WO2011133882A1 - Certain amino-pyridazines, compositions thereof, and methods of their use - Google Patents

Certain amino-pyridazines, compositions thereof, and methods of their use Download PDF

Info

Publication number
WO2011133882A1
WO2011133882A1 PCT/US2011/033605 US2011033605W WO2011133882A1 WO 2011133882 A1 WO2011133882 A1 WO 2011133882A1 US 2011033605 W US2011033605 W US 2011033605W WO 2011133882 A1 WO2011133882 A1 WO 2011133882A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
xll
membered
compound
optionally substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2011/033605
Other languages
French (fr)
Inventor
Luke W. Ashcraft
Gustave Bergnes
Scott Collibee
Chihyuan Chuang
Jeff Gardina
Bradley P. Morgan
Alex R. Muci
Xiangping Qian
Jeffrey Warrington
Zhe Yang
Pu-Ping Lu
Antonio Romero
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cytokinetics Inc
Original Assignee
Cytokinetics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=44834527&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2011133882(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to JP2013506327A priority Critical patent/JP5918217B2/en
Priority to MYPI2012004644A priority patent/MY191829A/en
Priority to CA2796390A priority patent/CA2796390C/en
Priority to EP11772778.4A priority patent/EP2563365B1/en
Priority to NZ603593A priority patent/NZ603593A/en
Priority to US13/642,207 priority patent/US8969346B2/en
Priority to EA201201377A priority patent/EA024881B1/en
Priority to SG2012077871A priority patent/SG184954A1/en
Priority to HK13109022.8A priority patent/HK1181662B/en
Priority to CN201180021470.0A priority patent/CN103002897B/en
Priority to MX2012012259A priority patent/MX343264B/en
Application filed by Cytokinetics Inc filed Critical Cytokinetics Inc
Priority to KR1020127029537A priority patent/KR101825735B1/en
Priority to KR1020187002999A priority patent/KR101960642B1/en
Priority to PH1/2012/502097A priority patent/PH12012502097B1/en
Priority to EP16166061.8A priority patent/EP3127541B1/en
Priority to AU2011242569A priority patent/AU2011242569B2/en
Priority to BR112012026950-0A priority patent/BR112012026950B1/en
Publication of WO2011133882A1 publication Critical patent/WO2011133882A1/en
Priority to IL222465A priority patent/IL222465A/en
Anticipated expiration legal-status Critical
Priority to US14/594,274 priority patent/US9604965B2/en
Priority to AU2016202617A priority patent/AU2016202617B2/en
Priority to IL250824A priority patent/IL250824B/en
Priority to US15/463,288 priority patent/US10076519B2/en
Priority to PH12017501192A priority patent/PH12017501192A1/en
Priority to AU2018201953A priority patent/AU2018201953B2/en
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the cytoskeleton of skeletal and cardiac muscle cells is unique compared to that of all other cells. It consists of a nearly crystalline array of closely packed cytoskeletal proteins called the sarcomere.
  • the sarcomere is elegantly organized as an interdigitating array of thin and thick filaments.
  • the thick filaments are composed of myosin, the motor protein responsible for transducing the chemical energy of ATP hydrolysis into force and directed movement.
  • the thin filaments are composed of actin monomers arranged in a helical array.
  • myosin-ll is responsible for contraction of skeletal, cardiac, and smooth muscle.
  • This class of myosin is significantly different in amino acid composition and in overall structure from myosin in the other twelve distinct classes.
  • Myosin-ll forms homo-dimers resulting in two globular head domains linked together by a long alpha-helical coiled-coiled tail to form the core of the sarcomere's thick filament.
  • the globular heads have a catalytic domain where the actin binding and ATPase functions of myosin take place. Once bound to an actin filament, the release of phosphate (cf.
  • ADP-Pi to ADP signals a change in structural conformation of the catalytic domain that in turn alters the orientation of the light-chain binding lever arm domain that extends from the globular head; this movement is termed the powerstroke.
  • This change in orientation of the myosin head in relationship to actin causes the thick filament of which it is a part to move with respect to the thin actin filament to which it is bound.
  • Unbinding of the globular head from the actin filament (Ca 2+ regulated) coupled with return of the catalytic domain and light chain to their starting conformation/orientation completes the catalytic cycle, responsible for intracellular movement and muscle contraction.
  • Tropomyosin and troponin mediate the calcium effect on the interaction on actin and myosin.
  • the troponin complex is comprised of three polypeptide chains: troponin C, which binds calcium ions; troponin I, which binds to actin; and troponin T, which binds to tropomyosin.
  • the skeletal troponin- tropomyosin complex regulates the myosin binding sites extending over several actin units at once.
  • Troponin a complex of the three polypeptides described above, is an accessory protein that is closely associated with actin filaments in vertebrate muscle.
  • the troponin complex acts in conjunction with the muscle form of tropomyosin to mediate the Ca 2+ dependency of myosin ATPase activity and thereby regulate muscle contraction.
  • the troponin polypeptides T, I, and C are named for their tropomyosin binding, inhibitory, and calcium binding activities, respectively.
  • Troponin T binds to tropomyosin and is believed to be responsible for positioning the troponin complex on the muscle thin filament.
  • Troponin I binds to actin, and the complex formed by troponins I and T, and tropomyosin inhibits the interaction of actin and myosin.
  • Skeletal troponin C is capable of binding up to four calcium molecules. Studies suggest that when the level of calcium in the muscle is raised, troponin C exposes a binding site for troponin I, recruiting it away from actin. This causes the tropomyosin molecule to shift its position as well, thereby exposing the myosin binding sites on actin and stimulating myosin ATPase activity.
  • Human skeletal muscle is composed of different types of contractile fibers, classified by their myosin type and termed either slow or fast fibers. Table 1 summarizes the different proteins that make up these types of muscle. Table 1
  • Fast skeletal muscle fibers tend to exert greater force but fatigue faster than slow skeletal muscle fibers and are functionally useful for acute, large scale movements such as rising from a chair or correcting falls.
  • Muscle contraction and force generation is controlled through nervous stimulation by innervating motor neurons.
  • Each motor neuron may innervate many (approximately 100-380) muscle fibers as a contractile whole, termed a motor unit.
  • motor neurons send stimuli as nerve impulses (action potentials) from the brain stem or spinal cord to each fiber within the motor unit.
  • the contact region between nerve and muscle fibers is a specialized synapse called the neuromuscular junction (NMJ).
  • NMJ neuromuscular junction
  • ACh neurotransmitter acetylcholine
  • ACh triggers a second action potential in the muscle that spreads rapidly along the fiber and into invaginations in the membrane, termed t-tubules.
  • T-tubules are physically connected to Ca2+ stores within the sarcoplasmic reticulum (SR) of muscle via the
  • DHPR dihydropyridine receptor
  • Muscle function can become compromised in disease by many mechanisms. Examples include the frailty associated with old age (termed sarcopenia) and cachexia syndromes associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), and chronic kidney disease/dialysis. Severe muscular dysfunction can arise from neuromuscular diseases (such as Amyotrophic Lateral Sclerosis (ALS), spinal muscular atrophy (SMA) and myasthenia gravis) or muscular myopathies (such as muscular dystrophies). Additionally, muscle function may become compromised due to rehabilitation-related deficits, such as those associated with recovery from surgery (e.g. post-surgical muscle weakness), prolonged bed rest, or stroke rehabilitation. Additional examples of diseases or conditions where muscle function becomes compromised include peripheral vascular disease (e.g., claudication), chronic fatigue syndrome, metabolic syndrome, and obesity.
  • peripheral vascular disease e.g., claudication
  • chronic fatigue syndrome e.g., metabolic syndrome, and obesity.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X and m are as defined herein.
  • composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • Also provided are methods for treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere for example, modulation of the troponin complex of the fast skeletal muscle sarcomere through one or more of fast skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.
  • references to a compound of Formula I includes all subgroups of Formula I defined herein, including all substructures, subgenera, preferences, embodiments, examples and particular compounds defined and/or described herein.
  • references to a compound of Formula I and subgroups thereof include ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co- crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes and/or protected forms thereof.
  • references to a compound of Formula I and subgroups thereof include polymorphs, solvates, co-crystals, isomers, tautomers and/or oxides thereof.
  • references to a compound of Formula I and subgroups thereof include polymorphs, salts, solvates, and/or co- crystals thereof.
  • Formula I and subgroups thereof include isomers, tautomers and/or oxides thereof.
  • references to a compound of Formula I and subgroups thereof include solvates thereof.
  • salts includes solvates of salts of compounds.
  • C-i-6 alkyl includes C-i , C2, C3, C 4 , C5, C6, C-i-6, C2-6, C3-6, C4-6, C5-6, C-i-5, C2-5, C3-5, C4-5, C-i-4, C-2-4, C3-4, C-i-3, C2-3, and C-i-2 alkyl.
  • a moiety When a moiety is defined as being optionally substituted, it may be substituted as itself or as part of another moiety.
  • R x is defined as "C-i-6 alkyl or OC-i-6 alkyl, wherein C-i-6 alkyl is optionally subsituted with halogen"
  • both the C-i -6 alkyl group alone and the C-i -6 alkyl that makes up part of the OC-i -6 alkyl group may be substituted with halogen.
  • Alkyl encompasses straight and branched carbon chains having the indicated number of carbon atoms, for example, from 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms.
  • C-i -6 alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms.
  • alkyl residue having a specific number of carbons is named, all branched and straight chain versions having that number of carbons are intended to be encompassed; thus, for example, "propyl” includes n-propyl and isopropyl; and "butyl” includes n-butyl, sec-butyl, isobutyl and t-butyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
  • “Lower alkyl” refers to alkyl groups having 1 to 6 carbons.
  • Haloalkyl includes straight and branched carbon chains having the indicated number of carbon atoms (e.g., 1 to 6 carbon atoms) substituted with at least one halogen atom. In instances wherein the haloalkyl group contains more than one halogen atom, the halogens may be the same (e.g.,
  • haloalkyl groups include, but are not limited to, chloromethyl, dichloromethyl,
  • Alkenyl refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one carbon-carbon double bond derived by the removal of one molecule of hydrogen from adjacent carbon atoms of the corresponding alkyl.
  • the group may be in either the cis or trans configuration (Z or E configuration) about the double bond(s).
  • Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1 -en-1 -yl, prop-1 -en-2-yl, prop- 2-en-1 -yl (allyl), prop-2-en-2-yl), and butenyl (e.g., but-1 -en-1 -yl, but-1 -en-2-yl, 2-methyl-prop-1 -en-1 -yl, but-2-en-1 -yl, but-2-en-1 -yl, but-2-en-2-yl, buta-1 ,3- dien-1 -yl, buta-1 ,3-dien-2-yl).
  • “Lower alkenyl” refers to alkenyl groups having 2 to 6 carbons.
  • Alkynyl refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond derived by the removal of two molecules of hydrogen from adjacent carbon atoms of the corresponding alkyl.
  • Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1 -yn-1 -yl, prop-2-yn-1 -yl) and butynyl (e.g., but-1 -yn-1 -yl, but-1 -yn-3-yl, but-3-yn-1 -yl).
  • “Lower alkynyl” refers to alkynyl groups having 2 to 6 carbons.
  • Cycloalkyi indicates a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, for example, 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms. Cycloalkyi groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyi groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl and cyclohexyl, as well as bridged and caged ring groups (e.g., norbornane, bicyclo[2.2.2]octane).
  • one ring of a polycyclic cycloalkyi group may be aromatic, provided the polycyclic cycloalkyi group is bound to the parent structure via a non- aromatic carbon.
  • a 1 ,2,3,4-tetrahydronaphthalen-1 -yl group (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is a cycloalkyi group
  • 1 ,2,3,4-tetrahydronaphthalen-5-yl is not considered a cycloalkyi group.
  • Examples of polycyclic cycloalkyi groups consisting of a cycloalkyi group fused to an aromatic ring are described below.
  • Cycloalkenyl indicates a non-aromatic carbocyclic ring, containing the indicated number of carbon atoms (e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms) and at least one carbon-carbon double bond derived by the removal of one molecule of hydrogen from adjacent carbon atoms of the corresponding cycloalkyi.
  • Cycloalkenyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and
  • cyclohexenyl as well as bridged and caged ring groups (e.g.,
  • one ring of a polycyclic cycloalkenyl group may be aromatic, provided the polycyclic alkenyl group is bound to the parent structure via a non-aromatic carbon atom.
  • inden-1 -yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is considered a cycloalkenyl group
  • inden-4-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a cycloalkenyl group.
  • polycyclic cycloalkenyl groups consisting of a cycloalkenyl group fused to an aromatic ring are described below.
  • Aryl indicates an aromatic carbon ring having the indicated number of carbon atoms, for example, 6 to 12 or 6 to 10 carbon atoms.
  • Aryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some instances, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other instances, polycyclic aryl groups may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to an aromatic ring, provided the polycyclic aryl group is bound to the parent structure via an atom in the aromatic ring.
  • a 1 ,2,3,4- tetrahydronaphthalen-5-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group
  • 1 ,2,3,4-tetrahydronaphthalen-1 -yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered an aryl group.
  • aryl does not encompass or overlap with "heteroaryl", as defined herein, regardless of the point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups).
  • aryl is phenyl or naphthyl.
  • aryl is phenyl. Additional examples of aryl groups comprising an aromatic carbon ring fused to a non-aromatic ring are described below.
  • Alkyl refers to a residue having the indicated number of carbon atoms (e.g., 7 to 12 or 7 to 10 carbon atoms) in which an aryl moiety is attached to the parent structure via an alkyl residue.
  • the alkyl residue may be straight-chain or branched. Examples include, benzyl, phenethyl and 1 -phenylethyl.
  • Heteroaryl indicates an aromatic ring containing the indicated number of atoms (e.g., 5 to 12, or 5 to 10 membered heteroaryl) made up of one or more heteroatoms (e.g., 1 , 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon. Heteroaryl groups do not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some
  • the total number of S and O atoms in heteroaryl group is not more than 1 .
  • heteroaryl groups may be bound to the parent structure by a carbon or nitrogen atom, as valency permits.
  • pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl groups
  • pyrrolyl includes 1 -pyrrolyl, 2-pyrrolyl and 3-pyrrolyl groups.
  • nitrogen is present in a heteroaryl ring, it may, where the nature of the adjacent atoms and groups permits, exist in an oxidized state (i.e., N + -O " ).
  • sulfur is present in a heteroaryl ring, it may, where the nature of the adjacent atoms and groups permits, exist in an oxidized state (i.e., S + -O " or SO2).
  • Heteroaryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).
  • a heteroaryl group is monocyclic.
  • examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1 ,2,3-triazole, 1 ,2,4- triazole, 1 ,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1 ,2,3-oxadiazole, 1 ,2,4-oxadiazole, 1 ,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1 ,2,3-thiadiazole, 1 ,2,4-thiadiazole, 1 ,3,4- thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1 ,2,4- triazine, 1 ,3,5-tria
  • both rings of a polycyclic heteroaryl group are aromatic.
  • examples include indole, isoindole, indazole, benzoimidazole, benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole, 1 H- pyrrolo[2,3-b]pyridine, 1 H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1 ,2,3]triazolo[4,5-b]pyridine, 1 H-pyrrolo[3,2-b]pyridine, 1 H-pyrazolo[4,3- bjpyridine, 1 H-imidazo[4,5-b]pyridine, 1 H-[1 ,2,3]triazolo[4,5-b]pyridine, 1 H- pyrrolo[2,3-c]pyridine
  • quinazoline quinoxaline, phthalazine, naphthyridine (e.g., 1 ,8-naphthyridine, 1 ,7-naphthyridine, 1 ,6-naphthyridine, 1 ,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), imidazo[1 ,2-a]pyridine, 1 H-pyrazolo[3,4-d]thiazole, 1 H- pyrazolo[4,3-d]thiazole and imidazo[2,1 -b]thiazole.
  • naphthyridine e.g., 1 ,8-naphthyridine, 1 ,7-naphthyridine, 1 ,6-naphthyridine, 1 ,5-naphthyridine, 2,7-naphthyridine, 2,6-
  • polycyclic heteroaryl groups may include a non- aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl,
  • heterocycloalkenyl fused to a heteroaryl ring
  • polycyclic heteroaryl group is bound to the parent structure via an atom in the aromatic ring.
  • a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered a heteroaryl group
  • 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl is not considered a heteroaryl group.
  • polycyclic heteroaryl groups consisting of a heteroaryl ring fused to a non-aromatic ring are described below.
  • Heterocycloalkyl indicates a non-aromatic, fully saturated ring having the indicated number of atoms (e.g., 3 to 10, or 3 to 7, membered
  • heterocycloalkyl made up of one or more heteroatoms (e.g., 1 , 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon.
  • Heterocycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.
  • heterocycloalkyl ring When nitrogen is present in a heterocycloalkyl ring, it may, where the nature of the adjacent atoms and groups permits, exist in an oxidized state (i.e., N + -O " ). Examples include piperidinyl N-oxide and morpholinyl-N-oxide. Additionally, when sulfur is present in a heterocycloalkyl ring, it may, where the nature of the adjacent atoms and groups permits, exist in an oxidized state (i.e., S + -O " or -SO2-). Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide.
  • one ring of a polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl), provided the polycyclic heterocycloalkyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom.
  • a 1 ,2,3,4-tetrahydroquinolin-1 -yl group (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkyl group
  • 1 ,2,3,4-tetrahydroquinolin-8-yl group is not considered a heterocycloalkyl group.
  • heterocycloalkyl groups consisting of a heterocycloalkyl group fused to an aromatic ring are described below.
  • Heterocycloalkenyl indicates a non-aromatic ring having the indicated number of atoms (e.g., 3 to 10, or 3 to 7, membered heterocycloalkyl) made up of one or more heteroatoms (e.g., 1 , 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon, and at least one double bond derived by the removal of one molecule of hydrogen from adjacent carbon atoms, adjacent nitrogen atoms, or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl.
  • Heterocycloalkenyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).
  • heterocycloalkenyl ring When nitrogen is present in a heterocycloalkenyl ring, it may, where the nature of the adjacent atoms and groups permits, exist in an oxidized state (i.e., N + -O " ). Additionally, when sulfur is present in a heterocycloalkenyl ring, it may, where the nature of the adjacent atoms and groups permits, exist in an oxidized state (i.e., S + -O " or -SO 2 -).
  • heterocycloalkenyl groups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3- dihydro-1 H-pyrrolyl, 2,5-dihydro-1 H-pyrrolyl), dihydroimidazolyl (e.g., 2,3- dihydro-1 H-imidazolyl, 4,5-dihydro-1 H-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridinyl (e.g., 1 ,2,3,4-tetrahydropyridinyl, 1 ,
  • one ring of a polycyclic heterocycloalkenyl group may be aromatic (e.g., aryl or heteroaryl), provided the polycyclic heterocycloalkenyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom.
  • a 1 ,2-dihydroquinolin-1 -yl group (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is considered a heterocydoalkenyl group
  • 1 ,2-dihydroquinolin-8-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a heterocydoalkenyl group.
  • heterocydoalkenyl groups consisting of a heterocydoalkenyl group fused to an aromatic ring are described below.
  • polycyclic rings consisting of an aromatic ring (e.g., aryl or heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocydoalkyi, heterocydoalkenyl)
  • a non-aromatic ring e.g., cycloalkyl, cycloalkenyl, heterocydoalkyi, heterocydoalkenyl
  • indenyl 2, 3-dihydro-1 H-indenyl, 1 ,2,3,4-tetrahydronaphthalenyl, benzo[1 ,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1 ,4]dioxinyl, indolinyl, isoindolinyl, 2, 3-dihydro-1 H-indazolyl, 2,3-dihydro-1 H-
  • each ring is considered an aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocydoalkyi or heterocydoalkenyl group is determined by the atom through which the moiety is bound to the parent structure.
  • Halogen or halo refers to fluorine, chlorine, bromine or iodine.
  • “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. "Enantiomers” are stereoisomers that are non- superimposable mirror images of each other. A 1 :1 mixture of a pair of enantiomers is a “racemic” mixture. The symbol “( ⁇ )” may be used to designate a racemic mixture where appropriate. "Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. A “meso compound” or “meso isomer” is a non- optically active member of a set of stereoisomers.
  • Meso isomers contain two or more stereocenters but are not chiral (i.e., a plane of symmetry exists within the molecule).
  • the absolute stereochemistry is specified according to the Cahn-lngold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon can be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • compounds disclosed and/or described herein include all such possible enantiomers, diastereomers, meso isomers and other stereoisomeric forms, including racemic mixtures, optically pure forms and intermediate mixtures. Enantiomers, diastereomers, meso isomers and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Unless specified otherwise, when the compounds disclosed and/or described herein contain olefinic double bonds or other centers of geometric asymmetry, it is intended that the compounds include both E and Z isomers.
  • stereochemistry depicted in the structures of cyclic meso compounds is not absolute; rather the stereochemistry is intended to indicate the positioning of the substituents relative to one another, e.g., cis or trans.
  • substituents e.g., cis or trans.
  • Tautomers are structurally distinct isomers that interconvert by tautomerization.
  • Tautomerization is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry.
  • Prototropic tautomerization or proton-shift tautomenzation involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomenzation is possible (e.g. in solution), a chemical equilibrium of tautomers can be reached.
  • An example of tautomenzation is keto-enol tautomerization.
  • keto-enol tautomenzation is the interconverision of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • Another example of tautomerization is phenol-keto
  • phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1 H)-one tautomers.
  • compounds described herein contain moieties capable of tautomerization, and unless specified otherwise, it is intended that the compounds include all possible tautomers.
  • Protecting group has the meaning conventionally associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site, and such that the group can readily be removed after the selective reaction is complete.
  • a variety of protecting groups are disclosed, for example, in T.H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999).
  • a "hydroxy protected form” contains at least one hydroxy group protected with a hydroxy protecting group.
  • amines and other reactive groups may similarly be
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of the compounds described herein and are not biologically or otherwise undesirable. Examples of
  • compositions described 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, and phosphoric acid.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2- hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid and salicylic acid.
  • 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, and aluminum.
  • 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; and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the
  • pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt
  • a suitable organic solvent may be used to dissolve the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds (see, e.g., Berge et al., Pharmaceutical Salts, J.
  • a “solvate” is formed by the interaction of a solvent and a compound.
  • suitable solvents include, for example, water and alcohols (e.g., ethanol).
  • Solvates include hydrates having any ratio of compound to water, such as monohydrates, dihydrates and hemi-hydrates.
  • a “chelate” is formed by the coordination of a compound to a metal ion at two (or more) points.
  • the term “compound” is intended to include chelates of compounds.
  • salts includes chelates of salts and "solvates” includes chelates of solvates.
  • a “non-covalent complex” is formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding). Such non-covalent complexes are included in the term "compound”.
  • prodrug refers to a substance administered in an inactive or less active form that is then transformed (e.g., by metabolic processing of the prodrug in the body) into an active compound.
  • the rationale behind administering a prodrug is to optimize absorption, distribution, metabolism, and/or excretion of the drug
  • Prodrugs may be obtained by making a derivative of an active compound (e.g., a compound of Formula I or another compound disclosed and/or described herein) that will undergo a
  • the transformation of the prodrug to the active compound may proceed spontaneously (e.g., by way of a hydrolysis reaction) or it can be catalyzed or induced by another agent (e.g., an enzyme, light, acid or base, and/or temperature).
  • the agent may be endogenous to the conditions of use (e.g., an enzyme present in the cells to which the prodrug is administered, or the acidic conditions of the stomach) or the agent may be supplied
  • Prodrugs can be obtained by converting one or more functional groups in the active compound into another functional group, which is then converted back to the original functional group when administered to the body.
  • a hydroxyl functional group can be converted to a sulfonate, phosphate, ester or carbonate group, which in turn can be hydrolyzed in vivo back to the hydroxyl group.
  • an amino functional group can be converted, for example, into an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenyl functional group, which can be hydrolyzed in vivo back to the amino group.
  • a carboxyl functional group can be converted, for example, into an ester (including silyl esters and thioesters), amide or hydrazide functional group, which can be hydrolyzed in vivo back to the carboxyl group.
  • prodrugs include, but are not limited to, phosphate, acetate, formate and benzoate derivatives of functional groups (such as alcohol or amine groups) present in the compounds of Formula I and other compounds disclosed and/or described herein.
  • the compounds disclosed and/or described herein can be enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
  • the compound contains at least one deuterium atom.
  • deuterated forms can be made, for example, by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997.
  • deuterated compounds may improve the efficacy and increase the duration of action of compounds disclosed and/or described herein.
  • Deuterium substituted compounds can be synthesized using various methods, such as those described in: Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled
  • 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.
  • 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
  • compositions is contemplated.
  • Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
  • an active agent is used to indicate a compound that has biological activity.
  • an “active agent” is a compound having therapeutic utility.
  • the compound enhances at least one aspect of skeletal muscle function or activity, such as power output, skeletal muscle force, skeletal muscle endurance, oxygen consumption, efficiency, and/or calcium sensitivity.
  • an active agent is a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • patient and “subject” refer to an animal, such as a mammal bird or fish. In some embodiments, the patient or subject is a mammal.
  • Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows and humans.
  • the patient or subject is a human, for example a human that has been or will be the object of treatment, observation or experiment.
  • the compounds, compositions and methods described herein can be useful in both human therapy and veterinary applications.
  • skeletal muscle includes skeletal muscle tissue as well as components thereof, such as skeletal muscle fibers, the myofibrils comprising the skeletal muscle fibers, the skeletal sarcomere which
  • skeletal sarcomere comprises the myofibrils, and the various components of the skeletal sarcomere described herein, including skeletal myosin, actin, tropomyosin, troponin C, troponin I, troponin T and fragments and isoforms thereof.
  • skeletal muscle includes fast skeletal muscle tissue as well as components thereof, such as fast skeletal muscle fibers, the myofibrils comprising the fast skeletal muscle fibers, the fast skeletal sarcomere which comprises the myofibrils, and the various components of the fast skeletal sarcomere described herein, including fast keletal myosin, actin, tropomyosin, troponin C, troponin I, troponin T and fragments and isoforms thereof.
  • Skeletal muscle does not include cardiac muscle or a combination of sarcomeric components that occurs in such combination in its entirety in cardiac muscle.
  • the term “therapeutic” refers to the ability to modulate the contractility of fast skeletal muscle.
  • modulation refers to a change in function or efficiency of one or more components of the fast skeletal muscle sarcomere, including myosin, actin, tropomyosin, troponin C, troponin I, and troponin T from fast skeletal muscle, including fragments and isoforms thereof, as a direct or indirect response to the presence of a compound described herein, relative to the activity of the fast skeletal sarcomere in the absence of the compound.
  • the change may be an increase in activity
  • modulation is a potentiation of function or efficiency of one or more
  • components of the fast skeletal muscle sarcomere including myosin, actin, tropomyosin, troponin C, troponin I, and troponin T from fast skeletal muscle, including fragments and isoforms thereof. Modulation may be mediated by any mechanism and at any physiological level, for example, through
  • efficiency means the ratio of mechanical work output to the total metabolic cost.
  • therapeutically effective amount refers to that amount of a compound disclosed and/or described herein that is sufficient to affect treatment, as defined herein, when administered to a patient in need of such treatment.
  • a therapeutically effective amount of a compound may be an amount sufficient to treat a disease responsive to modulation of fast skeletal muscle.
  • the therapeutically effective amount will vary depending upon, for example, the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound, the dosing regimen to be followed, timing of administration, the manner of administration, all of which can readily be determined by one of ordinary skill in the art.
  • the therapeutically effective amount may be ascertained experimentally, for example by assaying blood concentration of the chemical entity, or theoretically, by calculating
  • Treatment includes one or more of: preventing a disease or disorder (i.e., causing the clinical symptoms of the disease or disorder not to develop); inhibiting a disease or disorder; slowing or arresting the development of clinical symptoms of a disease or disorder; and/or relieving a disease or disorder (i.e., causing relief from or regression of clinical symptoms).
  • compounds described and/or disclosed herein may prevent an existing disease or disorder from worsening, assist in the management of the disease or disorder, or reduce or eliminate the disease or disorder.
  • the compounds disclosed and/or described herein may prevent a disease or disorder from developing or lessen the extent of a disease or disorder that may develop.
  • power output of a muscle means work/cycle time and may be scaled up from PoLo/cycle time units based on the properties of the muscle. Power output may be modulated by changing, for example, activating parameters during cyclical length changes, including timing of activation (phase of activation) and the period of activation (duty cycle.)
  • ATPase refers to an enzyme that hydrolyzes ATP.
  • ATPases include proteins comprising molecular motors such as the myosins.
  • selective binding refers to preferential binding to a target protein in one type of muscle or muscle fiber as opposed to other types.
  • a compound selectively binds to fast skeletal troponin C if the compound preferentially binds troponin C in the troponin complex of a fast skeletal muscle fiber or sarcomere in comparison with troponin C in the troponin complex of a slow muscle fiber or sarcomere or with troponin C in the troponin complex of a cardiac sarcomere.
  • R 1 is selected from hydrogen, halogen, CN, C-i -6 alkyl, C-i -6 haloalkyl, C(O)OR a , C(O)NR b R c , OR a , NR b R c , C 6- io aryl and 5-10 membered heteroaryl;
  • R 2 is selected from C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, 5-10
  • heterocycloalkenyl, C6-io aryl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, (CH 2 ) n OR a , (CH 2 ) n OC(O)R a , (CH 2 ) n OC(O)OR a , (CH 2 ) n OC(O)NR b R c , (CH 2 ) n NR d C(O)R a , (CH 2 ) n NR d C(O)OR a , (CH 2 ) n NR d C(O)NR b R c , (CH 2 ) n NR d C(O)C(O)NR b R c , (CH 2 ) n NR d C(S)R a , (CH 2 )
  • R 3 is selected from hydrogen, halogen, CN, C-i-6 alkyl, C-i-6 haloalkyl, C(O)OR a , C(O)NR b R c , OR a , NR b R c , C 6- io aryl and 5-10 membered heteroaryl;
  • R 4 is selected from hydrogen, C-i -6 alkyl, C-i -6 haloalkyl, C(O)R a , C(O)OR a , C(O)NR b R c and SO 2 R a ;
  • R 5 and R 6 are each independently selected from hydrogen, halogen, C-i-6 alkyl and C-i-6 haloalkyl;
  • R 5 and R 6 together with the carbon atom to which they are bound form C 3- 8 cycloalkyl, C 3- 8 cycloalkenyl, 3-8 membered
  • heterocycloalkyl or 3-8 membered heterocycloalkenyl each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR a , OC(O)R a , OC(O)OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , S(O)R a , SO 2 R a , SO 2 NR b R c , C -6 alkyl and C -6 haloalkyl;
  • R 7 is selected from C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl and 5-10 membered heteroaryl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR a , OC(O)R a , OC(O)OR a , OC(O)NR b R c , NR b R c , NR d C(O)R a , NR d C(O)OR a , NR d C(O)NR b R c ,
  • heterocycloalkenyl, C6-io aryl, C 7- n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 R f substituents;
  • R 8 and R 9 are each independently selected from hydrogen, halogen and C-i-6 alkyl;
  • X is selected from a bond, -(CH 2 ) P -, -(CH 2 ) p C(O)(CH 2 ) q -, - (CH 2 )pO(CH 2 ) q -, -(CH 2 )pS(CH 2 ) q -, -(CH 2 ) p NR d (CH 2 ) q -, -(CH 2 ) p C(O)O(CH 2 ) q -, -(CH 2 ) p OC(O)(CH 2 )q-, -(CH 2 )pNR d C(O)(CH 2 ) q -, -(CH 2 ) p C(O)NR d (CH 2 ) q -, -(CH 2 )p C(O)NR d (CH 2 ) q -, -(CH 2 )pNR d C(O)NR d (CH 2 ) q -,
  • X, R 2 and R 3 together with the carbon atoms to which they are bound, form a 5-6 membered ring optionally containing one or more heteroatoms selected from oxygen nitrogen and sulfur, and optionally containing one or more double bonds, and optionally substituted with 1 , 2, 3, 4 or 5 R f substituents;
  • R a is independently selected from hydrogen, C-i -6 alkyl, C-i-6 haloalkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C 7- i i aralkyl and 5-10 membered heteroaryl, wherein each of the C-i -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 8 cycloalkyl, C 3- 8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C 7- n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 R f substituent
  • R b and R c are each independently selected from hydrogen, C-i-6 alkyl, C-i-6 haloalkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3- 8 cycloalkyl, C 3- 8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6- io aryl, C 7- n aralkyl, 5-10 membered heteroaryl, C(O)R g , C(0)OR g , C ⁇ NR ⁇ and SO 2 R g , wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C 7- n aralkyl and
  • R d at each occurrence, is independently selected from hydrogen and Ci-6 alkyl
  • R e at each occurrence, is independently selected from hydrogen, CN, OH, C-i-6 alkoxy, C-i -6 alkyl and C-i -6 haloalkyl;
  • R f is independently selected from halogen, CN, OR h , OC(O)R h , OC(O)OR h , OC JNR ⁇ , NR'R j , NR d C(O)R h , NR d C(O)OR h , NR d C(O)NR'R j , NR d C(O)C(O)NR i R j , NR d C(S)R h , NR d C(S)OR h , NR d C(S)NR'R j , NR d C(NR e )NR'R j , NR d S(O)R h , NR d SO 2 R h , NR d SO 2 NR'R j , C(O)R h , C(O)OR h , ⁇ ( ⁇ ) ⁇ , C(S)R h , C(O)OR h ,
  • heterocycloalkenyl C 6- io aryl, C 7- n aralkyl and 5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered
  • heterocycloalkenyl, C 6- io aryl, C 7- n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 R k substituents;
  • R f substituents bound to a single carbon atom, together with the carbon atom to which they are both bound, form a group selected from carbonyl, C 3- 8 cycloalkyl and 3-8 membered heterocycloalkyl;
  • R g at each occurrence, is independently selected from C-i -6 alkyl, C-i -6 haloalkyl, phenyl, naphthyl, and C 7- n aralkyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, OH, C-i-6 alkoxy, C-i-6 alkyl and C-i -6 haloalkyl;
  • R h is independently selected from hydrogen, C-i -6 alkyl, C-i-6 haloalkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C7.11 aralkyl and 5-10 mennbered heteroaryl, wherein each of the Ci -6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3-8 cycloalkyl, C 3- 8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C-6-10 aryl, C7.11 aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 R k substituents;
  • R' and R j are each independently selected from hydrogen, C1-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered
  • heterocycloalkenyl C 6- io aryl, C 7- n aralkyl, 5-10 membered heteroaryl, C(O)R g , and C(O)OR g , wherein each of the Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, s-io aryl, C7.11 aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, OH, Ci_ 6 alkoxy, Ci -6 alkyl and Ci-6 haloalkyl;
  • R k at each occurrence, is independently selected from halogen, CN, OH, C1-6 alkoxy, NH 2 , NH(Ci -6 alkyl), N(Ci -6 alkyl) 2 , NHC(O)d -6 alkyl,
  • n 0, 1 or 2;
  • n at each occurrence, independently is 0, 1 or 2;
  • p 0, 1 or 2;
  • R 7 is not piperidinyl or morpholino.
  • X is a bond and R 2 is optionally substituted phenyl, then R 7 is not piperidinyl or morpholino.
  • the compound of Formula I is not 6-(4-chlorophenyl)-5- methyl-N-(2-methyl-2-(piperidin-1 -yl)propyl)pyridazin-3-amine, N-(2-methyl-2- (piperidin-1 -yl)propyl)-6-phenyl-5-propylpyridazin-3-amine or N-(2-methyl-2- morpholinopropyl)-6-phenyl-5-propylpyridazin-3-amine.
  • m is 0, i.e., a compound of Formula II, or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and X are as defined herein.
  • m is 1 , i.e., a compound of Formula III, or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and X are as defined herein.
  • one of R 5 and R 6 is hydrogen and the other is C-i-6 alkyl.
  • R 5 and R 6 are each independently C-i -6 alkyl. In some embodiments of compounds of Formula I, II or III, R 5 and R 6 are each methyl.
  • the compounds are of Formula IV(a) or IV(b), or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 and X are as defined herein.
  • R 7 is not piperidinyl or morpholinyl.
  • R 5 and R 6 together with the carbon atom to which they are bound form C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl or 3-8 membered
  • heterocydoalkenyl each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR a , OC(O)R a , OC(O)OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , S(O)R a , SO 2 R a , SO 2 NR b R c , C 1-6 alkyl and C 1-6 haloalkyl.
  • R 5 and R 6 together with the carbon to which they are bound, form C3-6 cycloalkyl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR a , OC(O)R a , OC(O)OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , S(O)R a , SO 2 R a , SO 2 NR b R c , C 1-6 alkyl and C 1-6 haloalkyl.
  • R 5 and R 6 together with the carbon to which they are bound, form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR a , OC(O)R a , OC(O)OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , S(O)R a , SO 2 R a , SO 2 NR b R c , C 1-6 alkyl and C-i-6 haloalkyl.
  • R 5 and R 6 together with the carbon to which they are bound, form cyclobutyl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR a , OC(O)R a , OC(O)OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , S(O)R a , SO 2 R a , SO 2 NR b R c , Ci -6 alkyl and Ci -6 haloalkyl.
  • R 5 and R 6 together with the carbon to which they are bound, form cyclobutyl substituted with one substituent selected from halogen, CN, oxo, OR a , OC(O)R a ,
  • R 5 and R 6 together with the carbon to which they are bound, form cyclobutyl substituted with one substituent selected from halogen, CN, oxo, OR a , OC(O)R a ,
  • the compounds are of Formula V(a) or V(b), or a pharmaceutically acceptable salt thereof:
  • R m and R n are each independently selected from hydrogen, halogen and C1-6 alkyl, and R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 and X are as defined herein.
  • R m and R n are each hydrogen.
  • R m and R n are each halogen.
  • R m and R n are each fluorine.
  • one of R m and R n is hydrogen and the other is halogen.
  • the halogen and R 7 are in a trans configuration with respect to one another on the cyclobutyl ring. In some embodiments of such
  • one of R m and R n is hydrogen and the other is fluorine.
  • the fluorine and R 7 are in a trans configuration with respect to one another on the cyclobutyl ring. In some embodiments of such
  • R 5 and R 6 together with the carbon atom to which they are bound, form 3-6 membered heterocycloalkyl, each of which is optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR a , OC(O)R a , OC(O)OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , S(O)R a , SO 2 R a , SO 2 NR b R c , C 1-6 alkyl and C-i-6 haloalkyl.
  • R 5 and R 6 together with the carbon atom to which they are bound, form aziridine, azetidine, pyrrolidine, oxirane, oxetane or tetrahydrofuran, each of which is optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR a , OC(O)R a , OC(O)OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , S(O)R a , SO 2 R a , SO 2 NR b R c , C 1-6 alkyl and C 1-6 haloalkyl.
  • R 5 and R 6 are each independently C-i-6 alkyl, or R 5 and R 6 together with the carbon atom to which they are bound form C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl or 3-8 membered heterocydoalkenyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR a , OC(O)R a , OC(O)OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , S(O)R a , SO 2 R a , SO 2 NR b R c , Ci -6 alkyl and Ci -6 haloalkyl.
  • R 5 and R 6 are each methyl, or R 5 and R 6 together with the carbon atom to which they are bound form C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl or 3-8 membered heterocydoalkenyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR a , OC(O)R a ,
  • R 5 and R 6 are each independently C-i -6 alkyl, or R 5 and R 6 , together with the carbon to which they are bound, form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR a , OC(O)R a , OC(O)OR a , N R b R c , C(O)R a , C(O)OR a , C(O)NR b R c , S(O)R a , SO 2 R a , SO 2 NR b R c , C 1-6 alkyl and C 1-6 haloalkyl.
  • R 5 and R 6 are each methyl, or R 5 and R 6 , together with the carbon to which they are bound, form cyclobutyl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR a , OC(O)R a , OC(O)OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , S(O)R a , SO 2 R a , SO 2 NR b R c , C 1-6 alkyl and C 1-6 haloalkyl.
  • R 7 is selected from C 3- 8 cycloalkyl, C 3- 8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6- io aryl and 5-10 membered heteroaryl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR a , OC(O)R a , OC(O)OR a , OC(O)NR b R c , N R b R c , NR d C(O)R a , NR d C(O)OR a , NR d C(O)NR b R c ,
  • heterocycloalkenyl, C 6- io aryl, C 7- n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 R f substituents.
  • R 7 is not piperidinyl or morpholinyl.
  • R 7 is phenyl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR a , OC(O)R a , OC(O)OR a , OC(O)NR b R c , NR b R c , N R d C(O)R a , NR d C(O)OR a , NR d C(O)NR b R c , NR d C(O)C(O)NR b R c , NR d C(S)R a , N R d C(S)OR a , NR d C(S)NR b R c , NR d C(NR e )NR b R c , NR d S(O)R a , NR d
  • the compounds are of Formula VI, or a pharmaceutically acceptable salt thereof:
  • r is 0, 1 , 2, 3 or 4, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R f , X and m are as defined herein.
  • the compounds are of Formula Vll(a) or Vll(b), or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 4 , R 8 , R 9 , R f and X are as defined herein.
  • the compounds are of Formula Vlll(a) or Vlll(b), or a pharmaceutically acceptable salt thereof:
  • R m and R n are each independently selected from hydrogen, halogen and C -6 alkyl; r is 0, 1 , 2, 3 or 4; and R 1 , R 2 , R 3 , R 4 , R 8 , R 9 , R f and X are as defined herein.
  • R m and R n are each hydrogen.
  • R m and R n are each halogen.
  • R m and R n are each fluorine.
  • one of R m and R n is hydrogen and the other is halogen.
  • the halogen and the phenyl ring are in a trans configuration with respect to one another on the cyclobutyl ring.
  • the halogen and the phenyl ring are in a cis configuration with respect to one another on the cyclobutyl ring.
  • one of R m and R n is hydrogen and the other is fluorine.
  • the fluorine and the phenyl ring are in a trans configuration with respect to one another on the cyclobutyl ring.
  • the fluorine and the phenyl ring are in a cis configuration with respect to one another on the cyclobutyl ring.
  • R 7 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 2, 4- difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 4-fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2, 4-dichlorophenyl, 3,4- dichlorophenyl, 3,5-dichlorophenyl, 2-methylphenyl, 3-methylphenyl, 2, 4- dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2- (hydroxymethyl)phenyl, 3-(hydroxymethyl)phenyl, 4-(hydroxymethyl)phenyl, 2- (aminomethyl)phenyl, 3-(aminomethyl)phenyl, 4-(aminomethyl)phenyl, 2- phenol, 3-
  • R 7 is 5-10 membered heteroaryl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR a , OC(O)R a ,
  • heterocycloalkenyl, C 6- io aryl, C 7- n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 R f substituents.
  • R 7 is pyridyl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR a , OC(O)R a , OC(O)OR a , OC(O)NR b R c , NR b R c , N R d C(O)R a , NR d C(O)OR a , NR d C(O)NR b R c , NR d C(O)C(O)NR b R c , NR d C(S)R a , N R d C(S)OR a , NR d C(S)NR b R c , NR d C(NR e )NR b R c , NR d S(O)R a , NR
  • R 7 is selected from 2-pyridyl, 3-pyridyl and 4-pyridyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR a , OC(O)R a , OC(O)OR a , OC(O)NR b R c , N R b R c , NR d C(O)R a , NR d C(O)OR a , NR d C(O)NR b R c , NR d C(O)C(O)NR b R c , NR d C(S)R a , NR d C(S)OR a , NR d C(S)NR b R c , NR d C(NR e )NR b R
  • the compounds are of Formula IX, or a pharmaceutically acceptable salt thereof:
  • r is 0, 1 , 2, 3 or 4, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R f , X and m are as defined herein.
  • the compounds are of Formula X(a) or X(b), or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 4 , R 8 , R 9 , R f and X are as defined herein.
  • the compounds are of Formula Xl(a) or Xl(b), or a pharmaceutically acceptable salt thereof:
  • R m and R n are each independently selected from hydrogen, halogen and C -6 alkyl; r is 0, 1 , 2, 3 or 4; and R 1 , R 2 , R 3 , R 4 , R 8 , R 9 , R f and X are as defined herein.
  • R m and R n are each hydrogen.
  • R m and R n are each halogen.
  • R m and R n are each fluorine.
  • one of R m and R n is hydrogen and the other is halogen.
  • the halogen and the pyridyl ring are in a trans configuration with respect to one another on the cyclobutyl ring.
  • the halogen and the pyridyl ring are in a cis configuration with respect to one another on the cyclobutyl ring.
  • one of R m and R n is hydrogen and the other is fluorine.
  • the fluorine and the pyridyl ring are in a trans configuration with respect to one another on the cyclobutyl ring.
  • the fluorine and the pyridyl ring are in a cis configuration with respect to one another on the cyclobutyl ring.
  • R 7 is selected from pyrid-2-yl, 3-fluoro-pyrid-2-yl, 4-fluoro-pyrid-2- yl, 5-fluoro-pyrid-2-yl, 6-fluoro-pyrid-2-yl, 3-chloro-pyrid-2-yl, 4-chloro-pyrid-2- yl, 5-chloro-pyrid-2-yl, 6-chloro-pyrid-2-yl, 3-cyano-pyrid-2-yl, 4-cyano-pyrid-2- yl, 5-cyano-pyrid-2-yl, 6-cyano-pyrid-2-yl, 3-methyl-pyrid-2-yl, 4-methyl-pyrid- 2-yl, 5-methyl-pyrid-2-yl, 6-methyl-pyrid-2-yl, 3-difluoromethyl-pyrid
  • R 7 is selected from pyrid-3-yl, 2-fluoro-pyrid-3-yl, 4-fluoro-pyrid-3- yl, 5-fluoro-pyrid-3-yl, 6-fluoro-pyrid-3-yl, 2-chloro-pyrid-3-yl, 4-chloro-pyrid-3- yl, 5-chloro-pyrid-3-yl, 6-chloro-pyrid-3-yl, 2-cyano-pyrid-3-yl, 4-cyano-pyrid-3- yl, 5-cyano-pyrid-3-yl, 6-cyano-pyrid-3-yl, 2-methyl-pyrid-3-yl, 4-methyl-pyrid-
  • X is selected from a bond, -(CH 2 ) P -, -(CH 2 )pC(O)(CH 2 ) q -, -(CH 2 )pO(CH 2 ) q -, - (CH 2 ) p S(CH 2 ) q -, -(CH 2 ) p NR d (CH 2 ) q -, -(CH 2 ) p C(O)O(CH 2 ) q -,
  • X is a bond.
  • the compound is of Formula Xll(a), XI 1(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), XI 1(1), Xll(m), Xll(n) or Xll(o), or a pharmaceutically acceptable salt thereof:
  • R 7 is not piperidinyl or morpholinyl.
  • R 7 is not piperidinyl or morpholinyl.
  • X is - O-.
  • X is selected from -CH 2 O- and -OCH 2 -.
  • X is - NR d -.
  • X is selected from -CH 2 NR d - and -NR d CH 2 -.
  • X is sleeted from -NR d C(O)- and -C(O)NR d -.
  • X is sleeted from -CH 2 NR d C(O)- and -C(O)NR d CH 2 -.
  • R 2 is selected from C 3- 8 cycloalkyl, C 3- 8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl and 5-10 membered heteroaryl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents for R 2 .
  • heterocycloalkyl (CH 2 ) n phenyl, (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, (CH 2 ) n C3-8 cycloalkyl, (CH 2 ) n 3-8 membered heterocycloalkyl, (CH 2 ) n phenyl, (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 R f substituents.
  • R 2 is phenyl optionally substituted with 1 , 2, 3, 4 or 5
  • heterocycloalkyl (CH 2 ) n phenyl, (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl, wherein each of the C-i -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, (CH 2 ) n C 3- 8 cycloalkyl, (CH 2 ) n 3-8 membered heterocycloalkyl, (CH 2 ) n phenyl, (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 R f substituents.
  • R 2 is phenyl substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, (CH 2 ) n OR a , (CH 2 ) n OC(O)R a , (CH 2 ) n OC(O)OR a , (CH 2 ) n OC
  • (CH 2 ) n phenyl, (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl wherein each of the Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, (CH 2 ) n C 3- 8 cycloalkyl, (CH 2 ) n 3- 8 membered heterocycloalkyl, (CH 2 ) n phenyl, (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 R f substituents; wherein at least one substitutent is bonded at the meta position.
  • R 2 is phenyl substituted with a substituent selected from (CH 2 ) n C(O)OR a and (CH 2 ) n C(O)NR b R c ; and optionally substituted with 1 , 2 or 3 additional substituents selected from halogen, CN, (CH 2 ) n OR a
  • (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl wherein each of the C-
  • R 2 is phenyl substituted with a substituent selected from C(O)OH, C(O)NH 2 , C(O)OCi -6 alkyl, C(O)NHCi -6 alkyl and C(O)N(Ci -6 alkyl) 2 ; and optionally substituted with 1 , 2 or 3 additional
  • R 2 is phenyl substituted at the meta position with a substituent selected from (CH 2 ) n C(O)OR a and (CH 2 ) n C(O)NR b R c ; and optionally
  • (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl wherein each of the C-
  • R 2 is phenyl substituted at the meta position with a substituent selected from (CH 2 ) n C(O)OR a and (CH 2 ) n C(O)NR b R c , and optionally
  • R 2 is phenyl substituted at the meta position with a substituent selected from C(O)OH, C(O)NH 2 , C(O)OCi -6 alkyl, C(O)NHCi -6 alkyl and C(O)N(Ci-6 alkyl) 2 ; and optionally substituted with 1 ,
  • R 2 is phenyl substituted with (CH 2 ) n NR d C(O)R a , wherein R a is Ci-6 alkyl or 3-8 membered heterocycloalkyl, each optionally substituted with 1 , 2 or 3 substituents selected from halogen, CN, oxo, (
  • R 2 is phenyl substituted with (CH 2 ) n NR d C(O)R a , wherein R a is selected from C-i -6 alkyl, Ci -6 alkyl-OH and C-i -6 alkyl-NH 2 , each optionally substituted with 1 , 2 or 3 substituents
  • heterocycloalkyl (CH 2 ) n phenyl, (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, (CH 2 ) n C 3- 8 cycloalkyl, (CH 2 ) n 3-8 membered heterocycloalkyl, (CH 2 ) n phenyl, (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 R f substituents.
  • R 2 is selected from 3-benzamide, N-methyl-3-benzamide, N,N- dimethyl-3-benzamide, 4-fluoro-3-benzamide, N-methyl-4-fluoro-3-benzamide, N,N-dimethyl-4-fluoro-3-benzamide, 3-benzoic acid, methyl-3-benzoate, 4- fluor
  • R 2 is 5-10 membered heteroaryl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, (CH 2 ) n OR a ,
  • (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl wherein each of the C-i- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, (CH 2 ) n C 3- 8 cycloalkyl, (CH 2 ) n 3-8 membered heterocycloalkyl, (CH 2 ) n phenyl, (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 R f substituents.
  • R 2 is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, iso
  • (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl wherein each of the C-i- 6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, (CH 2 ) n C3-8 cycloalkyl, (CH 2 ) n 3-8 membered heterocycloalkyl, (CH 2 ) n phenyl, (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 R f substituents.
  • R 2 is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, iso
  • heterocycloalkyl (CH 2 ) n phenyl, (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl, wherein each of the C-i -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, (CH 2 ) n C 3- 8 cycloalkyl, (CH 2 ) n 3-8 membered heterocycloalkyl, (CH 2 ) n phenyl, (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 R f substituents.
  • R 2 is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl and triazyl, each optionally substituted with (CH 2 ) n C(O)NR b R c .
  • R 2 is selected from furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each
  • R 2 is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl and triazyl, each optionally substituted with (CH 2 )nC(O)NH 2 .
  • R 2 is selected from furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each
  • R 2 is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, iso
  • heterocycloalkyl (CH 2 ) n phenyl, (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, (CH 2 ) n C 3- 8 cycloalkyl, (CH 2 ) n 3-8 membered heterocycloalkyl, (CH 2 ) n phenyl, (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 R f substituents.
  • R 2 is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl and triazyl, each optionally substituted with (CH 2 ) n NR d C(O)R a , wherein R a is selected from C-i -6 alkyl, C-i
  • R 2 is selected furanyl, pyrrolyl, thiophenyl, thiazolyl,
  • R 2 is selected from indolyl, indazolyl, benzimidazolyl, benzoxazolyl and benzoisoxazolyl, each optionally substituted with 1 , 2, 3 or 4 substituents selected from halogen, CN, oxo, (CH 2 ) n OR a , (
  • heterocycloalkyl (CH 2 ) n phenyl, (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, (CH 2 ) n C3-8 cycloalkyl, (CH 2 ) n 3-8 membered heterocycloalkyl, (CH 2 ) n phenyl, (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 R f substituents.
  • R 2 is selected from 1 H-indazol-6-yl, 1 H-indazol-5-yl, 1 H- indazol-4-yl, 3-amino(1 H-indazol-5-yl), 3-amino(1 H-indazol-6-yl), 3-amino(1 H-indazol-6-yl), 3-amino(1 H- indazol-6-yl), 3-amino(1 H- indazol-6-yl), 3-amino(1 H- indazol-6-yl), 3-amino(1 H- indazol-6-yl), 3-amino(1 H- indazol-6-yl), 3-amino(1 H- indazol-6-yl), 3-amino(1 H- indazol-6-yl), 3-amino(1 H- indazol-6-yl), 3-amino(1 H- indazol-6-yl), 3-amino(1 H- in
  • R 2 is selected from 3-6 membered heterocycloalkyl and 3-6 membered heterocycloalkenyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, (CH 2 ) n OR a , (CH 2 ) n OC(O),
  • heterocycloalkyl (CH 2 ) n phenyl, (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl, wherein each of the C-i -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, (CH 2 ) n C3-8 cycloalkyl, (CH 2 ) n 3-8 membered heterocycloalkyl, (CH 2 ) n phenyl, (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 R f substituents.
  • R 2 is selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, (CH 2 ) n
  • (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl wherein each of the C-i- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, (CH 2 ) n C 3- 8 cycloalkyl, (CH 2 ) n 3-8 membered heterocycloalkyl, (CH 2 ) n phenyl, (CH 2 ) n naphthyl and (CH 2 ) n 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 R f substituents.
  • R 2 is NR b R c , wherein R b and R c are as defined herein.
  • R 2 is NR b R c , wherein one of R b and R c is hydrogen and the other is C-i -6 alkyl optionally substituted with 1 , 2, 3, 4 or 5 R f substituents.
  • X is - C(O)- and R 2 is NR b R c , wherein R b and R c are as defined herein.
  • X is -C(O)- and R 2 is NR b R c , wherein one of R b and R c is hydrogen and the other is C-i-6 alkyl optionally substituted with 1 , 2, 3, 4 or 5 R f substituents.
  • X is - (CH 2 ) P - and R 2 is NR b R c , wherein R b and R c are as defined herein.
  • X is -(CH 2 ) P - and R 2 is NR b R c , wherein one of R b and R c is hydrogen and the other is C-i-6 alkyl optionally substituted with 1 , 2, 3, 4 or 5 R f substituents.
  • X, R 2 and R 3 together with the carbon atoms to which they are bound, form a 5-6 membered ring optionally containing one or more heteroatoms selected from oxygen nitrogen and sulfur, and optionally containing one or more double bonds, and optionally substituted with 1 , 2, 3, 4 or 5 R f substituents.
  • the compound is of Formula XIII, or a
  • A is a 5 or 6 membered ring optionally containing one or more heteroatoms selected from oxygen nitrogen and sulfur, and optionally containing one or more double bonds; t is 0, 1 , 2, 3 or 4; and R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R f and m are as defined herein.
  • ring A together with the pyridazine ring to which it is bound form a group selected from cinnoline, pyrido[2,3-c]pyridazine, pyrido[3,4-c]pyridazine, pyrido[4,3- c]pyridazine, pyrido[3,2-c]pyridazine, 5,6,7,8-tetrahydrocinnoline, 5,6,7,8- tetrahydropyrido[2,3-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,4-c]pyridazine, 5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,2- c]pyridazine, thieno[2,3-
  • R 1 is selected from hydrogen, halogen, CN, C-i -6 alkyl, C-
  • R 1 is selected from hydrogen, halogen, CN, C-i-6 alkyl, C-i- 6 haloalkyl, hydroxyl, C-i-6 alkoxy, NH 2 , NHCi-6 alkyl, and N(Ci-6 alkyl) 2 .
  • R 1 is selected from hydrogen, halogen, CN, CF 3 and methyl.
  • R 1 is hydrogen.
  • R 3 is selected from hydrogen, halogen, CN, C-i -6 alkyl, Ci -6 haloalkyl, C(O)OR a , C(O)NR b R c , OR a , NR b R c , C 6- io aryl and 5-10 membered heteroary
  • R 3 is selected from hydrogen, halogen, CN, C-i-6 alkyl, Ci-6 haloalkyl, hydroxyl, Ci-6 alkoxy, NH 2 , NHC-i-6 alkyl, and N(Ci-6 alkyl) 2 .
  • R 3 is selected from hydrogen, halogen, CN, CF 3 and methyl.
  • R 3 is hydrogen.
  • R 1 and R 3 are each hydrogen.
  • R 4 is selected from hydrogen, C-i-6 alkyl, Ci-6 haloalkyl, C(O)R a , C(O)OR a , C(O)NR b R c and SO 2 R a .
  • R 4 is hydrogen.
  • R 1 , R 3 and R 4 are each hydrogen.
  • R 8 and R 9 are each independently selected from hydrogen, halogen and C-i -6 alkyl.
  • R 8 and R 9 at each occurrence, are each hydrogen.
  • the compound is selected from the compounds in Table 2, or a pharmaceutically acceptable salt thereof.
  • the compounds and compositions described and/or disclosed herein modulate the contractility of the skeletal sarcomere. Specifically, the compounds modulate the troponin complex of the fast skeletal muscle sarcomere through one or more of fast skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. As used in this context, "modulate” means either increasing or decreasing activity.
  • the compounds described and/or disclosed herein potentiate (i.e., increase activity) of one or more of fast skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. In other instances, the compounds described and/or disclosed herein inhibit (i.e., decrease activity) of one or more of fast skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.
  • activators of the fast skeletal troponin complex have been shown to amplify the response of fast skeletal muscle to nerve stimulation, resulting in an increase in muscle force development at sub-maximal muscle activation (see, e.g., Russell et al., "The Fast Skeletal Troponin Activator, CK-2017357, Increases Skeletal Muscle Force in vitro and in situ", 2009 Experimental Biology Conference, New La, LA, April 2009).
  • Activators of the fast skeletal troponin complex have been shown to increase the sensitivity of skinned skeletal muscle fibers to calcium, and in living muscle to the frequency of
  • a compound or composition described and/or disclosed herein that selectively binds the troponin complex of fast skeletal muscle fiber or sarcomere.
  • the compound disclosed and/or described herein activates fast skeletal muscle fibers or sarcomeres.
  • administration of a compound disclosed and/or described herein results in an increase in fast skeletal muscle power output.
  • administration of a compound disclosed and/or described herein results in increased sensitivity of fast skeletal muscle fibers or sarcomeres to calcium ion, as compared to fast skeletal muscle fibers or sarcomeres untreated with the compound.
  • a compound disclosed and/or described herein results in increased sensitivity of fast skeletal muscle fibers or sarcomeres to calcium ion, as compared to fast skeletal muscle fibers or sarcomeres untreated with the compound.
  • administration of a compound disclosed and/or described herein results in a lower concentration of calcium ions causing fast skeletal muscle myosin to bind to actin. In some embodiments, administration of a compound disclosed and/or described herein results in the fast skeletal muscle fiber generating force to a greater extent at submaximal levels of muscle activation.
  • Also provided is a method for sensitizing a fast skeletal muscle fiber to produce force in response to a lower concentration of calcium ion comprising contacting the fast skeletal muscle fiber with a compound or composition described and/or disclosed herein that selectively binds to troponin complexes in the fast skeletal muscle sarcomere.
  • contacting the fast skeletal muscle fiber with the compound results in activation of the fast skeletal muscle fiber at a lower calcium ion concentration than in an untreated fast skeletal muscle fiber.
  • contacting the fast skeletal muscle fiber with the compound results in the production of increased force at a lower calcium ion concentration in comparison with an untreated fast skeletal muscle fiber.
  • the compound binds to form ligand-troponin-calcium ion complexes that activate the fast skeletal muscle fibers.
  • formation of the complexes and/or activation of the fast skeletal muscle fibers results in enhanced force and/or increased time to fatigue as compared to untreated fast skeletal muscle fibers contacted with a similar calcium ion concentration.
  • the compounds and pharmaceutical compositions described and/or disclosed herein are capable of modulating the contractility of the fast skeletal sarcomere in vivo, and can have application in both human and animal disease. Modulation would be desirable in a number of conditions or diseases, including, but not limited to, 1 ) neuromuscular disorders, such as Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), peripheral neuropathies and myasthenia gravis; 2) disorders of voluntary muscle, including muscular dystrophies, myopathies and conditions of muscle wasting, such as sarcopenia and cachexia syndromes (e.g., cachexia syndromes caused by diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), and chronic kidney disease/dialysis), and rehabilitation-related deficits, such as those associated with recovery from surgery (e.g.
  • central nervous system disorders in which muscle weakness, atrophy and fatigue are prominent symptoms, such as multiple sclerosis, Parkinson's disease, stroke and spinal cord injury; and 4) muscle symptoms stemming from systemic disorders, including Peripheral Vascular Disease (PVD) or Peripheral Arterial Disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity and frailty due to aging.
  • PVD Peripheral Vascular Disease
  • PAD Peripheral Arterial Disease
  • Neuromuscular diseases include, for example: 1 ) diseases of the motor unit, including but not limited to Amyotrophic Lateral Sclerosis (ALS) including bulbar and primary lateral sclerosis (PLS) variants; spinal muscular atrophy types 1 -4; Kennedy syndrome; post-polio syndrome; motor neuropathies including, for example, critical illness polyneuropathy; multifocal motor neuropathy with conduction block; Charcot-Marie-Tooth disease and other hereditary motor and sensory neuropathies; and Guillain- Barre Syndrome, 2) disorders of the neuromuscular junction, including myasthenia gravis, Lambert-Eaton myasthenic syndrome, and prolonged neuromuscular blockade due to drugs or toxins; and 3) peripheral s of the motor unit, including but not limited to Amyotrophic Lateral Sclerosis (ALS) including bulbar and primary lateral sclerosis (PLS) variants; spinal muscular atrophy types 1 -4; Kennedy syndrome; post-polio syndrome; motor neuropathies including, for example, critical illness polyneuropathy; multifocal
  • neuropathies such as acute inflammatory demyelinating
  • demyelinating polyradiculoneuropathy demyelinating polyradiculoneuropathy, traumatic peripheral nerve lesions, neuropathy of leprosy,vasculitic neuropathy, dermatomyositis/polymyositis and neuropathy of Friedreich Ataxia.
  • the compounds and compositions described and/or disclosed herein may be used to treat disorders of voluntary muscle.
  • Disorders of voluntary muscle include 1 ) muscular dystrophies (including, for example, Duchenne, Becker, Limb-Girdle, Facioscapulohumeral, limb girdle, Emery-Dreyfus, oculopharyngeal and congenital muscular dystrophies); and 2) myopathies, such as nemaline myopathy, central core disease, congenital myopathies, mitochondrial myopathies, acute myopathy; inflammatory myopathies (such as dermatomyositis/polymyositis and inclusion body myositis), endocrine myopathies (such as those associated with hyper- or hypothyroidism), Cushing's or Addison's syndrome or disease and pituitary gland disorders, metabolic myopathies (such as glycogen storage diseases, e.g., McArdle's disease, Pompe disese, etc), drug-induced myopathy (
  • ALS Amyotrophic Lateral Sclerosis
  • SMA Spinal Muscular Atrophy
  • Myasthenia gravis is a chronic autoimmune neuromuscular disease wherein the body produces antibodies that block, alter, or destroy proteins involved in signaling at the neuromuscular junction, thus preventing muscle contraction from occurring. These proteins include nicotinic acetylcholine receptor (AChR) or, less frequently, a muscle-specific tyrosine kinase (MuSK) involved in AChR clustering (see, e.g., Drachman, N. Eng. J. of Med., 330:1797-1810, 1994). The disease is characterized by varying degrees of weakness of the skeletal (voluntary) muscles of the body.
  • AChR nicotinic acetylcholine receptor
  • MoSK muscle-specific tyrosine kinase
  • myasthenia gravis The hallmark of myasthenia gravis is muscle weakness that increases during periods of activity and improves after periods of rest.
  • myasthenia gravis may affect any voluntary muscle, certain muscles, such as those that control eye and eyelid movement, facial expression, chewing, talking, and swallowing are often, but not always, involved in the disorder.
  • the muscles that control breathing and neck and limb movements may also be affected.
  • the first noticeable symptom is weakness of the eye muscles.
  • difficulty in swallowing and slurred speech may be the first signs.
  • the degree of muscle weakness involved in myasthenia gravis varies greatly among patients, ranging from a localized form, limited to eye muscles (ocular myasthenia), to a severe or generalized form in which many muscles - sometimes including those that control breathing - are affected.
  • Symptoms which vary in type and severity, may include a drooping of one or both eyelids (ptosis), blurred or double vision (diplopia) due to weakness of the muscles that control eye movements, unstable or waddling gait, weakness in arms, hands, fingers, legs, and neck, a change in facial expression, difficulty in swallowing and shortness of breath, and impaired speech (dysarthria).
  • ptosis eyelids
  • di vision blurred or double vision
  • Generalized weakness develops in approximately 85% of patients.
  • sarcopenia e.g., sarcopenia associated with aging or disease (e.g. HIV infection).
  • Sarcopenia is characterized by a loss of skeletal muscle mass, quality, and strength.
  • Clinically a decline in skeletal muscle tissue mass (muscle atrophy) contributes to frailty in older individuals.
  • muscle atrophy contributes to frailty in older individuals.
  • muscle mass declines by one-third between the ages of 50 and 80.
  • extended hospitalization can result in further disuse atrophy leading to a potential loss of the ability for independent living and to a cascade of physical decline.
  • Muscle weakness is also a major factor prediposing the elderly to falls and the resulting morbidity and mortality.
  • Cachexia is a state often associated with cancer or other serious diseases or conditions, (e.g, chronic obstructive pulmonary disease, heart failure, chronic kidney disease, kidney dialysis), that is characterized by progressive weight loss, muscle atrophy and fatigue, due to the deletion of adipose tissue and skeletal muscle.
  • diseases or conditions e.g, chronic obstructive pulmonary disease, heart failure, chronic kidney disease, kidney dialysis
  • Muscular dystrophy can be characterized by progressive muscle weakness, destruction and regeneration of the muscle fibers, and eventual replacement of the muscle fibers by fibrous and fatty connective tissue.
  • the compounds and compositions described and/or disclosed herein may be used to treat post-surgical muscle weakness, which is a reduction in the strength of one or more muscles following surgical procedure. Weakness may be generalized (i.e. total body weakness) or localized to a specific area, side of the body, limb, or muscle.
  • the compounds and compositions described and/or disclosed herein may be used to treat post-traumatic muscle weakness, which is a reduction in the strength of one or more muscles following a traumatic episode (e.g. bodily injury). Weakness may be generalized (i.e. total body weakness) or localized to a specific area, side of the body, limb, or muscle.
  • Peripheral vascular disease is a disease or disorder of the circulatory system outside of the brain and heart.
  • Peripheral artery disease also known as peripheral artery occlusive disease (PAOD)
  • PAOD peripheral artery occlusive disease
  • PVD and/or PAD can result from, for example, atherosclerosis, inflammatory processes leading to stenosis, embolus/ thrombus formation, or damage to blood vessels due to disease (e.g., diabetes), infection or injury.
  • PVD and/or PAD can cause either acute or chronic ischemia, typically of the legs.
  • the symptoms of PVD and/or PAD include pain, weakness, numbness, or cramping in muscles due to decreased blood flow (claudication), muscle pain, ache, cramp, numbness or fatigue that occurs during exercise and is relieved by a short period of rest (intermittent claudication), pain while resting (rest pain) and biological tissue loss (gangrene).
  • the symptoms of PVD and/or PAD often occur in calf muscles, but symptoms may also be observed in other muscles such as the thigh or hip.
  • Risk factors for PVD and/or PAD include age, obesity, sedentary lifestyle, smoking, diabetes, high blood pressure, and high cholesterol (i.e., high LDL, and/or high triglycerides and/or low HDL). People who have coronary heart disease or a history of heart attack or stroke generally also have an increased frequency of having PVD and/or PAD.
  • Activators of the fast skeletal troponin complex have been shown to reduce muscle fatigue and/or to increase the overall time to fatigue in in vitro and in situ models of vascular insufficiency (see, e.g., Russell et al., "The Fast Skeletal Troponin Activator, CK-2017357, Increases Skeletal Muscle Force and Reduces Muscle Fatigue in vitro and in situ", 5th Cachexia Conference, Barcelona, Spain, December 2009; Hinken et al., "The Fast Skeletal Troponin Activator, CK-2017357, Reduces Muscle Fatigue in an in situ Model of Vascular Insufficiency", Society for Vascular Medicine's 2010 Annual Meeting: 21 st Annual Scientific Sessions, Cleveland, OH, April 2010).
  • frailty e.g., frailty associated with aging.
  • Frailty is characterized by one or more of unintentional weight loss, muscle weakness, slow walking speed, exhaustion, and low physical activity.
  • the compounds and compositions described and/or disclosed herein may be used to treat muscle weakness and/or fatigue due to wasting syndrome, which is a condition characterized by involuntary weight loss associated with chronic fever and diarrhea. In some instances, patients with wasting syndrome lose 10% of baseline body weight within one month.
  • the compounds and compositions described and/or disclosed herein may be used to treat muscular diseases and conditions caused by structural and/or functional abnormalities of skeletal muscle tissue, including muscular dystrophies, congenital muscular dystrophies, congenital myopathies, distal myopathies, other myopathies (e.g., myofibrillar, inclusion body), myotonic syndromes, ion channel muscle diseases, malignant hyperthermias, metabolic myopathies, congenital myasthenic syndromes, sarcopenia, muscle atrophy and cachexia.
  • muscular dystrophies congenital muscular dystrophies, congenital myopathies, distal myopathies, other myopathies (e.g., myofibrillar, inclusion body), myotonic syndromes, ion channel muscle diseases, malignant hyperthermias, metabolic myopathies, congenital myasthenic syndromes, sarcopenia, muscle atrophy and cachexia.
  • the compounds and compositions described and/or disclosed herein also may be used to treat diseases and conditions caused by muscle dysfunction originating from neuronal dysfunction or transmission, including amyotrophic lateral sclerosis, spinal muscular atrophies, hereditary ataxias, hereditary motor and sensory neuropathies, hereditary paraplegias, stroke, multiple sclerosis, brain injuries with motor deficits, spinal cord injuries, Alzheimer's disease, Parkinson's disease with motor deficits, myasthenia gravis and Lambert-Eaton syndrome.
  • diseases and conditions caused by muscle dysfunction originating from neuronal dysfunction or transmission including amyotrophic lateral sclerosis, spinal muscular atrophies, hereditary ataxias, hereditary motor and sensory neuropathies, hereditary paraplegias, stroke, multiple sclerosis, brain injuries with motor deficits, spinal cord injuries, Alzheimer's disease, Parkinson's disease with motor deficits, myasthenia gravis and Lambert-Eaton syndrome.
  • the compounds and compositions described and/or disclosed herein also may be used to treat diseases and conditions caused by CNS, spinal cord or muscle dysfunction originating from endocrine and/or metabolic dysregulation, including claudication secondary to peripheral artery disease, hypothyroidism, hyper- or hypo-parathyroid ism, diabetes, adrenal dysfunction, pituitary dysfunction and acid/base imbalances.
  • compositions described and/or disclosed herein may be administered alone or in combination with other therapies and/or therapeutic agents useful in the treatment of the aforementioned disorders.
  • the compounds and compositions described and/or disclosed herein may be combined with one or more other therapies to treat ALS.
  • suitable therapies include riluzole, baclofen, diazepam, trihexyphenidyl and amitriptyline.
  • the compounds and compositions described and/or disclosed herein are combined with riluzole to treat a subject suffering from ALS.
  • Suitable therapies include administration of anticholinesterase agents (e.g., neostigmine, pyridostigmine), which help improve neuromuscular transmission and increase muscle strength; administration of anticholinesterase agents (e.g., neostigmine, pyridostigmine), which help improve neuromuscular transmission and increase muscle strength; administration of anticholinesterase agents (e.g., neostigmine, pyridostigmine), which help improve neuromuscular transmission and increase muscle strength; administration of
  • immunosuppressive drugs e.g., prednisone, cyclosporine, azathioprine, mycophenolate mofetil
  • thymectomy i.e., the surgical removal of the thymus gland, which often is abnormal in myasthenia gravis patients
  • plasmapheresis i.e., the surgical removal of the thymus gland, which often is abnormal in myasthenia gravis patients
  • intravenous immune globulin e.g., prednisone, cyclosporine, azathioprine, mycophenolate mofetil
  • PVD vascular endothelial artery disease
  • PAD a progressive neurode deficiency artery disease characterized by a wide range of diseases and conditions in which PVD and PAD are associated.
  • Treatment of PVD and PAD is generally directed to increasing arterial blood flow, such as by smoking cessation, controlling blood pressure, controlling diabetes, and exercising.
  • Treatment can also include medication, such as medicines to help improve walking distance (e.g., cilostazol, pentoxifylline), antiplatelet agents (e.g., aspirin, ticlopidine, clopidogrel), anticoagulents (e.g., heparin, low molecular weight heparin, warfarin, enoxaparin) throbmolytics, antihypertensive agents (e.g., diuretics, ACE inhibitors, calcium channel blockers, beta blockers, angiotensin II receptor antagonists), and cholesterol-lowering agents (e.g., statins).
  • angioplasty, stenting, or surgery e.g., bypass surgery or surgery to remove an atherosclerotic plaque
  • surgery e.g., bypass surgery or surgery to remove an atherosclerotic plaque
  • Suitable therapeutic agents include, for example, anti-obesity agents, anti-sarcopenia agents, anti-wasting syndrome agents, anti-frailty agents, anti-cachexia agents, anti-muscle spasm agents, agents against post-surgical and post-traumatic muscle weakness, and anti-neuromuscular disease agents.
  • Suitable additional therapeutic agents include, for example: orlistat, sibramine, diethylpropion, phentermine, benzaphetamine, phendimetrazine, estrogen, estradiol, levonorgestrel, norethindrone acetate, estradiol valerate, ethinyl estradiol, norgestimate, conjugated estrogens, esterified estrogens, medroxyprogesterone acetate, testosterone, insulin-derived growth factor, human growth hormone, riluzole, cannabidiol, prednisone, albuterol, nonsteroidal anti-inflammatory drugs, and botulinum toxin.
  • Suitable therapeutic agents include TRH, diethylstilbesterol, theophylline, enkephalins, E series prostaglandins, compounds disclosed in U.S. Patent No. 3,239,345 (e.g., zeranol), compounds disclosed in U.S.
  • Patent No. 4,036,979 e.g., sulbenox
  • peptides disclosed in U.S. Patent No. 4,41 1 ,890 growth hormone secretagogues such as GHRP-6, GHRP-1 (disclosed in U.S. Patent No.
  • pyridostigmine parathyroid hormone
  • PTH(1 -34) parathyroid hormone
  • bisphosphonates such as MK-217 (alendronate).
  • Still other suitable therapeutic agents include estrogen, testosterone, selective estrogen receptor modulators, such as tamoxifen or raloxifene, other androgen receptor modulators, such as those disclosed in Edwards, J. P. et. al., Bio. Med. Chem. Let., 9, 1003-1008 (1999) and Hamann, L. G. et. al., J. Med. Chem., 42, 210-212 (1999), and progesterone receptor agonists
  • PRA levonorgestrel
  • MPA medroxyprogesterone acetate
  • Suitable therapeutic agents include anabolic agents, such as selective androgen receptor modulators (SARMs); antagonists of the activin receptor pathway, such as anti-myostatin antibodies or soluble activin receptor decoys, including ACE-031 (Acceleron Pharmaceuticals, a soluble activin receptor type MB antagonist), MYO-027/PFE-3446879 (Wyeth/Pfizer, an antibody myostatin inhibitor), AMG-745 (Amgen, a peptibody myostatin inhibitor), and an ActRIIB decoy receptor (see Zhou et al., Cell, 142, 531-543, August 20, 2010); and anabolic steroids.
  • SARMs selective androgen receptor modulators
  • Still other suitable therapeutic agents include aP2 inhibitors, such as those disclosed in U.S. Patent No. 6,548,529, PPAR gamma antagonists, PPAR delta agonists, beta 3 adrenergic agonists, such as AJ9677
  • sibutramine topiramate (Johnson & Johnson) or axokine (Regeneron)
  • a thyroid receptor beta drug such as a thyroid receptor ligand as disclosed in WO 97/21993, WO 99/00353, and GB98/284425
  • anorectic agents such as dexamphetamine, phentermine, phenylpropanolamine or mazindol.
  • HIV and AIDS therapies such as indinavir sulfate, saquinavir, saquinavir mesylate, ritonavir, lamivudine, zidovudine, lamivudine/zidovudine combinations, zalcitabine, didanosine, stavudine, and megestrol acetate.
  • Still other suitable therapeutic agents include antiresorptive agents, hormone replacement therapies, vitamin D analogues, elemental calcium and calcium supplements, cathepsin K inhibitors, MMP inhibitors, vitronectin receptor antagonists, Src SH.sub.2 antagonists, vacuolar H + -ATPase inhibitors, ipriflavone, fluoride, Tibo lone, pro stanoids, 17-beta hydroxysteroid dehydrogenase inhibitors and Src kinase inhibitors.
  • a daily dose ranges from about 0.05 to 100 mg/kg of body weight; in some embodiments, from about 0.10 to 10.0 mg/kg of body weight, and in some embodiments, from about 0.15 to 1 .0 mg/kg of body weight.
  • the dosage range would be about from 3.5 to 7000 mg per day; in some embodiments, about from 7.0 to 700.0 mg per day, and in some embodiments, about from 10.0 to 100.0 mg per day.
  • an exemplary dosage range for oral administration is from about 70 mg to about 700 mg per day
  • an exemplary intravenous administration dosage is from about 70 mg to about 700 mg per day, each depending upon the compound
  • Administration of the compounds and compositions disclosed and/or described herein can be via any accepted mode of administration for therapeutic agents including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration.
  • the compound or composition is administered orally or intravenously.
  • the compound or composition disclosed and/or described herein is administered orally.
  • compositions include solid, semi-solid, liquid and aerosol dosage forms, such as tablet, capsule, powder, liquid, suspension, suppository, and aerosol forms.
  • the compounds disclosed and/or described herein can also be administered in sustained or controlled release dosage forms (e.g., controlled/sustained release pill, depot injection, osmotic pump, or transdermal (including electrotransport) patch forms) for prolonged timed, and/or pulsed administration at a predetermined rate.
  • sustained or controlled release dosage forms e.g., controlled/sustained release pill, depot injection, osmotic pump, or transdermal (including electrotransport) patch forms
  • the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
  • mannitol e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium
  • the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate,
  • the pharmaceutical composition will contain about 0.005% to 95%, or about 0.5% to 50%, by weight of a compound disclosed and/or described herein.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
  • the compositions will take the form of a pill or tablet and thus the composition may contain, along with a compounds disclosed and/or described herein, one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and/or a binder (e.g., starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives).
  • a diluent e.g., lactose, sucrose, dicalcium phosphate
  • a lubricant e.g., magnesium stearate
  • a binder e.g., starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives.
  • Other solid dosage forms include a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides)
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing or suspending etc. a compound disclosed and/or described herein and optional pharmaceutical additives in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension.
  • a carrier e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like
  • injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection.
  • the percentage of the compound contained in such parenteral compositions depends, for example, on the physical nature of the compound, the activity of the compound and the needs of the subject.
  • composition will comprise from about 0.2 to 2% of a compound disclosed and/or described herein in solution.
  • compositions of the compounds disclosed and/or described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of the pharmaceutical composition may have diameters of less than 50 microns, or in some embodiments, less than 10 microns.
  • compositions can include a compound disclosed and/or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, and the like.
  • additional medicinal agents include those described herein.
  • Example 1 Preparation of N-(5-(6-(2-(4-Fluorophenyl)-2- methylpropylamino)pyridazin-3-yl)-1 H-indazol-3-yl)acetamide
  • Step 1 To a solution of pyrazole (3.69 g, 25 mmol, 1 .0 equiv) in NMP (25 ml_) was added sodium hydride (60% dispersion in mineral oil, 1 .5 g, 38 mmol, 1 .5 equiv). The mixture was stirred for 15 min, followed by the addition of 3,6-dichloropyridazine (3.02 g, 25 mmol, 1 .0 equiv). The reaction mixture was stirred for 1 .5 h and then diluted with water (50 ml_) and ethyl acetate (100 ml_).
  • Step 2 To a 5 mL microwave vial was added 3-chloro-6-(1 H-pyrazol-1 - yl)pyridazine (320 mg, 1 .8 mmol, 1 .0 equiv), 2-(4-fluorophenyl)-2- methylpropan-1 -amine (386 mg, 2.3 mmol, 1 .3 equiv), diisopropylethylamine (620 ⁇ , 3.6 mmol, 2.0 equiv), and NMP (4 mL). The reaction was heated in a microwave reactor to 250 °C and stirred for 15 min.
  • Methyl 6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-3- carboxylate To a 25 mL round bottom flask was added methyl 6- chloropyridazine-3-carboxylate (0.50 g, 2.90 mmol, 1 .0 equiv), 2-(4- fluorophenyl)-2-methylpropan-1 -amine (0.60 g, 3.6 mmol, 1 .2 equiv), potassium carbonate (300 mg, 2.2 mmol, 0.75 equiv), and isopropanol (3 mL). The reaction mixture was stirred and heated at 120 °C for 12 h.
  • Tributyl(1 -ethoxyvinyl)stannane (475 ⁇ , 1 .4 mmol, 1 .3 equiv) and trans-dichlorobis(triphenylphosphine)palladium (30 mg, 0.04 mmol, 0.03 equiv) were then added, and the reaction was heated in a microwave reactor at 150 °C for 20 min.
  • the reaction was concentrated, dissolved in EtOAc (25 mL), and mixed with 2.0 M potassium fluoride (5 mL). The mixture was filtered through celite, and then washed with water, dried over Na 2 SO , filtered, and concentrated.
  • the crude solid was redissolved in 50%
  • Step 1 To a 5 mL microwave reaction vial was added 6-chloro-N-(2- (4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine (123 mg, 441 ⁇ , 1 .0 equiv), 2,4,6-trivinyl-1 ,3,5,2,4,6-trioxatriborinane (159 mg, 661 ⁇ , 1 .5 equiv), CI 2 Pd(dppf) (54 mg, 66 ⁇ , 0.15 equiv), potassium carbonate (182 mg, 1 .32 mmol, 3 equiv), and dioxane (21 mL).
  • the reaction was heated in a microwave reactor at 140 °C for 12 min and then diluted with water (20 mL) and ethyl acetate (50 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (1 x 20 mL). The organic layer was then dried over
  • Methyl 6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazine-3-carboxylate To a 20 dram vial was added methyl 6-chloropyridazine-3-carboxylate (510 mg, 2.7 mmol, 1 .0 equiv), (1 -(3-fluoropyridin-2-yl)cyclobutyl)methanamine (738 mg, 4 mmol, 1 .5 equiv), DIPEA (0.7 mL, 4 mmol, 1 .5 equiv), and NMP (2 mL).
  • Example 8 Preparation of 1 -(6-((1 -(3-Fluoropyridin-2- l)cyclobutyl)methylamino)pyridazin-3-yl)ethanone
  • 6-((1 -(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazine-3- carbonitrile To a 20 dram vial was added 6-chloropyridazine-3-carbonitrile (1 .0 g, 7.2 mmol, 1 .0 equiv), (1 -(3-fluoropyridin-2-yl)cyclobutyl)methanamine (1 .36 g, 7.6 mmol, 1 .05 equiv), triethylamine (2.1 mL, 14.4 mmol, 2.0 equiv), and NMP (2 mL).
  • the reaction was heated at 130 °C for 12 h and then diluted with water (20 ml_) and ethyl acetate (50 ml_). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (1 x 20 ml_). The organic layer was then dried over Na 2 SO 4 , filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (20-30%
  • reaction was then concentrated, followed by the addition of te/t-butyl 6-bromopyridazin-3-yl(2-(4-fluorophenyl)-2- methylpropyl)carbamate (423 mg, 1 .0 mmol, 1 .0 equiv), Pd(Ph 3 P) 4 (172 mg, 0.15 mmol, 0.15 equiv), and DMF (3.3 ml_).
  • the reaction was stirred and heated to 100 °C for 3 h. After cooling to room temperature, the reaction was diluted with aqueous potassium fluoride (5 mL), extracted with ethyl acetate (20 mL) and washed with brine (20 mL).
  • the reaction was concentrated, brought to pH of 1 1 through the addition of saturated potassium carbonate (20 mL), and then diluted with ethyl acetate (50 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and washed with lithium chloride (1 x 20 mL). The organic layer was then dried over Na 2 SO 4 , filtered, and concentrated to give 3-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)pyridin-2-ol (1 .6 g, 95%) as a tan powder.
  • the isolated product (1 .3 g, 3.7 mmol, 1 .0 equiv) was transferred to a 100 mL round bottom flask, followed by the addition of a mixture of phosphorous oxytrichloride (24 mL) and DMF (8 mL). The reaction was heated to 90 °C and stirred for 6 h. The reaction was concentrated and carefully quenched with a 50% mixture of saturated sodium bicarbonate and lithium chloride until gas evolution ceased. The mixture was extracted with ethyl acetate (100 mL). The combined organic layers were then dried over Na 2 SO , filtered, concentrated, and purified by silica gel column
  • 6-(2-Aminopyridin-3-yl)-N-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)pyridazin-3-amine 6-(2-chloropyridin-3-yl)-N-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)pyridazin-3-amine (750 mg, 2.0 mmol), hydrazine hydrate (1 mL), and dioxane (4 mL).
  • Benzyl 2-(5-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)-1 H-indazol-3- ylamino)ethylcarbamate 48 mg, 84 ⁇ was dissolved in acetonitrile (5 mL), and TMSI (0.5 mL) was added.
  • Example 13 Preparation of 6-(5-Aminopyridin-2-yl)-N-((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine 2-Bromo-5-(2,5-dimethyl-1 H-pyrrol-1 -yl)pyridine.
  • 6-(5-Aminopyridin-2-yl)-N-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)pyridazin-3-amine was added to a 20 dram vial.
  • This product was transferred to a 100 mL round bottom flask to which was added hydroxylamine hydrochloride (270 mg), triethylamine (5 mL), and ethanol (20 mL). The reaction mixture was heated to reflux overnight and then concentrated, diluted with sodium bicarbonate (20 mL) and extracted with ethyl acetate (40 mL).
  • 6-Chloro-3-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-4- carboxamide 6-Chloro-3-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-4- carboxamide.
  • 3,6- dichloropyridazine-4-carboxamide 2.6 g, 13 mmol, 1 .0 equiv
  • (2-(4- fluorophenyl)-2-methylpropan-1 -amine 2.5 g, 15 mmol, 1 .1 equiv
  • diisopropylethylamine 2.8 ml_, 16 mmol, 1 .2 equiv
  • CH 3 CN 54 mL
  • 6-Chloro-3-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-4- carbonitrile To a portion of 6-chloro-3-(2-(4-fluorophenyl)-2- methylpropylamino)pyridazine-4-carboxamide (3.4 g, 1 1 mmol, 1 .0 equiv) was added POCI3 (10 mL) at room temperature. The mixture was stirred at reflux for 3 hours and then quenched by pouring it into ice water containing
  • 1 -(3-Fluoropyridin-2-yl)cyclobutanecarboxamide To a 250 mL round bottom flask containing DMSO (60 mL), 1 -(3-fluoropyridin-2- yl)cyclobutanecarbonitrile (2.96 g, 16.8 mmol, 1 .0 equiv) was added and the mixture was stirred until homogenous. Potassium carbonate (7.0 g, 50.4 mmol, 3.0 equiv) was then added and the reaction mixture was cooled to 0 °C, followed by the addition of 35% hydrogen peroxide (6.5 mL). The reaction was stirred at 0 °C for 30 min and then warmed to room temperature.
  • reaction was diluted with water (50 mL) and ethyl acetate (100 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (3 x 50 mL). The organic layer was then dried over Na 2 SO , filtered, and concentrated to give a crude solid that was purified by silica gel chromatography (10%
  • 1 -(3- fluoropyridin-2-yl)cyclobutanecarboxamide (1 .92 g, 9.88 mmol, 1 .0 equiv) was dissolved in methanol (20 mL) and potassium hydroxide (1 .1 1 g, 19.8 mmol, 2.0 equiv) was added. The mixture was sonicated until homogeneous, followed by the addition of iodosobenzene diacetate (4.77 g, 14.8 mmol, 1 .5 equiv).
  • the reaction was warmed to 0 °C, stirred for 30 min, and added to a stirring mixture of i-butyl 6- chloropyridazin-3-yl((1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (100 g, 0.26 mol), tetrakis(triphenylphosphine)palladium(0) (56 g, 0.05 mol), and THF (2000 mL) heated to 80 °C. The reaction mixture was stirred overnight at 80 °C. The reaction was concentrated and then slurried in ethyl acetate and brine.
  • f-butyl 6-(5-(chloromethyl)thiazol-2-yl)pyridazin-3-yl((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)carbamate To a solution of f-butyl (1 - (3-fluoropyhdin-2-yl)cyclobutyl)methyl(6-(5-(hydroxymethyl)thiazol-2- yl)pyridazin-3-yl)carbannate (44.1 g, 93.8 mmol) in dioxane (235 mL) was added thionyl chloride (27.3 mL, 375.3 mmol). The reaction was stirred until it was homogeneous.
  • f-butyl 6-(5-(cyanomethyl)thiazol-2-yl)pyridazin-3-yl((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)carbamate To a solution of f-butyl 6- (5-(chloromethyl)thiazol-2-yl)pyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate (33.1 g, 68 mmol) in CH 2 CI 2 (450 mL) was added tetrabutylammonium cyanide (36 g, 135 mmol).
  • f-butyl 6-(5-(Azidomethyl)thiazol-2-yl)pyridazin-3-yl((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)carbamate To a stirring solution of f- butyl 6-(5-(chloromethyl)thiazol-2-yl)pyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate (60.7 g, 124 mmol) in DMF (800 mL) was added sodium azide (22.2 g, 341 mmol) and DIPEA (31 .1 mL, 171 mmol).
  • reaction was heated to 60 °C and stirred for 1 h.
  • the reaction was poured into ethyl acetate (2000 mL), washed with water (3x400 mL), and the combined organic layers were separated, dried over Na 2 SO , filtered, concentrated, and purified by silica gel chromatography (EtOAC/hexanes) to afford 20.0 g of f-butyl 6-(5-(azidomethyl)thiazol-2-yl)pyridazin-3-yl((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a yellow oil.
  • f-butyl 6-(5-(Aminomethyl)thiazol-2-yl)pyridazin-3-yl((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)carbamate Tin(ll) chloride dihydrate (15.5 g, 80 mmol) was added to a solution of f-butyl 6-(5-(azidomethyl)thiazol- 2-yl)pyridazin-3-yl((1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (20 g, 40 mmol) in methanol (400 mL) and the reaction was stirred at rt for 30 min. The reaction was poured into ethyl acetate (1000 mL), washed with water (3x200 mL), and the combined organic layers were separated, dried over Na 2 SO , filtered, concentrated, and purified using silica gel column
  • f-butyl 6-(3-Cyano-1 H-pyrrol-1 -yl)pyridazin-3-yl((1 -(3-fluoropyridin- 2-yl)cyclobutyl)methyl)carbamate To a stirring solution of f-butyl 6- fluoropyridazin-3-yl((1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (200 mg, 551 ⁇ ) in DMF (2 mL) was added 3-cyanopyrrole (61 mg, 661 ⁇ ) and potassium carbonate (152 mg, 1 .1 mmol). The reaction was heated to 1 10 °C and stirred for 30 min.
  • f-butyl 6-Carbamothioylpyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate NMP (40 mL) and DIPEA (10 mL) were added to f-butyl 6-cyanopyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate (3.9 g, 10 mmol), and hydrogen sulfide was bubbled through the reaction mixture for 2 h.
  • diethylbromomalonate (2 mL, 12 mmol), and toluene were added to a round bottom flask, heated to 90 °C, and stirred for 40 min.
  • the reaction was concentrated and purified using reverse phase chromatography to yield 219 mg of ethyl 2-(6-(f-butoxycarbonyl((1 -(3-fluoropyhdin-2- yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-hydroxy-2,5-dihydrothiazole-5- carboxylate as an off-white solid.
  • Example 28 Preparation of 4-fluoro-3-(6-(((frans)-3-fluoro-1 -(3- fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-2- hydroxybenzamide
  • Example 30 Preparation of 5-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)-1 H-pyrazole-3-carboxamide f-Butyl 6-(1 -ethoxyvinyl)pyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate.
  • f-Butyl (1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-vinylpyridazin- 3-yl)carbamate f-Butyl 6-chloropyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate (2.5 g, 6.36 mmol), triethenylboroxin pyridine complex (1 .0 g, 4.13 mmol), Pd(PPh 3 ) 4 (0.3 g, 0.25 mmol), nitrogen-sparged dioxane (13.2 mL) and aq.
  • the crude mixture was then diluted in THF (2 mL) and pyridine (57 mg, 0.72 mmol) then treated with NCS (0.58 g, 4.35 mmol) and heated to 40 °C for 1 .5 h.
  • the crude mixture was then treated with methyl propiolate (0.30 g, 3.56 mmol) and TEA (0.36, 3.56 mmol), and the reaction was stirred for 45 min.
  • the reaction mixture was concentrated and diluted with EtOAc, and then washed with satd. aq. NaHCO3 and brine.
  • the organic layer was dried over sodium sulfate, filtered, concentrated, and
  • f-Butyl 6-(5-cyanothiophen-2-yl)pyridazin-3-yl((1 -(3-fluoropyridin- 2-yl)cyclobutyl)methyl)carbamate f-Butyl 6-chloropyridazin-3-yl((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (900 mg, 2.29 mmol, 1 equiv), 5-cyanothiophen-2-ylboronic acid (390 mg, 2.52 mmol, 1 .1 equiv), (dppf)PdCI 2 (164 mg, 0.23 mmol, 0.1 equiv), nitrogen-sparged dioxane (6.0 mL) and aq.
  • Example 36 Preparation of 6-(5-(1 H-pyrazol-3-yl)thiazol-2-yl)-N-((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine f-Butyl 6-(5-bromothiazol-2-yl)pyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate.
  • reaction mixture was then was poured into ethyl acetate (200 mL), washed with water (100 mL), dried over Na 2 SO , filtered, concentrated, and purified by silica gel chromatography (EtOAc/hex) to afford 1 .8 g of f-butyl 6-(5- bromothiazol-2-yl)pyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate.
  • Example 37 Preparation of 6-(6-((fraA7s-3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)imidazo[2,1 -b]thiazole-3- carboxami
  • Ethyl 6-(6-chloropyridazin-3-yl)imidazo[2,1 -b]thiazole-3- carboxylate To a 20 dram vial was added 2-bromo-1 -(6-chloropyridazin-3- yl)ethanone (4.2 g, 18 mmol), ethyl-2-aminothiazole-4-carboxylate (3.1 g, 18 mmol), and methylethyl ketone (40 mL). The mixture was heated to 90 °C and stirred overnight.
  • Ethyl 6-(6-fluoropyridazin-3-yl)imidazo[2,1 -b]thiazole-3- carboxylate To a 20 dram vial was added ethyl 6-(6-chloropyridazin-3- yl)imidazo[2,1 -b]thiazole-3-carboxylate (1 .0 g, 3.2 mmol), 1 ,8- bis(dimethylamino)naphthalene (1 .4 g, 6.4 mmol), and Et 3 N-3HF (30 mL). The reaction was heated in a microwave to 140 °C and stirred for 1 .5 h.
  • reaction mixture was poured into ethyl acetate (100 mL), washed with water (50 mL), dried over Na 2 SO 4 , filtered, concentrated, and purified by silica gel chromatography to afford 760 mg of ethyl 6-(6-fluoropyridazin-3- yl)imidazo[2,1 -b]thiazole-3-carboxylate as a yellow solid.
  • Example 38 Preparation of 4-Fluoro-3-(6-(((frans)-3-fluoro-1 -(3- fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)benzamide and 4-fluoro-3-(6-(((c s)-3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)benzamide
  • Myofibrils were prepared from rabbit psoas muscle purchased from Pel-Freez Biologicals (Arkansas) within 2 days of ordering, stored on ice. Minced muscle was homogenized in 10 volumes of ice-cold "standard" buffer (50mM Tris, pH 7.4, 0.1 M potassium acetate, 5 mM KCI, 2 mM DTT, 0.2 mM PMSF, 10 ⁇ leupeptin, 5 ⁇ pepstatin, and 0.5 mM sodium azide) containing 5 mM EDTA and 0.5% Triton X-100 using an Omni- Macro homogenizer.
  • standard buffer 50mM Tris, pH 7.4, 0.1 M potassium acetate, 5 mM KCI, 2 mM DTT, 0.2 mM PMSF, 10 ⁇ leupeptin, 5 ⁇ pepstatin, and 0.5 mM sodium azide
  • Myofibrils were recovered by low speed centrifugation (3000 rpm for 10 minutes) and washed 2 times in the Triton X-100 containing buffer to ensure removal of cellular membrane. Following the Triton washes, myofibrils were washed 3 times in "standard" buffer containing 2 mM magnesium acetate. A final wash in assay buffer (12 mM PIPES, pH 6.8, 60 mM KCI, 1 mM DTT) was performed and brought to 10% sucrose for flash freezing in liquid nitrogen and storage at -80°C.
  • Fast fiber activators were identified by measuring the enzymatic activity of muscle myofibril preparations
  • Drying Place the filtered residue spread on a cheesecloth in a large glass tray and leave in a hood overnight. When the residue is dry, put in a wide mouth plastic bottle and store at 20 °C.
  • Extract buffer see below. Homogenize the meat in a blender, 4 times 15 sec on blend with 15 sees in between. Do this with 1 volume (weight/volume) of buffer taken from the 5 volumes already prepared. Add the homogenate back to the extract buffer and stir until well mixed (5 minutes).
  • Step 3 Repeat Step 3 four more times. At the end, do not resuspend in extraction buffer but proceed to Step 5.
  • the pellets should be yellow white.
  • Step 6 a total of three times.
  • EXTRACT BUFFER 50 mM KCI, 5 mM Tris pH 8.0 Prepare as 50 times concentrate. For 2L: 250 mM Tris pH 8.0. Tris Base (121 .14 g/mol, 60.6 g), pH to 8.0 with cone. HCI, then add 2.5 M KCI (74.55 g/mol, 372 g).
  • G-Actin Collect supernatant (G-Actin). Save a sample for gel analysis and determination of protein concentration. 12. To polymerize G-actin for storage, add KCI to 50 mM (from 3 M stock), MgCI 2 to 1 mM, and NaN 3 to 0.02% (from 10% stock). Store at 4 °C. Do not freeze.
  • Buffer A 2 mM tris/HCI, 0.2 mM CaCI 2 , 0.5 mM (36 ⁇ /L) 2-mercaptoethanol,
  • Solution A 0.3 M KCI, 0.15 M potassium phosphate, 0.02 M EDTA, 0.005 M MgCI 2 , 0.001 M ATP, pH 6.5.
  • Solution B 1 M KCI, 0.025 M EDTA, 0.06 M potassium phosphate, pH 6.5.
  • Solution C 0.6 M KCI, 0.025 M potassium phosphate, pH 6.5.
  • Solution D 0.6 M KCI, 0.05 M potassium phosphate, pH 6.5.
  • Solution E 0.15 M potassium phosphate, 0.01 M EDTA, pH 7.5.
  • Solution F 0.04 M KCI, 0.01 M potassium phosphate, 0.001 M DTT, pH 6.5.
  • Solution G 3 M KCI, 0.01 M potassium phosphate, pH 6.5.
  • the myosin is then cut with chymotrypsin or papain in the presence of EDTA to generate the S1 fragment which is soluble at the low salt conditions optimal for ATPase activity (Margossian, supra).
  • Myosin is prepared by precipitation from salt extracts of rabbit psoas muscle, and a soluble S1 fraction is prepared by digestion with chymotrypsin (Margossian and Lowey, 1982).
  • Actin is purified by first preparing an ether powder of cardiac muscle (Zot HG and Potter J D. (1981 ) Preparative Biochemistry 1 1 :381 -395) as described above. Subsequently, actin is cycled between the filamentous and soluble state through rounds of centrifugation and dialysis (Spudich J A and Watt S. (1971 ) J. Biol. Chem. 246:4866-4871 ).
  • Tropomyosin is extracted from the ether powder and separated from the other proteins based on pH dependent precipitations followed by successive ammonium sulfate cuts at 53% and 65% (Smillie LB. (1981 ) Methods Enzymol 85 Pt B:234-41 ).
  • the troponins are isolated as an intact complex of TnC, TnT, and Tnl.
  • Ether powder is extracted in a high salt buffer. Successive ammonium sulfate cuts of 30% and 45% are done; the precipitate is solubilized by dialysis into a low salt buffer and then further purified on a DEAE Toyopearl column with a 25-350 mM KCI gradient. There is no measurable ATPase in any of the components except for myosin which naturally had a very low basal ATPase in the absence of actin.
  • the actin, tropomyosin, and troponin complex Prior to screening, the actin, tropomyosin, and troponin complex are mixed together in the desired ratio (e.g., 7:1 :1 ) to achieve maximal calcium regulation of the actin filament.
  • the screen is conducted at a concentration that gives 25% activation. This calcium concentration is in the physiological range during muscle contraction.
  • a pyruvate kinase/lactate dehydrogenase/NADH coupled enzyme system (PK/LDH) is added to the actin.
  • the myosin is kept separately, and added to the regulated thin filaments to initiate the reaction. Oxidation of NADH is monitored in real time, so that kinetic curves are obtained.
  • Compounds are dissolved in DMSO and spotted onto the bottoms of 384 well plates at 10 to 40 g/ml final concentration.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Cardiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Child & Adolescent Psychology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

Provided are compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, X and m are as defined herein. Also provided is a pharmaceutically acceptable composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof. Also provided are methods of using a compound of Formula I, or a pharmaceutically acceptable salt thereof.

Description

Certain Amino-Pyridazines, Compositions Thereof, and
Methods of Their Use
This application claims the benefit of U.S. Provisional Application Nos. 61/327,538, filed April 23, 2010, and 61/412,302, filed November 10, 2010, each of which is incorporated by reference in its entirety for all purposes.
The cytoskeleton of skeletal and cardiac muscle cells is unique compared to that of all other cells. It consists of a nearly crystalline array of closely packed cytoskeletal proteins called the sarcomere. The sarcomere is elegantly organized as an interdigitating array of thin and thick filaments. The thick filaments are composed of myosin, the motor protein responsible for transducing the chemical energy of ATP hydrolysis into force and directed movement. The thin filaments are composed of actin monomers arranged in a helical array. There are four regulatory proteins bound to the actin filaments, which allows the contraction to be modulated by calcium ions. An influx of intracellular calcium initiates muscle contraction; thick and thin filaments slide past each other driven by repetitive interactions of the myosin motor domains with the thin actin filaments.
Of the thirteen distinct classes of myosin in human cells, the myosin-ll class is responsible for contraction of skeletal, cardiac, and smooth muscle. This class of myosin is significantly different in amino acid composition and in overall structure from myosin in the other twelve distinct classes. Myosin-ll forms homo-dimers resulting in two globular head domains linked together by a long alpha-helical coiled-coiled tail to form the core of the sarcomere's thick filament. The globular heads have a catalytic domain where the actin binding and ATPase functions of myosin take place. Once bound to an actin filament, the release of phosphate (cf. ADP-Pi to ADP) signals a change in structural conformation of the catalytic domain that in turn alters the orientation of the light-chain binding lever arm domain that extends from the globular head; this movement is termed the powerstroke. This change in orientation of the myosin head in relationship to actin causes the thick filament of which it is a part to move with respect to the thin actin filament to which it is bound. Unbinding of the globular head from the actin filament (Ca2+ regulated) coupled with return of the catalytic domain and light chain to their starting conformation/orientation completes the catalytic cycle, responsible for intracellular movement and muscle contraction.
Tropomyosin and troponin mediate the calcium effect on the interaction on actin and myosin. The troponin complex is comprised of three polypeptide chains: troponin C, which binds calcium ions; troponin I, which binds to actin; and troponin T, which binds to tropomyosin. The skeletal troponin- tropomyosin complex regulates the myosin binding sites extending over several actin units at once.
Troponin, a complex of the three polypeptides described above, is an accessory protein that is closely associated with actin filaments in vertebrate muscle. The troponin complex acts in conjunction with the muscle form of tropomyosin to mediate the Ca2+ dependency of myosin ATPase activity and thereby regulate muscle contraction. The troponin polypeptides T, I, and C, are named for their tropomyosin binding, inhibitory, and calcium binding activities, respectively. Troponin T binds to tropomyosin and is believed to be responsible for positioning the troponin complex on the muscle thin filament. Troponin I binds to actin, and the complex formed by troponins I and T, and tropomyosin inhibits the interaction of actin and myosin. Skeletal troponin C is capable of binding up to four calcium molecules. Studies suggest that when the level of calcium in the muscle is raised, troponin C exposes a binding site for troponin I, recruiting it away from actin. This causes the tropomyosin molecule to shift its position as well, thereby exposing the myosin binding sites on actin and stimulating myosin ATPase activity.
Human skeletal muscle is composed of different types of contractile fibers, classified by their myosin type and termed either slow or fast fibers. Table 1 summarizes the different proteins that make up these types of muscle. Table 1
Figure imgf000004_0001
*MHC Mb is not expressed in human muscle but is present in rodents and other
mammals.
In healthy humans most skeletal muscles are composed of both fast and slow fibers, although the proportions of each vary with muscle type. Slow skeletal fibers, often called type I fibers, have more structural similarity with cardiac muscle and tend to be used more for fine and postural control. They usually have a greater oxidative capacity and are more resistant to fatigue with continued use. Fast skeletal muscle fibers, often called type II fibers, are classified into fast oxidative (I la) and fast glycolytic (type llx/d) fibers. While these muscle fibers have different myosin types, they share many
components including the troponin and tropomyosin regulatory proteins. Fast skeletal muscle fibers tend to exert greater force but fatigue faster than slow skeletal muscle fibers and are functionally useful for acute, large scale movements such as rising from a chair or correcting falls.
Muscle contraction and force generation is controlled through nervous stimulation by innervating motor neurons. Each motor neuron may innervate many (approximately 100-380) muscle fibers as a contractile whole, termed a motor unit. When a muscle is required to contract, motor neurons send stimuli as nerve impulses (action potentials) from the brain stem or spinal cord to each fiber within the motor unit. The contact region between nerve and muscle fibers is a specialized synapse called the neuromuscular junction (NMJ). Here, membrane depolarizing action potentials in the nerve are translated into an impulse in the muscle fiber through release of the
neurotransmitter acetylcholine (ACh). ACh triggers a second action potential in the muscle that spreads rapidly along the fiber and into invaginations in the membrane, termed t-tubules. T-tubules are physically connected to Ca2+ stores within the sarcoplasmic reticulum (SR) of muscle via the
dihydropyridine receptor (DHPR). Stimulation of the DHPR activates a second Ca2+ channel in the SR, the ryanodine receptor, to trigger the release of Ca2+ from stores in the SR to the muscle cytoplasm where it can interact with the troponin complex to initiate muscle contraction. If muscle stimulation stops, calcium is rapidly taken back up into the SR through the ATP
dependent Ca2+ pump, SERCA.
Muscle function can become compromised in disease by many mechanisms. Examples include the frailty associated with old age (termed sarcopenia) and cachexia syndromes associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), and chronic kidney disease/dialysis. Severe muscular dysfunction can arise from neuromuscular diseases (such as Amyotrophic Lateral Sclerosis (ALS), spinal muscular atrophy (SMA) and myasthenia gravis) or muscular myopathies (such as muscular dystrophies). Additionally, muscle function may become compromised due to rehabilitation-related deficits, such as those associated with recovery from surgery (e.g. post-surgical muscle weakness), prolonged bed rest, or stroke rehabilitation. Additional examples of diseases or conditions where muscle function becomes compromised include peripheral vascular disease (e.g., claudication), chronic fatigue syndrome, metabolic syndrome, and obesity.
Accordingly, there is a need for the development of new compounds that modulate skeletal muscle contractility. There remains a need for agents that exploit new mechanisms of action and which may have better outcomes in terms of relief of symptoms, safety, and patient mortality, both short-term and long-term and an improved therapeutic index.
Provide is a compound of Formula I:
Figure imgf000006_0001
Formula I
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, X and m are as defined herein.
Also provided is a pharmaceutically acceptable composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Also provided are methods for treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere, for example, modulation of the troponin complex of the fast skeletal muscle sarcomere through one or more of fast skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.
As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
Throughout this application, unless the context indicates otherwise, references to a compound of Formula I includes all subgroups of Formula I defined herein, including all substructures, subgenera, preferences, embodiments, examples and particular compounds defined and/or described herein.
References to a compound of Formula I and subgroups thereof include ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co- crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes and/or protected forms thereof. "Crystalline form," "polymorph," and "novel form" may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), co-crystals, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to. In some embodiments, references to a compound of Formula I and subgroups thereof include polymorphs, solvates, co-crystals, isomers, tautomers and/or oxides thereof. In some embodiments, references to a compound of Formula I and subgroups thereof include polymorphs, salts, solvates, and/or co- crystals thereof. In some embodiments, references to a compound of
Formula I and subgroups thereof include isomers, tautomers and/or oxides thereof. In some embodiments, references to a compound of Formula I and subgroups thereof include solvates thereof. Similarly, the term "salts" includes solvates of salts of compounds.
By "optional" or "optionally" is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more
substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non- feasible, and/or inherently unstable.
When a range of values is given (e.g., C-i-6 alkyl), each value within the range as well as all intervening ranges are included. For example, "C-i-6 alkyl" includes C-i , C2, C3, C4, C5, C6, C-i-6, C2-6, C3-6, C4-6, C5-6, C-i-5, C2-5, C3-5, C4-5, C-i-4, C-2-4, C3-4, C-i-3, C2-3, and C-i-2 alkyl.
When a moiety is defined as being optionally substituted, it may be substituted as itself or as part of another moiety. For example, if Rx is defined as "C-i-6 alkyl or OC-i-6 alkyl, wherein C-i-6 alkyl is optionally subsituted with halogen", then both the C-i-6 alkyl group alone and the C-i-6 alkyl that makes up part of the OC-i-6 alkyl group may be substituted with halogen.
"Alkyl" encompasses straight and branched carbon chains having the indicated number of carbon atoms, for example, from 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms. For example, C-i-6 alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms. When an alkyl residue having a specific number of carbons is named, all branched and straight chain versions having that number of carbons are intended to be encompassed; thus, for example, "propyl" includes n-propyl and isopropyl; and "butyl" includes n-butyl, sec-butyl, isobutyl and t-butyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. "Lower alkyl" refers to alkyl groups having 1 to 6 carbons.
"Haloalkyl" includes straight and branched carbon chains having the indicated number of carbon atoms (e.g., 1 to 6 carbon atoms) substituted with at least one halogen atom. In instances wherein the haloalkyl group contains more than one halogen atom, the halogens may be the same (e.g.,
dichloromethyl) or different (e.g., chlorofluoromethyl). Examples of haloalkyl groups include, but are not limited to, chloromethyl, dichloromethyl,
trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl,
chlorofluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,
1 ,2-difluoroethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl,
1 ,2-dichloroethyl, pentachloroethyl, and pentafluoroethyl.
"Alkenyl" refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one carbon-carbon double bond derived by the removal of one molecule of hydrogen from adjacent carbon atoms of the corresponding alkyl. The group may be in either the cis or trans configuration (Z or E configuration) about the double bond(s). Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1 -en-1 -yl, prop-1 -en-2-yl, prop- 2-en-1 -yl (allyl), prop-2-en-2-yl), and butenyl (e.g., but-1 -en-1 -yl, but-1 -en-2-yl, 2-methyl-prop-1 -en-1 -yl, but-2-en-1 -yl, but-2-en-1 -yl, but-2-en-2-yl, buta-1 ,3- dien-1 -yl, buta-1 ,3-dien-2-yl). "Lower alkenyl" refers to alkenyl groups having 2 to 6 carbons.
"Alkynyl" refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond derived by the removal of two molecules of hydrogen from adjacent carbon atoms of the corresponding alkyl. Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1 -yn-1 -yl, prop-2-yn-1 -yl) and butynyl (e.g., but-1 -yn-1 -yl, but-1 -yn-3-yl, but-3-yn-1 -yl). "Lower alkynyl" refers to alkynyl groups having 2 to 6 carbons.
"Cycloalkyi" indicates a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, for example, 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms. Cycloalkyi groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyi groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl and cyclohexyl, as well as bridged and caged ring groups (e.g., norbornane, bicyclo[2.2.2]octane). In addition, one ring of a polycyclic cycloalkyi group may be aromatic, provided the polycyclic cycloalkyi group is bound to the parent structure via a non- aromatic carbon. For example, a 1 ,2,3,4-tetrahydronaphthalen-1 -yl group (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is a cycloalkyi group, while 1 ,2,3,4-tetrahydronaphthalen-5-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a cycloalkyi group. Examples of polycyclic cycloalkyi groups consisting of a cycloalkyi group fused to an aromatic ring are described below.
"Cycloalkenyl" indicates a non-aromatic carbocyclic ring, containing the indicated number of carbon atoms (e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms) and at least one carbon-carbon double bond derived by the removal of one molecule of hydrogen from adjacent carbon atoms of the corresponding cycloalkyi. Cycloalkenyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and
cyclohexenyl, as well as bridged and caged ring groups (e.g.,
bicyclo[2.2.2]octene). In addition, one ring of a polycyclic cycloalkenyl group may be aromatic, provided the polycyclic alkenyl group is bound to the parent structure via a non-aromatic carbon atom. For example, inden-1 -yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is considered a cycloalkenyl group, while inden-4-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a cycloalkenyl group. Examples of polycyclic cycloalkenyl groups consisting of a cycloalkenyl group fused to an aromatic ring are described below. "Aryl" indicates an aromatic carbon ring having the indicated number of carbon atoms, for example, 6 to 12 or 6 to 10 carbon atoms. Aryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some instances, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other instances, polycyclic aryl groups may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to an aromatic ring, provided the polycyclic aryl group is bound to the parent structure via an atom in the aromatic ring. Thus, a 1 ,2,3,4- tetrahydronaphthalen-5-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1 ,2,3,4-tetrahydronaphthalen-1 -yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered an aryl group. Similarly, a 1 ,2,3,4-tetrahydroquinolin-8-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1 ,2,3,4-tetrahydroquinolin-1 -yl group (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, the term "aryl" does not encompass or overlap with "heteroaryl", as defined herein, regardless of the point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some instances, aryl is phenyl or naphthyl. In certain instances, aryl is phenyl. Additional examples of aryl groups comprising an aromatic carbon ring fused to a non-aromatic ring are described below.
"Aralkyl" refers to a residue having the indicated number of carbon atoms (e.g., 7 to 12 or 7 to 10 carbon atoms) in which an aryl moiety is attached to the parent structure via an alkyl residue. The alkyl residue may be straight-chain or branched. Examples include, benzyl, phenethyl and 1 -phenylethyl.
"Heteroaryl" indicates an aromatic ring containing the indicated number of atoms (e.g., 5 to 12, or 5 to 10 membered heteroaryl) made up of one or more heteroatoms (e.g., 1 , 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon. Heteroaryl groups do not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some
embodiments, the total number of S and O atoms in heteroaryl group is not more than 1 . Unless otherwise indicated, heteroaryl groups may be bound to the parent structure by a carbon or nitrogen atom, as valency permits. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl and 4-pyridyl groups, and "pyrrolyl" includes 1 -pyrrolyl, 2-pyrrolyl and 3-pyrrolyl groups. When nitrogen is present in a heteroaryl ring, it may, where the nature of the adjacent atoms and groups permits, exist in an oxidized state (i.e., N+-O"). Additionally, when sulfur is present in a heteroaryl ring, it may, where the nature of the adjacent atoms and groups permits, exist in an oxidized state (i.e., S+-O" or SO2).
Heteroaryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).
In some instances, a heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1 ,2,3-triazole, 1 ,2,4- triazole, 1 ,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1 ,2,3-oxadiazole, 1 ,2,4-oxadiazole, 1 ,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1 ,2,3-thiadiazole, 1 ,2,4-thiadiazole, 1 ,3,4- thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1 ,2,4- triazine, 1 ,3,5-triazine) and tetrazine.
In some instances, both rings of a polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzoimidazole, benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole, 1 H- pyrrolo[2,3-b]pyridine, 1 H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1 ,2,3]triazolo[4,5-b]pyridine, 1 H-pyrrolo[3,2-b]pyridine, 1 H-pyrazolo[4,3- bjpyridine, 1 H-imidazo[4,5-b]pyridine, 1 H-[1 ,2,3]triazolo[4,5-b]pyridine, 1 H- pyrrolo[2,3-c]pyridine, 1 H-pyrazolo[3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-[1 ,2,3]triazolo[4,5-c]pyridine, 1 H-pyrrolo[3,2-c]pyridine, 1 H-pyrazolo[4,3- cjpyridine, 1 H-imidazo[4,5-c]pyridine, 1 H-[1 ,2,3]triazolo[4,5-c]pyridine, furo[2,3-b]pyridine, oxazolo[5,4-b]pyridine, isoxazolo[5,4-b]pyridine,
[1 ,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1 ,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c] pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1 ,2,3]oxadiazolo[5,4- cjpyridine, furo[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine, [1 ,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1 ,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2- bjpyridine, thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1 ,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine, thiazolo[5,4-c]pyridine, isothiazolo[5,4-c] pyridine, [1 ,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2- c]pyridine, thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine,
[1 ,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline,
quinazoline, quinoxaline, phthalazine, naphthyridine (e.g., 1 ,8-naphthyridine, 1 ,7-naphthyridine, 1 ,6-naphthyridine, 1 ,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), imidazo[1 ,2-a]pyridine, 1 H-pyrazolo[3,4-d]thiazole, 1 H- pyrazolo[4,3-d]thiazole and imidazo[2,1 -b]thiazole.
In other instances, polycyclic heteroaryl groups may include a non- aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl,
heterocycloalkenyl) fused to a heteroaryl ring, provided the polycyclic heteroaryl group is bound to the parent structure via an atom in the aromatic ring. For example, a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl group. Examples of polycyclic heteroaryl groups consisting of a heteroaryl ring fused to a non-aromatic ring are described below.
"Heterocycloalkyl" indicates a non-aromatic, fully saturated ring having the indicated number of atoms (e.g., 3 to 10, or 3 to 7, membered
heterocycloalkyl) made up of one or more heteroatoms (e.g., 1 , 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon. Heterocycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. When nitrogen is present in a heterocycloalkyl ring, it may, where the nature of the adjacent atoms and groups permits, exist in an oxidized state (i.e., N+-O"). Examples include piperidinyl N-oxide and morpholinyl-N-oxide. Additionally, when sulfur is present in a heterocycloalkyl ring, it may, where the nature of the adjacent atoms and groups permits, exist in an oxidized state (i.e., S+-O" or -SO2-). Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. In addition, one ring of a polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl), provided the polycyclic heterocycloalkyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom. For example, a 1 ,2,3,4-tetrahydroquinolin-1 -yl group (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkyl group, while 1 ,2,3,4-tetrahydroquinolin-8-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkyl group. Examples of polycyclic
heterocycloalkyl groups consisting of a heterocycloalkyl group fused to an aromatic ring are described below.
"Heterocycloalkenyl" indicates a non-aromatic ring having the indicated number of atoms (e.g., 3 to 10, or 3 to 7, membered heterocycloalkyl) made up of one or more heteroatoms (e.g., 1 , 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon, and at least one double bond derived by the removal of one molecule of hydrogen from adjacent carbon atoms, adjacent nitrogen atoms, or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl. Heterocycloalkenyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). When nitrogen is present in a heterocycloalkenyl ring, it may, where the nature of the adjacent atoms and groups permits, exist in an oxidized state (i.e., N+-O"). Additionally, when sulfur is present in a heterocycloalkenyl ring, it may, where the nature of the adjacent atoms and groups permits, exist in an oxidized state (i.e., S+-O" or -SO2-). Examples of heterocycloalkenyl groups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3- dihydro-1 H-pyrrolyl, 2,5-dihydro-1 H-pyrrolyl), dihydroimidazolyl (e.g., 2,3- dihydro-1 H-imidazolyl, 4,5-dihydro-1 H-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridinyl (e.g., 1 ,2,3,4-tetrahydropyridinyl, 1 ,2,3,6-tetrahydropyridinyl) and
dihydropyridine (e.g., 1 ,2-dihydropyridine, 1 ,4-dihydropyridine). In addition, one ring of a polycyclic heterocycloalkenyl group may be aromatic (e.g., aryl or heteroaryl), provided the polycyclic heterocycloalkenyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom. For example, a 1 ,2-dihydroquinolin-1 -yl group (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is considered a heterocydoalkenyl group, while 1 ,2-dihydroquinolin-8-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a heterocydoalkenyl group. Examples of polycyclic
heterocydoalkenyl groups consisting of a heterocydoalkenyl group fused to an aromatic ring are described below.
Examples of polycyclic rings consisting of an aromatic ring (e.g., aryl or heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocydoalkyi, heterocydoalkenyl) include indenyl, 2, 3-dihydro-1 H-indenyl, 1 ,2,3,4-tetrahydronaphthalenyl, benzo[1 ,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1 ,4]dioxinyl, indolinyl, isoindolinyl, 2, 3-dihydro-1 H-indazolyl, 2,3-dihydro-1 H-benzo[d]imidazolyl, 2,3-dihydrobenzofuranyl,
1 ,3-dihydroisobenzofuranyl, 1 ,3-dihydrobenzo[c]isoxazolyl,
2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydrobenzo[d]oxazolyl,
2,3-dihydrobenzo[b]thiophenyl, 1 ,3-dihydrobenzo[c]thiophenyl,
1 ,3-dihydrobenzo[c]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl,
2,3-dihydrobenzo[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[d]thiazolyl,
4,5,6,7-tetrahydrobenzo[d]thiazolyl, 5,6-dihydro-4H-pyrrolo[3,4-d]thiazolyl , 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, indolin-2-one, indolin-3-one, isoindolin-1 -one, 1 ,2-dihydroindazol-3-one, 1 H-benzo[d]imidazol-2(3H)-one, benzofuran-2(3H)-one, benzofuran-3(2H)-one, isobenzofuran-1 (3H)-one, benzo[c]isoxazol-3(1 H)-one, benzo[d]isoxazol-3(2H)-one, benzo[d]oxazol- 2(3H)-one, benzo[b]thiophen-2(3H)-one, benzo[b]thiophen-3(2H)-one, benzo[c]thiophen-1 (3H)-one, benzo[c]isothiazol-3(1 H)-one,
benzo[d]isothiazol-3(2H)-one, benzo[d]thiazol-2(3H)-one, 4,5- dihydropyrrolo[3,4-d]thiazol-6-one, 1 ,2-dihydropyrazolo[3,4-d]thiazol-3-one, quinolin-4(3H)-one, quinazolin-4(3H)-one, quinazoline-2,4(1 H,3H)-dione, quinoxalin-2(1 H)-one, quinoxaline-2,3(1 H,4H)-dione, cinnolin-4(3H)-one, pyridin-2(1 H)-one, pyrimidin-2(1 H)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)- one, 1 H-pyrrolo[3,2-b]pyridin-2(3H)-one, 1 H-pyrrolo[3,2-c]pyridin-2(3H)-one, 1 H-pyrrolo[2,3-c]pyridin-2(3H)-one, 1 H-pyrrolo[2,3-b]pyridin-2(3H)-one, 1 ,2- dihydropyrazolo[3,4-d]thiazol-3-one and 4,5-dihydropyrrolo[3,4-d]thiazol-6- one. As discussed herein, whether each ring is considered an aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocydoalkyi or heterocydoalkenyl group is determined by the atom through which the moiety is bound to the parent structure.
"Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.
"Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. "Enantiomers" are stereoisomers that are non- superimposable mirror images of each other. A 1 :1 mixture of a pair of enantiomers is a "racemic" mixture. The symbol "(±)" may be used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. A "meso compound" or "meso isomer" is a non- optically active member of a set of stereoisomers. Meso isomers contain two or more stereocenters but are not chiral (i.e., a plane of symmetry exists within the molecule). The absolute stereochemistry is specified according to the Cahn-lngold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
Certain of the compounds disclosed and/or described herein contain one or more asymmetric centers and can thus give rise to enantiomers,
diastereomers, meso isomers and other stereoisomeric forms. Unless otherwise indicated, compounds disclosed and/or described herein include all such possible enantiomers, diastereomers, meso isomers and other stereoisomeric forms, including racemic mixtures, optically pure forms and intermediate mixtures. Enantiomers, diastereomers, meso isomers and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Unless specified otherwise, when the compounds disclosed and/or described herein contain olefinic double bonds or other centers of geometric asymmetry, it is intended that the compounds include both E and Z isomers.
The stereochemistry depicted in the structures of cyclic meso compounds is not absolute; rather the stereochemistry is intended to indicate the positioning of the substituents relative to one another, e.g., cis or trans. For example,
Figure imgf000016_0001
is intended to designate a compound wherein the fluorine and pyridyl substituents on the cyclobutyl ring are in a cis configuration to one another, while
Figure imgf000016_0002
is intended to designate a compound wherein the fluorine and pyridyl substituents on the cyclobutyl ring are in a trans configuration to one another.
When a compound can exist as one or more meso isomers, all possible meso isomers are intended to be included. For example, the compound 3-[6-({[3-fluoro-1 -(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)pyridazin-3-yl]benzenecarbonitrile is inten
Figure imgf000016_0003
and mixtures thereof. Unless otherwise indicated, compounds disclosed and/or described herein include all possible meso isomers and mixtures thereof.
"Tautomers" are structurally distinct isomers that interconvert by tautomerization. Tautomerization is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. Prototropic tautomerization or proton-shift tautomenzation involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomenzation is possible (e.g. in solution), a chemical equilibrium of tautomers can be reached. An example of tautomenzation is keto-enol tautomerization. A specific example of keto-enol tautomenzation is the interconverision of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto
tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1 H)-one tautomers. When the compounds described herein contain moieties capable of tautomerization, and unless specified otherwise, it is intended that the compounds include all possible tautomers.
"Protecting group" has the meaning conventionally associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site, and such that the group can readily be removed after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in T.H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For example, a "hydroxy protected form" contains at least one hydroxy group protected with a hydroxy protecting group. Likewise, amines and other reactive groups may similarly be
protected.
The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compounds described herein and are not biologically or otherwise undesirable. Examples of
pharmaceutically acceptable salts can be found in Berge et al.,
Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1 ), 1 -19. In many cases, the compounds described 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, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2- hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid and salicylic acid. 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, and aluminum. 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; and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the
pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
If the compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt.
Conversely, if the compound is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds (see, e.g., Berge et al., Pharmaceutical Salts, J.
Pharmaceutical Sciences, January 1977, 66(1 ), 1 -19). Those skilled in the art will recognize various synthetic methodologies that may be used to prepare pharmaceutically acceptable addition salts.
A "solvate" is formed by the interaction of a solvent and a compound. Suitable solvents include, for example, water and alcohols (e.g., ethanol). Solvates include hydrates having any ratio of compound to water, such as monohydrates, dihydrates and hemi-hydrates.
A "chelate" is formed by the coordination of a compound to a metal ion at two (or more) points. The term "compound" is intended to include chelates of compounds. Similarly, "salts" includes chelates of salts and "solvates" includes chelates of solvates. A "non-covalent complex" is formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding). Such non-covalent complexes are included in the term "compound".
The term "prodrug" refers to a substance administered in an inactive or less active form that is then transformed (e.g., by metabolic processing of the prodrug in the body) into an active compound. The rationale behind administering a prodrug is to optimize absorption, distribution, metabolism, and/or excretion of the drug Prodrugs may be obtained by making a derivative of an active compound (e.g., a compound of Formula I or another compound disclosed and/or described herein) that will undergo a
transformation under the conditions of use (e.g., within the body) to form the active compound. The transformation of the prodrug to the active compound may proceed spontaneously (e.g., by way of a hydrolysis reaction) or it can be catalyzed or induced by another agent (e.g., an enzyme, light, acid or base, and/or temperature). The agent may be endogenous to the conditions of use (e.g., an enzyme present in the cells to which the prodrug is administered, or the acidic conditions of the stomach) or the agent may be supplied
exogenously. Prodrugs can be obtained by converting one or more functional groups in the active compound into another functional group, which is then converted back to the original functional group when administered to the body. For example, a hydroxyl functional group can be converted to a sulfonate, phosphate, ester or carbonate group, which in turn can be hydrolyzed in vivo back to the hydroxyl group. Similarly, an amino functional group can be converted, for example, into an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenyl functional group, which can be hydrolyzed in vivo back to the amino group. A carboxyl functional group can be converted, for example, into an ester (including silyl esters and thioesters), amide or hydrazide functional group, which can be hydrolyzed in vivo back to the carboxyl group. Examples of prodrugs include, but are not limited to, phosphate, acetate, formate and benzoate derivatives of functional groups (such as alcohol or amine groups) present in the compounds of Formula I and other compounds disclosed and/or described herein.
The compounds disclosed and/or described herein can be enriched isotopic forms, e.g., enriched in the content of 2H, 3H, 11C, 13C and/or 14C. In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be made, for example, by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. Such deuterated compounds may improve the efficacy and increase the duration of action of compounds disclosed and/or described herein. Deuterium substituted compounds can be synthesized using various methods, such as those described in: Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled
Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000; 6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21 ), 6601 -21 ; and Evans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981 , 64(1 -2), 9-32.
The term "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
pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
The term "active agent" is used to indicate a compound that has biological activity. In some embodiments, an "active agent" is a compound having therapeutic utility. In some embodiments, the compound enhances at least one aspect of skeletal muscle function or activity, such as power output, skeletal muscle force, skeletal muscle endurance, oxygen consumption, efficiency, and/or calcium sensitivity. In some embodiments, an active agent is a compound of Formula I, or a pharmaceutically acceptable salt thereof.
The terms "patient" and "subject" refer to an animal, such as a mammal bird or fish. In some embodiments, the patient or subject is a mammal.
Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows and humans. In some embodiments, the patient or subject is a human, for example a human that has been or will be the object of treatment, observation or experiment. The compounds, compositions and methods described herein can be useful in both human therapy and veterinary applications.
As used herein, "skeletal muscle" includes skeletal muscle tissue as well as components thereof, such as skeletal muscle fibers, the myofibrils comprising the skeletal muscle fibers, the skeletal sarcomere which
comprises the myofibrils, and the various components of the skeletal sarcomere described herein, including skeletal myosin, actin, tropomyosin, troponin C, troponin I, troponin T and fragments and isoforms thereof. In some embodiments, "skeletal muscle" includes fast skeletal muscle tissue as well as components thereof, such as fast skeletal muscle fibers, the myofibrils comprising the fast skeletal muscle fibers, the fast skeletal sarcomere which comprises the myofibrils, and the various components of the fast skeletal sarcomere described herein, including fast keletal myosin, actin, tropomyosin, troponin C, troponin I, troponin T and fragments and isoforms thereof.
Skeletal muscle does not include cardiac muscle or a combination of sarcomeric components that occurs in such combination in its entirety in cardiac muscle.
As used herein, the term "therapeutic" refers to the ability to modulate the contractility of fast skeletal muscle. As used herein, "modulation" (and related terms, such as "modulate", "modulated", "modulating") refers to a change in function or efficiency of one or more components of the fast skeletal muscle sarcomere, including myosin, actin, tropomyosin, troponin C, troponin I, and troponin T from fast skeletal muscle, including fragments and isoforms thereof, as a direct or indirect response to the presence of a compound described herein, relative to the activity of the fast skeletal sarcomere in the absence of the compound. The change may be an increase in activity
(potentiation) or a decrease in activity (inhibition), and may be due to the direct interaction of the compound with the sarcomere, or due to the
interaction of the compound with one or more other factors that in turn affect the sarcomere or one or more of its components. In some embodiments, modulation is a potentiation of function or efficiency of one or more
components of the fast skeletal muscle sarcomere, including myosin, actin, tropomyosin, troponin C, troponin I, and troponin T from fast skeletal muscle, including fragments and isoforms thereof. Modulation may be mediated by any mechanism and at any physiological level, for example, through
sensitization of the fast skeletal sarcomere to contraction at lower Ca2+ concentrations. As used herein, "efficiency" or "muscle efficiency" means the ratio of mechanical work output to the total metabolic cost.
The term "therapeutically effective amount" or "effective amount" refers to that amount of a compound disclosed and/or described herein that is sufficient to affect treatment, as defined herein, when administered to a patient in need of such treatment. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease responsive to modulation of fast skeletal muscle. The therapeutically effective amount will vary depending upon, for example, the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound, the dosing regimen to be followed, timing of administration, the manner of administration, all of which can readily be determined by one of ordinary skill in the art. The therapeutically effective amount may be ascertained experimentally, for example by assaying blood concentration of the chemical entity, or theoretically, by calculating
bioavailability.
"Treatment" (and related terms, such as "treat", "treated", "treating") includes one or more of: preventing a disease or disorder (i.e., causing the clinical symptoms of the disease or disorder not to develop); inhibiting a disease or disorder; slowing or arresting the development of clinical symptoms of a disease or disorder; and/or relieving a disease or disorder (i.e., causing relief from or regression of clinical symptoms). The term
encompasses situations where the disease or disorder is already being experienced by a patient, as well as situations where the disease or disorder is not currently being experienced but is expected to arise. The term covers both complete and partial reduction or prevention of the condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder. Thus, compounds described and/or disclosed herein may prevent an existing disease or disorder from worsening, assist in the management of the disease or disorder, or reduce or eliminate the disease or disorder. When used in a prophylactic manner, the compounds disclosed and/or described herein may prevent a disease or disorder from developing or lessen the extent of a disease or disorder that may develop.
As used herein, "power output" of a muscle means work/cycle time and may be scaled up from PoLo/cycle time units based on the properties of the muscle. Power output may be modulated by changing, for example, activating parameters during cyclical length changes, including timing of activation (phase of activation) and the period of activation (duty cycle.)
"ATPase" refers to an enzyme that hydrolyzes ATP. ATPases include proteins comprising molecular motors such as the myosins.
As used herein, "selective binding" or "selectively binding" refers to preferential binding to a target protein in one type of muscle or muscle fiber as opposed to other types. For example, a compound selectively binds to fast skeletal troponin C if the compound preferentially binds troponin C in the troponin complex of a fast skeletal muscle fiber or sarcomere in comparison with troponin C in the troponin complex of a slow muscle fiber or sarcomere or with troponin C in the troponin complex of a cardiac sarcomere.
Provided is a compound of Formula I:
Figure imgf000023_0001
Formula I
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from hydrogen, halogen, CN, C-i-6 alkyl, C-i-6 haloalkyl, C(O)ORa, C(O)NRbRc, ORa, NRbRc, C6-io aryl and 5-10 membered heteroaryl;
R2 is selected from C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, 5-10
membered heteroaryl and NRbRc, wherein each of the C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered
heterocycloalkenyl, C6-io aryl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, (CH2)nORa, (CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc, (CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa,
(CH2)nNRdC(S)NRbRc, (CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra,
(CH2)nNRdSO2Ra, (CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc,
(CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra,
(CH2)nSO2NRbRc, C -6 alkyl, C -6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3- 8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nC6-io aryl and (CH2)n5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nC6-io aryl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents;
R3 is selected from hydrogen, halogen, CN, C-i-6 alkyl, C-i-6 haloalkyl, C(O)ORa, C(O)NRbRc, ORa, NRbRc, C6-io aryl and 5-10 membered heteroaryl;
R4 is selected from hydrogen, C-i-6 alkyl, C-i-6 haloalkyl, C(O)Ra, C(O)ORa, C(O)NRbRc and SO2Ra;
R5 and R6 are each independently selected from hydrogen, halogen, C-i-6 alkyl and C-i-6 haloalkyl;
or alternatively, R5 and R6 together with the carbon atom to which they are bound form C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered
heterocycloalkyl or 3-8 membered heterocycloalkenyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, S(O)Ra, SO2Ra, SO2NRbRc, C -6 alkyl and C -6 haloalkyl;
R7 is selected from C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl and 5-10 membered heteroaryl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, OC(O)NRbRc, NRbRc, NRdC(O)Ra, NRdC(O)ORa, NRdC(O)NRbRc,
NRdC(O)C(O)NRbRc, NRdC(S)Ra, NRdC(S)ORa, NRdC(S)NRbRc, NRdC(NRe)NRbRc, N RdS(O)Ra, NRdSO2Ra, NRdSO2NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, C(S)Ra, C(S)ORa, C(S)NRbRc, C(NRe)NRbRc, SRa, S(O)Ra, SO2Ra, SO2NRbRc, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C7-n aralkyl, and 5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered
heterocycloalkenyl, C6-io aryl, C7-n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents;
R8 and R9, at each occurrence, are each independently selected from hydrogen, halogen and C-i-6 alkyl;
X is selected from a bond, -(CH2)P-, -(CH2)pC(O)(CH2)q-, - (CH2)pO(CH2)q-, -(CH2)pS(CH2)q-, -(CH2)pNRd(CH2)q-, -(CH2)pC(O)O(CH2)q-, -(CH2)pOC(O)(CH2)q-, -(CH2)pNRdC(O)(CH2)q-, -(CH2)pC(O)NRd(CH2)q-, -(CH2)pNRdC(O)NRd(CH2)q-, -(CH2)pNRdSO2(CH2)q-, and
-(CH2)pSO2NRd(CH2)q-;
or alternatively, X, R2 and R3, together with the carbon atoms to which they are bound, form a 5-6 membered ring optionally containing one or more heteroatoms selected from oxygen nitrogen and sulfur, and optionally containing one or more double bonds, and optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents;
Ra, at each occurrence, is independently selected from hydrogen, C-i-6 alkyl, C-i-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C7-i i aralkyl and 5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C7-n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents;
Rb and Rc, at each occurrence, are each independently selected from hydrogen, C-i-6 alkyl, C-i-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C7-n aralkyl, 5-10 membered heteroaryl, C(O)Rg, C(0)ORg, C^NR^ and SO2Rg, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C7-n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents;
Rd, at each occurrence, is independently selected from hydrogen and Ci-6 alkyl;
Re, at each occurrence, is independently selected from hydrogen, CN, OH, C-i-6 alkoxy, C-i-6 alkyl and C-i-6 haloalkyl;
Rf, at each occurrence, is independently selected from halogen, CN, ORh, OC(O)Rh, OC(O)ORh, OC JNR^, NR'Rj, NRdC(O)Rh, NRdC(O)ORh, NRdC(O)NR'Rj, NRdC(O)C(O)NRiRj, NRdC(S)Rh, NRdC(S)ORh, NRdC(S)NR'Rj, NRdC(NRe)NR'Rj, NRdS(O)Rh, NRdSO2Rh, NRdSO2NR'Rj, C(O)Rh, C(O)ORh, Ο(Ο)Ν^, C(S)Rh, C(S)ORh, C^NR^, C(NRe)NR'Rj, SRh, S(O)Rh, SO2Rh, SO2NR'Rj, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered
heterocycloalkenyl, C6-io aryl, C7-n aralkyl and 5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered
heterocycloalkenyl, C6-io aryl, C7-n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rk substituents;
or two Rf substituents bound to a single carbon atom, together with the carbon atom to which they are both bound, form a group selected from carbonyl, C3-8 cycloalkyl and 3-8 membered heterocycloalkyl;
Rg, at each occurrence, is independently selected from C-i-6 alkyl, C-i-6 haloalkyl, phenyl, naphthyl, and C7-n aralkyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, OH, C-i-6 alkoxy, C-i-6 alkyl and C-i-6 haloalkyl;
Rh, at each occurrence, is independently selected from hydrogen, C-i-6 alkyl, C-i-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C7.11 aralkyl and 5-10 mennbered heteroaryl, wherein each of the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C-6-10 aryl, C7.11 aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rk substituents;
R' and Rj, at each occurrence, are each independently selected from hydrogen, C1-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered
heterocycloalkenyl, C6-io aryl, C7-n aralkyl, 5-10 membered heteroaryl, C(O)Rg, and C(O)ORg, wherein each of the Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, s-io aryl, C7.11 aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, OH, Ci_6 alkoxy, Ci-6 alkyl and Ci-6 haloalkyl;
Rk, at each occurrence, is independently selected from halogen, CN, OH, C1-6 alkoxy, NH2, NH(Ci-6 alkyl), N(Ci-6 alkyl)2, NHC(O)d-6 alkyl,
NHC(O)C7-i i aralkyl, N HC(O)OCi-6 alkyl, N HC(O)OC7-n aralkyl, OC(O)d-6 alkyl, OC(O)C7-n aralkyl, OC(O)OCi-6 alkyl, OC(O)OC7-n aralkyl, C(O)Ci-6 alkyl, C(O)C7-n aralkyl, C(O)OCi-6 alkyl, C(O)OC7-n aralkyl, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C7-n aralkyl substituent is optionally substituted with 1 , 2 or 3 substituents selected from OH, Ci-6 alkoxy, N H2, NH(Ci-6 alkyl), N(Ci-6 alkyl)2, NHC(O)Ci-6 alkyl, NHC(O)C7-n aralkyl, NHC(O)OCi-6 alkyl, and NHC(O)OC7- 11 aralkyl;
or two Rk substituents bound to a single carbon atom, together with the carbon atom to which they are both bound, form a carbonyl group;
m is 0, 1 or 2;
n, at each occurrence, independently is 0, 1 or 2;
p is 0, 1 or 2; and
q is 0, 1 or 2. In some embodiments of compounds of Formula I, when m is 1 and R5 and R6 are each methyl, then R7 is not piperidinyl or morpholino. In some embodiments of compounds of Formula I, when m is 1 , X is a bond and R2 is optionally substituted phenyl, then R7 is not piperidinyl or morpholino. In some embodiments, the compound of Formula I is not 6-(4-chlorophenyl)-5- methyl-N-(2-methyl-2-(piperidin-1 -yl)propyl)pyridazin-3-amine, N-(2-methyl-2- (piperidin-1 -yl)propyl)-6-phenyl-5-propylpyridazin-3-amine or N-(2-methyl-2- morpholinopropyl)-6-phenyl-5-propylpyridazin-3-amine.
In some embodiments of compounds of Formula I, m is 0, i.e., a compound of Formula II, or a pharmaceutically acceptable salt thereof:
Figure imgf000028_0001
Formula II
wherein R1, R2, R3, R4, R5, R6, R7 and X are as defined herein.
In some embodiments of compounds of Formula I, m is 1 , i.e., a compound of Formula III, or a pharmaceutically acceptable salt thereof:
Figure imgf000028_0002
Formula III
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and X are as defined herein.
In some embodiments of compounds of Formula I, II or III, one of R5 and R6 is hydrogen and the other is C-i-6 alkyl.
In some embodiments of compounds of Formula I, II or III, R5 and R6 are each independently C-i-6 alkyl. In some embodiments of compounds of Formula I, II or III, R5 and R6 are each methyl.
In some embodiments, the compounds are of Formula IV(a) or IV(b), or a pharmaceutically acceptable salt thereof:
Figure imgf000029_0001
Formula IV(b)
wherein R1, R2, R3, R4, R7, R8, R9 and X are as defined herein.
In some embodiments of compounds of Formula IV(b), R7 is not piperidinyl or morpholinyl.
In some embodiments of compounds of Formula I, II or III, R5 and R6 together with the carbon atom to which they are bound form C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl or 3-8 membered
heterocydoalkenyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, S(O)Ra, SO2Ra, SO2NRbRc, C1-6 alkyl and C1-6 haloalkyl.
In some embodiments of compounds of Formula I, II or III, R5 and R6, together with the carbon to which they are bound, form C3-6 cycloalkyl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, S(O)Ra, SO2Ra, SO2NRbRc, C1-6 alkyl and C1-6 haloalkyl.
In some embodiments of compounds of Formula I, II or III, R5 and R6, together with the carbon to which they are bound, form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, S(O)Ra, SO2Ra, SO2NRbRc, C1-6 alkyl and C-i-6 haloalkyl.
In some embodiments of compounds of Formula I, II or III, R5 and R6, together with the carbon to which they are bound, form cyclobutyl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, S(O)Ra, SO2Ra, SO2NRbRc, Ci-6 alkyl and Ci-6 haloalkyl.
In some embodiments of compounds of Formula I, II or III, R5 and R6, together with the carbon to which they are bound, form cyclobutyl substituted with one substituent selected from halogen, CN, oxo, ORa, OC(O)Ra,
OC(O)ORa, NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, S(O)Ra, SO2Ra,
SO2NRbRc, Ci-6 alkyl and C-i-6 haloalkyl, wherein the substituent and R7 are in a trans configuration with respect to one another on the cyclobutyl ring.
In some embodiments of compounds of Formula I, II or III, R5 and R6, together with the carbon to which they are bound, form cyclobutyl substituted with one substituent selected from halogen, CN, oxo, ORa, OC(O)Ra,
OC(O)ORa, NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, S(O)Ra, SO2Ra,
SO2NRbRc, C-i-6 alkyl and C-i-6 haloalkyl, wherein the substituent and R7 are in a cis configuration with respect to one another on the cyclobutyl ring.
In some embodiments, the compounds are of Formula V(a) or V(b), or a pharmaceutically acceptable salt thereof:
Figure imgf000031_0001
Figure imgf000031_0002
Formula V(b) wherein Rm and Rn are each independently selected from hydrogen, halogen and C1-6 alkyl, and R1 , R2, R3, R4, R7, R8, R9 and X are as defined herein.
In some embodiments of compounds of Formula V(a) or V(b), Rm and Rn are each hydrogen.
In some embodiments compounds of Formula V(a) or V(b), Rm and Rn are each halogen.
In some embodiments compounds of Formula V(a) or V(b), Rm and Rn are each fluorine.
In some embodiments compounds of Formula V(a) or V(b), one of Rm and Rn is hydrogen and the other is halogen. In some embodiments of such compounds, the halogen and R7 are in a trans configuration with respect to one another on the cyclobutyl ring. In some embodiments of such
compounds, the halogen and R7 are in a cis configuration with respect to one another on the cyclobutyl ring.
In some embodiments compounds of Formula V(a) or V(b), one of Rm and Rn is hydrogen and the other is fluorine. In some embodiments of such compounds, the fluorine and R7 are in a trans configuration with respect to one another on the cyclobutyl ring. In some embodiments of such
compounds, the fluorine and R7 are in a cis configuration with respect to one another on the cyclobutyl ring.
In some embodiments of compounds of Formula I, II or III, R5 and R6, together with the carbon atom to which they are bound, form 3-6 membered heterocycloalkyl, each of which is optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, S(O)Ra, SO2Ra, SO2NRbRc, C1-6 alkyl and C-i-6 haloalkyl.
In some embodiments of compounds of Formula I, II or III, R5 and R6, together with the carbon atom to which they are bound, form aziridine, azetidine, pyrrolidine, oxirane, oxetane or tetrahydrofuran, each of which is optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, S(O)Ra, SO2Ra, SO2NRbRc, C1-6 alkyl and C1-6 haloalkyl.
In some embodiments of compounds of Formula I, II or III, R5 and R6 are each independently C-i-6 alkyl, or R5 and R6 together with the carbon atom to which they are bound form C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl or 3-8 membered heterocydoalkenyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, S(O)Ra, SO2Ra, SO2NRbRc, Ci-6 alkyl and Ci-6 haloalkyl.
In some embodiments of compounds of Formula I, II or III, R5 and R6 are each methyl, or R5 and R6 together with the carbon atom to which they are bound form C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl or 3-8 membered heterocydoalkenyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra,
OC(O)ORa, NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, S(O)Ra, SO2Ra,
SO2NRbRc, Ci-6 alkyl and Ci-6 haloalkyl.
In some embodiments of compounds of Formula I, II or III, R5 and R6 are each independently C-i-6 alkyl, or R5 and R6, together with the carbon to which they are bound, form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, N RbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, S(O)Ra, SO2Ra, SO2NRbRc, C1-6 alkyl and C1-6 haloalkyl.
In some embodiments of compounds of Formula I, II or III, R5 and R6 are each methyl, or R5 and R6, together with the carbon to which they are bound, form cyclobutyl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, S(O)Ra, SO2Ra, SO2NRbRc, C1-6 alkyl and C1-6 haloalkyl.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a) or V(b), R7 is selected from C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl and 5-10 membered heteroaryl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, OC(O)NRbRc, N RbRc, NRdC(O)Ra, NRdC(O)ORa, NRdC(O)NRbRc,
NRdC(O)C(O)NRbRc, N RdC(S)Ra, NRdC(S)ORa, N RdC(S)NRbRc,
NRdC(NRe)NRbRc, N RdS(O)Ra, NRdSO2Ra, NRdSO2NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, C(S)Ra, C(S)ORa, C(S)NRbRc, C(NRe)NRbRc, SRa, S(O)Ra, SO2Ra, SO2NRbRc, C -6 alkyl, C -6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C7.11 aralkyl, and 5-10 membered heteroaryl, wherein each of the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-s cycloalkyl, C3-s cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered
heterocycloalkenyl, C6-io aryl, C7-n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments of compounds of Formula I, III or IV(b), when R5 and R6 are each methyl, R7 is not piperidinyl or morpholinyl.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a) or V(b), R7 is phenyl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, OC(O)NRbRc, NRbRc, N RdC(O)Ra, NRdC(O)ORa, NRdC(O)NRbRc, NRdC(O)C(O)NRbRc, NRdC(S)Ra, N RdC(S)ORa, NRdC(S)NRbRc, NRdC(NRe)NRbRc, NRdS(O)Ra, NRdSO2Ra, NRdSO2NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, C(S)Ra, C(S)ORa, C(S)NRbRc, C(NRe)NRbRc, SRa, S(O)Ra, SO2Ra, SO2NRbRc, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C7- 11 aralkyl, and 5-10 membered heteroaryl, wherein each of the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C7-n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments, the compounds are of Formula VI, or a pharmaceutically acceptable salt thereof:
Figure imgf000034_0001
Formula VI
wherein r is 0, 1 , 2, 3 or 4, and R1, R2, R3, R4, R5, R6, R8, R9, Rf, X and m are as defined herein.
In some embodiments, the compounds are of Formula Vll(a) or Vll(b), or a pharmaceutically acceptable salt thereof:
Figure imgf000034_0002
Formula Vll(a)
Figure imgf000035_0001
Formula Vll(b)
wherein r is 0, 1 , 2, 3 or 4, and R1, R2, R3, R4, R8, R9, Rf and X are as defined herein.
In some embodiments, the compounds are of Formula Vlll(a) or Vlll(b), or a pharmaceutically acceptable salt thereof:
Figure imgf000035_0002
Formula Vlll(a)
Figure imgf000035_0003
Formula Vlll(b)
wherein Rm and Rn are each independently selected from hydrogen, halogen and C -6 alkyl; r is 0, 1 , 2, 3 or 4; and R1, R2, R3, R4, R8, R9, Rf and X are as defined herein.
In some embodiments of compounds of Formula Vlll(a) or Vlll(b), Rm and Rn are each hydrogen.
In some embodiments compounds of Formula VI 11(a) or VI 11(b), Rm and Rn are each halogen.
In some embodiments compounds of Formula VI 11(a) or VI 11(b), Rm and Rn are each fluorine.
In some embodiments compounds of Formula VI 11(a) or VI 11 (b), one of Rm and Rn is hydrogen and the other is halogen. In some embodiments of such compounds, the halogen and the phenyl ring are in a trans configuration with respect to one another on the cyclobutyl ring. In some embodiments of such compounds, the halogen and the phenyl ring are in a cis configuration with respect to one another on the cyclobutyl ring.
In some embodiments compounds of Formula VI 11(a) or Vlll(b), one of Rm and Rn is hydrogen and the other is fluorine. In some embodiments of such compounds, the fluorine and the phenyl ring are in a trans configuration with respect to one another on the cyclobutyl ring. In some embodiments of such compounds, the fluorine and the phenyl ring are in a cis configuration with respect to one another on the cyclobutyl ring.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a) or V(b), R7 is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 2, 4- difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 4-fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2, 4-dichlorophenyl, 3,4- dichlorophenyl, 3,5-dichlorophenyl, 2-methylphenyl, 3-methylphenyl, 2, 4- dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2- (hydroxymethyl)phenyl, 3-(hydroxymethyl)phenyl, 4-(hydroxymethyl)phenyl, 2- (aminomethyl)phenyl, 3-(aminomethyl)phenyl, 4-(aminomethyl)phenyl, 2- phenol, 3-phenol, 4-phenol, 2-methoxyphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 4- difluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4- trifluoromethoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2- benzamine, 3-benzamide, 4-benzamide, N-mehtyl-2-benzamine, N-methyl-3- benzamide, N-methyl-4-benzamide, N,N-dimethyl-2-benzamine, N,N- dimethyl-3-benzamide, and N,N-dimethyl-4-benzamide. In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a) or V(b), R7 is 5-10 membered heteroaryl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra,
OC(O)ORa, OC(O)NRbRc, N RbRc, NRdC(O)Ra, NRdC(O)ORa, NRdC(O)NRbRc, NRdC(O)C(O)NRbRc, N RdC(S)Ra, NRdC(S)ORa, N RdC(S)NRbRc,
NRdC(NRe)NRbRc, N RdS(O)Ra, NRdSO2Ra, NRdSO2NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, C(S)Ra, C(S)ORa, C(S)NRbRc, C(NRe)NRbRc, SRa, S(O)Ra, SO2Ra, SO2NRbRc, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C7-n aralkyl, and 5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered
heterocycloalkenyl, C6-io aryl, C7-n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a) or V(b), R7 is pyridyl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, OC(O)NRbRc, NRbRc, N RdC(O)Ra, NRdC(O)ORa, NRdC(O)NRbRc, NRdC(O)C(O)NRbRc, NRdC(S)Ra, N RdC(S)ORa, NRdC(S)NRbRc, NRdC(NRe)NRbRc, NRdS(O)Ra, NRdSO2Ra, NRdSO2NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, C(S)Ra, C(S)ORa, C(S)NRbRc, C(NRe)NRbRc, SRa, S(O)Ra, SO2Ra, SO2NRbRc, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C7- 11 aralkyl, and 5-10 membered heteroaryl, wherein each of the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C7-n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a) or V(b), R7 is selected from 2-pyridyl, 3-pyridyl and 4-pyridyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, OC(O)NRbRc, N RbRc, NRdC(O)Ra, NRdC(O)ORa, NRdC(O)NRbRc, NRdC(O)C(O)NRbRc, NRdC(S)Ra, NRdC(S)ORa, NRdC(S)NRbRc, NRdC(NRe)NRbRc, NRdS(O)Ra, NRdSO2Ra, NRdSO2NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, C(S)Ra, C(S)ORa, C(S)NRbRc, C(NRe)NRbRc, SRa, S(O)Ra, SO2Ra, SO2NRbRc, Ci-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, 3-6 mennbered heterocycloalkyi, 3-6 membered heterocycloalkenyl, phenyl, naphthyl, C7-n aralkyl, and 5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyi, 3-8 membered heterocycloalkenyl, C6-io aryl, C7-n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments, the compounds are of Formula IX, or a pharmaceutically acceptable salt thereof:
Figure imgf000038_0001
Formula IX
wherein r is 0, 1 , 2, 3 or 4, and R1 , R2, R3, R4, R5, R6, R8, R9, Rf, X and m are as defined herein.
In some embodiments, the compounds are of Formula X(a) or X(b), or a pharmaceutically acceptable salt thereof:
Figure imgf000038_0002
Formula X(a)
Figure imgf000039_0001
Formula X(b)
wherein r is 0, 1 , 2, 3 or 4, and R1, R2, R3, R4, R8, R9, Rf and X are as defined herein.
In some embodiments, the compounds are of Formula Xl(a) or Xl(b), or a pharmaceutically acceptable salt thereof:
Figure imgf000039_0002
Formula Xl(b)
wherein Rm and Rn are each independently selected from hydrogen, halogen and C -6 alkyl; r is 0, 1 , 2, 3 or 4; and R1, R2, R3, R4, R8, R9, Rf and X are as defined herein.
In some embodiments of compounds of Formula Xl(a) or Xl(b), Rm and Rn are each hydrogen.
In some embodiments compounds of Formula Xl(a) or Xl(b), Rm and Rn are each halogen.
In some embodiments compounds of Formula Xl(a) or Xl(b), Rm and Rn are each fluorine.
In some embodiments compounds of Formula Xl(a) or Xl(b), one of Rm and Rn is hydrogen and the other is halogen. In some embodiments of such compounds, the halogen and the pyridyl ring are in a trans configuration with respect to one another on the cyclobutyl ring. In some embodiments of such compounds, the halogen and the pyridyl ring are in a cis configuration with respect to one another on the cyclobutyl ring.
In some embodiments compounds of Formula Xl(a) or Xl(b), one of Rm and Rn is hydrogen and the other is fluorine. In some embodiments of such compounds, the fluorine and the pyridyl ring are in a trans configuration with respect to one another on the cyclobutyl ring. In some embodiments of such compounds, the fluorine and the pyridyl ring are in a cis configuration with respect to one another on the cyclobutyl ring.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a) or V(b), R7 is selected from pyrid-2-yl, 3-fluoro-pyrid-2-yl, 4-fluoro-pyrid-2- yl, 5-fluoro-pyrid-2-yl, 6-fluoro-pyrid-2-yl, 3-chloro-pyrid-2-yl, 4-chloro-pyrid-2- yl, 5-chloro-pyrid-2-yl, 6-chloro-pyrid-2-yl, 3-cyano-pyrid-2-yl, 4-cyano-pyrid-2- yl, 5-cyano-pyrid-2-yl, 6-cyano-pyrid-2-yl, 3-methyl-pyrid-2-yl, 4-methyl-pyrid- 2-yl, 5-methyl-pyrid-2-yl, 6-methyl-pyrid-2-yl, 3-difluoromethyl-pyrid-2-yl, 4-difluoromethyl-pyrid-2-yl, 5-difluoromethyl-pyrid-2-yl, 6-difluoromethyl-pyrid-
2- yl, 3-trifluoromethyl-pyrid-2-yl, 4-trifluoromethyl-pyrid-2-yl, 5-trifluoromethyl- pyrid-2-yl, 6-trifluoromethyl-pyrid-2-yl, 3-hydroxymethyl-pyrid-2-yl,
4- hydroxymethyl-pyrid-2-yl, 5-hydroxymethyl-pyrid-2-yl, 6-hydroxymethyl- pyrid-2-yl, 3-aminomethyl-pyrid-2-yl, 4-aminomethyl-pyrid-2-yl,
5- aminomethyl-pyrid-2-yl, 6-aminomethyl-pyrid-2-yl, 3-hydroxy-pyrid-2-yl, 4-hydroxy-pyrid-2-yl, 5-hydroxy-pyrid-2-yl, 6-hydroxy-pyrid-2-yl, 3-methoxy- pyrid-2-yl, 4-methoxy-pyrid-2-yl, 5-methoxy-pyrid-2-yl, 6-methoxy-pyrid-2-yl,
3- difluoromethoxy-pyrid-2-yl, 4-difluoromethoxy-pyrid-2-yl, 5-difluoromethoxy- pyrid-2-yl, 6-difluoromethoxy-pyrid-2-yl, 3-trifluoromethoxy-pyrid-2-yl,
4-trifluoronnethoxy-pyrid-2-yl, 5-trifluoromethoxy-pynd-2-yl, 6-trifluoronnethoxy- pyrid-2-yl, 3-methylthio-pyrid-2-yl, 4-methylthio-pyrid-2-yl, 5-methylthio-pyrid-
2- yl, 6-methylthio-pyrid-2-yl, 3-carboxamide-pyrid-2-yl, 4-carboxamide-pyrid-2- yl, 5- carboxamide-pyrid-2-yl, 6- carboxamide-pyrid-2-yl and 3-fluoro-6- methyl-pyrid-2-yl.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a) or V(b), R7 is selected from pyrid-3-yl, 2-fluoro-pyrid-3-yl, 4-fluoro-pyrid-3- yl, 5-fluoro-pyrid-3-yl, 6-fluoro-pyrid-3-yl, 2-chloro-pyrid-3-yl, 4-chloro-pyrid-3- yl, 5-chloro-pyrid-3-yl, 6-chloro-pyrid-3-yl, 2-cyano-pyrid-3-yl, 4-cyano-pyrid-3- yl, 5-cyano-pyrid-3-yl, 6-cyano-pyrid-3-yl, 2-methyl-pyrid-3-yl, 4-methyl-pyrid-
3- yl, 5-methyl-pyrid-3-yl, 6-methyl-pyrid-3-yl, 2-difluoromethyl-pyrid-3-yl,
4- difluoromethyl-pyrid-3-yl, 5-difluoromethyl-pyrid-3-yl, 6-difluoromethyl-pyrid-
3- yl, 2-trifluoromethyl-pyrid-3-yl, 4-trifluoromethyl-pyrid-3-yl, 5-trifluoromethyl- pyrid-3-yl, 6-trifluoromethyl-pyrid-3-yl, 2-hydroxymethyl-pyrid-3-yl,
4- hydroxymethyl-pyrid-3-yl, 5-hydroxymethyl-pyrid-3-yl, 6-hydroxymethyl- pyrid-3-yl, 2-aminomethyl-pyrid-3-yl, 4-aminomethyl-pyrid-3-yl,
5- aminomethyl-pyrid-3-yl, 6-aminomethyl-pyrid-3-yl, 2-hydroxy-pyrid-3-yl, 4-hydroxy-pyrid-3-yl, 5-hydroxy-pyrid-3-yl, 6-hydroxy-pyrid-3-yl, 2-methoxy- pyrid-3-yl, 4-methoxy-pyrid-3-yl, 5-methoxy-pyrid-3-yl, 6-methoxy-pyrid-3-yl,
2- difluoromethoxy-pyrid-3-yl, 4-difluoromethoxy-pyrid-3-yl, 5-difluoromethoxy- pyrid-3-yl , 6-d if luoromethoxy-pyrid-3-yl , 2-trif luoromethoxy-pyrid-3-yl ,
4-trifluoromethoxy-pyrid-3-yl, 5-trifluoromethoxy-pyrid-3-yl, 6-trifluoromethoxy- pyrid-3-yl, 2-methylthio-pyrid-3-yl, 4-methylthio-pyrid-3-yl, 5-methylthio-pyrid-
3- yl, 6-methylthio-pyrid-3-yl, 2-carboxamide-pyrid-3-yl, 4-carboxamide-pyrid-3- yl, 5- carboxamide-pyrid-3-yl and 6- carboxamide-pyrid-3-yl.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a) or Xl(b), X is selected from a bond, -(CH2)P-, -(CH2)pC(O)(CH2)q-, -(CH2)pO(CH2)q-, - (CH2)pS(CH2)q-, -(CH2)pNRd(CH2)q-, -(CH2)pC(O)O(CH2)q-,
-(CH2)pOC(O)(CH2)q-, -(CH2)pNRdC(O)(CH2)q-, -(CH2)pC(O)NRd(CH2)q-, -(CH2)pNRdC(O)NRd(CH2)q-, -(CH2)pNRdSO2(CH2)q-, and
-(CH2)pSO2NRd(CH2)q-. In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a) or XI(b), X is a bond.
In some embodiments, the compound is of Formula Xll(a), XI 1(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), XI 1(1), Xll(m), Xll(n) or Xll(o), or a pharmaceutically acceptable salt thereof:
Figure imgf000042_0001
Formula Xll(a)
Figure imgf000042_0002
Formula Xll(c)
Figure imgf000043_0001
Formula Xll(g)
Figure imgf000044_0001
Formula Xll(k)
Figure imgf000045_0001
Figure imgf000045_0002
Figure imgf000045_0003
Figure imgf000045_0004
Formula Xll(o)
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, Rf, Rm, Rn, m and r are as defined herein. In some embodiments of compounds of Formula Xll(c), R7 is not piperidinyl or morpholinyl. In some embodiments of compounds of Formula Xll(c), when R2 is optionally substituted phenyl, then R7 is not piperidinyl or morpholinyl.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a) or Xl(b), X is - O-.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a) or Xl(b), X is selected from -CH2O- and -OCH2-.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a) or Xl(b), X is - NRd-.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a) or Xl(b), X is selected from -CH2NRd- and -NRdCH2-.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a) or Xl(b), X is sleeted from -NRdC(O)- and -C(O)NRd-.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a) or Xl(b), X is sleeted from -CH2NRdC(O)- and -C(O)NRdCH2-.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), XI 1(1), Xll(m), Xll(n) or XII(o), R2 is selected from C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl and 5-10 membered heteroaryl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, (CH2)nORa, (CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc, (CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa, (CH2)nNRdC(S)NRbRc, (CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra, (CH2)nNRdSO2Ra, (CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc, (CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra, (CH2)nSO2NRbRc, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8
membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n) or Xll(o), R2 is phenyl optionally substituted with 1 , 2, 3, 4 or 5
substituents selected from halogen, CN, (CH2)nORa, (CH2)nOC(O)Ra,
(CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc, (CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa, (CH2)nNRdC(S)NRbRc,
(CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra, (CH2)nNRdSO2Ra,
(CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc, (CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra, (CH2)nSO2NRbRc, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8
membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n) or Xll(o), R2 is phenyl substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, (CH2)nORa, (CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc, (CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra,
(CH2)nNRdC(S)ORa, (CH2)nNRdC(S)NRbRc, (CH2)nNRdC(NRe)NRbRc,
(CH2)nNRdS(O)Ra, (CH2)nNRdSO2Ra, (CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa,
(CH2)nC(S)NRbRc, (CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra,
(CH2)nSO2Ra, (CH2)nSO2NRbRc, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl,
(CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl, wherein each of the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3- 8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents; wherein at least one substitutent is bonded at the meta position.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n) or Xll(o), R2 is phenyl substituted with a substituent selected from (CH2)nC(O)ORa and (CH2)nC(O)NRbRc; and optionally substituted with 1 , 2 or 3 additional substituents selected from halogen, CN, (CH2)nORa,
(CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc,
(CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc,
(CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa,
(CH2)nNRdC(S)NRbRc, (CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra,
(CH2)nNRdSO2Ra, (CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc,
(CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra,
(CH2)nSO2NRbRc, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3- 8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl,
(CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl, wherein each of the C-|. 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), XI 1(1), Xll(m), Xll(n) or Xll(o), R2 is phenyl substituted with a substituent selected from C(O)OH, C(O)NH2, C(O)OCi-6 alkyl, C(O)NHCi-6 alkyl and C(O)N(Ci-6 alkyl)2; and optionally substituted with 1 , 2 or 3 additional substituents selected from halogen, C-i-6 alkyl and C-i-6 haloalkyl.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n) or XII(o), R2 is phenyl substituted at the meta position with a substituent selected from (CH2)nC(O)ORa and (CH2)nC(O)NRbRc; and optionally
substituted with 1 , 2 or 3 additional substituents selected from halogen, CN, (CH2)nORa, (CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc,
(CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc, (CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa,
(CH2)nNRdC(S)NRbRc, (CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra,
(CH2)nNRdSO2Ra, (CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc,
(CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra,
(CH2)nSO2NRbRc, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3- 8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl,
(CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl, wherein each of the C-|. 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n) or XII(o), R2 is phenyl substituted at the meta position with a substituent selected from (CH2)nC(O)ORa and (CH2)nC(O)NRbRc, and optionally
substituted with 1 , 2 or 3 additional substituents selected from halogen, hydroxyl, C-i-6 alkoxy, CN, C-i-6 alkyl and C-i-6 haloalkyl.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), XI 1(1), Xll(m), Xll(n) or XII(o), R2 is phenyl substituted at the meta position with a substituent selected from C(O)OH, C(O)NH2, C(O)OCi-6 alkyl, C(O)NHCi-6 alkyl and C(O)N(Ci-6 alkyl)2; and optionally substituted with 1 , 2 or 3 additional substituents selected from halogen, hydroxyl, C-i-6 alkoxy, CN, C-i-6 alkyl and C-i-6 haloalkyl.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n) or XII(o), R2 is phenyl substituted with (CH2)nNRdC(O)Ra, wherein Ra is Ci-6 alkyl or 3-8 membered heterocycloalkyl, each optionally substituted with 1 , 2 or 3 substituents selected from halogen, CN, oxo, (CH2)nORa,
(CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc,
(CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc,
(CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa,
(CH2)nNRdC(S)NRbRc, (CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra,
(CH2)nNRdSO2Ra, (CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc,
(CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra,
(CH2)nSO2NRbRc, C -6 alkyl, C -6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3- 8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl,
(CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl; and optionally substituted with 1 , 2 or 3 additional substituents selected from halogen, CN, (CH2)nORa, (CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc,
(CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc, (CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa,
(CH2)nNRdC(S)NRbRc, (CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra,
(CH2)nNRdSO2Ra, (CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc,
(CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra,
(CH2)nSO2NRbRc, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3- 8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl, wherein each of the C-|. 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n) or XII(o), R2 is phenyl substituted with (CH2)nNRdC(O)Ra, wherein Ra is selected from C-i-6 alkyl, Ci-6 alkyl-OH and C-i-6 alkyl-NH2, each optionally substituted with 1 , 2 or 3 substituents selected from halogen, CN, oxo,
(CH2)nORa, (CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc,
(CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc, (CH2)nNRdSO2Ra, (CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra, (CH2)nSO2NRbRc, C-i-6 alkyl, C-i-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, and (CH2)n5-10 membered heteroaryl; and optionally substituted with 1 , 2 or 3 additional substituents selected from halogen, CN, (CH2)nORa, (CH2)nOC(O)Ra,
(CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc, (CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa, (CH2)nNRdC(S)NRbRc,
(CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra, (CH2)nNRdSO2Ra,
(CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc, (CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra, (CH2)nSO2NRbRc, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8
membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), XI 1(1), Xll(m), Xll(n) or XII(o), R2 is selected from 3-benzamide, N-methyl-3-benzamide, N,N- dimethyl-3-benzamide, 4-fluoro-3-benzamide, N-methyl-4-fluoro-3-benzamide, N,N-dimethyl-4-fluoro-3-benzamide, 3-benzoic acid, methyl-3-benzoate, 4- fluoro-3-benzoic acid, and methyl-4-fluoro-3-benzoate.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), XI 1(1), Xll(m), Xll(n) or XII(o), R2 is 5-10 membered heteroaryl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, (CH2)nORa,
(CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc,
(CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc,
(CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa,
(CH2)nNRdC(S)NRbRc, (CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra,
(CH2)nNRdSO2Ra, (CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc,
(CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra,
(CH2)nSO2NRbRc, C -6 alkyl, C -6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3- 8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl,
(CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl, wherein each of the C-i- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n) or XII(o), R2 is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionally substituted with 1 , 2, 3 or 4 substituents selected from halogen, CN, oxo, (CH2)nORa, (CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc,
(CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc, (CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa, (CH2)nNRdC(S)NRbRc, (CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra,
(CH2)nNRdSO2Ra, (CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc,
(CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra,
(CH2)nSO2NRbRc, C -6 alkyl, C -6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3- 8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl,
(CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl, wherein each of the C-i- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n) or XII(o), R2 is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionally substituted with a substituent selected from (CH2)nC(O)ORa and
(CH2)nC(O)NRbRc; and optionally substituted with 1 , 2 or 3 additional substituents selected from halogen, CN, oxo, (CH2)nORa, (CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc, (CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa, (CH2)nNRdC(S)NRbRc,
(CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra, (CH2)nNRdSO2Ra,
(CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc, (CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra, (CH2)nSO2NRbRc, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8
membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), XI 1(1), Xll(m), Xll(n) or XII(o), R2 is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl and triazyl, each optionally substituted with (CH2)nC(O)NRbRc.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), XI 1(1), Xll(m), Xll(n) or XII(o), R2 is selected from furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionally substituted with (CH2)nC(O)NRbRc.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), XI 1(1), Xll(m), Xll(n) or XII(o), R2 is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl and triazyl, each optionally substituted with (CH2)nC(O)NH2.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), XI 1(1), Xll(m), Xll(n) or XII(o), R2 is selected from furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionally substituted with (CH2)nC(O)NH2.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), XI 1(1), Xll(m), Xll(n) or XII(o), R2 is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionally substituted with (CH2)nNRdC(O)Ra, wherein Ra is Ci-6 alkyl or 3-8 membered heterocycloalkyl, each optionally substituted with 1 , 2 or 3 substituents selected from halogen, CN, oxo, (CH2)nORa, (CH2)nOC(O)Ra,
(CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc, (CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa, (CH2)nNRdC(S)NRbRc, (CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra, (CH2)nNRdSO2Ra,
(CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc, (CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra, (CH2)nSO2NRbRc, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8
membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n) or XII(o), R2 is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl and triazyl, each optionally substituted with (CH2)nNRdC(O)Ra, wherein Ra is selected from C-i-6 alkyl, C-i-6 alkyl-OH and C-i-6 alkyl-NH2, each optionally substituted with 1 , 2 or 3 substituents selected from halogen, CN, (CH2)nORa, (CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc,
(CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc,
(CH2)nNRdSO2Ra, (CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra, (CH2)nSO2NRbRc, Ci-6 alkyl, C-i-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n) or XII(o), R2 is selected furanyl, pyrrolyl, thiophenyl, thiazolyl,
isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, innidazolyl, triazolyl and tetrazolyl, each optionally substituted with (CH2)nNRdC(O)Ra, wherein Ra is selected from C-i-6 alkyl, C-i-6 alkyl-OH and Ci-6 alkyl-NH2, each optionally substituted with 1 , 2 or 3 substituents selected from halogen, CN, (CH2)nORa, (CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc,
(CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc,
(CH2)nNRdSO2Ra, (CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra, (CH2)nSO2NRbRc, Ci-6 alkyl, C-i-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n) or XII(o), R2 is selected from indolyl, indazolyl, benzimidazolyl, benzoxazolyl and benzoisoxazolyl, each optionally substituted with 1 , 2, 3 or 4 substituents selected from halogen, CN, oxo, (CH2)nORa, (CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc, (CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa, (CH2)nNRdC(S)NRbRc,
(CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra, (CH2)nNRdSO2Ra,
(CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc, (CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra, (CH2)nSO2NRbRc, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8
membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n) or XII(o), R2 is selected from 1 H-indazol-6-yl, 1 H-indazol-5-yl, 1 H- indazol-4-yl, 3-amino(1 H-indazol-5-yl), 3-amino(1 H-indazol-6-yl), 3-amino(1 H- indazol-7-yl), 1 -methyl(1 H-indazol-6-yl), 3-methyl(1 H-indazol-6-yl), 3-amino-1 - methyl(1 H-indazol-5-yl), 3-cyano(1 H-indazol-5-yl), 3-carboxamide(1 H-indazol- 5-yl), 3-carboxamidine(1 H-indazol-5-yl), 3-vinyl(1 H-indazol-5-yl), 3-ethyl(1 H- indazol-5-yl), 3-acetamide(1 H-indazol-5-yl), 3-methylsulfonylannine(1 H- indazol-5-yl), 3-methoxycarboxannide(1 H-indazol-5-yl), 3-methylannino(1 H- indazol-5-yl), 3-dimethylannino(1 H-indazol-5-yl), 3-ethylamino(1 H-indazol-5- yl), 3-(2-aminoethyl)annino(1 H-indazol-5-yl), 3-(2-hydroxyethyl)amino(1 H- indazol-5-yl), 3-[(methylethyl)annino](1 H-indazol-5-yl), 6-benzimidazol-5-yl, 6- (2-methylbenzinnidazol-5-yl), 2-aminobenzinnidazol-5-yl, 2- hydroxybenzimidazol-5-yl, 2-acetamidebenzinnidazol-5-yl, 3-aminobenzo[3,4- d]isoxazol-5-yl, 3-aminobenzo[d]isoxazol-6-yl, 3-aminobenzo[d]isoxazol-7-yl, 2-methylbenzoxazol-5-yl and 2-methylbenzoxazol-6-yl.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n) or XII(o), R2 is selected from 3-6 membered heterocycloalkyl and 3-6 membered heterocycloalkenyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, (CH2)nORa, (CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc, (CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa, (CH2)nNRdC(S)NRbRc,
(CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra, (CH2)nNRdSO2Ra,
(CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc, (CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra, (CH2)nSO2NRbRc, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8
membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n) or XII(o), R2 is selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, (CH2)nORa,
(CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc,
(CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa,
(CH2)nNRdC(S)NRbRc, (CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra,
(CH2)nNRdSO2Ra, (CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc,
(CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra,
(CH2)nSO2NRbRc, C -6 alkyl, C -6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3- 8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl,
(CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl, wherein each of the C-i- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a) or Xl(b), R2 is NRbRc, wherein Rb and Rc are as defined herein.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a) or Xl(b), R2 is NRbRc, wherein one of Rb and Rc is hydrogen and the other is C-i-6 alkyl optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a) or Xl(b), X is - C(O)- and R2 is NRbRc, wherein Rb and Rc are as defined herein.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a) or Xl(b), X is -C(O)- and R2 is NRbRc, wherein one of Rb and Rc is hydrogen and the other is C-i-6 alkyl optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a) or Xl(b), X is - (CH2)P- and R2 is NRbRc, wherein Rb and Rc are as defined herein. In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a) or Xl(b), X is -(CH2)P- and R2 is NRbRc, wherein one of Rb and Rc is hydrogen and the other is C-i-6 alkyl optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments, X, R2 and R3, together with the carbon atoms to which they are bound, form a 5-6 membered ring optionally containing one or more heteroatoms selected from oxygen nitrogen and sulfur, and optionally containing one or more double bonds, and optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments, the compound is of Formula XIII, or a
pharmaceutically acceptable salt thereof:
Figure imgf000059_0001
Formula XIII
wherein A is a 5 or 6 membered ring optionally containing one or more heteroatoms selected from oxygen nitrogen and sulfur, and optionally containing one or more double bonds; t is 0, 1 , 2, 3 or 4; and R1, R4, R5, R6, R7, R8, R9, Rf and m are as defined herein.
In some embodiments of compounds of Formula XIII, ring A together with the pyridazine ring to which it is bound form a group selected from cinnoline, pyrido[2,3-c]pyridazine, pyrido[3,4-c]pyridazine, pyrido[4,3- c]pyridazine, pyrido[3,2-c]pyridazine, 5,6,7,8-tetrahydrocinnoline, 5,6,7,8- tetrahydropyrido[2,3-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,4-c]pyridazine, 5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,2- c]pyridazine, thieno[2,3-c]pyridazine, thiazolo[5,4-c]pyridazine, 7H-pyrrolo[2,3- c]pyridazine, 7H-imidazo[4,5-c]pyridazine, thieno[3,2-c]pyridazine,
thiazolo[4,5-c]pyridazine, 5H-pyrrolo[3,2-c]pyridazine, 5H-imidazo[4,5- c]pyridazine, 1 H-pyrazolo[4,3-c]pyridazine, 1 H-pyrazolo[3,4-c]pyridazine, 3H- [1 ,2,3]triazolo[4,5-c]pyridazine, 6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine, 6,7- dihydro-5H-pyrrolo[3,4-c]pyridazine, 6,7-dihydro-5H-pyrrolo[3,2-c]pyridazine and 6,7-dihydro-5H-cyclopenta[c]pyridazine, each optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n), Xll(o) or XIII, R1 is selected from hydrogen, halogen, CN, C-i-6 alkyl, C-|. 6 haloalkyl, C(O)ORa, C(O)NRbRc, ORa, NRbRc, C6-io aryl and 5-10 membered heteroaryl.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n), Xll(o) or XIII, R1 is selected from hydrogen, halogen, CN, C-i-6 alkyl, C-i- 6 haloalkyl, hydroxyl, C-i-6 alkoxy, NH2, NHCi-6 alkyl, and N(Ci-6 alkyl)2.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n), Xll(o) or XIII, R1 is selected from hydrogen, halogen, CN, CF3 and methyl.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n), Xll(o) or XIII, R1 is hydrogen.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n) or XII(o), R3 is selected from hydrogen, halogen, CN, C-i-6 alkyl, Ci-6 haloalkyl, C(O)ORa, C(O)NRbRc, ORa, NRbRc, C6-io aryl and 5-10 membered heteroaryl.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), XI 1(1), Xll(m), Xll(n) or XII(o), R3 is selected from hydrogen, halogen, CN, C-i-6 alkyl, Ci-6 haloalkyl, hydroxyl, Ci-6 alkoxy, NH2, NHC-i-6 alkyl, and N(Ci-6 alkyl)2.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n) or XII(o), R3 is selected from hydrogen, halogen, CN, CF3 and methyl.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n) or XII(o), R3 is hydrogen.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n) or XII(o), R1 and R3 are each hydrogen.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n), Xll(o), or XIII, R4 is selected from hydrogen, C-i-6 alkyl, Ci-6 haloalkyl, C(O)Ra, C(O)ORa, C(O)NRbRc and SO2Ra.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n) or XII(o), R4 is hydrogen.
In some embodiments of compounds of Formula I, II, III, IV(a), IV(b), V(a), V(b), VI, Vll(a), Vll(b), Vlll(a), Vlll(b), IX, X(a), X(b), Xl(a), Xl(b), Xll(a), Xll(b), Xll(c), Xll(d), Xll(e), Xll(f), Xll(g), Xll(h), Xll(i), Xll(j), Xll(k), Xll(l), Xll(m), Xll(n), Xll(o), or XIII, R1, R3 and R4 are each hydrogen.
In some embodiments of compounds of Formula I, III, IV(b), V(b), VI, Vll(b), Vlll(b), IX, X(b), Xl(b), Xll(a), Xll(c), Xll(e), Xll(f), Xll(h), Xll(j), Xll(k), Xll(m), Xll(o) or XIII, R8 and R9, at each occurrence, are each independently selected from hydrogen, halogen and C-i-6 alkyl.
In some embodiments of compounds of Formula I, III, IV(b), V(b), VI, Vll(b), Vlll(b), IX, X(b), Xl(b), Xll(a), Xll(c), Xll(e), Xll(f), Xll(h), Xll(j), Xll(k), Xll(m), Xll(o) or XIII, R8 and R9, at each occurrence, are each hydrogen.
In some embodiments, the compound is selected from the compounds in Table 2, or a pharmaceutically acceptable salt thereof.
The compounds and compositions described and/or disclosed herein modulate the contractility of the skeletal sarcomere. Specifically, the compounds modulate the troponin complex of the fast skeletal muscle sarcomere through one or more of fast skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. As used in this context, "modulate" means either increasing or decreasing activity. In some instances, the compounds described and/or disclosed herein potentiate (i.e., increase activity) of one or more of fast skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. In other instances, the compounds described and/or disclosed herein inhibit (i.e., decrease activity) of one or more of fast skeletal myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.
In both preclinical and clinical settings, activators of the fast skeletal troponin complex have been shown to amplify the response of fast skeletal muscle to nerve stimulation, resulting in an increase in muscle force development at sub-maximal muscle activation (see, e.g., Russell et al., "The Fast Skeletal Troponin Activator, CK-2017357, Increases Skeletal Muscle Force in vitro and in situ", 2009 Experimental Biology Conference, New Orleans, LA, April 2009). Activators of the fast skeletal troponin complex have been shown to increase the sensitivity of skinned skeletal muscle fibers to calcium, and in living muscle to the frequency of
stimulation, each of which results in an increase in muscle force
development at sub-maximal muscle activation. Such activators have also been shown to reduce muscle fatigue and/or to increase the overall time to fatigue in normal and low oxygenated conditions (see, e.g., Russell et al., "The Fast Skeletal Troponin Activator, CK-2017357, Increases Skeletal Muscle Force and Reduces Muscle Fatigue in vitro and in situ", 5th Cachexia Conference, Barcelona, Spain, December 2009; Hinken et al., "The Fast Skeletal Troponin Activator, CK-2017357, Reduces Muscle Fatigue in an in situ Model of Vascular Insufficiency", Society for Vascular Medicine's 2010 Annual Meeting: 21 st Annual Scientific Sessions, Cleveland, OH, April 2010). The increase in muscle force in response to nerve input has been
demonstrated in healthy human volunteers as well (see, e.g., Hansen et al., "CK-2017357, a Novel Activator of Fast Skeletal Muscle, Increases Isometric Force Evoked by Electrical Stimulation of the Anterior Tibialis Muscle in Healthy Male Subjects", Society for Neuroscience 40th Annual Meeting:
Neuroscience 2010, November 2010). Work in additional preclinical models of muscle function suggests that activators of the fast skeletal troponin complex also cause an increase in muscle power and/or endurance. These pharmacological properties suggest this mechanism of action could have application in conditions, for example, where neuromuscular function is impaired.
Provided are methods for enhancing fast skeletal muscle efficiency in a patient in need thereof, comprising administering to said patient an effective amount of a compound or composition described and/or disclosed herein that selectively binds the troponin complex of fast skeletal muscle fiber or sarcomere. In some embodiments, the compound disclosed and/or described herein activates fast skeletal muscle fibers or sarcomeres. In some embodiments, administration of a compound disclosed and/or described herein results in an increase in fast skeletal muscle power output. In some embodiments, administration of a compound disclosed and/or described herein results in increased sensitivity of fast skeletal muscle fibers or sarcomeres to calcium ion, as compared to fast skeletal muscle fibers or sarcomeres untreated with the compound. In some embodiments,
administration of a compound disclosed and/or described herein results in a lower concentration of calcium ions causing fast skeletal muscle myosin to bind to actin. In some embodiments, administration of a compound disclosed and/or described herein results in the fast skeletal muscle fiber generating force to a greater extent at submaximal levels of muscle activation.
Also provided is a method for sensitizing a fast skeletal muscle fiber to produce force in response to a lower concentration of calcium ion, comprising contacting the fast skeletal muscle fiber with a compound or composition described and/or disclosed herein that selectively binds to troponin complexes in the fast skeletal muscle sarcomere. In some embodiments, contacting the fast skeletal muscle fiber with the compound results in activation of the fast skeletal muscle fiber at a lower calcium ion concentration than in an untreated fast skeletal muscle fiber. In some embodiments, contacting the fast skeletal muscle fiber with the compound results in the production of increased force at a lower calcium ion concentration in comparison with an untreated fast skeletal muscle fiber.
Also provided is a method for increasing time to fast skeletal muscle fatigue in a patient in need thereof, comprising contacting fast skeletal muscle fibers with a compound or composition described and/or disclosed herein that selectively binds to the troponin complexes of the fast skeletal muscle fibers. In some embodiments, the compound binds to form ligand-troponin-calcium ion complexes that activate the fast skeletal muscle fibers. In some
embodiments, formation of the complexes and/or activation of the fast skeletal muscle fibers results in enhanced force and/or increased time to fatigue as compared to untreated fast skeletal muscle fibers contacted with a similar calcium ion concentration.
The compounds and pharmaceutical compositions described and/or disclosed herein are capable of modulating the contractility of the fast skeletal sarcomere in vivo, and can have application in both human and animal disease. Modulation would be desirable in a number of conditions or diseases, including, but not limited to, 1 ) neuromuscular disorders, such as Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), peripheral neuropathies and myasthenia gravis; 2) disorders of voluntary muscle, including muscular dystrophies, myopathies and conditions of muscle wasting, such as sarcopenia and cachexia syndromes (e.g., cachexia syndromes caused by diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), and chronic kidney disease/dialysis), and rehabilitation-related deficits, such as those associated with recovery from surgery (e.g. post-surgical muscle weakness) prolonged bed rest or stroke rehabilitation; 3) central nervous system (CNS) disorders in which muscle weakness, atrophy and fatigue are prominent symptoms, such as multiple sclerosis, Parkinson's disease, stroke and spinal cord injury; and 4) muscle symptoms stemming from systemic disorders, including Peripheral Vascular Disease (PVD) or Peripheral Arterial Disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity and frailty due to aging.
The compounds and compositions described and/or disclosed herein may be used to treat neuromuscular diseases, i.e., diseases that affect any part of the nerve-muscle unit. Neuromuscular diseases include, for example: 1 ) diseases of the motor unit, including but not limited to Amyotrophic Lateral Sclerosis (ALS) including bulbar and primary lateral sclerosis (PLS) variants; spinal muscular atrophy types 1 -4; Kennedy syndrome; post-polio syndrome; motor neuropathies including, for example, critical illness polyneuropathy; multifocal motor neuropathy with conduction block; Charcot-Marie-Tooth disease and other hereditary motor and sensory neuropathies; and Guillain- Barre Syndrome, 2) disorders of the neuromuscular junction, including myasthenia gravis, Lambert-Eaton myasthenic syndrome, and prolonged neuromuscular blockade due to drugs or toxins; and 3) peripheral
neuropathies, such as acute inflammatory demyelinating
polyradiculoneuropathy, diabetic neuropathy, chronic inflammatory
demyelinating polyradiculoneuropathy, traumatic peripheral nerve lesions, neuropathy of leprosy,vasculitic neuropathy, dermatomyositis/polymyositis and neuropathy of Friedreich Ataxia.
The compounds and compositions described and/or disclosed herein may be used to treat disorders of voluntary muscle. Disorders of voluntary muscle include 1 ) muscular dystrophies (including, for example, Duchenne, Becker, Limb-Girdle, Facioscapulohumeral, limb girdle, Emery-Dreyfus, oculopharyngeal and congenital muscular dystrophies); and 2) myopathies, such as nemaline myopathy, central core disease, congenital myopathies, mitochondrial myopathies, acute myopathy; inflammatory myopathies (such as dermatomyositis/polymyositis and inclusion body myositis), endocrine myopathies (such as those associated with hyper- or hypothyroidism), Cushing's or Addison's syndrome or disease and pituitary gland disorders, metabolic myopathies (such as glycogen storage diseases, e.g., McArdle's disease, Pompe disese, etc), drug-induced myopathy (statins, ant-retroviral drugs, steroid myopathy) restrictive lung disease, sarcoidosis, Schwartz- Jampel Syndrome, focal muscular atrophies, and distal myopathies.
The compounds and compositions described and/or disclosed herein may be used to treat or Amyotrophic Lateral Sclerosis (ALS). ALS is a disease that generally arises later in life (Age 50+) and has a rapid
progression from initial limb weakness to paralysis and death. Common life expectancy after diagnosis is 3-5 years. The cause of disease for most ALS patients is unknown (termed the spontaneous form) while a small proportion of patients have an inherited form (familial) of disease. The condition causes progressive death of motor neurons through causes that are not clear.
Surviving motor units attempt to compensate for dying ones by innervating more fibers (termed sprouting) but this can only partially correct muscle function, as muscles are subsequently more prone to problems of
coordination and fatigue. Eventually, surviving motor neurons die, resulting in complete paralysis of the affected muscle. The disease is commonly fatal through the eventual loss of innervation to the diaphragm, resulting in respiratory failure. Current treatment options for ALS are limited.
The compounds and compositions described and/or disclosed herein may be used to treat Spinal Muscular Atrophy (SMA). SMA is a genetic disorder that arises through the mutation of a protein, SMN1 , that appears to be required for the survival and health of motor neurons. The disease is most common in children as the majority of patients only survive until 1 1 -12 years of age. There is currently no available treatment for SMA.
The compounds and compositions described and/or disclosed herein may be used to treat myasthenia gravis. Myasthenia gravis is a chronic autoimmune neuromuscular disease wherein the body produces antibodies that block, alter, or destroy proteins involved in signaling at the neuromuscular junction, thus preventing muscle contraction from occurring. These proteins include nicotinic acetylcholine receptor (AChR) or, less frequently, a muscle- specific tyrosine kinase (MuSK) involved in AChR clustering (see, e.g., Drachman, N. Eng. J. of Med., 330:1797-1810, 1994). The disease is characterized by varying degrees of weakness of the skeletal (voluntary) muscles of the body. The hallmark of myasthenia gravis is muscle weakness that increases during periods of activity and improves after periods of rest. Although myasthenia gravis may affect any voluntary muscle, certain muscles, such as those that control eye and eyelid movement, facial expression, chewing, talking, and swallowing are often, but not always, involved in the disorder. The muscles that control breathing and neck and limb movements may also be affected. In most cases, the first noticeable symptom is weakness of the eye muscles. In others, difficulty in swallowing and slurred speech may be the first signs. The degree of muscle weakness involved in myasthenia gravis varies greatly among patients, ranging from a localized form, limited to eye muscles (ocular myasthenia), to a severe or generalized form in which many muscles - sometimes including those that control breathing - are affected. Symptoms, which vary in type and severity, may include a drooping of one or both eyelids (ptosis), blurred or double vision (diplopia) due to weakness of the muscles that control eye movements, unstable or waddling gait, weakness in arms, hands, fingers, legs, and neck, a change in facial expression, difficulty in swallowing and shortness of breath, and impaired speech (dysarthria). Generalized weakness develops in approximately 85% of patients.
The compounds and compositions described and/or disclosed herein may be used to treat sarcopenia, e.g., sarcopenia associated with aging or disease (e.g. HIV infection). Sarcopenia is characterized by a loss of skeletal muscle mass, quality, and strength. Clinically, a decline in skeletal muscle tissue mass (muscle atrophy) contributes to frailty in older individuals. In human males, muscle mass declines by one-third between the ages of 50 and 80. In older adults, extended hospitalization can result in further disuse atrophy leading to a potential loss of the ability for independent living and to a cascade of physical decline. Moreover, the physical aging process profoundly affects body composition, including significant reductions in lean body mass and increases in central adiposity. The changes in overall adiposity and fat distribution appear to be important factors in many common age-related diseases such as hypertension, glucose intolerance and diabetes,
dyslipidemia, and atherosclerotic cardiovascular disease. In addition, it is possible that the age-associated decrement in muscle mass, and
subsequently in strength and endurance, may be a critical determinant for functional loss, dependence and disability. Muscle weakness is also a major factor prediposing the elderly to falls and the resulting morbidity and mortality.
The compounds and compositions described and/or disclosed herein may be used to treat cachexia. Cachexia is a state often associated with cancer or other serious diseases or conditions, (e.g, chronic obstructive pulmonary disease, heart failure, chronic kidney disease, kidney dialysis), that is characterized by progressive weight loss, muscle atrophy and fatigue, due to the deletion of adipose tissue and skeletal muscle.
The compounds and compositions described and/or disclosed herein may be used to treat muscular dystrophies. Muscular dystrophy can be characterized by progressive muscle weakness, destruction and regeneration of the muscle fibers, and eventual replacement of the muscle fibers by fibrous and fatty connective tissue.
The compounds and compositions described and/or disclosed herein may be used to treat post-surgical muscle weakness, which is a reduction in the strength of one or more muscles following surgical procedure. Weakness may be generalized (i.e. total body weakness) or localized to a specific area, side of the body, limb, or muscle.
The compounds and compositions described and/or disclosed herein may be used to treat post-traumatic muscle weakness, which is a reduction in the strength of one or more muscles following a traumatic episode (e.g. bodily injury). Weakness may be generalized (i.e. total body weakness) or localized to a specific area, side of the body, limb, or muscle.
The compounds and compositions described and/or disclosed herein may be used to treat muscle weakness and fatigue produced by peripheral vascular disease (PVD) or peripheral artery disease (PAD). Peripheral vascular disease is a disease or disorder of the circulatory system outside of the brain and heart. Peripheral artery disease (PAD), also known as peripheral artery occlusive disease (PAOD), is a form of PVD in which there is partial or total blockage of an artery, usually one leading to a leg or arm. PVD and/or PAD can result from, for example, atherosclerosis, inflammatory processes leading to stenosis, embolus/ thrombus formation, or damage to blood vessels due to disease (e.g., diabetes), infection or injury. PVD and/or PAD can cause either acute or chronic ischemia, typically of the legs. The symptoms of PVD and/or PAD include pain, weakness, numbness, or cramping in muscles due to decreased blood flow (claudication), muscle pain, ache, cramp, numbness or fatigue that occurs during exercise and is relieved by a short period of rest (intermittent claudication), pain while resting (rest pain) and biological tissue loss (gangrene). The symptoms of PVD and/or PAD often occur in calf muscles, but symptoms may also be observed in other muscles such as the thigh or hip. Risk factors for PVD and/or PAD include age, obesity, sedentary lifestyle, smoking, diabetes, high blood pressure, and high cholesterol (i.e., high LDL, and/or high triglycerides and/or low HDL). People who have coronary heart disease or a history of heart attack or stroke generally also have an increased frequency of having PVD and/or PAD.
Activators of the fast skeletal troponin complex have been shown to reduce muscle fatigue and/or to increase the overall time to fatigue in in vitro and in situ models of vascular insufficiency (see, e.g., Russell et al., "The Fast Skeletal Troponin Activator, CK-2017357, Increases Skeletal Muscle Force and Reduces Muscle Fatigue in vitro and in situ", 5th Cachexia Conference, Barcelona, Spain, December 2009; Hinken et al., "The Fast Skeletal Troponin Activator, CK-2017357, Reduces Muscle Fatigue in an in situ Model of Vascular Insufficiency", Society for Vascular Medicine's 2010 Annual Meeting: 21 st Annual Scientific Sessions, Cleveland, OH, April 2010).
The compounds and compositions described and/or disclosed herein may be used to treat symptoms of frailty, e.g., frailty associated with aging. Frailty is characterized by one or more of unintentional weight loss, muscle weakness, slow walking speed, exhaustion, and low physical activity.
The compounds and compositions described and/or disclosed herein may be used to treat muscle weakness and/or fatigue due to wasting syndrome, which is a condition characterized by involuntary weight loss associated with chronic fever and diarrhea. In some instances, patients with wasting syndrome lose 10% of baseline body weight within one month.
The compounds and compositions described and/or disclosed herein may be used to treat muscular diseases and conditions caused by structural and/or functional abnormalities of skeletal muscle tissue, including muscular dystrophies, congenital muscular dystrophies, congenital myopathies, distal myopathies, other myopathies (e.g., myofibrillar, inclusion body), myotonic syndromes, ion channel muscle diseases, malignant hyperthermias, metabolic myopathies, congenital myasthenic syndromes, sarcopenia, muscle atrophy and cachexia.
The compounds and compositions described and/or disclosed herein also may be used to treat diseases and conditions caused by muscle dysfunction originating from neuronal dysfunction or transmission, including amyotrophic lateral sclerosis, spinal muscular atrophies, hereditary ataxias, hereditary motor and sensory neuropathies, hereditary paraplegias, stroke, multiple sclerosis, brain injuries with motor deficits, spinal cord injuries, Alzheimer's disease, Parkinson's disease with motor deficits, myasthenia gravis and Lambert-Eaton syndrome.
The compounds and compositions described and/or disclosed herein also may be used to treat diseases and conditions caused by CNS, spinal cord or muscle dysfunction originating from endocrine and/or metabolic dysregulation, including claudication secondary to peripheral artery disease, hypothyroidism, hyper- or hypo-parathyroid ism, diabetes, adrenal dysfunction, pituitary dysfunction and acid/base imbalances.
The compounds and compositions described and/or disclosed herein may be administered alone or in combination with other therapies and/or therapeutic agents useful in the treatment of the aforementioned disorders.
The compounds and compositions described and/or disclosed herein may be combined with one or more other therapies to treat ALS. Examples of suitable therapies include riluzole, baclofen, diazepam, trihexyphenidyl and amitriptyline. In some embodiments, the compounds and compositions described and/or disclosed herein are combined with riluzole to treat a subject suffering from ALS.
The compounds and compositions described and/or disclosed herein may be combined with one or more other therapies to treat myasthenia gravis. Examples of suitable therapies include administration of anticholinesterase agents (e.g., neostigmine, pyridostigmine), which help improve neuromuscular transmission and increase muscle strength; administration of
immunosuppressive drugs (e.g., prednisone, cyclosporine, azathioprine, mycophenolate mofetil) which improve muscle strength by suppressing the production of abnormal antibodies; thymectomy (i.e., the surgical removal of the thymus gland, which often is abnormal in myasthenia gravis patients); plasmapheresis; and intravenous immune globulin.
The compounds and compositions described and/or disclosed herein may be combined with one or more other therapies to treat PVD or PAD (e.g., claudication). Treatment of PVD and PAD is generally directed to increasing arterial blood flow, such as by smoking cessation, controlling blood pressure, controlling diabetes, and exercising. Treatment can also include medication, such as medicines to help improve walking distance (e.g., cilostazol, pentoxifylline), antiplatelet agents (e.g., aspirin, ticlopidine, clopidogrel), anticoagulents (e.g., heparin, low molecular weight heparin, warfarin, enoxaparin) throbmolytics, antihypertensive agents (e.g., diuretics, ACE inhibitors, calcium channel blockers, beta blockers, angiotensin II receptor antagonists), and cholesterol-lowering agents (e.g., statins). In some patients, angioplasty, stenting, or surgery (e.g., bypass surgery or surgery to remove an atherosclerotic plaque) may be necessary.
Suitable therapeutic agents include, for example, anti-obesity agents, anti-sarcopenia agents, anti-wasting syndrome agents, anti-frailty agents, anti-cachexia agents, anti-muscle spasm agents, agents against post-surgical and post-traumatic muscle weakness, and anti-neuromuscular disease agents.
Suitable additional therapeutic agents include, for example: orlistat, sibramine, diethylpropion, phentermine, benzaphetamine, phendimetrazine, estrogen, estradiol, levonorgestrel, norethindrone acetate, estradiol valerate, ethinyl estradiol, norgestimate, conjugated estrogens, esterified estrogens, medroxyprogesterone acetate, testosterone, insulin-derived growth factor, human growth hormone, riluzole, cannabidiol, prednisone, albuterol, nonsteroidal anti-inflammatory drugs, and botulinum toxin.
Other suitable therapeutic agents include TRH, diethylstilbesterol, theophylline, enkephalins, E series prostaglandins, compounds disclosed in U.S. Patent No. 3,239,345 (e.g., zeranol), compounds disclosed in U.S.
Patent No. 4,036,979 (e.g., sulbenox), peptides disclosed in U.S. Patent No. 4,41 1 ,890, growth hormone secretagogues such as GHRP-6, GHRP-1 (disclosed in U.S. Patent No. 4,41 1 ,890 and publications WO 89/071 10 and WO 89/071 1 1 ), GHRP-2 (disclosed in WO 93/04081 ), NN703 (Novo Nordisk), LY44471 1 (Lilly), MK-677 (Merck), CP424391 (Pfizer) and B-HT920, growth hormone releasing factor and its analogs, growth hormone and its analogs and somatomedins including IGF-1 and IGF-2, alpha-adrenergic agonists, such as clonidine or serotonin 5-HTD agonists, such as sumatriptan, agents which inhibit somatostatin or its release, such as physostigmine,
pyridostigmine, parathyroid hormone, PTH(1 -34), and bisphosphonates, such as MK-217 (alendronate).
Still other suitable therapeutic agents include estrogen, testosterone, selective estrogen receptor modulators, such as tamoxifen or raloxifene, other androgen receptor modulators, such as those disclosed in Edwards, J. P. et. al., Bio. Med. Chem. Let., 9, 1003-1008 (1999) and Hamann, L. G. et. al., J. Med. Chem., 42, 210-212 (1999), and progesterone receptor agonists
("PRA"), such as levonorgestrel, medroxyprogesterone acetate (MPA).
Other suitable therapeutic agents include anabolic agents, such as selective androgen receptor modulators (SARMs); antagonists of the activin receptor pathway, such as anti-myostatin antibodies or soluble activin receptor decoys, including ACE-031 (Acceleron Pharmaceuticals, a soluble activin receptor type MB antagonist), MYO-027/PFE-3446879 (Wyeth/Pfizer, an antibody myostatin inhibitor), AMG-745 (Amgen, a peptibody myostatin inhibitor), and an ActRIIB decoy receptor (see Zhou et al., Cell, 142, 531-543, August 20, 2010); and anabolic steroids.
Still other suitable therapeutic agents include aP2 inhibitors, such as those disclosed in U.S. Patent No. 6,548,529, PPAR gamma antagonists, PPAR delta agonists, beta 3 adrenergic agonists, such as AJ9677
(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer), other beta 3 agonists as disclosed in U.S. Patent Nos. 5,541 ,204, 5,770,615, 5,491 ,134, 5,776,983 and 5,488,064, a lipase inhibitor, such as orlistat or ATL-962 (Alizyme), a serotonin (and dopamine) reuptake inhibitor, such as
sibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron), a thyroid receptor beta drug, such as a thyroid receptor ligand as disclosed in WO 97/21993, WO 99/00353, and GB98/284425, and anorectic agents, such as dexamphetamine, phentermine, phenylpropanolamine or mazindol.
Still other suitable therapeutic agents include HIV and AIDS therapies, such as indinavir sulfate, saquinavir, saquinavir mesylate, ritonavir, lamivudine, zidovudine, lamivudine/zidovudine combinations, zalcitabine, didanosine, stavudine, and megestrol acetate.
Still other suitable therapeutic agents include antiresorptive agents, hormone replacement therapies, vitamin D analogues, elemental calcium and calcium supplements, cathepsin K inhibitors, MMP inhibitors, vitronectin receptor antagonists, Src SH.sub.2 antagonists, vacuolar H+-ATPase inhibitors, ipriflavone, fluoride, Tibo lone, pro stanoids, 17-beta hydroxysteroid dehydrogenase inhibitors and Src kinase inhibitors.
The above therapeutic agents, when employed in combination with the compounds and compositions disclosed and/or described herein, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
The compounds and compositions disclosed and/or described herein are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease state. While human dosage levels have yet to be optimized for the chemical entities described herein, generally, a daily dose ranges from about 0.05 to 100 mg/kg of body weight; in some embodiments, from about 0.10 to 10.0 mg/kg of body weight, and in some embodiments, from about 0.15 to 1 .0 mg/kg of body weight. Thus, for administration to a 70 kg person, in some embodiments, the dosage range would be about from 3.5 to 7000 mg per day; in some embodiments, about from 7.0 to 700.0 mg per day, and in some embodiments, about from 10.0 to 100.0 mg per day. The amount of the chemical entity administered will be dependent, for example, 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. For example, an exemplary dosage range for oral administration is from about 70 mg to about 700 mg per day, and an exemplary intravenous administration dosage is from about 70 mg to about 700 mg per day, each depending upon the compound
pharmacokinetics.
Administration of the compounds and compositions disclosed and/or described herein can be via any accepted mode of administration for therapeutic agents including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the compound or composition is administered orally or intravenously. In some embodiments, the compound or composition disclosed and/or described herein is administered orally.
Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms, such as tablet, capsule, powder, liquid, suspension, suppository, and aerosol forms. The compounds disclosed and/or described herein can also be administered in sustained or controlled release dosage forms (e.g., controlled/sustained release pill, depot injection, osmotic pump, or transdermal (including electrotransport) patch forms) for prolonged timed, and/or pulsed administration at a predetermined rate. In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
The compounds disclosed and/or described herein can be
administered either alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium
crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate,
triethanolamine acetate, triethanolamine oleate). Generally, depending on the intended mode of administration, the pharmaceutical composition will contain about 0.005% to 95%, or about 0.5% to 50%, by weight of a compound disclosed and/or described herein. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
In some embodiments, the compositions will take the form of a pill or tablet and thus the composition may contain, along with a compounds disclosed and/or described herein, one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and/or a binder (e.g., starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives). Other solid dosage forms include a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides) encapsulated in a gelatin capsule.
Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing or suspending etc. a compound disclosed and/or described herein and optional pharmaceutical additives in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of the compound contained in such parenteral compositions depends, for example, on the physical nature of the compound, the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.01 % to 10% in solution are employable, and may be higher if the composition is a solid which will be subsequently diluted to another concentration. In some embodiments, the composition will comprise from about 0.2 to 2% of a compound disclosed and/or described herein in solution.
Pharmaceutical compositions of the compounds disclosed and/or described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the pharmaceutical composition may have diameters of less than 50 microns, or in some embodiments, less than 10 microns.
In addition, pharmaceutical compositions can include a compound disclosed and/or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, and the like. Suitable medicinal and pharmaceutical agents include those described herein.
The following examples serve to more fully describe the invention described herein. It is understood that these examples in no way serve to limit the true scope of this invention, but rather are presented for illustrative purposes. Example 1 : Preparation of N-(5-(6-(2-(4-Fluorophenyl)-2- methylpropylamino)pyridazin-3-yl)-1 H-indazol-3-yl)acetamide
Figure imgf000076_0001
6-Chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine.
A solution of (2-(4-fluorophenyl)-2-methylpropan-1 -amine (27 g, 160 mmol, 1 .6 equiv), 3,6-dichloropyhdazine (15 g, 100 mmol, 1 .0 equiv) and K2CO3 (42 g, 302 mmol, 3.0 equiv) in isopropanol (15 ml_) was stirred at 100 °C for 36 hours. The cooled mixture was partitioned between water and EtOAc and the organic fraction was dried over Na2SO4 and concentrated in vacuo. Partial purification over silica gel using a 30 - 75% gradient of EtOAc/hexanes gave the desired product (29.6 g, 103%) which was used without further
purification.
Figure imgf000076_0002
2-Fluoro-5-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin- 3-yl)benzonitrile. To a solution of 6-chloro-N-(2-(4-fluorophenyl)-2- methylpropyl)pyridazin-3-amine (5.0 g, 23 mmol, 1 .0 equiv) and K2CO3 (9.4 g, 68 mmol, 3.0 equiv) in dioxane (35 ml_) was added Pd(dppf)CI2 (1 .7 g, 2.3 mmol, 0.1 equiv) and 3-cyano-4-fluorophenylboronic acid (5.0 g, 30 mmol, 1 .3 equiv). The mixture was stirred at 80 °C for 3 hours after which it was allowed to cool to room temperature and concentrated in vacuo. The residue was diluted with EtOAc, washed with saturated NaHCO3, dried over Na2SO and evaporated to dryness. The residue was purified by reverse phase HPLC using a CH3CN/water gradient to give the desired product (5.3 g, 63%).
Figure imgf000076_0003
5-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)-1 H- indazol-3-amine. To a solution of 2-fluoro-5-(6-(2-(4-fluorophenyl)-2- nnethylpropylannino)pyhdazin-3-yl)benzonithle (0.53 g, 1 .5 mmol, 1 .0 equiv) in n-butanol (10 ml_) was added hydrazine monohydrate (1 .0 ml_, 32 mmol, 20 equiv). The mixture was stirred at 1 10 °C for two hours followed by evaporation of the solvents in vacuo. Purification on a preparatory TLC plate using 5% MeOH/DCM as eluent gave the desired product (195 mg, 36%), m/z = +H].
Figure imgf000077_0001
N-(5-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)- 1 H-indazol-3-yl)acetamide. To a solution of 5-(6-(2-(4-fluorophenyl)-2- methylpropylamino)pyridazin-3-yl)-1 H-indazol-3-amine (50 mg, 133 μιτιοΙ) in pyridine (1 ml_) was added acetyl chloride (9.5 μΙ_, 133 μιτιοΙ). The mixture was stirred for 15 min, concentrated, purified by reverse phase
chromatography using a CH3CN/water gradient to afford 25 mg of white solid, m/z = 419.9 [M+H].
Example 2: Preparation of N-(2-(4-Fluorophenyl)-2-methylpropyl)-6-(1 H- pyrazol-1 -yl)pyridazin-3-amine
Figure imgf000077_0002
Step 1 : To a solution of pyrazole (3.69 g, 25 mmol, 1 .0 equiv) in NMP (25 ml_) was added sodium hydride (60% dispersion in mineral oil, 1 .5 g, 38 mmol, 1 .5 equiv). The mixture was stirred for 15 min, followed by the addition of 3,6-dichloropyridazine (3.02 g, 25 mmol, 1 .0 equiv). The reaction mixture was stirred for 1 .5 h and then diluted with water (50 ml_) and ethyl acetate (100 ml_). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (3 x 50 mL). The organic layer was then dried over Na2SO , filtered, and concentrated to give 3.89 g of 3-chloro-6-(1 H-pyrazol-1 -yl)pyridazine as a crude tan solid that was used directly in the next step.
Step 2: To a 5 mL microwave vial was added 3-chloro-6-(1 H-pyrazol-1 - yl)pyridazine (320 mg, 1 .8 mmol, 1 .0 equiv), 2-(4-fluorophenyl)-2- methylpropan-1 -amine (386 mg, 2.3 mmol, 1 .3 equiv), diisopropylethylamine (620 μί, 3.6 mmol, 2.0 equiv), and NMP (4 mL). The reaction was heated in a microwave reactor to 250 °C and stirred for 15 min. A portion (roughly a third) of the reaction was purified by reverse phase chromatography and then silica gel chromatography (10% MeOH/DCM) to give 61 mg of N-(2-(4- fluorophenyl)-2-methylpropyl)-6-(1 H-pyrazol-1 -yl)pyridazin-3-amine, m/z = 312.1 [M+H].
Example 3: Preparation of 5-(6-(2-(4-fluorophenyl)-2-methylpropylamino) pyridazin-3-yl)-1 ,3,4-oxadiazol-2(3H)-one
Figure imgf000078_0001
Methyl 6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-3- carboxylate. To a 25 mL round bottom flask was added methyl 6- chloropyridazine-3-carboxylate (0.50 g, 2.90 mmol, 1 .0 equiv), 2-(4- fluorophenyl)-2-methylpropan-1 -amine (0.60 g, 3.6 mmol, 1 .2 equiv), potassium carbonate (300 mg, 2.2 mmol, 0.75 equiv), and isopropanol (3 mL). The reaction mixture was stirred and heated at 120 °C for 12 h. The reaction was then filtered through celite, concentrated, and purified by silica gel chromatography (0-40% EtOAC/hexanes) to afford 360 mg (43%) of methyl 6- (2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-3-carboxylate as an off- white foam.
Figure imgf000079_0001
5-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)- 1 ,3,4-oxadiazol-2(3H)-one. To a 25 mL round bottom flask was added methyl 6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-3-carboxylate (100 mg, 0.3 mmol, 1 .0 equiv), hydrazine hydrate (1 mL), and ethanol (5 mL)). The reaction was refluxed for 2 h and concentrated. Ν,Ν'- Carbonyldiimidazole (100 mg, 0.6 mmol, 2.0 equivj and DMF (1 mL) were then added to the crude product and the reaction was heated to 90 °C for 1 .5 h. The reaction mixture was directly purified by reverse phase column chromatography to afford 72 mg (67%) of 5-(6-(2-(4-fluorophenyl)-2- methylpropylamino)pyridazin-3-yl)-1 ,3,4-oxadiazol-2(3H)-one as a white solid, m/z = 330.0 [M+H].
Example 4: Preparation of 6-(2-Amino-1 H-imidazol-4-yl)-N-(2-(4- fluorophenyl)-2-methylpropyl)pyridazin-3-amine
Figure imgf000079_0002
2-Bromo-1 -(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin- 3-yl)ethanone. 6-chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3- amine (300 mg, 1 .1 mmol, 1 .0 equiv) and dioxane (5 mL) were added to a microwave vial and sonication was applied until the mixture was
homogeneous. Tributyl(1 -ethoxyvinyl)stannane (475 μί, 1 .4 mmol, 1 .3 equiv) and trans-dichlorobis(triphenylphosphine)palladium (30 mg, 0.04 mmol, 0.03 equiv) were then added, and the reaction was heated in a microwave reactor at 150 °C for 20 min. The reaction was concentrated, dissolved in EtOAc (25 mL), and mixed with 2.0 M potassium fluoride (5 mL). The mixture was filtered through celite, and then washed with water, dried over Na2SO , filtered, and concentrated. The crude solid was redissolved in 50%
THF/water (4 ml_), followed by the addition of NBS (300 mg, 1 .7 mmol, 1 .5 equiv). The reaction mixture was stirred for 1 h and then diluted with brine (20 ml_) and ethyl acetate (20 ml_). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer. The organic layer was then dried over Na2SO4, filtered, and concentrated to give a brown oil that was purified by silica gel chromatography (0-100%
EtOAC/hexanes) to afford 270 mg of 2-bromo-1 -(6-(2-(4-fluorophenyl)-2- methylpropylamino)pyridazin-3-yl)ethanone as an orange oil.
Figure imgf000080_0001
N-(4-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)- 1 H-imidazol-2-yl)acetamide. To a 3 ml_ microwave reaction vial was added 2-bromo-1 -(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3- yl)ethanone (125 mg, 0.3 mmol, 1 .0 equiv), acetyl guanidine (90 mg, 0.6 mmol, 2.0 equiv) and acetonitrile (2 ml_). The reaction was heated in a microwave reactor at 100 °C for 13 min. The reaction was filtered and directly purified by reverse phase column chromatography to afford N-(4-(6-(2-(4- fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)-1 H-imidazol-2-yl)acetamide (70 mg) as an white solid, m/z = 369.2 [M+H]+.
Figure imgf000080_0002
6-(2-Amino-1 H-imidazol-4-yl)-N-(2-(4-fluorophenyl)-2- methylpropyl)pyridazin-3-amine. To a 10 mL round bottom flask was added N-(4-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)-1 H- imidazol-2-yl)acetamide (22 mg, 59 μιτιοΙ), concentrated HCI (100 μΙ_) and methanol (1 mL). The reaction was refluxed for 12 h and then concentrated, redissolved in EtOAc (10 mL), washed with saturated sodium carbonate (2 x 10 mL) and brine (1 x 10 mL), dried (Na2SO4) and concentrated to yield 8 mg (42%) of 6-(2-amino-1 H-imidazol-4-yl)-N-(2-(4-fluorophenyl)-2- methylpropyl)pyridazin-3-amine as a pale yellow solid, m/z = 327.2 [M+H].
Example 5: Preparation of 6-(5-Amino-1 H-pyrazol-3-yl)-N-(2-(4- fluorophenyl)-2-methylpropyl)pyridazin-3-amine
Figure imgf000081_0001
To a 20 dram vial was added 2-bromo-1 -(6-(2-(4-fluorophenyl)-2- methylpropylamino)pyridazin-3-yl)ethanone (13 mg, 35 μιτιοΙ, 1 .0 equiv), sodium cyanide (25 mg, 500 μιτιοΙ, 15.0 equiv) and ethanol (1 mL). The reaction mixture was heated to 60 °C for 30 min. After cooling to room temperature, the reaction was filtered. Hydrazine hydrate (250 μί) was then added, and the reaction mixture was heated to 100 °C for 2 h. The reaction was filtered and directly purified by reverse phase column chromatography to afford 6-(5-amino-1 H-pyrazol-3-yl)-N-(2-(4-fluorophenyl)-2- methylpropyl)pyridazin-3-amine (2 mg) as an white solid, m/z = 327.2 [M+H].
Example 6: Preparation of 6-Ethyl-N-(2-(4-fluorophenyl)-2-methylpropyl) pyridazin-3-amine
Figure imgf000081_0002
Step 1 : To a 5 mL microwave reaction vial was added 6-chloro-N-(2- (4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine (123 mg, 441 μιτιοΙ, 1 .0 equiv), 2,4,6-trivinyl-1 ,3,5,2,4,6-trioxatriborinane (159 mg, 661 μιτιοΙ, 1 .5 equiv), CI2Pd(dppf) (54 mg, 66 μιτιοΙ, 0.15 equiv), potassium carbonate (182 mg, 1 .32 mmol, 3 equiv), and dioxane (21 mL). The reaction was heated in a microwave reactor at 140 °C for 12 min and then diluted with water (20 mL) and ethyl acetate (50 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (1 x 20 mL). The organic layer was then dried over
Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (20-50% EtOAc/hexanes) to give 50 mg (46%) of N-(2-(4-fluorophenyl)-2-methylpropyl)-6-vinylpyridazin-3-amine as a white solid.
Step 2: The isolated product from Step 1 was dissolved in ethanol (10 mL) and transferred to a 20 dram vial. Palladium (10% on carbon, 10 mg) was then added, and the reaction was stirred under 60 psi of hydrogen for 3 days. The reaction was then filtered, concentrated, and purified by reverse phase column chromatography to afford 3 mg (10%) of 6-ethyl-N-(2-(4- fluorophenyl)-2-methylpropyl) pyridazin-3-amine as a clear oil, m/z = 274
[M+H].
Example 7: Preparation of 2-(6-((1 -(3-Fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)propan-2-ol
Figure imgf000082_0001
Methyl 6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazine-3-carboxylate. To a 20 dram vial was added methyl 6-chloropyridazine-3-carboxylate (510 mg, 2.7 mmol, 1 .0 equiv), (1 -(3-fluoropyridin-2-yl)cyclobutyl)methanamine (738 mg, 4 mmol, 1 .5 equiv), DIPEA (0.7 mL, 4 mmol, 1 .5 equiv), and NMP (2 mL). The reaction was heated at 120 °C for 40 min and then diluted with water (20 mL) and ethyl acetate (50 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (1 x 20 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (20-100% EtOAc/hexanes) to give 440 mg (48%) of methyl 6-((1 -(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazine-3-carboxylate as a w
Figure imgf000083_0001
2-(6-((1 -(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3- yl)propan-2-ol. A portion of the isolated methyl 6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazine-3-carboxylate (99 mg, 0.3 mmol, 1 .0 equiv) was dissolved in THF (10 mL) and transferred to a 20 dram vial. The mixture was cooled to 0 °C and MeMgBr (3M in Et2O, 0.5 mL, 1 .5 mmol, 5 equiv) was added. The reaction was allowed to warm to rt and then stirred for 15 min. The reaction mixture was poured into a mixture of EtOAc (30 mL) and saturated ammonium chloride (15 mL). The organic layer was separated, dried over Na2SO , filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (0-20% MeOH/CH2Cl2) to give 42 mg (43%) of 2-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)propan-2-ol as a white powder, m/z = 317 [M+H]+.
Example 8: Preparation of 1 -(6-((1 -(3-Fluoropyridin-2- l)cyclobutyl)methylamino)pyridazin-3-yl)ethanone
Figure imgf000083_0002
6-((1 -(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazine-3- carbonitrile. To a 20 dram vial was added 6-chloropyridazine-3-carbonitrile (1 .0 g, 7.2 mmol, 1 .0 equiv), (1 -(3-fluoropyridin-2-yl)cyclobutyl)methanamine (1 .36 g, 7.6 mmol, 1 .05 equiv), triethylamine (2.1 mL, 14.4 mmol, 2.0 equiv), and NMP (2 mL). The reaction was heated at 130 °C for 12 h and then diluted with water (20 ml_) and ethyl acetate (50 ml_). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (1 x 20 ml_). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (20-30%
EtOAc/hexanes) to give 507 mg (25%) of 6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazine-3-carbonitrile. m/z = 284 [M+H]+.
Figure imgf000084_0001
1 -(6-((1 -(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3- yl)ethanone. 6-((1 -(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazine- 3-carbonitrile (500 mg, 1 .8 mmol, 1 .0 equiv) was dissolved in THF (4.5 ml_) and transferred to a 20 dram vial. The mixture was cooled to 0 °C and MeMgBr (1 .8 ml_, 5.3 mmol of a 3M solution in Et2O, 2.9 equiv) was added. The reaction was stirred at this temperature for 15 min. The reaction mixture was poured into ice water, acidified to pH of 2 with 2N aqueous hydrochloric acid, and then extracted EtOAc (30 ml_). The organic layer was then separated, dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (50% EtOAc/hexanes) to give 104 mg (18%) of 1 -(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)ethanone as a white powder, m/z = 301 .1 [M+H]+.
Example 9: Preparation of N-(2-(4-fluorophenyl)-2-methylpropyl)-6- (pyridin-2-yl)pyridazin-3-amine
Figure imgf000084_0002
To a 25 ml_ round bottom flask was added 2-bromopyridine (500 mg, 3.2 mmol, 1 .0 equiv), triisopropylborate (654 mg, 3.5 mmol, 1 .1 equiv), and an 80% toluene/THF mixture (16 ml_). The mixture was cooled to -78 °C. After stirring for 10 min, n-BuLi (1 .7 ml_, 3.48 mmol, 1 .1 equiv of a 2.0 M/hexanes solution) was slowly added over an hour. After the addition was complete, the reaction mixture was stirred for 30 min and allowed to warm to rt and stirred overnight. The reaction was then concentrated at 100 °C and dried in vacuo for 2 h. To 100 mg of this crude solid in a microwave vial was added 6-chloro- N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine (70 mg, 0.25 mmol), Pd2dba3 (10 mg, 0.01 1 mmol), PO(fBu)3 (5 mg, 0.030 mmol), potassium fluoride (43 mg, 0.75 mmol), and dioxane (0.75 ml_). The reaction was degassed with nitrogen for 5 minutes and then heated in a microwave reactor at 160 °C for 15 min. The reaction was then concentrated, dissolved in EtOAc (25 ml_), washed with water, dried over Na2SO , filtered, concentrated, and purified by reverse phase column chromatography to give 5 mg of N-(2- (4-fluorophenyl)-2-methylpropyl)-6-(pyridin-2-yl)pyridazin-3-amine as a white solid. m/z = 323.1 [M+H]+.
Example 10: Preparation of 6-(6-(2-(4-fluorophenyl)-2- m hylpropylamino)pyridazin-3-yl)nicotinamide
Figure imgf000085_0001
To a 20 dram vial was added 2-bromo-5-cyanopyridine (182 mg, 1 .0 mmol, 1 .0 equiv), hexamethylditin (639 mg, 1 .1 mmol, 1 .1 equiv),
CI2Pd(Ph3P)2 (91 mg, 0.13 mmol, 0.13 equiv), triphenylarsine (34 mg, 0.1 1 mmol, 0.1 1 equiv), and dioxane (7 ml_). The reaction mixture was stirred and heated to 80 °C for 12 h. The reaction was then concentrated, followed by the addition of te/t-butyl 6-bromopyridazin-3-yl(2-(4-fluorophenyl)-2- methylpropyl)carbamate (423 mg, 1 .0 mmol, 1 .0 equiv), Pd(Ph3P)4 (172 mg, 0.15 mmol, 0.15 equiv), and DMF (3.3 ml_). The reaction was stirred and heated to 100 °C for 3 h. After cooling to room temperature, the reaction was diluted with aqueous potassium fluoride (5 mL), extracted with ethyl acetate (20 mL) and washed with brine (20 mL). The organic layer was then dried (Na2SO4), filtered, and concentrated to give crude terf-butyl 6-(5-cyanopyridin- 2-yl)pyridazin-3-yl(2-(4-fluorophenyl)-2-methylpropyl)carbamate.
To a 20 dram vial was added crude te/f-butyl 6-(5-cyanopyridin-2- yl)pyridazin-3-yl(2-(4-fluorophenyl)-2-methylpropyl)carbamate, hydrogen peroxide (2 mL), and potassium carbonate (150 mg). The reaction was stirred for 30 min and then diluted with water (20 mL) and ethyl acetate (50 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (20 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was subsequently treated with 4N HCI/dioxane (1 mL). The reaction was stirred for 1 h at room temperature, concentrated, quenched with aqueous sodium bicarbonate, and extracted with ethyl acetate (20 mL). The organic layer was then dried (Na2SO4), filtered, and concentrated to give a crude solid that was purified by reverse phase column chromatography to afford 10 mg of 6-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3- yl)nicotinamide, m/z = 366.1 [M+H].
Example 11 : Preparation of 6-(2-aminopyridin-3-yl)-N-((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine
Figure imgf000086_0001
N-((1 -(3-Fluoropyridin-2-yl)cyclobutyl)methyl)-6-(2- methoxypyridin-3-yl)pyridazin-3-amine. To a 20 dram vial was added 6- chloro-N-((1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine (1 .8 g, 6.23 mmol, 1 .0 equiv), 2-methoxypyridin-3-ylboronic acid (1 .0 g, 6.54 mmol, 1 .1 equiv), CI2Pd(dppf) (350 mg, 0.43 mmol, 0.07 equiv), 2M potassium carbonate (8 mL, 15.5 mmol, 2.5 equiv), and dioxane (21 mL). The reaction was stirred and heated to 90 °C for 2h and then diluted with water (20 mL) and ethyl acetate (50 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with lithium chloride (1 x 20 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography to give N-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)-6-(2-methoxypyridin-3-yl)pyridazin-3-amine (1 .7 g, 77%) as an off-white solid.
Figure imgf000087_0001
6-(2-Chloropyridin-3-yl)-N-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)pyridazin-3-amine. To a 50 mL round bottom flask was added N-((1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)-6-(2-methoxypyridin- 3-yl)pyridazin-3-amine (1 .7 g, 4.7 mmol), concentrated hydrochloric acid (15 mL), and methanol (15 mL). The reaction was heated to 90 °C and stirred for 12 h. The reaction was concentrated, brought to pH of 1 1 through the addition of saturated potassium carbonate (20 mL), and then diluted with ethyl acetate (50 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and washed with lithium chloride (1 x 20 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give 3-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)pyridin-2-ol (1 .6 g, 95%) as a tan powder. The isolated product (1 .3 g, 3.7 mmol, 1 .0 equiv) was transferred to a 100 mL round bottom flask, followed by the addition of a mixture of phosphorous oxytrichloride (24 mL) and DMF (8 mL). The reaction was heated to 90 °C and stirred for 6 h. The reaction was concentrated and carefully quenched with a 50% mixture of saturated sodium bicarbonate and lithium chloride until gas evolution ceased. The mixture was extracted with ethyl acetate (100 mL). The combined organic layers were then dried over Na2SO , filtered, concentrated, and purified by silica gel column
chromatography to give 1 .2 g (88%) of 6-(2-chloropyridin-3-yl)-N-((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine as an off-white solid.
Figure imgf000088_0001
6-(2-Aminopyridin-3-yl)-N-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)pyridazin-3-amine. To a 5 mL microwave reaction vessel was added 6-(2-chloropyridin-3-yl)-N-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)pyridazin-3-amine (750 mg, 2.0 mmol), hydrazine hydrate (1 mL), and dioxane (4 mL). The reaction was heated in a microwave reactor to 160 °C for 15 min, then diluted with ethyl acetate (50 mL), and washed with brine (20 mL). The organic layer was dried over Na2SO , filtered, and concentrated to give a crude solid that was purified by reverse phase column chromatography to give 150 mg of N-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)-6-(2-hydrazinylpyridin-3-yl)pyridazin-3-amine as an off- white solid. The isolated product was then dissolved in methanol and added to a vial containing ~1 mL of Raney Nickel suspension in water. The mixture was then stirred under 50 psi of hydrogen for 2 h. The reaction was then filtered, concentrated, and purified by reverse phase column chromatography to give 10 mg (88%) of 6-(2-aminopyridin-3-yl)-N-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)pyridazin-3-amine as an off-white solid, m/z = 351 .1
[M+H].
Example 12: Preparation of N1 -(5-(6-((1 -(3-Fluoropyridin-2- yl)cyclobutyl)methylamino) pyridazin-3-yl)-1 H-indazol-3-yl)ethane-1 ,2- diamine
Figure imgf000088_0002
Benzyl 2-(2-Fluoro-5-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)benzamido)ethylcarbamate. To a 20 dram vial was added 2-fluoro-5-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)benzoic acid (320 mg, 0.8 mmol, 1 .0 equiv), benzyl 2-aminoethylcarbamate (242 mg, 1 .0 mmol, 1 .3 equiv), HOBt (141 mg, 1 .0 mmol, 1 .3 equiv), EDC HCI (200 mg, 1 .0 mmol, 1 .3 equiv), DIPEA (550 μΙ_, 3.8 equiv) and CH2CI2 (5 mL). The reaction was stirred for 4 h and then concentrated and then purified using a silica gel column (50%- 100% EtOAc/hexanes) to afford 230 mg (50%) of benzyl 2-(2-fluoro-5-(6-((1 - (3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3- yl)benzamido)ethylcarbamate as a white foam.
CbzH
Figure imgf000089_0001
Benzyl 2-(2-fluoro-5-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3- yl)phenylthioamido)ethylcarbamate. In a 20 dram vial containing benzyl 2- (2-fluoro-5-(6-((1 -(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3- yl)benzamido)ethylcarbamate (230 mg, 0.5 mmol, 1 equiv) was added Lawesson's reagent (162 mg, 0.4 mmol, 0.8 equiv) and dioxane (10 mL). The reaction was heated to 100 °C and stirred for 1 h, concentrated, and then purified using a silica gel column (35%-100% EtOAc/hexanes) to give 203 mg (86%) of benzyl 2-(2-fluoro-5-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)phenylthioamido)ethylcarbamate as a pale yellow oil.
Figure imgf000089_0002
Benzyl 2-(5-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)-1 H-indazol-3- ylamino)ethylcarbamate. The isolated benzyl 2-(2-fluoro-5-(6-((1 -(3- fluoropyhdin-2-yl)cyclobutyl)methylannino)pyhdazin-3- yl)phenylthioamido)ethyl-carbannate was transferred to a 20 dram vial, followed by the addition of hydrazine hydrate (0.1 mL) and dioxane (2 mL). The reaction was heated to 100 °C and stirred for 12 h, concentrated, and then purified using a silica gel column (5%-10% MeOH/EtOAc) to yield 48 mg (25%) of benzyl 2-(5-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)-1 H-indazol-3- ylamino)ethylcarbamate as a pale yellow oil.
Figure imgf000090_0001
N1 -(5-(6-((1 -(3-Fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)-1 H-indazol-3-yl)ethane-1,2- diamine. Benzyl 2-(5-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)-1 H-indazol-3- ylamino)ethylcarbamate (48 mg, 84 μιτιοΙ) was dissolved in acetonitrile (5 mL), and TMSI (0.5 mL) was added. The reaction was stirred for 15 min, diluted with methanol (15 mL), concentrated, and was directly purified by reverse phase column chromatography to yield 20 mg (88%) of N1 -(5-(6-((1 -(3- fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-1 H-indazol-3- yl)ethane-1 ,2-diamine as a yellow solid, m/z = 433 [M+H].
Example 13: Preparation of 6-(5-Aminopyridin-2-yl)-N-((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine
Figure imgf000090_0002
2-Bromo-5-(2,5-dimethyl-1 H-pyrrol-1 -yl)pyridine. To a 25 ml_ round bottom flask was added 5-amino-2-bromopyhdine (600 mg, 3.5 mmol, 1 .0 equiv), hexane-2,5-dione (420 mg, 4.2 mmol, 1 .2 equiv), p-toluenesulfonic acid (5 mg), and toluene (3.5 ml_). A Dean-Stark trap was fitted on top of the round bottom flask and the reaction mixture was heated to reflux for 2 h. The reaction was then concentrated and purified by silica gel column
chromatography (5% ethyl acetate/hexanes) to give 660 mg (76%) of 2- bromo-5-(2,5-dimethyl-1 H-pyrrol-1 -yl)pyridine.
Figure imgf000091_0001
ferf-Butyl-6-(5-(2,5-dimethyl-1 H-pyrrol-1 -yl)pyridin-2-yl)pyridazin-3- yl((1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate. THF (8.5 ml_) was cooled to -78 °C under a nitrogen atmosphere. fBuLi (1 .7 ml_, 2.9 mmol, 2.0 equiv) was added, followed by the addition of 2-bromo-5-(2,5-dimethyl-1 H- pyrrol-1 -yl)pyridine (370 mg, 1 .47 mmol, 1 .0 equiv dissolved in 2 ml_ THF) over 2 min. The reaction as stirred for 45 min at -78 °C. Zinc chloride (510 mg, 3.75 mmol, 2.5 equiv dissolved in 5 ml_ of THF) was added and the reaction was allowed to warm to rt and stirred for 3 h. (f-Bu3P)2Pd (41 mg, 0.015 mmol, 0.10 equiv dissolved in 5 ml_ of THF) and i-butyl 6- chloropyridazin-3-yl((1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (393 mg, 0.1 mmol, 0.07 equiv dissolved in 5 ml_ of THF) were added and the reaction was refluxed for 4 h followed by dilution with sodium bicarbonate (20 ml_), and extraction with ethyl acetate (40 ml_). The organic layer was dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (35% EtOAc/hexanes) to give 245 mg (46%) of terf-butyl 6-(5-(2,5-dimethyl-1 H-pyrrol-1 -yl)pyridin-2-yl)pyridazin-3- yl((1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate.
Figure imgf000092_0001
6-(5-Aminopyridin-2-yl)-N-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)pyridazin-3-amine. To a 20 dram vial was added tert- butyl 6-(5-(2,5-dimethyl-1 H-pyrrol-1 -yl)pyridin-2-yl)pyridazin-3-yl((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (245 mg, 0.5 mmol) and a 5 mL of a 50% mixture of TFA and CH2CI2. The reaction was stirred for 15 min, concentrated, and then diluted with sodium bicarbonate (20 mL) and extracted with ethyl acetate (40 mL). The organic layer was dried over Na2SO , filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (60% EtOAc/hexanes) to give 91 mg (46%) of 6-(5-(2,5- dimethyl-1 H-pyrrol-1 -yl)pyridin-2-yl)-N-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)pyridazin-3-amine. This product was transferred to a 100 mL round bottom flask to which was added hydroxylamine hydrochloride (270 mg), triethylamine (5 mL), and ethanol (20 mL). The reaction mixture was heated to reflux overnight and then concentrated, diluted with sodium bicarbonate (20 mL) and extracted with ethyl acetate (40 mL). The organic layer was dried over Na2SO , filtered, and concentrated to give a crude solid that was purified by reverse phase column chromatography to afford 28 mg of 6-(5-aminopyridin-2-yl)-N-((1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin- 3-amine, m/z = 351 .2 [M+H].
Example 14: Preparation of 3-(6-(2-(4-Fluorophenyl)-2- methylpropylamino)-4-methylpyridazin-3-yl)benzamide
Figure imgf000092_0002
6-Chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)-5-methylpyridazin- 3-amine. A solution of (2-(4-fluorophenyl)-2-methylpropan-1 -amine (5.5 g, 33 mmol, 1 .8 equiv), 3,6-dichloro-4-methylpyridazine (3.0 g, 18 mmol, 1 .0 equiv) and K2CO3 (5.1 g, 37 mmol, 2.0 equiv) in isopropanol (7.5 mL) was stirred at 100 °C under a blanket of nitrogen for 18 hours. The cooled mixture was partitioned between water and EtOAc and the organic fraction was
concentrated in vacuo. Purification over silica gel using a 20 - 35% gradient of EtOAc/hexanes gave the desired product (0.80 g, 15%) of a yellow oil which was determined b HPLC to be a 5:1 mixture of regioisomers by HPLC.
Figure imgf000093_0001
2-Fluoro-5-(6-(2-(4-fluorophenyl)-2-methylpropylamino)-4- methylpyridazin-3-yl)benzonitrile. To a solution of 6-chloro-N-(2-(4- fluorophenyl)-2-methylpropyl)-5-methylpyridazin-3-amine (0.8 g, 2.7 mmol, 1 .0 equiv) and 2 M aqueous K2CO3 (2.0 mL, 8.2 mmol, 3.0 equiv) in dioxane (14 mL) was added Pd(dppf)CI2 (0.1 1 g, 0.14 mmol, 0.05 equiv) and 3- cyanophenylboronic acid (0.48 g, 3.3 mmol, 1 .2 equiv). The mixture was stirred at 80 °C for 2 hours under a blanket of nitrogen. This was followed by addition of another 100 mg (0.68 mmol, 0.25 equiv) of the boronic acid and 30 mg (0.037 mmol, 0.013 equiv) of Pd(dppf)Cl2 and another 1 h of heating at 100 °C. The mixture was allowed to cool to room temperature.and then was diluted with EtOAc. The solution was washed with 50% NaCI solution, dried over Na2SO and evaporated to dryness. The residue was purified by over silica gel using a 20 - 50% EtOAc/hexanes stepwise gradient to give the
Figure imgf000093_0002
3-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)-4-methylpyridazin- 3-yl)benzamide. A 0 °C solution of 2-fluoro-5-(6-(2-(4-fluorophenyl)-2- methylpropylamino)-4-methylpyridazin-3-yl)benzonitrile (0.80 g, 2.2 mmol, 1 .0 equiv), 30% hydrogen peroxide (0.45 mL, 4.4 mmol, 2.0 equiv), and K2CO3 (600 mg, 4.4 mmol, 2.0 equiv) in DMSO (9.0 mL) was stirred for 1 hour. The mixture was diluted with EtOAc, washed with saturated NaCI, water and saturated NaCI again, and then dried over Na2SO . Purification by reverse phase HPLC using a gradient of 20 - 70% CH3CN/water gave the desired product (420 mg, 51 %) as a yellow solid, m/z = 379. 1 [M+H]+.
Example 15: Preparation of 3-(5-Cyano-6-(2-(4-fluorophenyl)-2- methylpropylamino)pyridazin-3-yl)benzamide
Figure imgf000094_0001
3,6-Dichloropyridazine-4-carboxamide. A solution of NH4OH (1 .1 ml_, 17 mmol, 1 .2 equiv) and diisopropylethylamine (6.2 ml_, 36 mmol, 2.1 equiv) in THF (57 ml_) was sonicated until homogeneous after which was added DMAP (1 .0 g, 14 mmol, 1 .0 equiv). 3,6-dichloropyridazine-4-carbonyl chloride (3.0 g, 14 mmol, 1 .0 equiv) was then added and the solution was stirred at room temperature for 20 minutes. The solution was filtered and partitioned between EtOAc and 1 M KHSO4 solution. The organic layer was washed once more with 1 M KHSO and saturated NaCI, dried over Na2SO , and vaporated to dryness to give the desired product (2.6 g, 96%).
Figure imgf000094_0002
6-Chloro-3-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-4- carboxamide. Using a similar procedure as was used for 6-chloro-N-(2-(4- fluorophenyl)-2-methylpropyl)-5-methylpyridazin-3-amine in example 14, 3,6- dichloropyridazine-4-carboxamide (2.6 g, 13 mmol, 1 .0 equiv), (2-(4- fluorophenyl)-2-methylpropan-1 -amine (2.5 g, 15 mmol, 1 .1 equiv), and diisopropylethylamine (2.8 ml_, 16 mmol, 1 .2 equiv) in CH3CN (54 mL) was heated at 60 - 90 °C for 48 hours. The product was purified over silica gel with 100% EtOAc to give the desired product (3.4 g, 78%) as a yellow foamy solid.
Figure imgf000094_0003
6-Chloro-3-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-4- carbonitrile. To a portion of 6-chloro-3-(2-(4-fluorophenyl)-2- methylpropylamino)pyridazine-4-carboxamide (3.4 g, 1 1 mmol, 1 .0 equiv) was added POCI3 (10 mL) at room temperature. The mixture was stirred at reflux for 3 hours and then quenched by pouring it into ice water containing
NaHCO3. Dioxane and EtOAc were added to facilitate mixing of the layers. The layers were allowed to separate and the aqueous layer was extracted with EtOAc and the combined organic phases were washed with saturated NaCI. The organics were dried over Na2SO4 and evaporated to dryness in vacuo. Purification over silica gel using a gradient of 10 - 20 %
Figure imgf000095_0001
3-(5-Cyano-6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3- yl)benzamide. To a solution of 6-chloro-3-(2-(4-fluorophenyl)-2- methylpropylamino)pyridazine-4-carbonitrile (550 mg, 1 .8 mmol, 1 .0 equiv), 3- aminocarbonylphenylboronic acid, pinacol ester (330 mg, 2.0 mmol, 1 .1 equiv) and aqueous K2CO3 (2.0 M, 5.0 mL, 5.4 mmol, 3.0 equiv) in dioxane (18 mL) was added Pd(dppf)Cl2 (150 mg, 0.18 mmol, 0.1 equiv). The mixture was stirred at 120 °C for 10 minutes in a microwave and allowed to cool to room temperature. The solvents were evaporated in vacuo, and the residue was dissolved in dichloromethane. The solution was filtered and the solvent dried over Na2SO4. Purification over silica gel using a gradient of 40 - 80% EtOAc/hexanes gave a yellow solid that was slurried with CH3CN to give the desired product (30 mg, 4.3%) as a yellow solid, m/z = 390.2 [M+H]+.
Example -2-(4-Fluorophenyl)propan-1 -amine
Figure imgf000095_0002
(S)-4-Benzyl-3-(2-(4-fluorophenyl)acetyl)oxazolidin-2-one. To a cooled (-78 °C) solution of (S)-4-benzyloxazolidin-2-one (10 g, 58 mmol, 1 .0 equiv) in 100 ml_ THF was added dropwise n-BuLi (40 ml_, 1 .6 M in hexanes, 64 mmol, 1 .1 equiv). After stirring for 30 minutes, 4-fluorophenylacetyl chloride (10 g, 0.58 mmol, 1 .0 equiv) was added dropwise. After stirring for an additional 30 minutes, the reaction mixture was allowed to warm to room temperature. The reaction was quenched with saturated aq. NH4CI, extracted with dichloromethane, and washed with brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel (10 - 20% EtOAc/hexanes) provided the title compound as a thick oil (14.7 g,
Figure imgf000096_0001
(S)-4-Benzyl-3-((S)-2-(4-fluorophenyl)propanoyl)oxazolidin-2-one.
To a room-temperature solution of (S)-4-benzyl-3-(2-(4- fluorophenyl)acetyl)oxazolidin-2-one (5.1 g, 16.3 mmol, 1 .0 equiv) in dry THF (100 ml_) was added iodomethane (1 .0 ml_, 16.2 mmol, 1 .0 equiv) by syringe. The resulting mixture was cooled to -78 °C, and NaHMDS (8.15 ml_, 2M in THF, 16.3 mmol, 1 .0 equiv) was added dropwise by syringe. After stirring for 15 minutes at -78 °C, the reaction mixture was allowed to warm to room temperature. The reaction was quenched with saturated aq. NH CI, and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (7 - 20% EtOAc/hexanes) provided the title compound (2.6 g, 49%).
Figure imgf000096_0002
(S)-2-(4-Fluorophenyl)propan-1 -ol. To a room-temperature solution of (S)-4-benzyl-3-((S)-2-(4-fluorophenyl) propanoyl)oxazolidin-2-one (1 .8 g, 5.5 mmol, 1 .0 equiv) in THF (18 ml_) was added a solution of NaBH (1 .0 g, 26.4 mmol, 4.8 equiv) in water (6.0 ml_). The reaction mixture was stirred for 3 h at room temperature and then quenched by the careful addition of aq. 1 M HCI. The reaction mixture was diluted with water and ethyl acetate. The layers were separated and the organic layer was subsequently washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (10 - 75% EtOAc/Hexanes) provided the title compoun (0.824 g, 97%).
Figure imgf000097_0001
(S)-2-(2-(4-Fluorophenyl)propyl)isoindoline-1 ,3-dione. To a solution of (S)-2-(4-fluorophenyl)propan-1 -ol (0.82 g, 5.35 mmol, 1 .0 equiv), phthalimide (0.82 g, 5.6 mmol, 1 .05 equiv), and triphenyl phosphine (2.1 g, 8.03 mmol, 1 .5 equiv) in dry THF (18 mL) was added dropwise
diethylazodicarboxylate (3.6 mL, 15% in toluene, 8.0 mmol, 1 .5 equiv). The reaction mixture was stirred over 72 h and then concentrated in vacuo.
Purification by silica gel chromatography (15 - 25% EtOAc/Hexanes) provided the title mpound (0.9 g, 59%).
Figure imgf000097_0002
(S)-2-(4-Fluorophenyl)propan-1 -amine. To a room-temperature solution of (S)-2-(2-(4-fluorophenyl)propyl)isoindoline-1 ,3-dione (900 mg, 3.2 mmol, 1 .0 equiv) in toluene (14 mL) was added hydrazine hydrate (1 .4 mL, 45 mmol, 14 equiv) by syringe. The resulting mixture was heated to 80 °C for 30 minutes and then cooled to room temperature. The resulting solution was decanted from the solid in the reaction mixture, and the solid was washed with additional toluene. The combined organic layers were combined and concentrated in vacuo to provide the title compound (491 mg, 99%), which was used without further purification.
Example 17: Preparation of 2-(4-Fluorophenyl)-2-methylpropan-1 -amine
To a solution of 4-fluorophenylacetonitrile (50 g, 370 mmol, 1 .0 eq and iodomethane (70 mL, 1 .1 mol, 3 equiv) in THF (370 mL) was added KOf- Bu (124 g, 1 .1 mol, 3 equiv) as a solid in portions such that the reaction mixture did not exceed 50 °C. The reaction mixture was stirred overnight and then quenched by the addition of brine. The mixture was diluted with EtOAc and washed twice with brine. The organic layer was dried over Na2SO , filtered, and concentrated in vacuo to provide 2-(4-fluorophenyl)-2- methylpropanenitrile as a yellow oil (57 g, 94%), which was used without further purification in the next step. To a solution of the nitrile in dry THF (800 mL) was added a solution of lithium aluminum hydride (210 mL, 2 M in ether, 420 mmol, 1 .2 equiv). After the mixture was heated at reflux overnight, the reaction was allowed to cool to room temperature, and a Fieser and Fieser work-up (300 uL water/mmol, 1 .0 mL 3N NaOH/mmol, 300 uL water/mmol) was performed. Filtration of the resulting solids provided the title compound as an orange oil (57 g, 92%).
Example 1 : Preparation (1 -(4-Fluorophenyl)cyclobutyl)methanamine
Figure imgf000098_0001
A solution of 4-fluorophenylacetonitrile (6.7 g, 75 mmol, 1 .5 equiv), 1 ,3- dibromopropane (10 mL, 50 mmol, 1 equiv), KOH (27 g, 150 mmol, 3.0 equiv), and tetrabutylammonium bromide (100 mg) in toluene (135 mL) was heated to 100 °C for 3 hours. The organic layer was separated and
concentrated to dryness. Silica gel chromatography using a gradient of 0 - 30% EtOAc/hexanes resulted in partially purified product which was further purified by Kugelrohr distillation at 200 °C to provide 3.76 g (22 mmol) of the intermediate nitrile product as an oil. The residue was dissolved in dry THF (22 mL) and treated with a solution of LAH (27 mL, 2 M in ether, 55 mmol, 2.5 equiv). The mixture was stirred at 0 °C for 2 hours followed by a Fieser and Fieser work-up (38 uL water/mmol, 1 18 uL 3N NaOH/mmol, 38 uL
water/mmol). The organic layer was concentrated to dryness to provide the desired product (3.6 g, 40% overall) as a yellow oil. Example 19: Preparation of (1 -(6-Methoxypyridin-2- yl)cyclobutyl)methanamine
Figure imgf000099_0001
1 -(6-Fluoropyridin-2-yl)cyclobutanecarbonitrile. Following the same procedure as described for 2-(3-fluoropyridin-2-yl)acetonitrile (Example 18), 2,6-difluoropyridine (5.0 g, 43 mmol, 1 .0 equiv), cyclobutylcarbonitrile (3.5 g, 43 mmol, 1 .0 equiv) and NaHMDS (2.0 M in THF, 24 ml_, 47 mmol, 1 .1 equiv) in toluene (100 ml_) gave the desired product (4.9 g, 64%) as a colorless oil following purification over silica gel using 25% EtOAc/hexanes as eluent.
Figure imgf000099_0002
1 -(6-Methoxypyridin-2-yl)cyclobutanecarbonitrile. To stirred 6.0 ml_ of anhydrous methanol at 0 °C under nitrogen was added sodium metal (~1 g) and the mixture stirred for 30 minutes. To this was added 1 -(6-fluoropyridin-2- yl)cyclobutanecarbonitrile (1 .6 g, 9.1 mmol) and the resulting mixture heated to 75 °C for 45 minutes. The solution was cooled to room temperature and partitioned between water and EtOAc. The layers were separated, the aqueous phase was extracted with EtOAc, and the combined organic phases were washed with saturated NaCI, dried over Na2SO4 and concentrated in vacuo to give
Figure imgf000099_0003
(1 -(6-Methoxypyridin-2-yl)cyclobutyl)methanamine. To a stirred solution of 1 -(6-methoxypyridin-2-yl)cyclobutanecarbonitrile (1 .7 g, 8.8 mmol, 1 .0 equiv) in THF (20 ml_) was added lithium aluminum hydride solution (1 .0 M in THF, 1 1 ml_, 1 1 mmol, 1 .1 equiv). The mixture was refluxed for 1 .5 hours and allowed to cool to room temperature. Water (0.43 ml_) was added slowly followed by 0.43 ml_ of 3 M NaOH and then three additions of 0.43 ml_ of water (Fieser and Fieser workup). The resulting mixture was filtered through diatomaceous earth and rinsed with THF. The combined organics were dried over Na2SO4 and concentrated to dryness to give the desired product (1 .6 g, 97%) as a viscous oil.
Example ation of 1-(3-Fluoropyridin-2-yl)cyclobutanamine
Figure imgf000100_0001
1 -(3-Fluoropyridin-2-yl)cyclobutanecarboxamide. To a 250 mL round bottom flask containing DMSO (60 mL), 1 -(3-fluoropyridin-2- yl)cyclobutanecarbonitrile (2.96 g, 16.8 mmol, 1 .0 equiv) was added and the mixture was stirred until homogenous. Potassium carbonate (7.0 g, 50.4 mmol, 3.0 equiv) was then added and the reaction mixture was cooled to 0 °C, followed by the addition of 35% hydrogen peroxide (6.5 mL). The reaction was stirred at 0 °C for 30 min and then warmed to room temperature. At this time, the reaction was diluted with water (50 mL) and ethyl acetate (100 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (3 x 50 mL). The organic layer was then dried over Na2SO , filtered, and concentrated to give a crude solid that was purified by silica gel chromatography (10%
EtOAC/hexanes) to afford 1 .92 g (59%) of 1 -(3-fluoropyridin-2- yl)cyclobutanecarboxamide as a white solid.
Figure imgf000100_0002
Methyl 1 -(3-fluoropyridin-2-yl)cyclobutylcarbamate. 1 -(3- fluoropyridin-2-yl)cyclobutanecarboxamide (1 .92 g, 9.88 mmol, 1 .0 equiv) was dissolved in methanol (20 mL) and potassium hydroxide (1 .1 1 g, 19.8 mmol, 2.0 equiv) was added. The mixture was sonicated until homogeneous, followed by the addition of iodosobenzene diacetate (4.77 g, 14.8 mmol, 1 .5 equiv). The reaction was stirred for 20 min and then diluted with water (100 mL) and ethyl acetate (125 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer, and the aqueous layer was extracted with EtOAc (50 ml_). The combined organic layers were then dried over Na2SO , filtered, and concentrated to give a crude oil that was purified by silica gel chromatography (40% EtOAC/hexanes) to afford 1 .47 g (67%) of methyl 1 -(3-fluoropyridin-2-yl)cyclobutylcarbamate as a white soli
Figure imgf000101_0001
1 -(3-Fluoropyridin-2-yl)cyclobutanamine. To a 20 ml_ microwave reaction vial was added methyl 1 -(3-fluoropyridin-2-yl)cyclobutylcarbamate (1 .47 g, 6.56 mmol), ethanol (12 ml_) and 3N aqueous sodium hydroxide (7 ml_). The reaction mixture was heated in the microwave reactor at 150 °C for 30 min. The ethanol was evaporated under reduced pressure and the mixture was extracted with ethyl acetate (30 ml_). The aqueous layer was then extracted with ethyl acetate (2 x 30 ml_). The organic layers were combined, dried over Na2SO , filtered, and concentrated to give 1 -(3-fluoropyridin-2- yl)cyclobutanamine (1 .01 g, 93%) as a crude yellow oil that was used in the next reaction step without further purification.
Example 21 : Preparation of 2-(3-Fluoropyridin-2yl)acetonitrile
Figure imgf000101_0002
To a 0 °C solution of 2-chloro-3-fluoropyridine (3.0 g, 23 mmol, 1 .0 equiv) and acetonitrile (1 .3 ml_, 25 mmol, 1 .1 equiv) in toluene (50 ml_) was added sodium hexamethyldisilazide (NaHMDS) (2.0 M in THF, 13 ml_, 25 mmol, 1 .1 equiv). The resulting mixture was stirred for 2 hours at 0 °C and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic phases were washed with saturated NaCI, dried over Na2SO and concentrated in vacuo to provide the crude desired product as an oil which was used without further purification. Example 22: Preparation of 6-Chloro-N-(2-phenylpropan-2-yl)pyridazin- 3-ami
Figure imgf000102_0001
To a 5 mL microwave reaction vial was added 3,6-dichloropyridazine (544 mg, 3.7 mmol, 1 .0 equiv), cumylamine (500 mg, 3.7 mmol, 1 .0 equiv), and DIPEA (640 μί, 3.7 mmol, 1 .0 equiv). The reaction was heated in a microwave reactor to 225 °C for 15 min and then diluted with brine (20 mL) and extracted with ethyl acetate (40 mL). The organic layer was dried over Na2SO , filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (20% EtOAc/hexanes) to yield 48 mg (5%) of 6-chloro-N-(2-phenylpropan-2-yl)pyridazin-3-amine as a white solid.
Example 23: Preparation of 2-(2-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl methylamino)pyridazin-3-yl)thi zol-5-yl)acetamide
Figure imgf000102_0002
5-((f-Butyldimethylsilyloxy)methyl)thiazole. Thiazole-5-methanol (65 g, 0.56 mol), imidazole (58 g, 0.85 mol), and CH2CI2 (700 mL) were added to a round bottom flask, followed by TBSCI (93 g, 0.62 mol). The reaction was stirred for 20 min and the resultant white solid was filtered off. The filtrate was washed with saturated sodium bicarbonate, dried over sodium sulfate, concentrated, and purified by silica gel chromatography (10%
EtOAC/hexanes) to afford 140 g of 5-((f-butyldimethylsilyloxy)methyl)thiazole as a clear oil.
Figure imgf000102_0003
f-butyl 6-(5-((f-butyldimethylsilyloxy)methyl)thiazol-2-yl)pyridazin- 3-yl((1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate. To a stirring mixture of THF (2000 mL) and diisopropylamine (79.3 mL, 0.56 mol) at -78 °C was added n-BuLi (244 mL, 0.56 mol) dropwise. After stirring for 20 min at - 78 °C, a solution of 5-((i-butyldimethylsilyloxy)methyl)thiazole (1 10.9 g, 0.49 mol in 300 mL of THF) was added dropwise to the reaction mixture while maintaining a temperature less than -70 °C. After the addition was complete, the reaction was stirred for an additional 30 min and a solution of zinc bromide (126.6 g, 0.56 mol in 300 mL of THF) was added dropwise to the reaction mixture while maintaining a temperature less than -65 °C. The reaction was warmed to 0 °C, stirred for 30 min, and added to a stirring mixture of i-butyl 6- chloropyridazin-3-yl((1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (100 g, 0.26 mol), tetrakis(triphenylphosphine)palladium(0) (56 g, 0.05 mol), and THF (2000 mL) heated to 80 °C. The reaction mixture was stirred overnight at 80 °C. The reaction was concentrated and then slurried in ethyl acetate and brine. The resultant solid was filtered off, and the filtrate was dried over sodium sulfate, concentrated, and purified twice by silica gel chromatography (EtOAc/hexanes) to afford 1 12.5 g of i-butyl 6-(5-((tert- butyldimethylsilyloxy)methyl)thiazol-2-yl)pyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate as a dark oil.
Figure imgf000103_0001
f-butyl (1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(5- (hydroxymethyl)thiazol-2-yl)pyridazin-3-yl)carbamate. To a solution of t- butyl 6-(5-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl)pyridazin-3-yl((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (1 12.5 g, 0.19 mol) in THF (1000 mL) was added TBAF (105 mL, 0.29 mol, 75% w/w). The reaction was stirred for 30 min followed by the addition of ammonium chloride (200 mL). The organic layer was separated, washed with brine (300 mL x 3), and concentrated (this wash was repeated once). Ethyl acetate was added to the oil, resulting in a white solid. Filtration of the solid afforded 44 g of f-butyl (1 - (3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(5-(hydroxymethyl)thiazol-2- yl)pyridazin-3-yl)carbamate.
Figure imgf000104_0001
f-butyl 6-(5-(chloromethyl)thiazol-2-yl)pyridazin-3-yl((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)carbamate. To a solution of f-butyl (1 - (3-fluoropyhdin-2-yl)cyclobutyl)methyl(6-(5-(hydroxymethyl)thiazol-2- yl)pyridazin-3-yl)carbannate (44.1 g, 93.8 mmol) in dioxane (235 mL) was added thionyl chloride (27.3 mL, 375.3 mmol). The reaction was stirred until it was homogeneous. The reaction was then slowly quenched by pouring into a mixture of saturated potassium carbonate solution and ethyl acetate. The organic layer was then separated, dried over Na2SO , filtered, concentrated, and purified by silica gel chromatography (EtOAC/hexanes) to afford 33.1 g of f-butyl 6-(5-(chloromethyl)thiazol-2-yl)pyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate as a white solid.
Figure imgf000104_0002
f-butyl 6-(5-(cyanomethyl)thiazol-2-yl)pyridazin-3-yl((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)carbamate. To a solution of f-butyl 6- (5-(chloromethyl)thiazol-2-yl)pyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate (33.1 g, 68 mmol) in CH2CI2 (450 mL) was added tetrabutylammonium cyanide (36 g, 135 mmol). The reaction was heated to 45 °C and stirred for 1 h, followed by concentration and purification by silica gel chromatography (EtOAc/hexanes) to afford 13.4 g of f-butyl 6-(5- (cyanomethyl)thiazol-2-yl)pyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate as an off-white solid.
Figure imgf000104_0003
2-(2-(6-((1 -(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin- 3-yl)thiazol-5-yl)acetamide. To a solution of f-butyl 6-(5- (cyanomethyl)thiazol-2-yl)pyridazin-3-yl((1 -(3-fluoropyndin-2- yl)cyclobutyl)methyl)carbamate (12.5 g, 26.0 mmol) in DMSO (260 ml_) was added potassium carbonate (14.4 g, 104.1 mmol). The mixture was cooled to 0 °C and hydrogen peroxide (86 ml_) was slowly added. The reaction was warmed to rt and stirred for 90 min. The reaction was diluted with EtOAc (200 ml_) and water (500 ml_), and the organic layer was washed three times with brine (150 ml_). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel
chromatography (CH3CN/CH2CI2) to afford 6.2 g of f-butyl 6-(5-(2-amino-2- oxoethyl)thiazol-2-yl)pyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate as a reddish solid. This compound was combined with other batches (15.5 g overall), dissolved in 25% TFA CH2CI2, and stirred for 1 h. The reaction was then concentrated, dissolved in ethyl acetate (75 ml_), and washed three times with potassium carbonate. The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was recrystallized with THF to give 10.8 g of 1 -(2-((-3-fluoro- 1 -(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyrimidin-5-yl)-1 H-pyrrole-3- carboxamide as an off-white solid (M+H=399.1 ).
Example 24: Preparation of 2-(2-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)thiazol-5-yl)-N- methylacetamide
Figure imgf000105_0001
A solution of f-butyl 6-(5-(cyanomethyl)thiazol-2-yl)pyridazin-3-yl((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (1 g, 2 mmol) in HCI (30 ml_, cone) was heated to 105 °C in a microwave reactor and stirred for 15 min. The reaction was concentrated to give 900 mg (2.3 mmol) of a crude reddish solid. To this solid was added methylamine hydrochloride (183 mg, 2.7 mmol), HOBt (365 mg, 2.7 mmol), EDC (516 mg, 2.7 mmol), DMF (30 ml_), and TEA (1 .3 ml_, 9 mmol). The reaction was stirred at rt overnight. The reaction was then poured into ethyl acetate (200 ml_), washed with water (3x100 mL), and the organic layer was separated, dried over Na2SO4, filtered, concentrated, and recrystallized from EtOAc to give 408 mg of 2-(2-(6-((1 -(3- Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)thiazol-5-yl)-N- methylacetamide as a white solid (M+H=413.3).
Example 25: Preparation of N-((2-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)thiazol-5-yl)methyl)-2- hydroxyacetamide
Figure imgf000106_0001
f-butyl 6-(5-(Azidomethyl)thiazol-2-yl)pyridazin-3-yl((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)carbamate. To a stirring solution of f- butyl 6-(5-(chloromethyl)thiazol-2-yl)pyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate (60.7 g, 124 mmol) in DMF (800 mL) was added sodium azide (22.2 g, 341 mmol) and DIPEA (31 .1 mL, 171 mmol). The reaction was heated to 60 °C and stirred for 1 h. The reaction was poured into ethyl acetate (2000 mL), washed with water (3x400 mL), and the combined organic layers were separated, dried over Na2SO , filtered, concentrated, and purified by silica gel chromatography (EtOAC/hexanes) to afford 20.0 g of f-butyl 6-(5-(azidomethyl)thiazol-2-yl)pyridazin-3-yl((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a yellow oil.
Figure imgf000106_0002
f-butyl 6-(5-(Aminomethyl)thiazol-2-yl)pyridazin-3-yl((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)carbamate. Tin(ll) chloride dihydrate (15.5 g, 80 mmol) was added to a solution of f-butyl 6-(5-(azidomethyl)thiazol- 2-yl)pyridazin-3-yl((1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (20 g, 40 mmol) in methanol (400 mL) and the reaction was stirred at rt for 30 min. The reaction was poured into ethyl acetate (1000 mL), washed with water (3x200 mL), and the combined organic layers were separated, dried over Na2SO , filtered, concentrated, and purified using silica gel column
chromatography (9% MeOH/90% EtOAc/1 % TEA) to give 35 g of f-butyl 6-(5- (aminomethyl)thiazol-2-yl)pyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate as a yellow oil.
Figure imgf000107_0001
N-((2-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)thiazol-5-yl)methyl)-2- hydroxyacetamide. f-butyl 6-(5-(aminomethyl)thiazol-2-yl)pyridazin-3-yl((1 - (3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (4.8 g, 10 mmol), glycolic acid (0.9 g, 12 mmol), HOBt (1 .6 g, 12 mmol), EDC (2.3 g, 12 mmol), DMF (50 mL), and TEA (5.9 mL) were added to a 250 mL round bottom flask and the reaction was heated to 60 °C and stirred for 1 h. The reaction was poured into ethyl acetate (400 mL), washed with water (3x100 mL), and the combined organic layers were separated, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (EtOAC/hexanes) to afford 3.9 g of t- butyl (1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(5-((2- hydroxyacetamido)methyl)thiazol-2-yl)pyridazin-3-yl)carbamate as a white solid. This compound was dissolved in 30% TFA CH2CI2 (30 mL) and stirred for 1 h. The reaction was concentrated, dissolved in EtOAc (200 mL), washed with potassium carbonate (3x30 mL), concentrated, and then recrystallized with ethanol to give a white solid that was further purified with reverse phase chromatography to give 305 mg of A/-((2-(6-((1 -(3-fluoropyhdin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)thiazol-5-yl)methyl)-2- hydroxyacetamide as a white solid (M+H=429.1 ). Example 26: Preparation of 1 -(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)-1 H-pyrrole-3-carboxamide
Figure imgf000108_0001
f-butyl 6-(3-Cyano-1 H-pyrrol-1 -yl)pyridazin-3-yl((1 -(3-fluoropyridin- 2-yl)cyclobutyl)methyl)carbamate. To a stirring solution of f-butyl 6- fluoropyridazin-3-yl((1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (200 mg, 551 μηηοΙ) in DMF (2 mL) was added 3-cyanopyrrole (61 mg, 661 μηηοΙ) and potassium carbonate (152 mg, 1 .1 mmol). The reaction was heated to 1 10 °C and stirred for 30 min. The reaction was then poured into ethyl acetate (100 mL), washed with water (3x25 mL), and the organic layer was separated, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (EtOAC/hexanes) to afford 130 mg of f-butyl 6-(3-cyano-1 H- pyrrol-1 -yl)pyridazin-3-yl((1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a pale yellow solid.
Figure imgf000108_0002
1 -(6-((1 -(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3- yl)-1 H-pyrrole-3-carboxamide. f-butyl 6-(3-cyano-1 H-pyrrol-1 -yl)pyridazin-3- yl((1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (120 mg, 267 μιτιοΙ), potassium carbonate (147 mg, 1 .1 mmol), and DMSO (3 mL) were combined in a vial and cooled to 0 °C. Hydrogen peroxide (700 uL) was added dropwise, and the reaction was warmed to rt and stirred for 1 h. The reaction was then poured into ethyl acetate (50 mL), washed with water (3x20 mL), and the organic layer was separated, dried over Na2SO4, filtered, and concentrated. The crude solid was dissolved in 50% TFA CH2CI2 (2 mL) and stirred for 30 min. The reaction was then concentrated and purified using reverse phase chromatography to give 29 mg of 1 -(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)-1 H-pyrrole-3-carboxamide as a tan solid (M+H=367.1 ).
Example 27: Preparation of 2-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)-4-hydroxy-2,5-dihydrothiazole- -carboxamide
Figure imgf000109_0001
f-butyl 6-Cyanopyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate. To a solution of 6-((1 -(3-fluoropyhdin-2- yl)cyclobutyl)methylannino)pyndazine-3-carbonitnle (3.3 g, 4.7 mmol) in THF (30 mL) was added di-i-butyl dicarbonate (2.8 g, 13 mmol), and DMAP (0.5 g, 4.3 mmol). The reaction mixture was ref I uxed for 2 h. The reaction was concentrated and then poured into ethyl acetate (150 mL) and washed with 0.1 M HCI (50 mL, aq) and brine (50 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated to give a crude oil that was purified by silica gel column chromatography (EtOAC/hexanes) to afford 3.9 g of f-butyl 6-cyanopyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate as a white solid.
Figure imgf000109_0002
f-butyl 6-Carbamothioylpyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate. NMP (40 mL) and DIPEA (10 mL) were added to f-butyl 6-cyanopyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate (3.9 g, 10 mmol), and hydrogen sulfide was bubbled through the reaction mixture for 2 h. The reaction was diluted with water, and the resultant yellow solid was filtered and dried under vacuum to give 2.1 g of f-butyl 6-carbamothioylpyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate as a yellow solid.
Figure imgf000110_0001
Ethyl 2-(6-(f-butoxycarbonyl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-hydroxy-2,5- dihydrothiazole-5-carboxylate. i-Butyl 6-carbamothioylpyridazin-3-yl((1 -(3- fluoropyridin-2-yl)cyclobutyl)nnethyl)carbannate (1 .0 g, 2.4 mmol),
diethylbromomalonate (2 mL, 12 mmol), and toluene were added to a round bottom flask, heated to 90 °C, and stirred for 40 min. The reaction was concentrated and purified using reverse phase chromatography to yield 219 mg of ethyl 2-(6-(f-butoxycarbonyl((1 -(3-fluoropyhdin-2- yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-hydroxy-2,5-dihydrothiazole-5- carboxylate as an off-white solid.
Figure imgf000110_0002
2-(6-(f-Butoxycarbonyl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-methoxy-2,5- dihydrothiazole-5-carboxylic acid. To a stirring solution of ethyl 2-(6-(f- butoxycarbonyl((1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3- yl)-4-hydroxy-2,5-dihydrothiazole-5-carboxylate (350 mg, 0.7 mmol) in DMF (4 mL) was added methyl iodide (200 μί, 3.3 mmol) and sodium hydride (60% dispersion in mineral oil, 40 mg, 1 mmol). The reaction was stirred at rt for 1 h and at 40 °C for 45 min. The reaction was then concentrated and quenched with water (5 mL), poured into ethyl acetate (150 mL), and washed with 0.1 M HCI (50 mL, aq) and brine (50 mL). The organic layer was separated, dried over Na2SO , filtered, concentrated and purified by silica gel column chromatography (EtOAC/hexanes) to afford 205 mg of ethyl 2-(6-(tert- butoxycarbonyl((1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3- yl)-4-methoxy-2,5-dihydrothiazole-5-carboxylate. This compound was dissolved in methanol (4 mL) and 1 M KOH (aq, 2 mL). The reaction mixture was heated to 75 °C and stirred for 45 min. The reaction was cooled and the pH was adjusted to 4 using 1 M HCI. The reaction was then poured into ethyl acetate (50 mL), washed with brine (15 mL), dried over Na2SO , filtered, and concentrated to give 175 mg of 2-(6-(f-butoxycarbonyl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-methoxy-2,5-dihydrothiazole-5- carboxylic acid as a white foam.
Figure imgf000111_0001
f-butyl 6-(5-Carbamoyl-4-methoxy-2,5-dihydrothiazol-2- yl)pyridazin-3-yl((1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate.
To a 50 dram vial was added 2-(6-(f-butoxycarbonyl((1 -(3-fluoropyhdin-2- yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-methoxy-2,5-dihydrothiazole-5- carboxylic acid (175 mg, 0.34 mmol), HATU (194 mg, 0.51 mmol), HOAt (70 mg, 0.51 mmol), DIPEA (296 μΙ_, 1 .7 mmol), NMP (2 mL), and ammonium chloride (180 mg, 3.4 mmol). The reaction was stirred overnight at rt. The reaction was then poured into ethyl acetate (50 mL), washed with aqueous sodium bicarbonate, and brine (50 mL). The organic layer was separated, dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (EtOAC/hexanes) to afford 120 mg of f-butyl 6-(5-carbamoyl- 4-methoxy-2,5-dihydrothiazol-2-yl)pyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate.
Figure imgf000111_0002
2-(6-((1 -(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3- yl)-4-hydroxy-2,5-dihydrothiazole-5-carboxamide. To a stirring mixture of f-butyl 6-(5-carbamoyl-4-methoxy-2,5-dihydrothiazol-2-yl)pyridazin-3-yl((1 -(3- fluoropyridin-2-yl)cyclobutyl)nnethyl)carbannate (60 mg, 0.12 μηηοΙ) in CH2CI2 (2 mL) was added BBr3 (140 μί, 1 .2 mmol). The reaction was stirred at rt for 2 h and then at 60 °C for 15 min. The reaction was cooled to rt and carefully diluted with methanol (2 mL). The reaction was concentrated, diluted with ethyl acetate (20 mL), and saturated sodium bicarbonate (10 mL) was added. The mixture was agitated and then filtered. The subsequent crude solid was then purified using reverse phase chromatography to give 15 mg of 2-(6-((1 - (3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-4-hydroxy-2,5- dihydrothiazole-5-carboxamide as a yellow solid (M+H=401 .3)
Example 28: Preparation of 4-fluoro-3-(6-(((frans)-3-fluoro-1 -(3- fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-2- hydroxybenzamide
Figure imgf000112_0001
f-butyl 6-(3-Bromo-6-fluoro-2-methoxyphenyl)pyridazin-3- yl(((fraA7s)-3-fluoro-1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate. f-Butyl 6-Bromopyhdazin-3-yl(((frans)-3-fluoro-1 -(3-fluoropyhdin-2- yl)cyclobutyl)methyl)carbamate (3.0 g, 6.61 mmol), 3-bromo-6-fluoro-2- methoxyphenylboronic acid (1 .64 g, 6.61 mmol), (dppf)PdCI2 ( 0.48 g, 0.66 mmol), nitrogen-sparged dioxane (13.2 mL) and aq. 2 N K2CO3 (0.6 mL) were combined and heated in a microwave reactor at 125 °C. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Silica gel chromatography afforded the title compound as a yellow solid (1 .4 g, 3 +H] = 579.1 ).
Figure imgf000112_0002
f-butyl 6-(3-cyano-6-fluoro-2-methoxyphenyl)pyridazin-3- yl(((fraA7s)-3-fluoro-1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate. i-Butyl 6-(3-Bromo-6-fluoro-2-methoxyphenyl)pyridazin-3-yl(((irans)-3-fluoro-1 - (3-fluoropyridin-2-yl)cyclobutyl)nnethyl)carbannate (1 .4 g, 3.0 mmol), zinc cyanide (0.42 g, 3.6 mmol), Pd(PPh3)4 (1 .0 g, 0.9 mmol), DMF (3 mL) were combined and heated to 100 °C. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Silica gel chromatography afforded the title compound as a yellow solid (1 .0 g, 63%), (m/z [M+H] = 5
Figure imgf000113_0001
f-butyl 6-(3-carbamoyl-6-fluoro-2-methoxyphenyl)pyridazin-3- yl(((fraA7s)-3-fluoro-1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate. f-Butyl 6-(3-cyano-6-fluoro-2-methoxyphenyl)pyridazin-3-yl(((frans)-3-fluoro-1 - (3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (1 .0 g, 1 .9 mmol), K2CO3 (0.8 g, 5.8 mmol), and DMSO (10 mL) were combined in a round bottom flask, cooled to 0 °C, and H2O2 (2 mL of 35% solution) was added dropwise. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Silica gel chromatography afforded the title compound as a white s +H] = 545.1 ).
Figure imgf000113_0002
4-Fluoro-3-(6-(((frans)-3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)-2-hydroxybenzamide. f-Butyl 6-(3-carbamoyl-6-fluoro-2-methoxyphenyl)pyridazin-3-yl(((frans)-3-fluoro-1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (0.32 g, 0.59 mmol), lithium iodide (0.71 g, 5.34 mmol), and pyridine (5 mL) were combined in a
microwave reactor and heated to 125 °C. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Reverse phase chromatography provided 4-fluoro-3-(6-(((E)-3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)-2-hydroxybenzamide as a white solid (0.024 g, 10%), (m/z [M+H] = 430.1 ).
Example 29: Preparation of 4-fluoro-5-(6-(((frans)-3-fluoro-1 -(3- fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-2- hydroxybenzamide
Figure imgf000114_0001
f-Butyl 6-(5-bromo-2-fluoro-4-methoxyphenyl)pyridazin-3- yl(((fraA7s)-3-fluoro-1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate. i-Butyl 6-bromopyridazin-3-yl(((frans)-3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate (3.0 g, 6.61 mmol), 2-(5-bromo-2-fluoro-4- methoxyphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (2.2 g, 6.61 mmol), (dppf)PdCI2 (0.48 g, 0.66 mmol), nitrogen-sparged dioxane (13.2 mL) and aq. 2 N K2CO3 (0.6 mL) were combined and heated to 90 °C. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Silica gel chromatography provided a light yellow solid (1 .7 g, 44%), (m/z
[M+H] = 579.1 ).
Figure imgf000114_0002
f-Butyl 6-(5-cyano-2-fluoro-4-methoxyphenyl)pyridazin-3- yl(((fraA7s)-3-fluoro-1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate. f-Butyl 6-(5-bromo-2-fluoro-4-methoxyphenyl)pyridazin-3-yl(((frans)-3-fluoro-1 - (3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (1 .7 g, 3.6 mmol), zinc cyanide (0.51 g, 4.3 mmol), Pd(PPh3)4 (1 .26 g, 1 .0 mmol), DMF (5 mL) were combined and heated to 100 °C. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Silica gel chromatography pr +H] = 526.2).
Figure imgf000115_0001
f-Butyl 6-(5-carbamoyl-2-fluoro-4-methoxyphenyl)pyridazin-3- yl(((fraA7s)-3-fluoro-1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate. f-Butyl 6-(5-cyano-2-fluoro-4-nnethoxyphenyl)pyridazin-3-yl(((irans)-3-fluoro-1 - (3-fluoropyridin-2-yl)cyclobutyl)methyl)carbannate (0.21 g, 0.4 mmol), K2CO3 (0.22 g, 1 .6 mmol), and DMSO (4 mL) were combined in a round bottom flask, cooled to 0 °C, and H2O2 (1 .3 mL of 35%) was added dropwise. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Silica gel chromatography provided a white solid (0.10 g, 46%), (m/z [M+H] = 54
Figure imgf000115_0002
4-Fluoro-5-(6-(((fraA7s)-3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)-2-hydroxybenzamide. f-Butyl 6-(5-carbamoyl-2-fluoro-4-methoxyphenyl)pyridazin-3-yl(((frans)-3-fluoro-1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (0.10 g, 0.18 mmol), lithium iodide (0.22 g, 1 .65 mmol) and pyridine (3 mL) were combined in a microwave reactor and heated to 125 °C. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Reverse phase
chromatography provided the title compound as a white solid (0.023 g, 30%), (m/z [M+H] = 430.1 ).
Example 30: Preparation of 5-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)-1 H-pyrazole-3-carboxamide
Figure imgf000115_0003
f-Butyl 6-(1 -ethoxyvinyl)pyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate. i-Butyl 6-chloropyridazin-3-yl((1 -(3- fluoropyridin-2-yl)cyclobutyl)nnethyl)carbannate (5.1 g, 13.0 mmol), tributyl(1 - ethoxyvinyl)stannane (6.1 g, 16.9 mmol), (PPh3)2PdCI2 (2.3 g, 3.2 mmol), and nitrogen-sparged dioxane (18 mL) were combined and heated in a microwave reactor at 150 °C. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Silica gel chromatography provided a light yellow +H] = 429.2).
Figure imgf000116_0001
f-Butyl 6-acetylpyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate. f-Butyl 6-(1 -ethoxyvinyl)pyridazin-3-yl((1 - (3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (1 .0 g, 2.3 mmol), EtOH (75 mL), and 1 N HCI (15 mL) were combined at 0 °C, warmed to 25 °C, and stirred for 1 h. The reaction mixture was concentrated and silica gel chromatography provided a colorless oil (0.6 g, 64%), (m/z [M+H] = 401 .1 ).
Figure imgf000116_0002
Ethyl 5-(6-(tert-butoxycarbonyl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-1 H-pyrazole-3-carboxylate. t-
Butyl 6-acetylpyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate (2.5 g, 6.2 mmol) in THF (150 mL) was treated with NaOEt (3.44 g, 10.6 mmol, 21 % in EtOH). The resulting mixture was then treated with diethyl oxalate (1 .7 mL, 12.5 mmol), heated to 45 °C, and stirred for 4 h. The reaction mixture was added to 1 N HCI, extracted with EtOAc, and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. A portion of the resultant oil was dissolved in AcOH and hydrazine (0.41 g, 13.2 mmol) was added and stirred at 80 °C. Concentration afforded a yellow oil which was purified by reverse-phase chromatography to give solid (0.285 g, 62%), (m/z [M+ = 497.2).
Figure imgf000117_0001
5-(6-((1 -(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3- yl)-1 H-pyrazole-3-carboxamide. Ethyl 5-(6-(f-butoxycarbonyl((1 -(3- fluoropyndin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-1 H-pyrazole-3- carboxylate (0.28 g, 0.56 mmol) and 7N ammonia in MeOH were combined in a microwave reactor and heated to 1 10 °C for 1 h. The reaction mixture was then concentrated, diluted with EtOAc, and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The resultant oil was diluted in 10 mL of DCM and TFA (15 ml_) was added. The reaction mixture was then concentrated and purified by reverse phase chromatography to give the title compound as a white solid (18 mg, 12%), (m/z [M+H] = 368.1 ).
Example 31 : Preparation of 3-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)isoxazole-5-carboxamide
Figure imgf000117_0002
f-Butyl (1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-vinylpyridazin- 3-yl)carbamate. f-Butyl 6-chloropyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate (2.5 g, 6.36 mmol), triethenylboroxin pyridine complex (1 .0 g, 4.13 mmol), Pd(PPh3)4 (0.3 g, 0.25 mmol), nitrogen-sparged dioxane (13.2 mL) and aq. 2 N K2CO3 (0.9 mL) were combined and heated to 1 10 °C for 25 min. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Silica gel chromatography provided a light yellow oi +H] = 385.2).
Figure imgf000117_0003
f-Butyl (1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl(6- formylpyridazin-3-yl)carbamate. i-Butyl (1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl(6-vinylpyridazin-3-yl)carbannate (3.4 g, 8.84 mmol) was added as a dioxane (100 mL) solution to a mixture of sodium periodate (10.8 g, 50.5 mmol) and 4% osmium tetraoxide solution (6.5 mL) in H2O (30 mL) at 0 °C. The reaction was stirred for 2 h. The reaction mixture was filtered through a pad of celite and washed with EtOAc. The organic layer was washed with satd. aq. NaHCO3, brine and dried over sodium sulfate, filtered, and concentrated. Silica gel chromatography provided a colorless oil (1 .4 g, 41 +H] = 387.2).
Figure imgf000118_0001
Methyl-3-(6-(tert-butoxycarbonyl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyridazin-3-yl)isoxazole-5-carboxylate. To t- butyl (1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-formylpyridazin-3- yl)carbamate (1 .4 g, 3.6 mmol) in ethanol (10 mL) and water (2 mL) was added hydroxylamine hydrochloride (0.27 g, 3.8 mmol) followed by sodium acetate (0.32 g, 3.8 mmol) and stirred at 24 °C for 30 min. The crude reaction mixture was concentrated and diluted with EtOAc. The organic layer was washed with satd. aq. NaHCO3 and brine, then dried over sodium sulfate, filtered, and concentrated. The crude mixture was then diluted in THF (2 mL) and pyridine (57 mg, 0.72 mmol) then treated with NCS (0.58 g, 4.35 mmol) and heated to 40 °C for 1 .5 h. The crude mixture was then treated with methyl propiolate (0.30 g, 3.56 mmol) and TEA (0.36, 3.56 mmol), and the reaction was stirred for 45 min. The reaction mixture was concentrated and diluted with EtOAc, and then washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, concentrated, and
Figure imgf000118_0002
3-(6-((1 -(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3- yl)isoxazole-5-carboxamide. Methyl 3-(6-(tert-butoxycarbonyl((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyndazin-3-yl)isoxazole-5- carboxylate (0.53 g, 1 .1 mmol), methanol (5 mL) and concentrated ammonium hydroxide (8 mL) were combined in a microwave reactor and heated to 100 °C for 60 min. The reaction mixture was then concentrated and diluted with EtOAc and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Resultant oil was diluted in 10 mL of DCM and TFA (6 mL) was added and the reaction was stirred for 35 min. The reaction mixture was then concentrated and purified by reverse phase chromatography to give the title compound as a white solid (144 mg, 36%), (m/z [M+H] = 369.1 ).
Example 32: Preparation of 2-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)thiazole-5-carboxamide
Figure imgf000119_0001
Ethyl 2-(6-(tert-butoxycarbonyl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyridazin-3-yl)thiazole-5-carboxylate. tert- butyl 6-chloropyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate (500 mg, 1 .27 mmol), ethyl thiazole-5- carboxylate (300 mg, 1 .91 mmol), Pd(OAc)2 (86 mg, 0.13 mmol), JohnPhos (92 mg, 0.26 mmol) and Cs2CO3 (827 mg, 2.54 mmol) in toluene (10 mL) were combined and heated in a microwave reactor for 30 min at 145 °C. The reaction mixture was filtered through a celite plug and the filtrate was concentrated. The resulting residue was purified on silica gel using a mixture of ethyl acetate and hexanes to provide the title compound as yellow oil (162
+H+) m/z 514.3.
Figure imgf000119_0002
f-Butyl 6-(5-carbamoylthiazol-2-yl)pyridazin-3-yl((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)carbamate. To a solution of ethyl 2- (6-(tert-butoxycarbonyl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)annino)pyridazin-3-yl)thiazole-5-carboxylate (162 mg, 0.32 mmol) in MeOH (8 mL) was purged with NH3 gas for 5 min. The reaction mixture was sealed and heated in a microwave reactor for 30 min at 120 °C. The reaction mixture was concentrated and used in next step without purifi +H+) m/z 484.2.
Figure imgf000120_0001
2-(6-((1 -(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3- yl)thiazole-5-carboxamide. To a crude mixture of f-butyl 6-(5- carbamoylthiazol-2-yl)pyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate (141 mg, crude) in DCM (6 mL) was added TFA (2 mL) at rt. The reaction mixture was further stirred at rt for 2 hr followed by concentration to dryness. The crude mixture was purified on RP- HPLC using a mixture of acetonitrile and H2O to provide the title compound as a pale yellow solid (98.5 mg, 99% for 2 steps), LRMS (M+H+) m/z 385.2.
Example 33: Preparation of 5-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)isoxazole-3-carboxamide
Figure imgf000120_0002
Ethyl 5-(6-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)isoxazole-3-carboxylate. To t- butyl 6-(1 -ethoxyvinyl)pyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate (439 mg, 1 .02 mmol) in THF (5.0 mL) was added (E)-ethyl 2-chloro-2-(hydroxyimino)acetate (465 mg, 3.06 mmol) and TEA (1 .4 mL, 10.2 mmol). The reaction mixture was stirred at rt for 30 min followed by addition of TFA (5 mL) and then heated to reflux overnight. The mixture was then concentrated and purified by reverse phase chromatography to give 415 mg of the title compound as a colorless oil, LRMS (M+H+) m/z 3
Figure imgf000121_0001
5-(6-((1 -(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3- yl)isoxazole-3-carboxamide. To a solution of ethyl 5-(6-((1 -(3-fluoropyridin- 2-yl)cyclobutyl)methylamino)pyridazin-3-yl)isoxazole-3-carboxylate (200 mg, 0.40 mmol) in THF/MeOH mixture (12 mL, 5:1 ) was added LiOH (1 M, 1 .2 mL) at rt. The reaction mixture was stirred overnight and concentrated. To this crude mixture was added NH4CI (60 mg, 1 .2 mmol), HBTU (246 mg, 0.65 mmol), DIEA (132 uL, 0.8 mmol), and DMF (5.0 mL). The mixture was stirred at rt overnight, filtered, and purified by reverse phase chromatography to provide the title compound as a white solid (23.2 mg, 16%), LRMS (M+H+) m/z 369.2.
Example 34: Preparation of 5-(5-(6-((1 -(3-Fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)thiophen-2-yl)-2H-1 ,2,4-triazol-
3(4 -one
Figure imgf000121_0002
f-Butyl 6-(5-cyanothiophen-2-yl)pyridazin-3-yl((1 -(3-fluoropyridin- 2-yl)cyclobutyl)methyl)carbamate. f-Butyl 6-chloropyridazin-3-yl((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (900 mg, 2.29 mmol, 1 equiv), 5-cyanothiophen-2-ylboronic acid (390 mg, 2.52 mmol, 1 .1 equiv), (dppf)PdCI2 (164 mg, 0.23 mmol, 0.1 equiv), nitrogen-sparged dioxane (6.0 mL) and aq. 2 N K2CO3 (2.3 mL) were combined and heated in a microwave reactor for 30 min at 140 °C. The reaction mixture was filtered through a Celite plug and the filtrate was concentrated. The resulting residue was purified on silica gel using a mixture of ethyl acetate and hexanes to provide the title compound as a yel +H+) m/z 466.3.
Figure imgf000122_0001
tert-butyl (1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(5-(5-oxo-4,5- dihydro-1 H-1 ,2,4-triazol-3-yl)thiophen-2-yl)pyridazin-3-yl)carbamate. To a solution of tert-butyl 6-(5-cyanothiophen-2-yl)pyridazin-3-yl((1 -(3- fluoropyhdin-2-yl)cyclobutyl)methyl)carbannate (340 mg, 0.73 mmol, 1 equiv) in MeOH (10 mL) was added sodium methoxide (0.59 g, 1 .1 mmol, 1 .5 equiv). The reaction mixture was stirred at rt overnight followed by addition of hydrazine (0.5 mL). The mixture was then heated to reflux for 2 h and concentrated to dryness. The crude mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO , filtered, and concentrated. The crude product was dissolved in dioxane (3 mL), combined with CDI (137 mg, 1 .46 mmol, 2 equiv), and heated for 4 h at 100 °C. The mixture was cooled, filtered, and purified by reverse phase chromatography to give the title compound as a yellow solid (86 mg, 23% ove +H+) m/z 524.3.
Figure imgf000122_0002
5-(5-(6-((1 -(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin- 3-yl)thiophen-2-yl)-2H-1 ,2,4-triazol-3(4H)-one. To tert-butyl (1 (3- fluoropyridin-2-yl)cyclobutyl)methyl(6-(5-(5-oxo-4,5-dihydro-1 H-1 ,2,4-triazol-3- yl)thiophen-2-yl)pyridazin-3-yl)carbamate (86 mg, 0.16 mmol) in DCM (6 mL) was added TFA (2 mL) at rt. The reaction mixture was stirred at rt for 2 hr followed by concentration to dryness. The crude mixture was purified by reverse phase chromatography to provide the title compound as a pale yellow solid (73.6 mg, quantitative). LRMS (M+H+) m/z 424.2. Example 35: Preparation of 4-fluoro-3-(6-(((frans)-3-fluoro-1 -(3- fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-N- methylbenzamide
Figure imgf000123_0001
1 -(3-Fluoropyridin-2-yl)-3-methylenecyclobutanecarbonitrile. To a solution of 3-methylenecyclobutanecarbonithle (150 g, 1 .61 mol, 1 equiv) and 2-chloro-3-fluoropyridine (212 g, 1 .61 mmol, 1 equiv) in toluene (1 L) was added NaHMDS (2 M in THF, 885 mL, 1 .1 equiv) dropwise at 0-10 °C. Upon completion of addition, the reaction mixture was warmed to rt, stirred overnight, and quenched with NH CI(Sat.) solution. The organic layer was washed with water (500 mL x 2) and brine (500 mL), dried over Na2SO , filtered, and concentrated to give a crude title compound (272 g, 90%), which was used in the next step without further purification, LRMS (M+H+) m/z 189.1 .
Figure imgf000123_0002
1 -(3-Fluoropyridin-2-yl)-3-oxocyclobutanecarbonitrile. To a mixture of 1 -(3-fluoropyridin-2-yl)-3-methylenecyclobutanecarbonitrile (272 g, 1 .45 mol) and RuCI3.H2O (9.0 g, 0.044 mol) in DCM (1 L), acetonitrile (1 L), and water (1 .5 L) was added solid NalO (1235 g, 5.8 mol) portionwise at 10-30 °C. Upon completion of the addition, the reaction was stirred 1 h at 15 °C and overnight at rt. The solid precipitate was filtered off and washed with DCM (1 L x 2). The organic layer was washed with water (500 mL x 2) and brine (500 mL), dried over Na2SO , and concentrated to provide the title compound as a crude dark solid (238 g, 86.3%), LRMS (M+H+) m/z 191 .1 .
Figure imgf000123_0003
1 -(3-Fluoropyridin-2-yl)-3-hydroxycyclobutanecarbonitrile. To a solution of 1 -(3-fluoropyridin-2-yl)-3-oxocyclobutanecarbonitrile (231 g, 1 .22 mol) in a mixture of DCM (2 L) and MeOH (200 ml_) was added NaBH4 portion-wise at -78 °C. The reaction mixture was stirred 1 h at -78 °C and then quenched with a mixture of methanol and water (1/1 ). The organic layer was washed with water (500 ml_ x 3), dried over Na2SO , and concentrated. The residue was purified on silica gel (50% EtOAc in Hexanes) to provide the title compound as an am r oil (185.8 g, 77.5%), LRMS (M+H+) m/z 193.2.
Figure imgf000124_0001
fraA7s-3-Fluoro-1-(3-fluoropyridin-2-yl)cyclobutanecarbonitrile. To a solution of 1 -(3-fluoropyridin-2-yl)-3-hydroxycyclobutanecarbonitrile (185 g, 0.96 mol) in DCM (1 L)was added DAST portion-wise at 0-10 °C. Upon the completion of addition, the reaction was refluxed for 6 h. The reaction was cooled to rt and poured onto sat. NaHCO3 solution. The mixture was separated and the organic layer was washed with water, dried over Na2SO , and concentrated. The residue was purified on silica gel (100% DCM) to provide the title compound as a brown oil (1 16 g, 62%) with a trans/cis ratio of 8:1 as determined by 1H NMR. The above brown oil (107 g) was dissolved in a mixture of toluene (1 10 ml_) and hexanes (330 ml_) at 70 °C. The solution was cooled to 0 °C and stirred at 0 °C overnight. The precipitate was filtered and washed with hexanes to provide a single trans-isomer white solid (87.3 g, 81 .6%), LRMS (M+H+ m/z 195.1 .
Figure imgf000124_0002
fraA7s-3-Fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methanamine. A mixture of frans-3-fluoro-1 -(3-fluoropyhdin-2-yl)cyclobutanecarbonitrile (71 g, 0.37 mol) and Raney nickel (~7 g) in 7N ammonia in methanol (700 ml_) was charged with hydrogen (60 psi) for 2 days. The reaction was filtered through a celite pad and washed with methanol. The filtrate was concentrated under high vaccum to provide the title compound as a light green oil (70 g, 98%),
+H+) m/z 199.2.
Figure imgf000125_0001
f-Butyl 6-chloropyridazin-3-yl(((fraA7s)-3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate. 3-Chloro-6-fluoropyridazine (10.1 1 g, 76.30 mmol, 1 equiv), frans-3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methanamine (15.10 g, 76.30 mmol, 4:1 trans/cis ratio), and K2CO3 (29.27 g, 304.9 mmol) in CH3CN (20 mL) were refluxed overnight. Upon cooling, water was added into the mixture. The precipitate was collected and dried to give 9.2 g (39 %) of desired product with ratio of trans:cis greater than 20:1 . To this solid (9.2 g) and DMAP (353 mg, 2.9 mmol) in THF (100 mL) was added (Boc)2O (12.8 g, 58.7 mmol). The mixture was then refluxed for 2 h, cooled, and concentrated. The residue was purified on silica gel to provide the title compound as a white solid (9 g, 75%), LRMS +ΗΓ) m/z 41 1 .2.
Figure imgf000125_0002
Methyl 3-(6-(f-butoxycarbonyl(((frans)-3-fluoro-1 -(3-fluoropyridin- 2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-fluorobenzoate. To f-butyl 6-chloropyhdazin-3-yl(((frans)-3-fluoro-1 -(3-fluoropyhdin-2- yl)cyclobutyl)methyl)carbamate (30.3 g, 73.9 mmol, 1 equiv), 2-fluoro-5- (methoxycarbonyl)phenylboronic acid (16.1 g, 81 .3 mmol, 1 .1 equiv),
(dppf)PdCI2 (6.0 g, 7.39 mmol, 0.1 equiv), K2CO3 (40.8 g, 296 mmol, 4 equiv) were added dioxane (160 mL) and water (40 mL). The mixture was heated 2 h at 80 °C, cooled and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO , filtered, and concentrated. The residue was purified on silica gel to provide the title compound as pale orange solid (29.4
+H+) m/z 529.2.
Figure imgf000126_0001
3-(6-(f-butoxycarbonyl(((fraA7s)-3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-fluorobenzoic acid.
To a 500 mL round bottom flask was added methyl 3-(6-(f- butoxycarbonyl(((frans)-3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-fluorobenzoate (29.4 g, 55.7 mmol, 1 equiv), THF (200 mL), MeOH (100 mL), and NaOH (74.2 mL of a 3N aqueous solution, 222 mmol). The mixture was heated 30 min at 60 °C, cooled, acidified to pH 3 with NaHSO (1 N), and concentrated. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to provide the title compound as a pale orange solid (29 g, crude), LRMS (M+H+) m/z 515.2.
Figure imgf000126_0002
f-Butyl ((frans)-3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl(6-(2-fluoro-5-(methylcarbamoyl)phenyl)pyridazin-3- yl)carbamate. To 3-(6-(f-butoxycarbonyl(((frans)-3-fluoro-1 -(3-fluoropyridin- 2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-4-fluorobenzoic acid (29 g, 55.7 mmol, 1 equiv) in DCM (200 mL) was added oxalyl chloride (19.4 mL, 222 mmol, 4 equiv). The reaction was stirred for 1 h, concentrated, and azeotroped twice with toluene. The crude product was then dissolved in DCM and cooled to 0 °C. To this mixture was added NH2Me (2 M/THF, 278 mL, 556.8 mmol). The mixture was warmed to rt and stirred at rt for 30 min. The solid was filtered off and the filtrate was concentrated. The crude product was purified on silica gel to provide the title compound as pale yellow solid (28.1 g,
+H+) m/z 528.2.
Figure imgf000127_0001
4-fluoro-3-(6-(((fraA7s)-3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)-N-methylbenzamide.
To tert-butyl ((frans)-3-fluoro-1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(2- fluoro-5-(methylcarbamoyl)phenyl)pyridazin-3-yl)carbamate (28.1 g, 53.3 mmol) in DCM (100 mL) was added TFA (40 ml_, 533 mmol, 10 equiv) at rt. The reaction mixture was further stirred at rt for 2 h followed by concentration to dryness. The residue was partitioned between EtOAc and NaHCO3. The pH was further adjusted to pH 9 with NaOH (1 N). The organic layer was washed with brine, dried over Na2SO , filtered, and concentrated to give 25.2 g of a pale yellow solid. The solid was dissolved in EtOH (80 mL), warmed to 66 °C and diluted with water (80 mL) at 66 °C. The mixture was slowly cooled to rt with stirring. The precipitate was filtered, washed with water, and dried to provide the title compound as a white solid (21 .2 g, 93%), LRMS (M+H+) m/z 428.2.
Example 36: Preparation of 6-(5-(1 H-pyrazol-3-yl)thiazol-2-yl)-N-((1 -(3- fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine
Figure imgf000127_0002
f-Butyl 6-(5-bromothiazol-2-yl)pyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate. To a 100 mL round bottom flask was added f-butyl (1 -(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(thiazol-2- yl)pyridazin-3-yl)carbamate (2.0 g, 4.6 mmol), NBS (1 .6 g, 9.1 mmol), and DMF (20 mL). The reaction was heated to 100 °C and stirred overnight. The reaction mixture was then was poured into ethyl acetate (200 mL), washed with water (100 mL), dried over Na2SO , filtered, concentrated, and purified by silica gel chromatography (EtOAc/hex) to afford 1 .8 g of f-butyl 6-(5- bromothiazol-2-yl)pyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate.
Figure imgf000128_0001
6-(5-(1 H-pyrazol-3-yl)thiazol-2-yl)-N-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)pyridazin-3-amine. To a microwave vial was added t- butyl 6-(5-bromothiazol-2-yl)pyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate (100 mg, 0.19 mmol), 1 H-pyrazol-5-ylboronic acid (32 mg, 0.29 mmol), (dppf)PdCI2 (16 mg, 0.02 mmol), dioxane (2 mL), and K2CO3 (0.2 mL of a 2M aqueous solution, 38 mmol). The mixture was heated to 140 °C in a microwave reactor and stirred for 20 min. The reaction mixture was then poured into ethyl acetate (50 mL), washed with water (20 mL), dried over Na2SO , filtered, concentrated, and purified by silica gel chromatography (EtOAc/hex) to afford 38 mg of i-butyl 6-(5-(1 H-pyrazol-3- yl)thiazol-2-yl)pyridazin-3-yl((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)carbamate. This compound was dissolved in CH2CI2 (5 mL) and TFA (1 mL). The reaction was stirred for 30 min at rt, concentrated, and then purified using reverse phase chromatography to give 15 mg of 6-(5- (1 H-pyrazol-3-yl)thiazol-2-yl)-N-((1 -(3-fluoropyridin-2- yl)cyclobutyl)methyl)pyridazin-3-amine, (M+H=408.3).
Example 37: Preparation of 6-(6-((fraA7s-3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)imidazo[2,1 -b]thiazole-3- carboxami
Figure imgf000128_0002
2-Bromo-1 -(6-chloropyridazin-3-yl)ethanone. To a stirring solution of dioxane (100 mL, degassed) was added 3,6-dichloropyridazine (5.0 g, 34 mmol), CI2Pd(PPh3)2 (2.4 g, 3.4 mmol), and tributyl(1 ethoxyvinyl)tin (18.2 g, 50 mmol). The reaction was heated to 100 °C and stirred for 1 h. The reaction was then concentrated, followed by the addition of EtOAc (100 mL) and potassium fluoride (50 mL of a saturated aqueous solution). The mixture was stirred for 30 min and then filtered through a pad of Celite. The filtrate was concentrated and then dissolved in THF (80 mL) and water (80 mL). NBS (18.1 g, 102 mmol) was then added, and the reaction was stirred for 20 min at rt. The reaction mixture was poured into ethyl acetate (200 mL), washed twice with brine (50 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography to afford 4.2 g of 2-bromo-1 -(6- chloropyridazin-3-yl)ethanone.
Figure imgf000129_0001
Ethyl 6-(6-chloropyridazin-3-yl)imidazo[2,1 -b]thiazole-3- carboxylate. To a 20 dram vial was added 2-bromo-1 -(6-chloropyridazin-3- yl)ethanone (4.2 g, 18 mmol), ethyl-2-aminothiazole-4-carboxylate (3.1 g, 18 mmol), and methylethyl ketone (40 mL). The mixture was heated to 90 °C and stirred overnight. The reaction was then concentrated and purified by silica gel chromatography (EtOAc/hex) to afford 1 .0 g of ethyl 6-(6-chloropyridazin- 3-yl)imidazo[2,1 -b]thiazole-3-carboxylate as a yellow solid.
Figure imgf000129_0002
Ethyl 6-(6-fluoropyridazin-3-yl)imidazo[2,1 -b]thiazole-3- carboxylate. To a 20 dram vial was added ethyl 6-(6-chloropyridazin-3- yl)imidazo[2,1 -b]thiazole-3-carboxylate (1 .0 g, 3.2 mmol), 1 ,8- bis(dimethylamino)naphthalene (1 .4 g, 6.4 mmol), and Et3N-3HF (30 mL). The reaction was heated in a microwave to 140 °C and stirred for 1 .5 h. The reaction mixture was poured into ethyl acetate (100 mL), washed with water (50 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography to afford 760 mg of ethyl 6-(6-fluoropyridazin-3- yl)imidazo[2,1 -b]thiazole-3-carboxylate as a yellow solid.
Figure imgf000130_0001
Ethyl 6-(6-(((frans)-3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)imidazo[2,1 -b]thiazole-3- carboxylate. Ethyl 6-(6-fluoropyridazin-3-yl)imidazo[2,1 -b]thiazole-3- carboxylate (65 mg, 0.2 mmol), (frans-3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methanamine (56 mg, 0.29 mmol), DIPEA (1 14 μΙ_, 0.66 mmol), and NMP (3 mL). The reaction was heated to 165 °C and stirred for 2 h. The reaction was then purified directly using reverse phase chromatography to give 15 mg of ethyl 6-(6-(((frans)-3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)imidazo[2,1 -b]thiazole-3-carboxylate.
Figure imgf000130_0002
6-(6-(((frans)-3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)imidazo[2,1 -b]thiazole-3- carboxamide. To a solution of ethyl 6-(6-(((frans)-3-fluoro-1 -(3-fluoropyridin- 2-yl)cyclobutyl)methylamino)pyridazin-3-yl)imidazo[2,1 -b]thiazole-3- carboxylate (20 mg, 0.05 mmol) in dioxane (0.5 mL) was added LiOH (1 M, 0.15 mL, 0.15 mmol). The reaction mixture was stirred at rt for 1 h and then concentrated. To this crude mixture was added NH CI (28 mg, 0.5 mmol), HATU (28 mg, 0.075 mmol), HOAt (10 mg, 0.075 mmol), DIEA (19 mg, 0.15 mmol), and DMF (1 mL). The mixture was stirred at 50 °C for 30 min and then was purified directly by reverse phase chromatography to provide 2 mg of 6-(6-(((frans)-3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)imidazo[2,1 -b]thiazole-3- carboxamide as a white solid, (M+H=442.1 ). Example 38: Preparation of 4-Fluoro-3-(6-(((frans)-3-fluoro-1 -(3- fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)benzamide and 4-fluoro-3-(6-(((c s)-3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)benzamide
Figure imgf000131_0001
To a solution of 4-fluoro-3-(6-((3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methylannino)pyndazin-3-yl)benzonitrile (482 mg, 1 .22 mmol, 95:5 cis/trans ratio) in DMSO (3 ml_) was added potassium carbonate (673 mg, 4.88 mmol). The mixture was cooled to 0 °C and hydrogen peroxide (0.6 ml_) was slowly added. The reaction was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc (75 ml_) and water (50 ml_), and the organic layer was washed three times with brine (50 ml_). The organic layer was then dried over Na2SO4, filtered, concentrated, and purified by reverse phase chromatography to afford 470 mg of 4-fluoro-3-(6-(((frans)-3-fluoro-1 - (3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)benzamide and 6 mg of 4-fluoro-3-(6-(((c/'s)-3-fluoro-1 -(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazin-3-yl)benzamide as white solids
(M+H=414.3).
Example 39: Preparation and assay of fast skeletal myofibrils
Preparation of fast skeletal myofibrils. Rabbit skeletal myofibrils were prepared based upon the method of Herrmann et al. (Biochem.
32(28):7255-7263(1993). Myofibrils were prepared from rabbit psoas muscle purchased from Pel-Freez Biologicals (Arkansas) within 2 days of ordering, stored on ice. Minced muscle was homogenized in 10 volumes of ice-cold "standard" buffer (50mM Tris, pH 7.4, 0.1 M potassium acetate, 5 mM KCI, 2 mM DTT, 0.2 mM PMSF, 10 μΜ leupeptin, 5 μΜ pepstatin, and 0.5 mM sodium azide) containing 5 mM EDTA and 0.5% Triton X-100 using an Omni- Macro homogenizer. Myofibrils were recovered by low speed centrifugation (3000 rpm for 10 minutes) and washed 2 times in the Triton X-100 containing buffer to ensure removal of cellular membrane. Following the Triton washes, myofibrils were washed 3 times in "standard" buffer containing 2 mM magnesium acetate. A final wash in assay buffer (12 mM PIPES, pH 6.8, 60 mM KCI, 1 mM DTT) was performed and brought to 10% sucrose for flash freezing in liquid nitrogen and storage at -80°C.
Activation of Fast Skeletal Myofibrils. Fast fiber activators were identified by measuring the enzymatic activity of muscle myofibril preparations
TM
using the proprietary PUMA (see, e.g., U.S. Patent Nos. 6,410,254,
6,743,599, 7,202,051 , and 7,378,254) assay system. Myofibril preparations consisted of rabbit skeletal muscle (approximately 90% fast fibers) that had been mechanically homogenized and washed with a detergent (triton X-100) to remove cellular membranes. This preparation retained all of the
sarcomeric components in a native conformation and the enzymatic activity was still regulated by calcium. Compounds were tested using a myofibril suspension and a level of calcium sufficient to increase enzymatic activity of the myofibrils to 25% of their maximal rate (termed pCa25). Enzymatic activity was tracked via a pyruvate kinase and lactate dehydrogenase-coupled enzyme system. This assay regenerates myosin-produced ADP into ATP by oxidizing NADH, producing an absorbance change at 340 nm. The buffering system was 12 mM Pipes, 2 mM MgCI2, 1 mM DTT at pH 6.8 (PM12 buffer). Data was reported as AC1 .4, which is the concentration at which the compound increased the enzymatic activity by 40%. The results are summarized in Table 2 below.
Example 40: Preparation and Assay of Sarcomeric Proteins from
Skeletal Muscle
Powder Preparation
1 . Volumes are given per about 1000 g of the minced muscle.
2. Pre-cut and boil cheesecloth for 10 min in water. Drain and dry.
3. Mince chicken breast in a prechilled meat grinder.
4. Extract with stirring in 2 L of 0.1 M KCI, 0.15 M K-phosphate, pH 6.5 for 10 min at 4 °C. Spin 5000 rpm, 10 min, 4 °C in J LA. Collect the pellet.
5. Extract pellets with stirring with 2 L of 0.05 M NaHCO3 for 5 min. Spin 5000 rpm, 10min, 4 °C in JLA. Collect the pellet. Repeat the extraction once more.
6. Extract the filtered residue with 2 L of 1 mM EDTA, pH 7.0 for 10 min with stirring.
7. Extract with 2 L of H2O for 5 min with stirring. Spin 10000 rpm, 15min, 4 °C in JLA. Carefully collect the pellet, part of which will be loose and gelatinous.
8. Extract 5 times with acetone (2 L of acetone for 10 min each with stirring). Squeeze through cheesecloth gently. All acetone extractions are performed at room temperature. Acetone should be prechilled to 4 °C.
9. Drying: Place the filtered residue spread on a cheesecloth in a large glass tray and leave in a hood overnight. When the residue is dry, put in a wide mouth plastic bottle and store at 20 °C.
Alternate Powder Preparation
(See Zot & Potter (1981 ) Prep. Biochem. 1 1 (4) pp. 381 -395)
1 . Dissect left ventricles of the cardiac muscle. Remove as much of the pericardial tissue and fat as possible. Grind in a prechilled meat grinder.
Weigh.
2. Prepare 5 volumes of Extract buffer (see below). Homogenize the meat in a blender, 4 times 15 sec on blend with 15 sees in between. Do this with 1 volume (weight/volume) of buffer taken from the 5 volumes already prepared. Add the homogenate back to the extract buffer and stir until well mixed (5 minutes).
3. Filter through one layer of cheesecloth in large polypropylene strainer. Resuspend back into 5 volumes of extract buffer as above.
4. Repeat Step 3 four more times. At the end, do not resuspend in extraction buffer but proceed to Step 5. The pellets should be yellow white.
5. Resuspend in 3 volumes (according to original weight) of 95% cold ethanol. Stir for 5 min and squeeze through cheesecloth as above, repeat two more times.
6. Weigh squeezed residue and then resuspend in 3 volumes (new weight/volume) of cold diethyl ether.
7. Repeat Step 6 a total of three times.
8. Leave overnight in a single layer on a cheesecloth in a glass tray. 9. When dry, collect the powder, weigh and store in a wide-mouth jar at 4 °C.
EXTRACT BUFFER: 50 mM KCI, 5 mM Tris pH 8.0 Prepare as 50 times concentrate. For 2L: 250 mM Tris pH 8.0. Tris Base (121 .14 g/mol, 60.6 g), pH to 8.0 with cone. HCI, then add 2.5 M KCI (74.55 g/mol, 372 g).
Actin Preparation
1 . Extract powder (as described above) with 20 ml buffer A (see below, add BME and ATP just prior to use in each of the following steps) per gram of powder (200 ml per 10 g). Use a large 4 L beaker for 150 g of powder. Mix vigorously to dissolve powder. Stir at 4 °C. for 30 min.
2. Separate extract from the hydrated powder by squeezing through several layers of cheesecloth. Cheesecloth should be pre-sterilized by microwaving damp for 1 -2 min.
3. Re-extract the residue with the same volume of buffer A and combine extracts.
4. Spin in JLA10 rotor(s) for 1 hr at 10K rpm (4 °C). Collect supernatant through 2 layers of cheesecloth.
5. Add ATP to 0.2 mM and MgCI2 to 50 mM. Stir on stir plate at 4 °C for 60 minutes to allow actin to polymerize/form para-crystals.
6. Slowly add solid KCI to 0.6 M (45 g/l). Stir at 4 °C for 30 min.
7. Spin in JLA10 rotor(s) at 10K rpm for 1 hr.
8. Depolymerization: Quickly rinse surface of pellets with buffer A and dispose of wash. Soften the pellets by pre-incubation on ice with small amount of buffer A in each tube (use less than half of final resuspension volume total in all tubes). Resuspend by hand first with cell scraper and combine pellets. Wash tubes with extra buffer using a 25 ml pipette and motorized pipettor, aggressively removing actin from sides of tubes.
Homogenize in large dounce in cold buffer A on ice. Use 3 ml per gram of powder originally extracted.
9. Dialyze against buffer A with 4 changes over 48 hour period.
10. Collect dialyzed actin and spin in the 45Ti rotor at 40K rpm for 1 .5 hr (4 °C).
1 1 . Collect supernatant (G-Actin). Save a sample for gel analysis and determination of protein concentration. 12. To polymerize G-actin for storage, add KCI to 50 mM (from 3 M stock), MgCI2 to 1 mM, and NaN3 to 0.02% (from 10% stock). Store at 4 °C. Do not freeze.
Buffer A: 2 mM tris/HCI, 0.2 mM CaCI2, 0.5 mM (36 μΙ/L) 2-mercaptoethanol,
0.2 mM Na2 ATP (added fresh), and 0.005% Na-azide; pH 8.0.
Purification of Skeletal Muscle Myosin
(See Margossian, S.S. and Lowey, S. (1982) Methods Enzymol. 85, 55-123; and Goldmann, W.H. and Geeves, M.A. (1991 ) Anal. Biochem. 192, 55-58) Solution A: 0.3 M KCI, 0.15 M potassium phosphate, 0.02 M EDTA, 0.005 M MgCI2, 0.001 M ATP, pH 6.5.
Solution B: 1 M KCI, 0.025 M EDTA, 0.06 M potassium phosphate, pH 6.5.
Solution C: 0.6 M KCI, 0.025 M potassium phosphate, pH 6.5.
Solution D: 0.6 M KCI, 0.05 M potassium phosphate, pH 6.5.
Solution E: 0.15 M potassium phosphate, 0.01 M EDTA, pH 7.5.
Solution F: 0.04 M KCI, 0.01 M potassium phosphate, 0.001 M DTT, pH 6.5.
Solution G: 3 M KCI, 0.01 M potassium phosphate, pH 6.5.
All procedures are carried out at 4 °C.
1 . Obtain approx. 1000 g skeletal muscle, such as rabbit skeletal muscle.
2. Grind twice; extract with 2 L solution A for 15 min while stirring; add 4 L cold H2O, filter through gauze; dilute with cold H2O to ionic strength of 0.04, (about 10-fold); let settle for 3 h; collect precipitate at 7,000 rpm in GSA rotor for 15 min.
3. Disperse pellet in 220 ml solution B; dialyze overnight against 6 L solution C; slowly add -400 ml equal volume cold distilled H2O; stir for 30 min; centrifuge at 10,000 rpm for 10 min in GSA rotor.
4. Centrifuge supernatant at 19,000 rpm for 1 h.
5. Dilute supernatant to ionic strength of 0.04 (~8-fold); let myosin settle overnight; collect about 5-6 L fluffy myosin precipitate by centrifuging at 10,000 rpm for 10 min in GSA rotor.
6. Resuspend pellet in minimal volume of solution G; dialyze overnight against 2 L solution D; centrifuge at 19,000 rpm for 2 h, in cellulose nitrate tubes; puncture tubes and separate myosin from fat and insoluble pellet.
7. Dilute supernatant to 5-10 mg/ml and dialyze against solution E extensively, load onto DEAE-sephadex column. 8. Pre-equilibrate with solution E; apply 500-600 g myosin at 30 ml/h; wash with 350 ml solution E; elute with linear gradient of 0-0.5 M KCI in solution E (2 x 1 liter); collect 10 ml fractions; pool myosin fractions (>0.1 M KCI); concentrate by overnight dialysis against solution F; centrifuge at 25,000 rpm for 30 min; store as above.
9. The myosin is then cut with chymotrypsin or papain in the presence of EDTA to generate the S1 fragment which is soluble at the low salt conditions optimal for ATPase activity (Margossian, supra).
Preparation and Assay
Myosin is prepared by precipitation from salt extracts of rabbit psoas muscle, and a soluble S1 fraction is prepared by digestion with chymotrypsin (Margossian and Lowey, 1982).
Actin is purified by first preparing an ether powder of cardiac muscle (Zot HG and Potter J D. (1981 ) Preparative Biochemistry 1 1 :381 -395) as described above. Subsequently, actin is cycled between the filamentous and soluble state through rounds of centrifugation and dialysis (Spudich J A and Watt S. (1971 ) J. Biol. Chem. 246:4866-4871 ).
Tropomyosin is extracted from the ether powder and separated from the other proteins based on pH dependent precipitations followed by successive ammonium sulfate cuts at 53% and 65% (Smillie LB. (1981 ) Methods Enzymol 85 Pt B:234-41 ). The troponins are isolated as an intact complex of TnC, TnT, and Tnl. Ether powder is extracted in a high salt buffer. Successive ammonium sulfate cuts of 30% and 45% are done; the precipitate is solubilized by dialysis into a low salt buffer and then further purified on a DEAE Toyopearl column with a 25-350 mM KCI gradient. There is no measurable ATPase in any of the components except for myosin which naturally had a very low basal ATPase in the absence of actin.
Prior to screening, the actin, tropomyosin, and troponin complex are mixed together in the desired ratio (e.g., 7:1 :1 ) to achieve maximal calcium regulation of the actin filament. The screen is conducted at a concentration that gives 25% activation. This calcium concentration is in the physiological range during muscle contraction.
To measure the generation of ADP during the reaction, a pyruvate kinase/lactate dehydrogenase/NADH coupled enzyme system (PK/LDH) is added to the actin. The myosin is kept separately, and added to the regulated thin filaments to initiate the reaction. Oxidation of NADH is monitored in real time, so that kinetic curves are obtained. Compounds are dissolved in DMSO and spotted onto the bottoms of 384 well plates at 10 to 40 g/ml final concentration.
Using procedures similar to those described herein, utilizing reagents and intermediates commercially available (e.g., Sigma-Aldrich, St. Louis, MO) or readily synthesized by one of skill in the art, the compounds in Table 2 were synthesized, characterized and tested. AC1 .4 values were determined according to the procedure described in Example 39, and the reported median AC1 .4 values are as follows: A = < 1 uM; B = 1 -10 uM; C = 10-20 uM; D = >20 uM.
Table 2 m/z Mean
Compound Structure
(M+H) AC1.4
3- (6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)benzamide
4- (6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)benzamide
5- (6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)pyridine-3-carbonitrile
Figure imgf000137_0001
381.1 B
366.1 B
312.1 B
281.6 B
286.1 B
351.0 B
351.0 B
Figure imgf000138_0001
353.1
353.1 B
353.1 B
333.2 C
337.1 D
349.1 D
Figure imgf000139_0001
276.1 D
304.2 C
369.0 D
387.0 C
387.0 C
355.1 D
Figure imgf000140_0001
355.1
355.1
320.1
Figure imgf000141_0001
yl}benzamide
320.1 D
Figure imgf000141_0002
yl}benzamide
320.1
Figure imgf000141_0003
yl}benzamide
319.1
Figure imgf000141_0004
yl}benzamide 319.1 D
Figure imgf000142_0001
yl}benzamide
333.1 B
337.1 C
319.1 D
299.2
Figure imgf000142_0002
yl}benzamide
3-{6-[(2-pyrazin-2- ylethyl)amino]pyrid 321.1 D yl}benzamide
3-(6-{[2-(2-chlorophenyl)-2- methylpropyl]amino}pyridazin-3- 381.1 A yl)benzamide
Figure imgf000142_0003
Figure imgf000143_0001
methylpropyl]amine
Figure imgf000144_0001
carboxamide 5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)-3-hydrobenzimidazol-2-one
3-(6-{[2-(3-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)benzamide
(6-(1 H-1 ,2,3,4-tetraazol-5- yl)pyridazin-3-yl)[2-(4- fluorophenyl)-2- methylpropyl]amine
5-(6-{[2-(2-chlorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)pyridine-3-carboxamide
5-(6-{[2-(2-chlorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)pyridine-3-carbonitrile
[(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)methyl](methylsulfonyl)amine
Figure imgf000145_0001
N-[(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)methyl]methoxycarboxanriide
[6-(3-amino(1 H-indazol-5- yl))pyridazin-3-yl][2-(4- fluorophenyl)-2- methylpropyl]amine
[6-(3-amino(1 H-indazol-7- yl))pyridazin-3-yl][2-(4- fluorophenyl)-2- methylpropyl]amine
[6-(3-aminobenzo[3,4-d]isoxazol- 5-yl)pyridazin-3-yl][2-(4- fluorophenyl)-2- methylpropyl]amine
[6-(3-am inobenzo[d]isoxazol-7- yl)pyridazin-3-yl][2-(4- fluorophenyl)-2- methylpropyl]amine
[2-(2-chlorophenyl)-2- methylpropyl](6-(3- pyridyl)pyridazin-3-yl)amine
Figure imgf000146_0001
340.1 B
379.1 A
Figure imgf000147_0001
3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}-5- methylpyridazin-3- yl)benzenecarbonitrile
3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}-5- methylpyridazin-3-yl)benzamide
3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}-4- methylpyridazin-3- yl)benzenecarbonitrile
3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}-4- methylpyridazin-3-yl)benzamide
[3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)phenyl]-N-(2- hydroxyethyl)carboxamide
Figure imgf000147_0002
N-(2 , 3-d ihyd roxypropyl)[3-(6-{[2- (4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)phenyl]carboxamide
3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)phenyl piperidyl ketone
3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)phenyl morpholin-4-yl ketone
N-(2-am inoethyl)[3-(6-{[2-(4- fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)phenyl]carboxamide
[3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)phenyl]-N-(2-{[3-(6-{[2-(4- fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)phenyl]carbonylamino}ethyl)car boxamide
Figure imgf000148_0001
Figure imgf000149_0001
y ro enz m azo - -one
[2-(4-fluorophenyl)-2- methylpropyl][6-(1-methyl(1 H- indazol-6-yl))pyridazin-3-yl]amine
3- (6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)phenyl piperazinyl ketone
1 -[(6-{[2-(4-f luorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)carbonyl]pyrrolidine-2- carboxamide
Figure imgf000149_0002
ethyl 1-[(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)carbonylamino]cyclopropanecar boxylate
Figure imgf000150_0001
Figure imgf000150_0002
Figure imgf000151_0001
late
1 -[(6-{[2-(4-f luorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)carbonyl]azetidine-2- carboxamide
1 -[(6-{[2-(4-f luorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)carbonyl]piperidine-2- carboxamide
4-[(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)carbonyl]piperazin-2-one
Figure imgf000151_0002
5-(6-{[2-(2-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)-3-hydrobenzimidazol-2-one
[6-(3-amino(1 H-indazol-6- yl))pyridazin-3-yl][2-(4- fluorophenyl)-2- methylpropyl]amine
[6-(3-am inobenzo[d]isoxazol-6- yl)pyridazin-3-yl][2-(4- fluorophenyl)-2- methylpropyl]amine
3-fluoro-5-(6-{[2-(4-fluorophenyl)-
2-methylpropyl]amino}pyridazin-3- yl)benzamide
N-(1-carbamoyl-3-methylbutyl)(6- {[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)carboxamide
N-((1 S)-1-carbamoyl-2- hydroxyethyl)(6-{[2-(4- fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)carboxamide
Figure imgf000152_0001
Figure imgf000153_0001
carboxamide
(2S, 1 R)-2-[(6-{[2-(4-fluorophenyl)- 2-methylpropyl]amino}pyridazin-3- yl)carbonylamino]cyclopentanecar boxamide
Figure imgf000153_0002
Figure imgf000154_0001
in-3-yl)benzamide
6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3-yl 358.0 piperazinyl ketone
Figure imgf000154_0002
Figure imgf000155_0001
piperidyl))carboxamide
4-[(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)carbonylamino]piperidinecarbox amide
Figure imgf000155_0002
Figure imgf000156_0001
yl)phenyl]carboxamide
(6-benzimidazol-5-ylpyridazin-3- yl)[2-(4-fluorophenyl)-2- 362.2 A methylpropyl]amine
Figure imgf000156_0002
Figure imgf000157_0001
[2-(4-fluorophenyl)-2- methylpropyl][6-(2- methylbenzoxazol-6-yl)pyridazin- 3-yl]amine
1 -[(6-{[2-(4-f luorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)carbonyl]piperidine-4- carboxamide
N-((1 S)-1-carbamoyl-2- phenylethyl)(6-{[2-(4- fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)carboxamide
N-((1 R)-1-carbamoyl-2- phenylethyl)(6-{[2-(4- fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)carboxamide
N-(carbamoylmethyl)(6-{[2-(4- fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)carboxamide
N-(1 ,3-dicarbamoylpropyl)(6-{[2- (4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)carboxamide
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
[2-(4-fluorophenyl)-2- methylpropyl](6-(4-1 ,2,5,6- tetrahydropyridyl)pyridazin-3- yl)amine
[2-(4-fluorophenyl)-2- methylpropyl](6-pyrazol-3- ylpyridazin-3-yl)amine
1- acetyl-4-(6-{[2-(4-fluorophenyl)-
2- methylpropyl]amino}pyridazin-3- yl)-1 ,2,5,6-tetrahydropyridine
Figure imgf000160_0002
Figure imgf000160_0003
4-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)-1-(methylsulfonyl)-1 ,2,5,6- tetrahydropyridine
Figure imgf000160_0004
Figure imgf000161_0001
b]pyridin-5-ylpyridazin-3-yl)amine
Figure imgf000162_0001
mine
Figure imgf000162_0002
Figure imgf000163_0001
mine
Figure imgf000164_0001
5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)-1 H-indazole-3-carboxamide
[4-(2-{[6-(3-am ino( 1 H-indazol-5- yl))pyridazin-3-yl]amino}-tert- butyl)phenyl]methan-1-ol
{[4-(2-{[6-(3-am ino( 1 H-indazol-5- yl))pyridazin-3-yl]amino}-tert- butyl)phenyl]methyl}dimethylanriin
[2-(4-fluorophenyl)-2- methylpropyl][6-(3-vinyl( 1 H- indazol-5-yl))pyridazin-3-yl]am
[6-(3-ethyl(1 H-indazol-5- yl))pyridazin-3-yl][2-(4- fluorophenyl)-2- methylpropyl]amine
3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin- yl)-1 ,2,4-oxadiazole-5- carboxamide
Figure imgf000165_0001
[6-(3-amino(1 H-indazol-5- yl))pyridazin-3-yl][2-(3-fluoro(2- pyridyl))-2-methylpropyl]amine
[6-(3-amino(1 H-indazol-6- yl))pyridazin-3-yl][2-(3-fluoro(2- pyridyl))-2-methylpropyl]amine
[6-(3-amino(1 H-indazol-5- yl))pyridazin-3-yl][2-(5-fluoro(2- pyridyl))-2-methylpropyl]amine
[6-(3-amino(1 H-indazol-6- yl))pyridazin-3-yl][2-(5-fluoro(2- pyridyl))-2-methylpropyl]amine
1 -[5-(6-{[2-(4-f luorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)-1 H-indazol-3-yl]ethane-1 ,2-diol
2-amino-6-(6-{[2-(4-fluorophenyl)- 2-methylpropyl]amino}pyridazin-3- yl)-3-hydropyrimidin-4-one
Figure imgf000166_0001
N-[6-(2-amino-6- oxohydropyrimidin-4-yl)pyridazin- 3-yl](tert-butoxy)-N-[2-(4- fluorophenyl)-2- methylpropyl]carboxamide
6-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)-3-hydroquinazolin-4-one
[6-(3-amino(1 H-indazol-5- yl))pyridazin-3-yl](2-methyl-2-(1 ,3- oxazol-2-yl)propyl)amine
ethyl 2-fluoro-5-(6-{[2-(4- fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)benzoate
2-amino-6-(6-{[2-(4-fluorophenyl)- 2-methylpropyl]amino}pyridazin-3- yl)-3-hydroquinazolin-4-one
Figure imgf000167_0001
4-(2-{[6-(3-am ino( 1 H-indazol-5- yl))pyridazin-3-yl]amino}-tert- butyl)benzenecarbonitrile
4- (2-{[6-(3-amino(1 H-indazol-5- yl))pyridazin-3-yl]amino}-tert- butyl)benzamide
[6-(3-amino(1 H-indazol-5- yl))pyridazin-3-yl]{2-[4- (aminomethyl)phenyl]-2- methylpropyl}amine
5- (6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)-1 H-indazole-3-carboxamidine
2-[4-(2-{[6-(3-am ino( 1 H-indazol-5- yl))pyridazin-3-yl]amino}-tert- butyl)phenyl]propan-2-ol
Figure imgf000168_0001
[3-(2-{[6-(3-am ino( 1 H-indazol-5- yl))pyridazin-3-yl]amino}-tert- butyl)phenyl]methan-1-ol
2- [5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)-1 H-indazol-3-yl]propan-2-ol
3- (6-{[2-(3,5-difluoro(2-pyridyl))-2- methylpropyl]amino}pyridazin-3- yl)benzamide
[5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)-1 H-indazol-3-yl]methan-1-ol
{[3-(2-{[6-(3-am ino( 1 H-indazol-5- yl))pyridazin-3-yl]amino}-tert- butyl)phenyl]methyl}dimethyl amine
3-(2-{[6-(3-am ino( 1 H-indazol-5- yl))pyridazin-3-yl]amino}-tert- butyl)benzenecarbonitrile
Figure imgf000169_0001
3-(2-{[6-(3-amino(1 H-indazol-5- yl))pyridazin-3-yl]amino}-tert- butyl)benzamide
2- [3-(2-{[6-(3-am ino( 1 H-indazol-5- yl))pyridazin-3-yl]amino}-tert- butyl)phenyl]propan-2-ol
[6-(3-amino(1 H-indazol-5- yl))pyridazin-3-yl][2-(3,5- difluoro(2-pyridyl))-2- methylpropyl]amine
[6-(3-amino(1 H-indazol-5- yl))pyridazin-3-yl]{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
3- [6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]benzamide
N-[5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)-1 H-indazol-3-yl]acetamide
Figure imgf000170_0001
[6-(3-aminopyrazolo[5,4-b]pyridin-
5-yl)pyridazin-3-yl][2-(4- fluorophenyl)-2- methylpropyl]amine
[3-(2-{[6-(3-am ino( 1 H-indazol-5- yl))pyridazin-3-yl]amino}-tert- butyl)phenyl]-N- methylcarboxamide
[3-(2-{[6-(3-am ino( 1 H-indazol-5- yl))pyridazin-3-yl]amino}-tert- butyl)phenyl]-N,N- dimethylcarboxamide
[5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)(1 H-indazol-3- yl )]( m ethyls u If onyl )am i ne
Figure imgf000171_0001
Figure imgf000171_0002
Figure imgf000172_0001
y ropyr m n- -one
5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)-1 H-indazole-7-carboxamide
[6-(3-amino(1 H-indazol-5- yl))pyridazin-3-yl][2-(3- methoxyphenyl)-2- methylpropyl]amine
[6-(3-amino(1 H-indazol-5- yl))pyridazin-3-yl][2-methyl-2-(4- methylphenyl)propyl]amine
2- [3-(2-{[6-(3-am ino( 1 H-indazol-5- yl))pyridazin-3-yl]amino}-tert- butyl)phenyl]ethan-1 -ol
[6-(3-amino(1 H-indazol-5- yl))pyridazin-3-yl]{[(5-fluoro(2- pyridyl))cyclobutyl]methyl}amine
3- [6-({[(5-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]benzamide
Figure imgf000172_0002
(tert-butoxy)-N-[6-(2 , 3-d ioxo( 1 ,4- dihydroquinoxalin-6-yl))pyridazin- 3-yl]-N-[2-(4-fluorophenyl)-2- methylpropyl]carboxamide
{2-[3-(2-{[6-(3-am ino( 1 H-indazol-
5- yl))pyridazin-3-yl]amino}-tert- butyl)phenyl]ethyl}dimethylamine
3-(2-{[6-(3-am ino( 1 H-indazol-5- yl))pyridazin-3-yl]amino}-tert- butyl)phenol
6- (6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)-1 ,4-dihydroquinoxaline-2,3- dione
[6-(3-amino(1 H-indazol-5- yl))pyridazin-3-yl]{2-[2- (methoxymethyl)phenyl]-2- methylpropyl}amine
3-(6-{(tert-butoxy)-N-[2-(3- fluoro(2-pyridyl))-2- methylpropyl]carbonylamino}pyrid azin-3-yl)benzamide
Figure imgf000173_0001
(tert-butoxy)-N-[2-(3-fluoro(2- pyridyl))-2-methylpropyl]-N-[6-(2- hyd roxybenzim idazol-5- yl)pyridazin-3-yl]carboxamide
5-(6-{[2-(3-fluoro(2-pyridyl))-2- methylpropyl]amino}pyridazin-3- yl)benzim idazol-2-ol
(6-(1 H-indazol-5-yl)pyridazin-3- yl)[2-(3-fluoro(2-pyridyl))-2- methylpropyl]amine
N-[6-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)benzimidazol-2-yl]acetamide
6-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)-1 ,3-dihydroquinazoline-2,4- dione
4-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]benzamide
4-fluoro-3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzamide
Figure imgf000174_0001
(6-(1 H-indazol-5-yl)pyridazin-3- yl){[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
2-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)pyridine-4-carboxamide
6-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)pyridine-2-carboxamide
3-(6-{(tert-butoxy)-N-[2-(4- fluorophenyl)-2- methylpropyl]carbonylamino}pyrid azin-3-yl)benzamide
3-(6-{(tert-butoxy)-N-[2-(4- fluorophenyl)-2- methylpropyl]carbonylamino}pyrid azin-3-yl)-4-fluorobenzamide
Figure imgf000175_0001
Figure imgf000176_0001
3-fluoro-4-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzamide
2-fluoro-4-(6-{[2-(4-fluorophenyl)- 2-methylpropyl]amino}pyridazin-3- yl)benzoic acid methyl 3-amino-5-(6-{[2-(4- fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)-1 H-indazolecarboxylate methyl 5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)-3-(methoxycarbonylamino)-1 H- indazolecarboxylate
N-[5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)(1 H-indazol-3- yl)] m ethoxycarboxam ide
[3-amino-5-(6-{[2-(4-fluorophenyl)-
2- methylpropyl]amino}pyridazin-3- yl)(1 H-indazolyl)]-N,N- dimethylcarboxamide
6-({[(6-( 1 H-indazol-5-yl)pyridazin-
3- yl)amino]methyl}cyclobutyl) pyridin-2-ol
Figure imgf000177_0001
6-({[(6-( 1 H-indazol-6-yl)pyridazin-
3- yl)amino]methyl}cyclobutyl) 373.1 pyridin-2-ol
4- fluoro-3-[6-({[(6-hydroxy(2- pyridyl))cyclobutyl]methyl}amino)p 394.1 yridazin-3-yl]benzamide
2- ({[(6-( 1 H-indazol-5-yl)pyridazin-
3- yl)amino]methyl}cyclobutyl) 373.1 pyridin-4-ol
4-fluoro-3-[6-({[(4-methoxy(2- pyridyl))cyclobutyl]methyl}amino)p 408.2 B yridazin-3-yl]benzamide
(6-(1 H-indazol-5-yl)pyridazin-3- yl){[(4-methoxy(2- 387.2 A pyridyl))cyclobutyl]methyl}amine
(6-(1 H-indazol-6-yl)pyridazin-3- yl){[(4-methoxy(2- 387.2 A pyridyl))cyclobutyl]methyl}amine
2- ({[(6-( 1 H-indazol-6-yl)pyridazin-
3- yl)amino]methyl}cyclobutyl) 373.2 pyridin-4-ol
4- fluoro-3-[6-({[(4-hydroxy(2- pyridyl))cyclobutyl]methyl}amino)p 394.2 yridazin-3-yl]benzamide
Figure imgf000178_0001
Figure imgf000179_0001
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(1- methylpyrazol-4-yl)pyridazin-3- yl]amine
6- (6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)-3,3-dimethylindolin-2-one
2-amino-7-(6-{[2-(4-fluorophenyl)-
2- methylpropyl]amino}pyridazin-3- yl)-3-hydroquinazolin-4-one
3- [6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]benzenesu Ifonam ide
Figure imgf000179_0002
{4-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3- yl]phenyl}(methylsulfonyl)amine
{3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3- yl]phenyl}(methylsulfonyl)amine
3- {6-[(2-m ethyl-2-pyrim id in-2- ylpropyl)amino]pyridazin-3- yl}benzamide
4- fluoro-3-[6-({[(3-methoxy(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzamide
(6-(1 H-indazol-5-yl)pyridazin-3- yl){[(3-methoxy(2- pyridyl))cyclobutyl]methyl}amine
(6-(1 H-indazol-6-yl)pyridazin-3- yl){[(3-methoxy(2- pyridyl))cyclobutyl]methyl}amine
4-fluoro-3-[6-({[(5-methoxy(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzamide
Figure imgf000180_0001
387.2 B
387.2 B
373.1
373.2
377.3 A
392.3 B
382.2 B
Figure imgf000181_0001
pyridine-3-carbonitrile B
B
A
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
methyl 3-({[6-(3- carbamoylphenyl)pyridazin-3- yl]amino}methyl)-3-(3-fluoro(2- pyridyl))azetidinecarboxylate
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}{6-[3- (methylamino)(1 H-indazol-5- yl)]pyridazin-3-yl}amine
2-fluoro-5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzoic acid
{2-fluoro-5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}-N- methylcarboxamide
N-{5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 H-indazol-3- yl}acetamide
2-amino-N-{5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 H-indazol-3- yl)}acetamide
Figure imgf000185_0001
{5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 H-indazol-3- yl)}(methylsulfonyl)amine
3-amino-5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-1 H- indazolecarboxamide
[6-(3-aminophenyl)pyridazin-3- yl]{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
[6-(4-aminophenyl)pyridazin-3- yl]{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
(6-{3-[(2-aminoethyl)amino](1 H- indazol-5-yl)}pyridazin-3-yl){[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amine amino{3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3- yl]phenyl}carboxamidine
amino{4-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3- yl]phenyl}carboxamidine
Figure imgf000186_0001
3-(6-{[(pyrazin-2- ylcyclobutyl)methyl]amino}pyridazi n-3-yl)benzamide
(6-(1 H-indazol-6-yl)pyridazin-3- yl)[(pyrazin-2- ylcyclobutyl)methyl]amine
(6-(1 H-indazol-5-yl)pyridazin-3- yl)[(pyrazin-2- ylcyclobutyl)methyl]amine amino-N-{3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}amide
5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]benzene-1 ,3- dicarboxylic acid
5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]benzene-1 ,3- dicarboxamide
3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3- yl]benzenecarboxamidine
Figure imgf000187_0001
3-[6-({[1 -acetyl-3-(3-f luoro(2- pyridyl))azetidin-3- yl]methyl}amino)pyridazin-3- yl]benzamide
1-acetyl-3-(3-fluoro(2-pyridyl))-3- {[(6-(1 H-indazol-5-yl)pyridazin-3- yl)amino]methyl}azetidine
(6-(1 H-indazol-5-yl)pyridazin-3- yl){[3-(3-fluoro(2-pyridyl))azetidin-
3-yl]methyl}amine
3-[6-({[3-(3-fluoro-2- pyridyl)azetidin-3- yl]methyl}amino)pyridazin-3- yl]benzamide
3-(3-fluoro(2-pyridyl))-3-{[(6-(1 H- indazol-5-yl)pyridazin-3- yl)amino]methyl}-1-
(m ethylsu lfonyl)azetid i ne
3-[6-({[3-(3-fluoro(2-pyridyl))-1- (m ethylsu lfonyl)azetid i n-3- yl]methyl}amino)pyridazin-3- yl]benzamide
(6-(1 H-indazol-5-yl)pyridazin-3- yl){[3-(3-fluoro(2-pyridyl))azetidin-
3-yl]methyl}(methylsulfonyl)amine
Figure imgf000188_0001
amino{5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 H-indazol-3- yl)}carboxamidine
3-[6-({[3-(4-fluorophenyl)oxetan-3- yl]methyl}amino)pyridazin-3- yl]benzamide
[2-(4-fluorophenyl)-2- methylpropyl](6-{3- [(methylethyl)amino](1 H-indazol- 5-yl)}pyridazin-3-yl)amine
[6-(2-aminopyrimidin-5- yl)pyridazin-3-yl][2-(4- fluorophenyl)-2- methylpropyl]amine
[2-(4-fluorophenyl)-2- methylpropyl]{6-[3-
(methylamino)(1 H-indazol-5- yl)]pyridazin-3-yl}amine
[2-(4-fluorophenyl)-2- methylpropyl][6-(2- methoxypyrimidin-5-yl)pyridazin-3- yl]amine
[2-(4-fluorophenyl)-2- methylpropyl][6-(2-methoxy(3- pyridyl))pyridazin-3-yl]amine
Figure imgf000189_0001
{6-[3-(ethylamino)(1 H-indazol-5- yl)]pyridazin-3-yl}[2-(4- fluorophenyl)-2- methylpropyl]amine
[2-(4-fluorophenyl)-2- methylpropyl](6-phenylpyridazin-
3-yl)amine
5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)hydropyridin-2-one
[6-(2-amino(4-pyridyl))pyridazin-3- yl][2-(4-fluorophenyl)-2- methylpropyl]amine
[6-(4-aminophenyl)pyridazin-3- yl][2-(4-fluorophenyl)-2- methylpropyl]amine
[6-(3-aminophenyl)pyridazin-3- yl][2-(4-fluorophenyl)-2- methylpropyl]amine
3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)pyridin-2-ol
Figure imgf000190_0001
5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)-3-hydropyrimidin-2-one
5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)-1 ,3,4-oxadiazolin-2-one
[6-(6-amino(3-pyridyl))pyridazin-3- yl][2-(4-fluorophenyl)-2- methylpropyl]amine
[2-(4-fluorophenyl)-2- methylpropyl](6-vinylpyridazin-3- yl)amine
[6-(5-aminopyrazol-3-yl)pyridazin-
3-yl][2-(4-fluorophenyl)-2- methylpropyl]amine
[2-(4-fluorophenyl)-2- methylpropyl][6-(6-methoxy(2- pyridyl))pyridazin-3-yl]amine
N-[4-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)imidazol-2-yl]acetamide
Figure imgf000191_0001
5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)pyridine-2-carbonitrile
[6-(2-aminoimidazol-4- yl)pyridazin-3-yl][2-(4- fluorophenyl)-2- methylpropyl]amine
5- (6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)pyridine-2-carboxamide
6- (6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)pyridin-2-ol
{6-[6-(aminomethyl)(3- pyridyl)]pyridazin-3-yl}[2-(4- fluorophenyl)-2- methylpropyl]amine
[2-(4-fluorophenyl)-2- methylpropyl][6-(2- fluorophenyl)pyridazin-3-yl]amine
Figure imgf000192_0001
[2-(4-fluorophenyl)-2- methylpropyl][6-(3- fluorophenyl)pyridazin-3-yl]am
[2-(4-fluorophenyl)-2- methylpropyl][6-(4- fluorophenyl)pyridazin-3-yl]am
[6-(2-chlorophenyl)pyridazin-3 yl][2-(4-fluorophenyl)-2- methylpropyl]amine
[6-(3-chlorophenyl)pyridazin-3 yl][2-(4-fluorophenyl)-2- methylpropyl]amine
[6-(4-chlorophenyl)pyridazin-3 yl][2-(4-fluorophenyl)-2- methylpropyl]amine
4-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin- yl)benzenecarbonitrile
Figure imgf000193_0001
[2-(4-fluorophenyl)-2- methylpropyl](6-(3- 323.1 B pyridyl)pyridazin-3-yl)amine
[6-(6-amino(2-pyridyl))pyridazin-3- yl][2-(4-fluorophenyl)-2- 338.2 B methylpropyl]amine
N-{[5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- 394.2 yl)-2-pyridyl]methyl}acetamide
Figure imgf000194_0001
N-{[5-(6-{[2-(4-fluorophenyl)-2-
A
Figure imgf000194_0002
[2-(4-fluorophenyl)-2- methylpropyl](6-(2- pyridyl)pyridazin-3-yl)amine
N-{4-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]imidazol-2- yl}acetamide
[6-(2-aminoimidazol-4- yl)pyridazin-3-yl]{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6-{3-
[(methylethyl)amino](1 H-indazol-
5-yl)}pyridazin-3-yl)amine
{6-[3-(ethylamino)(1 H-indazol-5- yl)]pyridazin-3-yl}[(2- pyridylcyclobutyl)methyl]amine
[6-((1 E)prop-1-enyl)pyridazin-3- yl][2-(4-fluorophenyl)-2- methylpropyl]amine
[2-(4-fluorophenyl)-2- methylpropyl][6-(2-methylprop-1- enyl)pyridazin-3-yl]am ine
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
methylpropyl]amine
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}{6-[2-
(trifluoromethoxy)phenyl]pyridazin
-3-yl}amine
{2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]phenyl}methan-1-ol
[2-(4-fluorophenyl)-2- methylpropyl][6-(5-methoxy(2- pyridyl))pyridazin-3-yl]amine
6-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)pyridin-3-ol
[6-(5-amino(2-pyridyl))pyridazin-3- yl]{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
Figure imgf000197_0002
[2-(4-fluorophenyl)-2- methylpropyl](6-{3-[(2,2,2- trifluoroethyl)amino](1 H-indazol-5- yl)}pyridazin-3-yl)amine
[6-(6-amino(3-pyridyl))pyridazin-3- yl]{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine [6-(4-amino-3- fluorophenyl)pyridazin-3-yl]{[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amine
(6-benzotriazol-6-ylpyridazin-3- yl){[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
4-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]indolin-2-one
(6-benzimidazol-5-ylpyridazin-3- yl){[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
N-{3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]phenyl}acetamide
Figure imgf000198_0001
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(4- morpholin-4-ylphenyl)pyridazin-3- yl]amine
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(2- methylpyrimidin-5-yl)pyridazin-3- yl]amine
[5-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridazin-3- yl)(1 H-indazol-3-yl)]dimethylamine
[2-(4-fluorophenyl)-2- methylpropyl][6-(3-{[2- (phenylmethoxy)ethyl]amino}(1 H- indazol-5-yl))pyridazin-3-yl]amine
Figure imgf000199_0001
Figure imgf000199_0002
pyrazin-2-ylpyridazin-3-yl)amine ethyl 6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazi ne-3-carboxylate
2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]propan-2-ol
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6- phenylpyridazin-3-yl)amine
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6- vinylpyridazin-3-yl)amine
(6-ethylpyridazin-3-yl){[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
N-{4-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]phenyl}acetamide
[6-(2-aminopyrimidin-5- yl)pyridazin-3-yl]{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
Figure imgf000200_0001
N-{5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]pyrimidin-2- yl}acetamide
N-{5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]pyrimidin-2- yl}methoxycarboxamide
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(5- methoxy(2-pyridyl))pyridazin-3- yl]amine
6-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]pyridin-3-ol
{5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]pyrimidin-2- yl}(methylsulfonyl)amine
[6-(2,3-difluorophenyl)pyridazin-3- yl]{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(3- fluoro(2-pyridyl))pyridazin-3- yl]amine
Figure imgf000201_0001
Figure imgf000202_0001
one
N-{3-[6-({[(3-fluoro(2-
Figure imgf000202_0002
tert-butyl 4-{5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]pyrimidin-2- yl}piperazinecarboxylate
2-({5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]pyrimidin-2- yl}amino)acetamide
Figure imgf000202_0003
Figure imgf000203_0001
pyridyl))cyclobutyl]methyl}amine
Figure imgf000203_0002
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(2- piperazinylpyrimidin-5- yl)pyridazin-3-yl]amine
(6-(1 H-indazol-6-yl)pyridazin-3- yl)(2,2-difluoro-2-(2- pyridyl)ethyl)amine
3-{6-[(2,2-difluoro-2-(2- pyridyl )ethyl)am ino] pyridazi n-3- yl}benzamide
[6-(3-chloro(2-pyridyl))pyridazin-3- yl]{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
Figure imgf000203_0003
6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazine-3-carbonitrile
1- [6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]ethan-1-one
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(2- methyl(3-pyridyl))pyridazin-3- yl]amine
3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]pyridine-2-carbonitrile
3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]pyridine-2- carboxamide methyl 3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]pyridine-2-carboxylate
2- {3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-2-pyridyl}propan-2-ol
Figure imgf000204_0001
amino-N-{4-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}amide
2- amino-2-{3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}acetamide
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6- pyridazin-4-ylpyridazin-3-yl)amine
3- [6-({[3,3-difluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzamide
(6-(1 H-indazol-5-yl)pyridazin-3- yl){[3,3-difluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2-(methylethyl)-1 H-
2-hydroindazol-3-one
5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-1-(methylethyl)-1 H-
2-hydroindazol-3-one
Figure imgf000205_0001
B
B
A
Figure imgf000206_0001
dazin-3-yl)benzamide
Figure imgf000206_0002
4-{6-[(1 -methyl- 1- phenylethyl)amino]pyridazin-3- yl}benzamide
(6-(1 H-indazol-5-yl)pyridazin-3- yl)(1-methyl-1-phenylethyl)amine
[6-(6-amino(3-pyridyl))pyridazin-3- yl]( 1 -methyl- 1 -phenylethyl)am ine amino-N-{5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](2-pyridyl)}amide
(1-methyl-1-phenylethyl)(6- phenylpyridazin-3-yl)amine
1 -am ino-1 -{4-[6-({[(3-f luoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}-2- methylpropan-2-ol amino-N-{5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]pyrimidin-2-yl}amide
(6-(1 H-indazol-6-yl)pyridazin-3- yl){[3,3-difluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
Figure imgf000207_0001
[6-(2-amino(3-pyridyl))pyridazin-3- yl]{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
[6-(6-amino-5-fluoro(3- pyridyl))pyridazin-3-yl]{[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amine
6-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]indolin-2-one
[6-(2-aminopyrimidin-5- yl)pyridazin-3-yl][(4- fluorophenyl)cyclobutyl]amine
Figure imgf000208_0001
Figure imgf000208_0002
dazin-3-yl)benzamide 351.1 B
363.2 B
Figure imgf000209_0001
dazin-3-yl)benzamide
Figure imgf000209_0002
3-yl)benzamide
Figure imgf000210_0001
Figure imgf000211_0001
dazin-3-yl)pyridine-2-carbonitrile
364.2 B
Figure imgf000211_0002
dazin-3-yl)pyridine-2-carboxamide
Figure imgf000211_0003
yl phenyl] methylsulonyl amine
351.2 A
419.2 B
379.1 B
Figure imgf000211_0004
idazin-3-yl)benzamide
Figure imgf000212_0001
-3-yl)benzamide [3-(6-{[(6-methoxy(2- pyridyl))cyclobutyl]amino}pyridazin 426.1 B
-3-yl)phenyl](methylsulfonyl)amine
[3-(6-{[(3-fluoro(2- pyridyl))cyclobutyl]amino}pyridazin 414.1 B
-3-yl)phenyl](methylsulfonyl)amine amino-N-[4-(6-{[(3-fluoro(2- pyridyl))cyclobutyl]amino}pyridazin 379.2 B
-3-yl)phenyl]amide
(6-(1 H-indazol-6-yl)pyridazin-3- yl)[(3-fluoro(2- 361.1 B pyridyl))cyclobutyl]amine
(6-benzimidazol-6-ylpyridazin-3- yl)[(3-fluoro(2- 361.2 B pyridyl))cyclobutyl]amine
3-[6-({[6-(difluoromethoxy)-2- pyridyl]cyclobutyl}amino)pyridazin- 412.0 A
3-yl]benzamide
3-[6-({[6-(difluoromethoxy)(2- pyridyl)]cyclobutyl}amino)pyridazin 430.1 A
-3-yl]-4-fluorobenzamide
Figure imgf000213_0001
methylcarboxamide (6-(1 H-indazol-5-yl)pyridazin-3- yl)[(3-fluoro(2- pyridyl))cyclobutyl]amine
[6-(6-fluoro(1 H-indazol-5- yl))pyridazin-3-yl][(3-fluoro(2- pyridyl))cyclobutyl]amine
amino-N-[4-fluoro-3-(6-{[(3- fluoro(2- pyridyl))cyclobutyl]amino}pyridazin -3-yl)phenyl]amide amino[4-fluoro-3-(6-{[(3-fluoro(2- pyridyl))cyclobutyl]amino}pyridazin
-3-yl)phenyl]sulfonamide
Figure imgf000215_0001
Figure imgf000215_0002
3-[6-({1-[6-(difluoromethoxy)(2- pyridyl)]- isopropyl}amino)pyridazin-3-yl]-4- fluorobenzamide
3-[6-({1-[6-(difluoromethoxy)(2- pyridyl)]- isopropyl}am ino)pyridazin-3- yl]benzamide
{3-[6-({1-[6-(difluoromethoxy)(2- pyridyl)]- isopropyl}am ino)pyridazin-3- yl]phenyl}(methylsulfonyl)amine
3-(6-{[(4-cyano(2- pyridyl))cyclobutyl]amino}pyridazin
-3-yl)-4-fluorobenzamide
2- ({[6-(3-carbamoyl-6- fluorophenyl)pyridazin-3- yl]amino}cyclobutyl)pyridine-4- carboxamide
3- (6-{[(5-cyano(2- pyridyl))cyclobutyl]amino}pyridazin -3-yl)-4-fluorobenzamide
3-(6-{[(6-cyano(2- pyridyl))cyclobutyl]amino}pyridazin
-3-yl)-4-fluorobenzamide
Figure imgf000216_0001
6-({[6-(3-carbamoyl-6- fluorophenyl)pyridazin-3- yl]amino}cyclobutyl)pyridine-2- carboxamide
4-fluoro-3-(6-{[(3-hydroxy(2- pyridyl))cyclobutyl]amino}pyridazin
-3-yl)benzamide
4-fluoro-3-(6-{[(3-methoxy(2- pyridyl))cyclobutyl]amino}pyridazin
-3-yl)benzamide
3-[6-({[3-(difluoromethoxy)(2- pyridyl)]cyclobutyl}amino)pyridazin
-3-yl]-4-fluorobenzamide
3-[6-({[3-(difluoromethoxy)-2- pyridyl]cyclobutyl}amino)pyridazin-
3-yl]benzamide
{3-[6-({[3-(difluoromethoxy)(2- pyridyl)]cyclobutyl}amino)pyridazin -3-yl] phenyl}(m ethylsu Ifonyl )am ine
4-fluoro-3-(6-{[(5-methoxy(2- pyridyl))cyclobutyl]amino}pyridazin
-3-yl)benzamide
Figure imgf000217_0001
3-[6-({[5-(difluoromethoxy)(2- pyridyl)]cyclobutyl}amino)pyridazin
-3-yl]-4-fluorobenzamide
4-fluoro-3-(6-{[(5-hydroxy(2- pyridyl))cyclobutyl]amino}pyridazin
-3-yl)benzamide
[(3-fluoro(2-pyridyl))cyclobutyl](6- vinylpyridazin-3-yl)amine
4-fluoro-3-(6-{[(3-fluoro(2- pyridyl))cyclobutyl]amino}pyridazin
-3-yl)benzenecarbonitrile
[(3-fluoro(2-pyridyl))cyclobutyl](6- phenylpyridazin-3-yl)amine
(6-cyclohexylpyridazin-3-yl)[(3- fluoro(2-pyridyl))cyclobutyl]amine
(6-cyclohex-1-enylpyridazin-3- yl)[(3-fluoro(2- pyridyl))cyclobutyl]amine
(6-cyclohex-1-enylpyridazin-3- yl){[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine 4-fluoro-3-{6-
[(methylcyclobutyl)amino]pyridazin -3-yl}benzamide
Figure imgf000218_0001
(6-cyclohexylpyridazin-3-yl){[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amine
ethyl (2E)-3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]prop-2-enoate ethyl (2E)-3-(6-{[(3-fluoro(2- pyridyl))cyclobutyl]amino}pyridazin
-3-yl)prop-2-enoate
diethyl 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]propane-1 , 3-d ate
(1 S,2S)-2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3- yl]cyclopropanecarboxamide
(2S,1 R)-2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3- yl]cyclopropanecarboxamide
Figure imgf000219_0001
amino-N-{4-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]cyclohexyl}amide
amino-N-{4-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]cyclohexyl}amide
4-fluoro-3-(6-{[(3-fluoro(2- pyridyl))cyclopentyl]amino}pyridazi n-3-yl)benzamide
amino-N-{3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]cyclobutyl}amide
amino-N-{3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]cyclobutyl}amide amino-N-{4-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]cyclohex-3- enyl}amide
Figure imgf000220_0001
phenylmethyl 3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py D ridazin-3-yl]azetidinecarboxylate
(6-azetidin-3-ylpyridazin-3-yl){[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amine methyl 3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py
ridazin-3-yl]azetidinecarboxylate
3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py
ridazi n-3-yl]azetid inecarboxam ide
1 -acetyl-3-[6-({[(3-f luoro(2- pyridyl))cyclobutyl]methyl}amino)p
yridazin-3-yl]azetidine ethyl 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py
ridazi n-3-yl] isoxazole-3- carboxylate
Figure imgf000221_0001
Figure imgf000221_0002
acid 5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazi n-3-yl] isoxazole-3- carboxamide
amino-N-{5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 H-indazol-3- yl)}amide
4-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-1-methylimidazole-2- carboxamide
4-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2- methoxybenzamide
4- [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2-hydroxybenzamide
5- [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2- methoxybenzamide
5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2-hydroxybenzamide
Figure imgf000222_0001
Figure imgf000223_0001
3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-1-methylpyrazole-5- carboxamide
5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-1-methylpyrazole-3- carboxamide
2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-oxazole-5- carboxamide
2- [6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazole-4- carboxamide
1- [(6-{[(3-fluoro-2- pyridyl)cyclobutyl]amino}pyridazin-
3- yl)m ethyl] pyrazole-4- carboxamide
5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazi n-3-yl]- 1 ,2 ,4-oxad iazole-3- carboxamide
2- [6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-2-imidazoline-5- carboxamide
Figure imgf000224_0001
methyl 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-2-imidazoline-5- carboxylate
2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-2-imidazoline-5- carboxylic acid
2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-oxazole-4- carboxamide
2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazole-5- carboxamide methyl 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-oxazole-4- carboxylate
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}{6-[6- ({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]pyridazin-3-yl}amine
Figure imgf000225_0001
methyl 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazole-4- carboxylate methyl 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-oxazole-5- carboxylate
2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]imidazole-4- carboxamide methyl 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]imidazole-4- carboxylate
4- [6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazole-2- carboxamide
5- [6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazole-2- carboxamide
Figure imgf000226_0001
3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazi n-3-yl]- 1 ,2 ,4-oxad iazole-5- carboxamide
5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-4H-1 ,2,4-triazole-3- carboxamide methyl 2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-1-methylimidazole-4- carboxylate
2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-1-methylimidazole-4- carboxamide
2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-1-methylimidazole-5- carboxamide
2- (6-{[(3-fluoro-2- pyridyl)cyclobutyl]amino}pyridazin-
3- yl)-1 ,3-thiazole-5-carboxamide
5-(6-{[(3-fluoro(2- pyridyl))cyclobutyl]amino}pyridazin
-3-yl)-2-hydroxybenzamide
Figure imgf000227_0001
5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]thiophene-2- carboxamide
[6-(3-amino(1 H-indazol-5- yl))pyridazin-3-yl][(3-fluoro(2- pyridyl))cyclobutyl]amine
5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3,4-thiadiazole-2- carboxamide
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6-(1 ,3- thiazol-2-yl)pyridazin-3-yl)amine
(6-(2H-1 ,2,3,4-tetraazol-5- yl)pyridazin-3-yl){[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazi n-3-yl]- 1 ,3 ,4-oxad iazole-2- carboxamide
2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-4-methyl-1 ,3- thiazole-5-carboxamide
Figure imgf000228_0001
Figure imgf000229_0001
carboxamide
5-(6-{[(3-fluoro-2- pyridyl)cyclobutyl]amino}pyridazin- 3-yl)thiophene-2-carboxylic acid 2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazi n-3-yl]-1 ,3-thiazole-5- carbonitrile
Figure imgf000229_0002
Figure imgf000229_0003
2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-4-hydroxy-1 ,3- thiazole-5-carboxamide
5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazi n-3-yl]-3-pyrazol ino[3 ,4- d]1 ,3-thiazol-3-one
2-[6-({1-[6-(difluoromethoxy)(2- pyridyl)]- isopropyl}amino)pyridazin-3-yl]- 1 ,3-thiazole-5-carboxamide
{2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazi n-3-yl]-1 ,3-thiazol-5- yl}methan-1-ol
[6-(5-(2H-1 ,2,3,4-tetraazol-5- yl)(1 ,3-thiazol-2-yl))pyridazin-3- yl]{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine 5-{2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazi n-3-yl]-1 ,3-thiazol-5-yl}-1 ,3,4- oxadiazolin-2-one ethyl 3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-5-hydroxypyrazole- 4-carboxylate
Figure imgf000230_0001
3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-3-pyrazolin-5-one
3-{2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazol-5-yl}-1 ,2,4- triazolin-5-one
3-{2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazol-5-yl}-1 ,2,4- oxadiazolin-5-one
ethyl 2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-4-hydroxy-1 ,3- thiazole-5-carboxylate
2-(6-{[2-(3-fluoro(2-pyridyl))-2- methylpropyl]amino}pyridazin-3- yl)-1 ,3-thiazole-5-carboxamide
2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-4-methoxy-1 ,3- thiazole-5-carboxamide
2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-4-methoxy-1 ,3- thiazole-5-carboxylic acid
Figure imgf000231_0001
Figure imgf000232_0001
1-one 2- {2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py
ridazin-3-yl]-1 ,3-thiazol-5- yl}propan-2-ol
Figure imgf000233_0001
1 ,1 , 1 -trifluoro-2-{2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p 454.2 yridazin-3-yl](1 ,3-thiazol-5-
Figure imgf000233_0002
yl)}propan-2-ol
{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
yridazin-3-yl](1 ,3-thiazol-5-yl)}-N- methylcarboxamide
Figure imgf000233_0003
B
B
Figure imgf000233_0004
2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
383.1 yridazin-3-yl]-4-hydroxy-1 ,3- thiazole-5-carbonitrile
Figure imgf000234_0001
A
Figure imgf000234_0002
car oxy c ac
3- {5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py
ridazin-3-yl]-2-thienyl}-1 ,2,4- triazolin-5-one
3-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py
ridazi n-3-yl]- 1 ,2 ,4-triazoli n-5-one amino{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
yridazin-3-yl](1 ,3-thiazol-5- yl)}methane-1 -thione
Figure imgf000234_0003
2,2,2-trifluoro-1-{2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p 456.2 B yridazin-3-yl](1 ,3-thiazol-5-
Figure imgf000234_0004
yl)}ethane-1 ,1-diol {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}{6-[5-
(2,2,2-trifluoroethyl)(1 ,3-thiazol-2- yl)]pyridazin-3-yl}amine
5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]thiophene-2- carbonitrile
2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]thiopheno[2,3-c]3- pyrrolin-6-one
{6-[5-(1-amino-2,2,2- trifluoroethyl)(1 ,3-thiazol-2- yl)]pyridazin-3-yl}{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
[6-(2-aminopyrimidin-4- yl)pyridazin-3-yl]{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
2-{5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazi n-3-yl]- 1 ,2, 3 ,4-tetraazol-2- yl}acetamide
{6-[2-(2-aminoethyl)(1 ,2,3,4- tetraazol-5-yl)]pyridazin-3-yl}{[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amine
Figure imgf000235_0001
Figure imgf000236_0001
N-((2-(6-((1-(3-fluoropyridin-2- yl)cyclobutyl)methylamino)pyridazi n-3-yl)thiazol-5-yl)methyl)-2- methylpropane-2-sulfinamide
Figure imgf000236_0002
{6-[5-(aminoethyl)(1 ,3-thiazol-2- yl)]pyridazin-3-yl}{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
{6-[5-(3-aminooxetan-3-yl)(1 ,3- thiazol-2-yl)]pyridazin-3-yl}{[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amine
2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]pyrimidine-4- carboxamide
{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-yl)}-N- (2-hydroxyethyl)carboxamide ethyl 5-chloro-2-[5-chloro-6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-1 ,3-thiazole-4- carboxylate
N-{4-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]pyrimidin-2- yl}acetamide
Figure imgf000237_0001
{4-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yr id azi n-3-yl] pyr i m id i n-2- yl}(methylsulfonyl)amine
(2E)-3-amino-3-{2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-yl)}-2- azaprop-2-enenitrile
N-({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazol-5- yl}methyl)acetamide
({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)(methylsulfonyl)amine
N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- y I )} m et h y I ) m et hoxyca r boxa m id e
2,2-difluoro-1-{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}ethan-1-ol
N-(carbamoylmethyl)[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]carboxamide
Figure imgf000238_0001
2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-yl) morpholin-4-yl ketone
N-(2-aminoethyl){2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}carboxamide
N-(2 , 3-d ihyd roxypropyl){2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}carboxamide
{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-yl)}-N- pyrrol id in-3-ylcarboxam ide
2-{2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazol-5- yl}acetamide
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(5- pyrazol-4-yl(1 ,3-thiazol-2- yl))pyridazin-3-yl]amine
Figure imgf000239_0001
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(5- pyrazol-3-yl(1 ,3-thiazol-2- yl))pyridazin-3-yl]amine
4-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]pyrimidine-2- carboxamide
6-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]pyrimidine-4- carboxamide
[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-N-pyrazol-5- ylcarboxamide
Figure imgf000240_0001
N-(carbamoylmethyl){2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}carboxamide
4-({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazol-5- yl}carbonyl)piperazine-2-
Figure imgf000240_0002
carboxamide [6-(5-chloro(1 ,3-thiazolino[5,4- b]pyridin-2-yl))pyridazin-3-yl]{[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amine {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6-(1 ,3- thiazolino[5,4-b]pyridin-2- yl)pyridazin-3-yl)amine
[6-(5-amino(1 ,3-thiazolino[5,4- b]pyridin-2-yl))pyridazin-3-yl]{[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amine amino{4-fluoro-3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}sulfonamide
2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-yl) 3- hydroxypyrrolidinyl ketone
4-({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazol-5- yl}carbonyl)-1 ,4-
Figure imgf000241_0001
thiazaperhydroine-1 ,1-dione
N-(1 , 1-dioxothiolan-3-yl){2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-
Figure imgf000241_0002
yl)}carboxamide {2-[6-({[(3-fluoro(2-
491.2 A
Figure imgf000242_0001
(methylsulfonyl)ethyl]carboxamide
2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
yridazin-3-yl](1 ,3-thiazol-5-yl) 3- hydroxypiperidyl ketone
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6- pyrazolo[5,4-d]1 ,3-thiazol-5- ylpyridazin-3-yl)amine
2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
yridazin-3-yl](1 ,3-thiazol-5-yl) 4- hydroxypiperidyl ketone
4-({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py
ridazin-3-yl]-1 ,3-thiazol-5- yl}carbonyl)piperazin-2-one
{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
yridazin-3-yl](1 ,3-thiazol-5-yl)}-N-
(oxolan-2-ylmethyl)carboxamide
Figure imgf000242_0002
1- ({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py
ridazin-3-yl]-1 ,3-thiazol-5- yl}carbonyl)piperidine-3- carboxamide
[6-(3-(2H-1 ,2,3,4-tetraazol-5- yl)phenyl)pyridazin-3-yl][2-(3- fluoro(2-pyridyl))-2- methylpropyl]amine
2- [6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py
ridazin-3-yl]-1 ,3-thiazolino[5,4- b]pyridine-5-carboxamide
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(5- methoxy(1 ,3-thiazolino[5,4- b]pyridin-2-yl))pyridazin-3- yl]amine
2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py
ridazin-3-yl]-1 ,3-thiazolino[5,4- b]pyridin-5-ol
Figure imgf000243_0001
N-((2R)-2,3-dihydroxypropyl){2-[6- ({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p 459.3 B yridazin-3-yl](1 ,3-thiazol-5-
Figure imgf000243_0002
yl)}carboxamide N-((2S)-2 , 3-d ihyd roxypropyl){2-[6- ({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}carboxamide
N-(2-amino-3,3,3- trifluoropropyl){2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}carboxamide
N-(3-amino-2,2-difluoropropyl){2- [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}carboxamide
{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-yl)}-
N , N-d im ethylcarboxam ide
N-(2,2-difluoro-3- hydroxypropyl){2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}carboxamide
{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-yl)}-N-
(2-oxopyrrolidin-3-yl)carboxamide
Figure imgf000244_0001
3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzamide
4-fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzamide
2-amino-N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl )} m ethyl )acetam id e
Figure imgf000245_0001
((2S)pyrrolidin-2-yl)-N-({2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-
Figure imgf000245_0002
yl)}methyl)carboxamide
((2R)pyrrolidin-2-yl)-N-({2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-
Figure imgf000245_0003
yl)}methyl)carboxamide
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6-(3- pyrrolino[3,4-d]1 ,3-thiazol-2- yl)pyridazin-3-yl)amine
2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-5-(methylsulfonyl)-3- pyrrolino[3,4-d]1 ,3-thiazole
Figure imgf000245_0004
N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)-2-hydroxyacetamide
2-[({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazol-5- yl}methyl)amino]acetanriide
Figure imgf000246_0001
((2S)-5-oxopyrrolidin-2-yl)-N-({2-
[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-
Figure imgf000246_0002
yl)}methyl)carboxamide
N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)-2-hydroxy-2-
Figure imgf000246_0003
methylpropanamide
N-((3S)pyrrolidin-3-yl){2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-
Figure imgf000246_0004
yl)}carboxamide
N-((3R)pyrrolidin-3-yl){2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-
Figure imgf000246_0005
yl)}carboxamide 2-[2-(6-{[1-(3-fluoro(2-pyridyl))- isopropyl]amino}pyridazin-3-yl)- 1 ,3-thiazol-5-yl]acetamide
((3S)morpholin-3-yl)-N-({2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-
Figure imgf000247_0001
yl)}methyl)carboxamide
N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)pyrazol-5-
Figure imgf000247_0002
ylcarboxamide
N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)imidazol-2-
Figure imgf000247_0003
ylcarboxamide
N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)pyrazol-4-
Figure imgf000247_0004
ylcarboxamide
((4S)-2-oxoim idazolid i n-4-yl )-N- ({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-
Figure imgf000247_0005
yl)}methyl)carboxamide ((3S)-6-oxo(3-piperidyl))-N-({2-[6- ({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)carboxamide
Figure imgf000248_0001
2H-1 ,2,3-triazol-4-yl-N-({2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-
Figure imgf000248_0002
yl)}methyl)carboxamide
(2S)-2-am ino-N-({2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-
Figure imgf000248_0003
yl)}methyl)-3-hydroxypropanamide (2R)-2-amino-N-({2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-
Figure imgf000248_0004
yl)}methyl)-3-hydroxypropanamide
((2S)-4-acetylpiperazin-2-yl)-N- ({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)carboxamide
Figure imgf000248_0005
[(2S)-4-(methylsulfonyl)piperazin- 2-yl]-N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)carboxamide
((3S)morpholin-3-yl)-N-({2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)carboxamide
Figure imgf000249_0001
1 H-1 ,2,4-triazol-5-yl-N-({2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-
Figure imgf000249_0002
yl)}methyl)carboxamide
((2R)-6-oxo(2-piperidyl))-N-({2-[6- ({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)carboxamide
Figure imgf000249_0003
N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)imidazol-5-
Figure imgf000249_0004
ylcarboxamide
2-amino-N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)-2-methylpropananriide
Figure imgf000249_0005
(2S)-2-am ino-N-({2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)propanamide
N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)(2-hydroxyimidazol-5- yl)carboxamide
(2S)-2-am ino-N-({2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)-3-hydroxy-3- methylbutanamide
(2R)-2-amino-N-({2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)propanamide
((3R)-1 ,1-dioxo(1 ,4- thiazaperhydroin-3-yl))-N-({2-[6-
({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-
Figure imgf000250_0001
yl)}methyl)carboxamide ((2S)-4,4-difluoropyrrolidin-2-yl)-N-
({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)carboxamide
tert-butyl (2S)-4,4-difluoro-2-[N-
({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)carbamoyl]pyrrolidineca rboxylate
((2S)-4,4-difluoro-1- formylpyrrolidin-2-yl)-N-({2-[6-
({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)carboxamide
((2R,4R)-4-fluoropyrrolidin-2-yl)-N-
({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)carboxamide
N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)-2-methylpropananriide
4-f luoro-3-(6-{[1 -(3-f luoro(2- pyridyl))- isopropyl]amino}pyridazin-3- yl)benzamide
Figure imgf000251_0001
amino-N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)amide
((3S)-1 , 1-dioxo(1 ,4- thiazaperhydroin-3-yl))-N-({2-[6-
({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)carboxamide
N-({2-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-1 ,3-thiazol-5- yl}methyl)acetamide
N-({2-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-1 ,3-thiazol-5- yl}methyl)acetamide
Figure imgf000252_0001
((2S)pyrrolidin-2-yl)-N-{[2-(6-{[2-
(3-fluoro(2-pyridyl))-2- methylpropyl]amino}pyridazin-3- yl)(1 ,3-thiazol-5-
Figure imgf000252_0002
yl)]methyl}carboxamide
2-(6-{[1-(3-chloro(2-pyridyl))- isopropyl]amino}pyridazin-3-yl)- 1 ,3-thiazole-5-carboxamide
Figure imgf000252_0003
4-fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzamide
4-fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzenecarbonitrile
3- [6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-4-hydroxybenzamide
4- fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzoic acid
3-(6-{[2-(3-chloro(2-pyridyl))-2- methylpropyl]amino}pyridazin-3- yl)benzamide
3-(6-{[2-(3-chloro(2-pyridyl))-2- methylpropyl]amino}pyridazin-3- yl)-4-fluorobenzamide
Figure imgf000253_0001
N-((2R)-2 , 3-d ihyd roxypropyl){4- fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}carboxamide
N-((3R)pyrrolidin-3-yl){4-fluoro-3- [6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}carboxamide
N-((3S)pyrrolidin-3-yl){4-fluoro-3- [6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}carboxamide
[6-(3-(2H-1 ,2,3,4-tetraazol-5- yl)phenyl)pyridazin-3-yl]{[3-fluoro-
1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
3-(6-{[2-(3-chloro(2-pyridyl))-2- methylpropyl]amino}pyridazin-3- yl)benzenecarbonitrile
3-(6-{[2-(3-chloro(2-pyridyl))-2- methylpropyl]amino}pyridazin-3- yl)-4-fluorobenzenecarbonitrile
Figure imgf000254_0001
2- [6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazole-5- sulfonamide
(aminocyclopropyl)-N-({2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)carboxamide
(N-{1-[N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)carbamoyl]- isopropyl}carbamoyloxy)ethyl 2- methylpropanoate
3- [6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzoic acid
3-(6-{[(3-fluoro-1 -(2- pyridyl)cyclobutyl)methyl]amino}py ridazin-3-yl)benzoic acid
3-(6-{[(3-fluoro-1 -(2- pyridyl)cyclobutyl)methyl]amino}py ridazin-3-yl)benzoic acid
Figure imgf000255_0001
3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzenecarbonitrile
N-((2S)-2,3-dihydroxypropyl){4- fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}carboxamide methyl 4-fluoro-3-[6-({[3-fluoro-1- (3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzoate
{4-fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}-N-
Figure imgf000256_0001
methylcarboxamide
{4-fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}-N- (methylethyl)carboxamide methyl 3-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzoate
Figure imgf000256_0002
methylethyl 4-fluoro-3-[6-({[3- fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzoate
6-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]imidazo[2, 1-b]1 ,3- thiazoline-3-carboxamide
6-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]imidazo[2, 1-b]1 ,3- thiazoline-3-carboxylic acid
6-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]imidazo[2, 1-b]1 ,3- thiazoline-3-carboxamide
Figure imgf000257_0001
N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl){3-
[benzylam ino]oxetan-3-
Figure imgf000257_0002
yl}carboxamide
3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzenesu Ifonam ide
{5-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 H-indazol-3- yl)}(methylsulfonyl)amine
Figure imgf000257_0003
{[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}{6-[3-
(methylamino)(1 H-indazol-5- yl)]pyridazin-3-yl}amine
{6-[3-(ethylamino)(1 H-indazol-5- yl)]pyridazin-3-yl}{[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amine
[6-(3-amino(1 H-indazol-5- yl))pyridazin-3-yl]{[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amine ethyl 2-fluoro-5-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzoate
2-fluoro-5-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzoic acid
2-{4-fluoro-3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}acetamide
Figure imgf000258_0001
methyl 2-{4-fluoro-3-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}acetate
N-({4-fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3- yl]phenyl}methyl)acetamide
N-({3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3- yl]phenyl}methyl)acetamide
{2-fluoro-5-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}-N- methylcarboxamide
N-ethyl{2-fluoro-5-[6-({[3-fluoro-1- (3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}carboxamide methyl 5-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2-
(methylamino)benzoate
Figure imgf000259_0001
ethyl 5-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
yridazin-3-yl]-2- (methylamino)benzoate
{3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
yridazin-3-yl]phenyl}methan-1-ol
2-[2-(6-{[2-(3-chloro(2-pyridyl))-2- methylpropyl]amino}pyridazin-3- yl)-1 ,3-thiazol-5-yl]acetamide
2-amino-N-{[2-(6-{[2-(3-chloro(2- pyridyl))-2- methylpropyl]amino}pyridazin-3- yl)(1 ,3-thiazol-5-yl)]methyl}-2- methylpropanamide
Figure imgf000260_0001
((2S)azetidin-2-yl)-N-({2-[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p 454.1 A yridazin-3-yl](1 ,3-thiazol-5-
Figure imgf000260_0002
yl)}methyl)carboxamide
ethyl 2-{2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py
ridazin-3-yl]-1 ,3-thiazol-4- yl}acetate
Figure imgf000260_0003
2-{2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazol-4- yl}acetamide
6-(6-{[1-(3-chloro(2-pyridyl))- isopropyl]amino}pyridazin-3- yl)imidazo[2, 1-b]1 ,3-thiazoline-3- carboxamide
6-(6-{[2-(3-chloro(2-pyridyl))-2- methylpropyl]amino}pyridazin-3- yl)imidazo[2, 1-b]1 ,3-thiazoline-3- carboxamide
6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazine-3-carboxamide
2-{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-yl)}-2- methylpropanenitrile
2- {2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-yl)}-2- methylpropanamide
3- {2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazol-5- yl}propanamide
Figure imgf000261_0001
3-{2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazol-5- yl}propanoic acid
methyl 3-{2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazol-5- yl}propanoate
6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazine-3-carboxylic acid
[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-N- methylcarboxamide
[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-N,N- dimethylcarboxamide
2-amino-N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)-2-methyl-N-
Figure imgf000262_0001
methylpropanamide
2-{2-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-1 ,3-thiazol-5- yl}acetamide
Figure imgf000262_0002
2-{2-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
yridazin-3-yl]-1 ,3-thiazol-5- yl}acetic acid
2-[2-(6-{[1-(3-chloro(2-pyridyl))- isopropyl]amino}pyridazin-3-yl)- 1 ,3-thiazol-5-yl]acetamide
Figure imgf000263_0001
(3-aminooxetan-3-yl)-N-({2-[6- ({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p 470.1 A yridazin-3-yl](1 ,3-thiazol-5-
Figure imgf000263_0002
yl)}methyl)carboxamide
{3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
yridazin-3-yl]phenyl}-N- methylcarboxamide
{4-fluoro-3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
yridazin-3-yl]phenyl}-N- methylcarboxamide
N-({5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py
ridazin-3-yl]-1 ,3-thiazol-2- yl}methyl)acetamide
N-({4-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py
ridazin-3-yl]-1 ,3-thiazol-2- yl}methyl)acetamide
Figure imgf000263_0003
2-{2-[6-({[1-(3-chloro(2-pyridyl))-3- fluorocyclobutyl]methyl}amino)pyri dazin-3-yl]-1 ,3-thiazol-5- yl}acetamide
{3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}-N- methylcarboxamide
2-{2-[6-({[(3-chloro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazol-5- yl}acetamide
Figure imgf000264_0001
Figure imgf000264_0002
acid
2-{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-yl)}-N- methylacetamide
2-{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5-yl)}-
N , N-d im ethylacetam ide
[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-N-isoxazol-3- ylcarboxamide
Figure imgf000264_0003
[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-N-(1 ,3-oxazol-2- yl)carboxamide
[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-N-(1 ,3-thiazol-2- yl)carboxamide
[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-N-(1 ,3,4-thiadiazol-
2-yl)carboxamide
[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-N-imidazol-2- ylcarboxamide
Figure imgf000265_0001
N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)-2-methyl-2-
Figure imgf000265_0002
(methylamino)propananriide [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-N-( 1 -methylpyrazol- 3-yl)carboxamide
N-(1 H-1 ,2,4-triazol-5-yl)[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]carboxamide
N-(4-cyanoimidazol-5-yl)[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]carboxamide
N-(4-cyanopyrazol-5-yl)[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]carboxamide ethyl 4-{[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]carbonylamino}-1- methylimidazole-2-carboxylate ethyl 2-{[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]carbonylamino}-1 ,3- oxazole-4-carboxylate
Figure imgf000266_0001
N-((3S)-2-oxopyrrolidin-3-yl)[6- ({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]carboxamide
N-((3R)-2-oxopyrrolidin-3-yl)[6- ({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]carboxamide
N-ethyl{4-fluoro-3-[6-({[3-fluoro-1- (3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}carboxamide
N-(2-fluoroethyl){4-fluoro-3-[6-({[3- fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}carboxamide
N-(2,2-difluoroethyl){4-fluoro-3-[6-
({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}carboxamide
{4-fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}-N-(2,2,2-
Figure imgf000267_0001
trifluoroethyl)carboxamide {4-fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p 442.3 B yridazin-3-yl]phenyl}-N , N-
Figure imgf000268_0001
dimethylcarboxamide
Figure imgf000268_0002
2- {[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]carbonylamino}-1 ,3- oxazole-4-carboxamide
{3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-4-hydroxyphenyl}-N- methylcarboxamide
3- [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-4-hydroxybenzamide
5-{[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3- yl]carbonylamino}pyrazole-4- carboxamide
5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2-methoxypyridine-
3-carbonitrile
5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2-methoxypyridine-
3-carboxamide
Figure imgf000269_0001
5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2-oxohydropyridine-
3-carboxylic acid
5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2-oxohydropyridine-
3-carboxamide
[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-N-(pyrazol-5- ylmethyl)carboxamide
[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-N-[(1-methylpyrazol- 5-yl)methyl]carboxamide
[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-N-[(1-methylpyrazol- 3-yl)methyl]carboxamide
[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-N-[(5-oxopyrrolidin-
3-yl)methyl]carboxamide
N-((3S)-6-oxo(3-piperidyl))[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]carboxamide
Figure imgf000270_0001
N-((3R)-6-oxo(3-piperidyl))[6-({[(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]carboxamide
[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-N-(2- pyridylmethyl)carboxamide
[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-N-(3- pyridylmethyl)carboxamide
[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-N-(4- pyridylmethyl)carboxamide
[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-N-(1 ,3-thiazol-2- ylmethyl)carboxamide
[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-N-methyl-N-(1 ,3- thiazol-2-ylmethyl)carboxamide ethyl 2-{[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]carbonylamino}-1 ,3- thiazole-5-carboxylate
Figure imgf000271_0001
Figure imgf000272_0001
acid
{3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}i
yridazin-3-yl]phenyl}-N-[2- hydroxy-1-
Figure imgf000272_0002
(hydroxymethyl)ethyl]carboxamide
{5-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2-hydroxyphenyl}-N- methylcarboxamide
Figure imgf000272_0003
5-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2-hydroxybenzamide
{3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-4-hydroxyphenyl}-N- methylcarboxamide
2-{[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]carbonylamino}-1 ,3- thiazole-4-carboxamide
{5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](2-thienyl)}-N- methylcarboxamide
2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-4,5,6- trihydrocyclopenta[1 ,2-d]1 ,3- thiazole-4-carboxamide
2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-4,5,6- trihydrocyclopenta[1 ,2-d]1 ,3- thiazole-4-carboxylic acid
Figure imgf000273_0001
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6-
(4,5,6,7-tetrahydro-1 ,3- thiazolo[5,4-c]pyridin-2- yl)pyridazin-3-yl)amine
N-{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](4,5,6- trihydrocyclopenta[2,3-d]1 ,3- th iazo l-4-yl )} m et hoxycarboxam id e
2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazi n-3-yl]-4 ,5, 6, 7-tetrahyd ro- 1 ,3-thiazolo[5,4-c]pyridine-5- carboxamide
5-acetyl-2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-4, 5, 6, 7-tetrahyd ro- 1 ,3-thiazolo[5,4-c]pyridine
Figure imgf000274_0001
2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-5-(methylsulfonyl)-
4,5,6,7-tetrahydro-1 ,3-
Figure imgf000274_0002
thiazolo[5,4-c]pyridine
{5-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2-hydroxyphenyl}- N , N-d im ethylcarboxam ide
Figure imgf000274_0003
4- [6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]isoindolin-1-one
5- [6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]isoindolin-1-one
6- [6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]isoindolin-1-one
[6-(6-amino(4,5,6,7- tetrahydrobenzothiazol-2- yl))pyridazin-3-yl]{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine amino-N-{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](4,5,6J- tetrahydrobenzothiazol-6-
Figure imgf000275_0001
yl)}amide
N-{3-fluoro-4-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3- yl]phenyl}(methylamino)carboxanrii
Figure imgf000275_0002
de N-{4-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}-N- methyl(methylanriino)carboxanriide
N-[4-(carbamoylmethyl)(1 ,3- thiazol-2-yl)][6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]carboxamide
2-(2-{[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]carbonylam ino}( 1 ,3- thiazol-4-yl))-N-methylacetamide
2- {2-[6-({[1-(3-chloro(2-pyridyl))-3- fluorocyclobutyl]methyl}amino)pyri dazin-3-yl](1 ,3-thiazol-5-yl)}-N- methylacetamide
3- {6-[4-(3-fluoro(2-pyridyl))-2- azabicyclo[2.1.1 ] hex-2- yl] pyridazi n-3-yl}-4- hydroxybenzamide
Figure imgf000276_0001
A
Figure imgf000277_0001
2-{2-[6-({[(3-chloro(2- pyridyl))cyclobutyl]methyl}amino)p
yridazin-3-yl](1 ,3-thiazol-5-yl)}-N- methylacetamide
N-cyclopropyl{4-fluoro-3-[6-({[3- fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
yridazin-3-yl]phenyl}carboxamide
Figure imgf000277_0002
5-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazi n-3-yl]-8-hyd ro-3- pyrazolino[1 ,5-a]pyrimidin-7-one
7-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazi n-3-yl]-4-hyd ro-4- imidazolino[1 ,2-a]pyrimidin-5-one
{4-fluoro-5-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2-hydroxyphenyl}-N- methylcarboxamide
4-fluoro-5-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2-hydroxybenzamide
3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-4-methyl-3- pyrazolin-5-one
3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-4 ,4-d imethyl-2- pyrazolin-5-one
Figure imgf000278_0001
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6- benzylpyridazin-3-yl]am ine
3- [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-
4- methylpyridazin-3- yl]benzenecarbonitrile
3- [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-
4- methylpyridazin-3-yl]benzamide
N-cyclobutyl{4-fluoro-3-[6-({[3- fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}carboxamide
4-fluoro-3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-
4-methylpyridazin-3-yl]benzamide
N-(3,3-difluorocyclobutyl){4-fluoro-
3- [6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}carboxamide
4- fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2-hydroxybenzamide
Figure imgf000279_0001
2- [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-
4- methylpyridazin-3-yl]-1 ,3- thiazole-5-carboxamide
3- [6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-
5- methylpyridazin-3-yl]benzamide
N-cyclopropyl{3-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}carboxamide
[6-(2-aminopyrimidin-5- yl)pyridazin-3-yl]{[3-fluoro-1 -(3- fluoro(2- pyridyl))cyclobutyl]methyl}amine N-azetidin-3-yl{3-[6-({[3-fluoro-1- (3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}carboxamide
N-( 1 -acetylazetid i n-3-yl ){3-[6-({[3- fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}carboxamide
{3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}-N-[1-
(m ethylsu lfonyl)azetid i n-3- yl]carboxamide
Figure imgf000280_0001
{3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}-N-(2- hydroxy-2- methylpropyl)carboxamide
{3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}-N-(1- methylazetid i n-3-yl )carboxam ide
{3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}-N-oxetan-3- ylcarboxamide
2-{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-
4-methylpyridazin-3-yl]-1 ,3- thiazol-5-yl}acetic acid
{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-
4-methylpyridazin-3-yl]-1 ,3- thiazol-5-yl}methan-1-ol
2-{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-
4-methylpyridazin-3-yl](1 ,3- thiazol-5-yl)}-N-methylacetamide
2-{2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-
4-methylpyridazin-3-yl]-1 ,3- thiazol-5-yl}acetamide
Figure imgf000281_0001
{4-fluoro-3-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}-N-(1- methylazetid i n-3-yl )carboxam ide
N-(1-acetylazetidin-3-yl){4-fluoro-
3- [6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}carboxamide
{3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}-N-(3- hyd roxycyclobu tyl )carboxa m id e
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}{6-[5- (piperazinylmethyl)(1 ,3-thiazol-2- yl)]pyridazin-3-yl}amine
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}{6-[5-
(morpholin-4-ylmethyl)(1 ,3-thiazol-
2-yl)]pyridazin-3-yl}amine
4- ({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazol-5- yl}methyl)-1 ,4-thiazaperhydroine-
Figure imgf000282_0001
1 ,1-dione {[(3-fluoro(2- pyridyl))cyclobutyl]methyl}(6-{5- [(4-methylpiperazinyl)methyl](1 ,3- thiazol-2-yl)}pyridazin-3-yl)amine
Figure imgf000283_0001
{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(5-
Figure imgf000283_0002
yl]amine
1-acetyl-4-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
482.3 yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)piperazine
Figure imgf000283_0003
1-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
yridazin-3-yl](1 ,3-thiazol-5- 518.3 yl)}methyl)-4-
Figure imgf000283_0004
(methylsulfonyl)piperazine
470.3 B
470.3
Figure imgf000283_0005
N-(2H-3 ,4 , 5, 6-tetrahyd ropyran-4- yl){3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}carboxamide
{3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}-N-(3- hydroxy-3- methylcyclobutyl)carboxamide
N-((3S)oxolan-3-yl){3-[6-({[3- fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}carboxamide
N-((3R)oxolan-3-yl){3-[6-({[3- fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}carboxamide
N-((3S,4S)-4-hydroxy-1 , 1- dioxothiolan-3-yl){3-[6-({[3-fluoro-
1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}carboxamide
N-(1 , 1-dioxothiolan-3-yl){3-[6-({[3- fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}carboxamide
3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2-hydroxybenzamide
Figure imgf000284_0001
3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2-hydroxybenzamide
5-amino-3-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzenecarbonitrile
3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-5- (trifluoromethyl)benzamide
5-chloro-3-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzamide
3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-5-hydroxybenzamide
5-amino-3-[6-({[3-fluoro-1-(3- fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]benzamide
{3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2-hydroxyphenyl}-N- methylcarboxamide
Figure imgf000285_0001
3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2- hydroxybenzenecarbonitrile
3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2- methoxybenzenecarbonitrile
Figure imgf000286_0001
Figure imgf000286_0002
N-( 1 , 1 -d ioxoth ietan-3-yl ){3-[6-({[3- fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]phenyl}carboxamide
4-fluoro-3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2-hydroxybenzamide
4-fluoro-5-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl]-2-hydroxybenzamide
Figure imgf000286_0003
{3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
yridazin-3-yl]phenyl}-N- 466.1 A
[(hydroxycyclopropyl)methyl]carbo
Figure imgf000287_0001
xamide
{3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
yridazin-3-yl]-5-methylphenyl}-N- methylcarboxamide
3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
yridazin-3-yl]-5-methylbenzamide
3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
yrid azi n-3-yl]-2- hyd roxy-5- methylbenzamide
3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
yrid azi n-3-yl]-2- hyd roxy-5- methylbenzenecarbonitrile
5-bromo-3-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
yridazin-3-yl]-2- hydroxybenzenecarbonitrile
3-[6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p
yridazin-3-yl]-2- methoxybenzamide
Figure imgf000287_0002
Figure imgf000288_0001
pyridyl))cyclobutyl]methyl}amine {[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}{6-[6- (methylamino)(3- pyridyl)]pyridazin-3-yl}amine
{6-[6-(cyclopropylamino)(3- pyridyl)]pyridazin-3-yl}{[3-fluoro-1-
(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
{6-[6-amino-5-(trifluoromethyl)(3- pyridyl)]pyridazin-3-yl}{[3-fluoro-1-
(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
[N-({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazol-5- yl}methyl)carbamoyl]nriethyl acetate
[N-({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazol-5- yl}methyl)carbamoyl]methyl (2S)- 2-amino-3-methylbutanoate
[N-({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazol-5- yl}methyl)carbamoyl]nriethyl (2S)- 2-aminopropanoate
Figure imgf000289_0001
{[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}[6-(6- methoxy-5-methyl(3- pyridyl))pyridazin-3-yl]amine
[6-(6-amino-5-methyl(3- pyridyl ))pyridazin-3-yl]{[3-f I uoro- 1 -
(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine
(2S)-N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)-2-hydroxypropanamide (2R)-N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)-2-hydroxypropanamide
2-[({2-[6-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)py ridazin-3-yl]-1 ,3-thiazol-5- yl}methyl)amino]ethan-1-ol
N-({2-[6-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)p yridazin-3-yl](1 ,3-thiazol-5- yl)}methyl)-2-hydroxy-N-
Figure imgf000290_0001
methylacetamide
Figure imgf000291_0001
methylbutanoate
While the present invention has been described with reference to the specific embodiments described herein, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, modifications may be made to adapt a particular situation, material, composition of matter and/or process to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims

What is claimed is:
1. A compound of Formula I:
Figure imgf000292_0001
Formula I or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from hydrogen, halogen, CN, C-i-6 alkyl, C-i-6 haloalkyl, C(O)ORa, C(O)NRbRc, ORa, NRbRc, C6-io aryl and 5-10 membered heteroaryl;
R2 is selected from C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyi, 3-8 membered heterocycloalkenyl, C6-io aryl, 5-10
membered heteroaryl and NRbRc, wherein each of the C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyi, 3-8 membered
heterocycloalkenyl, C6-io aryl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, (CH2)nORa, (CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc, (CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa,
(CH2)nNRdC(S)NRbRc, (CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra,
(CH2)nNRdSO2Ra, (CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc,
(CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra,
(CH2)nSO2NRbRc, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3- 8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyi, (CH2)nC6-io aryl and (CH2)n5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyi, (CH2)nC6-io aryl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents;
R3 is selected from hydrogen, halogen, CN, C-i-6 alkyl, C-i-6 haloalkyl, C(O)ORa, C(O)NRbRc, ORa, NRbRc, C6-io aryl and 5-10 membered heteroaryl; R4 is selected from hydrogen, C-i-6 alkyl, C-i-6 haloalkyl, C(O)Ra,
C(O)ORa, C(O)NRbRc and SO2Ra;
R5 and R6 are each independently selected from hydrogen, halogen, C-i-6 alkyl and C-i-6 haloalkyl;
or alternatively, R5 and R6 together with the carbon atom to which they are bound form a group selected from C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyi and 3-8 membered heterocycloalkenyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, S(O)Ra, SO2Ra, SO2NRbRc, C1-6 alkyl and C1-6 haloalkyl;
R7 is selected from C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyi, 3-8 membered heterocycloalkenyl, C6-io aryl and 5-10 membered heteroaryl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, OC(O)NRbRc, NRbRc, NRdC(O)Ra, NRdC(O)ORa, NRdC(O)NRbRc,
NRdC(O)C(O)NRbRc, NRdC(S)Ra, NRdC(S)ORa, NRdC(S)NRbRc,
NRdC(NRe)NRbRc, NRdS(O)Ra, NRdSO2Ra, NRdSO2NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, C(S)Ra, C(S)ORa, C(S)NRbRc, C(NRe)NRbRc, SRa, S(O)Ra, SO2Ra, SO2NRbRc, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyi, 3-8 membered heterocycloalkenyl, C6-io aryl, C7-n aralkyl, and 5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyi, 3-8 membered
heterocycloalkenyl, C6-io aryl, C7-n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents;
R8 and R9, at each occurrence, are each independently selected from hydrogen, halogen and C-i-6 alkyl;
X is selected from a bond, -(CH2)P-, -(CH2)pC(O)(CH2)q-, - (CH2)pO(CH2)q-, -(CH2)pS(CH2)q-, -(CH2)pNRd(CH2)q-, -(CH2)pC(O)O(CH2)q-, -(CH2)pOC(O)(CH2)q-, -(CH2)pNRdC(O)(CH2)q-, -(CH2)pC(O)NRd(CH2)q-, -(CH2)pNRdC(O)NRd(CH2)q-, -(CH2)pNRdSO2(CH2)q-, and
-(CH2)pSO2NRd(CH2)q-; or alternatively, X, R2 and R3, together with the carbon atoms to which they are bound, form a 5-6 membered ring optionally containing one or more heteroatoms selected from oxygen nitrogen and sulfur, and optionally containing one or more double bonds, and optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents;
Ra, at each occurrence, is independently selected from hydrogen, C-i-6 alkyl, d-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C-6-10 aryl, C7.11 aralkyl and 5-10 membered heteroaryl, wherein each of the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C-6-10 aryl, C7.11 aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents;
Rb and Rc, at each occurrence, are each independently selected from hydrogen, C1-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered
heterocycloalkenyl, C6-io aryl, C7-n aralkyl, 5-10 membered heteroaryl, C(O)Rg, C(O)ORg, C^NR^ and SO2Rg, wherein each of the d-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, s-io aryl, C7.11 aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents;
Rd, at each occurrence, is independently selected from hydrogen and C1-6 alkyl;
Re, at each occurrence, is independently selected from hydrogen, CN, OH, Ci-6 alkoxy, Ci-6 alkyl and Ci-6 haloalkyl;
Rf, at each occurrence, is independently selected from halogen, CN, ORh, OC(O)Rh, OC(O)ORh, OC JNR^, N R'Rj, N RdC(O)Rh, N RdC(O)ORh, NRdC(O)N R'Rj, NRdC(O)C(O)NRiRj, NRdC(S)Rh, N RdC(S)ORh, NRdC(S)NR'Rj, NRdC(NRe)NR'Rj, N RdS(O)Rh, N RdSO2Rh, N RdSO2NR'Rj, C(O)Rh, C(O)ORh, Ο(Ο)Ν^, C(S)Rh, C(S)ORh, C^NR^, C(NRe)NR'Rj, SRh, S(O)Rh, SO2Rh, SO2NR'Rj, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 mennbered heterocycloalkyl, 3-8 membered
heterocycloalkenyl, C6-io aryl, C7-n aralkyl and 5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered
heterocycloalkenyl, C6-io aryl, C7-n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rk substituents;
or two Rf substituents bound to a single carbon atom, together with the carbon atom to which they are both bound, form a group selected from carbonyl, C3-8 cycloalkyl and 3-8 membered heterocycloalkyl;
Rg, at each occurrence, is independently selected from C-i-6 alkyl, C-i-6 haloalkyl, phenyl, naphthyl, and C7-n aralkyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, OH, C-i-6 alkoxy, C-i-6 alkyl and C-i-6 haloalkyl;
Rh, at each occurrence, is independently selected from hydrogen, C-i-6 alkyl, C-i-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C7-i i aralkyl and 5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C7-n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rk substituents;
R' and Rj, at each occurrence, are each independently selected from hydrogen, C-i-6 alkyl, C-i-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered
heterocycloalkenyl, C6-io aryl, C7-n aralkyl, 5-10 membered heteroaryl, C(O)Rg, and C(O)ORg, wherein each of the C -6 alkyl, C -6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C7-n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, OH, C-i-6 alkoxy, C-i-6 alkyl and C-i-6 haloalkyl;
Rk, at each occurrence, is independently selected from halogen, CN, OH, C1-6 alkoxy, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NHC(O)C1-6 alkyl,
NHC(0)C7-i i aralkyl, N HC(O)OC1-6 alkyl, N HC(O)OC7-n aralkyl, OC(O)C1-6 alkyl, OC(O)C7-n aralkyl, OC(O)OCi-6 alkyl, OC(O)OC7-n aralkyl, C(O)Ci-6 alkyl, C(O)C7-n aralkyl, C(O)OCi-6 alkyl, C(O)OC7-n aralkyl, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein each C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C7-n aralkyl substituent is optionally substituted with 1 , 2 or 3 substituents selected from OH, C-i-6 alkoxy, N H2, NH(Ci-6 alkyl), N(Ci-6 alkyl)2, NHC(O)Ci-6 alkyl, NHC(O)C7-n aralkyl, NHC(O)OCi-6 alkyl, and NHC(O)OC7- 11 aralkyl;
or two Rk substituents bound to a single carbon atom, together with the carbon atom to which they are both bound, form a carbonyl group;
m is 0, 1 or 2;
n, at each occurrence, independently is 0, 1 or 2;
p is 0, 1 or 2; and
q is 0, 1 or 2;
provided the compound is not 6-(4-chlorophenyl)-5-methyl-N-(2-methyl- 2-(piperidin-1 -yl)propyl)pyridazin-3-amine, N-(2-methyl-2-(piperidin-1 - yl)propyl)-6-phenyl-5-propylpyridazin-3-amine or N-(2-methyl-2- morpholinopropyl)-6-phenyl-5-propylpyridazin-3-amine.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 0.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1 .
4. The compound of claim 3, wherein R8 and R9 are each hydrogen.
5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are each C-i-6 alkyl.
6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are each methyl.
7. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 together with the carbon atom to which they are bound form a group selected from C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl and 3-8 membered
heterocydoalkenyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, S(O)Ra, SO2Ra, SO2NRbRc, C1-6 alkyl and C1-6 haloalkyl.
8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 together with the carbon atom to which they are bound form C3-8 cycloalkyl optionally substituted with 1 , 2, 3, 4 or 5
substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, S(O)Ra, SO2Ra, SO2NRbRc, Ci-6 alkyl and C-i-6 haloalkyl.
9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 together with the carbon atom to which they are bound form a group selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, S(O)Ra, SO2Ra, SO2NRbRc, C1-6 alkyl and C1-6 haloalkyl.
10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 together with the carbon atom to which they are bound form cyclobutyl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, S(O)Ra, SO2Ra, SO2NRbRc, Ci-6 alkyl and Ci-6 haloalkyl.
1 1 . The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 together with the carbon atom to which they are bound form cyclobutyl optionally substituted with one or two halogens.
12. The compound of claim 1 1 , or a pharmaceutically acceptable salt thereof, wherein R5 and R6 together with the carbon atom to which they are bound form a group selected from cyclobutyl, 3-fluorocyclobutyl and 3,3- difluorocyclobutyl.
13. The compound of claim 10, wherein the compound is of Formula V(a) or V(b), or a pharmaceutically acceptable salt thereof:
Figure imgf000298_0001
Formula V(a)
Figure imgf000298_0002
Formula V(b)
wherein Rm and Rn are each independently selected from hydrogen, halogen and C-i-6 alkyl.
14. The compound of claim 13, wherein one of Rm and Rn is hydrogen and the other is halogen.
15. The compound of claim 14, wherein the halogen and R7 are in a trans configuration with respect to one another on the cyclobutyl ring.
16. The compound of claim 14, wherein the halogen and R7 are in a cis configuration with respect to one another on the cyclobutyl ring.
17. The compound of any one of claims 13-16, wherein one of Rm and Rn is hydrogen and the other is fluorine.
18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R7 is phenyl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, OC(O)NRbRc, N RbRc, NRdC(O)Ra, NRdC(O)ORa, NRdC(O)NRbRc, NRdC(O)C(O)NRbRc, N RdC(S)Ra, NRdC(S)ORa, N RdC(S)NRbRc,
NRdC(NRe)NRbRc, N RdS(O)Ra, NRdSO2Ra, NRdSO2NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, C(S)Ra, C(S)ORa, C(S)NRbRc, C(NRe)NRbRc, SRa, S(O)Ra, SO2Ra, SO2NRbRc, C -6 alkyl, C -6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 nnennbered heterocycloalkyi, 3-8 nnennbered heterocycloalkenyl, C6-io aryl, C7-n aralkyl, and 5-10 nnennbered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 nnennbered heterocycloalkyi, 3-8 nnennbered
heterocycloalkenyl, C6-io aryl, C7-n aralkyl and 5-10 nnennbered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
19. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R7 is 5-10 membered heteroaryl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, OC(O)NRbRc, NRbRc, N RdC(O)Ra, N RdC(O)ORa, NRdC(O)N RbRc, N RdC(O)C(O)NRbRc, N RdC(S)Ra, N RdC(S)ORa,
NRdC(S)NRbRc, NRdC(NRe)NRbRc, N RdS(O)Ra, NRdSO2Ra, NRdSO2NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, C(S)Ra, C(S)ORa, C(S)NRbRc, C(NRe)NRbRc, SRa, S(O)Ra, SO2Ra, SO2NRbRc, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyi, 3-8 membered heterocycloalkenyl, C6-io aryl, C7-n aralkyl, and 5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyi, 3-8 membered heterocycloalkenyl, C6-io aryl, C7-n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein R7 is pyridyl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, OC(O)NRbRc, N RbRc, NRdC(O)Ra, NRdC(O)ORa, NRdC(O)NRbRc,
NRdC(O)C(O)NRbRc, N RdC(S)Ra, NRdC(S)ORa, N RdC(S)NRbRc,
NRdC(NRe)NRbRc, N RdS(O)Ra, NRdSO2Ra, NRdSO2NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, C(S)Ra, C(S)ORa, C(S)NRbRc, C(NRe)NRbRc, SRa, S(O)Ra, SO2Ra, SO2NRbRc, C -6 alkyl, C -6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, phenyl, naphthyl, C7-n aralkyl, and 5-10 membered heteroaryl, wherein each of the d-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C7-n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
21 . The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R7 is 2-pyridyl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, ORa, OC(O)Ra, OC(O)ORa, OC(O)NRbRc, NRbRc, NRdC(O)Ra, NRdC(O)ORa, NRdC(O)NRbRc,
NRdC(O)C(O)NRbRc, NRdC(S)Ra, NRdC(S)ORa, NRdC(S)NRbRc,
NRdC(NRe)NRbRc, NRdS(O)Ra, NRdSO2Ra, NRdSO2NRbRc, C(O)Ra, C(O)ORa, C(O)NRbRc, C(S)Ra, C(S)ORa, C(S)NRbRc, C(NRe)NRbRc, SRa, S(O)Ra, SO2Ra, SO2NRbRc, C -6 alkyl, C -6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, phenyl, naphthyl, C7-n aralkyl, and 5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C6-io aryl, C7-n aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
22. The compound of any one of claims 1 to 21 , or a pharmaceutically acceptable salt thereof, wherein X is a bond.
23. The compound of claim 22, wherein the compound is of Formula Xll(a), or a pharmaceutically acceptable salt thereof:
Figure imgf000300_0001
Formula Xll(a).
24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R2 is phenyl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, (CH2)nORa, (CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc, (CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa, (CH2)nNRdC(S)NRbRc,
(CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra, (CH2)nNRdSO2Ra,
(CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc, (CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra, (CH2)nSO2NRbRc, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8
membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
25. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R2 is 5-10 membered heteroaryl optionally substituted with 1 , 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, (CH2)nORa, (CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc,
(CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc, (CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa,
(CH2)nNRdC(S)NRbRc, (CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra,
(CH2)nNRdSO2Ra, (CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc,
(CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra,
(CH2)nSO2NRbRc, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3- 8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl,
(CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl, wherein each of the C-|. 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionally substituted with 1 , 2, 3 or 4 substituents selected from halogen, CN, oxo, (CH2)nORa, (CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc, (CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa,
(CH2)nNRdC(S)NRbRc, (CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra,
(CH2)nNRdSO2Ra, (CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc,
(CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra,
(CH2)nSO2NRbRc, C1-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3- 8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl,
(CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl, wherein each of the C-|. 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionally substituted with a substituent selected from (CH2)nC(O)ORa and (CH2)nC(O)NRbRc; and optionally substituted with 1 , 2 or 3 additional substituents selected from halogen, CN, oxo, (CH2)nORa, (CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc, (CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa, (CH2)nNRdC(S)NRbRc,
(CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra, (CH2)nNRdSO2Ra,
(CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc, (CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra, (CH2)nSO2NRbRc, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8
membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionally substituted with (CH2)nC(O)NRbRc.
29. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionally substituted with (CH2)nNRdC(O)Ra, wherein Ra is C -6 alkyl or 3-8 membered heterocycloalkyl, each optionally substituted with 1 , 2 or 3 additional substituents selected from halogen, CN, oxo, (CH2)nORa,
(CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc,
(CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc,
(CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa,
(CH2)nNRdC(S)NRbRc, (CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra,
(CH2)nNRdSO2Ra, (CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc,
(CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra,
(CH2)nSO2NRbRc, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3- 8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl,
(CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl, wherein each of the C -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8
membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein R2 is is selected from furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionally substituted with (CH2)nNRdC(O)Ra, wherein Ra is selected from C-i-6 alkyl, C-i-6 alkyl-OH and C-i-6 alkyl-NH2, each optionally substituted with 1 , 2 or 3 additional substituents selected from halogen, CN, (CH2)nORa, (CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc,
(CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc, (CH2)nNRdSO2Ra, (CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra, (CH2)nSO2NRbRc, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl.
31 . The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from indolyl, indazolyl, benzimidazolyl, benzoxazolyl and benzoisoxazolyl, each optionally substituted with 1 , 2, 3 or 4 substituents selected from halogen, CN, oxo, (CH2)nORa, (CH2)nOC(O)Ra, (CH2)nOC(O)ORa, (CH2)nOC(O)NRbRc, (CH2)nNRbRc, (CH2)nNRdC(O)Ra, (CH2)nNRdC(O)ORa, (CH2)nNRdC(O)NRbRc, (CH2)nNRdC(O)C(O)NRbRc, (CH2)nNRdC(S)Ra, (CH2)nNRdC(S)ORa, (CH2)nNRdC(S)NRbRc,
(CH2)nNRdC(NRe)NRbRc, (CH2)nNRdS(O)Ra, (CH2)nNRdSO2Ra,
(CH2)nNRdSO2NRbRc, (CH2)nC(O)Ra, (CH2)nC(O)ORa, (CH2)nC(O)NRbRc, (CH2)nC(S)Ra, (CH2)nC(S)ORa, (CH2)nC(S)NRbRc, (CH2)nC(NRe)NRbRc, (CH2)nSRa, (CH2)nS(O)Ra, (CH2)nSO2Ra, (CH2)nSO2NRbRc, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8
membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl, wherein each of the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)nC3-8 cycloalkyl, (CH2)n3-8 membered heterocycloalkyl, (CH2)nphenyl, (CH2)nnaphthyl and (CH2)n5-10 membered heteroaryl groups is optionally substituted with 1 , 2, 3, 4 or 5 Rf substituents.
32. The compound of any one of claims 1 to 31 , or a pharmaceutically acceptable salt thereof, wherein R1 is selected from hydrogen, halogen, CN, CF3 and methyl.
33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.
34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from hydrogen, halogen, CN, CF3 and methyl.
35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen.
36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen.
37. A compound selected from the compounds in Table 2, or a
pharmaceutically acceptable salt thereof.
38. A pharmaceutical composition comprising a compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof.
39. The pharmaceutical composition of claim 38, wherein the
pharmaceutical composition is formulated for oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration.
40. The pharmaceutical composition of claim 39, wherein the
pharmaceutical composition is formulated for oral administration.
41 . The use of a compound of any one of claims 1 to 37, or a
pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disease or condition selected from neuromuscular disorders, conditions of muscle wasting, muscular myopathies, rehabilitation- related deficits, peripheral vascular disease, peripheral arterial disease, frailty, muscle atrophy and fatigue, metabolic syndrome, chronic fatigue syndrome, and obesity.
42. The use of a compound of any one of claims 1 to 37, or a
pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disease selected from Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA) and myasthenia gravis.
43. The use of a compound of any one of claims 1 to 37, or a
pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disease selected from peripheral vascular disease and peripheral arterial disease.
PCT/US2011/033605 2010-04-23 2011-04-22 Certain amino-pyridazines, compositions thereof, and methods of their use Ceased WO2011133882A1 (en)

Priority Applications (24)

Application Number Priority Date Filing Date Title
KR1020187002999A KR101960642B1 (en) 2010-04-23 2011-04-22 Certain amino-pyridazines, compositions thereof, and methods of their use
KR1020127029537A KR101825735B1 (en) 2010-04-23 2011-04-22 Certain amino-pyridazines, compositions thereof, and methods of their use
CA2796390A CA2796390C (en) 2010-04-23 2011-04-22 Amino-pyridazine skeletal muscle modulators
EP11772778.4A EP2563365B1 (en) 2010-04-23 2011-04-22 Certain amino-pyridazines, compositions thereof, and methods of their use
PH1/2012/502097A PH12012502097B1 (en) 2010-04-23 2011-04-22 Certain amino-pyridazines, compositions thereof, and methods of their use
US13/642,207 US8969346B2 (en) 2010-04-23 2011-04-22 Amino-pyridazine skeletal muscle modulators
EA201201377A EA024881B1 (en) 2010-04-23 2011-04-22 Certain amino-pyridazines, compositions thereof, and methods of their use
SG2012077871A SG184954A1 (en) 2010-04-23 2011-04-22 Certain amino-pyridazines, compositions thereof, and methods of their use
HK13109022.8A HK1181662B (en) 2010-04-23 2011-04-22 Certain amino-pyridazines, compositions thereof, and methods of their use
CN201180021470.0A CN103002897B (en) 2010-04-23 2011-04-22 Certain amino-pyridazines, compositions thereof, and methods of use thereof
MX2012012259A MX343264B (en) 2010-04-23 2011-04-22 CERTAIN AMINO-PYRIDAZINES, COMPOSITIONS OF THE SAME AND METHODS OF USE OF THE SAME.
MYPI2012004644A MY191829A (en) 2010-04-23 2011-04-22 Certain amino-pyridazines, compositions thereof, and methods of their use
BR112012026950-0A BR112012026950B1 (en) 2010-04-23 2011-04-22 AMINO PYRIDAZINE COMPOUNDS USEFUL IN MODULATING SKELETAL MUSCLE CONTRATILITY, PHARMACEUTICAL COMPOSITIONS AND USE OF COMPOUNDS
JP2013506327A JP5918217B2 (en) 2010-04-23 2011-04-22 Specific aminopyridazines, compositions thereof, and methods of use thereof
NZ603593A NZ603593A (en) 2010-04-23 2011-04-22 Certain amino-pyridazines, compositions thereof, and methods of their use
EP16166061.8A EP3127541B1 (en) 2010-04-23 2011-04-22 Certain amino-pyridazines, compositions thereof, and methods of their use
AU2011242569A AU2011242569B2 (en) 2010-04-23 2011-04-22 Certain amino-pyridazines, compositions thereof, and methods of their use
IL222465A IL222465A (en) 2010-04-23 2012-10-15 Certain amino-pyridazines, compositions thereof and methods for their use
US14/594,274 US9604965B2 (en) 2010-04-23 2015-01-12 Substituted pyridazines as skeletal muscle modulators
AU2016202617A AU2016202617B2 (en) 2010-04-23 2016-04-26 Certain amino-pyridazines, compositions thereof, and methods of their use
IL250824A IL250824B (en) 2010-04-23 2017-02-27 Certain amino-pyridazines, compositions thereof, and methods of their use
US15/463,288 US10076519B2 (en) 2010-04-23 2017-03-20 Substituted pyridazines as skeletal muscle modulators
PH12017501192A PH12017501192A1 (en) 2010-04-23 2017-06-23 Certain amino-pyridazines, compositions thereof, and methods of their use
AU2018201953A AU2018201953B2 (en) 2010-04-23 2018-03-19 Certain amino-pyridazines, compositions thereof, and methods of their use

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US32753810P 2010-04-23 2010-04-23
US61/327,538 2010-04-23
US41230210P 2010-11-10 2010-11-10
US61/412,302 2010-11-10

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US13/642,207 A-371-Of-International US8969346B2 (en) 2010-04-23 2011-04-22 Amino-pyridazine skeletal muscle modulators
US14/594,274 Continuation US9604965B2 (en) 2010-04-23 2015-01-12 Substituted pyridazines as skeletal muscle modulators

Publications (1)

Publication Number Publication Date
WO2011133882A1 true WO2011133882A1 (en) 2011-10-27

Family

ID=44834527

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2011/033605 Ceased WO2011133882A1 (en) 2010-04-23 2011-04-22 Certain amino-pyridazines, compositions thereof, and methods of their use

Country Status (21)

Country Link
US (3) US8969346B2 (en)
EP (2) EP2563365B1 (en)
JP (2) JP5918217B2 (en)
KR (2) KR101960642B1 (en)
CN (2) CN103002897B (en)
AR (1) AR081626A1 (en)
AU (3) AU2011242569B2 (en)
BR (1) BR112012026950B1 (en)
CA (1) CA2796390C (en)
CL (1) CL2012002945A1 (en)
CO (1) CO6630154A2 (en)
EA (1) EA024881B1 (en)
EC (1) ECSP12012292A (en)
IL (2) IL222465A (en)
MX (1) MX343264B (en)
MY (1) MY191829A (en)
NZ (2) NZ603593A (en)
PH (2) PH12012502097B1 (en)
SG (2) SG10201700219XA (en)
TW (1) TWI501963B (en)
WO (1) WO2011133882A1 (en)

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013061297A1 (en) * 2011-10-28 2013-05-02 Pfizer Limited Pyridazine Derivatives Useful in Therapy
JP2013536873A (en) * 2010-09-06 2013-09-26 グアンジョウ インスティテュート オブ バイオメディスン アンド ヘルス，チャイニーズ アカデミー オブ サイエンスィズ Amide compounds
WO2014028459A1 (en) * 2012-08-13 2014-02-20 Novartis Ag 1,4-disubstituted pyridazine analogs and methods for treating smn-deficiency-related conditions
JP2014533721A (en) * 2011-11-28 2014-12-15 ノバルティス アーゲー Novel trifluoromethyl-oxadiazole derivatives and their use in the treatment of diseases
US8962632B2 (en) 2010-04-23 2015-02-24 Cytokinetics, Inc. Certain amino-pyrimidines, compositions thereof, and methods for their use
US9040712B2 (en) 2013-01-23 2015-05-26 Novartis Ag Thiadiazole analogs thereof and methods for treating SMN-deficiency-related-conditions
US9133123B2 (en) 2010-04-23 2015-09-15 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
WO2015157005A1 (en) 2014-04-10 2015-10-15 E I Du Pont De Nemours And Company Substituted tolyl fungicide mixtures
US9403815B2 (en) 2010-06-24 2016-08-02 The Regents Of The University Of California Compounds and uses thereof in modulating levels of various amyloid beta peptide alloforms
KR20160108281A (en) 2016-09-06 2016-09-19 충남대학교산학협력단 Compounds with cardiac myosin activating function and pharmaceutical composition containing the same for treating or preventing heart failure
KR20170000426A (en) 2015-06-23 2017-01-03 충남대학교산학협력단 Chromenones derivatives with cardiac myosin activating function and pharmaceutical composition containing thereof for preventing or treating heart failure
US9604965B2 (en) 2010-04-23 2017-03-28 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
WO2017139526A1 (en) 2016-02-12 2017-08-17 Astellas Pharma Inc. Tetrahydroisoquinoline derivatives
US9938263B2 (en) 2013-03-12 2018-04-10 The General Hospital Corporation Gamma-secretase modulators
JP2018131460A (en) * 2012-04-02 2018-08-23 サイトキネティックス， インコーポレイテッド Methods for improving diaphragm function
US10472346B2 (en) 2014-10-31 2019-11-12 The General Hospital Corporation Potent gamma-secretase modulators
WO2020097266A1 (en) * 2018-11-06 2020-05-14 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
WO2020097265A1 (en) * 2018-11-06 2020-05-14 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
WO2020097012A1 (en) 2018-11-06 2020-05-14 Fmc Corporation Substituted tolyl as fungicides
US10906888B2 (en) 2016-07-14 2021-02-02 Pfizer Inc. Pyrimidine carboxamides as inhibitors of Vanin-1 enzyme
US11142516B2 (en) 2017-12-26 2021-10-12 Cytokinetics, Inc. Process for the preparation of an amino-pyrimidine and intermediates thereof
CN113543783A (en) * 2018-12-31 2021-10-22 西奈山伊坎医学院 Kinase inhibitor compounds and compositions and methods of use
WO2021226234A1 (en) 2020-05-06 2021-11-11 Fmc Corporation Substituted tolyl fungicides and their mixtures
WO2022150585A1 (en) * 2021-01-08 2022-07-14 Ifm Due, Inc. Heterobicyclic compounds having an urea or analogue and their compositions for treating conditions associated with sting activity
US11390606B2 (en) 2018-11-06 2022-07-19 Edgewise Therapecutics, Inc. Pyridazinone compounds and uses thereof
US11427558B1 (en) 2019-07-11 2022-08-30 ESCAPE Bio, Inc. Indazoles and azaindazoles as LRRK2 inhibitors
US11547712B2 (en) 2017-11-20 2023-01-10 Icahn School Of Medicine At Mount Sinai Kinase inhibitor compounds and compositions and methods of use
US11672799B2 (en) 2013-07-31 2023-06-13 Novartis Ag 1,4-disubstituted pyridazine quinolne analogs there of and methods for treating SMN-deficiency-related conditions
US11788064B2 (en) 2018-01-05 2023-10-17 Icahn School Of Medicine At Mount Sinai Method of increasing proliferation of pancreatic beta cells, treatment method, and composition
WO2023209368A1 (en) * 2022-04-26 2023-11-02 Cerevance, Inc. Nitrogen comprising heterocyclic derivatives for the treatment of disorders associated with gpr55 receptor
US11866427B2 (en) 2018-03-20 2024-01-09 Icahn School Of Medicine At Mount Sinai Kinase inhibitor compounds and compositions and methods of use
WO2024064745A1 (en) 2022-09-21 2024-03-28 Cytokinetics, Incorporated Synthesis of reldesemtiv
US12391667B2 (en) 2019-07-22 2025-08-19 Boehringer Ingelheim International Gmbh N-methyl, n-(6-(methoxy)pyridazin-3-yl) amine derivatives as Autotaxin (ATX) modulators for the treatment of inflammatory airway or fibrotic diseases
WO2025184010A1 (en) * 2024-03-01 2025-09-04 Merck Sharp & Dohme Llc N-biaryl sulfonamides as modulators of the hippo pathway
EP4461729A4 (en) * 2022-01-07 2026-03-25 Transthera Sciences Nanjing Inc Antigen-binding protein targeting MSLN and its use

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20140069235A (en) 2011-09-27 2014-06-09 노파르티스 아게 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh
UY34632A (en) 2012-02-24 2013-05-31 Novartis Ag OXAZOLIDIN- 2- ONA COMPOUNDS AND USES OF THE SAME
US9296733B2 (en) 2012-11-12 2016-03-29 Novartis Ag Oxazolidin-2-one-pyrimidine derivative and use thereof for the treatment of conditions, diseases and disorders dependent upon PI3 kinases
EP2970240B1 (en) 2013-03-14 2018-01-10 Novartis AG 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh
MX2016012208A (en) 2014-03-20 2017-01-26 Samumed Llc 5-substituted indazole-3-carboxamides and preparation and use thereof.
HUE057533T2 (en) 2014-04-29 2022-05-28 Cytokinetics Inc Methods of reducing decline in vital capacity
KR101720851B1 (en) * 2015-01-29 2017-03-28 포항공과대학교 산학협력단 Nanovesicles derived from cell membrane and use thereof
JP7312749B2 (en) 2017-08-04 2023-07-21 スカイホーク・セラピューティクス・インコーポレーテッド Methods and compositions for modulating splicing
EP3694503B1 (en) 2017-10-09 2023-08-02 Merck Sharp & Dohme LLC Novel substituted cyclobutylpyridine and cyclobutylpyrimidine compounds as indoleamine 2,3-dioxygenase (ido) inhibitors
WO2020163405A1 (en) 2019-02-05 2020-08-13 Skyhawk Therapeutics, Inc. Methods and compositions for modulating splicing
JP7551629B2 (en) 2019-02-05 2024-09-17 スカイホーク・セラピューティクス・インコーポレーテッド Methods and compositions for modulating splicing
JP7603594B2 (en) 2019-02-06 2024-12-20 スカイホーク・セラピューティクス・インコーポレーテッド Methods and compositions for modulating splicing
JP7603595B2 (en) 2019-02-06 2024-12-20 スカイホーク・セラピューティクス・インコーポレーテッド Methods and compositions for modulating splicing
WO2021055797A1 (en) * 2019-09-18 2021-03-25 Prelude Therapeutics, Incorporated Selective inhibitors of protein arginine methyltransferase 5 (prmt5)
WO2021071983A1 (en) * 2019-10-08 2021-04-15 Skyhawk Therapeutics, Inc. Compounds for modulating splicing
WO2021071981A1 (en) * 2019-10-08 2021-04-15 Skyhawk Therapeutics, Inc. Compounds for modulating splicing
WO2022099011A1 (en) 2020-11-06 2022-05-12 Cytokinetics, Inc. Bicyclic 1,4-diazepanones and therapeutic uses thereof
CN112772662B (en) * 2021-01-13 2022-02-15 南方科技大学 Application of small molecular compound in promoting plant growth and development
KR20220150625A (en) 2021-05-04 2022-11-11 주식회사 엘지화학 Method of manufacturing heterocyclic compound including nitrogen, heterocyclic compound including nitrogen, and medical or agriculture supplies comprising the same
WO2024006956A2 (en) * 2022-06-30 2024-01-04 Dana-Farber Cancer Institute, Inc. Deubiquitinase inhibitors and methods of use thereof
WO2024094185A1 (en) * 2022-11-04 2024-05-10 药捷安康(南京)科技股份有限公司 Nlrp3 inflammasome inhibitor and use thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007075377A2 (en) * 2005-12-15 2007-07-05 Cytokinetics, Inc. Certain chemical entities, compositions and methods
US20080318899A1 (en) * 2004-11-02 2008-12-25 Martin Watterson Pyridazine Compounds, Compositions and Methods

Family Cites Families (254)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH361573A (en) 1957-07-12 1962-04-30 Cilag Chemie Aktiengesellschaf Process for the preparation of new 5-aminomethyl-pyrimidines
US3239345A (en) 1965-02-15 1966-03-08 Estrogenic compounds and animal growth promoters
NL155156B (en) * 1968-07-11 1977-11-15 Philips Nv SWITCHING DEVICE FOR GENERATING, IN A TELEVISION DISPLAY DEVICE, A IMAGE CONTROL FREQUENCY SAW TOOTH-SHAPED CURRENT WITH A GRID FREQUENTLY VARYING AMPLITUDE.
US4411890A (en) 1981-04-14 1983-10-25 Beckman Instruments, Inc. Synthetic peptides having pituitary growth hormone releasing activity
GB1345880A (en) * 1971-06-18 1974-02-06 Cepbepe Pyridazine derivatives
US4036979A (en) 1974-01-25 1977-07-19 American Cyanamid Company Compositions containing 4,5,6,7-tetrahydrobenz[b]thien-4-yl-ureas or derivatives and methods of enhancing growth rate
US4157392A (en) 1977-05-17 1979-06-05 Diamond Shamrock Corporation Pharmacologically active substituted 1,2,4-triazines
HU175471B (en) 1977-06-13 1980-08-28 Gyogyszerkutato Intezet SPOSOB POLUCHENIA NOVYKH PROIZVODNYKH 3-SKOBKA-1-PIRAZOLIL-SKOBKA ZAKRYTA-PIRIDAZINA
DE2730467A1 (en) 1977-07-06 1979-01-18 Basf Ag BENZYLPYRIMIDINE, METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THE SAME
FR2510997A1 (en) * 1981-08-10 1983-02-11 Sanofi Sa NOVEL DERIVATIVES OF METHYL-4-PHENYL-6-PYRIDAZINE, PROCESS FOR THEIR PREPARATION AND ACTIVE MEDICINES ON CENTRAL NERVOUS SYSTEM CONTAINING THE SAME
US4565814A (en) 1983-01-28 1986-01-21 Sanofi Pyridazine derivatives having a psychotropic action and compositions
FR2540115B1 (en) 1983-01-28 1985-06-07 Sanofi Sa PYRIDAZINE DERIVATIVE HAVING PSYCHOTROPIC ACTION, METHOD OF PREPARATION THEREOF AND MEDICAMENTS CONTAINING SAME
US4868183A (en) 1986-07-21 1989-09-19 Otsuka Pharmaceutical Factory, Inc. N-pyrazinyl substituted P-aminophenols
JPS63165376A (en) 1986-12-27 1988-07-08 Nippon Soda Co Ltd Oxa(thia)diazole derivative and production thereof and acaricidal agent
KR960012208B1 (en) 1987-06-25 1996-09-16 일라이 릴리 앤드 캄파니 Process for preparing ureas and carbamates and carbamate derivatives
AU628322B2 (en) 1988-01-28 1992-09-17 Eastman Kodak Company Polypeptide compounds having growth hormone releasing activity
DE68922602T2 (en) 1988-01-28 1995-12-07 Polygen Holding Corp POLYPEPTIDES WITH A HORMONE GROWTH RELEASING EFFECT.
JPH01261381A (en) 1988-04-12 1989-10-18 Nippon Soda Co Ltd Oxa(thia)diazole derivative, its production and miticide
FR2636628B1 (en) 1988-08-25 1990-12-28 Sanofi Sa THIADIAZOLE-1,3,4 DERIVATIVES, PROCESS FOR OBTAINING SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
JPH02164863A (en) 1988-12-15 1990-06-25 Otsuka Pharmaceut Co Ltd Production of p-aminophenol derivative
US5461053A (en) * 1989-02-07 1995-10-24 Sanofi Pyridazine derivatives
FR2663326B2 (en) 1989-11-17 1992-10-16 Sanofi Sa PYRIDAZINE DERIVATIVES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME.
US5631255A (en) 1989-02-07 1997-05-20 Sanofi Pyridazine derivatives
GR900100380A (en) 1989-05-20 1991-10-10 Fisons Plc Method of preparation of anti-inflammatory derivatives of aminophenol.
IL96891A0 (en) 1990-01-17 1992-03-29 Merck Sharp & Dohme Indole-substituted five-membered heteroaromatic compounds,their preparation and pharmaceutical compositions containing them
GB9008123D0 (en) 1990-04-10 1990-06-06 Lilly Industries Ltd Pharmaceutical compounds
US5208248A (en) 1991-01-11 1993-05-04 Merck Sharpe & Dohme, Ltd. Indazole-substituted five-membered heteroaromatic compounds
US5317103A (en) 1991-01-15 1994-05-31 Merck Sharp & Dohme Limited Indole-substituted five-membered heteroaromatic compounds as 5-HT1 agonists
JP2651755B2 (en) 1991-03-01 1997-09-10 富士写真フイルム株式会社 Silver halide color photographic materials
AU1422392A (en) 1991-03-22 1992-10-21 Nippon Soda Co., Ltd. 2-substituted pyridine derivative, production thereof, and agrohorticultural bactericide
US5114958A (en) 1991-05-09 1992-05-19 Warner-Lambert Company 1,2,4-oxadiazole and 1,2,4-thiadiazole derivatives of fenamates as antiinflammatory agents
FR2676444B1 (en) 1991-05-16 1995-03-10 Sanofi Elf NOVEL AMINO-3 PYRIDAZINE DERIVATIVES ACTIVE IN THE CENTRAL NERVOUS SYSTEM, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME.
US5492919A (en) 1991-08-03 1996-02-20 Smithkline Beecham P.L.C. 5-HT4 receptor antagonists
US5663146A (en) 1991-08-22 1997-09-02 Administrators Of The Tulane Educational Fund Polypeptide analogues having growth hormone releasing activity
JPH05117255A (en) 1991-10-25 1993-05-14 Nippon Soda Co Ltd Oxadiazole and thiadiazole derivative and their production
WO1993019054A1 (en) 1992-03-26 1993-09-30 Dowelanco N-heterocyclic nitro anilines as fungicides
US5654322A (en) 1992-08-11 1997-08-05 Wakunaga Seiyaku Kabushiki Kaisha Biphenylmethane derivatives and pharmaceuticals containing the same
EP0703782A1 (en) 1993-06-15 1996-04-03 Pfizer Inc. H2-antagonists as immune stimulants in bacterial infections of cattle or swine
ZW8594A1 (en) 1993-08-11 1994-10-12 Bayer Ag Substituted azadioxacycbalkenes
US5776983A (en) 1993-12-21 1998-07-07 Bristol-Myers Squibb Company Catecholamine surrogates useful as β3 agonists
DE4424788A1 (en) 1993-12-22 1995-06-29 Bayer Ag Arylacetic acid derivatives
US6008257A (en) 1994-01-28 1999-12-28 Bayer Aktiengesellschaft Hydroxamic-acid derivatives, method of preparing them and their use as fungicides
GB9405347D0 (en) 1994-03-18 1994-05-04 Agrevo Uk Ltd Fungicides
US6334997B1 (en) 1994-03-25 2002-01-01 Isotechnika, Inc. Method of using deuterated calcium channel blockers
CN1087725C (en) 1994-03-25 2002-07-17 同位素技术有限公司 Enhancement of the effect of drugs by deuteration
US5488064A (en) 1994-05-02 1996-01-30 Bristol-Myers Squibb Company Benzo 1,3 dioxole derivatives
US5922751A (en) 1994-06-24 1999-07-13 Euro-Celtique, S.A. Aryl pyrazole compound for inhibiting phosphodiesterase IV and methods of using same
MX9701764A (en) 1994-09-09 1997-06-28 Bayer Ag Imidic acid derivatives and their use as pesticides.
US5491134A (en) 1994-09-16 1996-02-13 Bristol-Myers Squibb Company Sulfonic, phosphonic or phosphiniic acid β3 agonist derivatives
US5541204A (en) 1994-12-02 1996-07-30 Bristol-Myers Squibb Company Aryloxypropanolamine β 3 adrenergic agonists
MX9708802A (en) 1995-05-17 1998-02-28 Du Pont Fungicidal cyclic amides.
TW434240B (en) 1995-06-20 2001-05-16 Zeneca Ltd Aromatic compounds, preparation thereof and pharmaceutical composition comprising same
KR19990028230A (en) 1995-06-20 1999-04-15 미리암 디. 메코너헤이 Anthracnose and fungicidal cyclic amides
TW502026B (en) 1995-06-20 2002-09-11 Zeneca Ltd Aromatic compounds useful as antagonists of e-type prostaglandins, processes for the preparation thereof, pharmaceutical compositions comprising the compounds, and intermediates
EP0752421B1 (en) 1995-07-07 2005-10-12 AstraZeneca AB Ortho-substituted aromatic compounds, containing three (het)aryl moieties, their preparation and their use as prostaglandin E2-(PGE2)-antagonists
DE19525969A1 (en) 1995-07-17 1997-01-23 Bayer Ag Ether derivatives
US20070173465A9 (en) 1995-10-11 2007-07-26 Monahan Sean D Expression of zeta negative and zeta positive nucleic acids using a dystrophin gene
CN1056370C (en) 1995-10-17 2000-09-13 化学工业部沈阳化工研究院 4-aryloxy (arylthio or arylamino) pyrimidine derivative with herbicide active, and method for prepn. of same
AU717743B2 (en) 1995-12-13 2000-03-30 Regents Of The University Of California, The Nuclear receptor ligands and ligand binding domains
US6114537A (en) 1996-02-26 2000-09-05 Apotex Inc. Process for scavenging thiols
WO1997036897A1 (en) 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US5854265A (en) 1996-04-03 1998-12-29 Merck & Co., Inc. Biheteroaryl inhibitors of farnesyl-protein transferase
US5883105A (en) 1996-04-03 1999-03-16 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1997036898A1 (en) 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1997036881A1 (en) 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
AU706497B2 (en) 1996-04-03 1999-06-17 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US5874452A (en) 1996-04-03 1999-02-23 Merck & Co., Inc. Biheteroaryl inhibitors of farnesyl-protein transferase
US5859035A (en) 1996-04-03 1999-01-12 Merck & Co., Inc. Arylheteroaryl inhibitors of farnesyl-protein transferase
US5770615A (en) 1996-04-04 1998-06-23 Bristol-Myers Squibb Company Catecholamine surrogates useful as β3 agonists
TW414795B (en) 1996-07-01 2000-12-11 Yamanouchi Pharma Co Ltd A thiophene derivative and the pharmaceutical composition
BR9711816A (en) 1996-08-01 1999-08-31 Du Pont Compound, fungicidal composition, method to control plant diseases caused by plant fungal pathogens, arthropodicidal composition and method to control arthropods.
WO1998023155A1 (en) 1996-11-26 1998-06-04 E.I. Du Pont De Nemours And Company Arthropodicidal and fungicidal cyclic amides
US6187797B1 (en) 1996-12-23 2001-02-13 Dupont Pharmaceuticals Company Phenyl-isoxazoles as factor XA Inhibitors
US5939439A (en) 1996-12-30 1999-08-17 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
AR011164A1 (en) 1997-02-28 2000-08-02 Lilly Co Eli HETEROCICLIC COMPOUNDS, PHARMACEUTICAL COMPOSITIONS THAT UNDERSTAND THEM, AND METHODS TO INHIBIT THE RELEASE OF THE BETA-AMYLOID PEPTIDE AND / OR ITS SYNTHESIS THROUGH THE USE OF SUCH COMPOUNDS
US6699853B2 (en) 1997-06-16 2004-03-02 Hoechst Schering Agrevo Gmbh 4-haloalkyl-3-heterocyclylpyridines, 4-haloalkyl-5-heterocyclyl-pyrimidines and 4-trifluoromethyl-3-oxadiazolylpyridines, processes for their preparation, compositions comprising them, and their use as pesticides
DE19725450A1 (en) 1997-06-16 1998-12-17 Hoechst Schering Agrevo Gmbh 4-Haloalkyl-3-heterocyclylpyridines and 4-haloalkyl-5-heterocyclylpyrimidines, processes for their preparation, compositions containing them and their use as pesticides
GB9713739D0 (en) 1997-06-27 1997-09-03 Karobio Ab Thyroid receptor ligands
GB9716446D0 (en) 1997-08-05 1997-10-08 Agrevo Uk Ltd Fungicides
AU3289299A (en) 1998-02-19 1999-09-06 Tularik Inc. Antiviral agents
US6506782B1 (en) 1998-02-27 2003-01-14 Athena Neurosciences, Inc. Heterocyclic compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
DE19824175A1 (en) 1998-05-29 1999-12-02 Novartis Ag Amino azole compounds
TR200100462T2 (en) 1998-08-18 2001-09-21 Ucb, S.A. Muscarinic agonists and antagonists
AU1324300A (en) 1998-10-26 2000-05-15 Vertex Pharmaceuticals Incorporated Pentacyclic compounds useful as inhibitors of hepatitis c virus ns3 helicase
AU1455500A (en) 1998-10-29 2000-05-22 Trega Biosciences, Inc. Oxadiazole, thiadiazole and triazole derivatives and combinatorial libraries thereof
US20040053900A1 (en) * 1998-12-23 2004-03-18 Pharmacia Corporation Method of using a COX-2 inhibitor and an aromatase inhibitor as a combination therapy
GB9828442D0 (en) 1998-12-24 1999-02-17 Karobio Ab Novel thyroid receptor ligands and method II
EP1394150B1 (en) 1999-02-24 2011-01-19 F. Hoffmann-La Roche AG 4-Phenylpyridine derivatives and their use as NK-1 receptor antagonists
JP2000281579A (en) 1999-03-29 2000-10-10 Sumitomo Pharmaceut Co Ltd Proteoglycan production promoter containing oxadiazolyl-1,4-dihydropyridine derivative
US6548529B1 (en) 1999-04-05 2003-04-15 Bristol-Myers Squibb Company Heterocyclic containing biphenyl aP2 inhibitors and method
US6410254B1 (en) 1999-05-18 2002-06-25 Cytokinetics Compositions and assays utilizing ADP or phosphate for detecting protein modulators
US7202051B1 (en) 1999-05-18 2007-04-10 Cytokinetics, Inc. Compositions and assays utilizing ADP or phosphate for detecting protein modulators
US6743599B1 (en) 1999-05-18 2004-06-01 Cytokinetics, Inc. Compositions and assays utilizing ADP or phosphate for detecting protein modulators
WO2001007032A1 (en) 1999-07-23 2001-02-01 Shionogi & Co., Ltd. Th2 differentiation inhibitors
WO2001012625A2 (en) 1999-08-12 2001-02-22 Basf Aktiengesellschaft Substituted benzoxazoles
EP1078632A1 (en) * 1999-08-16 2001-02-28 Sanofi-Synthelabo Use of monoamine oxydase inhibitors for the manufacture of drugs intended for the treatment of obesity
JP4144978B2 (en) 1999-09-09 2008-09-03 富士フイルム株式会社 Synthesis method of 1,2,4-thiadiazole derivatives
US6632815B2 (en) 1999-09-17 2003-10-14 Millennium Pharmaceuticals, Inc. Inhibitors of factor Xa
US6844367B1 (en) 1999-09-17 2005-01-18 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
WO2001021160A2 (en) 1999-09-23 2001-03-29 Axxima Pharmaceuticals Aktiengesellschaft Carboxymide and aniline derivatives as selective inhibitors of pathogens
GB9927844D0 (en) 1999-11-26 2000-01-26 Glaxo Group Ltd Chemical compounds
KR20020058046A (en) 1999-11-29 2002-07-12 한스 루돌프 하우스, 헨리테 브룬너, 베아트리체 귄터 Pesticidal N-Heteroaryl Alpha-Alkoximino-Carboxamides
US6673820B2 (en) 1999-12-02 2004-01-06 Novartis Animal Health Us, Inc. Aminoheterocyclylamides as pesticides and antiparasitic agents
US6602872B1 (en) 1999-12-13 2003-08-05 Merck & Co., Inc. Substituted pyridazines having cytokine inhibitory activity
WO2001046165A2 (en) 1999-12-16 2001-06-28 Novartis Ag N-heteroaryl-amides and their use as parasiticides
TWI284639B (en) 2000-01-24 2007-08-01 Shionogi & Co A compound having thrombopoietin receptor agonistic effect
AU2001233044A1 (en) 2000-01-28 2001-08-07 Akkadix Corporation Methods for killing nematodes and nematode eggs using bis-amino-1,2,4-thiadiazoles
DE10006453A1 (en) 2000-02-14 2001-08-16 Bayer Ag New piperidylcarboxylic acid derivatives, are integrin antagonists useful for treating inflammatory, autoimmune or immunological diseases, e.g. atherosclerosis, asthma, diabetes, rheumatoid arthritis or transplant rejection
US7078536B2 (en) 2001-03-14 2006-07-18 Genesoft Pharmaceuticals, Inc. Charged compounds comprising a nucleic acid binding moiety and uses therefor
CN1431896A (en) 2000-04-04 2003-07-23 盐野义制药株式会社 Oily compsns. contg. highly fat-soluble drugs
WO2001076582A1 (en) 2000-04-05 2001-10-18 Shionogi & Co., Ltd. Oil-in-water microemulsions containing tricyclic compounds or preconcentrates thereof
AU2001268711A1 (en) 2000-06-23 2002-01-08 Bristol-Myers Squibb Pharma Company Heteroaryl-phenyl substituted factor xa inhibitors
EP1296982B1 (en) 2000-06-23 2007-09-19 Bristol-Myers Squibb Pharma Company 1-(heteroaryl-phenyl)-condensed pyrazol derivatives as factor xa inhibitors
PE20020384A1 (en) 2000-07-21 2002-05-28 Schering Corp PEPTIDES AS INHIBITORS OF THE HEPATITIS C VIRUS SERINE NS3 / NS4a PROTEASE
EP1178035B1 (en) 2000-08-04 2008-07-30 Bayer CropScience S.A. Fungicidal phenylimine derivatives
EP1178036A1 (en) 2000-08-04 2002-02-06 Aventis Cropscience S.A. Fungicidal phenylimidate derivatives
FR2812633A1 (en) 2000-08-04 2002-02-08 Aventis Cropscience Sa PHENYL (THIO) UREA AND PHENYL (THIO) CARBAMATE FUNGICIDES DERIVATIVES
EP1180512A1 (en) 2000-08-04 2002-02-20 Aventis Cropscience S.A. Fungicidal phenylimine derivatives
WO2002026712A2 (en) 2000-09-29 2002-04-04 Millennium Pharmaceuticals, Inc. Quaternary amines and related inhibitors of factor xa
US6667326B1 (en) 2000-11-16 2003-12-23 Novartis Animal Health Us, Inc. Pesticidal aminoheterocyclamide compounds
AUPR213700A0 (en) 2000-12-18 2001-01-25 Biota Scientific Management Pty Ltd Antiviral agents
JP2002212169A (en) 2001-01-12 2002-07-31 Sumitomo Pharmaceut Co Ltd 5-membered heteroaromatic compound
WO2002059099A1 (en) 2001-01-26 2002-08-01 Shionogi & Co., Ltd. Cyclic compounds having thrombopoietin receptor agonism
KR20040025891A (en) 2001-01-26 2004-03-26 시오노기세이야쿠가부시키가이샤 Halogen compounds having thrombopoietin receptor agonism
WO2002072145A1 (en) 2001-03-14 2002-09-19 Ono Pharmaceutical Co., Ltd. Remedies for depression containing ep1 antagonist as the active ingredient
US6960595B2 (en) 2001-03-23 2005-11-01 Bristol-Myers Squibb Pharma Company 5-6 to 5-7 Heterobicycles as factor Xa inhibitors
JP2002305083A (en) 2001-04-04 2002-10-18 Mitsubishi Chemicals Corp Organic electroluminescent device
KR20040004705A (en) 2001-06-08 2004-01-13 시토비아 인크. Substituted 3-aryl-5-aryl-[1,2,4]-oxadiazoles and analogs as activators of caspases and inducers of apoptosis and the use thereof
TWI331526B (en) 2001-09-21 2010-10-11 Bristol Myers Squibb Pharma Co Lactam-containing compounds and derivatives thereof as factor xa inhibitors
US6825221B2 (en) 2001-10-18 2004-11-30 Allergan, Inc. Arylsulfanyl and heteroarylsulfanyl derivatives for treating pain
US6921762B2 (en) 2001-11-16 2005-07-26 Amgen Inc. Substituted indolizine-like compounds and methods of use
JPWO2003043655A1 (en) 2001-11-19 2005-03-10 小野薬品工業株式会社 Frequent urine treatment
US20050113283A1 (en) 2002-01-18 2005-05-26 David Solow-Cordero Methods of treating conditions associated with an EDG-4 receptor
US6995144B2 (en) 2002-03-14 2006-02-07 Eisai Co., Ltd. Nitrogen containing heterocyclic compounds and medicines containing the same
US20040110757A1 (en) 2002-03-21 2004-06-10 Thomas Arrhenius Flt-1 ligands and their uses in the treatment of diseases regulatable by angiogenesis
CA2484233A1 (en) 2002-05-13 2003-11-27 Eli Lilly And Company Multicyclic compounds for use as melanin concentrating hormone antagonists in the treatment of obesity and diabetes
US7119111B2 (en) 2002-05-29 2006-10-10 Amgen, Inc. 2-oxo-1,3,4-trihydroquinazolinyl derivatives and methods of use
US7232616B2 (en) 2002-06-13 2007-06-19 Tsinghua University Organic electroluminescent materials and devices made from such materials
AU2003236720A1 (en) 2002-06-14 2003-12-31 Altana Pharma Ag Substituted diaminopyrimidines
AU2003244098A1 (en) 2002-06-28 2004-01-19 Yamanouchi Pharmaceutical Co., Ltd. Diaminopyrimidinecarboxa mide derivative
ES2295672T3 (en) 2002-08-07 2008-04-16 Neuraxon Inc. AMINOBENZOTIAZOL COMPOUNDS WITH INHIBITORY ACTIVITY OF NITRICO SINTASA OXIDE (NOS).
IL166510A0 (en) 2002-08-09 2006-01-15 Nps Pharma Inc 1,2,4"oxadiazole as modulators of metabotropic glutamate receptor-5
WO2004022561A1 (en) 2002-09-04 2004-03-18 Schering Corporation Pyrazolopyrimidines as cyclin-dependent kinase inhibitors
JP4487774B2 (en) 2002-09-30 2010-06-23 萬有製薬株式会社 2-aminobenzimidazole derivatives
EP1562938B1 (en) 2002-11-04 2007-08-29 Vertex Pharmaceuticals Incorporated Heteroaryl-pyrimidine derivatives as jak inhibitors
CA2505361A1 (en) 2002-11-11 2004-05-27 Bayer Healthcare Ag Phenyl or heteroaryl amino alkane derivatives as ip receptor antagonist
BR0317600A (en) 2002-12-20 2005-11-29 Pharmacia Corp heteroarylalkanoic acids as derivatives of integrin receptor antagonists
US20040147561A1 (en) 2002-12-27 2004-07-29 Wenge Zhong Pyrid-2-one derivatives and methods of use
US7202257B2 (en) 2003-12-24 2007-04-10 Deciphera Pharmaceuticals, Llc Anti-inflammatory medicaments
TW200418835A (en) 2003-01-24 2004-10-01 Tanabe Seiyaku Co A pyrazolopyrimidine compound and a process for preparing the same
CN100345853C (en) * 2003-01-24 2007-10-31 田边制药株式会社 Pyrazolopyrimidine compound and method for producing the same
AR042956A1 (en) 2003-01-31 2005-07-13 Vertex Pharma GIRASA INHIBITORS AND USES OF THE SAME
US7157455B2 (en) 2003-02-10 2007-01-02 Hoffmann-La Roche Inc. 4-Aminopyrimidine-5-one derivatives
US7223788B2 (en) 2003-02-14 2007-05-29 Sanofi-Aventis Deutschland Gmbh Substituted N-aryl heterocycles, process for their preparation and their use as medicaments
JP2006523184A (en) 2003-02-22 2006-10-12 メルク　パテント　ゲゼルシャフト　ミット　ベシュレンクテル　ハフトング Cyanopyridone derivatives as liquid crystals
US20050187266A1 (en) 2003-04-15 2005-08-25 Pfizer Inc Alpha substituted carboxylic acids
US7652044B2 (en) 2003-06-03 2010-01-26 Novartis A.G. P-38 inhibitors
JP2006526660A (en) 2003-06-05 2006-11-24 バーテックス　ファーマシューティカルズ　インコーポレイテッド VR1 receptor modulators
EP1354876B1 (en) 2003-06-13 2005-04-27 Les Laboratoires Servier Method for synthesis of (2S,3aS,7aS)-perhydroindole-2-carboxylic acid and esters thereof; and use in the synthesis of perindopril
WO2005000309A2 (en) 2003-06-27 2005-01-06 Ionix Pharmaceuticals Limited Chemical compounds
AU2004267094A1 (en) 2003-08-20 2005-03-03 Vertex Pharmaceuticals Incorporated (4 -amino -1,2, 5-oxadiazol-4-yl) -hetxiroaromatic compounds useful as protein kinase inhibitors
US7378409B2 (en) 2003-08-21 2008-05-27 Bristol-Myers Squibb Company Substituted cycloalkylamine derivatives as modulators of chemokine receptor activity
PT2213661E (en) 2003-09-26 2011-12-15 Exelixis Inc C-met modulators and methods of use
KR101104100B1 (en) 2003-11-19 2012-01-12 제이엔씨 석유 화학 주식회사 Photopolymerizable liquid crystal compositions, polymers or polymer compositions thereof, and optical compensation elements
JP4451849B2 (en) 2003-11-28 2010-04-14 日本曹達株式会社 Aryl heterocyclic derivatives and agricultural and horticultural fungicides and insecticides
GB0328295D0 (en) 2003-12-05 2004-01-07 Muscagen Ltd Therapeutic compounds
US20070191336A1 (en) 2003-12-24 2007-08-16 Flynn Daniel L Anti-inflammatory medicaments
US7319108B2 (en) 2004-01-25 2008-01-15 Sanofi-Aventis Deutschland Gmbh Aryl-substituted heterocycles, process for their preparation and their use as medicaments
WO2005077368A2 (en) 2004-02-03 2005-08-25 Astrazeneca Ab Treatment of gastro-esophageal reflux disease (gerd)
WO2005077345A1 (en) 2004-02-03 2005-08-25 Astrazeneca Ab Compounds for the treatment of gastro-esophageal reflux disease
WO2005077373A2 (en) 2004-02-03 2005-08-25 Astrazeneca Ab Treatment of gastro-esophageal reflux disease (gerd)
UA83416C2 (en) 2004-02-13 2008-07-10 Баниу Фармасьютикал Ко., Лтд. Fused ring 4-oxopyrimidine derivative
US7585881B2 (en) 2004-02-18 2009-09-08 Astrazeneca Ab Additional heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
DE102004008141A1 (en) 2004-02-19 2005-09-01 Abbott Gmbh & Co. Kg Guanidine compounds and their use as binding partners for 5-HT5 receptors
AU2005225471B2 (en) 2004-03-26 2011-05-12 Methylgene Inc. Inhibitors of histone deacetylase
JPWO2005095364A1 (en) 2004-03-30 2008-02-21 第一三共株式会社 Phenoxyacetic acid derivative and pharmaceutical using the same
WO2005095382A1 (en) 2004-03-30 2005-10-13 Kyowa Hakko Kogyo Co., Ltd. Anti-tumor agent
AU2005230902A1 (en) 2004-03-31 2005-10-20 Janssen Pharmaceutica, N.V. Non-imidazole heterocyclic compounds as histamine H3-receptor ligands
DE602005025222D1 (en) 2004-03-31 2011-01-20 Janssen Pharmaceutica Nv Heterocyclic nonimidazole compounds as histamine H3 receptor modulators
KR20070002081A (en) 2004-04-02 2007-01-04 버텍스 파마슈티칼스 인코포레이티드 Azaindole useful as an inhibitor of ROC and other protein kinases
US7439369B2 (en) 2004-06-22 2008-10-21 Loa Alamos National Security, Llc Method and system for hydrogen evolution and storage
ES2534605T3 (en) 2004-08-23 2015-04-24 Eli Lilly And Company Histamine H3 receptor agents, preparation and therapeutic uses
US7718801B2 (en) 2004-08-31 2010-05-18 Banyu Pharmaceutical Co., Ltd. Substituted imidazole derivative
US7767680B2 (en) * 2004-11-03 2010-08-03 Vertex Pharmaceuticals Incorporated Ion channel modulators and methods of use
EP1814883A1 (en) 2004-11-22 2007-08-08 Vertex Pharmaceuticals Incorporated Bicyclic inhibitors or rho kinase
MX2007006230A (en) 2004-11-30 2007-07-25 Amgen Inc Quinolines and quinazoline analogs and their use as medicaments for treating cancer.
US20070123572A1 (en) 2005-11-28 2007-05-31 Kalypsys, Inc. Novel method of preparation of 5-chloro-3-imidazol-1-yl-[1,2,4]thiadiazole and (3-imidazol-1-yl-[1,2,4]thiadiazol-5yl)-dialkyl-amines
US7786132B2 (en) 2004-12-17 2010-08-31 Amgen Inc. Aminopyrimidine compounds and methods of use
CA2589830A1 (en) 2005-01-05 2006-07-13 Rigel Pharmaceuticals, Inc. Ubiquitin ligase inhibitors
EP1954696B1 (en) 2005-01-19 2011-02-23 Bristol-Myers Squibb Company 2-phenoxy-n-(1,3,4-thiadizol-2-yl)pyridin-3-amine derivatives and related compounds as p2y1 receptor inhibitors for the treatment of thromboembolic disorders
AU2006208042A1 (en) * 2005-01-25 2006-08-03 Neurogen Corporation Substituted pyridazinyl-and pyrimidinyl-quinolin-4-ylamine analogues
DE602006010991D1 (en) 2005-01-26 2010-01-21 Schering Corp 3- (INDAZOL-5-YL) - (1,2,4) TRIAZINE DERIVATIVES AND RELATED COMPOUNDS AS PROTEIN KINASE INHIBITORS FOR THE TREATMENT OF CANCER
MX2007009388A (en) 2005-02-04 2007-09-25 Senomyx Inc Compounds comprising linked hetero aryl moieties and their use as novel umami flavor modifiers, tastants and taste enhancers for comestible compositions.
PT1853588E (en) 2005-02-16 2008-08-25 Astrazeneca Ab Chemical compounds
JP2006274133A (en) 2005-03-30 2006-10-12 Fuji Photo Film Co Ltd Liquid crystal composition, retardation plate, and elliptical polarization plate
US20080161305A1 (en) 2005-04-06 2008-07-03 Exelixis, Inc. C-Met Modulators and Methods of Use
US8350043B2 (en) 2005-06-07 2013-01-08 Pharmacopeia, Inc. Azinone and diazinone V3 inhibitors for depression and stress disorders
RU2499795C2 (en) 2005-07-04 2013-11-27 Хай Пойнт Фармасьютикалс, ЛЛС Histamine h3 receptor antagonists
WO2007012642A1 (en) 2005-07-29 2007-02-01 Basf Aktiengesellschaft 7-amino-6-thiadiazolyl- and -oxadiazolyl- 1, 2, 4-triazolo [1, 5 -a] pyrimidine compounds and use thereof for the prevention of fungal pests
EP1910385B1 (en) 2005-08-04 2013-07-24 Sirtris Pharmaceuticals, Inc. Benzothiazoles and thiazolopyridines as sirtuin modulators
US8093401B2 (en) 2005-08-04 2012-01-10 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
WO2007024922A1 (en) 2005-08-23 2007-03-01 Irm Llc Immunosuppressant compounds and compositions
JP2007093919A (en) 2005-09-28 2007-04-12 Fujifilm Corp Optical low-pass filter and manufacturing method thereof
JP2007093918A (en) 2005-09-28 2007-04-12 Fujifilm Corp Optical low-pass filter and manufacturing method thereof
WO2007037010A1 (en) 2005-09-29 2007-04-05 Daiichi Pharmaceutical Co., Ltd. Phenoxyacetic acid derivatives and drugs using the same
WO2007046809A1 (en) 2005-10-21 2007-04-26 Dow Agrosciences Llc Thieno-pyrimidine compounds having fungicidal activity
US7531482B2 (en) 2005-10-21 2009-05-12 Dow Agrosciences Llc Thieno-pyrimidine compounds having fungicidal activity
TW200800220A (en) * 2005-10-26 2008-01-01 Boehringer Ingelheim Int New (hetero)aryl compounds with MCH antagonistic activity and medicaments comprising these compounds
CN102775396B (en) 2005-11-08 2014-10-08 沃泰克斯药物股份有限公司 Modulators of ATP-binding cassette transporters
EP2455382B1 (en) 2005-12-13 2016-10-26 Incyte Holdings Corporation Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors
US7825120B2 (en) * 2005-12-15 2010-11-02 Cytokinetics, Inc. Certain substituted ((piperazin-1-ylmethyl)benzyl)ureas
EP1959962A2 (en) 2005-12-16 2008-08-27 Cytokinetics, Inc. Certain chemical entities, compositions, and methods
WO2007075896A2 (en) 2005-12-22 2007-07-05 Kemia, Inc. Heterocyclic cytokine inhibitors
WO2007076460A2 (en) 2005-12-23 2007-07-05 Kalypsys, Inc. Substituted thiazole ureas useful as inhibitors of protein kinases
CA2646429A1 (en) 2006-03-09 2007-09-13 Pharmacopeia, Inc. 8-heteroarylpurine mnk2 inhibitors for treating metabolic disorders
JP5243696B2 (en) * 2006-03-17 2013-07-24 田辺三菱製薬株式会社 Benzene derivatives
WO2007117399A2 (en) 2006-03-31 2007-10-18 Janssen Pharmaceutica N.V. Benzoimidazol-2-yl pyrimidines and pyrazines as modulators of the histamine h4 receptor
PE20080359A1 (en) 2006-04-19 2008-06-06 Novartis Ag BENZOXAZOLE AND BENZOTHIAZOLE 6-0-SUBSTITUTE COMPOUNDS AND METHODS OF INHIBITION OF CSF-1R SIGNALING
ZA200807263B (en) 2006-04-19 2009-11-25 Serono Lab Novel heteroaryl-substituted arylaminopyrldine derivatives as MEK inhibitors
WO2007130383A2 (en) * 2006-04-28 2007-11-15 Northwestern University Compositions and treatments using pyridazine compounds and secretases
US9150507B2 (en) * 2006-04-28 2015-10-06 Shionogi & Co., Ltd. Amine derivative having NPY Y5 receptor antagonistic activity
WO2007127475A2 (en) 2006-04-28 2007-11-08 Northwestern University Pyridazines for demyelinating diseases and neuropathic pain
CA2691214A1 (en) 2006-06-09 2007-12-21 Kemia, Inc. Therapy using cytokine inhibitors
US8435774B2 (en) 2006-06-28 2013-05-07 Qiagen Gmbh Enhancing reactivation of thermostable reversibly inactivated enzymes
PE20080401A1 (en) 2006-07-07 2008-06-23 Boehringer Ingelheim Int HETEROARYL-PHENYL DERIVATIVES SUBSTITUTED AS INHIBITORS OF B-Raf-KINASES
WO2008013622A2 (en) 2006-07-27 2008-01-31 E. I. Du Pont De Nemours And Company Fungicidal azocyclic amides
US8227603B2 (en) 2006-08-01 2012-07-24 Cytokinetics, Inc. Modulating skeletal muscle
CN101522681B (en) * 2006-08-02 2012-10-03 赛特凯恩蒂克公司 Specific chemical entities, compositions and methods
US20080103123A1 (en) 2006-08-30 2008-05-01 Biovitrum New compounds
WO2008063888A2 (en) 2006-11-22 2008-05-29 Plexxikon, Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
TW200831485A (en) * 2006-12-11 2008-08-01 Boehringer Ingelheim Int New pyridazine derivatives with MCH antagonistic activity and medicaments comprising these compounds
DE102007002717A1 (en) 2007-01-18 2008-07-24 Merck Patent Gmbh Heterocyclic indazole derivatives
WO2009011285A1 (en) 2007-07-13 2009-01-22 Taisho Pharmaceutical Co., Ltd. Heteroarylbenzene compounds
GB0720444D0 (en) * 2007-10-18 2007-11-28 Glaxo Group Ltd Novel compounds
US7943619B2 (en) * 2007-12-04 2011-05-17 Hoffmann-La Roche Inc. Isoxazolo-pyridazine derivatives
TW200940537A (en) 2008-02-26 2009-10-01 Astrazeneca Ab Heterocyclic urea derivatives and methods of use thereof
WO2009131947A2 (en) 2008-04-21 2009-10-29 Institute For Oneworld Health Compounds, compositions and methods comprising pyridazine derivatives
US20090264433A1 (en) 2008-04-21 2009-10-22 Institute For Oneworld Health Compounds, Compositions and Methods Comprising Triazine Derivatives
US20090325902A1 (en) 2008-06-04 2009-12-31 Astrazeneca Ab Heterocyclic urea derivatives and methods of use thereof
EP2346826A2 (en) 2008-06-09 2011-07-27 AWD.pharma GmbH & Co.KG Carboxylic acid salts of 2-amino-3-carbethoxyamino-6-(4-fluoro-benzylamino)-pyridine
SG192446A1 (en) 2008-06-30 2013-08-30 Janssen Pharmaceutica Nv Process for the preparation of benzoimidazol-2-yl pyrimidine derivatives
US20100025641A1 (en) 2008-08-04 2010-02-04 Fujifilm Corporation Infrared region selective reflection coat and infrared region selective reflection film
TWI409265B (en) 2008-08-20 2013-09-21 Merck Sharp & Dohme Substituted pyridine and pyrimidine derivatives and their use in treating viral infections
KR20120002581A (en) 2009-03-30 2012-01-06 아스텔라스세이야쿠 가부시키가이샤 Pyrimidine compounds
CA2773561A1 (en) 2009-09-14 2011-03-17 Phusis Therapeutics Inc. Pharmaceutical compositions and formulations including inhibitors of the pleckstrin homology domain and methods for using same
US9133123B2 (en) 2010-04-23 2015-09-15 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
AR081626A1 (en) 2010-04-23 2012-10-10 Cytokinetics Inc AMINO-PYRIDAZINIC COMPOUNDS, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND USE OF THE SAME TO TREAT CARDIAC AND SKELETIC MUSCULAR DISORDERS
AR081331A1 (en) 2010-04-23 2012-08-08 Cytokinetics Inc AMINO- PYRIMIDINES COMPOSITIONS OF THE SAME AND METHODS FOR THE USE OF THE SAME
MX2013006768A (en) * 2010-12-23 2013-07-22 Pfizer Glucagon receptor modulators.
US8759380B2 (en) 2011-04-22 2014-06-24 Cytokinetics, Inc. Certain heterocycles, compositions thereof, and methods for their use
SG10201701101YA (en) 2012-04-02 2017-04-27 Cytokinetics Inc Methods for improving diaphragm function
CN111840294A (en) 2012-04-11 2020-10-30 赛特凯恩蒂克公司 Method for improving resistance to skeletal muscle fatigue
HUE057533T2 (en) 2014-04-29 2022-05-28 Cytokinetics Inc Methods of reducing decline in vital capacity
JP6573618B2 (en) 2014-09-09 2019-09-11 アステラス製薬株式会社 Novel pharmaceutical composition for preventing and / or treating urinary incontinence

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080318899A1 (en) * 2004-11-02 2008-12-25 Martin Watterson Pyridazine Compounds, Compositions and Methods
WO2007075377A2 (en) * 2005-12-15 2007-07-05 Cytokinetics, Inc. Certain chemical entities, compositions and methods

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ALLINGHAM ET AL.: "The structural basis of blebbistatin inhibition and specificity for myosin II", NATURE STRUCTURAL & MOLECULAR BIOLOGY, vol. 12, no. 4, April 2005 (2005-04-01), pages 378 - 379, XP002529525, Retrieved from the Internet <URL:http://wwwprod.biochem.wisc.edu/biochem/faculty/rayment/publications/pub_pdfs/140_159/158.rayment05_allingham.pdf> *
See also references of EP2563365A4 *

Cited By (84)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10272030B2 (en) 2010-04-23 2019-04-30 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9604965B2 (en) 2010-04-23 2017-03-28 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US11369565B2 (en) 2010-04-23 2022-06-28 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9994528B2 (en) 2010-04-23 2018-06-12 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
US9730886B2 (en) 2010-04-23 2017-08-15 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9133123B2 (en) 2010-04-23 2015-09-15 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
US8962632B2 (en) 2010-04-23 2015-02-24 Cytokinetics, Inc. Certain amino-pyrimidines, compositions thereof, and methods for their use
US10765624B2 (en) 2010-04-23 2020-09-08 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9018223B2 (en) 2010-04-23 2015-04-28 Cytokinetics, Inc. Certain amino-pyrimidines, compositions thereof, and methods for their use
US10076519B2 (en) 2010-04-23 2018-09-18 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US9403815B2 (en) 2010-06-24 2016-08-02 The Regents Of The University Of California Compounds and uses thereof in modulating levels of various amyloid beta peptide alloforms
JP2013536873A (en) * 2010-09-06 2013-09-26 グアンジョウ インスティテュート オブ バイオメディスン アンド ヘルス，チャイニーズ アカデミー オブ サイエンスィズ Amide compounds
WO2013061297A1 (en) * 2011-10-28 2013-05-02 Pfizer Limited Pyridazine Derivatives Useful in Therapy
US9273011B2 (en) 2011-10-28 2016-03-01 Inhibitaxin Limited Substituted pyridazines for the treatment of pain
JP2014530902A (en) * 2011-10-28 2014-11-20 インヒビタクシン リミテッド Pyridazine derivatives useful for treatment
US10016420B2 (en) 2011-10-28 2018-07-10 Inhibitaxin Limited Substituted pyridazines for the treatment of pain
CN103958481A (en) * 2011-10-28 2014-07-30 因西必泰克新有限公司 Pyridazine derivatives useful in therapy
CN106220572A (en) * 2011-10-28 2016-12-14 因西必泰克新有限公司 The compound of pyridyl derivatives, purposes, compositions and test kit and preparation method
EP3243815A1 (en) * 2011-10-28 2017-11-15 Inhibitaxin Limited Pyridazine derivatives useful in therapy
CN103958481B (en) * 2011-10-28 2017-06-30 因西必泰克新有限公司 Pyridazine derivatives useful in therapy
JP2014533721A (en) * 2011-11-28 2014-12-15 ノバルティス アーゲー Novel trifluoromethyl-oxadiazole derivatives and their use in the treatment of diseases
JP2018131460A (en) * 2012-04-02 2018-08-23 サイトキネティックス， インコーポレイテッド Methods for improving diaphragm function
US10758533B2 (en) 2012-08-13 2020-09-01 Novartis Ag 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions
EA032005B1 (en) * 2012-08-13 2019-03-29 Новартис Аг 1,4-disubstituted pyridazine analogs and methods for treating smn-deficiency-related conditions
KR102368439B1 (en) 2012-08-13 2022-02-28 노파르티스 아게 1,4-disubstituted pyridazine analogs and methods for treating smn-deficiency-related conditions
US11229648B2 (en) 2012-08-13 2022-01-25 Novartis Ag 1,4-disubstituted pyridazine analogs thereof and methods for treating SMN-deficiency-related conditions
KR20150041655A (en) * 2012-08-13 2015-04-16 노파르티스 아게 1,4-disubstituted pyridazine analogs and methods for treating smn-deficiency-related conditions
CN104583196B (en) * 2012-08-13 2016-10-12 诺华股份有限公司 The method that 1,4-dibasic pyridazine analog and treatment lack relevant disease to SMN
EP4101849A1 (en) * 2012-08-13 2022-12-14 Novartis AG 1,4-disubstituted pyridazine analogs and methods for treating smn-deficiency-related conditions
WO2014028459A1 (en) * 2012-08-13 2014-02-20 Novartis Ag 1,4-disubstituted pyridazine analogs and methods for treating smn-deficiency-related conditions
JP2015524842A (en) * 2012-08-13 2015-08-27 ノバルティス アーゲー 1,4-disubstituted pyridazine analogs and methods for treating conditions associated with SMN deficiency
US10195196B2 (en) 2012-08-13 2019-02-05 Novartis Ag 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions
CN104583196A (en) * 2012-08-13 2015-04-29 诺华股份有限公司 1,4-disubstituted pyridazine analogs and methods for treating SMN-deficiency-related conditions
KR20200126016A (en) * 2012-08-13 2020-11-05 노파르티스 아게 1,4-disubstituted pyridazine analogs and methods for treating smn-deficiency-related conditions
KR102172911B1 (en) * 2012-08-13 2020-11-03 노파르티스 아게 1,4-disubstituted pyridazine analogs and methods for treating smn-deficiency-related conditions
EP3564233A1 (en) * 2012-08-13 2019-11-06 Novartis AG 1,4-disubstituted pyridazine analogs and methods for treating smn-deficiency-related conditions
US9040712B2 (en) 2013-01-23 2015-05-26 Novartis Ag Thiadiazole analogs thereof and methods for treating SMN-deficiency-related-conditions
US9938263B2 (en) 2013-03-12 2018-04-10 The General Hospital Corporation Gamma-secretase modulators
US11672799B2 (en) 2013-07-31 2023-06-13 Novartis Ag 1,4-disubstituted pyridazine quinolne analogs there of and methods for treating SMN-deficiency-related conditions
WO2015157005A1 (en) 2014-04-10 2015-10-15 E I Du Pont De Nemours And Company Substituted tolyl fungicide mixtures
US10472346B2 (en) 2014-10-31 2019-11-12 The General Hospital Corporation Potent gamma-secretase modulators
US11117884B2 (en) 2014-10-31 2021-09-14 The General Hospital Corporation Potent gamma-secretase modulators
KR20170000426A (en) 2015-06-23 2017-01-03 충남대학교산학협력단 Chromenones derivatives with cardiac myosin activating function and pharmaceutical composition containing thereof for preventing or treating heart failure
EP4032877A1 (en) 2016-02-12 2022-07-27 Cytokinetics, Incorporated Tetrahydroisoquinoline derivatives
US10259821B2 (en) 2016-02-12 2019-04-16 Astellas Pharma Inc. Tetrahydroisoquinoline derivatives
WO2017139526A1 (en) 2016-02-12 2017-08-17 Astellas Pharma Inc. Tetrahydroisoquinoline derivatives
US11479561B2 (en) 2016-02-12 2022-10-25 Cytokinetics, Incorporated Tetrahydroisoquinoline derivatives
US10689393B2 (en) 2016-02-12 2020-06-23 Astellas Pharma Inc. Tetrahydroisoquinoline derivatives
US9914741B2 (en) 2016-02-12 2018-03-13 Astellas Pharma Inc. Tetrahydroisoquinoline derivatives
US10906888B2 (en) 2016-07-14 2021-02-02 Pfizer Inc. Pyrimidine carboxamides as inhibitors of Vanin-1 enzyme
KR20160108281A (en) 2016-09-06 2016-09-19 충남대학교산학협력단 Compounds with cardiac myosin activating function and pharmaceutical composition containing the same for treating or preventing heart failure
US11547712B2 (en) 2017-11-20 2023-01-10 Icahn School Of Medicine At Mount Sinai Kinase inhibitor compounds and compositions and methods of use
US11142516B2 (en) 2017-12-26 2021-10-12 Cytokinetics, Inc. Process for the preparation of an amino-pyrimidine and intermediates thereof
US11788064B2 (en) 2018-01-05 2023-10-17 Icahn School Of Medicine At Mount Sinai Method of increasing proliferation of pancreatic beta cells, treatment method, and composition
US11866427B2 (en) 2018-03-20 2024-01-09 Icahn School Of Medicine At Mount Sinai Kinase inhibitor compounds and compositions and methods of use
US12421232B2 (en) 2018-03-20 2025-09-23 Icahn School Of Medicine At Mount Sinai Kinase inhibitor compounds and compositions and methods of use
WO2020097265A1 (en) * 2018-11-06 2020-05-14 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
US12240831B2 (en) 2018-11-06 2025-03-04 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
US11390606B2 (en) 2018-11-06 2022-07-19 Edgewise Therapecutics, Inc. Pyridazinone compounds and uses thereof
US20220106291A1 (en) 2018-11-06 2022-04-07 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
KR102885525B1 (en) 2018-11-06 2025-11-13 엣지와이즈 테라퓨틱스, 인크. Pyridazinone compounds and uses thereof
WO2020097266A1 (en) * 2018-11-06 2020-05-14 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
US11236065B2 (en) 2018-11-06 2022-02-01 Edgewise Therapecutics, Inc. Pyridazinone compounds and uses thereof
US12415794B2 (en) 2018-11-06 2025-09-16 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
AU2019376647B2 (en) * 2018-11-06 2025-03-06 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
KR20210100615A (en) * 2018-11-06 2021-08-17 엣지와이즈 테라퓨틱스, 인크. Pyridazinone compounds and uses thereof
US11091464B2 (en) 2018-11-06 2021-08-17 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
US12240833B2 (en) 2018-11-06 2025-03-04 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
EP4248973A3 (en) * 2018-11-06 2023-12-06 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
EP4248972A3 (en) * 2018-11-06 2023-12-06 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
WO2020097012A1 (en) 2018-11-06 2020-05-14 Fmc Corporation Substituted tolyl as fungicides
US12012395B2 (en) 2018-11-06 2024-06-18 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
CN113543783A (en) * 2018-12-31 2021-10-22 西奈山伊坎医学院 Kinase inhibitor compounds and compositions and methods of use
EP3906028A4 (en) * 2018-12-31 2022-10-12 Icahn School of Medicine at Mount Sinai KINASE INHIBITOR COMPOUNDS, COMPOSITIONS AND METHODS OF USE
US11427558B1 (en) 2019-07-11 2022-08-30 ESCAPE Bio, Inc. Indazoles and azaindazoles as LRRK2 inhibitors
US12391667B2 (en) 2019-07-22 2025-08-19 Boehringer Ingelheim International Gmbh N-methyl, n-(6-(methoxy)pyridazin-3-yl) amine derivatives as Autotaxin (ATX) modulators for the treatment of inflammatory airway or fibrotic diseases
WO2021226234A1 (en) 2020-05-06 2021-11-11 Fmc Corporation Substituted tolyl fungicides and their mixtures
CN117529475A (en) * 2021-01-08 2024-02-06 艾福姆德尤股份有限公司 Heterobicyclic compounds containing urea or analogues and compounds thereof for the treatment of diseases associated with STING activity
US12152018B2 (en) 2021-01-08 2024-11-26 Ifm Due, Inc. Compounds and compositions for treating conditions associated with STING activity
WO2022150585A1 (en) * 2021-01-08 2022-07-14 Ifm Due, Inc. Heterobicyclic compounds having an urea or analogue and their compositions for treating conditions associated with sting activity
EP4461729A4 (en) * 2022-01-07 2026-03-25 Transthera Sciences Nanjing Inc Antigen-binding protein targeting MSLN and its use
WO2023209368A1 (en) * 2022-04-26 2023-11-02 Cerevance, Inc. Nitrogen comprising heterocyclic derivatives for the treatment of disorders associated with gpr55 receptor
WO2024064745A1 (en) 2022-09-21 2024-03-28 Cytokinetics, Incorporated Synthesis of reldesemtiv
WO2025184010A1 (en) * 2024-03-01 2025-09-04 Merck Sharp & Dohme Llc N-biaryl sulfonamides as modulators of the hippo pathway

Also Published As

Publication number Publication date
JP2016166217A (en) 2016-09-15
NZ627973A (en) 2016-02-26
CN107266419A (en) 2017-10-20
PH12012502097A1 (en) 2017-09-26
IL250824A0 (en) 2017-04-30
US20150322018A1 (en) 2015-11-12
AU2011242569B2 (en) 2016-02-04
SG184954A1 (en) 2012-11-29
KR20180014870A (en) 2018-02-09
JP6470224B2 (en) 2019-02-13
CO6630154A2 (en) 2013-03-01
US20170281621A1 (en) 2017-10-05
CA2796390A1 (en) 2011-10-27
EP3127541A1 (en) 2017-02-08
EP2563365B1 (en) 2016-04-20
MX2012012259A (en) 2012-11-23
EA024881B1 (en) 2016-10-31
CN103002897B (en) 2017-06-09
KR101825735B1 (en) 2018-02-05
AU2018201953B2 (en) 2020-02-20
EP3127541B1 (en) 2019-07-17
AU2011242569A1 (en) 2012-12-06
EP2563365A1 (en) 2013-03-06
NZ603593A (en) 2014-10-31
BR112012026950A2 (en) 2016-07-12
US20130143862A1 (en) 2013-06-06
JP2013525376A (en) 2013-06-20
SG10201700219XA (en) 2017-02-27
CN103002897A (en) 2013-03-27
JP5918217B2 (en) 2016-05-18
US8969346B2 (en) 2015-03-03
MY191829A (en) 2022-07-18
US9604965B2 (en) 2017-03-28
ECSP12012292A (en) 2013-03-28
IL222465A (en) 2017-03-30
TW201204712A (en) 2012-02-01
EA201201377A1 (en) 2013-04-30
CN107266419B (en) 2021-05-11
AR081626A1 (en) 2012-10-10
PH12012502097B1 (en) 2018-03-09
KR101960642B1 (en) 2019-03-20
AU2018201953A1 (en) 2018-04-12
BR112012026950B1 (en) 2019-10-08
HK1181662A1 (en) 2013-11-15
CA2796390C (en) 2019-10-01
MX343264B (en) 2016-10-28
IL222465A0 (en) 2012-12-31
AU2016202617A1 (en) 2016-05-19
TWI501963B (en) 2015-10-01
EP2563365A4 (en) 2014-01-15
AU2016202617B2 (en) 2018-01-04
KR20130092403A (en) 2013-08-20
US10076519B2 (en) 2018-09-18
CL2012002945A1 (en) 2013-01-25
PH12017501192B1 (en) 2017-12-11
PH12017501192A1 (en) 2017-12-11
IL250824B (en) 2019-03-31

Similar Documents

Publication Publication Date Title
US10076519B2 (en) Substituted pyridazines as skeletal muscle modulators
US10765624B2 (en) Amino-pyrimidine skeletal muscle modulators
EP2560488B1 (en) Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
US20130060025A1 (en) Certain heterocycles, compositions thereof, and methods for their use
HK1233962A (en) Certain amino-pyridazines, compositions thereof, and methods of their use
HK1233962A1 (en) Certain amino-pyridazines, compositions thereof, and methods of their use
HK1181662B (en) Certain amino-pyridazines, compositions thereof, and methods of their use
HK1233962B (en) Certain amino-pyridazines, compositions thereof, and methods of their use
HK1233963A1 (en) Certain amino-pyrimidines, compositions thereof, and methods for their use
HK1233963B (en) Certain amino-pyrimidines, compositions thereof, and methods for their use

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11772778

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2796390

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2013506327

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: MX/A/2012/012259

Country of ref document: MX

Ref document number: 12012502097

Country of ref document: PH

WWE Wipo information: entry into national phase

Ref document number: 2012002945

Country of ref document: CL

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 9200/DELNP/2012

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 12189887

Country of ref document: CO

WWE Wipo information: entry into national phase

Ref document number: 201201377

Country of ref document: EA

ENP Entry into the national phase

Ref document number: 20127029537

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2011772778

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2011242569

Country of ref document: AU

Date of ref document: 20110422

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 13642207

Country of ref document: US

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112012026950

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112012026950

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20121019

WWE Wipo information: entry into national phase

Ref document number: 250824

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 12017501192

Country of ref document: PH

WWW Wipo information: withdrawn in national office

Ref document number: 603593

Country of ref document: NZ