WO2004075840A2 - Selective non-steroidal glucocorticoid receptor modulators - Google Patents

Selective non-steroidal glucocorticoid receptor modulators Download PDF

Info

Publication number
WO2004075840A2
WO2004075840A2 PCT/US2004/005199 US2004005199W WO2004075840A2 WO 2004075840 A2 WO2004075840 A2 WO 2004075840A2 US 2004005199 W US2004005199 W US 2004005199W WO 2004075840 A2 WO2004075840 A2 WO 2004075840A2
Authority
WO
WIPO (PCT)
Prior art keywords
group
independently selected
items
optionally substituted
halo
Prior art date
Application number
PCT/US2004/005199
Other languages
French (fr)
Other versions
WO2004075840A9 (en
WO2004075840A3 (en
Inventor
Amjad Ali
Richard Beresis
Steven L. Colletti
Donald W. Graham
James R. Tata
Christopher F. Thompson
Original Assignee
Merck & Co. Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck & Co. Inc. filed Critical Merck & Co. Inc.
Priority to DE602004026558T priority Critical patent/DE602004026558D1/en
Priority to AU2004216182A priority patent/AU2004216182B2/en
Priority to JP2006503780A priority patent/JP4648303B2/en
Priority to CA002516684A priority patent/CA2516684A1/en
Priority to US10/544,899 priority patent/US7411073B2/en
Priority to EP04713398A priority patent/EP1599201B1/en
Priority to AT04713398T priority patent/ATE464296T1/en
Publication of WO2004075840A2 publication Critical patent/WO2004075840A2/en
Publication of WO2004075840A3 publication Critical patent/WO2004075840A3/en
Publication of WO2004075840A9 publication Critical patent/WO2004075840A9/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • 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
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Hematology (AREA)
  • Dermatology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Pulmonology (AREA)
  • Psychiatry (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Oncology (AREA)
  • Virology (AREA)
  • Anesthesiology (AREA)
  • Communicable Diseases (AREA)
  • Child & Adolescent Psychology (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • Endocrinology (AREA)
  • Addiction (AREA)
  • Orthopedic Medicine & Surgery (AREA)

Abstract

The present invention encompasses compounds of Formula (I) or pharmaceutically acceptable salts or hydrates thereof, which are useful as novel non-steroidal selective glucocorticoid receptor modulators for treating a variety of autoimmune and inflammatory diseases or conditions, and possess advantages over steroidal glucocorticoid ligands with respect to undesireable side-effects, efficacy, toxicity and/or metabolism. Pharmaceutical compositions and methods of use are also included.

Claims

WHAT IS CLAIMED IS:
1. A compound represented by Formula I
Figure imgf000073_0001
or a pharmaceutically acceptable salt or hydrate thereof, wherein:
n is 0, 1 or 2;
J is selected from NRl or C(R1)(R2);
K is selected from NR3 or C(R3)(R4);
L is selected from NR5 or C(R5)(R6);
X is selected from the group consisting of:-ORa, -N(Rb)-Y-Rc or -S(O)j-Rd, wherein:
Y is selected from a bond, -C(O)-, -C(O)-O- wherein the point of attachment of the "-O-" group is to Rc forming an alkoxy moiety, -S(O)2- and -C(O)-N(Rl2)-, wherein the point of attachment of the nitrogen group is to'Rc, and
j is independently 0, 1 or 2,
Ra, Rb, RC5 Rd and R§ are each independently selected from the group consisting of:
(1) hydrogen, except that Rd is not hydrogen and Rc is hydrogen only when Y is a bond or -C(O)-N(Rl2)-,
(2) Ci-βalkyl, (3) C2-6alkenyl,
(4) C2-6alkynyl, (5) C3-6cycloalkyl,
(6) aryl,
(7) aralkyl,
(8) HETl, (9) -Cι_6alkyl-HET2,
(10) aralkenyl,
(11) aralkynyl and
(12) arylsulfonylalkyl, wherein items (2) to (5) above and the alkyl portions of items (7), (9) and (12) above and the alkenyl portion of item (10) above and the alkynyl portion of item (11) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, oxo, ORll, N(Rl2)2, C3_6cycloalkyl and Ci-4alkyl-S(O)m-, wherein m is 0, 1 or 2, and
wherein items (6) and (8) above and the aryl portion of items (7), (10), (11) and (12) above and the HET2 portion of item (9) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of:
(a) halo, (b) ORll,
(c) N(Rl2)2,
(d) Ci-6alkyl,
(e) C2-6alkenyl,
(f) C2-6akynyl, (g) Ci-6alkyl-S(O)p-, wherein p is 0, 1 or 2,
(h) aryl,
(i) aryl-S (O)q-, wherein q is 0, 1 or 2,
0) HET3,
(k) aralkyl, (1) aroyl,
(m) aryloxy,
(n) aralkoxy and
(o) CN, wherein items (d) to (g) above and the alkyl portions of item (k) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, ORll and N(Rl2)2, and
wherein items (h), (i), (j), (1) and (m) above and the aryl portions of items (k) and (n) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR12 and Cι_4alkyl,
Rl, R2, R3, R45 R5 and R6 are each independently selected from the group consisting of: (1) hydrogen,
(2) halo,
(3) Ci-6alkyl,
(4) C2-6alkenyl,
(5) C2-6akynyl, (6) C3_6cycloalkyl,
(7) Ci-6alkoxy,
(8) Cι_6alkyl-S(O)r, wherein r is 0, 1 or 2,
(9) aryl,
(10) aralkyl, (11) HET and
(12) -Ci-6alkyl-HET5, wherein items (3) to (8) above and the alkyl portions of items (10) and (12) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, ORll, N(Rl )2 and Cι_6alkyl-S(O)s- , wherein s is 0, 1 or 2; and
wherein items (9) and (11) and the aryl portion of items (10) and the HET portion of item (12) are optionally substituted from one up to the maximum number of substituable positions with a substituent independently selected from the group consisting of: (a) halo,
(b) ORll,
(c) N(Rl2)2,
(d) Cι_6alkyl,
(e) C2-6alkenyl, (f) C2-6akynyl and (g) Cι_6alkyl-S(O)t-, wherein t is 0, 1 or 2, wherein items (d) to (g) above are optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, ORll and N(Rl2)2,
or Rl and R3 or R3 and R5 may be joined together to form a double bond;
R7 is selected from the group consisting of: (1) hydrogen, (2) ORll,
(3) Cι. alkyl,
(4) aryl and
(5) aralkyl, wherein item (3) above and the alkyl portion of item (5) above are optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, ORl 1 and N(Rl2)2, and
wherein item (4) above and the aryl portion of item (5) above are optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of:
(a) halo,
(b) ORll,
(c) N(Rl2)2,
(d) Ci-6alkyl, (e) C2-6alkenyl and
(f) C2-6akynyl, wherein items (d) to (f) above are optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, ORll and N(Rl2)2;
each R9 and RlO is independently selected from the group consisting of:
(1) halo,
(2) Ci_6alkyl,
(3) C2-6alkenyl, (4) Ci-6alkoxy and (5) hydroxy,
wherein items (2) to (4) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR12, N(Rl 1)2 and Ci_6alkyl-S(O)u-, wherein u is 0, 1 or 2;
each RU and Rl is independently selected from the group consisting of hydrogen and Cι_ 4alkyl, optionally substituted from one up to the maximum number of substitutable positions with halo; and
HETl, HET2, HET3, HET4 and HET5 are each independently selected from the group of heterocycles consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbohnyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pynolyl, quinazolinyl, quinolyl, quinoxahnyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pynolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropynolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.
2. The compound according to Claim 1 wherein:
J is NRl;
K is NR3;
L is C(R5)(R6); and
R3 and R5 are joined together to form a double bond.
3. The compound according to Claim 1 wherein the optional double bond shown in ring A of the compound of Formula I is present.
4. The compound according to Claim 1 wherein X is -ORa.
5. The compound according to Claim 1 wherein X is -N(Rb)-Y-Rc, wherein Y is selected from -C(O)-, -C(O)-O- wherem the point of attachment of the "-O-" group is to R forming an alkoxy moiety, -S(O)2- and -C(O)-N(Rl2)-, wherein the point of attachment of the nitrogen group is to Rc.
6. The compound according to Claim 1 wherein X is -S(O)j-Rd.
7. The compound according to Claim 1 wherein n is 0 and the optional double bonds shown in ring B are not present.
8. A compound according to Claim 1 of Formula II:
Figure imgf000078_0001
π or a pharmaceutically acceptable salt or hydrate thereof, wherein:
X is selected from the group consisting of: -ORa, -N(Rb)-Y-Rc, -S(O)j-Rd, wherein:
Y is selected from a bond, -C(O)-, -C(O)-O- wherein the point of attachment of the "-O-" group is to R forming an alkoxy moiety, -S(O)2- and -C(O)-N(Rl2)-, wherein the point of attachment of the nitrogen group is to Rc, and
j is 0, 1 or 2, n is 1 or 2,
Ra, Rb, Rc, Rd and R8 are each independently selected from the group consisting of: (1) hydrogen, except that Rd is not hydrogen and Rc is hydrogen only when Y is a bond or -C(O)-N(Rl2)-,
(2) Cι_6alkyl,
(3) C2-6alkenyl,
(4) C2-6akynyl, (5) C3_6cycloalkyl,
(6) aryl,
(7) aralkyl,
(8) HETl,
(9) -Cι_6alkyl-HET2, (10) aralkenyl,
(11) aralkynyl and
(12) arylsulfonylalkyl, wherein items (2) to (5) above and the alkyl portions of items (7), (9) and (12) above and the alkenyl portion of item (10) above and the alkynyl portion of item (11) above are optionally substituted with oxo and optionally substituted with one to three substituents independently selected from the group consisting of: halo, ORll, N(Rl2)2, C3_6cycloalkyl and Cχ_4alkyl- S(O)m-, wherein m is 0, 1 or 2, and
wherem items (6) and (8) above and the aryl portion of items (7), (10), (11) and (12) above and the HET2 portion of item (9) above are optionally substituted with one to five substituents independently selected from the group consisting of:
(a) halo,
(b) ORll,
(c) N(Rl2)2, (d) Ci_6alkyl,
(e) C2-6alkenyl,
(f) C2-6akynyl,
(g) Ci_6alkyl-S(O)p-, wherein p is 0, 1 or 2,
(h) aryl, (i) aryl-S(O)q-, wherein q is 0, 1 or 2, (j) HET3,
(k) aralkyl,
(1) aroyl,
(m) aryloxy,
(n) aralkoxy and
(o) CN, wherein items (d) to (g) above and the alkyl portions of item (k) above are optionally substituted with one to three substituents independently selected from the group consisting of: halo, ORl 1 and N(Rl2)2, and
wherein items (h), (i), (j), (1) and (m) above and the aryl portions of items (k) and (n) above are optionally substituted with one to three substituents independently selected from the group consisting of: halo, OR12 and Cι_4alkyl,
each Rl 1 and Rl2 is independently selected from the group consisting of hydrogen and Cχ_ 4alkyl, optionally substituted with 1 to 3 halo groups; and
HETl, HET2 and HET3 are each independently selected from the group of heterocycles consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbohnyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pynolyl, quinazolinyl, quinolyl, quinoxahnyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pynolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropynolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.
9. The compound according to Claim 8 wherein
X is -ORa n is 1, and
Ra is selected from the group consisting of: (1) hydrogen,
(2) acetyl,
(3) benzyl,
(4) Cι_6alkyl,
(5) C2-6alkenyl,
(6) C2-6alkynyl and
(7) C3_6cycloalkyl,
R8 is selected from the group consisting of:
(1) hydrogen,
(2) Cι_6alkyl, (3) C2-6alkenyl,
(4) C2-6akynyl,
(5) C3-6cycloalkyl,
(6) aryl,
(7) aralkyl, (8) HETl,
(9) -Cι_6alkyl-HET2
(10) aralkenyl,
(11) aralkynyl, and
(12) arylsulfonylalkyl wherein items (2) to (5) above and the alkyl portions of items (7), (9) and (12) above and the alkenyl portion of item (10) above and the alkynyl portion of item (11) above are optionally substituted with oxo and optionally substituted with one to three substituents independently selected from the group consisting of: halo, ORl 1 and C3_6cycloalkyl,
wherein items (6) and (8) above and aryl portion of items (7), (10), (11) and (12) above and the HET2 portion of item (9) above are optionally substituted with one to five substituents independently selected from the group consisting of:
(a) halo,
(b) Ci_6alkyl, (c) Cl-4alkoxy and (d) aryl,
Rl 1 is selected from the group consisting of hydrogen and Ci_4alkyl, optionally substituted with 1 to 3 halo groups; and
HETl and HET2 are each independently selected from the group of heterocycles consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbohnyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pynolyl, quinazolinyl, quinolyl, quinoxahnyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4- dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pynolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropynolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.
10. The compound according to Claim 9 wherein:
RS is selected from the group consisting of:
(1) hydrogen,
(2) Ci_6alkyl, (3) C2-6alkenyl,
(4) C2-6akynyl,
(5) C3_6cycloalkyl,
(6) phenyl or naphthyl,
(7) benzyl or phenethyl, (8) benzothiophene,
(9) phenylethenyl,
(10) phenylethynyl, and
(11) phenylsulfonylmethyl, wherein items (2) to (5) above are optionally substituted with one to three substituents independently selected from the group consisting of: halo, OR 1 and C3_6cycloalkyl, wherein item (6) above and the phenyl portions of items (7), (9), (10) and (11) above are optionally substituted with one to five substituents independently selected from the group consisting of: (a) halo,
(b) Ci-βalkyl,
(c) Cι_4alkoxy and
(d) phenyl.
11. The compound according to Claim 8 wherein:
X is -N(Rb)-Y-Rc, wherein:
Y is selected from -C(O)-, -C(O)-O- wherein the point of attachment of the "-O-" group is to Rc forming an alkoxy moiety, -S(O)2- and -C(O)-N(Rl2)-, wherein the point of attachment of the nitrogen group is to Rc, and
n is 1,
R8 is hydrogen, and
Rb and Rc are each independently selected from the group cons:
(1) hydrogen, except that Rc is not hydrogen.
(2) Cχ_6alkyl,
(3) C2-6alkenyl,
(4) C2-6akynyl,
(5) C3-6cycloalkyl,
(6) aryl,
(7) aralkyl,
(8) HETl,
(9) -Ci-6aιkyl-HET2,
(10) aralkenyl,
(11) aralkynyl and
(12) arylsulfonylalkyl, wherein items (2) to (5) above and the alkyl portions of items (7), (9) and (12) above and the alkenyl portion of item (10) above and the alkynyl portion of item (11) above are optionally substituted with oxo and optionally substituted with with one to three substituents independently selected from the group consisting of: halo, ORll, N(Rl2)2, C3-6cycloalkyl and Cι_4alkyl- S(O)m-, wherein m is 0, 1 or 2, and
wherein items (6) and (8) above and the aryl portion of items (7), (10), (11) and (12) above and the HET2 portion of item (9) above are optionally substituted with one to five substituents independently selected from the group consisting of: (a) halo,
(b) ORll,
(c) N(R12)2,
(d) Ci-6alkyl,
(e) C2-6alkenyl, (f) C2-6akynyl,
(g) Cι_6alkyl-S(O)p-, wherein p is 0, 1 or 2,
(h) aryl,
(i) aryl-S(O)q-, wherein q is 0, 1 or 2,
(j) HET3, (k) aralkyl,
(1) aroyl, (m) aryloxy, (n) aralkoxy and (o) CN, wherein items (d) to (g) above and the alkyl portions of item (k) above are optionally substituted with one to three substituents independently selected from the group consisting of: halo, ORll and N(Rl2)2, and
wherein items (h), (i), (j), (1) and (m) above and the aryl portions of items (k) and (n) above are optionally substituted with one to three substituents independently selected from the group consisting of: halo, OR12 and Cχ-4alkyl,
each RU and Rl is independently selected from the group consisting of hydrogen and Ci_ 4alkyl, optionally substituted with 1 to 3 halo groups; and HETl, HET and HET3 are each independently selected from the group of heterocycles consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbohnyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pynolyl, quinazolinyl, quinolyl, quinoxahnyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pynolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropynolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.
12. The compound according to Claim 11 wherein:
Rb and R are each independently selected from the group consisting of:
(1) hydrogen, except that Rc is hydrogen only when Y is a bond or -C(O)- N(Rl2)-,
(2) Ci-6alkyl,
(3) C2-6alkenyl,
(4) C2-6akynyl, (5) C3_6cycloalkyl,
(6) aryl,
(7) aralkyl,
(8) HETl,
(9) -Ci-6alkyl-HET2, (10) aralkenyl, and
(11) aralkynyl, wherein items (2) to (5) above are optionally substituted with 1-3 halo groups, and wherein items (6) and (8) and aryl portion of items (7), (10) and (11) above and the HET2 portion of item (9) above are optionally substituted with one to five substituents independently selected from the group consisting of:
(a) halo, (b) Cι_4alkyl, optionally substituted with 1-3 halo groups, and
(c) Cι_4alkylthio,
HETl and HET2 are each independently selected from the group of heterocycles consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbohnyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pynolyl, quinazolinyl, quinolyl, quinoxahnyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4- dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pynolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropynolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.
13. The compound according to Claim 12 wherein:
Rb is selected from the group consisting of: hydrogen and Cι_4alkyl, and
Rc is selected from the group consisting of:
(1) C -4alkyl,
(2) phenyl or benzyl, each optionally substituted with 1 to 5 groups independently selected from fluoro, chloro and trifluoromethyl,
(3) naphthyl,
(4) thiopheneyl,
(5) pyridyl,
(6) isoquinolyl, (7) pyrimidyl and (8) pyrazyl, wherein items (4) to (8) above are optionally substitited with 1 to 5 groups independently selected from fluoro, chloro, methyl ,methylthio and trifluoromethyl.
14. The compound according to Claim 13, wherein Rc is phenyl, optionally substituted with 1 to 5 groups independently selected from fluoro, chloro and trifluoromethyl.
15. The compound according to Claim 8, wherein:
X is -S(O)j-Rd, wherein j is 0, 1 or 2,
n is 1,
R8 is hydrogen, and
Rd is selected from the group consisting of:
(1) Cι_6alkyl,
(2) C2-6alkenyl,
(3) C2-6akynyl, (4) C3_6cycloalkyl,
(5) aryl,
(6) aralkyl,
(7) HETl,
(8) -Cι_6alkyl-HET2 (9) aralkenyl, and
(10) aralkynyl, wherein items (1) to (4) above are optionally substituted with 1-3 halo groups, and
wherein items (5) and (7) and aryl portion of items (6), (9) and (10) above and the HET2 portion of item (8) above are optionally substituted with one to five substituents independently selected from the group consisting of:
(a) halo,
(b) Ci-4alkyl, optionally substituted with 1-3 halo groups, and
(c) Cι_4alkylthio, and HETl and HET are each independently selected from the group of heterocycles consisting of: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbohnyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pynolyl, quinazolinyl, quinolyl, quinoxahnyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4- dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pynolidinyl, morpholinyl, thiomorphohnyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropynolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.
16. The compound according to Claim 15, wherein
Rd is phenyl, optionally substituted with 1 to 5 groups independently selected from fluoro, chloro and trifluoromethyl.
17. A compound selected from the following group:
Figure imgf000088_0001
Figure imgf000089_0001
89
Figure imgf000090_0001
Table B
Figure imgf000090_0002
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0002
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Table D
Figure imgf000095_0002
Figure imgf000095_0003
Figure imgf000096_0002
Table E
Figure imgf000096_0001
Figure imgf000097_0001
Table F
Figure imgf000098_0001
Figure imgf000098_0002
Figure imgf000099_0001
Figure imgf000100_0002
Figure imgf000100_0001
Table H
Figure imgf000101_0001
Figure imgf000101_0002
Table I
Figure imgf000102_0001
Table J
Figure imgf000102_0002
Figure imgf000102_0003
Figure imgf000103_0001
Table L
Figure imgf000103_0002
Figure imgf000103_0003
Ar Group
2-(trifluoromethyl)phenyl
2,6-dichlorophenyl
2,4-dichlorophenyl
or a pharmaceutically acceptable salt of any compound selected from any of the tables above.
18. A pharmaceutical composition comprising a compound according to Claim 1 in combination with a pharmaceutically acceptable carrier.
19. A method for treating a glucocorticoid receptor mediated disease or condition in a mammalian patient in need of such treatment comprising administering the patient a compound according to Claim 1 in an amount that is effective for treating the glucocorticoid receptor mediated disease or condition.
20. The method according to Claim 19 wherein the glucocorticoid receptor mediated disease or condition is selected from the group consisting of: tissue rejection, leukemias, lymphomas, Cushing's syndrome, acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation apoptosis, HPA axis suppression and regulation, hypercortisolemia, stroke and spinal cord injury, hypercalcemia, hypergylcemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia, Little's syndrome, obesity, metabolic syndrome, inflammatory bowel disease, systemic lupus erythematosus, polyartitis nodosa,
Wegener's granulomatosis, giant cell arteritis, rheumatoid arthritis, juvenile rheumatoid arthritis, uveitis, hay fever, allergic rhinitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, organ transplantation, hepatitis, cinhosis, inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythematosus, inflamed cysts, atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, buflous pernphigoid, systemic lupus erythematosus, dermatomyositis, herpes gestationis, eosinophihc fasciitis, relapsing polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, type I reactive leprosy, capillary hemangiomas, contact dermatitis, atopic dermatitis, lichen planus, exfoliative dermatitus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiform, cutaneous T-cell lymphoma, Human hnmunodeficiency Virus (HTV), cell apoptosis, cancer, Kaposi's sarcoma, retinitis pigmentosa, cognitive performance, memory and learning enhancement, depression, addiction, mood disorders, chronic fatigue syndrome, schizophrenia, sleep disorders, and anxiety.
21. A method of selectively modulating the transactivation, transrepression, agonism and antagonism effects of the glucocorticoid receptor in a mammal comprising administering to the mammal a compound according to Claim 1 in an amount that is effective to modulate the glucocorticoid receptor.
PCT/US2004/005199 2003-02-25 2004-02-20 Selective non-steroidal glucocorticoid receptor modulators WO2004075840A2 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
DE602004026558T DE602004026558D1 (en) 2003-02-25 2004-02-20 SELECTIVE NON-TTEROIDAL GLUCOCORTICOID RECEPTOR MODULATORS
AU2004216182A AU2004216182B2 (en) 2003-02-25 2004-02-20 Selective non-steroidal glucocorticoid receptor modulators
JP2006503780A JP4648303B2 (en) 2003-02-25 2004-02-20 Selective non-steroidal glucocorticoid receptor modulators
CA002516684A CA2516684A1 (en) 2003-02-25 2004-02-20 Selective non-steroidal glucocorticoid receptor modulators
US10/544,899 US7411073B2 (en) 2003-02-25 2004-02-20 Selective non-steroidal glucocorticoid receptor modulators
EP04713398A EP1599201B1 (en) 2003-02-25 2004-02-20 Selective non-steroidal glucocorticoid receptor modulators
AT04713398T ATE464296T1 (en) 2003-02-25 2004-02-20 SELECTIVE NONSTEROID GLUCOCORTICOID RECEPTOR MODULATORS

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US45081103P 2003-02-25 2003-02-25
US60/450,811 2003-02-25

Publications (3)

Publication Number Publication Date
WO2004075840A2 true WO2004075840A2 (en) 2004-09-10
WO2004075840A3 WO2004075840A3 (en) 2005-02-03
WO2004075840A9 WO2004075840A9 (en) 2005-08-04

Family

ID=32927681

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/005199 WO2004075840A2 (en) 2003-02-25 2004-02-20 Selective non-steroidal glucocorticoid receptor modulators

Country Status (8)

Country Link
US (1) US7411073B2 (en)
EP (1) EP1599201B1 (en)
JP (1) JP4648303B2 (en)
AT (1) ATE464296T1 (en)
AU (1) AU2004216182B2 (en)
CA (1) CA2516684A1 (en)
DE (1) DE602004026558D1 (en)
WO (1) WO2004075840A2 (en)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1617806A2 (en) * 2003-04-23 2006-01-25 Merck & Co., Inc. Selective spirocyclic glucocorticoid receptor modulators
WO2006138373A2 (en) 2005-06-14 2006-12-28 Bristol-Myers Squibb Company MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-kB ACTIVITY AND USE THEREOF
WO2008051532A1 (en) * 2006-10-23 2008-05-02 Merck & Co., Inc. 2-[1-phenyl-5-hydroxy or methoxy-4alpha-methyl-hexahydroclopenta[f]indazol-5-yl]ethyl phenyl derivatives as glucocorticoid receptor ligands
EP1916896A2 (en) * 2005-08-26 2008-05-07 The Regents of The University of California Non-steroidal antiandrogens
WO2009054925A1 (en) * 2007-10-23 2009-04-30 Merck & Co., Inc. Process for making glucocorticoid receptor ligands
EP2268630A2 (en) * 2008-02-26 2011-01-05 Merck Sharp & Dohme Corp. Hexahydrocyclopentylýf¨indazole carboxamides and derivatives thereof as selective glucocorticoid receptor modulators
EP2482659A1 (en) * 2009-09-08 2012-08-08 Schering Corporation HEXAHYDROCYCLOPENTA[f]INDAZOLE 5-YL ETHANOLS AND DERIVATIVES THEREOF AS SELECTIVE GLUCOCORTICOID RECEPTOR MODULATORS
EP2493302A1 (en) * 2009-10-30 2012-09-05 Merck Sharp & Dohme Corp. Hexahydrocyclopentyl[f]indazole pyridyl ethanols and derivatives thereof as selective glucocorticoid receptor modulators
EP2493303A1 (en) * 2009-10-30 2012-09-05 Merck Sharp & Dohme Corp. 2- [1-PHENYL-5-HYDROXY-4a-SUBSTITUTED-HEXAHYDROCYCLOPENTA [F]INDAZOL-5-YL]ETHYL PHENYL DERIVATIVES AS GLUCOCORTICOID RECEPTOR LIGANDS
WO2018191283A1 (en) * 2017-04-11 2018-10-18 Oric Pharmaceuticals, Inc. Glucocorticoid receptor modulators
WO2020076999A1 (en) * 2018-10-10 2020-04-16 Oric Pharmaceuticals, Inc. Glucocorticoid receptor modulators
WO2020152193A1 (en) 2019-01-22 2020-07-30 Akribes Biomedical Gmbh Selective glucocorticoid receptor modifiers for treating impaired skin wound healing
CN112771046A (en) * 2018-07-20 2021-05-07 格吕伦塔尔有限公司 Other substituted triazoloquinoxaline derivatives

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2473886C (en) * 2002-01-22 2012-08-21 The Regents Of The University Of California Non-steroidal ligands for the glucocorticoid receptor, compositions and uses thereof
US7282591B2 (en) * 2002-04-11 2007-10-16 Merck & Co., Inc. 1h-benzo{f}indazol-5-yl derivatives as selective glucocorticoid receptor modulators
TW201422590A (en) 2012-09-07 2014-06-16 Abbvie Inc Heterocyclic nuclear hormone receptor modulators
WO2014094357A1 (en) 2012-12-21 2014-06-26 Abbvie Inc. Heterocyclic nuclear hormone receptor modulators

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4349559A (en) 1981-02-19 1982-09-14 Sterling Drug Inc. Anti-inflammatory spiro-2H-indene-[2,3']-3H-pyrazolo[4",5":7',6']naphtho[2,1-b]pyran-1,3-dione derivatives
WO2003086294A2 (en) 2002-04-11 2003-10-23 Merck & Co., Inc. 1h-benzo[f]indazol-5-yl derivatives as selective glucocorticoid receptor modulators

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3932388A (en) * 1974-04-22 1976-01-13 Schering Corporation -Azido-4,6-pregnadieno(3,2-c)pyrazoles, processes for their preparation and intermediates useful therein
NZ199618A (en) 1981-02-19 1985-04-30 Sterling Drug Inc Spiro-((1)benzopyrano(5,6-f)indazole-3(2h),5'(2'h)pyrimidine)-2',4'6'-(1'h,3'h)-trione derivatives and pharmaceutical compositions
US4307102A (en) * 1981-02-19 1981-12-22 Sterling Drug Inc. Phenanthro[2,3-c]pyrazole
US4349558A (en) * 1981-02-19 1982-09-14 Sterling Drug Inc. Anti-inflammatory 8H-phenanthro-[2,3-c]pyrazole derivatives
CA2473886C (en) * 2002-01-22 2012-08-21 The Regents Of The University Of California Non-steroidal ligands for the glucocorticoid receptor, compositions and uses thereof
WO2004026248A2 (en) 2002-09-20 2004-04-01 Merck & Co., Inc. Octahydro-2-h-naphtho[1,2-f] indole-4-carboxamide derivatives as selective glucocorticoid receptor modulators

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4349559A (en) 1981-02-19 1982-09-14 Sterling Drug Inc. Anti-inflammatory spiro-2H-indene-[2,3']-3H-pyrazolo[4",5":7',6']naphtho[2,1-b]pyran-1,3-dione derivatives
WO2003086294A2 (en) 2002-04-11 2003-10-23 Merck & Co., Inc. 1h-benzo[f]indazol-5-yl derivatives as selective glucocorticoid receptor modulators

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Recent Advances in Glucocorticoid Receptor Action", 2002, SPRINGER-VERLAG: BERLIN-HEIDELBERG
COGHLAN, M.J. ET AL.: "Annual Reports in Medicinal Chemistry", vol. 37, 2002, ACADEMIC PRESS, pages: 167 - 176

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1617806A4 (en) * 2003-04-23 2006-11-02 Merck & Co Inc Selective spirocyclic glucocorticoid receptor modulators
EP1617806A2 (en) * 2003-04-23 2006-01-25 Merck & Co., Inc. Selective spirocyclic glucocorticoid receptor modulators
US7662846B2 (en) 2003-04-23 2010-02-16 Merck Sharp & Dohme Corp. Selective spirocyclic glucocorticoid receptor modulators
WO2006138373A2 (en) 2005-06-14 2006-12-28 Bristol-Myers Squibb Company MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-kB ACTIVITY AND USE THEREOF
US7888381B2 (en) 2005-06-14 2011-02-15 Bristol-Myers Squibb Company Modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity, and use thereof
US7645885B2 (en) 2005-08-26 2010-01-12 The Regents Of The University Of California Non-steroidal antiandrogens
EP1916896A2 (en) * 2005-08-26 2008-05-07 The Regents of The University of California Non-steroidal antiandrogens
EP1916896A4 (en) * 2005-08-26 2010-08-11 Univ California Non-steroidal antiandrogens
JP2009506077A (en) * 2005-08-26 2009-02-12 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア Non-steroidal antiandrogen
WO2008051532A1 (en) * 2006-10-23 2008-05-02 Merck & Co., Inc. 2-[1-phenyl-5-hydroxy or methoxy-4alpha-methyl-hexahydroclopenta[f]indazol-5-yl]ethyl phenyl derivatives as glucocorticoid receptor ligands
WO2008060391A3 (en) * 2006-10-23 2008-09-25 Merck & Co Inc 2- [l-phenyl-5-hydr0xy-4alpha-methyl-hexahydr0cycl0penta[f] indaz0l-5-yl] ethyl phenyl derivatives as glucocorticoid receptor ligands
US8119681B2 (en) 2006-10-23 2012-02-21 Merck Sharp & Dohme Corp. 2-[1-phenyl-5-hydroxy or methoxy-4alpha-methyl-hexahydrocyclopenta [ƒ]indazole-5-YL]ethyl phenyl derivatives as glucocorticoid receptor ligands
WO2008060391A2 (en) * 2006-10-23 2008-05-22 Merck & Co., Inc. 2- [l-phenyl-5-hydr0xy-4alpha-methyl-hexahydr0cycl0penta[f] indaz0l-5-yl] ethyl phenyl derivatives as glucocorticoid receptor ligands
WO2009054925A1 (en) * 2007-10-23 2009-04-30 Merck & Co., Inc. Process for making glucocorticoid receptor ligands
EP2268630A4 (en) * 2008-02-26 2011-03-09 Merck Sharp & Dohme Hexahydrocyclopentylýf¨indazole carboxamides and derivatives thereof as selective glucocorticoid receptor modulators
US8338472B2 (en) 2008-02-26 2012-12-25 Merck Sharp & Dohme Corp. Hexahydrocyclopentyl[F]indazole carboxamides and derivatives thereof as selective glucocorticoid receptor modulators
EP2268630A2 (en) * 2008-02-26 2011-01-05 Merck Sharp & Dohme Corp. Hexahydrocyclopentylýf¨indazole carboxamides and derivatives thereof as selective glucocorticoid receptor modulators
EP2482659A1 (en) * 2009-09-08 2012-08-08 Schering Corporation HEXAHYDROCYCLOPENTA[f]INDAZOLE 5-YL ETHANOLS AND DERIVATIVES THEREOF AS SELECTIVE GLUCOCORTICOID RECEPTOR MODULATORS
EP2482659A4 (en) * 2009-09-08 2013-03-27 Merck Sharp & Dohme HEXAHYDROCYCLOPENTA[f]INDAZOLE 5-YL ETHANOLS AND DERIVATIVES THEREOF AS SELECTIVE GLUCOCORTICOID RECEPTOR MODULATORS
EP2493302A4 (en) * 2009-10-30 2013-04-24 Merck Sharp & Dohme Hexahydrocyclopentyl[f]indazole pyridyl ethanols and derivatives thereof as selective glucocorticoid receptor modulators
EP2493303A1 (en) * 2009-10-30 2012-09-05 Merck Sharp & Dohme Corp. 2- [1-PHENYL-5-HYDROXY-4a-SUBSTITUTED-HEXAHYDROCYCLOPENTA [F]INDAZOL-5-YL]ETHYL PHENYL DERIVATIVES AS GLUCOCORTICOID RECEPTOR LIGANDS
EP2493302A1 (en) * 2009-10-30 2012-09-05 Merck Sharp & Dohme Corp. Hexahydrocyclopentyl[f]indazole pyridyl ethanols and derivatives thereof as selective glucocorticoid receptor modulators
EP2493303A4 (en) * 2009-10-30 2013-06-26 Merck Sharp & Dohme 2- [1-PHENYL-5-HYDROXY-4a-SUBSTITUTED-HEXAHYDROCYCLOPENTA [F]INDAZOL-5-YL]ETHYL PHENYL DERIVATIVES AS GLUCOCORTICOID RECEPTOR LIGANDS
WO2018191283A1 (en) * 2017-04-11 2018-10-18 Oric Pharmaceuticals, Inc. Glucocorticoid receptor modulators
CN112771046A (en) * 2018-07-20 2021-05-07 格吕伦塔尔有限公司 Other substituted triazoloquinoxaline derivatives
CN112771046B (en) * 2018-07-20 2023-09-19 格吕伦塔尔有限公司 Other substituted triazoloquinoxaline derivatives
US11981677B2 (en) 2018-07-20 2024-05-14 Grünenthal GmbH Further substituted triazolo quinoxaline derivatives
WO2020076999A1 (en) * 2018-10-10 2020-04-16 Oric Pharmaceuticals, Inc. Glucocorticoid receptor modulators
WO2020152193A1 (en) 2019-01-22 2020-07-30 Akribes Biomedical Gmbh Selective glucocorticoid receptor modifiers for treating impaired skin wound healing

Also Published As

Publication number Publication date
AU2004216182B2 (en) 2008-11-20
EP1599201B1 (en) 2010-04-14
EP1599201A2 (en) 2005-11-30
US7411073B2 (en) 2008-08-12
CA2516684A1 (en) 2004-09-10
AU2004216182A1 (en) 2004-09-10
JP2006518752A (en) 2006-08-17
EP1599201A4 (en) 2007-01-24
WO2004075840A9 (en) 2005-08-04
ATE464296T1 (en) 2010-04-15
JP4648303B2 (en) 2011-03-09
DE602004026558D1 (en) 2010-05-27
WO2004075840A3 (en) 2005-02-03
US20060074120A1 (en) 2006-04-06

Similar Documents

Publication Publication Date Title
WO2004075840A2 (en) Selective non-steroidal glucocorticoid receptor modulators
AU2004207482B2 (en) 17-carbamoyloxy cortisol derivatives as selective glucocorticoid receptor modulators
AU2003270783C1 (en) Octahydro-2-H-naphtho[1,2-F] indole-4-carboxamide derivatives as selective glucocorticoid receptor modulators
AU2003221706B2 (en) 1H-Benzo[F]indazol-5-YL derivatives as selective glucocorticoid receptor modulators
WO2021259224A1 (en) Triazine benzoate compound and application thereof
AU2009217493B2 (en) Hexahydrocyclopentyl[f]indazole carboxamides and derivatives thereof as selective glucocorticoid receptor modulators
BRPI0619518A2 (en) glucocorticoid receptor modulators, pharmaceutical compositions comprising them and uses thereof
AU2004232301B2 (en) Selective spirocyclic glucocorticoid receptor modulators
US20120214847A1 (en) 2-[1-PHENYL-5-HYDROXY-4a-SUBSTITUTED-HEXAHYDROCYCLOPENTA[F]INDAZOL-5-YL]ETHYL PHENYL DERIVATIVES AS GLUCOCORTICOID RECEPTOR LIGANDS
WO2013075645A1 (en) 6-substituted phenyl quinazolone compound and use thereof
CA2716136A1 (en) Hexahydrocyclopentyl[f]indazole sulfonamides and derivatives thereof as selective glucocorticoid receptor modulators
US20120172397A1 (en) HEXAHYDROCYCLOPENTA[f]INDAZOLE 5-YL ETHANOLS AND DERIVATIVES THEREOF AS SELECTIVE GLUCOCORTICOID RECEPTOR MODULATORS
WO2010141247A1 (en) Hexahydrocyclopentyl[∫]indazole 5-hydroxymethyl ethanols and derivatives thereof as selective glucocorticoid receptor modulators

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2004216182

Country of ref document: AU

COP Corrected version of pamphlet

Free format text: PAGE 1, DESCRIPTION, ADDED

ENP Entry into the national phase

Ref document number: 2006074120

Country of ref document: US

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 10544899

Country of ref document: US

ENP Entry into the national phase

Ref document number: 2004216182

Country of ref document: AU

Date of ref document: 20040220

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2004216182

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2516684

Country of ref document: CA

Ref document number: 2004713398

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2006503780

Country of ref document: JP

WWP Wipo information: published in national office

Ref document number: 2004713398

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 10544899

Country of ref document: US