US20150266899A1 - Anti-fibrotic pyridinones - Google Patents

Anti-fibrotic pyridinones Download PDF

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Publication number
US20150266899A1
US20150266899A1 US14/432,881 US201314432881A US2015266899A1 US 20150266899 A1 US20150266899 A1 US 20150266899A1 US 201314432881 A US201314432881 A US 201314432881A US 2015266899 A1 US2015266899 A1 US 2015266899A1
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United States
Prior art keywords
optionally substituted
compound
alkyl
group
aryl
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Abandoned
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US14/432,881
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Inventor
Brad Owen Buckman
John Beamond Nicholas
Johnnie Y. Ramphal
Kumaraswamy Emayan
Scott D. Seiwert
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Genentech Inc
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Intermune Inc
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=50435378&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20150266899(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Intermune Inc filed Critical Intermune Inc
Priority to US14/432,881 priority Critical patent/US20150266899A1/en
Publication of US20150266899A1 publication Critical patent/US20150266899A1/en
Assigned to INTERMUNE, INC. reassignment INTERMUNE, INC. CERTIFICATE OF CHANGE OF COMPANY'S ADDRESS Assignors: INTERMUNE, INC.
Assigned to GENENTECH, INC. reassignment GENENTECH, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: INTERMUNE, INC.
Abandoned legal-status Critical Current

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    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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Definitions

  • Pyridinone compounds method of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent or diagnose diseases, disorders, or conditions associated with fibrosis are provided.
  • Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process.
  • fibrosis include, but are not limited to pulmonary fibrosis, liver fibrosis, dermal fibrosis, and renal fibrosis.
  • Pulmonary fibrosis also called idiopathic pulmonary fibrosis (IPF), interstitial diffuse pulmonary fibrosis, inflammatory pulmonary fibrosis, or fibrosing alveolitis
  • IPF idiopathic pulmonary fibrosis
  • interstitial diffuse pulmonary fibrosis interstitial diffuse pulmonary fibrosis
  • inflammatory pulmonary fibrosis or fibrosing alveolitis
  • R 1 is selected from the group consisting of halogen, —CN, —C(O)R 8 , —SO 2 R 16 , C 1-6 alkyl optionally substituted with one or more R 4 , C 2-6 alkenyl optionally substituted with one or more R 4 , C 2-6 alkynyl optionally substituted with one or more R 4 , C 6-10 aryl optionally substituted with one or more R 4 , 5-10 membered heteroaryl optionally substituted with one or more R 4 , C 3-10 carbocyclyl optionally substituted with one or more R 4 , and 3-10 membered heterocyclyl optionally substituted with one or more R 4 ;
  • R 2 is selected from the group consisting of halogen, —CN, —OR 5 , —SR 5 , —NR 6 R 7 , and —C(O)R 8 ;
  • R 3 is selected from the group consisting of hydrogen, —(CH 2 ) n —(C 6-10 aryl), —(CH 2 ) n -(5-10 membered heteroaryl), —(CH 2 ) n —(C 3-10 carbocyclyl), and —(CH 2 ) n -(3-10 membered heterocyclyl), each optionally substituted with one or more R 9 ;
  • each R 4 is independently selected from the group consisting of halogen, —CN, —OH, —C(O)R 8 , —SO 2 R 16 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , 5-10 membered heteroaryl optionally substituted with one or more R 11 , or independently two geminal R 4 together are oxo;
  • each R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 2-8 alkoxyalkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , and —(CH 2 ) n -(3-10 membered heterocyclyl) optionally substituted with one or more R 10 ;
  • R 6 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , and —C(O)OR 5 ;
  • R 7 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , and —C(O)OR 5 ;
  • R 6 and R 7 together with the nitrogen to which they are attached form a 3-10 membered heterocyclyl optionally substituted with one or more R 10 ;
  • each R 8 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;
  • each R 9 is independently selected from the group consisting of hydroxy, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkylthio, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 6-10 aryl, —OR 5 , —NR 14 R 15 , —C(O)R 8 , —CN, —SO 2 R 16 , and —NO 2 ;
  • each R 10 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, and optionally substituted C 2-6 alkynyl, or independently two geminal R 10 together are oxo;
  • each R 12 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
  • each R 13 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
  • R 14 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
  • R 15 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
  • each R 16 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;
  • Z is selected from oxygen and sulfur
  • each n is independently an integer from 0 to 4.
  • bonds represented by a solid and dashed line are independently selected from the group consisting of a single bond and a double bond, provided that
  • R 1 is selected from C 6-10 aryl optionally substituted with one or more R 4 , or 5-10 membered heteroaryl optionally substituted with one or more R 4 ;
  • R 3 cannot be —CH 2 -phenyl
  • R 2 when R 2 is methoxy, R 1 is 4-methoxyphenyl, and Z is O, then R 3 is not —(CH 2 )-2-fluro-4-chloro-phenyl;
  • R 3 is a phenyl
  • R 2 is OR 5 or NR 6 R 7 ; then R 1 is not triazolyl
  • R 3 is 4-methyl phenyl, R 2 is morpholinyl, and Z is O; then R 1 is not methyl; and
  • R 3 is 4-methyl phenyl
  • R 2 is —N(CH 3 ) 2
  • Z is O
  • R 1 is not methyl
  • R 2 is selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, and optionally substituted C 2-6 alkynyl;
  • R 3 is selected from the group consisting of hydrogen, —(CH 2 ) n —(C 6-10 aryl), —(CH 2 ) n -(5-10 membered heteroaryl), —(CH 2 ) n —(C 3-10 carbocyclyl), and —(CH 2 ) n -(3-10 membered heterocyclyl), each optionally substituted with one or more R 9 ;
  • Y is selected from N and CR 4 ;
  • each R 4 is independently selected from the group consisting of halogen, —CN, —OH, —C(O)R 8 , —SO 2 R 16 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , 5-10 membered heteroaryl optionally substituted with one or more R 11 ,
  • R 4 or independently two adjacent R 4 together with the carbon atoms to which they are attached form a fused ring selected from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, optionally substituted C 3-7 carbocyclyl, and optionally substituted 3-7 membered heterocyclyl;
  • each R 9 is independently selected from the group consisting of hydroxy, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkylthio, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 6-10 aryl, —OR 5 , —NR 14 R 15 , —C(O)R 8 , —CN, —SO 2 R 16 , and —NO 2 ;
  • R 14 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
  • R 15 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
  • each R 8 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;
  • each R 12 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
  • each R 13 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
  • each R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 2-8 alkoxyalkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , and —(CH 2 ) n -(3-1.0 membered heterocyclyl) optionally substituted with one or more R 10 ;
  • each R 10 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, and optionally substituted C 2-6 alkynyl, or independently two geminal R 10 together are oxo;
  • each R 11 is independently selected from the group consisting of halogen, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, and optionally substituted C 1-6 alkoxy;
  • each R 16 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;
  • Z is selected from oxygen and sulfur
  • each n is independently an integer from 0 to 4.
  • bonds represented by a solid and dashed line are independently selected from the group consisting of a single bond and a double bond.
  • R 1 is selected from the group consisting of halogen, —CN, —C(O)R 8 , —SO 2 R 16 , C 1-6 alkyl optionally substituted with one or more R 4 , C 2-6 alkenyl optionally substituted with one or more R 4 , C 2-6 alkynyl optionally substituted with one or more R 4 , C 6-10 aryl optionally substituted with one or more R 4 , 5-10 membered heteroaryl optionally substituted with one or more R 4 , C 3-10 carbocyclyl optionally substituted with one or more R 4 , and 3-10 membered heterocyclyl optionally substituted with one or more R 4 ;
  • R 3 is selected from the group consisting of hydrogen, —(CH 2 ) n —(C 6-10 aryl), —(CH 2 ) n -(5-10 membered heteroaryl), —(CH 2 ) n —(C 3-10 carbocyclyl), and —(CH 2 ) n -(3-10 membered heterocyclyl), each optionally substituted with one or more R 9 ;
  • ring A is selected from the group consisting of phenyl, 5-6 membered heteroaryl, C 3-7 carbocyclyl, and 3-7 membered heterocyclyl, each optionally substituted with one or more R 4 ;
  • each R 4 is independently selected from the group consisting of halogen, —CN, —OH, —C(O)R 8 , —SO 2 R 16 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , 5-10 membered heteroaryl optionally substituted with one or more R 11 , or independently two geminal R 4 together are oxo;
  • each R 9 is independently selected from the group consisting of hydroxy, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkylthio, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 6-10 aryl, —OR 5 , —NR 14 R 15 , —C(O)R 8 , —SO 2 R 16 , —CN and —NO 2 ;
  • R 14 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
  • R 15 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
  • each R 8 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , —OR 5 ;
  • each R 12 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
  • each R 13 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
  • each R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 2-8 alkoxyalkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , and —(CH 2 ) n -(3-10 membered heterocyclyl) optionally substituted with one or more R 10 ;
  • each R 10 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, and optionally substituted C 2-6 alkynyl, or independently two geminal R 10 together are oxo;
  • each R 11 is independently selected from the group consisting of halogen, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, and optionally substituted C 1-6 alkoxy;
  • each R 16 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;
  • Z is selected from oxygen and sulfur
  • each n is independently an integer from 0 to 4.
  • bonds represented by a solid and dashed line are independently selected from the group consisting of a single bond and a double bond, provided that
  • R 1 is selected from C 6-10 aryl optionally substituted with one or more R 4 , or 5-10 membered heteroaryl optionally substituted with one or more R 4 ;
  • R 3 is phenyl optionally substituted with one or more R 9 , and Z is O; then ring A cannot be optionally substituted phenyl;
  • R 3 is phenyl optionally substituted with one or more R 9 , and Z is O; then R 1 is not halogen, 3-methoxy phenyl or 3,5-dimethoxy phenyl;
  • R 1 when ring A is pyridyl, R 1 is optionally substituted phenyl, and Z is O; then n in R 3 is zero and R 3 is not halogen substituted phenyl;
  • R 3 is phenyl or benzyl, and Z is O; then R 1 is not methyl or benzyl;
  • R 3 is phenyl optionally substituted with one or more R 9 , and Z is O; then R 1 is not fluoro;
  • R 3 is phenyl optionally substituted with one or more R 9 , and Z is O; then R 1 is not methyl;
  • R 3 is 4-NO 2 -phenyl, and Z is O; then R 1 is not methyl.
  • R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl optionally substituted with one or more R 4 , C 2-6 alkenyl optionally substituted with one or more R 4 , C 2-6 alkynyl optionally substituted with one or more R 4 , C 6-10 aryl optionally substituted with one or more R 4 , 5-10 membered heteroaryl optionally substituted with one or more R 4 , C 3-10 carbocyclyl optionally substituted with one or more R 4 , and 3-10 membered heterocyclyl optionally substituted with one or more R 4 ;
  • each R 2 is independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, —CN, —OR 5 , —NR 6 R 7 , and —C(O)R 8 , or both R 2 together with the carbon atoms to which they are attached form a fused ring selected from the group consisting of phenyl, 5-6 membered heteroaryl, C 3-7 carbocyclyl, and 3-7 membered heterocyclyl, each optionally substituted with one or more R 4 ;
  • each R 4 is independently selected from the group consisting of halogen, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, and optionally substituted C 1-6 alkoxy;
  • each R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 2-8 alkoxyalkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —(CH 2 ) n -(3-10 membered heterocyclyl) optionally substituted with one or more R 10 , and —(CH 2 ) n —(C 6-10 aryl) optionally substituted with one or more R 11 ;
  • R 6 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , and —C(O)OR 5 ;
  • R 7 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , and —C(O)OR 5 ;
  • R 6 and R 7 together with the nitrogen to which they are attached form an 3-10 membered heterocyclyl optionally substituted with one or more R 10 ;
  • each R 8 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, —NR 12 R 13 , and —OR 5 ;
  • each Y is independently N or CR 9 ;
  • each R 9 is independently selected from the group consisting of halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, and —NR 14 R 15 ,
  • each R 10 is independently selected from the group consisting of oxo, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, and optionally substituted C 2-6 alkynyl;
  • each R 11 is independently selected from the group consisting of halogen, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, and optionally substituted C 1-6 alkoxy;
  • each R 12 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
  • each R 13 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
  • R 14 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
  • R 15 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
  • Z is selected from oxygen and sulfur
  • n is an integer from 0 to 4.
  • n is an integer from 1 to 4.
  • bonds represented by a solid and dashed line are independently selected from the group consisting of a single bond and a double bond.
  • A is a C 5-7 carbocyclyl optionally substituted with one or more R 4 ;
  • each R 2 is independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, —CN, —OR 5 , —NR 6 R 7 , and —C(O)R 8 ,
  • R 2 together with the carbon atoms to which they are attached form a fused ring selected from the group consisting of phenyl, 5-6 membered heteroaryl, C 3-7 carbocyclyl, and 3-7 membered heterocyclyl, each optionally substituted with one or more R 4 ;
  • R 3 is selected from the group consisting of —(CH 2 ) n —(C 6-10 aryl), —(CH 2 ) n -(5-10 membered heteroaryl), —(CH 2 ) n —(C 3-10 carbocyclyl), and —(CH 2 ) n -(3-10 membered heterocyclyl), each optionally substituted with one or more R 9 ;
  • each R 4 is independently selected from the group consisting of halogen, —CN, —OH, —C(O)R 8 , —SO 2 R 16 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , 5-10 membered heteroaryl optionally substituted with one or more R 11 , or independently two geminal R 4 together are oxo;
  • each R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 2-8 alkoxyalkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , and —(CH 2 ) n -(3-10 membered heterocyclyl) optionally substituted with one or more R 10 ;
  • R 6 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , and —C(O)OR 5 ;
  • R 7 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , and —C(O)OR 5 ;
  • R 6 and R 7 together with the nitrogen to which they are attached form an 3-10 membered heterocyclyl optionally substituted with one or more R 10 ;
  • each R 8 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;
  • each R 9 is independently selected from the group consisting of halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkylthio, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 6-10 aryl, —OR 5 , —NR 14 R 15 , —C(O)R 8 , —SO 2 R 16 , and —NO 2 ;
  • each R 10 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, and optionally substituted C 2-6 alkynyl, or independently two geminal R 10 together are oxo;
  • each R 11 is independently selected from the group consisting of halogen, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, and optionally substituted C 1-6 alkoxy;
  • each R 12 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
  • each R 13 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
  • R 14 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
  • R 15 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
  • each R 16 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;
  • Z is selected from oxygen and sulfur
  • each n is independently an integer from 0 to 4.
  • bonds represented by a solid and dashed line are independently selected from the group consisting of a single bond and a double bond.
  • R 1 is a C 4-7 carbocyclyl optionally substituted with one or more R 4 ;
  • each R 2 is independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, —CN, —OR 5 , —NR 6 R 7 , and —C(O)R 8 ,
  • R 2 together with the carbon atoms to which they are attached form a fused ring selected from the group consisting of phenyl, 5-6 membered heteroaryl, C 3-7 carbocyclyl, and 3-7 membered heterocyclyl, each optionally substituted with one or more R 4 ;
  • R 3 is selected from the group consisting of —(CH 2 ) n —(C 6-10 aryl), —(CH 2 ) n -(5-10 membered heteroaryl), —(CH 2 ) n —(C 3-10 carbocyclyl), and —(CH 2 ) n -(3-10 membered heterocyclyl), each optionally substituted with one or more R 9 ;
  • each R 4 is independently selected from the group consisting of halogen, —CN, —OH, —C(O)R 8 , —SO 2 R 16 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , 5-10 membered heteroaryl optionally substituted with one or more R 11 , or independently two geminal R 4 together are oxo;
  • each R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 2-8 alkoxyalkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , and —(CH 2 ) n -(3-10 membered heterocyclyl) optionally substituted with one or more R 10 ;
  • R 6 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , and —C(O)OR 5 ;
  • R 7 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , and —C(O)OR 5 ;
  • R 6 and R 7 together with the nitrogen to which they are attached form an 3-10 membered heterocyclyl optionally substituted with one or more R 10 ;
  • each R 8 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;
  • each R 9 is independently selected from the group consisting of halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkylthio, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 6-10 aryl, —OR 5 ,—NR 14 R 15 , —C(O)R 8 , —SO 2 R 16 , and —NO 2 ;
  • each R 10 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, and optionally substituted C 2-6 alkynyl, or independently two geminal R 10 together are oxo;
  • each R 11 is independently selected from the group consisting of halogen, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, and optionally substituted C 1-6 alkoxy;
  • each R 12 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
  • each R 13 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
  • R 14 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
  • R 15 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
  • each R 16 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;
  • Z is selected from oxygen and sulfur
  • each n is independently an integer from 0 to 4.
  • bonds represented by a solid and dashed line are independently selected from the group consisting of a single bond and a double bond.
  • each R 2 is independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, —CN, —OR 5 , —NR 6 R 7 , and —C(O)R 8 ,
  • R 2 together with the carbon atoms to which they are attached form a fused ring selected from the group consisting of phenyl, 5-6 membered heteroaryl, C 3-7 carbocyclyl, and 3-7 membered heterocyclyl, each optionally substituted with one or more R 4 ;
  • R 3 is selected from the group consisting of —(CH 2 ) n —(C 6-10 aryl), —(CH 2 ) n -(5-1.0 membered heteroaryl), —(CH 2 ) n —(C 3-10 carbocyclyl), and —(CH 2 ) n -(3-1.0 membered heterocyclyl), each optionally substituted with one or more R 9 ;
  • each R 4 is independently selected from the group consisting of halogen, —CN, —OH, —C(O)R 8 , —SO 2 R 16 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , 5-10 membered heteroaryl optionally substituted with one or more R 11 , or independently two geminal R 4 together are oxo;
  • each R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 2-8 alkoxyalkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , and —(CH 2 ) n -(3-10 membered heterocyclyl) optionally substituted with one or more R 10 ;
  • R 6 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , and —C(O)OR 5 ;
  • R 7 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , and —C(O)OR 5 ;
  • R 6 and R 7 together with the nitrogen to which they are attached form an 3-10 membered heterocyclyl optionally substituted with one or more R 10 ;
  • each R 8 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;
  • each R 9 is independently selected from the group consisting of halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkylthio, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 6-10 aryl, —OR 5 , —NR 14 R 15 , —C(O)R 8 , —SO 2 R 16 , and —NO 2 ;
  • each R 10 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, and optionally substituted C 2-6 alkynyl, or independently two geminal R 10 together are oxo;
  • each R 11 is independently selected from the group consisting of halogen, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, and optionally substituted C 1-6 alkoxy;
  • each R 12 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
  • each R 13 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
  • R 14 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
  • R 15 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
  • Q is selected from C(O) and S(O) t ;
  • each R 16 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;
  • Z is selected from oxygen and sulfur
  • each n is independently an integer from 0 to 4.
  • t 1 or 2;
  • bonds represented by a solid and dashed line are independently selected from the group consisting of a single bond and a double bond.
  • R 1 is selected from the group consisting of halogen, —CN, —C(O)R 8 , —SO 2 R 16 , C 1-6 alkyl optionally substituted with one or more R 4 , C 2-6 alkenyl optionally substituted with one or more R 4 , C 2-6 alkynyl optionally substituted with one or more R 4 , C 6-10 aryl optionally substituted with one or more R 4 , 5-10 membered heteroaryl optionally substituted with one or more R 4 , C 3-10 carbocyclyl optionally substituted with one or more R 4 , and 3-10 membered heterocyclyl optionally substituted with one or more R 4 ;
  • each R 2 is independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, —CN, —OR 5 , —NR 6 R 7 , and —C(O)R 8 ,
  • R 2 together with the carbon atoms to which they are attached form a fused ring selected from the group consisting of phenyl, 5-6 membered heteroaryl, C 3-7 carbocyclyl, and 3-7 membered heterocyclyl, each optionally substituted with one or more R 4 ;
  • R 3 is selected from the group consisting of —(CH 2 ) 1-4 —(C 6-10 aryl), —(CH 2 ) 1-4 45-10 membered heteroaryl), —(CH 2 ) 1-4 —(C 3-10 carbocyclyl), and —(CH 2 ) 1-4 43-10 membered heterocyclyl), each optionally substituted with one or more R 9 ;
  • each R 4 is independently selected from the group consisting of halogen, —CN, —OH, —C(O)R 8 , —SO 2 R 16 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , 5-10 membered heteroaryl optionally substituted with one or more R 11 , or independently two geminal R 4 together are oxo;
  • each R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 2-8 alkoxyalkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , and —(CH 2 ) n -(3-10 membered heterocyclyl) optionally substituted with one or more R 10 ;
  • R 6 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , and —C(O)OR 5 ;
  • R 7 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , and —C(O)OR 5 ;
  • R 6 and R 7 together with the nitrogen to which they are attached form an 3-10 membered heterocyclyl optionally substituted with one or more R 10 ;
  • each R 8 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;
  • each R 9 is independently selected from the group consisting of halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkylthio, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 6-10 aryl, —OR 5 , —NR 14 R 15 , —C(O)R 8 , —SO 2 R 16 , and —NO 2 ;
  • each R 10 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, and optionally substituted C 2-6 alkynyl, or independently two geminal R 10 together are oxo;
  • each R 11 is independently selected from the group consisting of halogen, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, and optionally substituted C 1-6 alkoxy;
  • each R 12 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
  • each R 13 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
  • R 14 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
  • R 15 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
  • each R 16 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;
  • Z is selected from oxygen and sulfur
  • each n is independently an integer from 0 to 4.
  • bonds represented by a solid and dashed line are independently selected from the group consisting of a single bond and a double bond; provided that
  • R 1 is selected from the group consisting of optionally substituted C 6-10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted 6 to 10 membered heterocyclyl, optionally substituted hexyl, optionally substituted alkyl, optionally substituted alkenyl; each of R 2 is hydrogen or one of R 2 is hydrogen and the other R 2 is methyl; and Z is O; then R 3 is not —CH 2 -phenyl substituted with one or more halogen atoms; and provided that
  • R 1 is not 4-methoxy phenyl.
  • R 3 is selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, —(CH 2 ) n —(C 6-10 aryl) optionally substituted with one or more R 9 , —(CH 2 ) n -(5-10 membered heteroaryl) optionally substituted with one or more R 9 , —(CH 2 ) n —(C 3-10 carbocyclyl) optionally substituted with one or more R 9 , and —(CH 2 ) n -(3-10 membered heterocyclyl) optionally substituted with one or more R 9 ;
  • each R 9 is independently selected from the group consisting of halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkylthio, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 6-10 aryl, —OR 5 , —NR 14 R 15 , —C(O)R 8 , —SO 2 R 16 , and —NO 2 ;
  • R 14 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
  • R 15 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
  • each R 8 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;
  • each R 12 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
  • each R 13 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
  • each R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 2-8 alkoxyalkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , and —(CH 2 ) n -(3-10 membered heterocyclyl) optionally substituted with one or more R 10 ;
  • each R 10 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, and optionally substituted C 2-6 alkynyl, or independently two geminal R 10 together are oxo;
  • each R 11 is independently selected from the group consisting of halogen, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, and optionally substituted C 1-6 alkoxy;
  • each R 17 is independently selected from the group consisting of hydrogen, oxo, halogen, —CN, —C(O)R 8 , —SO 2 R 16 , C 1-6 alkyl optionally substituted with one or more R 4 , C 2-6 alkenyl optionally substituted with one or more R 4 , C 2-6 alkynyl optionally substituted with one or more R 4 , C 6-10 aryl optionally substituted with one or more R 4 , 5-10 membered heteroaryl optionally substituted with one or more R 4 , C 3-10 carbocyclyl optionally substituted with one or more R 4 , and 3-10 membered heterocyclyl optionally substituted with one or more R 4 ,
  • each R 4 is independently selected from the group consisting of halogen, —CN, —OH, —C(O)R 8 , —SO 2 R 16 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , 5-10 membered heteroaryl optionally substituted with one or more R 11 , or independently two geminal R 4 together are oxo;
  • each R 16 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;
  • Z is selected from oxygen and sulfur
  • each n is independently an integer from 0 to 4.
  • s 0, 1, or 3;
  • bonds represented by a solid and dashed line are independently selected from the group consisting of a single bond and a double bond.
  • R 1 is selected from the group consisting of hydrogen, halogen, —CN, —C(O)R 8 , —SO 2 R 16 , C 1-6 alkyl optionally substituted with one or more R 4 , C 2-6 alkenyl optionally substituted with one or more R 4 , C 2-6 alkynyl optionally substituted with one or more R 4 , C 6-10 aryl optionally substituted with one or more R 4 , 5-10 membered heteroaryl optionally substituted with one or more R 4 , C 3-10 carbocyclyl optionally substituted with one or more R 4 , and 3-10 membered heterocyclyl optionally substituted with one or more R 4 ;
  • each R 2 is independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, —CN, —OR 5 , —NR 6 R 7 , and —C(O)R 8 ,
  • R 2 together with the carbon atoms to which they are attached form a fused ring selected from the group consisting of C 3-7 carbocyclyl and 3-7 membered heterocyclyl, each optionally substituted with one or more R 4 ;
  • R 3 is selected from the group consisting of —(CH 2 ) n —(C 6-10 aryl), —(CH 2 ) n -(5-10 membered heteroaryl), —(CH 2 ) n —(C 3-10 carbocyclyl), and —(CH 2 ) n -(3-10 membered heterocyclyl), each optionally substituted with one or more R 9 ;
  • each R 4 is independently selected from the group consisting of halogen, —CN, —OH, —C(O)R 8 , —SO 2 R 16 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , 5-10 membered heteroaryl optionally substituted with one or more R 11 , or independently two geminal R 4 together are oxo;
  • each R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 2-8 alkoxyalkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , and —(CH 2 ) n -(3-10 membered heterocyclyl) optionally substituted with one or more R 10 ;
  • R 6 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , and —C(O)OR 5 ;
  • R 7 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , and —C(O)OR 5 ;
  • R 6 and R 7 together with the nitrogen to which they are attached form an 3-10 membered heterocyclyl optionally substituted with one or more R 10 ;
  • each R 8 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;
  • each R 9 is independently selected from the group consisting of halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkylthio, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 6-10 aryl, —OR 5 , —NR 14 R 15 , —C(O)R 8 , —SO 2 R 16 , and —NO 2 ;
  • each R 10 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, and optionally substituted C 2-6 alkynyl, or independently two geminal R 10 together are oxo;
  • each R 11 is independently selected from the group consisting of halogen, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, and optionally substituted C 1-6 alkoxy;
  • each R 12 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
  • each R 13 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;
  • R 14 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
  • R 15 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;
  • each R 16 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;
  • Z is selected from oxygen and sulfur
  • each n is independently an integer from 0 to 4.
  • Some embodiments disclosed herein relate to methods of treating a fibrotic condition, comprising administering a therapeutically effective amount of a compound of any one of Formulae (I), (II), (III), (IV), (V), (VIa), (VIb), (VII), (VIII) and (IX), a compound selected from Table 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a subject in need thereof.
  • the method further comprises identifying the subject as having or at risk of having said fibrotic condition.
  • the fibrotic condition is selected from the group consisting of pulmonary fibrosis, dermal fibrosis, pancreatic fibrosis, liver fibrosis, and renal fibrosis.
  • the fibrotic condition is idiopathic pulmonary fibrosis.
  • the subject receiving such method of treatment is a human.
  • Some embodiments disclosed herein relate to use of a therapeutically effective amount of a compound of any one of Formulae (I), (II), (III), (IV), (V), (VIa), (VIb), (VII), (VIII) and (IX), a compound selected from Table 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating a fibrotic condition.
  • the use further comprises identifying the subject as having or at risk of having said fibrotic condition.
  • the fibrotic condition is selected from the group consisting of pulmonary fibrosis, dermal fibrosis, pancreatic fibrosis, liver fibrosis, and renal fibrosis.
  • the fibrotic condition is idiopathic pulmonary fibrosis.
  • the subject receiving such treatment is a human being.
  • Some embodiments disclosed herein relate to a therapeutically effective amount of a compound of any one of Formulae (I), (II), (III), (IV), (V), (VIa), (VIb), (VII), (VIII) and (IX), a compound selected from Table 1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treating a fibrotic condition.
  • the use further comprises identifying the subject as having or at risk of having said fibrotic condition.
  • the fibrotic condition is selected from the group consisting of pulmonary fibrosis, dermal fibrosis, pancreatic fibrosis, liver fibrosis, and renal fibrosis.
  • the fibrotic condition is idiopathic pulmonary fibrosis.
  • the subject receiving such treatment is a human being.
  • Solidvate refers to the compound formed by the interaction of a solvent and a compound described herein or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of a compound and, which are not biologically or otherwise undesirable for use in a pharmaceutical.
  • the compounds disclosed herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297, Johnston et al., published Sep. 11, 1987 (incorporated by reference herein in its entirety).
  • C a to C b or “C a-b ” in which “a” and “b” are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from “a” to “b”, inclusive, carbon atoms.
  • a “C 1 to C 4 alkyl” or “C 1-4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 —, CH 3 CH 2 —, CH 3 CH 2 CH 2 —, (CH 3 ) 2 CH—, CH 3 CH 2 CH 2 CH 2 —, CH 3 CH 2 CH(CH 3 )— and (CH 3 ) 3 C—.
  • halogen or “halo,” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.
  • alkyl refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds).
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 9 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 4 carbon atoms.
  • the alkyl group may be designated as “C 1-4 alkyl” or similar designations.
  • C 1-4 alkyl indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.
  • alkoxy refers to the formula OR wherein R is an alkyl as is defined above, such as “C 1-9 alkoxy”, including but not limited to methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, and the like.
  • alkylthio refers to the formula SR wherein R is an alkyl as is defined above, such as “C 1-9 alkylthio” and the like, including but not limited to methylmercapto, ethylmercapto, n-propylmercapto, 1-methylethylmercapto (isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec-butylmercapto, tert-butylmercapto, and the like.
  • alkenyl refers to a straight or branched hydrocarbon chain containing one or more double bonds.
  • the alkenyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • the alkenyl group may also be a medium size alkenyl having 2 to 9 carbon atoms.
  • the alkenyl group could also be a lower alkenyl having 2 to 4 carbon atoms.
  • the alkenyl group may be designated as “C 2-4 alkenyl” or similar designations.
  • C 2-4 alkenyl indicates that there are two to four carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl, 1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl, buta-1,2-dienyl, and buta-1,2-dien-4-yl.
  • Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl, and the like.
  • alkynyl refers to a straight or branched hydrocarbon chain containing one or more triple bonds.
  • the alkynyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • the alkynyl group may also be a medium size alkynyl having 2 to 9 carbon atoms.
  • the alkynyl group could also be a lower alkynyl having 2 to 4 carbon atoms.
  • the alkynyl group may be designated as “C 2-4 alkynyl” or similar designations.
  • C 2-4 alkynyl indicates that there are two to four carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl.
  • Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.
  • heteroalkyl refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the chain backbone.
  • the heteroalkyl group may have 1 to 20 carbon atom, although the present definition also covers the occurrence of the term “heteroalkyl” where no numerical range is designated.
  • the heteroalkyl group may also be a medium size heteroalkyl having 1 to 9 carbon atoms.
  • the heteroalkyl group could also be a lower heteroalkyl having 1 to 4 carbon atoms.
  • the heteroalkyl group may be designated as “C 1-4 heteroalkyl” or similar designations.
  • the heteroalkyl group may contain one or more heteroatoms.
  • C 1-4 heteroalkyl indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.
  • alkylene means a branched, or straight chain fully saturated di-radical chemical group containing only carbon and hydrogen that is attached to the rest of the molecule via two points of attachment (i.e., an alkanediyl).
  • the alkylene group may have 1 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkylene where no numerical range is designated.
  • the alkylene group may also be a medium size alkylene having 1 to 9 carbon atoms.
  • the alkylene group could also be a lower alkylene having 1 to 4 carbon atoms.
  • the alkylene group may be designated as “C 1-4 alkylene” or similar designations.
  • C 1-4 alkylene indicates that there are one to four carbon atoms in the alkylene chain, i.e., the alkylene chain is selected from the group consisting of methylene, ethylene, ethan-1,1-diyl, propylene, propan-1,1-diyl, propan-2,2-diyl, 1-methyl-ethylene, butylene, butan-1,1-diyl, butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 1-methyl-propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, and 1-ethyl-ethylene.
  • alkenylene means a straight or branched chain di-radical chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond that is attached to the rest of the molecule via two points of attachment.
  • the alkenylene group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkenylene where no numerical range is designated.
  • the alkenylene group may also be a medium size alkenylene having 2 to 9 carbon atoms.
  • the alkenylene group could also be a lower alkenylene having 2 to 4 carbon atoms.
  • the alkenylene group may be designated as “C 2-4 alkenylene” or similar designations.
  • C 2-4 alkenylene indicates that there are two to four carbon atoms in the alkenylene chain, i.e., the alkenylene chain is selected from the group consisting of ethenylene, ethen-1,1-diyl, propenylene, propen-1,1-diyl, prop-2-en-1,1-diyl, 1-methyl-ethenylene, but-1-enylene, but-2-enylene, but-1,3-dienylene, buten-1,1-diyl, but-1,3-dien-1,1-diyl, but-2-en-1,1-diyl, but-3-en-1,1-diyl, 1-methyl-prop-2-en-1,1-diyl, 2-methyl-prop-2-en-1,1-diyl, 1-ethyl-ethenylene, 1,2-dimethyl-ethenylene, 1-methyl-propenylene, 2-methyl
  • aromatic refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine).
  • carbocyclic aromatic e.g., phenyl
  • heterocyclic aromatic groups e.g., pyridine
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups provided that the entire ring system is aromatic.
  • aryl refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) containing only carbon in the ring backbone. When the aryl is a ring system, every ring in the system is aromatic.
  • the aryl group may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the term “aryl” where no numerical range is designated. In some embodiments, the aryl group has 6 to 10 carbon atoms.
  • the aryl group may be designated as “C 6-10 aryl,” “C 6 or C 10 aryl,” or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.
  • aryloxy and arylthio refers to RO— and RS—, in which R is an aryl as is defined above, such as “C 6-10 aryloxy” or “C 6-10 arylthio” and the like, including but not limited to phenyloxy.
  • an “aralkyl” or “arylalkyl” is an aryl group connected, as a substituent, via an alkylene group, such as “C 7-14 aralkyl” and the like, including but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl.
  • the alkylene group is a lower alkylene group (i.e., a C 1-4 alkylene group).
  • heteroaryl refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the ring backbone.
  • heteroaryl is a ring system, every ring in the system is aromatic.
  • the heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term “heteroaryl” where no numerical range is designated.
  • the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members.
  • the heteroaryl group may be designated as “5-7 membered heteroaryl,” “5-10 membered heteroaryl,” or similar designations.
  • heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.
  • heteroarylkyl or “heteroarylalkyl” is heteroaryl group connected, as a substituent, via an alkylene group. Examples include but are not limited to 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl.
  • the alkylene group is a lower alkylene group (i.e., a C 1-4 alkylene group).
  • carbocyclyl means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When the carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion. Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic. Thus, carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls.
  • the carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term “carbocyclyl” where no numerical range is designated.
  • the carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms.
  • the carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms.
  • the carbocyclyl group may be designated as “C 3-6 carbocyclyl” or similar designations.
  • carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle [2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.
  • a “(carbocyclyl)alkyl” is a carbocyclyl group connected, as a substituent, via an alkylene group, such as “C 4-10 (carbocyclyl)alkyl” and the like, including but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like.
  • the alkylene group is a lower alkylene group.
  • cycloalkyl means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • cycloalkenyl means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic.
  • An example is cyclohexenyl.
  • heterocyclyl means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system.
  • the heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term “heterocyclyl” where no numerical range is designated.
  • the heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members.
  • the heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members.
  • the heterocyclyl group may be designated as “3-6 membered heterocyclyl” or similar designations.
  • the heteroatom(s) are selected from one up to three of 0, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, or S.
  • heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydr
  • a “(heterocyclyl)alkyl” is a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.
  • acyl refers to C( ⁇ O)R, wherein R is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • R is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.
  • An “O-carboxy” group refers to a “—OC( ⁇ O)R” group in which R is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • C-carboxy refers to a “—C( ⁇ O)OR” group in which R is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • R is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • a non-limiting example includes carboxyl (i.e., —C( ⁇ O)OH).
  • a “cyano” group refers to a “—CN” group.
  • a “cyanato” group refers to an “—OCN” group.
  • An “isocyanato” group refers to a “—NCO” group.
  • a “thiocyanato” group refers to a “—SCN” group.
  • An “isothiocyanato” group refers to an “—NCS” group.
  • a “sulfinyl” group refers to an “—S( ⁇ O)R” group in which R is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • a “sulfonyl” group refers to an “—SO 2 R” group in which R is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • S-sulfonamido refers to a “—SO 2 NR A R B ” group in which R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • N-sulfonamido refers to a “—N(R A )SO 2 R B ” group in which R A and R b are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • An “O-carbamyl” group refers to a “—OC( ⁇ O)NR A R B ” group in which R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • N-carbamyl refers to an “—N(R A )OC( ⁇ O)R B ” group in which R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • An “O-thiocarbamyl” group refers to a “—OC( ⁇ S)NR A R B ” group in which R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • N-thiocarbamyl refers to an “—N(R A )OC( ⁇ S)R B ” group in which R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • a “C-amido” group refers to a “—C( ⁇ O)NR A R B ” group in which R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • N-amido refers to a “—N(R A )C( ⁇ O)R B ” group in which R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • amino group refers to a “—NR A R B ” group in which R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • a non-limiting example includes free amino (i.e., —NH 2 ).
  • aminoalkyl refers to an amino group connected via an alkylene group.
  • alkoxyalkyl refers to an alkoxy group connected via an alkylene group, such as a “C 2-8 alkoxyalkyl” and the like.
  • a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group.
  • substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 7 carbocyclyl (optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy), C 3 -C 7 -carbocyclyl-C 1 -C 6 -alkyl (optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1
  • radical naming conventions can include either a mono-radical or a di-radical, depending on the context.
  • a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical.
  • a substituent identified as alkyl that requires two points of attachment includes di-radicals such as —CH 2 —, —CH 2 CH 2 —, —CH 2 CH(CH 3 )CH 2 —, and the like.
  • Other radical naming conventions clearly indicate that the radical is a di-radical such as “alkylene” or “alkenylene.”
  • R groups are said to form a ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring) “together with the atom to which they are attached,” it is meant that the collective unit of the atom and the two R groups are the recited ring.
  • the ring is not otherwise limited by the definition of each R group when taken individually. For example, when the following substructure is present:
  • R 1 and R 2 are defined as selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 together with the nitrogen to which they are attached form a heterocyclyl, it is meant that R 1 and R 2 can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:
  • ring A is a heteroaryl ring containing the depicted nitrogen.
  • R 1 and R 2 are defined as selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 together with the atoms to which they are attached form an aryl or carbocylyl, it is meant that R 1 and R 2 can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:
  • A is an aryl ring or a carbocylyl containing the depicted double bond.
  • a substituent is depicted as a di-radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated.
  • isosteres of a chemical group are other chemical groups that exhibit the same or similar properties.
  • tetrazole is an isostere of carboxylic acid because it mimics the properties of carboxylic acid even though they both have very different molecular formulae. Tetrazole is one of many possible isosteric replacements for carboxylic acid.
  • carboxylic acid isosteres contemplated include —SO 3 H, —SO 2 HNR, —PO 2 (R) 2 , —PO 3 (R) 2 , —CONHNHSO 2 R, —COHNSO 2 R, and —CONRCN, where R is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • carboxylic acid isosteres can include 5-7 membered carbocycles or heterocycles containing any combination of CH 2 , O, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions.
  • the following structures are non-limiting examples of carbocyclic and heterocyclic isosteres contemplated.
  • the atoms of said ring structure may be optionally substituted at one or more positions with R as defined above.
  • the compound when chemical substituents are added to a carboxylic isostere, the compound retains the properties of a carboxylic isostere. It is contemplated that when a carboxylic isostere is optionally substituted with one or more moieties selected from R as defined above, then the substitution and substitution position is selected such that it does not eliminate the carboxylic acid isosteric properties of the compound.
  • the placement of one or more R substituents upon a carbocyclic or heterocyclic carboxylic acid isostere is not a substitution at one or more atom(s) that maintain(s) or is/are integral to the carboxylic acid isosteric properties of the compound, if such substituent(s) would destroy the carboxylic acid isosteric properties of the compound.
  • Subject as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.
  • mammal is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats, mice guinea pigs, or the like.
  • primates including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats, mice guinea pigs, or the like.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
  • various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press.
  • a therapeutic effect relieves, to some extent, one or more of the symptoms of a disease or condition, and includes curing a disease or condition. “Curing” means that the symptoms of a disease or condition are eliminated; however, certain long-term or permanent effects may exist even after a cure is obtained (such as extensive tissue damage).
  • Treatment refers to administering a compound or pharmaceutical composition to a subject for prophylactic and/or therapeutic purposes.
  • prophylactic treatment refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition.
  • therapeutic treatment refers to administering treatment to a subject already suffering from a disease or condition.
  • the compounds disclosed herein may exist as individual enantiomers and diastereomers or as mixtures of such isomers, including racemates. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. Furthermore, compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included in the scope of the compounds disclosed herein including any polymorphic forms. In addition, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included in the scope of the compounds disclosed herein.
  • Isotopes may be present in the compounds described. Each chemical element as represented in a compound structure may include any isotope of said element.
  • a hydrogen atom may be explicitly disclosed or understood to be present in the compound.
  • the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium).
  • reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
  • Some embodiments disclosed herein relate to a compound of formula (I) as described above or a pharmaceutically acceptable salt thereof.
  • R 2 is selected from the group consisting of halogen, —OR 5 , —NR 6 R 7 , and —C(O)R 8 ;
  • R 3 is selected from the group consisting of —(CH 2 ) n —(C 6-10 aryl), —(CH 2 ) n -(5-10 membered heteroaryl), —(CH 2 ) n —(C 3-10 carbocyclyl), and —(CH 2 ) n -(3-10 membered heterocyclyl), each optionally substituted with one or more R 9 ;
  • each R 9 is independently selected from the group consisting of halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkylthio, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C 3-10 carbocyclyl, optional
  • R 1 is a C 6-10 aryl optionally substituted with one or more R 4 . In some further embodiments, R 1 is a phenyl optionally substituted with one or more R 4 .
  • R 1 is a 5-10 membered heteroaryl optionally substituted with one or more R 4 .
  • R 1 is a pyrazolyl or 1-methyl pyrazolyl optionally substituted with one or more R 4 .
  • R 1 is a pyridazinyl optionally substituted with one or more R 4 .
  • R 1 is a pyrimidinyl optionally substituted with one or more R 4 .
  • each R 4 is independently selected from halogen, or optionally substituted C 1-6 alkyl.
  • R 4 is halogen.
  • R 4 is substituted C 1-6 alkyl.
  • R 4 is unsubstituted C 1-6 alkyl.
  • R 4 is fluoro.
  • R 4 is methyl.
  • R 2 is halogen. In some further embodiments, R 2 is selected from bromo or chloro.
  • R 2 is —CN.
  • R 2 is —OR 5 .
  • R 5 is selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-8 alkoxyalkyl, C 7-14 aralkyl optionally substituted with one or more R 11 , C 6-10 aryl optionally substituted with one or more R 11 , and —(CH 2 ) n -(3-1.0 membered heterocyclyl) optionally substituted with one or more R 10 .
  • R 5 is hydrogen.
  • R 5 is optionally substituted C 1-6 alkyl.
  • R 5 is methyl.
  • R 5 is halogen substituted ethyl.
  • R 5 is C 6-10 aryl optionally substituted with one or more R 11 .
  • R 5 is phenyl optionally substituted with one or more R 11 .
  • R 5 is unsubstituted phenyl.
  • R 5 is C 7-14 aralkyl optionally substituted with one or more R 11 .
  • R 5 is benzyl optionally substituted with one or more R 11 .
  • R 5 is unsubstituted benzy.
  • R 5 is optionally substituted C 2-8 alkoxyalkyl.
  • R 5 is selected from —(CH 2 ) 2 OCH 3 , —(CH 2 ) 2 OC 3 H 7 or —(CH 2 ) 2 O(CH 2 )OCH 3 .
  • R 5 is —(CH 2 ) n -(5 or 6 membered heterocyclyl) optionally substituted with one or more R 10 .
  • R 5 is
  • R 5 is selected from
  • R 5 can be optionally substituted
  • R 5 can be optionally substituted
  • R 5 can be optionally substituted
  • R 5 can be optionally substituted
  • R 5 can be optionally substituted
  • R 5 can be optionally substituted
  • R 5 can be optionally substituted
  • n is 0. In some embodiments of this paragraph, n is 1. In some embodiments of this paragraph, R 5 is substituted with one or more substituents selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl, —O(CH 2 ) 2 OCH 3 , halogen or —C(O)NH 2 .
  • R 2 is —NR 6 R 7 .
  • each R 6 and R 7 is independently selected from hydrogen, C 1-6 alkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , or —C(O)OR 5 .
  • R 6 is hydrogen.
  • R 6 is C 1-6 alkyl.
  • R 7 is hydrogen.
  • R 7 is C 1-6 alkyl.
  • R 7 is C 6-10 aryl optionally substituted with one or more R 11 . In some embodiments, R 7 is phenyl optionally substituted with one or more R 11 . In some other embodiments, R 7 is unsubstituted phenyl.
  • R 7 is C 7-14 aralkyl optionally substituted with one or more R 11 .
  • R 7 is benzyl or —(CH 2 ) 2 Ph, each optionally substituted with one or more R 11 .
  • R 7 is substituted with one or more substituents selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl, —O(CH 2 ) 2 OH 3 , halogen or —CN.
  • R 7 is unsubstituted benzyl. In some other embodiments, R 7 is unsubstituted —(CH 2 ) 2 Ph.
  • R 7 is (6 membered heteroaryl)alkyl optionally substituted with one or more R 11 .
  • R 7 is —CH 2 -pyridyl, —CH 2 -pyrimidinyl or —CH 2 -pyrazinyl, each optionally substituted with one or more R 11 .
  • R 7 is unsubstituted —CH 2 -pyridyl.
  • R 7 is unsubstituted —CH 2 -pyrazinyl.
  • R 7 is unsubstituted —CH 2 -pyrimidinyl.
  • R 7 is —C(O)R 8 .
  • R 8 is selected from C 1-6 alkyl, C 6-10 aryl, or —NR 12 R 13 .
  • R 8 is selected from methyl, ethyl, propyl, isopropyl, butyl, pentyl or phenyl.
  • R 8 is methyl.
  • R 8 is phenyl.
  • R 8 is —NR 12 R 13 .
  • each R 12 and R 13 is independently selected from hydrogen, C 1-6 alkyl, or benzyl.
  • R 7 is —C(O)OR 5 .
  • R 5 is selected from hydrogen, C 1-6 alkyl, C 6-10 aryl optionally substituted with one or more R 11 , or C 7-14 aralkyl optionally substituted with one or more R 11 .
  • R 5 is selected from methyl, ethyl, isopropyl, or butyl.
  • R 5 is selected from phenyl or benzyl, each optionally substituted with one or more R 11 .
  • R 6 and R 7 together with the nitrogen to which they are attached form a 6-10 membered heterocyclyl optionally substituted with one or more R 10 .
  • the heterocyclyl formed by R 6 and R 7 together with the nitrogen to which they are attached is selected from
  • R 6 and R 7 each optionally substituted with one or more R 10 .
  • the heterocyclyl formed by R 6 and R 7 together with the nitrogen to which they are attached can be optionally substituted
  • heterocyclyl formed by R 6 and R 7 together with the nitrogen to which they are attached can be optionally substituted
  • heterocyclyl formed by R 6 and R 7 together with the nitrogen to which they are attached can be optionally substituted
  • heterocyclyl formed by R 6 and R 7 together with the nitrogen to which they are attached can be optionally substituted
  • R 10 is C 1-6 alkyl. In some embodiments, two geminal R 10 together are oxo. In some other embodiments, the heterocyclyl formed by R 6 and R 7 together with the nitrogen to which they are attached is unsubstituted.
  • R 2 is —SR 5 .
  • R 5 is C 6-10 aryl optionally substituted with one or more R 11 .
  • R 5 is optionally substituted phenyl.
  • R 2 is —C(O)R 8 .
  • R 8 is selected from —NR 12 R 13 .
  • each R 12 and R 13 is independently selected from hydrogen, optionally substituted C 1-6 alkyl, C 6-10 aryl optionally substituted with one or more R 11 , or C 7-14 aralkyl optionally substituted with one or more R 11 .
  • each R 12 and R 13 is independently selected from hydrogen, C 1-6 alkyl, phenyl optionally substituted with one or more R 11 or benzyl optionally substituted with one or more R 11 .
  • the phenyl or benzyl is unsubstituted.
  • R 2 is —C(O)OR 5 .
  • R 5 is hydrogen or C 1-6 alkyl.
  • each R 11 is independently selected from —CN, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, O—(CH 2 ) n —C 2-8 alkoxy, or —C(O)NR 12 R 13 .
  • R 11 is selected from —CN, —Cl, —F, —CH 3 , —OCH 3 , —OC 2 H 5 , —CF 3 or —OCF 3 .
  • R 11 is —F.
  • R 11 is —OCF 3 .
  • R 11 is —OC 2 H 5 .
  • R 11 is methyl.
  • R 11 is —O—(CH 2 ) 2 —OCH 3 .
  • R 11 is —C(O)NH 2 .
  • R 3 is selected from the group consisting of —(CH 2 ) n —(C 6-10 aryl), —(CH 2 ) n -(5-10 membered heteroaryl), —(CH 2 ) n —(C 3-10 carbocyclyl), and —(CH 2 ) n -(3-10 membered heterocyclyl), each optionally substituted with one or more R 9 .
  • n is 0.
  • R 3 is —(CH 2 ) n —(C 6-10 aryl) optionally substituted with one or more R 9 . In some embodiments, R 3 is —(CH 2 ) n -phenyl, optionally substituted with one or more R 9 . In some embodiments, n is 0. In some other embodiments, R 3 is unsubstituted —(CH 2 ) n -phenyl. In some other embodiments, R 3 is unsubstituted phenyl.
  • R 9 is selected from halogen, optionally substituted C 1-6 alkyl, or —OR 5 .
  • R 9 is selected from fluoro, chloro.
  • R 9 is selected from methyl, ethyl, or trifluoromethyl.
  • R 9 is —OR 5 .
  • R 5 is selected from hydrogen, C 1-6 alkyl or halo substituted C 1-6 alkyl.
  • R 5 is selected from trifluoromethyl or ethyl.
  • R 5 is optionally substituted C 2-8 alkoxyalkyl.
  • R 9 is NR 14 R 15 .
  • R 9 is —NH—C(O)R 8 . In some further such embodiments, R 9 is selected from —NH—C(O)—C 1-6 alkyl, or —NH—C(O)—NH 2 . In some embodiments, R 9 is hydroxy.
  • R 3 is unsubstituted. In some other embodiments, R 3 is hydrogen.
  • Z is oxygen
  • bonds represented by a solid and dashed line are double bonds.
  • compounds of formula (I) are also represented by
  • the compound of formula (I) is selected from the group consisting of Compounds 85-162, 401-414, 523-545, 550, 551 and 664 in Table 1. In some further embodiments, the compound of formula (I) is selected from the group consisting of Compounds 85-162, 401-414, 523-538, 540, 541, 543, 545-, 664 and 696-707 of Table 1.
  • Some alternative embodiments provide compounds of formula (I) with the same variable definitions as provided above with the exception that R 2 is selected from 5-10 membered heteroaryl or 3-10 membered heterocyclyl, each optionally substituted with one or more R 4 .
  • R 2 is selected from 5-10 membered heteroaryl or 3-10 membered heterocyclyl, each optionally substituted with one or more R 4 .
  • One non-limiting example of these alternative embodiments is where the compound of formula (I) is Compound 708 of Table 1.
  • Some embodiments disclosed herein relate to a compound of formula (II) as described above or a pharmaceutically acceptable salt thereof.
  • R 3 is selected from the group consisting of —(CH 2 ) n —(C 6-10 aryl), —(CH 2 ) n -(5-10 membered heteroaryl), —(CH 2 ) n —(C 3-10 carbocyclyl), and —(CH 2 ) n -(3-10 membered heterocyclyl), each optionally substituted with one or more R 9 ; and each R 9 is independently selected from the group consisting of halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkylthio, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 6-10 aryl, —OR 5 , —NR 14 R 15 , —C(O)R 8 , —SO 2 R 16 , and —NO 2 .
  • R 2 is selected from optionally substituted C 1-6 alkyl. In some embodiments, R 2 is selected from methyl, ethyl, isopropyl, or trifluoromethyl. In some embodiments, R 2 is methyl.
  • R 3 is hydrogen.
  • the compound of formula (II) is selected from the group consisting of compounds 562-565, 567, 662 and 663 of Table 1.
  • R 3 is selected from the group consisting of —(CH 2 ) n —(C 6-10 aryl), —(CH 2 ) n -(5-10 membered heteroaryl), —(CH 2 ) n —(C 3-10 carbocyclyl), and —(CH 2 ) n -(3-10 membered heterocyclyl), each optionally substituted with one or more R 9 .
  • n is 0.
  • R 3 is selected from —(CH 2 ) n —(C 6-10 aryl), optionally substituted with one or more R 9 . In some embodiments, R 3 is —(CH 2 ) n -phenyl optionally substituted with one or more R 9 . In some embodiments, R 3 is phenyl, optionally substituted with one or more R 9 . In some embodiments, R 3 is unsubstituted phenyl. In some embodiments, R 3 is unsubstituted —(CH 2 ) n —(C 6-10 aryl).
  • R 3 is selected from —(CH 2 ) n -(9 membered heterocyclyl), optionally substituted with one or more R 9 . In some embodiments, R 3 is selected from
  • R 3 is optionally substituted
  • R 3 is optionally substituted
  • R 3 is optionally substituted
  • R 3 is optionally substituted
  • R 3 is unsubstituted.
  • R 3 is selected from —(CH 2 ) n -(10 membered heterocyclyl), optionally substituted with one or more R 9 . In some embodiments, n is 0. In some embodiments, R 3 is selected from
  • R 3 is unsubstituted.
  • each R 9 is independently selected from halogen, optionally substituted C 1-6 alkyl, —OR 5 , —NR 14 R 15 or —C(O)R 8 .
  • R 9 is selected from methyl, ethyl, propyl isopropyl, or trifluoromethyl.
  • R 9 is selected from fluoro or chloro.
  • R 9 is —OR 5 , and wherein R 5 is selected from optionally substituted C 1-6 alkyl. In some embodiments, R 5 is unsubstituted C 1-6 alkyl. In some embodiments, R 5 is selected from methyl, ethyl, propyl, isopropyl or trifluoromethyl. In some embodiments, R 5 is methyl. In some other embodiments, R 5 is trifluoromethyl.
  • R 9 is —NR 14 R 15 , and wherein each R 14 and R 15 is independently selected from hydrogen, C 1-6 alkyl or —C(O)R 8 .
  • R 8 is selected from optionally substituted C 1-6 alkyl, —OR 5 or —NR 12 R 13 .
  • each R 12 and R 13 is independently selected from hydrogen or C 1-6 alkyl.
  • each R 12 and R 13 is independently selected from hydrogen or methyl.
  • R 5 is selected from hydrogen or C 1-6 alkyl.
  • each R 14 and R 15 is independently selected from hydrogen, methyl, ethyl, —C(O)NH 2 , —C(O)NHCH 3 , —C(O)N(CH 3 ) 2 , —C(O)OH or —C(O)OEt.
  • R 9 is —C(O)R 8 .
  • R 8 is selected from optionally substituted C 1-6 alkyl or —NR 12 R 13 .
  • R 8 is selected from methyl, —NH 2 or —NHCH 3 .
  • all Y is CR 4 .
  • R 4 is selected from hydrogen, halogen, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy or 5 membered heteroaryl optionally substituted with one or more R 11 .
  • R 4 is selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or thiazolyl.
  • two adjacent R 4 together with the carbon atoms to which they are attached form a fused ring selected from optionally substituted 5 or 6 membered heteroaryl or optionally substituted 5 or 6 membered heterocyclyl.
  • the optionally substituted 5 or 6 membered heterocyclyl formed by two adjacent R 4 together with the carbon atoms to which they are attached is selected from
  • each R 17 is independently selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , or optionally substituted C 2-8 alkoxyalkyl.
  • R 17 is selected from hydrogen, methyl, ethyl, —(CH 2 ) 2 OH or —(CH 2 ) 2 OCH 3 .
  • the optionally substituted 5 or 6 membered heterocyclyl is selected from
  • the optionally substituted 5or 6 membered heterocyclyl is selected from
  • the optionally substituted 5 or 6 membered heterocyclyl is substituted with one or more substituents selected from C 1-6 alkyl or halogen. In some other embodiments, the 5 or 6 membered heterocyclyl is unsubstituted.
  • the optionally substituted 5 or 6 membered heteroaryl formed by two adjacent R 4 together with the carbon atoms to which they are attached is selected from
  • each R 18 is independently selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , or optionally substituted C 2-8 alkoxyalkyl.
  • R 18 is selected from hydrogen or methyl.
  • the optionally substituted 5 or 6 membered heteroaryl is selected from
  • the optionally substituted 5 or 6 membered heterocyclyl is substituted with one or more substituents selected from C 1-6 alkyl or halogen. In some other embodiments, the 5 or 6 membered heterocyclyl is unsubstituted.
  • the substituent on the 5 or 6 membered heteroaryl or 5 or 6 membered heterocyclyl formed by two adjacent R 4 together with the carbon atoms to which they are attached is selected from C 1-6 alkyl, C 1-6 alkoxy, oxo or halogen. In some further embodiments, the substituent is selected from methyl, fluoro, or oxo. In some embodiments, the substituent is oxo. In some such embodiments, the 5 or 6 membered heteroaryl or 5 or 6 membered heterocyclyl are selected from
  • R 17 is alkyl
  • Z is oxygen
  • the bonds represented by a solid and dashed line are double bonds, provided that when the optionally substituted 5 or 6 membered heteroaryl formed by two adjacent R 4 together with the carbon atoms to which they are attached is selected from
  • bonds represented by a solid and dashed line are double bonds in formula (IIa).
  • compounds of formula (II) are also represented by
  • the compound of formula (II) is selected from the group consisting of Compounds 163-216, 241-243, 245, 246, 248-252, 254, 255, 258-261, 263, 415-430, 432, 552-567, 629, 662 and 663 of Table 1. In some further embodiments, the compound of formula (II) is selected from the group consisting of Compounds 163-216, 241-243, 245, 246, 248-252, 254, 255, 258-261, 263, 415-430, 432, 552-561, 566 and 629 of Table 1.
  • Some embodiments disclosed herein relate to a compound of formula (III) as described above or a pharmaceutically acceptable salt thereof.
  • R 3 is selected from the group consisting of —(CH 2 ) n —(C 6-10 aryl), —(CH 2 ) n -(5-10 membered heteroaryl), —(CH 2 ) n —(C 3-10 carbocyclyl), and —(CH 2 ) n -(3-10 membered heterocyclyl), each optionally substituted with one or more R 9 ; and each R 9 is independently selected from the group consisting of halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkylthio, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 6-10 aryl, —OR 5 , —NR 14 R 15 , —C(O)R 8 , —SO 2
  • R 1 is selected from halogen, C 1-6 alkyl optionally substituted with one or more R 4 , C 6-10 aryl optionally substituted with one or more R 4 , or 5 to 6-membered heteroaryl optionally substituted with one or more R 4 .
  • R 1 is bromo or fluoro.
  • R 1 is methyl optionally substituted with one or more R 4 .
  • R 1 is methyl.
  • R 1 is phenyl optionally substituted with one or more R 4 .
  • R 1 is pyridazinyl optionally substituted with one or more R 4
  • R 1 is unsubstituted phenyl.
  • R 1 is pyrazolyl or 1-methyl pyrazolyl optionally substituted with one or more R 4 .
  • R 4 is selected from halogen.
  • R 3 is selected from the group consisting of —(CH 2 ) n —(C 6-10 aryl), —(CH 2 ) n -(5-10 membered heteroaryl), —(CH 2 ) n —(C 3-10 carbocyclyl), and —(CH 2 ) n -(3-10 membered heterocyclyl), each optionally substituted with one or more R 9 .
  • n is 0.
  • R 3 is selected from —(CH 2 ) n —(C 6-10 aryl) optionally substituted with one or more R 9 .
  • R 3 is phenyl, optionally substituted with one or more R 9 . In some other embodiments, R 3 is unsubstituted phenyl.
  • R 3 is hydrogen.
  • the compound of formula (III) is selected from the group consisting of compounds 576, 578, 590, 595, 611-613, 616, 618, 621-623, 637 and 638 of Table 1.
  • R 9 is selected from cyano, halogen, optionally substituted C 1-6 alkyl, or optionally substituted C 1-6 alkoxy. In some further embodiments, R 9 is selected from cyano, fluoro, chloro, methyl, ethyl, ethoxy, methoxy, trifluoromethyl or trifluoromethoxy. In some embodiments, R 9 is ethoxy. In some embodiments, R 9 is trifluoromethoxy. In still some other embodiment, R 9 is difluoromethoxy.
  • ring A is selected from 6-membered heteroaryl, 5-membered heterocyclyl or 6-membered heterocyclyl, each optionally substituted with one or more R 4 .
  • ring A is selected from
  • each optionally substituted with one or more R 4 and wherein each R 17 is independently selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C-carboxy, acyl, C 6-10 aryl optionally substituted with one or more R 11 , or C 7-14 aralkyl optionally substituted with one or more R 11 .
  • ring A is selected from
  • ring A is selected from
  • ring A is optionally substituted
  • ring A is optionally substituted
  • ring A is optionally substituted
  • ring A is optionally substituted
  • ring A is optionally substituted
  • ring A is optionally substituted
  • ring A is optionally substituted
  • ring A is optionally substituted
  • ring A is optionally substituted
  • ring A is optionally substituted
  • ring A is optionally substituted
  • ring A is optionally substituted
  • ring A is optionally substituted
  • ring A is optionally substituted
  • ring A is optionally substituted
  • ring A is optionally substituted
  • ring A is optionally substituted
  • R 17 is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, —(CH 2 ) 2 F, —(CH 2 ) 2 OH, —(CH 2 ) 2 OCH 3 , —(CH 2 ) 2 OC 2 H 5 , —(CH 2 ) 2 OC 3 H 7 , —C(O)O t Bu, —C(O)CH 3 or benzyl.
  • ring A is selected from
  • ring A is selected from
  • R 4 is selected from halogen, optionally substituted C 1-6 alkyl, or C 7-14 aralkyl optionally substituted with one or more R 11 , or two geminal R 4 together are oxo.
  • R 4 is selected from fluoro, methyl, trifluoromethyl, or benzyl.
  • two geminal R 4 together are oxo.
  • ring A is unsubstituted.
  • Z is oxygen
  • the bonds represented by a solid and dashed line are double bonds, provided that when ring A is
  • the compound of formula (III) is selected from the group consisting of Compounds 29-63, 392-400, 568-628, 630-661, and 665 of Table 1. In some further embodiments, the compound of formula (III) is selected from the group consisting of Compounds 29-63, 392-400, 568-574, 577, 579-584, 586-589, 591-594, 596-608, 614, 615, 617, 619, 620, 624-626, 631, 634-636, 640, 642-655, 657-661, 665, and 669-695 of Table 1.
  • Some embodiments disclosed herein relate to a compound of formula (IV) as described above or a pharmaceutically acceptable salt thereof.
  • R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl optionally substituted with one or more R 4 , or 5-membered heteroaryl optionally substituted with one or more R 4 .
  • R 1 is selected from methyl, phenyl, pyrazolyl, or 1-methyl pyrazolyl, each optionally substituted with one or more R 4 . In some embodiments, R 1 is methyl. In some embodiments, R 1 is unsubstituted phenyl. In some embodiments, R 1 is unsubstituted pyrazolyl. In yet some other embodiments, R 1 is unsubstituted 1-methyl pyrazolyl.
  • R 2 is selected from hydrogen or optionally substituted C 1-6 alkyl.
  • all Y are CR 4 . In some other embodiment, at least one Y is nitrogen.
  • R 4 is selected from halogen, C 1-6 alkyl or C 1-6 alkoxy. In some embodiments, R 4 is selected from fluoro or methyl.
  • n is 1. In some embodiments, m is 2. In some embodiments, m is 3.
  • Z is oxygen
  • the bonds represented by a solid and dashed line are double bonds.
  • the compound of formula (IV) is selected from the group consisting of Compounds 21-26 of Table 1.
  • Some embodiments disclosed herein relate to a compound of formula (V) as described above or a pharmaceutically acceptable salt thereof.
  • each R 2 is independently selected from hydrogen, C 1-6 alkyl or —OR 5 .
  • each R 2 is hydrogen.
  • R 3 is —(CH 2 ) n —(C 6-10 aryl), optionally substituted with one or more R 9 .
  • R 3 is phenyl, optionally substituted with one or more R 9 .
  • R 3 is unsubstituted phenyl.
  • R 9 is selected from halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-8 alkoxyalkyl, —OR 5 , or —NR 14 R 15 .
  • R 9 is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, —NHCH 3 , —NH 2 , or —NHC(O)CH 3 .
  • R 9 is trifluoromethoxy.
  • ring A is a C 5 carbocyclyl optionally substituted with one or more R 4 . In some embodiments, ring A is a C 6 carbocyclyl optionally substituted with one or more R 4 . In some other embodiments, ring A is unsubstituted.
  • R 4 is selected from halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, or independently two geminal R 4 together are oxo.
  • ring A is an unsubstituted C 5-7 carbocyclyl.
  • Z is oxygen
  • the bonds represented by a solid and dashed line are double bonds.
  • the compound of formula (V) is selected from the group consisting of Compounds 27 and 28 of Table 1.
  • Some embodiments disclosed herein relate to a compound of formula (VIa) as described above or a pharmaceutically acceptable salt thereof.
  • R 1 is a C 4 carbocyclyl optionally substituted with one or more R 4 .
  • R 1 is a C 5 carbocyclyl optionally substituted with one or more R 4 .
  • R 1 is a C 6 carbocyclyl optionally substituted with one or more R 4 .
  • R 4 is selected from halogen, optionally substituted C 1-6 alkyl, or optionally substituted C 1-6 alkoxy. In some embodiments, R 4 is selected from fluoro, chloro, methyl, methoxy, ethoxy, trifluoromethyl, or trifluoromethoxy.
  • R 1 is unsubstituted.
  • each R 2 is independently selected from hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR 5 or —NR 6 R 7 .
  • R 2 is hydrogen.
  • R 2 is halogen.
  • R 2 is optionally substituted C 1-6 alkyl. In some embodiments, R 2 is methyl. In some other embodiments, R 2 is trifluoromethyl.
  • R 3 is selected from —(CH 2 ) n —(C 6-10 aryl), optionally substituted with one or more R 9 . In some embodiments, R 3 is phenyl, optionally substituted with one or more R 9 .
  • R 9 is selected from halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-8 alkoxyalkyl, —OR 5 , or —NR 14 R 15 .
  • R 9 is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, —NHCH 3 , —NH 2 , or —NHC(O)CH 3 .
  • R 3 is unsubstituted phenyl.
  • Z is oxygen
  • the bonds represented by a solid and dashed line are double bonds.
  • the compound of formula (VIa) is selected from the group consisting of Compounds 64-66 of Table 1.
  • Some embodiments disclosed herein relate to a compound of formula (VII) as described above or a pharmaceutically acceptable salt thereof.
  • each R 2 is independently selected from hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR 5 or —NR 6 R 7 .
  • R 2 is hydrogen.
  • R 2 is halogen.
  • R 2 is optionally substituted C 1-6 alkyl.
  • R 2 is methyl or trifluoromethyl.
  • R 3 is selected from —(CH 2 ) n —(C 6-10 aryl), optionally substituted with one or more R 9 . In some embodiments, R 3 is phenyl optionally substituted with one or more R 9 .
  • R 9 is selected from halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-8 alkoxyalkyl, —OR 5 , or —NR 14 R 15 .
  • R 9 is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, —NHCH 3 , —NH 2 , or —NHC(O)CH 3 .
  • R 3 is unsubstituted phenyl.
  • Q is C(O). In some other embodiments, Q is S(O) t . In some embodiments, t is 2.
  • R 16 is selected from optionally substituted C 1-6 alkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , or —OR 5 .
  • R 16 is optionally substituted C 1-6 alkyl.
  • R 16 is selected from methyl, ethyl, propyl, isopropyl, or butyl.
  • R 16 is phenyl optionally substituted with one or more R 11 . In some other embodiments, R 16 is unsubstituted phenyl.
  • R 16 is benzyl optionally substituted with one or more R 11 . In some other embodiments, R 16 is unsubstituted benzyl. In some embodiments, R 16 is —NR 12 R 13 . In some embodiments, each R 12 and R 13 is independently selected from hydrogen or optionally substituted C 1-6 alkyl. In some embodiments, R 16 is —OR 5 . In some embodiments, R 5 is selected from hydrogen or optionally substituted C 1-6 alkyl. In some further embodiments, R 5 is selected from methyl, ethyl, propyl, isopropyl, or butyl.
  • Z is oxygen
  • the bonds represented by a solid and dashed line are double bonds.
  • the compound of formula (VII) is selected from the group consisting of Compounds 67-76 of Table 1.
  • Some embodiments disclosed herein relate to a compound of formula (VIb) as described above or a pharmaceutically acceptable salt thereof.
  • R 1 is selected from C 1-6 alkyl optionally substituted with one or more R 4 , C 6-10 aryl optionally substituted with one or more R 4 , or 5-10 membered heteroaryl optionally substituted with one or more R 4 .
  • R 1 is selected from C 1-6 alkyl optionally substituted with one or more R 4 .
  • R 1 is selected from methyl, ethyl, propyl, or isopropyl.
  • R 1 is phenyl optionally substituted with one or more R 4 .
  • R 1 is selected from 5 or 6 membered heteroaryl, each optionally substituted with one or more R 4 .
  • R 1 is selected from pyrazolyl or 1-methyl pyrazolyl, each optionally substituted with one or more R 4 . In some other embodiment, R 1 is unsubstituted.
  • R 4 is selected from halogen or optionally substituted C 1-6 alkyl. In some embodiments, R 4 is fluoro.
  • each R 2 is independently selected from hydrogen, halogen, or optionally substituted C 1-6 alkyl. In some embodiments, R 2 is hydrogen.
  • R 3 is —(CH 2 ) 1-4 —(C 6-10 aryl), optionally substituted with one or more R 9 .
  • R 3 is —(CH 2 ) 1-4 -phenyl, optionally substituted with one or more R 9 .
  • R 3 is unsubstituted.
  • R 3 is —(CH 2 )-phenyl, optionally substituted with one or more R 9 .
  • R 3 is —(CH 2 ) 2 -phenyl, optionally substituted with one or more R 9 .
  • R 3 is unsubstituted.
  • R 9 is selected from halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-8 alkoxyalkyl, —OR 5 , —C(O)R 8 or —NR 14 R 15 .
  • R 9 is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, —C(O)CH 3 , —NHCH 3 , —NH 2 , or —NHC(O)CH 3 .
  • Z is oxygen
  • the bonds represented by a solid and dashed line are double bonds.
  • the compound of formula (VIb) is selected from the group consisting of Compounds 77-80 of Table 1.
  • Some embodiments disclosed herein relate to a compound of formula (VIII) as described above or a pharmaceutically acceptable salt thereof.
  • R 3 is selected from optionally substituted C 1-6 alkyl or —(CH 2 ) n —(C 6-10 aryl) optionally substituted with one or more R 9 . In some embodiments, R 3 is —(CH 2 )—(C 6-10 aryl) optionally substituted with one or more R 9 . In some embodiments, R 3 is phenyl optionally substituted with one or more R 9 .
  • R 9 is selected from halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-8 alkoxyalkyl, —OR 5 , —C(O)R 8 or —NR 14 R 15 .
  • R 9 is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, —C(O)CH 3 , —NHCH 3 , —NH 2 , or —NHC(O)CH 3 .
  • R 9 is trifluoromethoxy.
  • R 3 is unsubstituted phenyl.
  • R 3 is optionally substituted C 1-6 alkyl. In some further embodiments, R 3 is C 1-6 alkyl.
  • each R 17 is independently selected from hydrogen, halogen, optionally substituted C 1-6 alkyl or oxo. In some embodiments, each R 17 is hydrogen.
  • two adjacent R 17 together with the carbon atoms to which they are attached form a fused phenyl optionally substituted with one or more R 4 .
  • at least one R 17 is oxo.
  • at least one R 17 is optionally substituted C 1-6 alkyl.
  • the fused phenyl is unsubstituted.
  • two adjacent R 17 together with the carbon atoms to which they are attached form a fused 5-6 membered heteroaryl, optionally substituted with one or more R 4 .
  • at least one R 17 is oxo.
  • at least one R 17 is optionally substituted C 1-6 alkyl.
  • the fused 5-6 membered heteroaryl is unsubstituted.
  • R 4 is selected from halogen or optionally substituted C 1-6 alkyl.
  • n is 0. In some other embodiments, n is 1. In yet some other embodiments, n is 3.
  • Z is oxygen
  • the compound of formula (VIII) is selected from the group consisting of Compounds 81, 82, and 513-519 of Table 1.
  • Some embodiments disclosed herein relate to a compound of formula (IX) as described above or a pharmaceutically acceptable salt thereof.
  • R 1 is selected from C 1-6 alkyl optionally substituted with one or more R 4 , C 6-10 aryl optionally substituted with one or more R 4 , or 5-10 membered heteroaryl optionally substituted with one or more R 4 .
  • R 1 is C 1-6 alkyl optionally substituted with one or more R 4 .
  • R 1 is C 6-10 aryl optionally substituted with one or more R 4 .
  • R 1 is phenyl optionally substituted with one or more R 4 . In some embodiments, R 1 is 5 or 6 membered heteroaryl optionally substituted with one or more R 4 . In some further embodiments, R 1 is pyrazolyl or 1-methyl pyrazolyl optionally substituted with one or more R 4 .
  • R 4 is selected from halogen, optionally substituted C 1-6 alkyl, or optionally substituted C 1-6 alkoxy.
  • R 1 is unsubstituted.
  • each R 2 is independently selected from hydrogen, halogen or optionally substituted C 1-6 alkyl. In some embodiments, R 2 is hydrogen.
  • R 3 is —(CH 2 ) n —(C 6-10 aryl), optionally substituted with one or more R 9 . In some further embodiments, R 3 is phenyl optionally substituted with one or more R 9 . In some other embodiments, R 3 is unsubstituted.
  • R 9 is selected from halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-8 alkoxyalkyl, —OR 5 , —C(O)R 8 or —NR 14 R 15 .
  • R 9 is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, —C(O)CH 3 , —NHCH 3 , —NH 2 , or —NHC(O)CH 3 .
  • Z is oxygen
  • the compound of formula (IX) is selected from the group consisting of Compounds 83, 84, 520-522 of Table 1.
  • Some embodiments described herein relate to one or more compounds selected from the group consisting of Compounds 1-20, 217-240, 244, 247, 253, 256, 257, 262, 264-283, 285, 287-339, 341-391, 431, 433, 434, 438-440, 442, 446-512, 546-549, 575, 585, 609, 610, 627, 628, 630, 632, 633, 639, 641, 656, 666-668, 708 and 709 of Table 1.
  • compounds are selected from the following compounds as listed in Table 1.
  • compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereoisomers, tautomers, polymorphs, and solvates thereof), or pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • a daily dose for most of the compounds described herein is from about 0.25 mg/kg to about 120 mg/kg or more of body weight, from about 0.5 mg/kg or less to about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of body weight, or from about 1.5 mg/kg to about 10 mg/kg of body weight.
  • the dosage range would be from about 17 mg per day to about 8000 mg per day, from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200 mg to about 3000 mg per day.
  • the amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.
  • Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly.
  • Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments.
  • the compounds useful as described above can be formulated into pharmaceutical compositions for use in treatment of these conditions.
  • Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21 st Ed., Lippincott Williams & Wilkins (2005), incorporated by reference in its entirety.
  • compositions containing a pharmaceutically-acceptable carrier include compositions containing a pharmaceutically-acceptable carrier.
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler diluents or encapsulating substances, which are suitable for administration to a mammal.
  • compatible means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction, which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations.
  • Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration preferably to an animal, preferably mammal being treated.
  • substances which can serve as pharmaceutically-acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free sugars,
  • a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.
  • compositions described herein are preferably provided in unit dosage form.
  • a “unit dosage form” is a composition containing an amount of a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice.
  • the preparation of a single or unit dosage form does not imply that the dosage form is administered once per day or once per course of therapy.
  • Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, though a single administration is not specifically excluded.
  • the skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.
  • compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration.
  • oral and nasal compositions include compositions that are administered by inhalation, and made using available methodologies.
  • pharmaceutically-acceptable carriers well-known in the art may be used.
  • Pharmaceutically-acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances.
  • Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
  • Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance.
  • inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose
  • binders such as starch, gelatin and sucrose
  • disintegrants such as starch, alginic acid and croscarmelose
  • lubricants such as magnesium stearate, stearic acid and talc.
  • Glidants such as silicon dioxide can be used to improve flow characteristics
  • Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets.
  • Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.
  • Peroral compositions also include liquid solutions, emulsions, suspensions, and the like.
  • the pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art.
  • Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate;
  • typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate.
  • Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
  • compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action.
  • dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
  • compositions described herein may optionally include other drug actives.
  • compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms.
  • Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
  • a liquid composition which is formulated for topical ophthalmic use, is formulated such that it can be administered topically to the eye.
  • the comfort should be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort.
  • the liquid should be formulated such that the liquid is tolerable to the patient for topical ophthalmic use.
  • an ophthalmically acceptable liquid should either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.
  • solutions or medicaments are often prepared using a physiological saline solution as a major vehicle.
  • Ophthalmic solutions should preferably be maintained at a comfortable pH with an appropriate buffer system.
  • the formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
  • Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate and phenylmercuric nitrate.
  • a useful surfactant is, for example, Tween 80.
  • various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
  • Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
  • buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
  • an ophthalmically acceptable antioxidant includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
  • excipient components which may be included in the ophthalmic preparations, are chelating agents.
  • a useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.
  • Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.
  • the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution.
  • a pharmaceutically acceptable diluent such as a saline or dextrose solution.
  • Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric acid.
  • the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7.
  • Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA.
  • excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety.
  • Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.
  • compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration.
  • a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration.
  • the compositions are provided in solution ready to administer parenterally.
  • the compositions are provided in a solution that is further diluted prior to administration.
  • the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.
  • Some embodiments described herein relate to a method of treating a fibrotic condition, which can include administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a subject.
  • the methods include identifying a subject at risk for or having a fibrotic condition and administering a compound to the subject in an effective amount for therapeutic treatment or prophylactic treatment of the fibrotic condition.
  • fibrotic condition fibroproliferative condition
  • fibrotic disease fibroproliferative disease
  • fibroproliferative disease fibrotic disorder
  • fibroproliferative disorder fibroproliferative disorder
  • Fibrotic disorders include, but are not limited to, pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis from a known etiology, dermal fibrosis, pancreatic fibrosis, liver fibrosis (e.g., hepatic fibrosis associated with chronic active hepatitis), and renal fibrosis.
  • pulmonary fibrosis including idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis from a known etiology
  • dermal fibrosis e.g., dermal fibrosis
  • pancreatic fibrosis e.g., liver fibrosis associated with chronic active hepatitis
  • renal fibrosis e.g., hepatic fibrosis associated with chronic active hepatitis
  • the subject is a human.
  • therapeutically effective amount refers to an amount of a compound sufficient to cure, ameliorate, slow progression of, prevent, or reduce the likelihood of onset of the identified disease or condition, or to exhibit a detectable therapeutic, prophylactic, or inhibitory effect.
  • the effect can be detected by, for example, the assays disclosed in the following examples.
  • the precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration.
  • Therapeutically and prophylactically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • the therapeutically or prophylactically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs.
  • the animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
  • Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (the dose therapeutically effective in 50% of the population) and LD 50 (the dose lethal to 50% of the population).
  • the dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, ED 50 /LD 50 .
  • Pharmaceutical compositions that exhibit large therapeutic indices are preferred. However, pharmaceutical compositions that exhibit narrow therapeutic indices are also within the scope of the invention.
  • the data obtained from cell culture assays and animal studies may be used in formulating a range of dosage for human use.
  • the dosage contained in such compositions is preferably within a range of circulating concentrations that include an ED 50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
  • the exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.
  • treating a condition described herein results in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects.
  • the average survival time is increased by more than about 30 days; more preferably, by more than about 60 days; more preferably, by more than about 90 days; and even more preferably by more than about 120 days.
  • An increase in survival time of a population may be measured by any reproducible means.
  • an increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • an increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • treating a condition described herein results in a decrease in the mortality rate of a population of treated subjects in comparison to a population of subjects receiving carrier alone. In another aspect, treating a condition described herein results in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. In a further aspect, treating a condition described herein results a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the embodiments, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof. Preferably, the mortality rate is decreased by more than about 2%; more preferably, by more than about 5%; more preferably, by more than about 10%; and most preferably, by more than about 25%.
  • a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means.
  • a decrease in the mortality rate of a population may be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound.
  • a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease related deaths per unit time following completion of a first round of treatment with an active compound.
  • treating a condition described herein results in a reduction in the rate of cellular proliferation.
  • the rate of cellular proliferation is reduced by at least about 5%; more preferably, by at least about 10%; more preferably, by at least about 20%; more preferably, by at least about 30%; more preferably, by at least about 40%; more preferably, by at least about 50%; even more preferably, by at least about 60%; and most preferably, by at least about 75%.
  • the rate of cellular proliferation may be measured by any reproducible means of measurement.
  • the rate of cellular proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.
  • treating a condition described herein results in a reduction in the proportion of proliferating cells.
  • the proportion of proliferating cells is reduced by at least about 5%; more preferably, by at least about 10%; more preferably, by at least about 20%; more preferably, by at least about 30%; more preferably, by at least about 40%; more preferably, by at least about 50%; even more preferably, by at least about 60%; and most preferably, by at least about 75%.
  • the proportion of proliferating cells may be measured by any reproducible means of measurement.
  • the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of nondividing cells in a tissue sample.
  • the proportion of proliferating cells is equivalent to the mitotic index.
  • treating a condition described herein results in a decrease in size of an area or zone of cellular proliferation.
  • size of an area or zone of cellular proliferation is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least about 10%; more preferably, reduced by at least about 20%; more preferably, reduced by at least about 30%; more preferably, reduced by at least about 40%; more preferably, reduced by at least about 50%; even more preferably, reduced by at least about 60%; and most preferably, reduced by at least about 75%.
  • Size of an area or zone of cellular proliferation may be measured by any reproducible means of measurement.
  • size of an area or zone of cellular proliferation may be measured as a diameter or width of an area or zone of cellular proliferation.
  • the methods described herein may include identifying a subject in need of treatment.
  • the methods include identifying a mammal in need of treatment.
  • the methods include identifying a human in need of treatment. Identifying a subject in need of treatment may be accomplished by any means that indicates a subject who may benefit from treatment. For example, identifying a subject in need of treatment may occur by clinical diagnosis, laboratory testing, or any other means known to one of skill in the art, including any combination of means for identification.
  • the compounds described herein may be formulated in pharmaceutical compositions, if desired, and can be administered by any route that permits treatment of the disease or condition.
  • a preferred route of administration is oral administration. Administration may take the form of single dose administration, or the compound of the embodiments can be administered over a period of time, either in divided doses or in a continuous-release formulation or administration method (e.g., a pump).
  • the compounds of the embodiments are administered to the subject, the amounts of compound administered and the route of administration chosen should be selected to permit efficacious treatment of the disease condition.
  • a combination can include a compound, composition, pharmaceutical composition described herein with an additional medicament.
  • Some embodiments include co-administering a compound, composition, and/or pharmaceutical composition described herein, with an additional medicament.
  • co-administration it is meant that the two or more agents may be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered.
  • the agents are administered simultaneously.
  • administration in combination is accomplished by combining the agents in a single dosage form.
  • the agents are administered sequentially.
  • the agents are administered through the same route, such as orally.
  • the agents are administered through different routes, such as one being administered orally and another being administered i.v.
  • the combination of active ingredients may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art.
  • the methods described herein may comprise administering or delivering the active ingredients sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e., serially
  • simultaneous therapy effective dosages of two or more active ingredients are administered together.
  • Various sequences of intermittent combination therapy may also be used.
  • Pulmonary fibrosis also called idiopathic pulmonary fibrosis (IPF), interstitial diffuse pulmonary fibrosis, inflammatory pulmonary fibrosis, or fibrosing alveolitis
  • IPF idiopathic pulmonary fibrosis
  • pulmonary fibrosis interstitial diffuse pulmonary fibrosis
  • inflammatory pulmonary fibrosis or fibrosing alveolitis
  • fibrosing alveolitis is a lung disorder and a heterogeneous group of conditions characterized by abnormal formation of fibrous tissue between alveoli caused by alveolitis comprising cellular infiltration into the alveolar septae with resulting fibrosis.
  • the effects of IPF are chronic, progressive, and often fatal.
  • the compounds and methods described herein are useful in the treatment of pulmonary fibrosis, such as IPF.
  • renal fibrosis is considered to be the common final pathway by which kidney disease progresses to end-stage renal failure.
  • the compounds and methods described herein are useful in the treatment of renal fibrosis.
  • the compounds disclosed herein may be synthesized by methods described below, or by modification of these methods. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc., known to those skilled in the art.
  • it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J. F. W. McOmie, Plenum Press, 1973); and P. G. M. Green, T. W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), which are both hereby incorporated herein by reference in their entirety.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • Synthetic chemistry transformations useful in synthesizing applicable compounds are known in the art and include e.g. those described in R. Larock, Comprehensive Organic Transformations , VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons, 1995, which are both hereby incorporated herein by reference in their entirety.
  • the routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.
  • II-5 (2.5 g, 8.9 mmol) was dissolved in Ac 2 O (30 mL) and the mixture was refluxed at 140° C. for 18 hrs. After being cooled to rt, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether/EtOAc (20:1) to give a mixture of II-6 and II-6A (1.5 g, 52% yield) as yellow solid.
  • III-1 (30 g, 0.162 mol, 1 eq.) in 300 mL of anhydrous THF was added dropwise a solution of n-BuLi (2.5M in hexane, 77.5 mL, 0.19 mol, 1.2 eq.) at ⁇ 70° C. After completion of addition, the mixture was stirred at ⁇ 70° C. for 20 min, followed by addition of a solution of N-methoxy-N-methylacetamide (33 g, 0.322 mol, 2 eq.) in 100 mL of anhydrous THF by drop wise, the solution was allowed to warm to rt and stirred for 2 hrs. The reaction was quenched with saturated aq.
  • n-BuLi 2.5M in hexane, 77.5 mL, 0.19 mol, 1.2 eq.
  • III-2 (5 g, 33 mmol) in 20 mL of EtOH was added aq. HBr (48%, 60 mL), the reaction mixture was heated to reflux overnight. After being cooled to rt., the mixture was neutralized by addition of saturated aq. NaHCO 3 , extracted with EtOAc (100 mL ⁇ 3). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated to supply crude III-3 (3 g, 65% yield) as white solid.
  • aq. HBr 48%, 60 mL
  • III-3 (1 eq.) in DCM (0.1 mmol/mL) was added boronic acid III-4 (2 eq.), Cu(OAc) 2 (1 eq), Pyridine (10 eq.) and Pyridine-N-Oxide (2 eq.), followed by addition of 4 ⁇ molecular sieve (quantity approx. equal to III-3).
  • the reaction mixture was stirred at rt under oxygen atmosphere overnight. After completion of the reaction indicated by TLC, the resulting mixture was filtered and washed with, the filtrate was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography on silica gel to give III-5.
  • Compound 24 was prepared following the similar procedure for obtaining Compound 23 using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate in place of V-4 as a yellow oil.
  • Compound 25 was prepared following the similar procedure for obtaining Compound 23 using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in place of V-4 as a yellow oil.
  • VI-2 (226 mg, 1.13 mmol) with aq. HBr (48%, 10 mL) was heated to reflux under nitrogen overnight. After being cooled to r.t., the mixture was neutralized by adding saturated aq. NaHCO 3 , and then extracted with EtOAc (80 mL ⁇ 3). The combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo to afford VI-3 (180 mg, 85% yield).
  • VII-1 (2 g, 20 mmol) was added dropwise to ammonia (7 mL) at ⁇ 70° C.
  • the reaction mixture was stirred at ⁇ 70° C. for 1 hour, and then the reaction mixture was warmed to rt for one additional hour.
  • the organic layer was separated and evaporated to produce VII-2, which was used directly for next step.
  • VII-2 (0.69 g, 10 mmol), VII-3 (1.56 g, 10 mmol), and Na 2 CO 3 (1.06 g, 10 mmol) in water (25 ml) was stirred at rt overnight. And then the mixture was extracted with EtOAc (50 mL ⁇ 3). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by flash chromatography on silica gel with PE/EtOAc (4/1) to yield VII-4 (0.55 g, 24% yield).
  • VIII-3 500 mg, 2.2 mmol, 1.0 eq.
  • VIII-4 (405 mg, 3.3 mmol, 1.5 eq.)
  • Cu(OAc) 2 1.2 g, 6.6 mmol, 3 eq.
  • pyridine-N-oxide 630 mg, 6.6 mmol, 3 eq.
  • pyridine 520 mg, 6.6 mmol, 3 eq.
  • 4 ⁇ molecular sieve 500 mg
  • Compound 35 was prepared following the similar procedure for obtaining Compound 29 using (4-ethoxy-2-methylphenyl)boronic acid in place of phenyl boronic acid (VIII-4) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in place of methyl boronic acid (VIII-6).
  • Compound 36 was prepared following the similar procedure for obtaining Compound 29 using (4-ethoxy-2-methylphenyl)boronic acid in place of phenyl boronic acid (VIII-4) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate in place of methyl boronic acid (VIII-6).
  • Compound 37 was prepared following the similar procedure for obtaining Compound 29 using (4-(trifluoromethoxy)phenyl)boronic acid in place of phenyl boronic acid (VIII-4) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate in place of methyl boronic acid (VIII-6) as white solid. Na 2 CO 3 was replaced with K 3 PO 4 .
  • X-3 (1.0 g, 4 mmol) was dissolved in water (10 mL), and then two drops H 2 O 2 (30%) and 2 drops conc. HCl was added. The mixture was stirred at 100° C. for 15 min under microwave. After being cooled to rt, the reaction mixture was extracted with EtOAc (50 mL ⁇ 3). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated in vacuo to afford X-4 (700 mg, 75% yield). X-4 was used in next step without further purification.
  • XI-6* with various R 1 groups can be prepared following the similar procedure described in the synthesis of XI-6.
  • the last Suzuki-Coupling step was conducted either using Method 1 or Method 2 as described herein.
  • Compounds 571, 572 and 579-581 were prepared by Suzuki-Coupling of XI-6* with the corresponding XI-8* using standard procedure described Method A using K 3 PO 4 in place of K 2 CO 3 .
  • the HCl salts were prepared by reacting the compounds with aq. HCl (1.0M, 1.1 eq) at 0° C. in dioxne for 20 mins then concentrated and dried in vacuo.
  • XII-2 (5.0 g, 18.9 mmol) and aqueous glyoxal (40%, 5 mL) was dissolved in n-BuOH (15 mL), the mixture was stirred at 80° C. for 2 hrs. The reaction mixture was cooled to rt, a solid was precipitated out, filtered, washed with PE and dried in vacuum to afford XII-3 (5.0 g, 92% yield) as a yellow solid, which was used in next step without further purification.
  • XII-3 (5.0 g, 17.3 mmol) and NaOMe (1.4 g, 26 mmol) were dissolved in MeOH (60 mL), and then the mixture was stirred at 60° C. for 0.5 h. Removed the solvent, diluted with EtOAc (100 mL), washed with brine, dried over Na 2 SO 4 and concentrated to give XII-4 (3.7 g, 89% yield) as a light yellow solid, which was used in next step without further purification.
  • Compound 576 was prepared by Suzuki-Coupling of XII-4 and XII-8b using the standard procedure described herein followed by reaction with BBr 3 in DCM. 4-1 NMR (DMSO-d 6 , 300 MHz) ⁇ 12.83 (s, 1H), 9.04 (s, 1H), 8.84 (s, 1H), 8.17 (s, 1H), 7.82 (s, 1H).
  • Compound 578 was prepared following the similar procedure described in the synthesis of Compound 576 using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in place of XII-8b. 4-1 NMR (DMSO-d 6 , 300 MHz) ⁇ 8.99 (s, 1H), 8.80 (s, 1H), 8.27 (s, 1H), 7.93 (s, 1H), 7.84 (s, 1H), 3.88 (s, 3H).
  • XIII-7 was prepared following the similar procedure for obtaining Compound 42 using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (XIII-6) in replace of XI-7. (150 mg, 51% yield). MS (ESI) m/z (M+H) + 228.9.
  • Compound 394 was prepared following the similar procedure for obtaining Compound 392 and using 4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridine in place of XIII-4, XIII-6 in place of XIII-6a, and methyl iodide in place of BnBr.
  • Compound 593 was prepared following the similar procedure for obtaining Compound 48 using XIII-4b in place of XIII-4 The ethylation by EtI and treatment with NaOMe were conducted following the similar procedure described in the synthesis of Compound 592 and XIII-5 After HBr hydrolysis, XIII-7b was subject to two Suzuki-Coupling reactions to afford Compound 593 as a white solid.
  • Compound 615 was obtained as a white solid by reacting Compound 593 with 2-(2-bromoethoxyl)tetrahydro-2H-pyran in the presence of Cs 2 CO 3 in DMF at 50° C., followed by hydroxy deprotection using TsOH in MeOH at 60° C.
  • Compound 614 was obtained by amino deprotection of Compound 596 using KO′Bu, followed by reaction with 2-(2-bromoethoxyl)tetrahydro-2H-pyran in the presence of Cs 2 CO 3 in DMF, then hydroxy deprotection using TsOH in MeOH.
  • Compound 597 was prepared by following the similar procedure for the preparation of Compound 48 using (4-cyanophenyl)boronic acid in place of XIII-10.

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9359379B2 (en) 2012-10-02 2016-06-07 Intermune, Inc. Anti-fibrotic pyridinones
USRE47142E1 (en) 2008-06-03 2018-11-27 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US10150767B2 (en) 2014-11-10 2018-12-11 Genentech, Inc. Therapeutic compounds and uses thereof
US10183009B2 (en) * 2014-11-10 2019-01-22 Genentech, Inc. Therapeutic compounds and uses thereof
US10202378B2 (en) 2015-01-29 2019-02-12 Genentech, Inc. Therapeutic compounds and uses thereof
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones
US10258603B2 (en) 2014-11-10 2019-04-16 Genentech, Inc. Therapeutic compounds and uses thereof
TWI775139B (zh) * 2019-10-03 2022-08-21 美商格芯（美國）集成電路科技有限公司 雙向崩潰矽控整流器

Families Citing this family (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2007009796A (es) 2007-08-14 2009-02-25 Cell Therapy And Technology S Gel conteniendo pirfenidona.
MX346763B (es) 2012-03-28 2017-03-31 Cell Therapy And Tech S A De C V Composición tópica semisólida conteniendo pirfenidona y dialil óxido de disulfuro modificado (odd-m) para eliminar o prevenir el acné.
AU2013276617B9 (en) 2012-06-13 2018-03-29 F. Hoffmann-La Roche Ag New diazaspirocycloalkane and azaspirocycloalkane
SI2900669T1 (sl) 2012-09-25 2019-12-31 F. Hoffmann-La Roche Ag Derivati heksahidropirolo(3,4-C)pirola in sorodne spojine kot zaviralci avtotaksina (ATX) in kot zaviralci tvorbe lizofosfatidne kisline (LPA) za zdravljenje npr. bolezni ledvic
US9315464B1 (en) 2013-01-31 2016-04-19 Nant Holdings Ip, Llc Small molecule inhibitors of influenza A RNA-dependent RNA polymerase
AR095079A1 (es) 2013-03-12 2015-09-16 Hoffmann La Roche Derivados de octahidro-pirrolo[3,4-c]-pirrol y piridina-fenilo
MY187449A (en) 2013-11-26 2021-09-22 Hoffmann La Roche New octahydro-cyclobuta [1,2-c;3,4-c']dipyrrol-2-yl
EP3091976A4 (en) 2014-01-10 2017-10-11 Genoa Pharmaceuticals Inc. Aerosol pirfenidone and pyridone analog compounds and uses thereof
PE20161223A1 (es) 2014-03-26 2016-11-12 Hoffmann La Roche Compuestos condensados de [1,4]diazepina como inhibidores de la produccion de autotaxina (atx) y acido lisofosfatidico (lpa)
DK3122750T3 (da) 2014-03-26 2019-11-04 Hoffmann La Roche Bicykliske forbindelser som autotaxin (ATX)- og lysofosfatidsyre (LPA)-produktionshæmmere
WO2015200341A1 (en) 2014-06-23 2015-12-30 Dr. Reddy's Laboratories Ltd. Substituted imidazo[1,2-a]pyridine compounds useful for the treatment of pain
MA41898A (fr) 2015-04-10 2018-02-13 Hoffmann La Roche Dérivés de quinazolinone bicyclique
MX2018001751A (es) 2015-08-11 2018-08-01 Neomed Inst Dihidroquinolinonas aril-sustituidas, su preparacion y su uso como farmaceuticos.
US10836742B2 (en) 2015-08-11 2020-11-17 Neomed Institute N-substituted bicyclic lactams, their preparation and their use as pharmaceuticals
AU2016305515A1 (en) 2015-08-12 2018-03-08 Neomed Institute Substituted benzimidazoles, their preparation and their use as pharmaceuticals
CN105085383B (zh) * 2015-08-19 2017-09-01 四川大学 5‑甲基‑2(1h)吡啶酮衍生物及其制备方法和用途
JP6886967B2 (ja) 2015-09-04 2021-06-16 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ フェノキシメチル誘導体
BR112018006024A2 (pt) 2015-09-24 2020-05-12 F. Hoffmann-La Roche Ag Compostos bicíclicos como inibidores de atx
MA42923A (fr) 2015-09-24 2021-04-28 Hoffmann La Roche Composés bicycliques comme inhibiteurs mixtes de atx/ca
CN107614505B (zh) 2015-09-24 2021-05-07 豪夫迈·罗氏有限公司 作为双重atx/ca抑制剂的新型二环化合物
JP6876685B2 (ja) 2015-09-24 2021-05-26 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Ａｔｘ阻害剤としての二環式化合物
US10501459B2 (en) 2015-10-21 2019-12-10 Neomed Institute Substituted imidazo[1,2-a]pyridines as bromodomain inhibitors
EP3365337A1 (en) * 2015-10-22 2018-08-29 Selvita S.A. Pyridone derivatives and their use as kinase inhibitors
CN108349987A (zh) * 2015-11-04 2018-07-31 出光兴产株式会社 苯并咪唑稠合杂芳族类
CN105330598B (zh) * 2015-12-02 2017-11-14 新发药业有限公司 一种吡非尼酮的制备方法
US10519151B2 (en) 2016-01-28 2019-12-31 Neomed Institute Substituted [1,2,4]triazolo[4,3-A]pyridines, their preparation and their use as pharmaceuticals
CN105541715B (zh) * 2016-02-02 2019-04-09 浙江工业大学 多取代吡啶-1(2h)-酮衍生物及其合成方法与应用
CN105732497B (zh) * 2016-02-02 2019-02-01 浙江工业大学 2-芳基-4-甲基环并吡啶-1(2h)-酮类衍生物及其合成方法与应用
AU2017251555B2 (en) * 2016-04-14 2021-04-29 Guangzhou Joyo Pharmatech Co., Ltd Pyridone derivative comprising heteroatomic ring butane substituent, for treating fibrosis and inflammatory diseases
RU2741808C2 (ru) 2016-04-15 2021-01-28 Эббви Инк. Ингибиторы бромодомена
WO2018019721A1 (en) 2016-07-26 2018-02-01 Basf Se Herbicidal pyridine compounds
WO2018019755A1 (en) 2016-07-26 2018-02-01 Basf Se Herbicidal pyridine compounds
CN116082225A (zh) * 2016-08-08 2023-05-09 北京康蒂尼药业股份有限公司 一种羟尼酮的制备方法
CN107698498A (zh) * 2016-08-08 2018-02-16 罗楹 一种羟尼酮的制备方法
GB201614934D0 (en) * 2016-09-02 2016-10-19 Glaxosmithkline Intellectual Property (No 2) Ltd Chemical compounds
CN110087651A (zh) * 2016-11-30 2019-08-02 吉宁特有限公司 施用抗纤维化疗法的方法
WO2018167113A1 (en) 2017-03-16 2018-09-20 F. Hoffmann-La Roche Ag New bicyclic compounds as atx inhibitors
RU2019132254A (ru) 2017-03-16 2021-04-16 Ф. Хоффманн-Ля Рош Аг Гетероциклические соединения, пригодные в качестве дуальных ингибиторов atx/ca
US10617680B2 (en) * 2017-04-18 2020-04-14 Celgene Quanticel Research, Inc. Therapeutic compounds
WO2019028062A1 (en) * 2017-07-31 2019-02-07 Washington University PIRFENIDONE DERIVATIVES FOR MODULATION OF B-LYMPHOCYTE ACTIVITY AND PROTECTION OF ORGANS
MX366086B (es) 2017-08-15 2019-06-27 Cell Therapy And Tech S A De C V Composicion topica semisolida conteniendo un agente antimicrobiano y pirfenidona para el tratamiento de daños cronicos de la piel.
US10513515B2 (en) 2017-08-25 2019-12-24 Biotheryx, Inc. Ether compounds and uses thereof
EP3459939A1 (en) * 2017-09-26 2019-03-27 Pragma Therapeutics Novel heterocyclic compounds as modulators of mglur7
CN111278820B (zh) * 2017-10-13 2022-11-08 广州嘉越医药科技有限公司 一种吡啶酮化合物的晶型、盐型及其制备方法
AU2019215172B2 (en) * 2018-02-02 2023-08-10 Genentech, Inc. Pharmaceutical compound, salts thereof, formulations thereof, and methods of making and using same
AU2019309894A1 (en) 2018-07-27 2021-01-28 Biotheryx, Inc. Bifunctional compounds as CDK modulators
CA3160410A1 (en) 2019-12-04 2021-06-10 Idorsia Pharmaceuticals Ltd Combination of an azetidine lpa1 receptor antagonist with pirfenidone and/or nintedanib for use in the treatment of fibrotic diseases
US11897930B2 (en) 2020-04-28 2024-02-13 Anwita Biosciences, Inc. Interleukin-2 polypeptides and fusion proteins thereof, and their pharmaceutical compositions and therapeutic applications
CA3186758A1 (en) * 2020-07-23 2022-01-27 Haiping Wu Compound having kinase inhibitory activity
CN114129517A (zh) * 2020-09-03 2022-03-04 苏州爱科百发生物医药技术有限公司 一种ak3287制剂及其制备方法和应用
MX2023009059A (es) * 2021-02-02 2023-09-15 Liminal Biosciences Ltd Antagonistas de gpr84 y usos de estos.
CN115364097B (zh) * 2021-05-20 2023-07-25 广州嘉越医药科技有限公司 一种含杂原子环丁烷取代基的吡啶酮衍生物的应用
CN113234013B (zh) * 2021-05-21 2022-05-24 杭州医学院 一种抑制胶原合成和沉积的化合物及其应用
WO2023107714A2 (en) * 2021-12-10 2023-06-15 Prothena Biosciences Limited Methods for treating neurological disorders
CN116332947A (zh) * 2021-12-24 2023-06-27 上海海和药物研究开发股份有限公司 具有mat2a抑制活性的嘧啶-2(1h)-酮并二环类化合物及其用途
CN116514803A (zh) * 2022-01-21 2023-08-01 上海赛岚生物科技有限公司 一种激酶抑制剂的盐晶型和自由碱晶型

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007058392A1 (ja) * 2005-11-21 2007-05-24 Japan Tobacco Inc. ヘテロ環化合物およびその医薬用途

Family Cites Families (557)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1070639B (de) 1959-12-10 Farbenfabriken Bayer Aktiengesellschaft, Levenkusen-Bayerwerk Verfahren zur Herstellung von Peptiderj
DE149666C (uk)
CH312530A (de) 1952-06-20 1955-12-31 Ciba Geigy Verfahren zur Herstellung eines Pyridazons.
CH312531A (de) 1952-06-20 1955-12-31 Ciba Geigy Verfahren zur Herstellung eines Pyridazons.
GB788393A (en) 1953-04-30 1958-01-02 Ciba Ltd Process for the manufacture of pyridazone compounds
CH333366A (de) 1953-09-04 1958-10-15 Ciba Geigy Verfahren zur Herstellung neuer Pyridazone
DE1070639C2 (uk) 1958-09-30 1964-04-16
US3014034A (en) 1959-01-22 1961-12-19 Ciba Pharm Prod Inc 1, 3-diaryl, 5-amino-pyridazinones
GB889317A (en) 1959-01-22 1962-02-14 Ciba Ltd New phenyl-diazines and a process for their manufacture
JPS422264Y1 (uk) 1966-08-10 1967-02-10
US3622340A (en) 1968-08-12 1971-11-23 Eastman Kodak Co 4-thiouracil compounds as fog inhibitors
US3644375A (en) * 1968-10-18 1972-02-22 Toray Industries Lactam dicarboxylic acids and process for producing them
GB1237031A (en) * 1969-03-07 1971-06-30 Toray Industries Lactam dicarboxylic acids and a process for their production
UST866035I4 (en) 1969-05-05 1969-09-30 Defensive publication
FR2081572B1 (uk) * 1970-03-12 1973-04-06 Rhone Poulenc Sa
BE787523A (fr) 1971-08-13 1973-02-12 Chem Pharmac Fabrik Dr Hermann Medicament a base de pyridone-2
DE2143744A1 (de) 1971-09-01 1973-03-08 Hoechst Ag 3,4-dihydro-2h-isochinolin-1-one und verfahren zu ihrer herstellung
US4052509A (en) 1972-12-18 1977-10-04 Affiliated Medical Research, Inc. Method for reducing serum uric acid levels
CA1049411A (en) 1972-12-18 1979-02-27 Affiliated Medical Research N-substituted pyridone and general method for preparing pyridones
US4042699A (en) 1972-12-18 1977-08-16 Affiliated Medical Research, Inc. Method for reducing serum glucose levels
US3839346A (en) 1972-12-18 1974-10-01 Affiliated Med Res N-substituted pyridone and general method for preparing pyridones
GB1458049A (en) 1972-12-18 1976-12-08 Affiliated Med Res Process for preparing aryl-substituted pyridones
AT333774B (de) 1974-09-24 1976-12-10 Chemie Linz Ag Verfahren zur herstellung von 3-phenylpyridazonen
JPS51128438A (en) 1975-04-26 1976-11-09 Yamanouchi Pharmaceut Co Ltd An antibacterial drug against fish diseases
DE2557342A1 (de) 1975-12-19 1977-06-30 Hoechst Ag Basisch substituierte indolderivate und verfahren zu ihrer herstellung
US4258052A (en) 1976-08-17 1981-03-24 Yu Ruey J Treatment of psoriasis with nicotinamide analogues
DE2707268A1 (de) 1977-02-19 1978-08-31 Hoechst Ag Indol-3-carbaldehyd-oxime und verfahren zu ihrer herstellung
GB1596887A (en) 1977-07-15 1981-09-03 Rohm & Haas 2-pyridone derivatives and their use as plant growth regulators
JPS557201A (en) 1978-05-23 1980-01-19 Shionogi & Co Ltd Derivative of tetrahydrothiopyrano(2,3-b)indole
GB2044272B (en) 1979-02-05 1983-03-16 Sandoz Ltd Stabilising polymers
DD149666A1 (de) 1979-06-27 1981-07-22 Karl Gewald Verfahren zur herstellung von 6-amino-und 6-hydroxy-1-aryl-5-cyan-2(1h)-pyridinonen und-thionen
JPS5721388A (en) 1980-07-11 1982-02-04 Nippon Nohyaku Co Ltd Condensed pyrazole derivative
JPS5777671A (en) 1980-10-31 1982-05-15 Yasumitsu Tamura Preparation of hydroxyindoles ( or 1,4-dihydroisoquinolones) and their intermediate
US4397854A (en) 1981-05-14 1983-08-09 Warner-Lambert Company Substituted 6-phenyl-3(2H)-pyridazinones useful as cardiotonic agents
US4404203A (en) 1981-05-14 1983-09-13 Warner-Lambert Company Substituted 6-phenyl-3(2H)-pyridazinones useful as cardiotonic agents
US4476307A (en) 1982-09-20 1984-10-09 Pfizer Inc. Heteroylidene indolone compounds
US4473696A (en) 1982-10-07 1984-09-25 Ici Americas Inc. Synthesis of 2-substituted-5-methyl-pyridines
US4645839A (en) 1982-12-17 1987-02-24 Ici Americas Inc. Sulphur dehydrogenation process to yield 5-methyl-2-pyridone
US4650804A (en) 1984-03-30 1987-03-17 Fujisawa Pharmaceutical Co., Ltd. Quinolizinone compounds and pharmaceutical composition comprising the same, useful as anti-ulcerative and anti-allergic agents
US4576942A (en) 1984-07-12 1986-03-18 Usv Pharmaceutical Corp. Anti-allergic and anti-inflammatory bi- and tri- cyclo-1,4-thiazine derivatives, composition, and method of use therefor
DE3583726D1 (de) * 1984-10-30 1991-09-12 Otsuka Pharma Co Ltd 5-fluoruracilderivate.
DE3585869D1 (de) * 1984-10-30 1992-05-21 Otsuka Pharma Co Ltd Zusammensetzung zur steigerung der antikrebsaktivitaet einer antikrebsverbindung.
JPS6256187A (ja) 1985-09-05 1987-03-11 Ricoh Co Ltd 感熱記録材料
US4760083A (en) 1986-04-10 1988-07-26 E. I. Dupont De Nemours & Company 3,3-disubstituted indolines
US5173489A (en) 1986-04-10 1992-12-22 The Dupont Merck Pharmaceutical Co. α,α-disubstituted aromatics and heteroaromatics as cognition enhancers
GB8621217D0 (en) 1986-09-03 1986-10-08 Ici Plc Chemical compounds
DE3805746C2 (de) 1987-03-05 2003-04-10 Clariant Finance Bvi Ltd 1:2-Chromkomplexfarbstoffe
JPS63290821A (ja) 1987-05-25 1988-11-28 Otsuka Pharmaceut Co Ltd 抗不整脈剤
DK641487A (da) 1987-12-07 1989-06-08 Gluetech Aps Fremgangsmaade til modificering af polymeroverflader
DE3807295A1 (de) 1988-03-05 1989-09-14 Basf Ag Neue n-heteroaryl-tetrahydrophthalimidverbindungen
JP2614081B2 (ja) 1988-05-27 1997-05-28 大塚化学株式会社 光学活性β−ラクタム誘導体の製造法
JPH022264A (ja) 1988-06-14 1990-01-08 Canon Inc メツセージ通信システム
US5167941A (en) 1988-11-29 1992-12-01 The Dow Chemical Company Quaternary polyamines as sulfite oxidation inhibitors in amine scrubbing of SO2
US5019365A (en) 1988-11-29 1991-05-28 The Dow Chemical Company Quaternary polyamines as sulfite oxidation inhibitors
GB8901836D0 (en) 1989-01-27 1989-03-15 Sobio Lab Compounds
US5047554A (en) 1989-04-18 1991-09-10 Pfizer Inc. 3-substituted-2-oxindole derivatives
US5077142A (en) 1989-04-20 1991-12-31 Ricoh Company, Ltd. Electroluminescent devices
WO1991000863A1 (en) 1989-07-07 1991-01-24 Pfizer Inc. Heteroaryl piperazine antipsychotic agents
JPH0343744A (ja) 1989-07-12 1991-02-25 Hitachi Chem Co Ltd 電子写真感光体
US5310562A (en) 1989-11-22 1994-05-10 Margolin Solomon B Composition and method for reparation and prevention of fibrotic lesions
US5716632A (en) 1989-11-22 1998-02-10 Margolin; Solomon B. Compositions and methods for reparation and prevention of fibrotic lesions
US5518729A (en) 1989-11-22 1996-05-21 Margolin; Solomon B. Compositions and methods for reparation and prevention of fibrotic lesions
JPH05505610A (ja) 1990-03-27 1993-08-19 スミスクライン・ビーチャム・コーポレイション ５―リポキシゲナーゼ阻害剤
JPH0444235A (ja) 1990-06-08 1992-02-14 New Japan Radio Co Ltd 高速バイポーラトランジスタの製造方法
JPH0449567A (ja) 1990-06-19 1992-02-18 Matsushita Electric Ind Co Ltd 磁気記録再生装置
ES2131506T3 (es) 1990-09-21 1999-08-01 Rohm & Haas Dihidropiridacinonas y piridacinonas como fungicidas.
JPH04223457A (ja) 1990-12-26 1992-08-13 Konica Corp ハロゲン化銀写真感光材料
AU1191292A (en) 1991-02-11 1992-09-07 Schering Agrochemicals Limited Imidazole pesticides
US5491148A (en) * 1991-04-26 1996-02-13 Syntex (U.S.A.) Inc. Isoquinolinone and dihydroisoquinolinone 5-HT3 receptor antagonists
AU658646B2 (en) 1991-05-10 1995-04-27 Rhone-Poulenc Rorer International (Holdings) Inc. Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
HUT67392A (en) 1991-05-15 1995-04-28 Univ Yale Determination of prodrugs metabolizable by the liver and therapeutic use thereof
JPH0519023A (ja) 1991-07-11 1993-01-26 Hitachi Ltd 集積回路装置
DE69115692T2 (de) 1991-09-10 1996-08-01 Agfa Gevaert Nv Thermisch übertragbare fluoreszierende Verbindungen
DK0548680T3 (da) 1991-12-26 1998-09-23 Mitsubishi Chem Corp Beta-oxo-beta-benzenpropanthioamidderivater
US5241065A (en) 1992-02-25 1993-08-31 Schering Corporation 2,3,4,5-tetrahydro-1h-3-benzazepines having anti-psychotic activity
EP0636132A1 (en) 1992-04-16 1995-02-01 The Du Pont Merck Pharmaceutical Company Substituted nitrogen containing spiro compounds for use in treating cognitive deficits
AU4376893A (en) 1992-05-19 1993-12-13 Immunopharmaceutics, Inc. Compounds that modulate endothelin activity
DE4237656A1 (de) 1992-06-13 1993-12-16 Merck Patent Gmbh Benzimidazolderivate
US5459269A (en) * 1992-06-18 1995-10-17 North Carolina State University 14-halo-camptothecins
US5457099A (en) 1992-07-02 1995-10-10 Sawai Pharmaceutical Co., Ltd. Carbostyril derivatives and antiallergic agent
CA2099743A1 (en) 1992-07-02 1994-01-03 Akihiko Ishida Pyridazinone derivatives and processes for preparing the same
US5877278A (en) 1992-09-24 1999-03-02 Chiron Corporation Synthesis of N-substituted oligomers
US5356904A (en) 1992-10-07 1994-10-18 Merck & Co., Inc. Carbostyril oxytocin receptor antagonists
DE4242451A1 (de) 1992-12-16 1994-06-23 Basf Ag Verfahren zur Herstellung von 5-Ringheterocyclen
WO1994017059A1 (en) 1993-01-29 1994-08-04 Nippon Soda Co., Ltd. Heterocyclic derivative
JPH06256187A (ja) 1993-03-02 1994-09-13 Fujisawa Pharmaceut Co Ltd キノリジノン化合物またはその塩を含有する鎮咳・去痰剤
WO1994026249A1 (en) 1993-05-07 1994-11-24 Margolin Solomon B Compositions and methods for reparation and prevention of fibrotic lesions
JP3507124B2 (ja) 1993-05-26 2004-03-15 塩野義製薬株式会社 ベンジリデン誘導体の製造法
DE4423934A1 (de) 1993-09-02 1995-03-09 Basf Ag 3(2H)-Pyridazinon-Derivate, Verfahren zu ihrer Herstellung und Verwendung
RU2146674C1 (ru) 1993-10-15 2000-03-20 Такеда Кемикал Индастриз, Лтд. Производные триазина, способы их получения, антипротозойная композиция, добавка в пищу животных, способ ингибирования протозои у животных
JPH07128793A (ja) 1993-11-05 1995-05-19 Konica Corp 染料の固体微粒子分散物および該分散物を含有するハロゲン化銀写真感光材料
EP0677519A4 (en) 1993-11-10 1996-04-03 Japan Tobacco Inc CHROMAN DERIVATIVE AND THERAPEUTIC USE THEREOF.
DE69430006T2 (de) 1993-12-15 2002-11-28 Smithkline Beecham Corp Verbindungen und verfahren
JPH07233072A (ja) 1993-12-28 1995-09-05 Tanabe Seiyaku Co Ltd 医薬組成物
CN1046724C (zh) 1993-12-29 1999-11-24 藤泽药品工业株式会社 吡唑并吡啶化合物、含有它们的药物组合物、及其制法与用途
JP3781200B2 (ja) 1994-04-27 2006-05-31 コニカミノルタホールディングス株式会社 ハロゲン化銀写真感光材料の処理方法
JP3261641B2 (ja) 1994-04-28 2002-03-04 コニカ株式会社 ハロゲン化銀写真感光材料の処理方法
US5466697A (en) 1994-07-13 1995-11-14 Syntex (U.S.A.) Inc. 8-phenyl-1,6-naphthyridin-5-ones
JP2794392B2 (ja) 1994-07-22 1998-09-03 大同テック株式会社 高圧ガス容器の保守装置
JPH08134371A (ja) 1994-11-02 1996-05-28 Konica Corp 固体微粒子分散物及びハロゲン化銀写真感光材料及び画像形成方法
EP0717143A1 (de) 1994-12-16 1996-06-19 Lignozym GmbH Mehrkomponentensystem zum Verändern, Abbau oder Bleichen von Lignin, ligninhaltigen Materialien oder ähnlichen Stoffen sowie Verfahren zu seiner Anwendung
US6323201B1 (en) 1994-12-29 2001-11-27 The Regents Of The University Of California Compounds for inhibition of ceramide-mediated signal transduction
ATE265851T1 (de) 1995-03-03 2004-05-15 Solomon B Margolin Behandlung von erkrankungen, die vom cytokinwachstumsfaktor verursacht werden
US6090822A (en) 1995-03-03 2000-07-18 Margolin; Solomon B. Treatment of cytokine growth factor caused disorders
US6114353A (en) 1995-03-03 2000-09-05 Margolin; Solomon B. Compositions and method for treatment of lymphomas, leukemias, and leiomyomas
US5869428A (en) 1995-03-13 1999-02-09 Ishihara Sangyo Kaisha Ltd. Pyridonesulfonylurea compounds, process for their production and herbicides containing them
US5635494A (en) 1995-04-21 1997-06-03 Rohm And Haas Company Dihydropyridazinones and pyridazinones and their use as fungicides and insecticides
WO1996033994A1 (fr) 1995-04-28 1996-10-31 Nippon Soda Co., Ltd. Derives amino-substitues, leur procede de preparation et herbicide
DE19520613A1 (de) 1995-06-06 1996-12-12 Bayer Ag Phenylpyridazinone
JPH0933072A (ja) 1995-07-18 1997-02-07 Hitachi Ltd 蓄熱水槽及びマルチ氷蓄熱ユニット
EP0842176A1 (en) 1995-07-31 1998-05-20 Novo Nordisk A/S Heterocyclic compounds, their preparation and use
JPH11509847A (ja) 1995-07-31 1999-08-31 ノボ ノルディスク アクティーゼルスカブ ヘテロ環式化合物、それらの調製及び使用
AU723064B2 (en) 1995-08-25 2000-08-17 Dow Agrosciences Llc Compositions having synergistic fungitoxic effects
BR9610480A (pt) 1995-09-19 1999-03-16 Solomon Begelfor Margolin Inibição do fator alfa de necrose tumoral
US5962478A (en) 1995-09-19 1999-10-05 Margolin; Solomon B. Inhibition of tumor necrosis factor α
DE19535501A1 (de) 1995-09-25 1997-03-27 Bayer Ag Pyridonmethidazofarbstoffe
JPH0995165A (ja) 1995-09-29 1997-04-08 Tachi S Co Ltd シートの前後チルト機構
JPH0995166A (ja) 1995-10-02 1997-04-08 Tatsuya Mikami 乗物用座席
JPH09249567A (ja) 1996-01-12 1997-09-22 Otsuka Pharmaceut Co Ltd 医薬組成物
JPH09204932A (ja) 1996-01-25 1997-08-05 Fujitsu Ltd リチウム二次電池用電解液及びリチウム二次電池
IT1286545B1 (it) 1996-02-09 1998-07-15 Antonio Guarna Derivati benzo(c) chinolizinici,loro preparazione ed uso come inibitori delle 5-alfa-riduttasi
JPH09244235A (ja) 1996-03-14 1997-09-19 Toshiba Corp アルカリ現像用レジスト
WO1997036863A1 (en) 1996-03-29 1997-10-09 Merck Frosst Canada Inc. Bisarylcyclobutene derivates as cyclooxygenase inhibitors
GB9607503D0 (en) 1996-04-11 1996-06-12 Merck Frosst Canada Inc Bisaryl cyclobutenes derivatives as cyclooxygenase inhibitors
JPH09319023A (ja) 1996-05-27 1997-12-12 Fuji Photo Film Co Ltd 感熱記録材料
JP3418624B2 (ja) 1996-06-10 2003-06-23 メルク エンド カンパニー インコーポレーテッド サイトカイン阻害活性を有する置換イミダゾール類
AU4778097A (en) 1996-09-26 1998-04-17 Novartis Ag Herbicidal composition
US6121251A (en) 1996-10-11 2000-09-19 Rohm And Haas Company Dihydropyridazinones and pyridazinones and their use as fungicides and insecticides
US5977134A (en) 1996-12-05 1999-11-02 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
DE19754348A1 (de) 1996-12-11 1998-06-18 Ciba Geigy Ag Neue Herbizide
CA2276150A1 (en) 1996-12-30 1998-07-09 Steven D. Young Inhibitors of farnesyl-protein transferase
US5855654A (en) 1997-01-30 1999-01-05 Rohm And Haas Company Pyridazinones as marine antifouling agents
US6117973A (en) 1997-02-24 2000-09-12 Georgia Tech Research Corp. PNA monomers with electron donor or acceptor
DE19708928A1 (de) 1997-03-05 1998-09-10 Bayer Ag Substituierte aromatische Aminoverbindungen
WO1998051772A1 (de) 1997-05-12 1998-11-19 Call, Krimhild Enzymatisches bleichsystem mit neuen enzymwirkungsverstärkenden verbindungen
DE19821263A1 (de) 1997-05-12 1998-11-19 Call Krimhild Enzymatisches Bleichsystem mit enzymwirkungsverstärkenden Verbindungen zur Behandlung von Textilien
JP3043744U (ja) 1997-05-26 1997-11-28 株式会社新和 バッグ
DE19726241A1 (de) 1997-06-20 1998-12-24 Call Krimhild Erweitertes enzymatisches Multikomponentensystem zur Behandlung von Abwässern, zur Herstellung von Holzverbundstoffen, zum Deinken von Altpapier, Colour stripping von Altpapier, zum Einsatz als Oxidationssystem bei der organischen Synthese und zum Einsatz bei der Kohleverflüssigung
DE19729061A1 (de) 1997-07-08 1999-01-14 Agfa Gevaert Ag Farbfotografisches Aufzeichnungsmaterial
SE9702651D0 (sv) 1997-07-09 1997-07-09 Astra Pharma Prod Novel compounds
DE19731784A1 (de) 1997-07-24 1999-02-04 Bayer Ag Substituierte N-Aryl-N-thioxocarbonyl-sulfonamide
SE9702794D0 (sv) 1997-07-24 1997-07-24 Astra Pharma Prod New compounds
JPH1149755A (ja) 1997-07-30 1999-02-23 Nippon Kayaku Co Ltd 新規含窒素ヘテロ環誘導体およびそれを有効成分とする殺虫殺ダニ組成物
ITFI970193A1 (it) 1997-08-01 1999-02-01 Applied Research Systems Uso di derivati benzo(c) chinolizinici come regolatori della crescita delle piante e composizioni ad uso agricolo che contengono tali
US6307047B1 (en) 1997-08-22 2001-10-23 Abbott Laboratories Prostaglandin endoperoxide H synthase biosynthesis inhibitors
EP1007515A1 (en) 1997-08-22 2000-06-14 Abbott Laboratories Arylpyridazinones as prostaglandin endoperoxide h synthase biosynthesis inhibitors
JP2002511887A (ja) 1997-08-22 2002-04-16 アボツト・ラボラトリーズ プロスタグランジンエンドペルオキシドｈシンターゼ生合成阻害薬
WO1999012903A1 (en) 1997-09-09 1999-03-18 Du Pont Pharmaceuticals Company Benzimidazolinones, benzoxazolinones, benzopiperazinones, indanones, and derivatives thereof as inhibitors of factor xa
US6355799B1 (en) 1997-10-27 2002-03-12 Isk Americas Incorporated Substituted benzene compounds, process for their preparation, and herbicidal and defoliant compositions containing them
WO1999026944A1 (en) 1997-11-21 1999-06-03 Astrazeneka Uk Limited New compounds which are p2-purinoceptor 7-transmembrane (tm) g-protein coupled receptor antagonists
US6174901B1 (en) 1998-12-18 2001-01-16 Amgen Inc. Substituted pyridine and pyridazine compounds and methods of use
JPH11180952A (ja) 1997-12-19 1999-07-06 Maruho Co Ltd ２−オキシインドール誘導体
ES2304797T3 (es) 1997-12-19 2008-10-16 Amgen Inc. Compuestos de piridina y piridazina sustituidos y su uso farmaceutico.
AU2108099A (en) * 1998-01-30 1999-08-16 Procept, Inc. Immunosuppressive agents
DE19803667A1 (de) 1998-01-30 1999-08-05 Max Planck Gesellschaft Verfahren zur Herstellung von 5-Alkoxy (bzw. 5-Aroxy) -2,3-dihydrofuran-2-onen
FR2774986A1 (fr) 1998-02-16 1999-08-20 Rhodia Chimie Sa Utilisation de pyrone(s) ou equivalent pour masquer des isocyanates, procede de masquage, isocyanates ainsi masques, composition en contenant, procede de revetement utilisant ces compositions, revetement aini obtenu
ATE266405T1 (de) 1998-03-17 2004-05-15 Solomon B Margolin Topische antiseptische zusammenstellungen und methoden
IL136605A0 (en) 1998-03-31 2001-06-14 Warner Lambert Co Quinolones as serine protease inhibitors
JP2002511452A (ja) 1998-04-09 2002-04-16 バイエル アクチェンゲゼルシャフト 置換フェニルピリダジノン類
AU3536699A (en) 1998-04-27 1999-11-16 Ihara Chemical Industry Co. Ltd. 3-arylphenyl sulfide derivatives and insecticides and miticides
BR9909976A (pt) 1998-04-27 2000-12-26 Centre Nat Rech Scient Composto, processo para a obtenção de compostos, derivado litiado, composições farmacêuticas, e, processos de tratamento de doenças relacionadas com hiv e de tratamento de infecção de hiv
US6521656B1 (en) 1998-06-01 2003-02-18 Fujisawa Pharmaceutical Co., Ltd. Remedies for male sterility
FR2779429B1 (fr) 1998-06-03 2000-07-13 Synthelabo Derives d'oxindole, leurs preparations et leurs applications en therapeutique
DE19826671A1 (de) 1998-06-16 1999-12-23 Hoechst Schering Agrevo Gmbh 1,3-Oxazolin- und 1,3-Thiazolin-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Schädlingsbekämpfungsmittel
US6492395B1 (en) 1998-09-18 2002-12-10 Mepha Ag Topical formulation of alkyl-, phenyl-pyridone
WO2000025789A1 (en) 1998-10-29 2000-05-11 Merck & Co., Inc. A method of treating endometriosis
JP3043744B1 (ja) 1999-03-17 2000-05-22 日本ピラー工業株式会社 単結晶ＳｉＣの育成方法
US6586447B1 (en) 1999-04-01 2003-07-01 Pfizer Inc 3,3-disubstituted-oxindole derivatives useful as anticancer agents
DE19918725A1 (de) 1999-04-24 2000-10-26 Bayer Ag Substituierte N-Cyano-sulfonsäureanilide
US6972296B2 (en) * 1999-05-07 2005-12-06 Encysive Pharmaceuticals Inc. Carboxylic acid derivatives that inhibit the binding of integrins to their receptors
US6723711B2 (en) 1999-05-07 2004-04-20 Texas Biotechnology Corporation Propanoic acid derivatives that inhibit the binding of integrins to their receptors
EP1189881B2 (en) 1999-05-07 2013-01-23 Encysive Pharmaceuticals, Inc. Propanoic acid derivatives that inhibit the binding of integrins to their receptors
WO2001012600A1 (en) 1999-08-12 2001-02-22 Cor Therapeutics, Inc. INHIBITORS OF FACTOR Xa
FR2797629B1 (fr) 1999-08-19 2001-09-21 Rhodia Chimie Sa Utilisation de pyrone(s) ou equivalent pour masquer des isocyanates, procede de masquage, isocyanates ainsi masques, composition en contenant, procede de revetement utilisant ces compositions, revetement ainsi obtenu
AT408223B (de) 1999-12-27 2001-09-25 Dsm Fine Chem Austria Gmbh Verfahren zur herstellung von oxindolen
ATE327230T1 (de) 2000-01-20 2006-06-15 Eisai Co Ltd Piperidinverbindungen und diese enthaltenden medikamente
EP1255741A2 (en) 2000-02-01 2002-11-13 Cor Therapeutics, Inc. 2- 1H]-QUINOLONE AND 2- 1H]-QUINOXALONE INHIBITORS OF FACTOR Xa
EP1263754A1 (en) 2000-02-01 2002-12-11 Millennium Pharmaceuticals, Inc. INDALONE AND BENZIMIDAZOLONE INHIBITORS OF FACTOR Xa
US6906063B2 (en) 2000-02-04 2005-06-14 Portola Pharmaceuticals, Inc. Platelet ADP receptor inhibitors
CA2400479C (en) 2000-02-04 2010-10-05 Millennium Pharmaceuticals, Inc. Platelet adp receptor inhibitors
GB0002740D0 (en) 2000-02-07 2000-03-29 Novartis Ag Organic compounds
AU2001230605A1 (en) 2000-02-09 2001-08-20 Shionogi And Co., Ltd. Apoptosis inhibitor
TR200202033T2 (tr) 2000-02-21 2003-01-21 Cymar Inc. Epilepsi Tedavisi İçin Terkipler ve Yöntemler
CA2404226A1 (en) 2000-03-23 2001-09-27 Takeda Chemical Industries, Ltd. Furoisoquinoline derivatives, process for producing the same and use thereof
WO2001072708A2 (en) 2000-03-24 2001-10-04 Cor Therapeutics, Inc. OXINDOLE INHIBITORS OF FACTOR Xa
DE10024938A1 (de) 2000-05-19 2001-11-22 Bayer Ag Substituierte Iminoazine
US20030194748A1 (en) 2000-05-29 2003-10-16 Tohru Nagasaki Method for labeling with tritium
DE60137426D1 (de) 2000-06-12 2009-03-05 Eisai R&D Man Co Ltd 1,2-dihydropyridinverbindungen, verfahren zu deren herstellung und deren verwendung
DE10034803A1 (de) 2000-07-18 2002-01-31 Bayer Ag Substituierte Sulfonsäureanilide
EP1308441B1 (en) 2000-08-11 2009-10-07 Eisai R&D Management Co., Ltd. 2-aminopyridine compounds and use thereof as drugs
US20020049211A1 (en) 2000-09-06 2002-04-25 Sobolov-Jaynes Susan Beth Combination treatment for depression and anxiety
AU2001290229B2 (en) 2000-09-18 2006-12-07 Eisai R&D Management Co., Ltd. Pyridazinones and triazinones and medicinal use thereof
JP2004509867A (ja) 2000-09-19 2004-04-02 サントル、ナショナール、ド、ラ、ルシェルシュ、シアンティフィク、（セーエヌエルエス） Ｈｉｖ阻害特性を有するピリジノンおよびピリジンチオン誘導体
CN1120151C (zh) 2000-10-24 2003-09-03 大连化学工业股份有限公司 制备内酰胺的方法
WO2002067675A2 (en) 2000-10-27 2002-09-06 Dow Agrosciences Llc Substituted 4,5-dihydro-1,2,4-triazin-6-ones, 1,2,4-triazin-6-ones, and their use as fungicides and insecticides
HUP0500543A2 (hu) 2000-11-20 2005-09-28 Bristol-Myers Squibb Company Piridonszármazékok mint aP2 inhibitorok és a vegyületeket tartalmazó gyógyszerkészítmények
US7160912B2 (en) 2000-12-26 2007-01-09 Dr.Reddy's Laboratories Ltd. Heterocyclic compounds having antibacterial activity: process for their preparation and pharmaceutical compositions containing them
YU52403A (sh) 2000-12-26 2006-03-03 Dr.Reddy's Research Foundation Heterociklična jedinjenja koja imaju antibakterijsko dejstvo, postupak za njihovo dobijanje i farmaceutske smeše koje ih sadrže
KR100828982B1 (ko) 2000-12-28 2008-05-14 시오노기세이야쿠가부시키가이샤 칸나비노이드 2형 수용체 친화 작용을 갖는 피리돈 유도체
WO2002060446A1 (en) 2001-01-29 2002-08-08 Shionogi & Co., Ltd. Medicinal preparation containing 5-methyl-1-phenyl-2-(1h)-pyridone as active ingredient
EP1368366A1 (en) * 2001-02-07 2003-12-10 Celltech R & D Limited Non-natural nucleotides and dinucleotides
DE10108995A1 (de) 2001-02-23 2002-09-05 Abbott Gmbh & Co Kg Substituierte Pyrimidinon-Derivate als Liganden von Integrinrezeptoren
JPWO2002085858A1 (ja) 2001-04-20 2004-08-12 旭硝子株式会社 精製されたピペリジン誘導体の製造方法
DE60218458T2 (de) 2001-05-08 2007-11-15 Kudos Pharmaceuticals Ltd. Isochinolinon derivate als parp inhibitoren
AU2002316180A1 (en) 2001-06-01 2002-12-16 The Regents Of The University Of California Inhibitors of cell proliferation, angiogenesis, fertility, and muscle contraction
JP2002371078A (ja) 2001-06-12 2002-12-26 Sankyo Co Ltd キノリン誘導体及びキノロン誘導体
JP4180254B2 (ja) 2001-06-29 2008-11-12 独立行政法人科学技術振興機構 窒素含有６員環の製造方法
JP2003021901A (ja) 2001-07-05 2003-01-24 Fuji Photo Film Co Ltd 感光性平版印刷版の光重合方法
JP4342940B2 (ja) 2001-08-06 2009-10-14 塩野義製薬株式会社 ５−メチル−１−フェニル−２（１ｈ）ピリジノンの製造方法
WO2003035650A1 (fr) 2001-09-25 2003-05-01 Takeda Chemical Industries, Ltd. Inhibiteur d'entree
GB0124848D0 (en) 2001-10-16 2001-12-05 Celltech R&D Ltd Chemical compounds
TWI301834B (en) 2001-10-22 2008-10-11 Eisai R&D Man Co Ltd Pyrimidone compound and pharmaceutical composition including the same
TWI330183B (uk) 2001-10-22 2010-09-11 Eisai R&D Man Co Ltd
CN1257901C (zh) 2001-11-08 2006-05-31 中国科学院上海药物研究所 一类四氢喹啉酮哌啶类化合物及其制备方法和用途
US7030141B2 (en) 2001-11-29 2006-04-18 Christopher Franklin Bigge Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade
GB0129260D0 (en) 2001-12-06 2002-01-23 Eisai London Res Lab Ltd Pharmaceutical compositions and their uses
GB0129391D0 (en) 2001-12-07 2002-01-30 Syngenta Participations Ag Microbiocidal n-phenyl-n-[4-(4-pyridyl)-2-pyrimidin-2-yl]-amine derivatives
JP2005170790A (ja) 2002-01-09 2005-06-30 Ajinomoto Co Inc Ｎ−アルキルスルフォニル置換アミド誘導体
BR0306988A (pt) 2002-01-18 2004-11-23 Pharmacia Corp Piridazinonas substituìdas como inibidores de p38
ES2334990T3 (es) 2002-02-14 2010-03-18 Pharmacia Corporation Piridinonas sustituidas como moduladores de p38 map quinasa.
JP2003238611A (ja) 2002-02-18 2003-08-27 Japan Polyolefins Co Ltd オレフィン類重合用触媒成分、オレフィン類重合用触媒及びポリオレフィン類の製造方法
WO2003070277A1 (fr) 2002-02-19 2003-08-28 Shionogi & Co., Ltd. Antiprurigineux
JP2003261535A (ja) 2002-03-08 2003-09-19 Mitsubishi Chemicals Corp ２−ヒドロキシ−５−メチルピリジンの製造方法
US20060046999A1 (en) 2002-03-14 2006-03-02 Cristina Alonso-Alija Monocyclic aroylpyridinones as antiinflammatory agents
WO2003082265A2 (en) 2002-04-02 2003-10-09 Fujisawa Pharmaceutical Co Pharmaceutical composition for treating or preventing virus infectious diseases
GB0210127D0 (en) 2002-05-02 2002-06-12 Merck Sharp & Dohme Therapeutic agents
WO2003097062A1 (en) 2002-05-13 2003-11-27 Merck & Co., Inc. Phenyl substituted imidazopyridines and phenyl substituted benzimidazoles
JP2004043458A (ja) 2002-05-22 2004-02-12 Kyorin Pharmaceut Co Ltd ４−アリール−５−ヒドロキシイソキノリン誘導体およびその製造法
CN1218942C (zh) 2002-06-11 2005-09-14 中南大学湘雅医学院 抗纤维化吡啶酮化合物及其生产工艺方法
JP2005532368A (ja) 2002-06-12 2005-10-27 アボット・ラボラトリーズ メラニン濃縮ホルモン受容体の拮抗薬
US20040006135A1 (en) 2002-06-19 2004-01-08 Pfizer Inc. Combination treatment for depression and anxiety
GB0214268D0 (en) 2002-06-20 2002-07-31 Celltech R&D Ltd Chemical compounds
GB0215293D0 (en) 2002-07-03 2002-08-14 Rega Foundation Viral inhibitors
AU2003249244A1 (en) 2002-07-15 2004-02-02 Combinatorx, Incorporated Methods for the treatment of neoplasms
ATE505462T1 (de) 2002-07-22 2011-04-15 Orchid Res Lab Ltd Neue biologischaktive molekü le
WO2004009556A1 (ja) * 2002-07-24 2004-01-29 Kyorin Pharmaceutical Co., Ltd. ４−置換アリール−５−ヒドロキシイソキノリノン誘導体
GB0218630D0 (en) 2002-08-10 2002-09-18 Tanabe Seiyaku Co Novel compounds
EP1537098A1 (en) 2002-08-13 2005-06-08 Warner-Lambert Company LLC Monocyclic derivatives as matrix metalloproteinase inhibitors
US20060110358A1 (en) 2002-08-28 2006-05-25 Hsu Henry H Combination therapy for treatment of fibrotic disorders
AU2003264386A1 (en) 2002-09-10 2004-04-30 Kyorin Pharmaceutical Co., Ltd. 4-(substituted aryl)-5-hydroxyisoquinolinone derivative
AU2003267098B2 (en) 2002-09-11 2008-11-20 Merck & Co., Inc. Dihydroxypyridopyrazine-1,6-dione compounds useful as HIV integrase inhibitors
CH696420A5 (de) 2002-09-13 2007-06-15 Mepha Ag Neue stabile Zubereitungen von Alkyl-, Phenyl-Pyridonen für topische Anwendung.
EP1400243A1 (en) 2002-09-19 2004-03-24 Tanabe Seiyaku Co., Ltd. Calcium-activated K channel activator
GB0222743D0 (en) 2002-10-01 2002-11-06 Celltech R&D Ltd Chemical compounds
EP1558606A4 (en) 2002-10-02 2008-05-07 Bristol Myers Squibb Co DIAMINOALKYL CONTAINING LACTAM, BETA AMINO ACIDS, ALPHA AMINO ACIDS AND DERIVATIVES THEREOF AS FACTOR XA INHIBITORS
AU2003274022A1 (en) * 2002-10-17 2004-05-04 Syngenta Participations Ag 3-heterocyclylpyridine derivatives useful as herbicides
AU2003274652A1 (en) 2002-10-23 2004-05-13 Obetherapy Biotechnology Compounds, compositions and methods for modulating fat metabolism
US6930117B2 (en) 2002-11-09 2005-08-16 The Procter & Gamble Company N-alkyl-4-methyleneamino-3-hydroxy-2-pyridones
AR042206A1 (es) 2002-11-26 2005-06-15 Novartis Ag Acidos fenilaceticos y derivados
JP4542743B2 (ja) 2002-12-26 2010-09-15 Ｋｄｌ株式会社 ピリドン誘導体の溶液状医薬組成物
US7144911B2 (en) 2002-12-31 2006-12-05 Deciphera Pharmaceuticals Llc Anti-inflammatory medicaments
US7202257B2 (en) 2003-12-24 2007-04-10 Deciphera Pharmaceuticals, Llc Anti-inflammatory medicaments
US20040142950A1 (en) 2003-01-17 2004-07-22 Bunker Amy Mae Amide and ester matrix metalloproteinase inhibitors
US7618974B2 (en) 2003-01-31 2009-11-17 Vertex Pharmaceuticals Incorporated Gyrase inhibitors and uses thereof
US7569591B2 (en) 2003-01-31 2009-08-04 Vertex Pharmaceuticals Incorporated Gyrase inhibitors and uses thereof
AR042956A1 (es) 2003-01-31 2005-07-13 Vertex Pharma Inhibidores de girasa y usos de los mismos
US7582641B2 (en) 2003-01-31 2009-09-01 Vertex Pharmaceuticals Incorporated Gyrase inhibitors and uses thereof
US20040157738A1 (en) 2003-02-12 2004-08-12 Ishihara Sangyo Kaisha, Ltd. Novel oxygen containing fused cyclic derivatives and herbicidal, desiccant and defoliate compositions containing them
CL2004000234A1 (es) * 2003-02-12 2005-04-15 Biogen Idec Inc Compuestos derivados 3-(piridin-2-il)-4-heteroaril-pirazol sustituidos, antagonistas de aik5 y/o aik4; composicion farmaceutica y uso del compuesto en el tratamiento de desordenes fibroticos como esclerodermia, lupus nefritico, cicatrizacion de herid
AU2004212957A1 (en) 2003-02-14 2004-09-02 Smithkline Beecham Corporation Novel compounds
US7012088B2 (en) 2003-02-24 2006-03-14 Pharmacia & Upjohn Company Indolone oxazolidinones and derivatives thereof
AU2004218474A1 (en) 2003-02-28 2004-09-16 Dekk-Tec, Inc. Resonance modulator for diagnosis and therapy
US20070072181A1 (en) 2003-02-28 2007-03-29 Blatt Lawrence M Combination therapy for treating alphavirus infection and liver fibrosis
JP2004269469A (ja) 2003-03-12 2004-09-30 Yamanouchi Pharmaceut Co Ltd ピリミジン誘導体又はその塩
JP4699358B2 (ja) 2003-04-08 2011-06-08 ビーエーエスエフ ソシエタス・ヨーロピア 除草剤又は乾燥性及び／若しくは落葉性化合物としてのベンゼンスルホンアミド誘導体
JP4089491B2 (ja) 2003-04-14 2008-05-28 コニカミノルタホールディングス株式会社 重合開始剤、重合組成物、ラジカル発生方法、平版印刷版材料および平版印刷版の作製方法
WO2004105684A2 (en) 2003-05-16 2004-12-09 Intermune, Inc. Combination therapy for proliferative disorders
US20070092488A1 (en) 2003-05-16 2007-04-26 Intermune Inc. Methods of treating idiopathic pulmonary fibrosis
US20070032457A1 (en) 2003-05-16 2007-02-08 Blatt Lawrence M Combination therapy for cancer treatment
JP2004359641A (ja) 2003-06-06 2004-12-24 Ono Pharmaceut Co Ltd Ｃｃｒ５活性化剤
US20080025986A1 (en) 2003-06-06 2008-01-31 Ozes Osman N Methods of Treating Tnf-Mediated Disorders
KR20060021905A (ko) 2003-06-20 2006-03-08 셀테크 알앤디 리미티드 키나아제 억제제로서의 티에노피리돈 유도체
JP2007516162A (ja) 2003-06-20 2007-06-21 セルテック アール アンド ディ リミテッド キナーゼ阻害剤としてのチエノピリドン誘導体
WO2005000818A1 (en) 2003-06-27 2005-01-06 Warner-Lambert Company Llc 5-substituted-4-`(substituted phenyl)!amino!-2-pyridone deviatives for use as mek inhibitors
JP2005013152A (ja) 2003-06-27 2005-01-20 Asahi Kasei Corp 細胞分化抑制剤及びこれを用いた細胞培養方法、培養液、培養された細胞
EP1640449A4 (en) 2003-06-27 2009-03-25 Asahi Chemical Ind CELL DIFFERENTIATION INHIBITOR AGENT, CELL CULTURE METHOD USING THE SAME, CULTURE MEDIUM AND CULTIVATED CELL LINE
US20060025337A1 (en) 2003-07-01 2006-02-02 President And Fellows Of Harvard College Sirtuin related therapeutics and diagnostics for neurodegenerative diseases
EP2236131A3 (en) 2003-07-01 2011-03-02 President and Fellows of Harvard College Sirt1 modulators for manipulating cell/organism lifespan/stress response
WO2005007632A1 (en) 2003-07-18 2005-01-27 Pharmacia Corporation Substituted pyridazinones as inhibitors of p38
TW200517381A (en) 2003-08-01 2005-06-01 Genelabs Tech Inc Bicyclic heteroaryl derivatives
NL1026826C2 (nl) 2003-08-13 2007-01-04 Pharmacia Corp Gesubstitueerde pyridinonen.
US7405300B2 (en) 2003-09-04 2008-07-29 Aventis Pharmaveuticals Inc. Substituted indoles as inhibitors of poly (ADP-ribose) polymerase (PARP)
WO2005030751A2 (en) 2003-09-08 2005-04-07 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
SE0302486D0 (sv) 2003-09-18 2003-09-18 Astrazeneca Ab Novel compounds
SE0302487D0 (sv) 2003-09-18 2003-09-18 Astrazeneca Ab Novel compounds
DE10345648A1 (de) 2003-10-01 2005-04-21 Studiengesellschaft Kohle Mbh Verfahren zur Herstellung von TMC-69-6H und verwandten Pyridonderivaten und deren Verwendung als Phosphatase-Inhibitoren
WO2005040758A2 (en) 2003-10-24 2005-05-06 Intermune, Inc. Use of pirfenidone in therapeutic regimens
WO2005039598A1 (en) 2003-10-24 2005-05-06 Intermune, Inc. Method of treating alcoholic liver disease
CA2545813C (en) 2003-11-14 2011-01-04 Shanghai Genomics, Inc. The derivatives of pyridone and use thereof
JP4170198B2 (ja) 2003-11-14 2008-10-22 一丸ファルコス株式会社 化粧料組成物
WO2005051906A2 (en) 2003-11-19 2005-06-09 Array Biopharma Inc. Heterocyclic inhibitors of mek and methods of use thereof
US7732616B2 (en) 2003-11-19 2010-06-08 Array Biopharma Inc. Dihydropyridine and dihydropyridazine derivatives as inhibitors of MEK and methods of use thereof
US7517994B2 (en) 2003-11-19 2009-04-14 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
EP1690863A1 (en) * 2003-11-26 2006-08-16 Dainippon Sumitomo Pharma Co., Ltd. Novel condensed imidazole derivative
DE10358004A1 (de) 2003-12-11 2005-07-14 Abbott Gmbh & Co. Kg Ketolactam-Verbindungen und ihre Verwendung
US20070191336A1 (en) 2003-12-24 2007-08-16 Flynn Daniel L Anti-inflammatory medicaments
BRPI0507180A (pt) 2004-01-29 2007-06-26 Pfizer derivados de 1-isopropil-2-oxo-1,2-diidropiridina-3-carboxamida tendo atividade agonìstica de receptor 5-ht4
GB0402812D0 (en) 2004-02-09 2004-03-10 Tanabe Seiyaku Co Novel compounds
JP2005255675A (ja) 2004-02-09 2005-09-22 Tanabe Seiyaku Co Ltd 医薬組成物
US7872123B2 (en) 2004-02-20 2011-01-18 Japan Science And Technology Agency Process of making α-aminooxyketone/α-aminooxyaldehyde and α-hydroxyketone/α-hydroxyaldehyde compounds and a process making reaction products from cyclic α,β-unsaturated ketone substrates and nitroso substrates
JPWO2005085200A1 (ja) 2004-03-05 2008-01-17 萬有製薬株式会社 ピリドン誘導体
PE20060285A1 (es) 2004-03-30 2006-05-08 Aventis Pharma Inc Piridonas sustituidas como inhibidores de pol(adp-ribosa)-polimerasa (parp)
EP1732541A4 (en) 2004-04-07 2008-03-05 Takeda Pharmaceutical CYCLIC COMPOUNDS
WO2005096784A2 (en) 2004-04-08 2005-10-20 Targegen, Inc. Benzotriazine inhibitors of kinases
EP1741702A1 (en) 2004-04-28 2007-01-10 Ono Pharmaceutical Co., Ltd. Nitrogen-containing heterocyclic compounds and medicinal use thereof
MY143245A (en) 2004-04-28 2011-04-15 Mitsubishi Tanabe Pharma Corp 4- 2-(cycloalkylamino)pyrimidin-4-yl-(phenyl)-imidazolin-2-one derivatives as p38 map-kinase inhibitors for the treatment of inflammatory diseases
DE102004028973A1 (de) * 2004-06-16 2006-01-05 Sanofi-Aventis Deutschland Gmbh Substituierte Tetrahydro-2H-isochinolin-1-on-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Medikament
US7696352B2 (en) 2004-06-18 2010-04-13 Millennium Pharmaceuticals, Inc. Factor Xa inhibitors
JP5020073B2 (ja) 2004-06-18 2012-09-05 ミレニアム ファーマシューティカルズ インク． 第Ｘａ因子阻害剤
MY148809A (en) 2004-07-06 2013-05-31 Eisai R&D Man Co Ltd Crystals of 1,2-dihydropyridine compound and their production process
US20090054358A1 (en) 2004-07-19 2009-02-26 The John Hopkins University Flt3 inhibitors for immune suppression
WO2006011024A2 (en) 2004-07-19 2006-02-02 Glenmark Pharmaceuticals Ltd. New tricyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
AR050365A1 (es) 2004-08-02 2006-10-18 Osi Pharm Inc Compuestos inhibidores de multi- quinasa pirrolopirimidina aril- amino sustituidos.
CA2578628A1 (en) 2004-08-31 2006-03-09 Biogen Idec Ma Inc. Pyrimidinylpyrazoles as tgf-beta inhibitors
GB0420722D0 (en) 2004-09-17 2004-10-20 Addex Pharmaceuticals Sa Novel allosteric modulators
US7694674B2 (en) * 2004-09-21 2010-04-13 Carleton Life Support Systems, Inc. Oxygen generator with storage and conservation modes
EA012452B1 (ru) 2004-09-22 2009-10-30 Янссен Фармацевтика Н.В. Ингибиторы взаимодействия между mdm2 и р53
US20060069260A1 (en) 2004-09-28 2006-03-30 Huiping Zhang Preparation of N-aryl pyridones
JP4223457B2 (ja) 2004-10-06 2009-02-12 本田技研工業株式会社 車両の電動ステアリング装置
WO2006038734A1 (en) 2004-10-08 2006-04-13 Astellas Pharma Inc. Pyridazinone derivatives cytokines inhibitors
AU2005295902A1 (en) 2004-10-12 2006-04-27 Decode Genetics Ehf Aryl sulfonamide peri-substituted bicyclics for occlusive artery disease
TWI360539B (en) 2004-10-28 2012-03-21 Shionogi & Co 3-carbamoyl-2-pyridone derivatives
ATE542817T1 (de) 2004-11-10 2012-02-15 Ono Pharmaceutical Co Stickstoffhaltige heterocyclische verbindung und deren pharmazeutische verwendung
JP2006142666A (ja) 2004-11-19 2006-06-08 Mitsubishi Chemicals Corp 光学記録媒体用色素
WO2006055918A2 (en) 2004-11-19 2006-05-26 Pharmacopeia Drug Discovery, Inc. One-dimensional qsar models
WO2006058012A2 (en) 2004-11-23 2006-06-01 Wyeth Gonadotropin releasing hormone receptor antagonists
EP1838675A1 (en) 2004-11-24 2007-10-03 Laboratoires Serono S.A. Novel 4-arylamino pyridone derivatives as mek inhibitors for the treatment of hyperproliferative disorders
NZ555565A (en) 2004-11-24 2008-11-28 Vertex Pharma 3-[2-(3-acylamino-2-oxo-2H-pyridin-1YL)-acetylamino]-4-oxo-pentanoic acid derivatives and their use as caspase inhibitors
US20080255134A1 (en) 2004-11-30 2008-10-16 Artesian Therapeutics, Inc. Cardiotonic Compounds With Inhibitory Activity Against Beta-Adrenergic Receptors And Phosphodiesterase
EP1820797A4 (en) 2004-12-01 2009-10-28 Banyu Pharma Co Ltd SUBSTITUTED PYRIDONE DERIVATIVE
MX2007007264A (es) 2004-12-17 2007-08-14 Anadys Pharmaceuticals Inc Compuestos de piridazinona.
ATE479662T1 (de) 2004-12-23 2010-09-15 Hui Yao Pyrimidinonverbindungen, ihre herstellung und ihre verwendung
CN101090889A (zh) * 2004-12-29 2007-12-19 纳幕尔杜邦公司 荆芥内酰胺及其n－取代衍生物
US20060148842A1 (en) * 2004-12-29 2006-07-06 Scialdone Mark A Nepetalactams and N-substituted derivatives thereof
WO2006072037A1 (en) * 2004-12-29 2006-07-06 E. I. Du Pont De Nemours And Company Dihydronepetalactams and n-substituted derivatives thereof
CN101090890A (zh) * 2004-12-29 2007-12-19 纳幕尔杜邦公司 二氢荆芥内酰胺及其n－取代衍生物
CA2595159A1 (en) 2005-01-13 2006-07-20 Sirtris Pharmaceuticals, Inc. Novel compositions for preventing and treating neurodegenerative and blood coagulation disorders
US20060276416A1 (en) 2005-01-20 2006-12-07 Sirtris Pharmaceuticals, Inc. Methods and compositions for treating flushing and drug induced weight gain
EP1847535A4 (en) * 2005-02-04 2011-03-09 Eisai R&D Man Co Ltd 1- (piperidin-4-yl) -1H-indole derivatives
US7534796B2 (en) 2005-02-18 2009-05-19 Wyeth Imidazo[4,5-b]pyridine antagonists of gonadotropin releasing hormone receptor
US7582634B2 (en) 2005-02-18 2009-09-01 Wyeth 7-substituted imidazo[4,5-c]pyridine antagonists of gonadotropin releasing hormone receptor
CN1676518B (zh) 2005-03-17 2010-05-12 南开大学 4-取代苯基哒嗪类化合物及除草活性
EP1871369A4 (en) 2005-04-04 2009-11-11 Eisai R&D Man Co Ltd DIHYDROPYRIDINE COMPOUNDS AND COMPOSITIONS FOR HEADACHES
KR20080004584A (ko) 2005-04-08 2008-01-09 에자이 알앤드디 매니지먼트 가부시키가이샤 불수의 운동 치료제
CN1846699A (zh) 2005-04-13 2006-10-18 中南大学湘雅医院 1－(取代苯基)－5－甲基－2－(1h) 吡啶酮(i)化合物用于制备抗除肾间质纤维化外其他器官纤维化或组织纤维化药物的应用
JO2787B1 (en) 2005-04-27 2014-03-15 امجين إنك, Alternative amide derivatives and methods of use
JP5053997B2 (ja) 2005-04-28 2012-10-24 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 炎症性疾患の治療用の新規化合物
PT1928454E (pt) 2005-05-10 2014-12-04 Intermune Inc Derivativos da piridona para modulação do sistema de proteína quinase ativada pelo stress
GB0511190D0 (en) 2005-06-01 2005-07-06 Sterix Ltd Use
EP1890697B1 (en) 2005-06-07 2015-03-04 Pharmacopeia, LLC Azinone and diazinone v3 inhibitors for depression and stress disorders
CN101193908B (zh) 2005-06-08 2012-04-11 诺瓦提斯公司 有机化合物
EP1891008B1 (en) 2005-06-10 2010-06-30 Merck Patent GmbH Oxindoles as kinase inhibitors
WO2006138418A2 (en) 2005-06-14 2006-12-28 President And Fellows Of Harvard College Improvement of cognitive performance with sirtuin activators
WO2006138118A2 (en) 2005-06-15 2006-12-28 New York Blood Center Anti-viral compositions comprising heterocyclic substituted phenyl furans and related compounds
CN103055313A (zh) 2005-07-07 2013-04-24 西特里斯药业公司 用于治疗或预防肥胖、胰岛素抵抗障碍和线粒体相关障碍的方法和相关组合物
WO2007006591A2 (fr) 2005-07-13 2007-01-18 Bayer Cropscience Sa Dihalogenation d'hydroxipyridones n,o-disubstituees et leurs utilisations
JP2007063268A (ja) 2005-08-05 2007-03-15 Tanabe Seiyaku Co Ltd 医薬組成物
JP2007056213A (ja) 2005-08-26 2007-03-08 Fujifilm Corp 焼結含油軸受油用組成物、並びにそれを用いた軸受け装置及び摺動部材
KR20080049758A (ko) 2005-09-01 2008-06-04 아스텔라스세이야쿠 가부시키가이샤 통증 치료용으로 사용되는 피리다지논 유도체
NZ591443A (en) 2005-09-22 2013-04-26 Intermune Inc Granule formation of pirfenidone and pharmaceutically acceptable excipients
WO2007037543A1 (ja) 2005-09-29 2007-04-05 Banyu Pharmaceutical Co., Ltd. ビアリールアミド誘導体
BRPI0616655A2 (pt) 2005-10-03 2011-06-28 Ono Pharmaceutical Co composto heterocìclico contendo nitrogênio e aplicação farmacêutica do mesmo
WO2007044796A2 (en) 2005-10-11 2007-04-19 Nps Pharmaceuticals, Inc. Pyridazinone compounds as calcilytics
WO2007048065A2 (en) 2005-10-21 2007-04-26 Exelixis, Inc. Pyrimidinones as casein kinase ii (ck2) modulators
JP2007145819A (ja) 2005-10-28 2007-06-14 Tanabe Seiyaku Co Ltd 医薬組成物
WO2007053610A2 (en) 2005-11-01 2007-05-10 The Regents Of The University Of California Methods of treating atrial fibrillation wtih pirfenidone
JP2009515926A (ja) 2005-11-18 2009-04-16 エフ．ホフマン−ラ ロシュ アーゲー アザインドール−２−カルボキサミド誘導体
AU2006318428A1 (en) 2005-11-23 2007-05-31 Intermune, Inc. Method of modulating stress-activated protein kinase system
AU2006320580B2 (en) 2005-11-30 2011-06-23 Vertex Pharmaceuticals Incorporated Inhibitors of c-Met and uses thereof
JPWO2007072868A1 (ja) 2005-12-21 2009-06-04 エーザイ・アール・アンド・ディー・マネジメント株式会社 １，２−ジヒドロピリジン化合物の結晶（ｉｖ型）
EP1970370A4 (en) 2005-12-21 2010-11-10 Eisai R&D Man Co Ltd AMORPHOUS FORM OF 1,2-DIHYDROPYRIDINE COMPOUND
US7709501B2 (en) 2005-12-23 2010-05-04 Amgen Inc. Vanilloid receptor ligands and their use in treatments
WO2007081897A2 (en) 2006-01-11 2007-07-19 Merck & Co., Inc. Fused triazole tachykinin receptor antagonists
UY30117A1 (es) 2006-01-31 2007-06-29 Tanabe Seiyaku Co Compuesto amina trisustituido
EP1982978B1 (en) 2006-02-02 2014-08-27 Kumiai Chemical Industry Co., Ltd. Pyridone derivative and herbicide
US7728031B2 (en) 2006-02-24 2010-06-01 Abbott Laboratories Octahydro-pyrrolo[3,4-b]pyrrole derivatives
TW200803855A (en) 2006-02-24 2008-01-16 Kalypsys Inc Quinolones useful as inducible nitric oxide synthase inhibitors
JP5302012B2 (ja) 2006-03-08 2013-10-02 タケダ カリフォルニア インコーポレイテッド グルコキナーゼ活性剤
CA2644716A1 (en) 2006-03-13 2007-09-27 Merck & Co., Inc. Ophthalmic compositions for treating ocular hypertension
CN100396669C (zh) 2006-03-15 2008-06-25 浙江省医学科学院 一种抗纤维化药物吡非尼酮的制备方法
ATE470665T1 (de) 2006-03-22 2010-06-15 Janssen Pharmaceutica Nv Cycloalkylaminderivate als inhibitoren der wechselwirkung zwischen mdm2 und p53
US20090275581A1 (en) 2006-04-05 2009-11-05 Baldwin John J Renin inhibitors
US20090264428A1 (en) 2006-04-05 2009-10-22 Baldwin John J Renin Inhibitors
WO2007120842A2 (en) 2006-04-13 2007-10-25 Cornell Research Foundation, Inc. Methods and compositions for targeting c-rel
CA2650711A1 (en) 2006-04-28 2007-11-08 Northwestern University Compositions and treatments using pyridazine compounds and cholinesterase inhibitors
WO2007127475A2 (en) 2006-04-28 2007-11-08 Northwestern University Pyridazines for demyelinating diseases and neuropathic pain
WO2007129040A1 (en) 2006-05-04 2007-11-15 Chroma Therapeutics Ltd. p38 MAP KINASE INHIBITORS
AR060768A1 (es) 2006-05-05 2008-07-10 Millennium Pharm Inc Compuestos de imidazol sustituidos inhibidores del factor x, composiciones farmaceuticas que los contienen y usos como agentes antitromboticos.
WO2007139150A1 (ja) 2006-05-30 2007-12-06 The University Of Tokushima ＴＮＦα阻害物質を含有してなる抗インフルエンザウイルス剤
AU2007257959A1 (en) 2006-06-09 2007-12-21 Kemia, Inc. Therapy using cytokine inhibitors
WO2007147297A1 (en) 2006-06-15 2007-12-27 Shanghai Genomics, Inc. The use of derviate of pyridone for preventing and treating radioactive injury of lungs
GB0724349D0 (en) 2007-12-13 2008-01-30 Prolysis Ltd Antibacterial agents
GB0612428D0 (en) 2006-06-22 2006-08-02 Prolysis Ltd Antibacterial agents
EP2037905B1 (en) 2006-06-23 2013-05-01 Radius Health, Inc. Treatment of vasomotor symptoms with selective estrogen receptor modulators
AU2007275805A1 (en) 2006-07-19 2008-01-24 University Of Georgia Research Foundation, Inc. Pyridinone diketo acids: Inhibitors of HIV replication in combination therapy
CA2658462C (en) 2006-07-20 2011-09-27 Amgen Inc. Substituted pyridone compounds and methods of use
PL2069312T3 (pl) 2006-07-25 2013-03-29 Cephalon Inc Pochodne pirydazynonu
EA015886B1 (ru) 2006-08-02 2011-12-30 Эл Джи Лайф Сайенсиз Лтд. Ингибиторы каспазы на основе пиридазинонового каркаса
JP4747985B2 (ja) 2006-08-02 2011-08-17 コニカミノルタオプト株式会社 光学フィルム、それを用いた偏光板及び液晶表示装置
EP2069327B1 (en) 2006-08-25 2013-10-16 Boehringer Ingelheim International GmbH New pyridone derivatives with mch antagonistic activity and medicaments comprising these compounds
CN100516126C (zh) 2006-09-06 2009-07-22 北京理工大学 一种离子液体
AR063706A1 (es) 2006-09-11 2009-02-11 Cgi Pharmaceuticals Inc Determinadas amidas sustituidas, el uso de las mismas para el tratamiento de enfermedades mediadas por la inhibicion de la actividad de btk y composiciones farmaceuticas que las comprenden.
JP2008076948A (ja) 2006-09-25 2008-04-03 Konica Minolta Medical & Graphic Inc 感光性平版印刷版材料
WO2008051416A2 (en) * 2006-10-19 2008-05-02 Synta Pharmaceuticals Corp. Compounds that inhibit the activity of hsp90 for treating infections
PL2089364T3 (pl) 2006-11-08 2013-11-29 Bristol Myers Squibb Co Związki pirydynonu
KR20080045538A (ko) 2006-11-20 2008-05-23 에스케이케미칼주식회사 피리딘 화합물을 포함하는 염증 및 면역질환 치료용 약제조성물
CN1962642A (zh) 2006-11-21 2007-05-16 南开大学 具有除草活性的三氟甲基苯基哒嗪类衍生物及制备方法
GB0624105D0 (en) 2006-12-01 2007-01-10 Sterix Ltd Use
MX2009005908A (es) 2006-12-05 2009-06-16 Janssen Pharmaceutica Nv Derivados novedosos de diaza-espiro-piridinona sustituidos para usarse en las enfermedades mediadas por la hormona concentradora de melanina 1.
CA2672601A1 (en) 2006-12-14 2008-06-19 Astellas Pharma Inc. Polycyclic acid compounds useful as crth2 antagonists and antiallergic agents
BRPI0721086A2 (pt) 2006-12-14 2014-02-25 Lilly Co Eli Derivados de 5-[4-(azetidin-3-ilóxi)-fenil]-2-fenil-5h-tiazolo[5,4-c]piri din-4-ona e seu emprego como antago-nistas de receptor de mch
EP2091947A2 (en) 2006-12-20 2009-08-26 Takeda San Diego, Inc. Glucokinase activators
WO2008080056A2 (en) 2006-12-21 2008-07-03 Sloan-Kettering Institute For Cancer Research Pyridazinones and furan-containing compounds
EP2125778A1 (en) 2006-12-22 2009-12-02 Millennium Pharmaceuticals, Inc. Certain pyrazoline derivatives with kinase inhibitory activity
MX2009005825A (es) 2006-12-27 2009-06-16 Sanofi Aventis Derivados de isoquinolina e isoquinolinona sustituidos en calidad de inhibidores de rho-quinasa.
EP2647376A1 (en) 2007-01-22 2013-10-09 Gtx, Inc. Nuclear receptor binding agents
US9623021B2 (en) * 2007-01-22 2017-04-18 Gtx, Inc. Nuclear receptor binding agents
CN101235030A (zh) 2007-01-30 2008-08-06 中南大学 1-取代-5-三氟甲基-2-(1h)吡啶酮化合物、制备方法及其用途
JP2010519204A (ja) 2007-02-16 2010-06-03 アムジエン・インコーポレーテツド 窒素含有複素環ケトン類およびそれらのｃ−Ｍｅｔ阻害薬としての使用
DE102007007751A1 (de) 2007-02-16 2008-08-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue substituierte Arylsulfonylglycine, deren Herstellung und deren Verwendung als Arzneimittel
WO2008106202A1 (en) 2007-02-27 2008-09-04 Housey Gerard M Theramutein modulators
JP5134834B2 (ja) 2007-03-01 2013-01-30 東ソー株式会社 ５，５−二置換−３−ピロリン−２−オン誘導体の製造方法
TW200900065A (en) 2007-03-07 2009-01-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-pyridinyloxy-phenyl)-pyridin-2-one derivatives
GB0722769D0 (en) 2007-11-21 2008-01-02 Biolipox Ab New compounds
US8586619B2 (en) 2007-03-12 2013-11-19 Vm Therapeutics Llc Agents of calcium ion channel modulators
CN101730692A (zh) 2007-03-15 2010-06-09 先灵公司 用作葡聚糖合成酶抑制剂的哒嗪酮衍生物
WO2008115263A2 (en) 2007-03-20 2008-09-25 Curis, Inc. Raf kinase inhibitors containing a zinc binding moiety
US8372380B2 (en) 2007-03-30 2013-02-12 The Regents Of The University Of California In vivo imaging of sulfotransferases
BRPI0809498A2 (pt) 2007-04-02 2014-09-23 Inst Oneworld Health Compostos inibidores de cftr e seus usos
WO2008124323A1 (en) 2007-04-03 2008-10-16 Array Biopharma Inc. Imidazo[1,2-a]pyridine compounds as receptor tyrosine kinase inhibitors
WO2008124582A1 (en) 2007-04-05 2008-10-16 Smithkline Beecham Corporation Renin inhibitors
WO2008124575A1 (en) 2007-04-05 2008-10-16 Smithkline Beecham Corporation Renin inhibitors
CL2008000973A1 (es) 2007-04-05 2009-01-02 Astrazeneca Ab Compuestos derivados de 1-oxo-isoquinolina; procedimiento de preparación; composición farmacéutica; y su uso en el tratamiento de enfermedades pulmonares obstructvas crónicas (epoc) y asma.
US20100129933A1 (en) 2007-04-26 2010-05-27 Forschungszentrum Karlsruhe Gmbh Method for detecting the binding between mdm2 and the proteasome
TW200904421A (en) 2007-05-03 2009-02-01 Astellas Pharma Inc New compounds
WO2008141119A2 (en) 2007-05-09 2008-11-20 Vertex Pharmaceuticals Incorporated Modulators of cftr
US8178091B2 (en) 2007-05-21 2012-05-15 University Of Washington Compositions and methods for the treatment of respiratory disorders
WO2008147169A2 (es) 2007-05-29 2008-12-04 Cell Therapy Technology, S.A. De C.V. Microemolsion conteniendo pirfenidona
MX2007006349A (es) 2007-05-29 2009-02-18 Cell Therapy And Technology S Nuevo proceso de sintesis para la obtencion de 5-metil-1-fenil-2-(ih)-piridona, composicion y uso de la misma.
US9603848B2 (en) 2007-06-08 2017-03-28 Senomyx, Inc. Modulation of chemosensory receptors and ligands associated therewith
US7928111B2 (en) 2007-06-08 2011-04-19 Senomyx, Inc. Compounds including substituted thienopyrimidinone derivatives as ligands for modulating chemosensory receptors
AU2008265595B2 (en) 2007-06-20 2014-12-04 PureTech LYT 100 Inc. Substituted N-Aryl pyridinones as fibrotic inhibitors
DE102007028406A1 (de) 2007-06-20 2008-12-24 Bayer Healthcare Ag Substituierte Oxazolidinone und ihre Verwendung
EP2164488A1 (en) 2007-07-13 2010-03-24 Eisai R&D Management Co., Ltd. Ampa receptor antagonists and aldose reductase inhibitors for neuropathic pain
WO2009011411A1 (en) 2007-07-13 2009-01-22 Eisai R & D Management Co., Ltd. Ampa receptor antagonists and zonisamide for neuropathic pain
CA2690110A1 (en) 2007-07-13 2009-01-22 Eisai R&D Management Co., Ltd. Ampa receptor antagonists for neuropathic pain
US8003796B2 (en) 2007-07-17 2011-08-23 Bristol-Myers Squibb Company Pyridone GPR119 G protein-coupled receptor agonists
DE102007035333A1 (de) 2007-07-27 2009-01-29 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue substituierte Arylsulfonylglycine, deren Herstellung und deren Verwendung als Arzneimittel
WO2009022548A1 (ja) 2007-08-10 2009-02-19 Kumiai Chemical Industry Co., Ltd. 有害生物防除剤組成物及び有害生物防除方法
MX2007009796A (es) 2007-08-14 2009-02-25 Cell Therapy And Technology S Gel conteniendo pirfenidona.
CN101371833A (zh) 2007-08-23 2009-02-25 中南大学 1-芳基-2(1h)-吡啶酮类化合物在制备治疗皮肤瘙痒药物中的应用
WO2009029625A1 (en) 2007-08-27 2009-03-05 Kalypsys, Inc. 4- [heterocyclyl-methyl] -8-fluoro-quinolin-2-ones useful as nitric oxide synthase inhibitors
WO2009035598A1 (en) 2007-09-10 2009-03-19 Concert Pharmaceuticals, Inc. Deuterated pirfenidone
TW200927731A (en) 2007-09-14 2009-07-01 Ortho Mcneil Janssen Pharm 1,3-disubstituted-4-phenyl-1H-pyridin-2-ones
CN101652138B (zh) 2007-09-19 2011-07-06 中南大学 1-取代芳基-2（1h）-吡啶酮化合物的新医药用途
CN101121697A (zh) * 2007-09-20 2008-02-13 东北师范大学 一种多取代吡啶-2(1h)-酮类化合物的合成方法
WO2009054544A1 (en) 2007-10-26 2009-04-30 Eisai R & D Management Co., Ltd. Ampa receptor antagonists for parkinson's disease and movement disorders
WO2009054543A1 (en) 2007-10-26 2009-04-30 Eisai R & D Management Co., Ltd. Ampa receptor antagonists and zonisamide for parkinson's disease and movement disorders
CA2699631A1 (en) 2007-10-31 2009-05-07 Nissan Chemical Industries, Ltd. Pyridazinone compounds and p2x7 receptor inhibitors
WO2009060835A1 (ja) 2007-11-05 2009-05-14 Kyoto University 新規ユビキリン結合性小分子
EP2225237A2 (de) 2007-11-22 2010-09-08 Boehringer Ingelheim International GmbH Organische verbindungen
CA2932121A1 (en) 2007-11-30 2009-06-11 Newlink Genetics Corporation Ido inhibitors
EP2235161A1 (en) 2007-12-11 2010-10-06 Research Development Foundation Small molecules for neuronal differentiation of embryonic stem cells
US20100297181A1 (en) 2007-12-26 2010-11-25 Eisai R&D Management Co., Ltd. AMPA Receptor Antagonists for Epilepsy, Mental Disorders or Deficits in Sensory Organ
JP2011507799A (ja) 2007-12-26 2011-03-10 エーザイ・アール・アンド・ディー・マネジメント株式会社 癲癇のためのａｍｐａ受容体アンタゴニストおよびゾニサミド
ES2531396T3 (es) 2008-01-23 2015-03-13 Bristol Myers Squibb Co Proceso para preparar compuestos de piridinona
KR20100105789A (ko) 2008-01-30 2010-09-29 세파론, 인코포레이티드 히스타민-3（ｈ3）수용체 리간드로서의 치환된 스피로사이클릭 피페리딘 유도체
US8372863B2 (en) 2008-02-25 2013-02-12 Merck Sharp & Dohme Corp. Tetrahydro-1H-pyrrolo fused pyridones
EP2262501B1 (en) 2008-03-07 2014-08-13 Solanan, Inc. Treatment of sepsis with 5-ethyl-1-phenyl-2(1h)-pyridone
US8349864B2 (en) 2008-03-25 2013-01-08 New Mexico Technical Research Foundation Pyrano [3,2-C] pyridones and related heterocyclic compounds as pharmaceutical agents for treating disorders responsive to apoptosis, antiproliferation or vascular disruption, and the use thereof
US20090246198A1 (en) 2008-03-31 2009-10-01 Takeda Pharmaceutical Company Limited Mapk/erk kinase inhibitors and methods of use thereof
WO2009124119A2 (en) 2008-04-01 2009-10-08 The Trustes of Columbia University in the City of New York Phosphodiesterase inhibitors and uses thereof
WO2009124553A2 (en) 2008-04-09 2009-10-15 Neurokey A/S Use of hypothermia inducing drugs
WO2009135299A1 (en) 2008-05-05 2009-11-12 Merck Frosst Canada Ltd. 3, 4 - substituted piperidine derivatives as renin inhibitors
EP2328586A2 (en) 2008-05-20 2011-06-08 Cephalon, Inc. Substituted pyridazinone derivatives as histamine-3 (h3) receptor ligands
JP5627574B2 (ja) 2008-06-03 2014-11-19 インターミューン， インコーポレイテッド 炎症性および線維性疾患を治療するための化合物および方法
EP2297133B1 (en) 2008-06-25 2017-09-13 Forum Pharmaceuticals Inc. 1, 2 disubstituted heterocyclic compounds
JP2011525924A (ja) 2008-06-25 2011-09-29 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー プロリルヒドロキシラーゼ阻害剤
BRPI0913966A2 (pt) 2008-06-27 2015-11-17 Novartis Ag compostos orgânicos
EP2331503B1 (en) 2008-07-11 2013-08-21 Irm Llc 4-phenoxymethylpiperidines as modulators of gpr119 activity
TW201006821A (en) 2008-07-16 2010-02-16 Bristol Myers Squibb Co Pyridone and pyridazone analogues as GPR119 modulators
US20110166124A1 (en) 2008-07-23 2011-07-07 Mccormick Kevin D Tricyclic spirocycle derivatives and methods of use
CN102186833A (zh) 2008-08-18 2011-09-14 耶鲁大学 Mif调节剂
JP2012500850A (ja) 2008-08-25 2012-01-12 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー プロリルヒドロキシラーゼ阻害剤
WO2010029299A1 (en) 2008-09-12 2010-03-18 Biolipox Ab Pyrimidinone derivaties for use as medicaments
CN102256966B (zh) 2008-10-17 2016-02-10 白头生物医学研究所 可溶性mTOR复合物和其调节剂
US8703962B2 (en) 2008-10-24 2014-04-22 Purdue Pharma L.P. Monocyclic compounds and their use as TRPV1 ligands
US20110288134A1 (en) 2008-10-29 2011-11-24 Pacific Therapeutics Ltd. Composition and method for treating fibrosis
US7635707B1 (en) 2008-11-10 2009-12-22 Intermune, Inc. Pirfenidone treatment for patients with atypical liver function
US20110313004A1 (en) 2008-12-04 2011-12-22 Concert Pharmaceuticals, Inc. Deuterated pyridinones
US9040508B2 (en) 2008-12-08 2015-05-26 Vm Pharma Llc Compositions of protein receptor tyrosine kinase inhibitors
JP2012511514A (ja) 2008-12-10 2012-05-24 メルク・カナダ・インコーポレイテツド レニン阻害剤としての３，４−置換ピペリジン誘導体
BRPI0923217A2 (pt) 2008-12-11 2017-05-23 Glaxosmithkline Llc processos para a preparação de um composto de piridona, e para a preparação de uma forma cristalina, composto, sal ou um hidrato deste, forma cristalina de um sal de sódio ou um hidrato deste, e, composição farmacêutica.
CA2772760A1 (en) 2008-12-23 2010-07-01 President And Fellows Of Harvard College Small molecule inhibitors of necroptosis
WO2010080795A2 (en) 2009-01-07 2010-07-15 Henkel Corporation Hydrogen peroxide complexes and their use in the cure system of anaerobic adhesives
US20100190731A1 (en) 2009-01-26 2010-07-29 Jeff Olgin Methods for treating acute myocardial infarctions and associated disorders
AU2010208480A1 (en) * 2009-02-02 2011-07-28 Msd K.K. Inhibitors of Akt activity
EP2393360B1 (en) 2009-02-05 2015-11-04 Takeda Pharmaceutical Company Limited Pyridazinone compounds
WO2010104830A1 (en) 2009-03-09 2010-09-16 Bristol-Myers Squibb Company Pyridone analogs useful as melanin concentrating hormone receptor-1 antagonists
US8278316B2 (en) 2009-03-09 2012-10-02 Bristol-Myers Squibb Company Aza pyridone analogs useful as melanin concentrating hormone receptor-1 antagonists
WO2010107816A2 (en) 2009-03-16 2010-09-23 Promega Corporation Nucleic acid binding dyes and uses therefor
EP2411366B8 (en) 2009-03-27 2015-07-15 Ardea Biosciences, Inc. Dihydropyridin sulfonamides and dihydropyridin sulfamides as mek inhibitors
CN102404993B (zh) 2009-04-20 2015-08-26 马罗内生物创新公司 用于控制软体动物的化学剂和生物学剂
BRPI1015259A2 (pt) 2009-04-27 2016-05-03 Elan Pharm Inc antagonistas de piridinona de integrinas alfa-4
JP2012131708A (ja) 2009-04-28 2012-07-12 Nissan Chem Ind Ltd ４位置換ピリダジノン化合物及びｐ２ｘ７受容体阻害剤
SG175877A1 (en) 2009-05-04 2011-12-29 Plexxikon Inc Compounds and methods for inhibition of renin, and indications therefor
AU2010248758A1 (en) 2009-05-15 2011-11-24 Intermune, Inc. Methods of treating HIV patients with anti-fibrotics
WO2010135470A1 (en) 2009-05-19 2010-11-25 Intermune, Inc. Pifenidone derivatives for treating bronchial asthma
KR101478133B1 (ko) 2009-05-25 2014-12-31 센트럴 사우스 유니버시티 1-（치환된 벤질기）-5-트리플루오로메틸-2-（1ｈ）피리돈 화합물 및 그 염의 제조방법 및 용도
CN102149682B (zh) 2009-05-25 2012-12-05 中南大学 1-(取代芳基)-5-三氟甲基-2-（1h）吡啶酮化合物及其盐的制备方法及其用途
US20100305326A1 (en) 2009-06-02 2010-12-02 Marquette University Chemical Fragment Screening and Assembly Utilizing Common Chemistry for NMR Probe Introduction and Fragment Linkage
TWI434833B (zh) 2009-06-03 2014-04-21 Intermune Inc 用於合成吡非尼酮（ｐｉｒｆｅｎｉｄｏｎｅ）的改良方法
EP2437601A4 (en) 2009-06-03 2012-10-31 Glaxosmithkline Llc BIS-PYRIDYLPYRIDONE AS MELANIN CONCENTRATION HORMONE RECEPTOR-1 ANTAGONISTS
WO2010141538A1 (en) 2009-06-03 2010-12-09 Glaxosmithkline Llc Bis-pyridylpyridones as melanin-concentrating hormone receptor 1 antagonists
WO2010141539A1 (en) 2009-06-03 2010-12-09 Glaxosmithkline Llc Bis-pyridylpyridones as melanin-concentrating hormone receptor 1 antagonists
JP2012528871A (ja) 2009-06-03 2012-11-15 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー メラニン凝集ホルモン受容体１アンタゴニストとしてのビス−ピリジルピリドン類
WO2011055270A1 (en) 2009-11-04 2011-05-12 Wyeth Llc Indole based receptor crth2 antagonists
US8084475B2 (en) 2009-12-04 2011-12-27 Intermune, Inc. Pirfenidone therapy and inducers of cytochrome P450
TW201143768A (en) 2009-12-15 2011-12-16 Lundbeck & Co As H Pyridone derivatives as NK3 antagonists
JPWO2011077711A1 (ja) 2009-12-22 2013-05-02 興和株式会社 新規な２−ピリドン誘導体及びこれを含有する医薬
CA2795732A1 (en) * 2010-04-08 2011-10-13 Bristol-Myers Squibb Company Pyrimidinylpiperidinyloxypyridinone analogues as gpr119 modulators
EP2560656A4 (en) 2010-04-23 2013-11-27 Kineta Inc ANTIVIRAL COMPOUNDS
SG186855A1 (en) * 2010-06-28 2013-02-28 Merck Patent Gmbh 2,4- diaryl - substituted [1,8] naphthyridines as kinase inhibitors for use against cancer
KR20120011357A (ko) * 2010-07-23 2012-02-08 현대약품 주식회사 치환된 피리디논 유도체 및 이의 제조방법
CN103140221A (zh) * 2010-08-10 2013-06-05 盐野义制药株式会社 新型杂环衍生物和含有其的药物组合物
US8946260B2 (en) 2010-09-16 2015-02-03 Novartis Ag 17α-hydroxylase/C17,20-lyase inhibitors
CN102432598A (zh) * 2010-09-29 2012-05-02 江苏恒瑞医药股份有限公司 三环化合物、其制备方法及其在医药上的应用
CN102020651B (zh) 2010-11-02 2012-07-18 北京赛林泰医药技术有限公司 6-芳基氨基吡啶酮甲酰胺mek抑制剂
US8643700B2 (en) * 2010-11-17 2014-02-04 Dell Products L.P. 3D content adjustment system
EP2649050A4 (en) 2010-12-06 2014-04-23 Glaxo Group Ltd LINKS
CN102558147B (zh) * 2010-12-23 2014-09-17 江苏先声药物研究有限公司 化合物、制备方法及应用
KR101928505B1 (ko) 2011-01-28 2018-12-12 에스케이바이오팜 주식회사 피리돈 유도체 및 이를 포함하는 약학적 조성물
KR101925971B1 (ko) 2011-01-28 2018-12-06 에스케이바이오팜 주식회사 피리돈 유도체 및 이를 포함하는 약학적 조성물
DK2670242T3 (da) 2011-01-31 2022-05-02 Avalyn Pharma Inc Aerosolpirfenidon- og pyridonanalogforbindelser og anvendelser deraf
US10105356B2 (en) 2011-01-31 2018-10-23 Avalyn Pharma Inc. Aerosol pirfenidone and pyridone analog compounds and uses thereof
WO2012107831A1 (en) 2011-02-11 2012-08-16 Signa S.A. De C.V. Method of making a pyridone compound, 5-ethyl-1-phenyl-2-(1h)-pyridone, and intermediates thereof
WO2012122165A2 (en) 2011-03-08 2012-09-13 Auspex Pharmaceuticals, Inc. Substituted n-aryl pyridinones
FI20115234A0 (fi) * 2011-03-08 2011-03-08 Biotie Therapies Corp Uusia pyridatsinoni- ja pyridoniyhdisteitä
SG195110A1 (en) 2011-05-25 2013-12-30 Intermune Inc Pirfenidone and anti-fibrotic therapy in selected patients
CN103582728A (zh) * 2011-05-27 2014-02-12 简森丹麦有限公司 一种用于进送衣物的方法和进送器
CN102816175B (zh) 2011-06-09 2015-12-16 上海汇伦生命科技有限公司 一种杂环并吡啶酮类化合物,其中间体、制备方法和用途
WO2012175514A1 (en) 2011-06-21 2012-12-27 Bayer Intellectual Property Gmbh Pyridinone derivatives and pharmaceutical compositions thereof
EP2729007A1 (de) * 2011-07-04 2014-05-14 Bayer Intellectual Property GmbH Verwendung substituierter isochinolinone, isochinolindione, isochinolintrione und dihydroisochinolinone oder jeweils deren salze als wirkstoffe gegen abiotischen pflanzenstress
MX2011007675A (es) 2011-07-19 2012-07-11 Cell Therapy And Technology S A De C V Procedimiento para la fabricacion de una composicion farmaceutica en forma de tabletas de liberacion prolongada conteniendo pirfenidona y su aplicacion en la regresion de la insuficiencia renal cronica, contractura capsular mamaria y fibrosis hepatica humanas.
JPWO2013018685A1 (ja) 2011-07-29 2015-03-05 東レ株式会社 ラクタム誘導体及びその医薬用途
CN102276616B (zh) 2011-08-04 2013-09-04 中国科学院长春应用化学研究所 一种呋喃[3,2-c]吡啶-4(5H)-酮类化合物合成方法
CN104023725B (zh) 2011-08-16 2019-04-26 卡迪欧拉有限公司 控释制剂
US20130116241A1 (en) * 2011-11-09 2013-05-09 Abbvie Inc. Novel inhibitor compounds of phosphodiesterase type 10a
PT2785695T (pt) * 2011-11-30 2020-08-20 Hoffmann La Roche Novos derivados bicíclicos de dihidroisoquinolina-1-ona
RU2650501C2 (ru) 2012-03-01 2018-04-16 Эррэй Биофарма Инк. Ингибиторы серин/треониновых киназ
WO2013142390A1 (en) 2012-03-21 2013-09-26 Gtx, Inc. Aldo-keto reductase subfamily 1c3 (akr1c3) inhibitors
US9434695B2 (en) 2012-07-18 2016-09-06 Sunshine Lake Pharma Co., Ltd Nitrogenous heterocyclic derivatives and their application in drugs
JP6501264B2 (ja) 2012-07-24 2019-04-17 アヴァリン ファーマ インク． エアロゾルのピルフェニドン及びピリドンのアナログの化合物、及び、その使用
AR092742A1 (es) 2012-10-02 2015-04-29 Intermune Inc Piridinonas antifibroticas
US20140094456A1 (en) 2012-10-02 2014-04-03 Intermune, Inc. Anti-fibrotic pyridinones
UA111305C2 (uk) * 2012-12-21 2016-04-11 Пфайзер Інк. Конденсовані лактами арилу та гетероарилу
JP6256187B2 (ja) 2014-05-14 2018-01-10 株式会社デンソー 判定帰還型等化器

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007058392A1 (ja) * 2005-11-21 2007-05-24 Japan Tobacco Inc. ヘテロ環化合物およびその医薬用途

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE47142E1 (en) 2008-06-03 2018-11-27 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US9359379B2 (en) 2012-10-02 2016-06-07 Intermune, Inc. Anti-fibrotic pyridinones
US9675593B2 (en) 2012-10-02 2017-06-13 Intermune, Inc. Anti-fibrotic pyridinones
US10376497B2 (en) 2012-10-02 2019-08-13 Intermune, Inc. Anti-fibrotic pyridinones
US10898474B2 (en) 2012-10-02 2021-01-26 Intermune, Inc. Anti-fibrotic pyridinones
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones
US10544161B2 (en) 2014-04-02 2020-01-28 Intermune, Inc. Anti-fibrotic pyridinones
US10150767B2 (en) 2014-11-10 2018-12-11 Genentech, Inc. Therapeutic compounds and uses thereof
US10183009B2 (en) * 2014-11-10 2019-01-22 Genentech, Inc. Therapeutic compounds and uses thereof
US10258603B2 (en) 2014-11-10 2019-04-16 Genentech, Inc. Therapeutic compounds and uses thereof
US10202378B2 (en) 2015-01-29 2019-02-12 Genentech, Inc. Therapeutic compounds and uses thereof
TWI775139B (zh) * 2019-10-03 2022-08-21 美商格芯（美國）集成電路科技有限公司 雙向崩潰矽控整流器

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