selecciona de arilo C6-10, heteroarilo C2-9 y 1-4 heteroátomos seleccionados de N, S(=O)0-2 y O, cicloalquilo C3-8, cicloalquenilo C5-8, todos los cuales pueden estar sustituidos con 1-3 de R10, o R9 se selecciona de heterocicloalquilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, heterocicloalquenilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, donde dicho heterocicloalquilo y dicho heterocicloalquenilo además puede estar fusionado con fenilo o un heteroarilo de 5-6 miembros de C2-5 y 1-3 heteroátomos seleccionados de N, S(=O)0-2 y O, y/o donde uno o más de los átomos de carbono en dicho heterocicloalquilo o heterocicloalquenilo pueden estar oxidados a C(=O), donde dicho heterocicloalquilo o dicho heterocicloalquenilo puede estar sustituido con 1-3 de R10; R14 se selecciona de cicloalquilo de C3-8, cicloalquenilo C5-8, heterocicloalquilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, y heterocicloalquenilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, todos los cuales pueden estar sustituidos con 1-3 de R10; R2 se selecciona de NR15R16, S(O)0-2R17, y OR17; R15 se selecciona de hidrogeno, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-8, cicloalquenilo C4-8, heterocicloalquilo de 5-7 miembros de C3-6, y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, heterocicloalquenilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados, de N, S(=O)0-2 y O, A-R9, C(=O)R18, C(=O)NHR18, S(=O)2NHR18; R18 se selecciona de arilo C6-10, heteroarilo C2-9 y 1-4 heteroátomos seleccionados de N, S(=O)0-2 y O, cicloalquilo C3-8, cicloalquenilo C4-8, heterocicloalquilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, y heterocicloalquenilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, todos los cuales pueden estar sustituidos con 1-3 de R10, o R18 se selecciona de alquilo C1-6, alquenilo C2-6, y alquinilo C2-6, todos los cuales pueden estar sustituidos con 1-3 de halogeno o alcoxi C1-6, o R18 es A-R9; R16 se selecciona C1-8, alquenilo C2-8, alquinilo C2-8, y A-R9, o R16 se selecciona de arilo C6-10, heteroarilo C2-9 y 1-4 heteroátomos seleccionados de N, S(=O)0-2 y O, cicloalquilo C3-8, cicloalquenilo C4-8, heterocicloalquilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, y heterocicloalquenilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, todos los cuales pueden estar sustituidos con 1-3 de R10; o R15 y R16 se combinan, junto con el átomo de nitrogeno al cual están unidos, para formar un heteroarilo C2-9 y 1-4 heteroátomos seleccionados de N, S(=O)0-2 y O, o un heterocicloalquilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, heterocicloalquenilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, donde dicho heterocicloalquilo y dicho heterocicloalquenilo además pueden estar fusionados con fenilo o un heteroarilo de 5-6 miembros de C2-5 y 1-3 heteroátomos seleccionados de N, S(=O)0-2 y O, y/o donde uno o más de los átomos de carbono en dicho heterocicloalquilo o heterocicloalquenilo pueden estar oxidados a C(=O), todos los cuales pueden estar sustituidos con 1-3 de R10; R17 se selecciona de alquilo C1-8, alquenilo C2-8, y alquinilo C2-8, haloalquilo C1-8, A-R9, o R17 se selecciona de arilo C6-10, heteroarilo C2-9 y 1-4 heteroátomos seleccionados de N, S(=O)0-2 y O, cicloalquilo C3-8, cicloalquenilo C4-8, heterocicloalquilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, y heterocicloalquenilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, todos los cuales pueden estar sustituidos con 1-3 de R10; R3 se selecciona de arilo C6-10, heteroarilo C2-9 y 1-4 heteroátomos seleccionados de N, S(=O)0-2 y O, cicloalquilo C3-8, heterocicloalquilo C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, cicloalquenilo C4-8, y heterocicloalquenilo C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, todos los cuales pueden estar sustituidos con 1-3 de R10, o R3 se selecciona de alquilo C1-6, alquenilo C2-6, alquinilo C2-6, haloalquilo C1-6, hidrogeno, nitro, halogeno, NR19R20, A-OR19, A-NR19R20, y A-R20; R19 y R20 se seleccionan en forma independiente de hidrogeno, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, haloalquilo C1-6, y A-R9, o R19 y R20 se seleccionan en forma independiente de arilo C6-10, heteroarilo C2-9 y 1-4 heteroátomos seleccionados de N, S(=O)0-2 y O, cicloalquilo C3-8, cicloalquenilo C5-8, heterocicloalquilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, heterocicloalquenilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, donde dicho heterocicloalquilo y dicho heterocicloalquenilo además puede estar fusionado con fenilo o un heteroarilo de 5-6 miembros de C2-5 y 1-3 heteroátomos seleccionados de N, S(=O)0-2 y O, y/o donde uno o más de los átomos de carbono en dicho heterocicloalquilo o heterocicloalquenilo pueden estar oxidados a C(=O), todos los cuales pueden estar sustituidos con 1-3 de R10; R4 se selecciona de =O, =S, y OR21; R21 es hidrogeno, o R21 se selecciona de alquilo C1-8, alquenilo C2-8, alquinilo C2-8, cicloalquilo C3-8, cicloalquenilo C4-8, heterocicloalquilo de 5-7 miembros de C3-6, y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, y heterocicloalquenilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados, de N, S(=O)0-2 y O, todos los cuales pueden estar sustituidos con 1-3 de R10, R5 y R6 se seleccionan en forma independiente de cicloalquilo C3-8, cicloalquenilo C4-8, arilo C6-10, y heteroarilo C2-9 y 1-4 heteroátomos, todos los cuales pueden estar sustituidos con 1-3 de R10, o R5 y R6 se seleccionan en forma independiente de heterocicloalquilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, y heterocicloalquenilo de 5-7 miembros de C3-6 y 1-2 heteroátomos seleccionados de N, S(=O)0-2 y O, donde dicho heterocicloalquilo y dicho heterocicloalquenilo además pueden estar fusionados con fenilo o un heteroarilo de 5-6 miembros de C2-5 y 1-3 heteroátomos seleccionados de N, S(=O)0-2 y O, y/o donde uno o más de los átomos de carbono en dicho heterocicloalquilo o heterocicloalquenilo pueden estar oxidados a C(=O), donde dicho heterocicloalquilo o dicho heterocicloalquenilo pueden estar sustituidos con 1-3 de R10, A-R23, A-NR24R25, C(=O)R24, C(=O)OR24, C(=O)NR24R25, S(=O)2R26, A- C(=O)R24, A-C(=O)OR24, o A-C(=O)NR24R25, o R5 y R6 se seleccionan en forma independiente de hidrogeno, halogeno, nitrilo, nitro, hidroxi, alquilo C1-8, alquenilo C2-8, alquinilo C2-8, haloalquilo C1-8, alcoxi C1-8, haloalcoxi C1-8, cicloalcoxi C3-8, A-R23, A(OR22)-R23, NR27R28, A-NR27R28, A-Q-R29, Q-R29, Q-A-NR24R25, C(=O)R24, C(=O)OR24, C(=O)NR24R25, A-C(=O)R24, A-C(=O)OR24, y A-C(=O)NR24R25; Q se selecciona de O y S(=O)0-2; R22 se selecciona de hidrogeno, alquilo C1-8, haloalquilo C1-8, y cicloalquilo C3-8; R23 se selecciona de hidroxi, alcoxi C1-8, haloalcoxi C1-8, y cicloalcoxi C3-8, o R23 se selecciona de cicloalquilo C3-8, cicloalqu1,6-naphthyridine and 1,8-naphthyridine derivatives, pharmaceutical compositions containing such derivatives, and methods for the treatment of diabetes and related disorders. Claim 1: A method for treating or preventing a disease or condition selected from the group consisting of diabetes (type 1 or type 2), juvenile diabetes of onset at maturity (MODY); adult autoimmune diabetes (LADA); glucose intolerance (IGT); altered baseline blood glucose (IFG), gestational diabetes, and metabolic syndrome X, which comprises administering to an individual an effective amount of a compound of formula (1), in which: R1 is selected from C1-8 alkyl, C2 alkenyl -8, C2-8 alkynyl, and A-R9, or R1 is selected from C6-10 aryl, C2-9 heteroaryl and 1-4 heteroatoms selected from N, S (= O) 0-2 and O, C3- cycloalkyl 8, C4-8 cycloalkenyl, 5-7 C3-6 heterocycloalkyl and 1-2 heteroatoms selected from N, S (= O) 0-2 and O, and 5-7 C3-6 and 1 heterocycloalkenyl -2 heteroatoms selected from N, S (= O) 0-2 and O, wherein said heterocycloalkyl and said heterocycloalkenyl can also be fused with phenyl or a 5-6 membered C2-5 heteroaryl and 1-3 heteroatoms selected from N , S (= O) 0-2 and O, and / or where one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (= O), all of which may be substituted with 1-3 of R10; R10 is selected from nitro, nitrile, hydroxy, halogen, C1-6 acyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3- cycloalkoxy 6, C6-10 aryl, C2-9 heteroaryl and 1-4 heteroatoms selected from N, S (= O) 0-2 and O, NR11R12, C (= O) OR11, C (= O) NHR11, NHC (= O) R13, NHS (= O) 2R13, S (= O) 0-2R13, S (= O) 2NHR11, C3-6 cycloalkyl, C3-6 cycloalkenyl, 5-7 membered C3-6 heterocycloalkyl and 1- 2 heteroatoms selected from NS (= O) 0-2 and O, and 5-7 C3-6 heterocycloalkenyl and 1-2 heteroatoms selected from N, S (= O) 0-2 and O, wherein said heterocycloalkyl and said heterocycloalkenyl may also be fused with phenyl or a 5-6-membered C2-5 and 1-3 heteroaryl selected from N, S (= O) 0-2 and O, and / or where one or more of the atoms of carbon in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (= O); R13 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, and C4-6 cycloalkenyl; R 11 and R 12 are independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 4-6 cycloalkenyl; A is selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C 1-8 haloalkyl; R9 is selected from hydroxy, C1-6 alkoxy, C3-6 cycloalkoxy, O-A-R14, NR11R12; or R9 is selected from C6-10 aryl, C2-9 heteroaryl and 1-4 heteroatoms selected from N, S (= O) 0-2 and O, C3-8 cycloalkyl, C5-8 cycloalkenyl, all of which may be substituted with 1-3 of R10, or R9 is selected from 5-7 C3-6 heterocycloalkyl and 1-2 heteroatoms selected from N, S (= O) 0-2 and O, 5-7 C3 heterocycloalkenyl -6 and 1-2 heteroatoms selected from N, S (= O) 0-2 and O, wherein said heterocycloalkyl and said heterocycloalkenyl may also be fused with phenyl or a 5-6-membered heteroaryl of C2-5 and 1-3 heteroatoms selected from N, S (= O) 0-2 and O, and / or where one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl can be oxidized to C (= O), where said heterocycloalkyl or said heterocycloalkenyl can be substituted with 1-3 of R10; R14 is selected from C3-8 cycloalkyl, C5-8 cycloalkenyl, 5-7 C3-6 heterocycloalkyl and 1-2 heteroatoms selected from N, S (= O) 0-2 and O, and 5- 5- heterocycloalkenyl 7 members of C3-6 and 1-2 heteroatoms selected from N, S (= O) 0-2 and O, all of which may be substituted with 1-3 of R10; R2 is selected from NR15R16, S (O) 0-2R17, and OR17; R15 is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C4-8 cycloalkenyl, 5-7 membered C3-6 heterocycloalkyl, and 1-2 heteroatoms selected from N , S (= O) 0-2 and O, 5-7-membered heterocycloalkenyl of C3-6 and 1-2 heteroatoms, of N, S (= O) 0-2 and O, A-R9, C (= O) R18, C (= O) NHR18, S (= O) 2NHR18; R18 is selected from C6-10 aryl, C2-9 heteroaryl and 1-4 heteroatoms selected from N, S (= O) 0-2 and O, C3-8 cycloalkyl, C4-8 cycloalkenyl, 5-7 membered heterocycloalkyl of C3-6 and 1-2 heteroatoms selected from N, S (= O) 0-2 and O, and 5-7 C3-6 heterocycloalkenyl and 1-2 heteroatoms selected from N, S (= O) 0- 2 and O, all of which may be substituted with 1-3 of R10, or R18 is selected from C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, all of which may be substituted with 1-3 halogen or C1-6 alkoxy, or R18 is A-R9; R16 is selected C1-8, C2-8 alkenyl, C2-8 alkynyl, and A-R9, or R16 is selected from C6-10 aryl, C2-9 heteroaryl and 1-4 heteroatoms selected from N, S (= O) 0-2 and O, C3-8 cycloalkyl, C4-8 cycloalkenyl, 5-7 C3-6 heterocycloalkyl and 1-2 heteroatoms selected from N, S (= O) 0-2 and O, and 5-heterocycloalkenyl -7 members of C3-6 and 1-2 heteroatoms selected from N, S (= O) 0-2 and O, all of which may be substituted with 1-3 of R10; or R15 and R16 combine, together with the nitrogen atom to which they are attached, to form a C2-9 heteroaryl and 1-4 heteroatoms selected from N, S (= O) 0-2 and O, or a heterocycloalkyl of 5 -7 members of C3-6 and 1-2 heteroatoms selected from N, S (= O) 0-2 and O, 5-7 heterocycloalkenyl members of C3-6 and 1-2 heteroatoms selected from N, S (= O ) 0-2 and O, wherein said heterocycloalkyl and said heterocycloalkenyl can also be fused with phenyl or a 5-6-membered heteroaryl of C2-5 and 1-3 heteroatoms selected from N, S (= O) 0-2 and O , and / or where one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (= O), all of which may be substituted with 1-3 of R10; R17 is selected from C1-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, C1-8 haloalkyl, A-R9, or R17 is selected from C6-10 aryl, C2-9 heteroaryl and 1-4 heteroatoms selected from N, S (= O) 0-2 and O, C3-8 cycloalkyl, C4-8 cycloalkenyl, 5-7 C3-6 heterocycloalkyl and 1-2 heteroatoms selected from N, S (= O) 0-2 and O, and 5-7 C3-6 heterocycloalkenyl and 1-2 heteroatoms selected from N, S (= O) 0-2 and O, all of which may be substituted with 1-3 of R10; R3 is selected from C6-10 aryl, C2-9 heteroaryl and 1-4 heteroatoms selected from N, S (= O) 0-2 and O, C3-8 cycloalkyl, C3-6 heterocycloalkyl and 1-2 heteroatoms selected from N , S (= O) 0-2 and O, C4-8 cycloalkenyl, and C3-6 heterocycloalkenyl and 1-2 heteroatoms selected from N, S (= O) 0-2 and O, all of which may be substituted with 1 -3 of R10, or R3 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, hydrogen, nitro, halogen, NR19R20, A-OR19, A-NR19R20, and A-R20 ; R19 and R20 are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and A-R9, or R19 and R20 are independently selected from C6-10 aryl , C2-9 heteroaryl and 1-4 heteroatoms selected from N, S (= O) 0-2 and O, C3-8 cycloalkyl, C5-8 cycloalkenyl, 5-7 member C3-6 heterocycloalkyl and 1-2 heteroatoms selected from N, S (= O) 0-2 and O, 5-7 C3-6 heterocycloalkenyl and 1-2 heteroatoms selected from N, S (= O) 0-2 and O, wherein said heterocycloalkyl and said heterocycloalkenyl may also be fused with phenyl or a 5-6-membered C2-5 and 1-3 heteroaryl selected from N, S (= O) 0-2 and O, and / or where one or more of the atoms of carbon in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C (= O), all of which may be substituted with 1-3 of R10; R4 is selected from = O, = S, and OR21; R21 is hydrogen, or R21 is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C4-8 cycloalkenyl, 5-7 membered C3-6 heterocycloalkyl, and 1-2 heteroatoms selected from N, S (= O) 0-2 and O, and heterocycloalkenyl of 5-7 members of C3-6 and 1-2 heteroatoms selected, from N, S (= O) 0-2 and O, all of which they may be substituted with 1-3 of R10, R5 and R6 are independently selected from C3-8 cycloalkyl, C4-8 cycloalkenyl, C6-10 aryl, and C2-9 heteroaryl and 1-4 heteroatoms, all of which may be substituted with 1-3 of R10, or R5 and R6 are independently selected from 5-7 C3-6 heterocycloalkyl and 1-2 heteroatoms selected from N, S (= O) 0-2 and O, and heterocycloalkenyl of 5-7 members of C3-6 and 1-2 heteroatoms selected from N, S (= O) 0-2 and O, wherein said heterocycloalkyl and said heterocycloalkenyl can also be fused with phenyl or a 5-6 membered heteroaryl of C2-5 and 1-3 heteroatoms are selected from N, S (= O) 0-2 and O, and / or where one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl can be oxidized to C (= O), where said heterocycloalkyl or said heterocycloalkenyl can be substituted with 1-3 of R10, A-R23, A-NR24R25, C (= O) R24, C (= O) OR24, C (= O) NR24R25, S (= O) 2R26, A- C (= O ) R24, AC (= O) OR24, or AC (= O) NR24R25, or R5 and R6 are independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, C1-8 alkyl, C2-8 alkenyl, C2 alkynyl -8, C1-8 haloalkyl, C1-8 alkoxy, C1-8 haloalkoxy, C3-8 cycloalkoxy, A-R23, A (OR22) -R23, NR27R28, A-NR27R28, AQ-R29, Q-R29, QA- NR24R25, C (= O) R24, C (= O) OR24, C (= O) NR24R25, AC (= O) R24, AC (= O) OR24, and AC (= O) NR24R25; Q is selected from O and S (= O) 0-2; R22 is selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl, and C3-8 cycloalkyl; R23 is selected from hydroxy, C1-8 alkoxy, C1-8 haloalkoxy, and C3-8 cycloalkoxy, or R23 is selected from C3-8 cycloalkyl, cycloalkyl

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